RU2380365C1 - Heterocyclic substituted pyrimidine derivatives and antifungal agent containing said derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof:

, where R¹ is a hydrogen atom, amino group, R¹¹-NH-, where R¹¹ is a C_1-6alkyl group, hydroxy-C_1-6alkyl group, C_1-6alkoxycarbonyl-C_1-6alkyl group, R¹²-(CO)-NH-, where R¹² is a C_1-6alkyl group or C_1-6alkoxy-C_1-6alkyl group, C_1-6alkyl group, hydroxy-C_1-6-alkyl group, C_1-6alkoxy group or C_1-6alkoxy-C_1-6alkyl group; R² is a hydrogen atom, C_1-6alkyl group, amino group or di-C_1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH₂O-, -OCH₂-, -NH-, -CH₂NH-, -NHCH₂-, -CH₂S- or -SCH₂-; R³ is hydrogen or a halogen atom, or C_1-6alkyl group, C_3-8cycloalkyl group, C_6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C_1-6alkyl group, C_1-6alkoxy group, C_1-6alkoxycarbonyl group, C_3-8cycloalkyl group, C_1-6alkenyl group and C_1-6alkynyl group; R⁴ is a hydrogen atom or halogen atom; except compounds in which all of R¹, R² and R⁴ represent a hydrogen atom while Z represents a single bond or R³ is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

Description

FIELD OF THE INVENTION

The present invention relates to heterocyclic substituted pyridine derivatives and antifungal agents containing them.

State of the art

In recent years, a set of measures associated with opportunistic infections has become increasingly important in connection with an increase in the number of elderly people and immunocompromised patients, which is a consequence of modern chemotherapy, etc. The facts indicate that opportunistic infections are sequentially caused by various avirulent pathogens, and it has been shown that the problem associated with an infectious disease will not be solved as long as there are underlying diseases that weaken the immune functions of patients. Therefore, in the near future, one of the important tasks for an aging society is the development of new strategies for the management of infectious diseases, including the solution of the problem associated with drug-resistant pathogens.

In the field of antifungal agents, for example, amphotericin B based on the polyene skeleton, fluconosole, itraconazole and voriconazole based on the azole skeleton and the like have been developed for the treatment of deep mycosis. Most of the commercially available drugs developed to date have a similar mechanism of action, and today the problem is the appearance of fungi resistant to azole, etc.

Recently, an inhibitor of 1,3-β-glucan synthetase has been developed having a new mechanism of action, caspofungin and micafungin and the like, cyclic hexapeptides, derivatives of naturally occurring compounds; however, due to the fact that these agents are only available as injections, from a practical point of view, they are still not suitable as antifungal agents.

In such a situation, when the existing antifungal agents are not suitable for the treatment of deep mycosis, there is a need to develop agents based on a new mechanism of action and which have a high degree of safety.

As the prior art relating to antifungal agents based on the new mechanism of action, Patent Documents 1 and 2 disclose pyridine derivatives that are effective against the onset, progression and persistence of infections and which inhibit the expression of cell wall proteins by inhibiting cell wall assembly, as well as adhesion on the cell surface and preventing the manifestation of pathogenicity of pathogens as a result of inhibition of the process of transport of GPI (glycosylphosphatidylinositol) -absorbed proteins cell wall.

However, the groups of compounds disclosed in Patent Document 1 have, as a general structure, 2-benzylpyridine functional groups that are structurally distinctly different from the compounds of the present invention. In addition, there is a problem with the group of compounds disclosed in Patent Document 1, which, although these compounds exhibit in vitro activity, they are readily subjected to a metabolic process within the body. The groups of compounds disclosed in Patent Document 2 exhibit excellent antifungal activity, but this group of representative compounds has the structure represented by the following formula:

A ¹ = optionally substituted 3-pyridyl or quinolyl and the like.

X ¹ = —C (= O) —NH, —NH — C - (= O) - etc.

E = furyl, thienyl, pyrrolyl, phenyl, pyridyl, tetrazolyl, thiazolyl or pyrazolyl.

Obviously, these compounds having skeletons consisting of pyridine rings are structurally different from the compounds of the present invention in that the overall structure has one ring linked by an amidomethylene linker at the 3-position of the pyridine ring.

Patent documents 3-5 also provide examples of the prior art having structures similar to the compounds of the present invention. Patent documents 3 and 4 describe pyridine derivatives substituted with a pyrazole ring that are used as inhibitors of glycine transporters or 5-HT receptor ligands, while patent document 5 describes 5-membered heterocyclic substituted pyridine derivatives that are used as an AGE destructor and inhibitor.

However, in patent documents 3-5, the compounds of the present invention are not disclosed, and the antifungal effects caused by the compounds described in patent documents 3-5 are not disclosed for fungi of the genus Candida , Aspergillus , Cryptococcus and the like, which are common fungi that cause fungal diseases in humans.

[Patent document 1] international publication WO 02/04626

[Patent document 2] international publication WO 05/033079

[Patent document 3] international publication WO 03/031435

[Patent document 4] international publication WO 04/089931

[Patent document 5] international publication WO 02/085897

SUMMARY OF THE INVENTION

Tasks Solved by the Present Invention

It is an object of the present invention to provide an antifungal agent having an excellent antifungal effect that the antifungal agents of the prior art do not possess and which is also excellent in terms of properties, safety and metabolic stability.

Means of solving the problem

As a result of comprehensive studies conducted taking into account the above circumstances, the inventors were able to synthesize new pyridine derivatives (hereinafter referred to as the compounds of the present invention) represented by the following formula (I):

and having a chemical structure in which a pyridine ring and a 5- or 6-membered heteroaryl ring or a benzene ring are linked to a 5-membered heteroarylmethyl group as a linker, and to improve the present invention by establishing that these compounds have excellent antifungal action.

Thus, the present invention provides:

[1] a compound represented by the following formula (I), or a salt thereof:

where R ¹ represents a hydrogen atom, a halogen atom, an amino group, R ¹¹ -NH- (where R ¹¹ represents a C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group or a C _1-6 alkoxycarbonyl-C _1-6 alkyl group), R ¹² - (CO) -NH- (where R ¹² represents a C _1-6 alkyl group or a C _1-6 alkoxy-C _1-6 alkyl group), A C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a cyano-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, a C _1-6 alkyl group, an amino group or a di-C _1-6 alkylamino group;

one of X and Y represents a nitrogen atom, while the other represents a nitrogen atom or an oxygen atom;

ring A represents a 5- or 6-membered heteroaryl ring or a benzene ring, which may have 1 or 2 halogen atoms, or 1 or 2 C _1-6 alkyl groups;

Z represents a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, -CH ₂ O-, -OCH ₂ -, -NH-, -CH ₂ NH-, -NHCH ₂ -, -CH ₂ S- or - SCH ₂ -;

R ³ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered heteroaryl group, or a 5- or 6-membered non-aromatic heterocyclic group, which may have 1 or 2 substituents selected from the group of α substituents: and

[group of α substituents]

the substituent group α represents a group consisting of a halogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group and a C _{2- 6} alkynyl groups,

R ⁴ represents a hydrogen atom or a halogen atom;

with the exception of compounds in which all R ¹ , R ² and R ⁴ represent a hydrogen atom at the time when Z represents a single bond or R ³ represents a hydrogen atom;

[2] a compound represented by the following formula (I '), or a salt thereof:

where 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;

one of X and Y represents a nitrogen atom, while the other represents a nitrogen atom or an oxygen atom;

ring A represents a 5- or 6-membered heteroaryl ring or a benzene ring;

Z represents a methylene group, an oxygen atom, —CH ₂ O—, —OCH ₂ -, —NH—, —NHCH ₂ - or —CH ₂ NH—;

and R ³ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _6-10 aryl group or a 5- or 6-membered heteroaryl group, which may have 1 or 2 substituents selected from the group of α substituents:

[group of α substituents]

the substituent group α represents a group consisting of 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;

[3] the compound according to paragraph [1] or [2] and its salt, in which part of the structure represented by formula (II):

in the compound represented by formula (I) or formula (I '):

represents a part of a structure selected from the group consisting of:

[4] the compound according to [1] or [2] or a salt thereof, in which one of X and Y represents a nitrogen atom and the other represents an oxygen atom;

[5] the compound according to paragraph [4] or its salt, in which part of the structure represented by formula (II):

in the compound represented by formula (I) or formula (I '):

represents a part of the structure represented by the following formula (III):

or a part of the structure represented by the following formula (IV):

;

;

[6] the compound according to [1] or [2] or a salt thereof, in which X and Y both represent a nitrogen atom;

[7] the compound according to paragraph [6] or its salt, in which part of the structure represented by formula (II):

in the compound represented by formula (I) or formula (I '):

represents a part of the structure represented by the following formula (V):

or a part of the structure represented by the following formula (VI):

;

;

[8] the compound according to any one of [1] to [7] or a salt thereof, in which R ² represents an amino group;

[9] the compound of [8] or a salt thereof, wherein R ¹ represents a hydrogen atom, an amino group or a C _1-6 alkoxy-C _1-6 alkyl group;

[10] the compound according to any one of [1] to [7] or a salt thereof, in which R ¹ represents an amino group and R ² represents a hydrogen atom;

[11] a compound according to any one of [1] to [10] or a salt thereof, in which ring A represents a pyridine ring, a benzene ring, a furan ring, a thiophene ring or a pyrrole ring;

[12] the compound according to [11] or a salt thereof, in which ring A represents a pyridine ring or a benzene ring;

[13] the compound according to any one of [1] to [12] or a salt thereof, in which Z represents an oxygen atom, —CH ₂ O— or —OCH ₂ -;

[14] a pharmaceutical composition comprising a compound according to any one of [1] to [13] or a salt thereof;

[15] a medicament containing a compound according to any one of paragraphs [1] to [13] or a salt thereof;

[16] an antifungal agent containing, as an active ingredient, a compound according to any one of [1] to [13] or a salt thereof;

[17] a method for preventing and / or treating a fungal infection, comprising administering a pharmacologically effective dose of a compound according to any one of paragraphs [1] to [13] or a salt thereof;

[18] the use of a compound according to any one of paragraphs [1] to [13] or a salt thereof for the manufacture of an antifungal agent.

Advantages of the Invention

Compound (I) of the present invention or its salt 1) acts against the appearance, progression and persistence of infections by inhibiting the biosynthesis of fungal GPI, thereby inhibiting the expression of cell wall proteins and blocking cell wall assembly, while preventing fungal attachment to cells, which prevents manifestation of pathogenicity by the pathogen, and 2) is excellent in terms of its physical properties, safety and metabolic stability, and is especially applicable as a prophylactic or therapist agent against fungal infections.

BEST MODE FOR CARRYING OUT THE INVENTION

Below the present invention is described in more detail with reference to the symbols and terms used and defined in the present description, and the following examples.

In the present description, for convenience of description, the structural formula of a compound sometimes represents a particular isomer. However, the compounds of the present invention may include all possible isomers, such as geometric isomers, possible in terms of structure, optical isomers resulting from the presence of asymmetric carbon atoms, stereoisomers, tautomers and mixtures of isomers, and are not limited to the formulas used for convenience of description; they can be either one of two isomers, or a mixture of both isomers. Thus, the compounds of the present invention can be either optically active compounds having an asymmetric carbon atom in their molecules, or their racemates, and are not limited to either of them, but include both isomers. Moreover, the compounds of the present invention can exhibit crystalline polymorphism, but they, likewise, are not limited to any one of the crystalline forms, but can be in any of these crystalline forms or exist as a mixture of two or more crystalline forms. The compounds of the present invention also include both anhydrous forms and solvates, for example hydrated forms.

As used herein, the term “C _1-6 alkyl group” refers to a straight or branched alkyl group with 1-6 carbon atoms, which is a monovalent group obtained by removing any one hydrogen atom from an aliphatic hydrocarbon with 1-6 hydrogen atoms. In particular, examples of the “C _1-6 alkyl group” include a 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-dimethyl utility 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-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group or the like, preferably methyl group, ethyl group, n-propyl group , isopropyl group, n-butyl group, isobutyl group, sec-butyl group or tert-butyl group or the like.

As used herein, the term “C _2-6 alkenyl group” refers to an unbranched or branched alkenyl group with 2-6 carbon atoms, which may contain 1 or 2 double bonds. In particular, examples of the “C _2-6 alkenyl group” include an ethenyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 2-methyl-1-propenyl group, pentenyl group, 3-methyl-2-butenyl group, hexenyl group, hexanedienyl group or the like, 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 or the like.

As used herein, the term “C _2-6 alkynyl group” refers to a straight or branched alkynyl chain with 2-6 carbon atoms, which may contain 1 or 2 triple bonds. In particular, examples of the “C _2-6 alkynyl group” include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a pentynyl group, a hexynyl group, a hexanediinyl group, and the like, preferably an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, or the like.

As used herein, the term “C _3-8 cycloalkyl group” refers to a cyclic aliphatic hydrocarbon group with 3-8 carbon atoms. In particular, examples of the “C _3-8 cycloalkyl group” include a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like, preferably a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or t .P.

As used herein, the term “C _1-6 alkoxy group” refers to a group in which an oxygen atom is attached to the end of the above “C _1-6 alkyl group”. In particular, examples of the “C _1-6 alkoxy group” include 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, an n-pentyloxy group, an isopentyloxy group, a sec-1-p-pentoxypentoxy group, sec-1-p 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-methylpentyloxybutyl, 1,1-dimethybutoxy, 1,2-dimethybutoxy, 1,2-dimethylbutyloxy , 2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group A -1-methylpropoxy group, 1-ethyl-2-methylpropoxy group or the like, preferably a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group or the like.

As used herein, the term “hydroxyl-C _1-6 alkyl group” refers to a group in which any of the hydrogen atoms in the above “C _1-6 alkyl group” is replaced by a hydroxyl group. In particular, examples of the “hydroxyl-C _1-6 alkyl group” include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxy n- propyl group, a 2-hydroxy n- propyl group, 3-hydroxy- n- propyl group, 1-hydroxyisopropyl group, 2-hydroxyisopropyl group, 3-hydroxyisopropyl group, 1-hydroxy- tert- butyl group or the like, preferably a hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group or the like. P.

As used herein, the term “C _1-6 alkoxycarbonyl group” refers to a group in which a carbonyl group is attached to the end of the above “C _1-6 alkoxy group”. In particular, examples of the “C _1-6 alkoxycarbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, an n- propoxycarbonyl group, an isopropoxycarbonyl group or the like.

The term "C _1-6 alkoxycarbonyl-C _1-6 alkyl group" as used herein refers to a group wherein the above-defined "C _1-6 alkyl group" is connected to the end of the above-defined "C _1-6 alkoxycarbonyl group". In particular, examples of the “C _1-6 alkoxycarbonyl-C _1-6 alkyl group” include a methoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylethyl group or the like.

As used herein, the term “C _6-10 aryl group” refers to an aromatic hydrocarbon ring group with 6-10 carbon atoms. In particular, examples of the “C _6-10 aryl group” include a phenyl group, 1-naphthyl group, 2-naphthyl group, indenyl group, azulenyl group, heptalenyl group or the like, preferably a phenyl group, 1-naphthyl group, 2 a naphthyl group or the like.

As used herein, the term “C _1-6 alkoxy-C _1-6 alkyl group” refers to a group in which any of the hydrogen atoms in the above defined “C _1-6 alkyl group” is replaced by the above defined “C _1-6 alkoxy group” . In particular, examples of the “C _1-6 alkoxy-C _1-6 alkyl group” include a methoxymethyl group, an ethoxymethyl group, an n- propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, and the like.

As used herein, the term “halogen atom” refers to a fluorine, chlorine, bromine or iodine atom.

As used herein, the term “heteroatom” refers to an atom of nitrogen, sulfur, or oxygen.

As used herein, the term “5- or 6-membered heteroaryl ring” refers to an aromatic ring in which the number of atoms forming the ring is 5 or 6, and 1 or more heteroatoms are included in the atoms forming this ring. In particular, examples of the “5- or 6-membered heteroaryl ring” include a furan ring, a thiophene ring, a pyrrole ring, a pyridine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, a triazole ring (1,2,3-triazole ring, 1, 2,4-triazole ring, etc.), tetrazole ring (1 H- tetrazole ring, 2 H- tetrazole ring, etc.), thiazole ring, pyrazole ring, oxazole ring, isoxazole ring, isothiazole ring, oxadiazole ring, a thiadisole ring and the like.

As used herein, the term “5- or 6-membered heteroaryl group” refers to a monovalent group formed by the removal of 1 hydrogen atom from any position in an aromatic ring in which the number of atoms forming it is 5 or 6, and into these ring-forming atoms 1 or more heteroatoms are included. In particular, examples of the “5- or 6-membered heteroaryl group” include a furyl group (2-furyl group or 3-furyl group, etc.), a thienyl group (2-thienyl group or 3-thienyl group, etc. .), a pyrrolyl group (1-pyrrolyl group, 2-pyrrolyl group or 3-pyrrolyl group, etc.), a pyridyl group (2-pyridyl group, 3-pyridyl group, 4-pyridyl group, etc.) , pyrazinyl group, pyridazinyl group (3-pyridazinyl group or 4-pyridazinyl group, etc.), pyrimidinyl group (2-pyrimidinyl group uppu, 4-pyrimidinyl group or 5-pyrimidinyl group, etc.), triazolyl group (1,2,3-triazolyl group or 1,2,4-triazolyl group, etc.), tetrazolyl group (1 H a tetrazolyl group or 2 H- tetrazolyl group, etc.), a thiazolyl group (2-thiazolyl group, 4-thiazolyl group or 5-thiazolyl group, etc.), a pyrazolyl group (3-pyrazolyl group or 4- pyrazolyl group, etc.), oxazolyl group (2-oxazolyl group, 4-oxazolyl group or 5-oxazolyl group, etc.), isoxazolyl group (3-isoxaz olyl group, 4-isoxazolyl group or 5-isoxazolyl group, etc.), isothiazolyl group (3-isothiazolyl group, 4-isothiazolyl group or 5-isothiazolyl group, etc.), oxadiazolyl group, thiadiazolyl group or t .P.

As used herein, the term “5- or 6-membered non-aromatic heterocyclic group” refers to a monovalent group formed by the removal of 1 hydrogen atom from any position in the non-aromatic ring, in which the number of atoms forming it is 5 or 6, and to form this ring atoms included 1 or more heteroatoms. In particular, examples of the “5- or 6-membered non-aromatic heterocyclic group” include a pyrrolidinyl group, a piperadinyl group, a piperidinyl group, a morpholinyl group, a tetrahydrofuryl group, a tetrahydropyronyl group or the like.

As used herein, the term “di-C _1-6 alkylamino group” refers to a group in which 2 hydrogen atoms of the amino group are substituted with the above “C _1-6 alkyl groups” that are the same or different from each other. In particular, examples of the term “di-C _1-6 alkylamino group” include an N, N-dimethylamino group, N, N-diethylamino group, N, N-di -n- propylamino group, N, N-di-isopropylamino group, N, N-di - n- butylamino group, N, N-isobutylamino group, N, N-di- sec - butylamino group, N, N-di- tert - butylamino group, N-ethyl-N-methylamino group, N -n- propylamino-N-methylamino group, N -isopropyl-N-methylamino group, N -n -butyl-N-methylamino group, N-isobutyl-N-methylamino group, N- sec -butyl-N-methylamino group, N- tert -butyl-N-methylamino group or the like, preferably N, N-dimethylamino group, N, N-die ylamino group, N-ethyl-N-methylamino group or the like

As used herein, the term “may have 1 or 2 substituents” means that regions capable of substitution may have 1 or 2 substituents in any combination.

R ¹ preferably represents a hydrogen atom, a halogen atom, an amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylamino group, a hydroxyl-C _1-6 alkylamino group or a C _1-6 alkoxy-C _1-6 alkyl a group and more preferably a hydrogen atom, an amino group or a C _1-6 alkoxy-C _1-6 alkyl group, wherein the C _1-6 alkoxy-C _1-6 alkyl group is preferably a methoxymethyl group.

R ² represents a hydrogen atom, an amino group or a di-C _1-6 alkylamino group with a hydrogen atom or an amino group, which is preferred.

One of X and Y represents a nitrogen atom, while the other represents a nitrogen atom or an oxygen atom.

The part of the structure that contains X and Y and which is represented by the following formula (II):

,

,

has a structure such as the following structures, which are preferably on the left side connected to the 3-position of the pyridine ring via a single bond, and on the right side are connected to the A ring via a methylene group:

In the case of part of the structure of formula (III), for example, the structure of the compounds of the present invention is represented by the following formula:

It is preferred that one of X and Y represents a nitrogen atom and the other represents an oxygen atom, or that both X and Y represent nitrogen atoms; and if one of X and Y represents a nitrogen atom, and the other represents an oxygen atom, then the partial structure that contains X and Y and which is represented by the following formula (II):

had a structure such as shown below by formula (III) or (IV), preferably with a left end connected to the 3-position of the pyridine ring via a single bond, and a right end connected to the A ring via a methylene group:

however, if X and Y both represent a nitrogen atom, then the part of the structure that contains X and Y and which is represented by the following formula (II):

,

,

had a structure such as shown below by formula (V) or (VI), preferably with the left end connected to the 3-position of the pyridine ring via a single bond, and the right end connected to the A ring via a methylene group:

.

.

Ring A represents a 5- or 6-membered heteroaryl ring or benzene ring, which may have a halogen atom or 1 or 2 C _1-6 alkyl groups, and preferably represents a pyridine ring, a benzene ring, a furan ring, a thiophene ring, or more preferably a pyridine ring, a benzene ring or a thiophene ring, most preferably a pyridine ring or a benzene ring.

Z preferably represents a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, -CH ₂ O-, -OCH ₂ -, -NH-, -NHCH ₂ -, -CH ₂ NH-, -CH ₂ -S- or -SCH ₂ -. Of these, preferred are a methylene group, an oxygen atom, -CH ₂ O- or -OCH ₂ -, and particularly preferred are an oxygen atom, -CH ₂ O- or -OCH ₂ -.

R ³ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _6-10 aryl group or a heteroaryl group with a 5- or 6-membered ring, which may have 1 or 2 substituents, each from which are selected from the group of α substituents:

[group of α substituents]

halogen atom, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkoxycarbonyl group, C _3-8 cycloalkyl group, C _2-6 alkenyl group and C _2-6 alkynyl group.

Examples of preferred R ³ groups include an n- butyl group, cyclopropyl group, phenyl group, fluorophenyl group, furyl group, chlorofuryl group, methylfuryl group, thienyl group, bromothienyl group, methylthienyl group, pyridyl group and methylpyridyl group, more preferably n - butyl group, cyclopropyl group, phenyl group, fluorophenyl group, pyridyl group or methylpyridyl group.

Z and R ³ may be a member of ring substituent A in any combination. Preferred examples of R ³ -Z- as a substituent of ring A thus formed include a phenoxy group, a benzyloxy group, a 2-fluorobenzyloxy group, a 3-fluorobenzyloxy group, a 4-fluorobenzyloxy group, a pyridin-2-yloxymethyl group, 6-methylpyridin-2-yloxymethyl group 2-ylmethoxy group, 6-methylpyridin-2-ylmethoxy group, 4-methylpyridin-2-ylmethoxy group, butoxymethyl group and cyclopropylmethoxy group and the like.

Preferred examples of the compounds of the present invention include the following compounds:

3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (4-methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine;

3- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (6-methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4-butoxymethylbenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine;

3- (3- (4-phenoxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine;

3- (3- (4- (4-methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine;

6-methoxymethyl-3- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (5- (4-benzyloxybenzyl) -isoxazol-3-yl) -pyridin-2-ylamine;

3- (5- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-3-yl) pyridin-2-ylamine;

3- (1- (4-benzyloxybenzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine;

3- (1- (4- (pyridin-2-yloxymethyl) benzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine;

3- (1- (4-butoxymethylbenzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine;

3- (1- (4-benzyloxybenzyl) -1 H -pyrazol-4-yl) pyridin-2,6-diamine;

3- (1- (4- (pyridin-2-yloxymethyl) benzyl) -1 H -pyrazol-4-yl) pyridin-2,6-diamine;

3- (1- (4-butoxymethylbenzyl) -1 H -pyrazol-4-yl) pyridin-2,6-diamine;

3- (3- (6-phenoxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (5-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (4-methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (6-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (4-chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (6-chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (6-phenoxymethylpyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (6-fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (6- (4-fluorobenzyloxy) pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4- (5-chlorofuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (3- (4-phenylaminomethylbenzyl) -isoxazol-5-yl) -pyridin-2-ylamine;

3- (3- (4- (4-methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (6-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (5-methylfuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (4-chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (6-chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (6-phenoxymethylpyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (5-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (6-fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (1-benzyl-1 H -pyrrol-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine;

3- (3- (6- (4-fluorobenzyloxy) pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4- (5-chlorofuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (6- (3-fluorophenoxy) pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (4-phenylaminomethylbenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine;

3- (3- (6- (4-fluorophenoxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine;

3- (3- (4- (thiazol-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;

3- (3- (5- (4-fluorophenoxy-thiophen-2-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine;

6-methoxymethyl-3- (3- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

6-methyl-3- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

5- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;

3- (1- (4- (pyridin-2-ylmethoxy) benzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine; and

3- (3- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridine.

Examples of the term “salt” as used herein include an inorganic acid salt, an organic acid salt, an acidic amino acid salt or the like. Among these salts, it is preferred that the salt used herein be pharmaceutically acceptable.

Preferred examples of the inorganic acid salt include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like. Preferred examples of the organic acid salt include salts of acetic acid, succinic acid, formic acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid or the like.

Preferred examples of an acidic amino acid salt include salts of aspartic acid, glutamic acid or the like. Preferable examples of salts DOS implicit amino acids include salts with arginine, lysine, ornithine, etc.

As used herein, the term “antifungal agent” refers to a prophylactic agent or therapeutic agent against fungal infection.

The compounds of the present invention or their salts or hydrates can be formulated by conventional methods in the form of dosage forms, such as tablets, powders, small granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, adhesive plasters, eye drops, nose drops, ear drops, poultices, lotions or the like.

Such dosage forms can be prepared using conventional diluents, binders, lubricants, colorants, flavorings and, if necessary, stabilizers, emulsifiers, absorbent substances, surfactants, pH modulators, preservatives, antioxidants or the like. and substances commonly used as ingredients for pharmaceutical preparations, according to conventional methods. For example, oral preparations can be made by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with a diluent and, if necessary, a binder, disintegrant, lubricant, colorant, flavor, or the like. and formulated by conventional methods in the form of a drug mixture such as powders, fine granules, granules, coated tablets, capsules or the like.

Examples of such substances include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and paraffin wax; vegetable oil esters such as octyldodecyl myristate and iso- propyl myristate; higher alcohols, such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives of hydrogenated castor oil and a block copolymer of polyloxyethylene-polyoxypropylene; water soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerol, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powder, such as anhydrous silicic acid, magnesium-aluminum silicate and aluminum silicate; and clear water. Examples of diluents include lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like. Examples of binders include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol polyoxyethylene block copolymer and the like, etc. Examples of disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, calcium carboxymethyl cellulose or the like. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silicon dioxide, hydrogenated vegetable oil or the like. Examples of dyes include pharmaceutically acceptable dyes. Examples of flavors include cocoa powder, peppermint camphor, powdered aromatic peppermint oil, Borneo camphor, cinnamon powder or the like. Tablets and granules may be sugar coated or, if necessary, other suitable coatings may be made. Solutions, such as syrups or injectable preparations intended for administration, can be formulated by conventional methods in the form of dosage forms by combining the compound of the present invention or its pharmaceutically acceptable salt with a pH modulator, solubilizing agent, isotonizing agent or the like. and, if necessary, with an auxiliary solubilizing agent, stabilizer or the like. Methods for the manufacture of external preparations are not limited, and such preparations can be made by conventional methods. In particular, various substances commonly used for the manufacture of pharmaceutical substances, quasi-drugs, cosmetics or the like can be used as basic substances for external medicinal compositions. More specifically, examples of the base materials used include animal and vegetable oils, mineral oils, essential oils, waxes, higher alcohols, fatty acids, silicone oil, surfactants, phospholipids, alcohols, polyols, water soluble polymers, mineral clays, pure water or etc. Moreover, the external preparations of the present invention may contain, if necessary, pH modulators, antioxidants, chelating agents, antibacterial / antifungal agents, dyes, odorous substances or the like. But this does not limit the type of materials used as a basis in the external preparations of the present invention. If necessary, the preparation may contain differentiation inducers, blood circulation improving agents, antibacterial agents, anti-inflammatory agents, cellular activators, vitamins, amino acids, wetting agents, keratolytic agents or the like. The amount of the above basic substances is regulated within the range of concentrations used for the manufacture of conventional external preparations.

With the introduction of the compounds of the present invention or its salts, the forms of the compounds are practically unlimited, and the compound can be administered orally or parenterally in the usual way. For example, the compound may be administered in a dosage form such as tablets, powders, granules, capsules, syrups, troches, volatile preparations, suppositories, injections, ointments, eye ointments, adhesive plasters, eye drops, nose drops, ear drops, poultices and lotions.

The dose of the drug of the present invention can be selected depending on the severity of the symptom, age, gender, body weight, type of administration, type of salts, specific type of disease, and the like.

Doses vary greatly depending on the patient’s disease, the severity of the symptom, the age and gender of the patient, his susceptibility to the drug, or the like. The oral preparations of the present invention are usually administered one or more times using a dose of 1 to 10,000 mg / adult / day, preferably 10 to 2,000 mg / adult / day. The injection of the present invention is usually administered using a dose of from 0.1 to 10,000 mg / adult / day, preferably from 1 to 2,000 mg / adult / day.

Conventional Synthesis Methods

The following discusses methods for producing the compounds of the present invention represented by formula (I) (hereinafter referred to as compounds (I)). Compounds of the present invention can be synthesized by conventional methods of organic synthesis, but, for example, among compounds (I), compounds represented by formula (1a), formula (2a), formula (3a), formula (4a), formula (5a), formula (6a-1), formula (6a-3), formula (7), formula (8a), formula (9a) and formula (10a) (hereinafter referred to as compound (1a), compound (2a), compound ( 3a), compound (4a), compound (5a), compound (6a-1), compound (6a-3), compound (7a), compound (8a), compound (9a) and compound (10a), respectively) may be si tezirovany processes described below in sections [Production Method 1 of Preparation - Method of obtaining 10], etc.

[Production Method 1]

The usual method of obtaining compounds (1a):

(where the ring A, R ¹ , R ² , R ³ and R ⁴ and Z are as defined above).

[Production Method 1-1] Method for the Preparation of Compound (1a):

(where the ring A, R ¹ , R ² , R ³ and Z have the same meanings as defined above).

Compound (1b), which is a commercially available product, can be used as it is, or compound (1b) can also be obtained from a commercially available product by well-known methods. In addition, compound (1b) can be prepared by the methods described in the Production Examples section of the Examples section or according to [Production Method 1-2-1] or the like.

Compound (1c) can be prepared by well-known methods from a commercially available product. Compound (1c) can also be prepared by the methods described in the Production Examples section in the Examples section or according to [Production Method 1-3-1] and the like.

[Stage 1]

This step is a step in which a compound (1a) is obtained by reacting a compound (1b) with a compound (1c) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; and water, methylene chloride, chloroform, ethyl acetate, dimethyl sulfoxide, mixed solvents of the above, and the like. Examples of the base used in this reaction include triethylamine, N, N-diisopropylethylamine, sodium bicarbonate, potassium carbonate, and the like. Compound (1c) can be used in an amount of from 1 to 3 equivalents, preferably 1-2 equivalents, based on the amount of compound (1b). The base can be used in an amount of 1 to 3 equivalents, based on the amount of compound (1c). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is 10 minutes to 24 hours.

[Production Method 1-2-1] Method 1 for the preparation of compound (1b):

(where R ¹ and R ^{2 are} defined above, Hal represents a halogen atom, and R ⁵ and R ⁶ each independently represents C _1-6 alkyl groups).

Compound (1b-1), which is a commercially available product, can be used as it is, or compound (1b-1) can also be obtained from commercially available products by well-known methods.

[Stage 1-1]

This step is a step in which a compound (1b-2) is obtained by reacting a 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 a copper catalyst. A phosphine ligand may also be added to obtain good results. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and 1,4-dioxane; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; and acetonitrile, dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the ethynylsilane derivative include trimethylsilylacetylene, triethylsilylacetylene, triisopropylsilylacetylene, tert- butyldimethylsilylacetylene and the like. Examples of palladium catalysts include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (tri- o- tolylphosphine) palladium (II), bis (tri- tert- butylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0) and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine and the like. Examples of the phosphine ligand include triphenylphosphine, tri- o- tolylphosphine, tri- tert- butylphosphine and the like. In this reaction, a copper catalyst may be added. Examples of a copper catalyst include copper, copper (I) iodide, copper (I) bromide, copper (I) chloride, and the like. The ethynylsilane derivative is used in an amount of from 1 to 5 equivalents based on the amount of compound (1b-1). The palladium catalyst is used in an amount of from 0.01 to 0.3 equivalents based on the amount of compound (1b-1). The base is used in an amount of from 2 to 5 equivalents, based on the amount of compound (1b-1). The phosphine ligand is used in an amount of from 0.01 to 1.2 equivalents based on the amount of compound (1b-1). The copper catalyst is used in an amount of from 0.001 to 0.3 equivalents based on the amount of compound (1b-1). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 24 hours.

[Stage 1-2]

This step is a step in which a compound (1b) is obtained by reacting a compound (1b-2) with a base. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of solvents in this step include ether solvents such as tetrahydrofuran and diethyl ether; alcohol solvents such as methanol and ethanol; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; and acetonitrile, dimethyl sulfoxide, water, mixed solvents of the foregoing, and the like. Examples of the base include potassium carbonate, sodium hydroxide, tetrabutylammonium fluoride, potassium fluoride, cesium fluoride and the like. The base is used in an amount of 0.05 to 10 equivalents, based on the amount of compound (1b-2). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 5 minutes to 24 hours.

[Production Method 1-2-2] Method 2 for the preparation of compound (1b):

(where R ¹ and R ^{2 are} defined above, and R ⁷ represents a C _1-6 alkyl group).

Compound (1b-3), which is a commercially available product, can be used as it is, or compound (1b-3) can also be obtained from a commercially available product by well-known methods.

[Stage 1-3]

This step is a step in which compound (1b-4) is obtained by the esterification reaction of compound (1b-3) in the presence of an acid. The solvent used in this reaction is preferably an alcohol solvent such as methanol, ethanol and the like. Examples of acids include sulfuric acid, hydrochloric acid, hydrobromic acid, and the like. The acid can be used in an amount from a catalytic amount to an amount of solvent based on the amount of compound (1b-3). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 1 hour to 72 hours.

The compound (1b-4) can also be obtained from the compound (1b-4) by the methods described below in the sections Alternative methods (1), (2) and (3).

Alternative Method (1): Compound (1b-4) can be converted to a methyl ester derivative using diazomethane or trimethylsilyldiazomethane. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; alcohol solvents such as methanol and ethanol; and methylene chloride, hexane, mixed solvents of the foregoing, and the like. Diazomethane or trimethylsilyldiazomethane is used in an amount of 1 to 2 equivalents based on the amount of compound (1b-3). The reaction temperature ranges 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. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; and water, acetone, acetonitrile, dimethyl sulfoxide, mixed solvents of the foregoing, and the like. An interfacial transfer catalyst such as tetrabutylammonium bromide may also be added in this reaction. Examples of the base used in this reaction include potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, cesium fluoride, and the like. Examples of alkylating agents include iodomethane, iodoethane, dimethyl sulfate and the like. The base is used in an amount of from 1 to 1.5 equivalents, based on the amount of compound (1b-3). The alkylating agent is used in an amount of 1 to 2 equivalents based on the amount of compound (1b-3). The reaction temperature ranges 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 to acid chloride using a halogenating agent and then converted to compound (1b-4) by adding alcohol. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; and acetonitrile, methylene chloride, 1,2-dichloroethane, mixed solvents of the foregoing, and the like. A halogenating agent can also be used as a solvent. A catalytic amount of pyridine or phase transfer catalyst such as benzyltriethylammonium chloride can also be added in this reaction. Examples of halogenating agents include thionyl chloride, phosphorus pentachloride and the like. Examples of alcohols include methanol, ethanol and the like. The halogenating agent is used in an amount of 1 to 20 equivalents based on the amount of compound (1b-3). Alcohol is used in an amount of 1 to 20 equivalents based on the amount of compound (1b-3). The reaction temperature during conversion to acid chloride is in the range of 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 48 hours. The reaction temperature for the reaction with alcohol ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 48 hours. In this reaction, alcohol can be used as a solvent. In this case, compound (1b-4) can be obtained by adding a halogenating agent to a mixture of solvent and compound (1b-3). The reaction temperature ranges from 0 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 1-4]

This step is a step in which a compound (1b-5) is obtained by reducing a compound (1b-4). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent without blocking the reaction, but tetrahydrofuran is preferred. Examples of the reducing agent in this reaction include lithium aluminum hydride, lithium aluminum hydride aluminum chloride (aluminum chloride in an amount of 1 to 1.5 equivalents based on the amount of lithium aluminum hydride), lithium borohydride and the like. The reducing agent is used in an amount of from 0.5 to 4 equivalents, based on the amount of compound (1b-4). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Stage 1-5]

This step is a step in which a compound (1b-6) is obtained by oxidizing a compound (1b-5). There are no restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; alcohol solvents such as methanol and ethanol; and methylene chloride, acetone, hexane, mixed solvents of the foregoing, and the like. Examples of the oxidizing agent used in this reaction include manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, activator dimethyl sulfoxide, tetrapropylammonium perruthenate, dichlorotris (triphenylphosphine) ruthenium (II), 1,1,1-tris (acetyloxy) -1,1-dihydro- 1,2-benziodoxol-3- (1H) -one (Dess-Martin periodinan), etc. The oxidizing agent is used in an amount of from a catalytic amount to 20 equivalents, based on the amount of compound (1b-5). When oxidized with a dimethyl sulfoxide activator, examples of such an activator include acid anhydrides such as acetic anhydride and trifluoroacetic anhydride; acid chlorides such as oxalyl chloride and thionyl chloride; and chlorin, N-chlorosuccinimide and the like. Dimethyl sulfoxide is used in an amount of 1 to 20 equivalents based on the amount of activator. When using tetrapropylammonium perrutinate or ruthenium (II) dichlorotris (triphenylphosphine) in a catalytic amount, an oxidizing agent such as N-methylmorpholine-N-oxide or bis (trimethylsilyl) peroxide can be used simultaneously. The reaction temperature is in the range of −78 ° C. to reflux temperature, and the reaction time is from 10 minutes to 72 hours.

[Stage 1-6]

This step is a step in which a compound (1b) is prepared from a compound (1b-6) in the presence of a base using a diazo compound. Examples of the diazocompound used in this reaction include trimethylsilidiazomethane, (1-diazo-2-oxopropyl) phosphoric acid dimethyl ester, diazomethylphosphoric acid dimethyl ester and the like. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; alcohol solvents such as methanol and ethanol; and methylene chloride, hexane, mixed solvents of the foregoing, and the like. When trimethylsilyldiazomethane is used as the diazo compound, n- butyllithium and lithium diisopropylamide can be used as the base. When a phosphoric acid ester derivative such as (1-diazo-2-oxopropyl) -phosphoric acid dimethyl ester and diazomethylphosphoric acid dimethyl ester is used as a diazo compound, potassium carbonate, potassium t -butoxide and the like can be used as a base. The diazo compound is used in an amount of from 1 to 1.5 equivalents, based on the amount of compound (1b-6). The base is used in an amount of 1 to 2 equivalents, based on the amount of compound (1b-6). The reaction temperature ranges from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

Compound (1b) can also be obtained from compound (1b-6) by the methods described below in the alternative method section (1).

Alternative method (1): Compound (1b-6) can be converted to dihaloalkene in the presence of a base, and then a reaction with a base is carried out to obtain compound (1b).

Dihaloalkene Synthesis: The solvent used in this reaction has no specific limitations, provided that it dissolves the starting materials to a certain extent without blocking the progress of the reaction. Examples of the solvent used in this synthesis include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; and hexane, mixed solvents of the foregoing, and the like. Examples of the reagent for converting compound (1b-6) to dihaloalkene include (dichloromethyl) phosphoric acid dimethyl ester, dibromomethyl triphenylphosphonium bromide ( Tetrahedron Letters , Vol. 40, No.49, 8575-8578) and the like. Examples of the base in this reaction include lithium diisopropylamide, potassium tert -butoxide and the like. The dihalogenalkene conversion reagent is used in an amount of 1 to 1.5 equivalents based on the amount of compound (1b-6). The base is used in an amount of 1 to 2 equivalents, based on the amount of compound (1b-6). The reaction temperature ranges from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

As another method for the synthesis of dihaloalkene, the following alternative method using carbon tetrabromide can be applied. Compound (1b-6) is converted to dihaloalkene by reaction of carbon tetrabromide with triphenylphosphine. Zinc can also be added in this reaction. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Preferred examples of the solvent used in this reaction include tetrahydrofuran and methylene chloride. Carbon tetrabromide is used in an amount of 1 to 2 equivalents based on the amount of compound (1b-6). Triphenylphosphine is used in an amount of 2 to 4 equivalents based on the amount of compound (1b-6). Zinc is used in an amount of 1 equivalent, based on the amount of carbon tetrabromide. The reaction temperature ranges from 0 ° C to room temperature, and the reaction time is from 10 minutes to 12 hours.

Synthesis of compound (1b) from dihaloalkene: There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent without blocking the progress of the reaction. Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; and hexane, mixed solvents of the foregoing, and the like. Examples of the base used in this reaction include n- butyllithium, tert- butyllithium, potassium tert -butoxide and the like. The base is used in an amount of 2 to 3 equivalents based on the amount of dihaloalkene. The reaction temperature ranges from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Production Method 1-2-3] Method for the Preparation of Compound (1b-3):

(where R ² and Hal are defined above and R ⁸ is C _1-6 alkyl).

Compound (1b-7), which is a commercially available product, can be used as it is, or compound (1b-7) can also be obtained from a commercially available product by well-known methods, see, for example, WO 2005 / 033079 A1, pp. 85-86, etc.

[Stage 1-7]

This step is a step in which a compound (1b-8) is obtained by reacting a compound (1b-7) with an alcohol in the presence of a base. This step is carried out according to the procedures described below [step 1-39] or the method disclosed in Journal of Medicinal Chemistry, Vol. 46, No. 5, p. 702-705 or the like. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents in this step include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; and dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base at this stage include sodium hydride, potassium tert -butoxide, potassium hexamethyldisilazide and the like. In this reaction, a copper catalyst may be added. Examples of a copper catalyst include copper, copper (I) iodide, copper (I) bromide, copper (I) chloride, and the like. The base can be used in an amount of from 1 to 20 equivalents, based on the amount of compound (1b-7). Alcohol can be used in an amount of from 1 to 20 equivalents based on the amount of compound (1b-7). The copper catalyst can be used in an amount of from 0.01 to 0.3 equivalents based on the amount of compound (1b-7). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 30 minutes to 48 hours.

[Production Method 1-2-4] Method 1 for the preparation of compound (1b-4):

(where R ² , R ⁷ and Hal are defined above, and R ⁹ represents a C _1-6 alkyl group).

Compound (1b-9), which is a commercially available product, can be used as it is, or compound (1b-9) can also be obtained from commercially available products by well known methods. Compound (1b-9-1), which is a commercially available product, can be used as it is, or compound (1b-9-1) can also be obtained from commercially available products by well-known methods (see, for example , WO 2005/033079 A1, pp. 85-86, etc.).

[Stage 1-8]

This step is a step in which compound (1b-10) is obtained by reacting compound (1b-9) with compound (1b-9-1) in the presence of a palladium catalyst. A phosphine ligand may also be added to obtain good results. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents in this step include 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, mixed solvents of the foregoing, and the like. 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- tert- butylphosphine) palladium (0), tetrakis (triphenylphosphine) palladium (0), 1,1'-bis (diphenylphosphinoferrocene) dichloropalladium (II), etc. Examples of the phosphine ligand include triphenylphosphine, tri- o- tolylphosphine, tri- tert- butylphosphine, diphenylphosphinoferrocene and the like. Compound (1b-9-1) is used in an amount of 1 to 3 equivalents based on the amount of compound (1b-9). The palladium catalyst is used in an amount of from 0.01 to 0.3 equivalents, based on the amount of compound (1b-9). The phosphine ligand is used in an amount of from 0.01 to 1.2 equivalents based on the amount of compound (1b-9). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production Method 1-2-5] Method 2 for the preparation of compound (1b-4)

(where Hal, R ² and R ^{7 are} defined above, R ¹⁰ and R ¹¹ each independently represents C _1-6 alkyl groups).

Compound (1b-9) and compound (1b-9-2), which are commercially available products, can be used as they are, or can be obtained from commercially available products by well-known methods.

[Stage 1-9]

This step is a step in which a compound (1b-11) is obtained by alkylation of a compound (1b-9) by reaction with a compound (1b-9-2) in the presence of a palladium catalyst. The compound (1b-11) can be obtained according to a method similar to the methods of [steps 1-8].

[Production Method 1-2-6] Method for the Preparation of Compound (1b-5)

(where R ¹ and R ^{2 are} defined above).

Compound (1b-3), which is a commercially available product, can be used as it is, or can be obtained from commercially available products by well-known methods.

[Stage 1-10]

This step is a step in which a compound (1b-5) is obtained by reducing a compound (1b-3). The compound (1b-5) can be obtained according to methods similar to the methods [stages 1-4].

[Production Method 1-2-7] Method for the Preparation of a Halogen-Modified Pyridine Ring Product

(where R ¹ , R ² and Hal are defined above; R ¹² represents a hydrogen atom, a hydroxy group, or OR ⁷ (R ^{7 is} defined above)).

Compound (1b-12), which is a commercially available product, can be used as it is, or can be obtained from commercially available products by well-known methods.

[Stage 1-11]

This step is a step in which compound (1b-13) is obtained by replacing a hydrogen atom with a halogen atom in the pyridine ring of compound (1b-12). This step can be performed according to, for example, European Journal of Medicinal Chemistry, Vol.12, No.6, 531-536, or Journal of Organic Chemistry, Vol.49, No.26, 5237-5243, or the like. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include halogen-containing solvents such as chloroform and dichloromethane; ether solvents such as tetrahydrofuran and diethyl ether; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; acidic solvents such as an aqueous solution of acetic acid and hydrochloric acid; dimethyl sulfoxide; acetonitrile; mixed solvents of the foregoing or the like Examples of the halogenation reagent include N-chlorosuccinimide, N-bromosuccinimide, chlorin and bromine. The halogenation reagent is used in an amount of 1.0 to 1.5 equivalents based on the amount of compound (1b-12). The reaction temperature ranges from room temperature to 50 ° C, and the reaction time is from 5 minutes to 24 hours.

[Production Method 1-2-8] Method for the Preparation of Compound (1b-6)

(where R ² and R ^{7 are} defined above).

Compound (1b-14) can be prepared according to the methods described in the above section [Production Method 1-2-4].

[Stage 1-12]

This step is a step in which a compound (1b-15) is obtained by reducing a compound (1b-14). The compound (1b-15) can be obtained according to methods similar to the methods of [stages 1-4].

[Stage 1-13]

This step is a step in which a compound (1b-16) is obtained by oxidizing a compound (1b-15). The compound (1b-16) can be obtained according to methods similar to the methods of [steps 1-5].

[Stage 1-14]

This step is a step in which a compound (1b-17) is obtained by reacting a compound (1b-16) with boron tribromide. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include halogenated hydrocarbon solvents such as methylene chloride; aromatic hydrocarbon solvents such as benzene and toluene; mixed solvents of the foregoing or the like Boron tribromide can be used in an amount of from 1 to 5 equivalents based on the amount of compound (1b-16), preferably 3 equivalents. The reaction temperature is in the range of −20 ° C. to room temperature and is preferably 0 ° C. The reaction time is from 10 minutes to 24 hours.

[Production Method 1-3-1] Method 1 for the preparation of compound (1c):

(where the ring A, R ³ , Z, and Hal are defined above, R ¹³ and R ^{13 ′} are C _1-6 alkyl groups or crosslinked - (CH ₂ ) _n -, H is 2 or 3, and R ¹⁴ is a hydrogen atom, sodium atom, potassium atom and lithium atom).

Each compound in the above reaction scheme, which is a commercially available product, can be used as it is, or each compound can also be obtained from commercially available products by well known methods. In addition, each compound can be prepared by the methods described in the Production Examples section of the Examples section and the methods described in the [Production Methods 1-3-1] - [Production Methods 1-3-23].

[Stage 1-15]

This step is a step in which compound (1c-6) is obtained by reacting a formylation reagent with an organometallic compound obtained by replacing a halogen atom with a metal atom in compound (1c-1). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Preferred examples of the solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether. Examples of organometallic compounds include organolithium compounds prepared using a base such as n- butyl lithium, sec- butyl lithium, tert-butyl lithium and lithium diisopropylamide, or Grignard reagents prepared using a base such as magnesium metal, ethyl magnesium bromide and isopropyl magnesium chloride. When preparing Grignard reagents using metallic magnesium, a catalytic amount of iodine, dibromomethane, and the like can be added. The temperature for preparing the organolithium compound is in the range of −78 ° C. to room temperature, preferably −78 ° C. to −40 ° C., the base is used in an amount of 1 to 1.5 equivalents based on the amount of the compound (1c-1) and the reaction time is from 30 minutes to 24 hours. The temperature for the preparation of Grignard reagents using metallic magnesium is in the range from room temperature to the reflux temperature of the solvent, metallic magnesium is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-1), and the reaction time is from 30 minutes to 24 hours. The temperature for the preparation of Grignard reagents using ethyl magnesium bromide or isopropyl magnesium chloride is in the range from -60 ° C to reflux temperature, ethyl magnesium bromide or isopropyl magnesium bromide is used in an amount of 1 to 1.6 equivalents, based on the amount of compound (1c-1), and the reaction time is from 5 minutes to 12 hours. Examples of formylation agents include dimethylformamide, N-formylpiperidine, N-formylmorpholine, N-methylformanilide and the like. The formylation reagent can be used in an amount of from 1 to 20 equivalents, preferably from 1 to 2 equivalents, based on the amount of the organometallic compound. In the case of organolithium compounds, the temperature during the reaction with the organometallic compound and the formylation reagent is from -78 ° C to room temperature, while the reaction time is from 5 minutes to 6 hours, while in the case of Grignard reagents, the reaction temperature is ranges from -78 ° C to the reflux temperature of the solvent, and the reaction time is from 5 minutes to 24 hours.

[Stage 1-16]

This step is a step in which compound (1c-6) is obtained by reacting an acid with an acetal of compound (1c-2) in order to protect the acetal. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide and water, mixed solvents of the foregoing, and the like. Examples of the acid in this reaction include inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; organic acids such as citric acid, trifluoroacetic acid, p- toluenesulfonic acid and the like. The acid can be used in an amount from a catalytic amount to an excess amount, based on the amount of compound (1c-2). The reaction temperature ranges from 0 ° C to the reflux temperature of the solvent, and the reaction time is from 5 minutes to 24 hours.

[Stage 1-17]

This step is a step in which a compound (1c-6) is obtained by oxidizing a compound (1c-3). The compound (1c-6) can be obtained according to methods similar to the methods of [steps 1-5].

[Stage 1-18]

This step is a step in which compound (1c-6) is prepared by reducing compound (1c-4). Compound (1c-6) can be obtained by a reduction reaction using a reducing reagent such as diisobutylaluminum hydride, sodium triethoxyaluminum hydride, lithium triethoxyaluminum hydride and the like. There are no particular restrictions on the solvent used, but in the case of a reduction reaction using a reducing reagent, hydrocarbons such as toluene and ethers such as tetrahydrofuran can be used. The reducing agent is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-4). The reaction temperature ranges from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 1-19]

This step is a step in which a compound (1c-5) is obtained by reducing a compound (1c-4). Compound (1c-5) can be prepared either by a reduction reaction using a reducing agent, such as lithium aluminum hydride or diisobutylaluminum hydride, or by catalytic hydrogenation using Raney nickel, palladium-carbon or another catalyst in a hydrogen atmosphere. There are no particular restrictions on the solvent used, but in the case of a reduction reaction using a reducing agent, esters such as tetrahydrofuran and diethyl ether or hydrocarbons such as toluene can preferably be used, while alcohols can preferably be used in the case of catalytic hydrogenation such as methanol, ethanol, propanol and the like. The reducing agent is used in an amount of 1 to 10 equivalents based on the amount of compound (1c-4). There are no specific restrictions on the reaction temperature, but in the case of a reduction reaction using a reducing agent, the reaction temperature is in the range of -78 ° C to the reflux temperature of the solvent used, while in the case of catalytic hydrogenation, the reaction temperature is in the range of room temperature temperature to the reflux temperature of the solvent used. The reaction time is from 10 minutes to 24 hours. In the case of catalytic hydrogenation, atmospheric pressure is in the range of 1 to 4 atmospheres. In catalytic hydrogenation, an amount of catalyst from catalytic to excess can be used.

[Stage 1-20]

This step is a step in which compound (1c-3) is obtained by converting the amino groups of compound (1c-5) to acetoxy groups by reaction with sodium nitrite and acetic acid, followed by hydrolysis using a base.

Acetoxylation reaction: A preferred example of the solvent used in this reaction includes a mixed solvent of acetic acid-water. More preferably, the ratio of acetic acid to water is from 1: 5 to 5: 1. Sodium nitrite is used in an amount of 1 to 20 equivalents, based on the amount of compound (1c-5). The reaction temperature ranges from 0 ° C to room temperature, and the reaction time is from 1 hour to 12 hours.

Hydrolysis reaction: There are no specific restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent without blocking the progress of the reaction. Examples of the solvent in this reaction include alcoholic solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; water, dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include sodium hydroxide, potassium hydroxide, potassium carbonate, and the like. The reaction temperature is from 0 ° C to 60 ° C, preferably from 20 ° C to 40 ° C, and the reaction time is from 30 minutes to 12 hours.

The compound (1c-3) can also be obtained from the compound (1c-5) by the method described below in the section Alternative method (1).

Alternative Method (1): This step is a step in which a compound (1c-3) is obtained by heating a compound (1c-5) in the presence of a strong base. A preferred example of a solvent in this step includes diethylene glycol, and a preferred example of a base includes potassium hydroxide. Potassium hydroxide is used in an amount of 5 to 30 equivalents based on the amount of compound (1c-5), the reaction temperature is in the range of 150 ° C to 230 ° C, and the reaction time is from 1 hour to 12 hours. It should be noted that during the reaction, the inactive gas is preferably replaced within the reaction container.

[Stage 1-21]

This step is a step in which compound (1c-7) is obtained by reacting compound (1c-6) with nitromethane in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include alcoholic solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and diethyl ether; etc. Examples of the base in this reaction include sodium methoxide, sodium ethoxide, n- butyl lithium, lithium diisopropylamide, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium t -butoxide and the like. Nitromethane can be used in an amount of 1 to 20 equivalents based on the amount of compound (1c-6). The base is used in an amount of 1 to 2 equivalents, based on the amount of compound (1c-6). The reaction temperature is in the range of −78 ° C. to reflux temperature, and the reaction time is from 5 minutes to 48 hours.

[Stage 1-22]

This step is a step in which compound (1c-8) is obtained by esterification of the hydroxyl groups of compound (1c-7) in the presence of a base, followed by their removal in situ . There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; and methylene chloride, dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base in this reaction include triethylamine, N, N-diisopropylethylamine and the like. Examples of esterification agents include acetic anhydride, methanesulfonyl chloride, p- toluenesulfonyl chloride and the like. The base is used in an amount of 1.0 to 4.0 equivalents based on the amount of compound (1c-7). An esterification agent is used in an amount of 1.0 to 2.0 equivalents based on the amount of compound (1c-7). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 24 hours.

The compound (1c-8) can also be obtained from the compound (1c-7) by the method described below in the section Alternative method (1).

Alternative Method (1): Compound (1c-8) can be prepared by dehydrogenating compound (1c-7) in acetic acid as a solvent in the presence of an acetic acid salt. Acetic acid is used as a solvent in this reaction, but a mixed solvent of acetic acid — methanol, tetrahydrofuran, and the like can also be used. Examples of the acetic acid salt include ammonium acetate, ethylene diamine diacetic acid salt and the like. The acetic acid salt is used in an amount of 1 to 20 equivalents based on the amount of compound (1c-7). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 72 hours.

[Stage 1-23]

This step is a step in which compound (1c-8) is obtained by reacting compound (1c-6) with nitromethane in the presence of a base and then dehydrogenated by adding acid to the reaction system. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent used in this reaction include water; alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and diethyl ether; mixed solvents of the foregoing and the like. Examples of the base used in this reaction include sodium methoxide, sodium ethoxide, n- butyl lithium, lithium diisopropylamide, sodium hydroxide, potassium hydroxide, potassium carbonate, potassium t -butoxide and the like. Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid, acetic acid, and the like. Nitromethane is used in an amount of 1 to 20 equivalents based on the amount of compound (1c-6). The base is used in an amount of 1 to 2 equivalents, based on the amount of compound (1c-6). Acid can be added in excess. The reaction temperature for the reaction with nitromethane is in the range of −78 ° C. to reflux temperature, and the reaction time is from 5 minutes to 48 hours. The reaction temperature for the dehydrogenation reaction ranges from room temperature to reflux temperature, and the reaction time is from 5 minutes to 48 hours.

The compound (1c-8) can also be obtained from the compound (1c-6) by the method described below in the section Alternative method (1).

Alternative Method (1): Compound (1c-8) can be prepared by reacting compound (1c-6) with nitromethane in the presence of an acetic acid salt. Acetic acid is used as a solvent in this reaction, but a mixed solvent of acetic acid-methanol, tetrahydrofuran and the like can also be used. Examples of the acetic acid salt used in this reaction include ammonium acetate, ethylene diamine diacetic acid salt and the like. Nitromethane is used in an amount of 1 to 10 equivalents based on the amount of compound (1c-6). The acetic acid salt is used in an amount of 1 to 20 equivalents based on the amount of compound (1c-6). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 72 hours.

[Stage 1-24]

This step is a step in which compound (1c-9) is obtained by reducing compound (1c-8). To obtain good results, an acid such as acetic acid or hydrochloric acid may be added. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include alcoholic solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran; and dimethyl sulfoxide and the like. Examples of the reducing agent used in this reaction include sodium borohydride, lithium borohydride and the like. The reducing agent is used in an amount of from 0.5 to 3 equivalents, based on the amount of compound (1c-8). The reaction temperature ranges from -20 ° C to 80 ° C, and the reaction time is from 10 minutes to 12 hours. If acid is added, it can be added in an amount of from 1 equivalent to the amount of solvent, based on the amount of reducing agent.

[Stage 1-25]

This step is a step in which compound (1c) is prepared by anionizing a nitroethyl functional group in compound (1c-9) using a base, followed by the addition of titanium (IV) chloride.

Anionization reaction of compound (1c-9): There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent without blocking the progress of the reaction. Examples of solvents used in this reaction include alcoholic solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran; etc. Examples of the base used in this reaction include lithium methoxide, sodium methoxide, potassium t -butoxide, n- butyllithium and the like. The base is used in an amount of 1 to 2 equivalents, based on the amount of compound (1c-9). The reaction temperature ranges from -78 ° C to room temperature, and the reaction time is from 5 minutes to 1 hour.

Reaction with titanium (IV) chloride: There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran; and methylene chloride, 1,2-dichloroethane, mixed solvents of the foregoing, and the like. Titanium (IV) chloride is used in an amount of 1 to 3 equivalents based on the amount of compound (1c-9). The reaction temperature ranges from -10 ° C to room temperature, and the reaction time is from 10 minutes to 12 hours.

[Stage 1-26]

This step is a step in which compound (1c) is obtained by reacting compound (1c-8) with titanium (IV) chloride in the presence of triethylsilane. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran; and methylene chloride, 1,2-dichloroethane, mixed solvents of the foregoing, and the like. Triethylsilane is used in an amount of 1 to 3 equivalents based on the amount of compound (1c-8). Titanium (IV) chloride is used in an amount of 1 to 3 equivalents based on the amount of compound (1c-8). The reaction temperature ranges from -20 ° C to room temperature, and the reaction time is from 10 minutes to 12 hours.

[Production Method 1-3-2] Method 2 for the preparation of compound (1c)

(where R ^{3 is} defined above; in this formula, R ¹⁵ represents a C _1-6 alkyl group which may be substituted with halogen or the like; L represents a leaving group such as a halogen atom, p- toluenesulfonyl group and trifluoromethanesulfonyl group).

Compound (1c-10), compound (1c-10-1) and compound (1c-10-2), which are commercially available products, can be used as they are, or can also be obtained from commercially available products by known methods.

[Stage 1-27]

This step is a step in which compound (1c-11) is obtained by reacting compound (1c-10) with an organophosphorus compound, an azo reagent and compound (1c-10-1). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; ethyl acetate; acetonitrile; methylene chloride; mixed solvents of the foregoing and the like. Examples of the organophosphorus compound include triphenylphosphine, trin -n- butylphosphine and the like. Examples of the azo compound include ester derivatives such as diethyl azodicarboxylate and diisopropyl azodicarboxylate, and amide derivatives such as 1,1 '- (azodicarbonyl) dipiperidine. Compound (1c-10-1) is used in an amount of 1 to 1.5 equivalents based on the amount of compound (1c-10). An organophosphorus compound is used in an amount of 1 to 3 equivalents based on the amount of the compound (1c-10). The azoreagent is used in an amount of 1 to 3 equivalents, based on the amount of compound (1c-10). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 5 minutes to 24 hours.

[Stage 1-28]

This step is a step in which a compound (1c-11) is obtained by reacting a compound (1c-10) with a compound (1c-10-2) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran, diethyl ether and the like; aromatic hydrocarbon solvents such as benzene, toluene and the like; amide solvents such as N, N-dimethylformamide, N-methylpyrrolidinone or the like; alcohol solvents such as methanol, ethanol or the like; dimethyl sulfoxide; mixed solvents of the foregoing and the like. Examples of the base include sodium hydride, potassium t -butoxide, sodium ethoxide, sodium methoxide, N, N-diisopropylethylamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like. The base is used in an amount of 1 to 5 equivalents based on the amount of the compound (1c-10-2). Compound (1c-10-2) is used in an amount of 1 to 20 equivalents based on the amount of compound (1c-10). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 5 minutes to 6 hours.

[Stage 1-29]

This step is a step in which compound (1c-12) is obtained by reacting compound (1c-11) with peroxide. Examples of the peroxide used in this reaction include m- chloroperbenzoic acid, hydrogen peroxide, dimethyldioxirane, benzoyl peroxide, peracetic acid, etc. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include halogen-containing solvents such as chloroform and methylene chloride; alcohol solvents such as methanol and ethanol; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; aromatic hydrocarbon solvents such as benzene and toluene, diethyl ether; acetone; acetonitrile; acetic acid; water, etc. Peroxide is used in an amount of 1 to 5 equivalents based on the amount of compound (1c-11). The reaction temperature ranges from -40 ° C to reflux temperature, and the reaction time is from 1 minute to 48 hours.

[Stage 1-30]

This step is a step in which compound (1c-13) is obtained by reacting compound (1c-12) with acetic anhydride. Examples of acetic anhydride used in this reaction include acetic anhydride, trifluoroacetic acid anhydride and the like. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include halogen-containing solvents such as chloroform and methylene chloride; aromatic hydrocarbon solvents such as benzene and toluene; acetic acid, trifluoroacetic acid and the like. Acid anhydride may also be used as a solvent. Acid anhydride is used in an amount from 1 equivalent to an excess based on the amount of compound (1c-12). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 1-31]

This step is a step in which a compound (1c-14) is obtained by hydrolyzing a compound (1c-13). Compound (1c-14) can be prepared by hydrolysing compound (1c-13), for example, in the presence of an acid, such as sulfuric acid, or, for example, in the presence of an alkali, such as sodium hydroxide, potassium hydroxide, sodium methoxide, potassium carbonate or sodium carbonate. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as 1,4-dioxane and tetrahydrofuran; alcohol solvents such as methanol and ethanol; halogen-containing 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, mixed solvents of the foregoing, and the like. The acid or base is used in an amount of from 1 equivalent to an excess amount, based on the amount of compound (1c-13). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 1-32]

This step is a step in which compound (1c-15) is obtained by converting the hydroxyl group of compound (1c-14) to a leaving group.

If L is a methanesulfonyloxy group, p- toluenesulfonyloxy group or another sulfuric acid ester; compound (1c-15) can be obtained by reacting compound (1c-14) with sulfonyl chloride under basic conditions. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide, methylene chloride, mixed solvents of the foregoing, and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like. Examples of sulfonyl chloride include methanesulfonyl chloride, p- toluenesulfonyl chloride and the like. The base is used in an amount of 1 to 3 equivalents, based on the amount of compound (1c-14). Sulfonyl chloride is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-14). The reaction temperature ranges from 0 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

If L is a chlorine atom or a bromine atom; Compound (1c-15) can be prepared by halogenating compound (1c-14) with carbon tetrachloride or tetrabromomethane in the presence of triphenylphosphine. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; and methylene chloride, mixed solvents of the foregoing, and the like. Also, tetrachloromethane or tetrabromomethane can be used as a solvent. Triphenylphosphine is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-14). Tetrachloromethane or tetrabromomethane is used in an amount of from 1 equivalent to the amount of solvent, based on the amount of compound (1c-14). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 12 hours.

Compound (1c-15) can also be obtained from compound (1c-14) according to the methods described below as alternative methods (1), (2) and (3).

Alternative Method (1): Compound (1c-14) can be converted to compound (1c-15) under acidic conditions. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ethereal solvents such as diethyl ether; water, ethyl acetate, mixed solvents of the foregoing, and the like. In this reaction, a phase transition agent such as tetrabutylammonium bromide can be used in an amount of from 0.01 to 2 equivalents based on the amount of compound (1c-14). Examples of the acid include hydrochloric acid, hydrobromic acid, and the like. Sulfuric acid can be added to get good results. The reaction temperature ranges from 0 ° C to room temperature, and the reaction time is from 10 minutes to 12 hours.

Alternative Method (2): Compound (1c-15) can be prepared by reacting compound (1c-14) with thionyl chloride. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include aromatic hydrocarbon solvents such as benzene and toluene; acetonitrile, chloroform, methylene chloride and the like; thionyl chloride can also be used as a solvent. To increase the yield, pyridine in a catalytic amount can also be added to the reaction mixture. Thionyl chloride is used in an amount of from 1 equivalent to the amount of solvent, based on the amount of compound (1c-14). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 12 hours.

Alternative Method (3): Compound (1c-15) can be prepared by reacting compound (1c-14) with phosphorus halide. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ethereal solvents such as diethyl ether; N, N-dimethylformamide, acetonitrile, chloroform and the like. Examples of phosphorus halide include phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide and the like. Phosphorus halide is used in an amount of 0.33 to 3 equivalents based on the amount of compound (1c-14). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 12 hours.

[Stage 1-33]

This step is a step in which a compound (1c-16) is obtained by converting a leaving group of a compound (1c-15) into a cyano group. In order to obtain good results, an inorganic salt such as sodium iodide and the like can also be added in an amount of 1 to 2 equivalents based on the amount of compound (1c-15). Examples of the cyanization agent used in this reaction include sodium cyanide, potassium cyanide, lithium cyanide and the like. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include alcoholic solvents such as methanol and ethanol; ether solvents such as 1,4-dioxane and tetrahydrofuran; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide; acetonitrile; acetone; water mixed solvents of the foregoing and the like. The cyanization agent is used in an amount of from 1 to 5 equivalents, based on the amount of compound (1c-15). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 48 hours.

[Stage 1-34]

This step is a step in which a compound (1c-17) is obtained by reacting a compound (1c-16) with hydroxylammonium chloride. Examples of the base used in this reaction include pyridine, sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and the like. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; sulfoxides such as dimethyl sulfoxide; esters such as tetrahydrofuran and 1,4-dioxane; alcohols such as methanol and ethanol; amides such as N-methylpyrrolidinone, N, N-dimethylformamide and N, N-dimethylacetamide; pyridine; water, mixed solvents of the above, and the like. Hydroxylammonium chloride is used in an amount of 1 to 5 equivalents based on the amount of compound (1c-16). The base is used in an amount from 1 equivalent to an excess based on the amount of compound (1c-16). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Stage 1-35]

This step is a step in which compound (1c-18) is obtained by reacting compound (1c-17) with sodium nitrite and a source of chlorine. Examples of the chlorine source used in this reaction include hydrochloric acid, copper chloride, and the like. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as 1,4-dioxane and tetrahydrofuran; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide; acetonitrile; acetone; an aqueous solution of hydrochloric acid; water mixed solvents of the foregoing and the like. Sodium nitrite can be used in an amount of from 1 to 10 equivalents, based on the amount of compound (1c-17). The chlorine source can be used in an amount of from 1 equivalent to an excess amount, based on the amount of compound (1c-17). The reaction temperature ranges from -40 ° C to reflux temperature, and the reaction time is from 1 minute to 24 hours.

[Production Method 1-3-3] Method 1 for the preparation of compound (1c-1):

(where R ³ and L are defined above).

The compound (1c-19), the compound (1c-20), the compound (1c-19-1) and the compound (1c-20-1), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by well-known methods.

[Stage 1-36]

This step is a step in which a compound (1c-21) is obtained by reacting a compound (1c-19) with a compound (1c-19-1) in the presence of a base. The compound (1c-21) can be obtained according to methods similar to the methods of [Step 1-28].

[Stage 1-37]

This step is a step in which a compound (1c-21) is obtained by reacting a compound (1c-20) with an organophosphorus compound, an azo reagent, and a compound (1c-19-1). The compound (1c-21) can be obtained according to methods similar to the methods of [Step 1-27].

[Stage 1-38]

This step is a step in which a compound (1c-21) is obtained by reacting a compound (1c-20) with a compound (1c-20-1) in the presence of a base. A catalytic amount of sodium iodide, potassium iodide or tetrabutylammonium iodide can also be added to obtain good results. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include sodium hydride, potassium t -butoxide, sodium ethoxide, sodium methoxide, N, N-diisopropylamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like. Examples of copper catalysts include copper, copper (I) iodide, copper (I) bromide, copper (I) chloride, and the like. Compound (1c-20-1) is used in an amount of 1 to 5 equivalents based on the amount of compound (1c-20). The base is used in an amount of 1 to 5 equivalents based on the amount of compound (1c-20). The copper catalyst can be used in an amount of from 0.01 to 0.3 equivalents based on the amount of compound (1b-20). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 5 minutes to 48 hours.

[Production Method 1-3-4] Method 2 for the preparation of compound (1c-1):

(where R ^{3 is} defined above).

Compound (1c-22) and compound (1c-10-1) can be commercially available products or can also be obtained from commercially available products by well known methods.

[Stage 1-39]

This step is a step in which compound (1c-23) is obtained by reacting compound (1c-22) with compound (1c-10-1) in the presence of a base. A copper catalyst can also be added to the reaction mixture. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide, mixed solvents of the foregoing and the like. Examples of the base include sodium hydride, potassium t -butoxide, sodium ethoxide, sodium methoxide, potassium hydroxide, sodium hydroxide, and the like. Examples of a copper catalyst include copper, copper (I) iodide, copper (I) bromide, copper (I) chloride, and the like. The base is used in an amount of 1 to 5 equivalents based on the amount of the compound (1c-10-1). Compound (1c-10-1) is used in an amount of 1.0 to 3.0 equivalents based on the amount of compound (1c-22). The copper catalyst can be used in an amount of from 0.01 to 1 equivalent, based on the amount of compound (1c-10-1). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Production Method 1-3-5] Method 3 for the Preparation of Compounds (1c-1), (1c-2) and (1c-6)

(where Hal, L, R ³ , R ¹³ and R ^{13 'are} defined above; in addition, R ¹⁶ and R ^{17 are} represented by a halogen group, a C _1-6 alkyl group and a C _1-6 alkoxy group; Hal ¹ represents a chlorine atom and an atom bromine; M ¹ represents a magnesium atom and a zinc atom).

Compound (1c-24), compound (1c-25), compound (1c-19-1), compound (1c-20-1), compound (1c-24-1) and compound (1c-26-1), which are commercially available products can be used as they are, or they can be obtained from commercially available products by well-known methods.

[Stage 1-40]

This step is a step in which compound (1c-25) is obtained by converting compound (1c-24) to an organometallic compound by replacing the halogen atom of compound (1c-24) with a metal atom and then using a formylation reagent. At this stage, there are no specific restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent without blocking the reaction, but diethyl ether is preferred. Examples of organometallic compounds include organolithium compounds obtained by using a base such as n- butyl lithium, sec- butyl lithium, t-butyl lithium and the like. The temperature at which the organolithium compound should be obtained is in the range from −100 ° C. to room temperature, and preferably from −78 ° C. to −40 ° C. The base can be used in an amount of from 1 to 1.2 equivalents based on the amount of compound (1c-24), and the reaction time is from 10 minutes to 24 hours. Examples of the formylation reagent include N, N-dimethylformamide, N-formylpiperidine, N-formylmorpholine, N-methylformanilide and the like. The formylation reagent can be used in an amount of from 1 to 20 equivalents, based on the amount of compound (1c-24), and preferably from 1 to 2 equivalents. The temperature for the reaction with the organometallic compound and the formylation reagent is in the range of −78 ° C. to room temperature, and the reaction time is from 5 minutes to 24 hours.

[Stage 1-41]

This step is a step in which compound (1c-26) is obtained by protecting the formyl group of compound (1c-25) with acetal in the presence of an alcohol and an acidic catalyst. Preferred examples of the alcohol used in this reaction include methanol, ethanol, ethylene glycol, propylene glycol and the like. Examples of the acid catalyst include hydrochloric acid, sulfuric acid, p- toluenesulfoxylate, acetic acid, ammonium chloride and the like. At this stage, there are no specific restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent without blocking the progress of the reaction. Examples of the solvent include alcoholic solvents such as methanol, ethanol and ethylene glycol; aromatic hydrocarbon solvents such as benzene and toluene; halogenated hydrocarbon solvents such as dichloromethane and chloroform and the like. Alcohol is used in an amount of from 1 equivalent to the amount of solvent, based on the amount of compound (1c-25). The acid catalyst is used in an amount of 0.05 equivalents to an excess based on the amount of compound (1c-25). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 1-42]

This step is a step in which compound (1c-27) is obtained by converting compound (1c-26) to an organometallic compound by replacing the halogen atom of compound (1c-26) with a metal atom and then using a formylation reagent. The compound (1c-27) can be obtained by methods similar to the methods of [Step 1-15].

[Stage 1-43]

This step is a step in which a compound (1c-28) is obtained by reducing a compound (1c-27). Examples of the reducing agent used in this reaction include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include alcoholic solvents such as methanol and ethanol; ether solvents such as diethyl ether and tetrahydrofuran; aromatic hydrocarbon solvents such as benzene and toluene; halogenated hydrocarbon solvents such as dichloromethane and chloroform; water, mixed solvents of the foregoing, and the like. In general, alcoholic solvents are preferred when a reducing agent is used, such as sodium borohydride; ethereal solvents are preferred when a reducing agent is used, such as lithium aluminum hydride. The reducing agent is used in an amount of 0.25 to 4 equivalents based on the amount of compound (1c-27). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 5 minutes to 24 hours.

[Stage 1-44]

This step is a step in which a compound (1c-29) is obtained by reacting a compound (1c-28) with a compound (1c-20-1) in the presence of a base. The compound (1c-29) can be obtained according to methods similar to the methods of [Step 1-38].

[Stage 1-45]

This step is a step in which a compound (1c-30) is obtained by reacting a compound (1c-24) with a compound (1c-24-1) in the presence of a base. Compound (1c-30) can be obtained according to methods similar to the methods of [Step 1-39].

[Stage 1-46]

This step is a step in which compound (1c-31) is obtained by reacting compound (1c-24) with compound (1c-19-1) in the presence of a base. Compound (1c-31) can be obtained according to methods similar to the methods of [Step 1-39].

[Stage 1-47]

This step is a step in which compound (1c-32) is obtained by converting compound (1c-31) to an organometallic compound by replacing the halogen atom of compound (1c-31) with a metal atom and then reacting with a formylation agent. The compound (1c-32) can be obtained according to methods similar to the methods of [Step 1-15].

[Stage 1-48]

This step is a step in which a compound (1c-32) is obtained by reacting a compound (1c-25) with a compound (1c-19-1) in the presence of a base. Compound (1c-32) can be obtained according to methods similar to the methods of [Step 1-39].

[Stage 1-49]

This step is a step in which compound (1c-33) is obtained by reacting compound (1c-26) with compound (1c-26-1) in the presence of a nickel catalyst. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Preferred examples of the solvent include ether solvents such as tetrahydrofuran, dioxane and diethyl ether. Examples of the nickel catalyst include 1,3-bis (diphenylphosphino) propane-nickel (II) chloride, bis (triphenylphosphine) nickel (II) chloride, 1,2-bis (diphenylphosphino) ethane-nickel (II) chloride, 1.1 ' bis (diphenylphosphino) ferrocene-nickel (II) chloride, etc. Compound (1c-26-1) is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-26), and the nickel catalyst is used in an amount of 0.02 to 0.2 equivalents based on the amount of compound (1c- 26). The reaction temperature ranges from -10 ° C to 80 ° C, and the reaction time is from 30 minutes to 12 hours.

In addition, if M ¹ represents a zinc atom, then the compound (1c-26-1) can be obtained in situ and used in the reaction, as described below. The reaction in [Step 1-49] can be carried out by in situ synthesis of compound (1c-26-1) using benzyl halide and activated zinc. In this case, activated zinc is used in an amount of from 1 to 1.3 equivalents, based on the amount of benzyl halide. The reaction temperature for the preparation of compound (1c-26-1) is in the range from −10 ° C. to room temperature, preferably from −5 ° C. to 10 ° C., and the reaction time is from 1 hour to 10 hours.

[Production Method 1-3-6] Method 1 for the preparation of compound (1c-2)

(where R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ represent a halogen, a C _1-6 alkyl group and a C _1-6 alkoxy group).

Compound (1c-34), compound (1c-34-1), compound (1c-34-2), compound (1c-34-3) and compound (1c-34-4), which are commercially available products, can be used as they are, or they can also be obtained from commercially available products by known methods.

[Stage 1-50]

This step is a step in which compound (1c-35) is obtained by converting compound (1c-34) to an organometallic compound by replacing the halogen atom of compound (1c-34) with a metal atom and then reacting with compound (1c-34-1 ) There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Preferred examples of the solvent include ether solvents such as tetrahydrofuran and diethyl ether. Examples of the organometallic compound include organolithium compounds obtained by using a base such as n- butyl lithium, sec- butyl lithium, t-butyl lithium, lithium diisopropylamide and the like. The temperature at which the organolithium compound should be obtained is in the range of −78 ° C. to room temperature, preferably −78 ° C. to −40 ° C. The base is used in an amount of from 1 to 1.5 equivalents, based on the amount of compound (1c-34). The reaction time is from 30 minutes to 24 hours. Compound (1c-34-1) is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-34). The reaction temperature of the metal organic compound and compound (1c-34-1) is in the range of −78 ° C. to room temperature, and the reaction time is from 5 minutes to 12 hours.

[Stage 1-51]

This step is a step in which a compound (1c-35) is obtained by reacting a compound (1c-34) with a compound (1c-34-2) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include sodium hydride, potassium t -butoxide, sodium ethoxide, sodium methoxide, potassium hydroxide, sodium hydroxide, and the like. The base is used in an amount of from 1 to 5 equivalents, based on the amount of compound (1c-34). Compound (1c-34-2) is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-34). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 5 minutes to 24 hours.

[Stage 1-52]

This step is a step wherein compound (1c-36) is obtained by converting compound (1c-34) to an organometallic compound by replacing the halogen atom of compound (1c-34) with a metal atom and then reacting with compound (1c-34-3) . The compound (1c-36) can be obtained according to methods similar to the methods of [Step 1-50].

[Stage 1-53]

This step is a step in which a compound (1c-36) is obtained by reacting a compound (1c-34) with a compound (1c-34-4) in the presence of a base. The compound (1c-36) can be obtained according to methods similar to the methods of [Step 1-51].

[Production Method 1-3-7] Method 2 for the Preparation of Compound (1c-2)

(where Hal is defined above; R ²² and R ²³ represent a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group).

Compound (1c-37) and compound (1c-37-1), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by known methods.

[Stage 1-54]

This step is a step in which compound (1c-38) is obtained by converting compound (1c-37) to an organometallic compound by replacing the hydrogen atom at the 5-position of compound (1c-37) with a metal atom and then reacting with compound (1c- 37-1). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Preferred examples of the solvent include ether solvents such as tetrahydrofuran and diethyl ether. Examples of the organometallic compound include organolithium compounds prepared using a base such as n- butyl lithium, sec- butyl lithium, t-butyl lithium, lithium diisopropylamide and the like. The temperature at which the organolithium compound should be obtained is in the range of −78 ° C. to room temperature, preferably −78 ° C. to −40 ° C. The base is used in an amount of 1 to 1.5 equivalents, based on the amount of compound (1c-37). The reaction time is from 30 minutes to 24 hours. Compound (1c-37-1) is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-37). The reaction temperature of the organometallic compound and compound (1c-37-1) is in the range of −78 ° C. to room temperature. The reaction time is from 5 minutes to 12 hours.

[Production Method 1-3-8] Method 1 for the preparation of compound (1c-3):

(where R ³ and L are defined above).

Compound (1c-39) and compound (1c-20-1) can be commercially available products or can be obtained from commercially available products by well known methods.

[Stage 1-55]

This step is a step in which a compound (1c-40) is obtained by reacting a compound (1c-39) with a compound (1c-20-1). Compound (1c-20-1) is used in an amount of 0.2 to 1.0 equivalents based on the amount of compound (1c-39). The compound (1c-40) can be obtained according to methods similar to the methods of [Step 1-38].

[Production Method 1-3-9] Method 2 for the preparation of compound (1c-3):

(where R ³ , R ¹³ , R13 'and Hal are defined above).

Compound (1c-41) and compound (1c-41-1) can be commercially available products or can also be obtained from commercially available products by well known methods.

[Stage 1-56]

This step is a step in which a halogen atom in a compound (1c-41) is replaced with a metal atom to produce an organometal compound, which is then used in a reaction with a compound (1c-41-1) to produce a compound (1c-42). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; mixed solvents of the foregoing and the like. Examples of the reagent for converting compound (1c-41) to an organometallic compound include n- butyl lithium, sec- butyl lithium, ethyl magnesium bromide, ethyl magnesium chloride, isopropyl magnesium chloride, magnesium, zinc and the like. The reagent for converting compound (1c-41) to an organometallic compound is used in an amount of 1 to 3 equivalents based on the amount of compound (1c-41). Compound (1c-41-1) is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-41). The reaction temperature in the reaction of converting compound (1c-41) to an organometallic compound is in the range from -78 ° C to reflux temperature, the reaction time is from 10 minutes to 12 hours. The reaction temperature when adding compound (1c-41-1) is in the range from -78 ° C to room temperature, the reaction time is from 10 minutes to 6 hours.

[Stage 1-57]

This step is a step in which a compound (1c-43) is obtained by removing the acetal protection of a compound (1c-42). Compound (1c-43) is prepared according to methods similar to the methods of [Step 1-16].

[Stage 1-58]

This step is a step in which a compound (1c-43) is obtained by reacting a compound (1c-41) with a compound (1c-41-1). At this stage, compound (1c-42) is obtained according to methods similar to the methods

[Steps 1-56], after which acid is added to the reaction system, or at the product collection step, to obtain compound (1c-43). Examples of acids used in this reaction include inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; organic acids such as citric acid, trifluoroacetic acid and p- toluenesulfonic acid; silicic acid gels and the like. The acid can be used in an amount from a catalytic amount to an amount of solvent based on the amount of compound (1c-41). The reaction temperature ranges from 0 ° C to the reflux temperature of the solvent, and the reaction time is from 5 minutes to 24 hours.

[Stage 1-59]

This step is a step in which a compound (1c-44) is obtained by reducing a compound (1c-43). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of solvents used in this reaction include ether solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; etc. Examples of the reducing agent include lithium aluminum hydride - aluminum chloride and the like. Lithium aluminum hydride is used in an amount of 2 to 6 equivalents based on the amount of compound (1c-43). Aluminum chloride is used in an amount of 2 to 9 equivalents based on the amount of compound (1c-43). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Production Method 1-3-10] Method 3 for Production of Compound (1c-3)

(where Hal is defined above; R ²⁴ represents a hydrogen atom, a halogen, a C _1-6 alkyl group and a C _1-6 alkoxy group and the like).

Compound (1c-45) and compound (1c-45-1), which are commercially available products, can be used as they are, or they can also be obtained from commercially available products by known methods.

[Stage 1-60]

This step is a step in which a compound (1c-46) is obtained by reacting a compound (1c-45) with a compound (1c-45-1). Compound (1c-46) can be obtained by reacting compound (1c-45) with compound (1c-45-1), for example, in a solvent such as tetrahydrofuran, N, N-dimethylformamide or dimethyl sulfoxide, for example, in the presence of a base such as tert -potassium butoxide. Compound (1c-45-1) is used in an amount of 1 to 1.5 equivalents based on the amount of compound (1c-45). The base is used in an amount of 1 to 1.5 equivalents, based on the amount of compound (1c-45). The reaction temperature ranges from room temperature to reflux temperature. The reaction time is from 30 minutes to 24 hours.

[Stage 1-61]

This step is a step in which a compound (1c-47) is obtained by reducing a compound (1c-46). The compound (1c-47) can be obtained according to methods similar to the methods of [Step 1-4].

[Manufacturing Method 1-3-11] Manufacturing Method 4 of Compound (1c-3)

(where R ³ , R ⁷ and Hal are defined above; in addition, R ²⁵ represents a C _1-6 alkyl group).

Compound (1c-48) and compound (1c-41-1), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by known methods.

[Stage 1-62]

This step is a step in which a compound (1c-49) is obtained by replacing a halogen atom of a compound (1c-48) with a phosphorus atom. This reaction is carried out by mixing compound (1c-48) and trialkylphosphite in a solvent or in the absence of a solvent and by heating. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include aromatic hydrocarbon solvents such as toluene and xylene, or mixed solvents of the foregoing. Trialkylphosphite is added in an amount of 1 to 1.2 equivalents based on the amount of compound (1c-48). The reaction temperature ranges from 100 ° C to 150 ° C, and the reaction time is from 30 minutes to 2 hours.

[Stage 1-63]

This step is a step in which a compound (1c-50) is obtained by adding a base to the compound (1c-49) and then reacting with the compound (1c-41-1). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; amide solvents such as N, N- dimethylformamide and N- methylpyrrolidinone; or mixed solvents of the foregoing. Examples of the base include metal hydrides such as sodium hydride and potassium hydride; metal alcoholates such as sodium methoxide and potassium tert -butoxide. Compound (1c-41-1) is added in an amount of 1 to 2 equivalents based on the amount of compound (1c-49). The reaction temperature ranges from room temperature to 80 ° C, and the reaction time is from 30 minutes to 12 hours.

[Stage 1-64]

This step is a step in which the double bond of compound (1c-50) is hydrogenated to give compound (1c-51). This step is a reaction by which, in a solvent and in a hydrogen atmosphere, a hydrogen atom is coupled to compound (1c-50) using a metal catalyst. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; alcohol solvents such as methanol and ethanol; esters such as ethyl acetate, or mixed solvents of the foregoing. Examples of the metal catalyst include palladium (II) oxide, palladium hydroxide, platinum (IV) oxide, Raney nickel, and the like. A metal catalyst is used ranging from a catalytic amount to an excess amount, based on the amount of compound (1c-50). The reaction temperature ranges from room temperature to 80 ° C, the reaction time is from 5 minutes to 24 hours. The pressure during the reaction is from 1 atmosphere to 4 atmospheres.

[Stage 1-65]

This step is a step in which the alcohol product (1c-52) is obtained by reducing the ester group of the compound (1c-51). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as ether and tetrahydrofuran; aromatic hydrocarbon solvents such as toluene and xylene; or mixed solvents of the foregoing. Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, diisobutyl aluminum hydride and the like. The reducing agent is added in an amount of from 0.5 to 2 equivalents of compound (1c-51). The reaction temperature ranges from −20 ° C. to the reflux temperature of the solvent, and the reaction time is from 10 minutes to 24 hours.

[Production Method 1-3-12] Method 5 for the preparation of compound (1c-3)

(where R ²⁶ and R ²⁷ represent a halogen atom, a C _1-6 alkyl group and a C _1-6 alkoxy group).

Compound (1c-53) and compound (1c-53-1), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by known methods.

[Stage 1-66]

This step is a step in which a compound (1c-54) is obtained by reacting a compound (1c-53) with a compound (1c-53-1). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include alcoholic solvents such as ethanol and methanol and the like. Compound (1c-53-1) is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-53). The reaction temperature is equal to the reflux temperature, and the reaction time is from 30 minutes to 12 hours.

[Stage 1-67]

This step is a step in which a compound (1c-55) is obtained by reducing a compound (1c-54). The compound (1c-55) can be obtained according to methods similar to the methods of [Step 1-4].

[Production Method 1-3-13] Method 1 for the preparation of compound (1c-4):

(where R ³ and Hal are defined above).

Compound (1c-56), compound (1c-58), compound (1c-60), compound (1c-62), compound (1c-64), compound (1c-19-1), compound (1c-41- 1) and compound (1c-56-1), which are commercially available products, can be used as they are, or they can also be obtained from commercially available products by well-known methods.

[Stage 1-68]

This step is a step in which a compound (1c-57) is obtained by reacting a compound (1c-56) with a compound (1c-19-1) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include sodium hydride, potassium t -butoxide, sodium ethoxide, sodium methoxide, N, N-diisopropylethylamine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like. The base is used in an amount of 1 to 5 equivalents based on the amount of the compound (1c-19-1). Compound (1c-19-1) is used in an amount of from 1 equivalent to the amount of solvent, based on the amount of compound (1c-56). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 48 hours.

[Stage 1-69]

This step is a step in which a compound (1c-59) is obtained by reacting a compound (1c-58) with a compound (1c-19-1). The compound (1c-59) can be obtained according to methods similar to the methods of [Step 1-37].

[Stage 1-70]

This step is a step in which a compound (1c-59) is obtained by reacting a compound (1c-60) with a compound (1c-19-1). Compound (1c-59) can be obtained according to methods similar to the methods of [Step 1-36].

[Stage 1-71]

This step is a step in which a compound (1c-61) is obtained by reacting a compound (1c-56) with a compound (1c-56-1) in the presence of a palladium catalyst. To obtain good results, a phosphine ligand can also be added to the reaction system. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent in this reaction include ether solvents such as 1,4-dioxane and tetrahydrofuran; alcohol solvents such as methanol and ethanol; aromatic hydrocarbons such as toluene and xylene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; and dimethyl sulfoxide, mixed solvents of the foregoing, and the like. 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- tert- butylphosphine) palladium (0), tetrakis (triphenylphosphine) palladium (0), palladium (0) pentadienone, etc. Examples of the phosphine ligand include triphenylphosphine, tri- o- tolylphosphine, tri- tert- butylphosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphinobiphenyl, 2-di- tert- butylphosphinobiphenyl, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl ) etc. Examples of the base include sodium tert -butoxide, cesium carbonate, potassium carbonate, potassium phosphate and the like. Compound (1c-56-1) is used in an amount of from 1 equivalent to an excess based on the amount of compound (1c-56). The palladium catalyst is used in an amount of from 0.01 to 0.3 equivalents, based on the amount of compound (1c-56). The phosphine ligand is used in an amount of from 0.01 to 1.2 equivalents based on the amount of compound (1c-56). The base is used in an amount of 1 to 4 equivalents based on the amount of the compound (1c-56). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 72 hours.

[Stage 1-72]

This step is a step in which a compound (1c-63) is obtained by reductive amination in which a compound (1c-62) is reacted with a compound (1c-56-1). Acetic acid may also be added to promote the reaction. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent in this reaction include ethereal solvents such as 1,4-dioxane and tetrahydrofuran; alcohol solvents such as methanol and ethanol; methylene chloride, mixed solvents of the foregoing, and the like. Examples of the reducing agent include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, 2-picoline borane and the like. Compound (1c-56-1) is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-62). The reducing agent is used in an amount of from 0.5 to 2 equivalents, based on the amount of compound (1c-62). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 1-73]

This step is a step in which a compound (1c-65) is obtained by reductive amination in which a compound (1c-64) is reacted with a compound (1c-41-1). The compound (1c-65) can be obtained according to methods similar to the methods of [Step 1-72].

[Production Method 1-3-14] Method 2 for the preparation of compound (1c-4):

(where R ³ and Hal are defined above).

Compound (1c-56) and compound (1c-41-1), which are commercially available products, can be used as they are, or compound (1c-56) and compound (1c-41-1) can also be obtained from commercially available products by well-known methods.

[Stage 1-74]

This step is a step in which a compound (1c-66) is obtained by reacting a compound (1c-56) with a compound (1c-41-1). The compound (1c-66) can be obtained according to methods similar to the methods of [Step 1-56].

[Stage 1-75]

This step is a step in which compound (1c-67) is obtained by reducing compound (1c-66) with iodotrimethylsilane. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran; acetonitrile, methylene chloride and the like, preferably methylene chloride and acetonitrile. Iodotrimethylsilane is used in an amount of from 2 to 10 equivalents, based on the amount of compound (1c-66). The reaction temperature ranges from 0 ° C to 60 ° C, and the reaction time is from 5 minutes to 6 hours. The iodotrimethylsilane used in this reaction may be a commercially available product, or it may be prepared during use by reacting sodium iodide with chlorotrimethylsilane in acetonitrile at room temperature.

[Production Method 1-3-15] Method 3 for the preparation of compound (1c-4):

(where R ^{3 is} defined above, and Q represents a sulfur atom and an oxygen atom).

Compound (1c-68) and compound (1c-41-1), which are commercially available products, can be used as they are, or they can also be prepared from commercially available products by well-known methods.

[Stage 1-76]

This step is a step in which one of the bromine atoms in the compound (1c-68) is anionized using an organometallic reagent that reacts with the compound (1c-41-1), then the other bromine atom in the compound (1c-68) is anionized by adding an additional amount of an organometallic reagent to the same container, which then reacts with the cyanization reagent to give compound (1c-69). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; mixed solvents of the foregoing and the like. Examples of the organometallic reagent include n- butyl lithium, sec- butyl lithium and the like. Preferred examples of the cyanization reagent include p- toluenesulfonyl cyanide. The organometallic reagent is used in a total amount of 2 to 3 equivalents, based on the amount of compound (1c-68). Compound (1c-41-1) is used in an amount of 1 to 1.5 equivalents based on the amount of compound (1c-68). The cyanization reagent is used in an amount of from 1 to 1.5 equivalents, based on the amount of compound (1c-68). The reaction temperature ranges from -78 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 1-77]

This step is a step in which a compound (1c-70) is obtained by reducing a compound (1c-69). The compound (1c-70) can be obtained according to methods similar to the methods of [Step 1-75].

[Production Method 1-3-16] Method 1 for the preparation of compound (1c-5):

(where R ^{3 is} defined above).

Compound (1c-66) can be obtained from a commercially available product by well-known methods, or compound (1c-66) can be obtained according to methods similar to the methods of [Step 1-74].

[Stage 1-78]

This step is a step in which compound (1c-71) is obtained by reducing compound (1c-66). There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene and the like. Examples of the reducing agent include lithium aluminum hydride - aluminum chloride. Lithium aluminum hydride is used in an amount of 3 to 8 equivalents based on the amount of compound (1c-66). Aluminum chloride is used in an amount of 3 to 10 equivalents based on the amount of compound (1c-66). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Production Method 1-3-17] Method 2 for the preparation of compound (1c-5):

(where R ³ and Q are as defined above).

The compound (1c-69) can be obtained from commercially available products by well known methods, or the compound (1c-69) can be obtained according to methods similar to the methods of [Step 1-76].

[Stage 1-79]

This step is a step in which compound (1c-72) is obtained by reducing compound (1c-69). The compound (1c-72) can be obtained according to methods similar to the methods of [Step 1-78].

[Production Method 1-3-18] Method 1 for the preparation of compound (1c-6):

(where R ³ , R ¹³ and R ^{13 'are} defined above).

Compound (1c-42) can be obtained from commercially available products by well known methods, or compound (1c-42) can be obtained according to methods similar to the methods of [Step 1-56].

[Stage 1-80]

This step is a step in which compound (1c-73) is obtained simultaneously by reducing and removing the acetal protection of compound (1c-42) using iodotrimethylsilane. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran, acetonitrile, methylene chloride and the like, and preferably methylene chloride or acetonitrile. Iodotrimethylsilane is used in an amount of from 2 to 10 equivalents based on the amount of compound (1c-42). The reaction temperature ranges from 0 ° C to 60 ° C, and the reaction time is from 5 minutes to 6 hours. The iodotrimethylsilane used in this reaction may be a commercially available product or may be obtained during use by reacting sodium iodide with chlorotrimethylsilane in acetonitrile at room temperature.

[Production Method 1-3-19] Method 2 for the Preparation of Compound (1c-6)

(where R ²⁸ represents a halogen or C _1-6 alkyl group).

Compound (1c-74) and compound (1c-74-1), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by known methods.

[Stage 1-81]

This step is a step in which a compound (1c-75) is obtained by reacting a compound (1c-74) with a compound (1c-74-1) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include sodium hydride, potassium tert -butoxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, and the like. Compound (1c-74) is used in an amount of 0.5 to 2 equivalents based on the amount of compound (1c-74-1). The base is used in an amount of 0.5 to 5 equivalents based on the amount of the compound (1c-74-1). The reaction temperature ranges from 100 ° C to 170 ° C, and the reaction time is from 30 minutes to 12 hours.

[Production Method 1-3-20] Method 3 for the Preparation of Compound (1c-6)

(where R ²⁹ and R ³⁰ are halogen, a C _1-6 alkyl group and a C _1-6 alkoxy group).

Compound (1c-76), compound (1c-79) and compound (1c-76-1), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by known methods.

[Stage 1-82]

This step is a step in which a compound (1c-77) is obtained by reacting a compound (1c-76) with a compound (1c-76-1) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include sodium hydride, potassium tert -butoxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, and the like. Compound (1c-76-1) is used in an amount of 1 to 2 equivalents based on the amount of compound (1c-76). The base is used in an amount of 2 to 3 equivalents based on the amount of the compound (1c-76). The reaction temperature ranges from room temperature to 80 ° C, and the reaction time is from 30 minutes to 72 hours.

[Stage 1-83]

This step is a step in which compound (1c-78) is obtained by reducing the cyano group of compound (1c-77). The compound (1c-78) can be obtained according to methods similar to the methods of [Stage 1-18].

[Stage 1-84]

This step is a step in which a compound (1c-78) is obtained by reacting a compound (1c-79) with a compound (1c-76-1) in the presence of a base. The compound (1c-78) can be obtained according to methods similar to the methods of [Stage 1-82].

[Production Method 1-3-21] Method 4 for the Preparation of Compound (1c-6)

(where R ³¹ and R ³² represent halogen, a C _1-6 alkyl group and a C _1-6 alkoxy group).

Compound (1c-80) and compound (1c-80-1), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by known methods.

[Stage 1-85]

This step is a step in which a compound (1c-81) is obtained by reacting a compound (1c-80) with a compound (1c-80-1). Examples of the solvent include acetic acid and the like. Compound (1c-80-1) is used in an amount of 1 equivalent based on the amount of compound (1c-80). The reaction temperature ranges from 50 ° C to 110 ° C, and the reaction time is from 5 minutes to 1 hours.

[Production Method 1-3-22] Method 5 for the preparation of compound (1c-6)

(where R ^{3 is} defined above).

Compound (1c-82) and compound (1c-56-1), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by known methods.

[Stage 1-86]

This step is a step in which compound (1c-83) is obtained by reductive amination of compound (1c-82) and compound (1c-56-1). The compound (1c-83) can be obtained according to methods similar to the methods of [Stage 1-72].

[Stage 1-87]

This step is a step in which compound (1c-84) is obtained by removing the acetal protection of compound (1c-83) by adding acid. The compound (1c-84) can be obtained according to methods similar to the methods of [Stage 1-16].

[Production Method 1-3-23] Method 6 for the preparation of compound (1c-6)

(where ring A and Hal are defined above; R ³³ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _6-10 aryl group, or a 5- or 6-membered ring heteroaryl group, which may have 1 or 2, respectively substituents selected from the group of α ¹ substituents; M ⁺ represents potassium cation and sodium cation.

[Group α ¹ substituents]

cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkoxycarbonyl group and C _3-8 cycloalkyl group).

Compound (1c-85), compound (1c-85-1), compound (1c-85-2) and compound (1c-85-3), which are commercially available products, can be used as they are eat, or they can also be obtained from commercially available products by known methods.

[Stage 1-88]

This step is a step in which a compound (1c-86) is obtained by reacting a compound (1c-85) with a compound (1c-85-1) or a compound (1c-85-2) in the presence of a palladium catalyst and a base. An inorganic salt such as lithium chloride can also be added to obtain good results; an ammonium salt such as tetrabutylammonium chloride; or phosphine ligand. This reaction can be carried out in an inert gas atmosphere such as nitrogen and argon. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include 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, water, mixed solvents of the foregoing, and the like. Examples of the palladium catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), palladium-carbon, bis (tri-tert-butylphosphine ) palladium (0), 1,1'-bis (diphenylphosphinoferrocene) dichloropalladium (II), etc. Examples of the phosphine ligand include triphenylphosphine, tri- o- tolylphosphine, tri- tert- butylphosphine, tricyclohexylphosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2', 4, 6, 6, 6, 6, 6, 6, 6 -di- tert- butylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2-di- tert- butylphosphinobiphenyl, 2-dicyclohexylphosphinobiphenyl, 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl, 2-di- tert- butylphosphino-2 '- (N, N-dimethylamino) biphenyl, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino )propane, 1,4-bis (diphenylphosphino) butane and the like. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, potassium phosphate, sodium hydroxide, barium hydroxide, potassium hydroxide and the like. Compound (1c-85-1) or compound (1c-85-2) is used in an amount of 1 to 3 equivalents based on the amount of compound (1c-85). The palladium catalyst is used in an amount of from 0.01 to 0.25 equivalents based on the amount of compound (1c-85). The phosphine ligand is used in an amount of from 0.01 to 1 equivalent, based on the amount of compound (1c-85). Inorganic salts, such as lithium chloride, or ammonium salts, such as tetrabutylammonium chloride, are used in an amount of from 0.5 to 2 equivalents. The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 72 hours.

[Stage 1-89]

This step is a step in which a compound (1c-86) is obtained by reacting a compound (1c-85) with a compound (1c-85-3) in the presence of a palladium catalyst. In order to obtain good results, an inorganic salt such as lithium chloride, an ammonium salt such as tetrabutylammonium chloride, a phosphine ligand or a copper reagent can also be added. This reaction can be carried out in an inert gas atmosphere such as nitrogen and argon. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include 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, mixed solvents of the foregoing, and the like. 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- tert- butylphosphine) palladium (0), tetrakis (triphenylphosphine) palladium (0), 1,1'-bis (diphenylphosphinoferrocene) dichloropalladium (II), etc. Examples of the phosphine ligand include triphenylphosphine, tri- o- tolylphosphine, tri- tert- butylphosphine, diphenylphosphinoferrocene and the like. Examples of the copper reagent include copper (I) iodide, copper (I) bromide, copper (I) chloride, and the like. Compound (1c-85-3) is used in an amount of 1 to 3 equivalents based on the amount of compound (1c-85). The palladium catalyst is used in an amount of from 0.01 to 0.25 equivalents based on the amount of compound (1c-85). The phosphine ligand is used in an amount of from 0.01 to 1 equivalent, based on the amount of compound (1c-85). The copper reagent is used in an amount of 0.1 to 3 equivalents based on the amount of compound (1c-85). An inorganic salt, such as lithium chloride, or an ammonium salt, such as tetrabutylammonium chloride, is used in an amount of from 0.5 to 2 equivalents. The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 72 hours.

[Production Method 1-3-24] Method for the Preparation of Compound (1c-85-2)

(where Hal and Hal 'each independently represents a halogen atom; R ³⁴ represents

A C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group, a C _3-8 cycloalkyl-C _1-6 alkyl group or a C _3-8 cycloalkyl group; M ⁺ represents potassium cation and sodium cation).

The compound (1c-87), the compound (1c-88-1), the compound (1c-90) and the compound (1c-91), which are commercially available products, can be used as they are, or they can be obtained from commercially available products by known methods. Compound (1c-91), which is a commercially available product, can be used as it is, or can be obtained from commercially available products by known methods (e.g., WO2005 / 033079 A1, pp. 82-84, and so on. .P.).

[Stage 1-90]

This step is a step in which compound (1c-88) is prepared by reacting an organometallic reagent with compound (1c-87) to produce an anionized compound that reacts with boric acid ester, then by neutralizing the reaction mixture by adding acid and finally by reaction with a diol, such as pinacol. This reaction can also be carried out by adding an organometallic reagent to a mixture consisting of compound (1c-87) and boric acid ester, while simultaneously forming an anion from compound (1c-87) and reacting with boric acid ester. This reaction can also be carried out in a stream or atmosphere of an inert gas such as nitrogen or argon. Examples of the compound (1c-87) include chloroiodomethane, dibromomethane, bromiodomethane and the like. and preferably chloroiodomethane and dibromomethane. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxymethane, methyl tert- butyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether and dicyclopentyl ether; aromatic hydrocarbon solvents such as benzene and toluene; aliphatic hydrocarbon solvents such as heptane and hexane, mixed solvents of the foregoing, and the like. and preferably tetrahydrofuran. Examples of boric acid ester include trimethyl borate, triisopropyl borate and the like. and preferably triisopropyl borate. Examples of the organometallic reagent include n- butyl lithium, sec- butyl lithium and the like. and preferably n- butyllithium. Examples of the acid include methanesulfonic acid, p- toluenesulfonic acid, a solution of hydrochloric acid-ethyl acetate, a solution of hydrochloric acid-methanol and the like, and preferably methanesulfonic acid and a solution of hydrochloric acid-ethyl acetate. The boric acid ester can be used in an amount of from 0.8 to 1.2 equivalents based on the amount of compound (1c-87), and preferably from 0.9 to 1 equivalent. The organometallic reagent can be used in an amount of from 0.8 to 1.2 equivalents, based on the amount of compound (1c-87), and preferably from 0.8 to 1 equivalent. A mixture of the anionized compound obtained at -78 ° C from compound (1c-87) and boric acid ester is stirred for 1-3 hours at the temperature indicated below. This mixture is neutralized at the temperature indicated below, then pinacol is added and stirred for 10-60 minutes at the temperature indicated below.

[Reaction temperature during the reaction of the anionized compound with boric acid ester]

A mixture of the anionized compound with boric acid ester is stirred at a temperature ranging from 0 ° C. to room temperature, and more preferably at room temperature.

[Reaction temperature during the neutralization reaction and the reaction with diol]

The temperature during the neutralization reaction and with the addition of the diol is in the range of −20 ° C. to room temperature and more preferably 0 ° C. The temperature after the addition of the diol is in the range of 0 ° C. to room temperature and more preferably equal to room temperature.

[Stage 1-91]

This step is a step in which, to obtain compound (1c-89), the anionized compound formed by the reaction of compound (1c-88-1) with a base is reacted with compound (1c-88) and then with a hydrofluoric acid salt (acid potassium fluoride or acid sodium fluoride). This step can also be carried out by adding a catalytic amount of an iodide compound, such as potassium iodide and tetrabutylammonium iodide. This reaction can be carried out in a stream or atmosphere of an inert gas such as nitrogen or argon. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, methyl tert- butyl ether, cyclopetyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether and dicyclopentyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. and preferably tetrahydrofuran or N, N-dimethylformamide. Examples of the base include sodium hydride, potassium bis (trimethylsilyl) amide, potassium hydride, and preferably sodium hydride and potassium bis (trimethylsilyl) amide. Compound (1c-88-1) can be used in an amount of 1 to 5 equivalents based on the amount of compound (1c-88), and preferably 2 to 3 equivalents. The above base can be used in an amount of from 1 to 5 equivalents, based on the amount of compound (1c-88), and preferably from 2 to 3 equivalents. The above salt of hydrofluoric acid can be used in an amount of from 2 to 8 equivalents, based on the amount of compound (1c-88), and preferably from 3 to 5 equivalents.

The reaction time for the anionization reaction of compound (1c-88-1) is preferably from 30 to 60 minutes under stirring at the temperature indicated below, and after adding to the mixture of compound (1c-88), the reaction time is from 1 to 12 hours under stirring at the temperature indicated below. After adding the salt of hydrofluoric acid to the reaction mixture, the reaction time is from 10 to 120 minutes under stirring at the temperature indicated below.

[Reaction temperature during the anionization reaction]

The temperature during the addition of the base is in the range of 0 ° C to room temperature, more preferably 0 ° C. The temperature after adding the base is in the range from 0 ° C to 70 ° C, more preferably from room temperature to 50 ° C.

[Reaction temperature during the reaction of the anionized compound with compound (1c-88)]

The temperature during the addition of compound (1c-88) is in the range of 0 ° C to room temperature and more preferably 0 ° C. The temperature after the addition of compound (1c-88) ranges from room temperature to 100 ° C, more preferably from room temperature to 70 ° C.

[Reaction temperature when adding hydrochloric acid salt]

The temperature during the addition of the reagent is in the range of 0 ° C to room temperature and more preferably 0 ° C. The temperature after adding the reagent is in the range from 0 ° C to room temperature and more preferably equal to room temperature.

[Stage 1-92]

This step is a step in which, to obtain compound (1c-89), an anionized compound formed by the reaction of an organometallic reagent with compound (1c-90) is reacted with boric acid ester, followed by reaction with a salt of hydrofluoric acid (potassium acid fluoride) or sodium hydrogen fluoride, etc.). At this stage, the reaction can be carried out in a solvent, or a large amount of compound (1c-90) can be used as a solvent. In addition, this step can be carried out in the presence of a base. This step can be carried out according to the general methods described, for example, 5 ^th Edition of Jikkenkagakukoza 18 (str.20-23), Tetrahedron Letters, vol. 24, No. 31, pp. 3165-3168, and the like. This reaction can be carried out in a stream or atmosphere of an inert gas such as nitrogen and argon. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include aliphatic hydrocarbon solvents such as heptane and hexane and the like. Preferably, the compound (1c-90) is used in the same amount as the solvent. Examples of the organometallic reagent include tert-butyl lithium, sec- butyl lithium and the like, preferably sec- butyl lithium. Examples of the base include potassium tert -butoxide, potassium sec -butoxide, potassium methoxide and the like, preferably potassium tert -butoxide. The organometallic reagent is added to a mixture of compound (1c-90) and a solvent at a temperature of from -75 to -60 ° C (preferably from -75 to -70 ° C), then the mixture is stirred for 5-30 minutes (preferably 5-10 minutes ) at a temperature of from -20 to 0 ° C (preferably from -10 to -5 ° C). Then boric acid ester is added to the mixture at a temperature of from -75 to -70 ° C, then the mixture is stirred for 10-60 minutes (preferably 10-30 minutes) at a temperature of 10 ° C to room temperature (preferably at room temperature). Hydrochloric acid salt is added to the mixture at a temperature of 0 to 5 ° C, then water is added at the same temperature, the reaction mixture is warmed to room temperature to obtain compound (1c-89). Preferably, compound (1c-90) is used in a solvent in an amount based on the amount of the organometallic reagent. The base can be used in an amount of preferably from 0.6 to 1 equivalent, based on the amount of the organometallic reagent. The boric acid ester can be used in an amount of from 1 to 2 equivalents, based on the amount of the organometallic reagent, and preferably from 1 to 1.8 equivalents. The above salt of hydrofluoric acid can be used in an amount of from 3 to 10 equivalents based on the above boric acid ester compound, and preferably from 3 to 5 equivalents.

[Stage 1-93]

This step is a step in which, to obtain compound (1c-89), an anionized compound formed by the reaction of an organometallic compound with compound (1c-91) is reacted with boric acid ester (triisopropyl borate, trimethyl borate, 2-isopropoxy-4, 4,5,5-tetramethyl-1,3,2-dioxaborolan and the like), and then the reaction with a salt of hydrofluoric acid (acid potassium fluoride or acid sodium fluoride, etc.). This reaction can also be carried out in a stream or atmosphere of an inert gas such as nitrogen or argon. There are no particular restrictions on the solvent used in this reaction, provided that it dissolves the starting materials to a certain extent, without blocking the progress of the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, methyl tert- butyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether and dicyclopentyl ether; aromatic hydrocarbon solvents such as benzene and toluene; aliphatic hydrocarbon solvents such as heptane and hexane, mixed solvents of the foregoing, and the like. and preferably tetrahydrofuran. Examples of the above organometallic reagent include n- butyl lithium, sec- butyl lithium, methyl lithium and the like, preferably n- butyl lithium. Compound (1c-89) can be prepared by the two methods described below. If it is difficult to carry out reaction (i), for example, due to the instability of the anion formed as a result of the reaction of the organometallic reagent with compound (1c-91), reaction (ii) is preferred.

(i) The organometallic reagent and compound (1c-91) are mixed in a solvent for 30-120 minutes (preferably 30-60 minutes) at a temperature of from -75 to -60 ° C (preferably from -75 to -70 ° C). Then boric acid ester is added to the mixture at a temperature of from -75 to -70 ° C, after which the mixture is stirred for another 10-120 minutes (preferably 20-80 minutes) at a temperature of from 0 ° C to room temperature (preferably from 0 to 5 ° C). Hydrochloric acid salt was added to the mixture at a temperature of 0 to 5 ° C, then water was added at the same temperature, and the reaction mixture was warmed to room temperature to obtain compound (1c-89).

(ii) In the presence of a solvent, an organometallic reagent is added to a mixture of boric acid ester and compound (1c-89) at a temperature of from -75 to -60 ° C (preferably from -75 to -70 ° C), the mixture is stirred for 10-120 minutes (preferably 20-60 minutes) at a temperature of from -75 to 5 ° C (preferably from 0 to 5 ° C). Hydrochloric acid salt was added to this mixture at a temperature of 0 to 5 ° C, after which water was added at the same temperature, and the reaction mixture was warmed to room temperature to obtain compound (1c-89).

The organometallic reagent can be used in an amount of from 0.8 to 1.2 equivalents, based on the amount of compound (1c-91), and preferably in an amount of 1 equivalent. The boric acid ester can be used in an amount of from 1 to 2 equivalents based on the amount of compound (1c-91), and preferably from 1 to 1.2 equivalents. The hydrofluoric acid salt can be used in an amount of from 3 to 10 equivalents, based on the amount of compound (1c-91), and preferably from 3 to 5 equivalents.

[Production Method 2] A common method for preparing the compound (2a):

(where the ring A, R ¹ , R ² , R ³ , R ⁴ and Z are as defined above).

[Production Method 2-1-1] Method 1 for the preparation of compound (2a):

(where the ring A, R ¹ , R ² , R ³ , R ⁴ and Z are as defined above).

Compound (2b) can be obtained from commercially available products by well-known methods or can also be obtained according to the methods described in the preparation examples in the examples section, the following [Production Method 2-2-1], and the like.

Compound (2c), which is a commercially available product, can be used as it is, or compound (2c) can also be obtained from commercially available products by well-known methods. Compound (2c) can additionally be prepared according to the methods described in the preparation examples in the Examples section, the following [production method 2-3], and the like.

[Stage 2]

This step is a step in which a compound (2a) is obtained by reacting a compound (2b) with a compound (2c) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; and dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include sodium hydride, potassium tert -butoxide, sodium ethoxide, triethylamine, sodium hydroxide, potassium hydroxide, and the like. Compound (2c) is used in an amount of 1 to 5 equivalents based on the amount of compound (2b). The base is used in an amount of 1 to 5 equivalents, based on the amount of compound (2b). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production Method 2-1-2] Method 2 for the preparation of compound (2a):

(where the ring A, R ¹ , R ² , R ³ , Hal and Z are defined above).

Compound (1b-1), which is a commercially available product, can be used as it is, or compound (1b-1) can also be obtained from commercially available products by well-known methods. Compound (2d) can be prepared from commercially available products by well-known methods, or it can be prepared according to the methods described in the production examples in the examples section, the following [production method 2-4], and the like.

[Stage 2-1]

This step is a step in which a compound (2a-1) is obtained by reacting a compound (1b-1) with a compound (2d) in the presence of a palladium catalyst. Inorganic salts such as lithium chloride, ammonium salts such as tetrabutylammonium chloride, phosphine ligands, or copper reagents can be added to obtain good results. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include 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, mixed solvents of the foregoing, and the like. 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- tert- butylphosphine) palladium (0) tetrakis (triphenylphosphine) palladium (0) and the like. Examples of the phosphine ligand include triphenylphosphine, tri- o- tolylphosphine, tri- tert- butylphosphine and the like. Examples of the copper reagent include copper (I) iodide, copper (I) bromide, copper (I) chloride, and the like. Compound (2d) is used in an amount of 1 to 3 equivalents based on the amount of compound (1b-1). The palladium catalyst is used in an amount of from 0.01 to 0.3 equivalents based on the amount of compound (1b-1). The phosphine ligand is used in an amount of from 0.01 to 1.2 equivalents based on the amount of compound (1b-1). The copper reagent is used in an amount of from 0.1 to 3 equivalents, based on the amount of compound (1b-1). Inorganic salts, such as lithium chloride, or ammonium salts, such as tetrabutylammonium chloride, are used in an amount of 1 to 3 equivalents based on the amount of compound (1b-1). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Production Method 2-1-3] Method 3 for the Preparation of Compound (2a)

(where the ring A, Hal, L, R ¹ , R ² and R ^{33 are as} defined above).

Compound (2b-1) can be obtained from commercially available products by known methods, and can also be obtained according to the methods described in the preparation examples in the Examples section or [production method 2-2-1], and the like. Compound (2c-1), which is a commercially available product, can be used as it is, or it can also be prepared from commercially available products by known methods. Compounds (1c-85-1), (1c-85-2) and (1c-85-3), which are commercially available products, can be used as they are, or they can also be obtained from commercially available products by known methods.

[Stage 2-2]

This step is a step in which a compound (2a-2) is obtained by reacting a compound (2b-1) with a compound (2c-1) in the presence of a base. The compound (2a-2) can be obtained according to methods similar to the methods of [Step 2].

[Stage 2-3]

This step is a step in which a compound (2a-3) is obtained by reacting a compound (1c-85-1) or a compound (1c-85-2) with a compound (2a-2) in the presence of a palladium catalyst and a base. The compound (2a-3) can be obtained according to methods similar to the methods of [Step 1-88].

[Stage 2-4]

This step is a step in which compound (2a-3) is obtained by reacting compound (1c-85-3) with compound (2a-2) in the presence of a palladium catalyst. The compound (2a-3) can be obtained according to methods similar to the methods of [Step 1-89].

[Production Method 2-2-1] Method 1 for the preparation of compound (2b):

(where R ¹ , R ² and Hal are defined above).

Regarding compound (2b-2), a commercially available product can be used as it is. Compound (1b-1), which is a commercially available product, can be used as it is, or compound (1b-1) can also be obtained from commercially available products by well-known methods.

[Stage 2-5]

This step is a step in which a compound (2b-3) is obtained by reacting a compound (2b-2) with chlorotriphenylmethane in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include triethylamine, sodium hydride, potassium tert -butoxide, potassium carbonate, sodium hydroxide, and the like. The base is used in an amount of 1 to 4 equivalents based on the amount of compound (2b-2). Chlorotriphenylmethane is used in an amount of 1 to 4 equivalents based on the amount of compound (2b-2). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 1 hour to 24 hours.

[Stage 2-6]

This step is a step in which a compound (2b-4) is obtained by reacting a compound (2b-3) with a boric acid derivative in the presence of a palladium catalyst and a base. A phosphine ligand may also be added to obtain good results. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ether solvents such as 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the palladium catalyst include palladium acetate (II), tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), bis (tri- tert -butilfosfin) palladium (0), tetrakis (triphenylphosphine) palladium (0), 1,1'-bis (diphenylphosphinoferrocene) dichloropalladium (II) and the like, preferably 1,1'-bis (diphenylphosphinoferrocene) dichloropalladium (II). Examples of the base include potassium acetate, triethylamine, N, N-diisopropylethylamine, potassium phenoxide, potassium carbonate and the like, preferably potassium acetate. Examples of the boric acid derivative include bis (pinacolyate) diborane, 4,4,5,5, -tetramethyl- [1,3,2] -dioxoborolan and the like. Examples of the phosphine ligand include triphenylphosphine, tri- tert- butylphosphine, tricyclohexylphosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphinobiphenyl and the like. The palladium catalyst is used in an amount of from 0.01 to 0.3 equivalents, based on the amount of compound (2b-3). The base is used in an amount of 1 to 10 equivalents, based on the amount of compound (2b-3). The boric acid derivative is used in an amount of from 1 to 3.0 equivalents based on the amount of compound (2b-3). The phosphine ligand is used in an amount of from 0.01 to 1.2 equivalents based on the amount of compound (2b-3). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

Compound (2b-4) can also be obtained from compound (2b-3) according to the method below as an alternative method (1).

Alternative method (1): Compound (2b-4) can be obtained first by anionizing the bromine atom of compound (2b-3) using an organometallic reagent, and then by reaction with boric acid ester. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; hexane, mixed solvents of the foregoing, and the like. Examples of the organometallic reagent include n- butyl lithium, sec- butyl lithium, t-butyl lithium and the like. Examples of boric acid ester include 2-methoxy-4,4,5,5-tetramethyl- [1,3,2] dioxaborolan, trimethyl borate, triisopropyl borate and the like. To obtain the compound (2b-4), (1-triphenylmethyl) -pyrazol-4-yl-boric acid, which is obtained as boric acid ester using trimethylborate or triisopropyl borate, can be converted into boric acid pinacol ester according to the data given in literary source (Journal of Heterocyclic Chemistry, Volume 41, No. 6, 931-939). The organometallic reagent is used in an amount of 1 to 1.5 equivalents based on the amount of compound (2b-3). The boric acid ester is used in an amount of 1 to 1.5 equivalents based on the amount of compound (2b-3). The reaction temperature for the anionization reaction ranges from -90 ° C to -60 ° C, and the reaction time is from 10 minutes to 24 hours. The temperature for the reaction with boric acid ester is in the range of -78 ° C to 0 ° C, and the reaction time is from 10 minutes to 12 hours.

It should be noted that as a substrate in [Step 2-7], instead of compound (2b-4), (1-triphenylmethyl) -pyrazol-4-yl-boric acid can be used, which is synthesized as an ester of boric acid if used in this reactions of trimethyl borate or triisopropyl borate.

[Stage 2-7]

This step is a step in which a compound (2b-5) is obtained by reacting a compound (2b-4) with a compound (1b-1) in the presence of a palladium catalyst and a base. A phosphine ligand may be added to obtain good results. You can also add a quaternary ammonium salt, such as tetrabutylammonium bromide, tetrabutylammonium chloride and the like, in an amount of from 0.1 to 2 equivalents based on the amount of compound (2b-4). There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ether solvents such as 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; dimethyl sulfoxide, water, mixed solvents of the foregoing, and the like. Examples of the palladium catalyst include palladium acetate (II), tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), bis (tri- tert -butilfosfin) palladium (0), tetrakis (triphenylphosphine) palladium (0), 1,1'-bis (diphenylphosphinoferrocene) dichloropalladium (II) and the like. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, potassium phosphate, sodium hydroxide, potassium hydroxide, and the like. Examples of the phosphine ligand include triphenylphosphine, tri- tert- butylphosphine, tricyclohexylphosphine, diphenylphosphinoferrocene, 2-dicyclohexylphosphinobiphenyl and the like. The palladium catalyst is used in an amount of from 0.01 to 0.3 equivalents based on the amount of compound (2b-4). The base is used in an amount of from 1.5 to 10 equivalents based on the amount of compound (2b-4). Compound (1b-1) is used in an amount of 1.0 to 3.0 equivalents based on the amount of compound (2b-4). The phosphine ligand is used in an amount of from 0.01 to 1.2 equivalents based on the amount of compound (2b-4). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 2-8]

This step is a step wherein compound (2b-1) is obtained by protecting the triphenylmethyl group of compound (2b-5) under acidic conditions. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ether solvents such as 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbon solvents such as benzene and toluene; alcohol solvents such as methanol and ethanol; methylene chloride, water, mixed solvents of the foregoing, and the like. Examples of the acid include hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, formic acid, and the like. The acid is used in an amount of from 2 equivalents to the amount of solvent, based on the amount of compound (2b-5). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Production Method 2-2-2] Method 2 for the Preparation of Compound (2b)

(where R ¹ , R ² and Hal are defined above).

Compound (2b-6), which is a commercially available product, can be used as it is, or it can be obtained from commercially available products by known methods. Compound (2b-4) can be prepared according to the methods described in [Production Method 2-2-1].

[Stage 2-9]

This step is a step in which compound (2b-7) is obtained by substituting a hydrogen atom in the pyridine ring of compound (2b-6) with a halogen atom. The compound (2b-7) can be obtained according to methods similar to the methods of [Stage 1-11].

[Stage 2-10]

This step is a step in which compound (2b-8) is obtained by reacting compound (2b-7) with compound (2b-4) in the presence of a palladium catalyst and a base. The compound (2b-8) can be obtained according to methods similar to the methods of [Step 2-7], provided that the compound (2b-4) is used in an amount of from 1 to 1.2 equivalents, based on the amount of compound (2b-7 )

[Stage 2-11]

This step is a step in which compound (2b-9) is obtained by protecting the triphenylmethyl group of compound (2b-8) under acidic conditions. The compound (2b-9) can be obtained according to methods similar to the methods of [Step 2-8].

[Production Method 2-3] Method for the Preparation of Compound (2c):

(where the ring A, L, R ³ and Z are defined above).

Compound (1c-3), which is a commercially available product, can be used as it is, or compound (1c-3) can also be obtained from commercially available products by well-known methods. Compound (1c-3) can also be prepared according to the methods described in the preparation examples in the Examples section below [production method 1-3-1] or the like.

[Stage 2-12]

This step is a step in which compound (2c) is obtained by converting the hydroxyl group of compound (1c-3) to a leaving group. Compound (2c) can be obtained according to methods similar to the methods of [Step 1-32].

[Production Method 2-4] Method for the Preparation of Compound (2d):

(where the ring A, L, R ³ and Z are defined above).

Compound (2c), which is a commercially available product, can be used as it is, or compound (2c) can also be obtained from commercially available products by well-known methods. Compound (2c) can also be prepared according to the methods described in the preparation examples in the Examples section below [production method 2-3] or the like. As for the compound (2b-2), the commercial product can be used as it is.

[Stage 2-13]

This step is a step in which a compound (2d-1) is obtained by reacting a compound (2c) with a compound (2b-2). The compound (2d-1) can be obtained by methods similar to the methods of [Step 2].

[Stage 2-14]

This step is a step in which compound (2d) is obtained by reacting compound (2d-1) with hexa ( n -butyl) diol in the presence of a palladium catalyst. To obtain good results, a phosphine ligand can be added to this reaction mixture. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include 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, mixed solvents of the foregoing, and the like. Examples of the palladium catalyst include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (tri- o- tolylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0) etc. Examples of the phosphine ligand include triphenylphosphine, tri- o- tolylphosphine and the like. Hexa ( n -butyl) diol is used in an amount of from 1 to 10 equivalents, preferably from 3 to 5 equivalents, based on the amount of compound (2d-1). The palladium catalyst is used in an amount of from 0.01 to 0.3 equivalents, based on the amount of compound (2d-1). The phosphine ligand is used in an amount of from 0.01 to 1.2 equivalents, based on the amount of compound (2d-1). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

Compound (2d) can also be obtained from compound (2d-1) according to the method below as an alternative method (1).

Alternative method (1): Compound (2d) can be obtained first by ionizing the bromine atom of compound (2d-1) with an organometallic reagent, and then by reaction with tri ( n -butyl) tin chloride. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; hexane, mixed solvents of the foregoing, and the like. Examples of the organometallic reagent include n- butyl lithium, sec- butyl lithium, t-butyl lithium and the like. The organometallic reagent is used in an amount of 1 to 1.5 equivalents based on the amount of compound (2d-1). Tri ( n -butyl) tin chloride is used in an amount of 1 to 1.5 equivalents based on the amount of compound (2d-1). The reaction temperature for the ionization reaction ranges from -90 ° C to -60 ° C, and the reaction time is from 10 minutes to 24 hours. The temperature for the reaction with tri ( n -butyl) tin chloride is in the range of -78 ° C to 0 ° C, and the reaction time is from 10 minutes to 12 hours.

[Production Method 3] A common method for preparing the compound (3a):

(where the ring A, R ¹ , R ² , R ³ and Z are as defined above).

[Production Method 3-1] Method for the Preparation of Compound (3a):

(where the ring A, R ¹ , R ² , R ³ and Z are as defined above).

Compound (3b) can be obtained from commercially available products by well-known methods, or compound (3b) can also be obtained according to the methods described in the production examples in the Examples section below [production method 3-2], and the like.

Compound (3c) can be obtained from a commercially available product by well-known methods, or compound (3c) can also be obtained according to the methods described in the production examples in the Examples section below [production method 3-3] and the like.

[Stage 3]

This step is a step in which a compound (3a) is obtained by reacting a compound (3b) with a compound (3c). Compound (3a) can be obtained according to methods similar to the methods of [Step 1-8].

[Production Method 3-2] Method for the Preparation of Compound (3b):

(where R ¹ and R ^{2 are as} defined above, and R ^2a represents a hydrogen atom and —NHR ^2b . R ^2b represents a protecting group such as tert -butoxycarbonyl, tert- butylcarbonyl and the like).

Compound (3b-1), which is a commercially available product, can be used as it is, or compound (3b-1) can also be obtained from commercially available products by well-known methods. As for the compound (2b-1), the commercial product can be used as it is.

[Stage 3-1]

This step is a step in which a compound (3b-2) is obtained by reacting a compound (3b-1) with a compound (2b-1) in the presence of a base and a copper catalyst. A copper ligand can also be added to increase yield. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ether solvents such as 1,4-dioxane and tetrahydrofuran; aromatic hydrocarbon solvents such as benzene, toluene and xylene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base used in this reaction include potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, etc. Examples of a copper catalyst include copper (I) iodide, copper (I) bromide, copper (I) chloride, and the like. Examples of the copper ligand include 1,2-cyclohexanediamine, N, N-dimethyl-cyclohexane-1,2-diamine, 1,10-phenanthroline and the like. Compound (2b-1) is used in an amount of 1 to 5 equivalents based on the amount of compound (3b-1). The base is used in an amount of from 1 to 5 equivalents based on the amount of compound (3b-1). The copper catalyst is used in an amount of from 0.01 to 0.3 equivalents, based on the amount of compound (3b-1). The copper ligand is used in an amount of 1 to 3 equivalents based on the amount of copper catalyst. The reaction temperature ranges from 50 ° C to reflux temperature, and the reaction time is from 30 minutes to 48 hours.

[Stage 3-2]

This step is a step in which compound (3b) is obtained by reacting an acid with compound (3b-2) to deprotect the amine functional group. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include alcoholic solvents such as methanol and ethanol; water, mixed solvents of the foregoing, and the like. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; organic acids such as trifluoroacetic acid, p- toluenesulfonic acid; etc. The acid is used in an amount of from 2 equivalents to the amount of solvent, based on the amount of compound (3b-2). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 72 hours.

[Production Method 3-3] Method for the Preparation of Compound (3c):

(where the ring A, L, R ³ and Z are defined above).

Compound (2c) can be obtained from commercially available products by well known methods, or compound (2c) can also be obtained according to the methods described in the production examples in the Examples section above [production method 2-3] and the like.

[Stage 3-3]

This step is a step in which compound (3c) is obtained by reacting compound (2c) with tributyltin anions. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene, toluene and xylene; mixed solvents of the foregoing and the like. The tributyltin anions used in this reaction can be synthesized by the reaction of an organometallic reagent with tributyltin hydride. Examples of the organometallic reagent include lithium diisopropylamide, isopropyl magnesium chloride, methyl magnesium iodide, and the like. Tributyltin hydride is used in an amount of 1 to 2 equivalents based on the amount of compound (2c). The organometallic reagent is used in an amount of 1 to 1.5 equivalents based on the amount of tributyltin hydride. The reaction temperature ranges from -78 ° C to room temperature, and the reaction time is from 10 minutes to 12 hours.

[Production Method 4] A general method for preparing the compound (4a):

(where the ring A, R ² , R ³ and Z are as defined above).

[Production Method 4-1] Method for the Preparation of Compound (4a):

(where the ring A, R ³ and Z are defined above).

Compound (4a-1) can be obtained from commercially available products in a well-known manner, or compound (4a-1) can be obtained according to the methods described in the production examples in the Examples section below [production method 4-2] and the like .

[Stage 4]

This step is a step in which a compound (4a) is obtained by substituting a chlorine atom of a compound (4a-1) with a hydrogen atom. Compound (4a) can be obtained by reacting compound (4a-1) in the presence of a palladium catalyst, a base and a hydrogen source. A phosphine ligand may also be added to obtain good results. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include 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, mixed solvents of the foregoing, and the like. Examples of the palladium catalyst include bis ( t-tert- butylphosphine) palladium (0), palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0) and etc. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like. Examples of the hydrogen source include formic acid, potassium formate, sodium formate, lithium formate, ammonium formate, and the like. Examples of the phosphine ligand include triphenylphosphine, tri- o- tolylphosphine, tri- tert- butylphosphine and the like. The palladium catalyst is used in an amount of from 0.01 to 0.3 equivalents based on the amount of compound (4a-1). The base is used in an amount of from 2 to 5 equivalents, based on the amount of compound (4a-1). The hydrogen source is used in an amount of 1 to 5 equivalents based on the amount of compound (4a-1). The phosphine ligand is used in an amount of 0.01 to 1.2 equivalents based on the amount of compound (4a-1). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 30 minutes to 24 hours.

[Production Method 4-2] Method for the Preparation of Compound (4a-1):

(where the ring A, R ³ and Z are defined above).

Compound (4b-1), which is a commercially available product, can be used as it is. Compound (4c) can be prepared from commercially available products by well-known methods, or compound (4c) can also be prepared according to the methods described in the production examples in the Examples section below [production method 4-3] and the like.

[Stage 4-1]

This step is a step in which a compound (4b-2) is obtained by reacting a compound (4b-1) with hydroxylamine or hydroxylamine hydrochloride in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include alcoholic solvents such as methanol and ethanol; methylene chloride, water, etc. As a solvent, a base can also be used. Examples of the base include pyridine, sodium hydroxide, potassium hydroxide, sodium acetate, sodium carbonate, sodium hydrogen carbonate, and the like. Hydroxylamine or hydroxylamine hydrochloride is used in an amount of 1 to 10 equivalents based on the amount of compound (4b-1). The base is used in an amount of from 1 equivalent to the amount of solvent, based on the amount of compound (4b-1). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 4-2]

This step is a step in which compound (4b-3) is obtained by reacting compound (4b-2) with a chlorinating agent. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ether solvents such as 1,4-dioxane and tetrahydrofuran; alcohol solvents such as methanol and ethanol; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; dimethyl sulfoxide, methylene chloride, water, mixed solvents of the foregoing, and the like. Examples of the chlorinating agent include N-chlorosuccinimide, sodium hypochlorite, chlorine and the like. The chlorinating agent is used in an amount of from 2 to 5 equivalents based on the amount of compound (4b-2). The reaction temperature ranges from 0 ° C to room temperature, and the reaction time is from 10 minutes to 24 hours.

[Stage 4-3]

This step is a step in which compound (4a-1) is obtained by reacting compound (4b-3) with compound (4c). The compound (4a-1) can be obtained according to methods similar to the methods of [Step 1].

[Production Method 4-3] Method for the Preparation of Compound (4c):

(where the ring A, R ³ , R ⁵ , R ⁶ , L and Z are as defined above).

Compound (2c) can be obtained from commercially available products by well-known methods, or compound (2c) can also be obtained according to the methods described in the preparation examples in the Examples section below [production method 2-3] and the like.

[Stage 4-4]

This step is a step in which compound (4c-1) is obtained by reacting compound (2c) with an ethynylsilane derivative. Compound (4c-1) can be obtained by reacting compound (2c) with an ethynylated Grignard reagent obtained by reacting an ethynylsilane derivative with a Grignard reagent. To obtain good results, you can also add a copper reagent such as copper (I) bromide, copper (I) iodide, etc. Examples of the ethynylsilane derivative include trimethylsilylacetylene, triethylsilylacetylene, triisopropylsilylacetylene, tert- butyldimethylsilylacetylene and the like. As the Grignard reagent, an alkyl magnesium halide such as ethyl magnesium bromide may be used in an amount of from 1 to 3 equivalents based on the amount of compound (2c). Grignard reagent can be used in an amount of 1 to 3 equivalents based on the amount of compound (2c). The copper reagent can be used in an amount of from 0.1 to 3 equivalents based on the amount of compound (2c). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 1 hour to 72 hours.

[Stage 4-5]

This step is a step in which compound (4c) is obtained by deprotecting the trimethylsilyl group of compound (4c-1). Compound (4c) can be obtained by a method similar to the methods of [Step 1-2].

[Production Method 5] A common method for preparing the compound (5a):

(where R ¹ , R ² , R ³ , R ⁴ , X, and Y are as defined above).

[Production Method 5-1] Method for the Preparation of Compound (5a):

(where R ¹ , R ² , R ³ , R ⁴ , X, and Y are as defined above).

Compound (5a-1) can be obtained according to the method described in the production examples in the Examples section, the following [production method 5-2], and the like. Compound (1c-10-1) and compound (1c-10-2), which are commercially available products, can be used as they are, or they can also be prepared from commercially available products by well-known methods.

[Stage 5-1]

This step is a step in which a compound (5a) is obtained by adding 1 equivalent of a base to a compound (5a-1) to produce phenoxide ions, and then a reaction is carried out with a compound (1c-10-2).

Preparation of Phenoxide Ions: Phenoxide ions can be prepared by adding 1 equivalent of base to compound (5a-1) in a solvent such as tetrahydrofuran or methanol. Examples of the base include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide and the like, preferably sodium hydroxide. The solvent is preferably concentrated for use in the subsequent reaction. The reaction temperature is equal to room temperature, and the reaction time is from 5 minutes to 1 hour.

The reaction of phenoxide ions with compound (1c-10-2): The reaction of phenoxide ions with compound (1c-10-2) is carried out in a solvent to obtain compound (5a). There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include amide solvents such as N, N-dimethylformamide, N-methylpyrrolidinone and hexamethylphosphoramide; dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Compound (1c-10-2) is used in an amount of 1 to 3 equivalents based on the amount of compound (5a-1). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

Compound (5a) can also be obtained from compound (5a-1) according to the method described below as an alternative method (1).

Alternative method (1): Compound (5a) can be obtained by reacting compound (5a-1) with compound (1c-10-2) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ether solvents such as tetrahydrofuran and diethyl ether, aromatic hydrocarbon solvents such as benzene and toluene, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; and dimethyl sulfoxide, mixed solvents of the foregoing, and the like. Examples of the base include sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and the like. To obtain good results, you can also add a catalytic amount of sodium iodide, or potassium iodide, or tetrabutylammonium iodide. The base is added in an amount of from 1 to 1.5 equivalents, based on the amount of compound (5a-1). The reaction temperature ranges from room temperature to reflux temperature, and the reaction time is from 10 minutes to 48 hours.

[Stage 5-2]

This step is a step in which a compound (5a) is obtained by reacting a compound (5a-1) with a compound (1c-10-1). Compound (5a) can be obtained according to methods similar to the methods of [Step 1-37].

[Production Method 5-2] Method for the Preparation of Compound (5a-1)]:

(where R ¹ , R ² , R ⁴ , X, and Y are as defined above).

Compound (5a-2) can be prepared according to the methods described in the production examples in the Examples section above [Production Method 1], [Production Method 2], [Production Method 3] and [Production Method 4] and the like.

[Stage 5-3]

This step is a step in which compound (5a-1) is obtained by reacting an acid with compound (5b-2). For best results, an additive such as thioanisole may be added to said reaction system. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ether solvents such as diethyl ether and tetrahydrofuran; methylene chloride, trifluoroacetic acid and the like. Examples of the acid include organic acids such as trifluoroacetic acid and methanesulfonic acid; inorganic acids such as sulfuric acid; Lewis acids such as boron trifluoride diethyl ether; etc. Examples of additives include thioanisole, ethanethiol, dl-methionine, and the like. The acid is used in an amount of from 1 equivalent to the amount of solvent, based on the amount of compound (5a-2). The additive is used in an amount of 1 to 5 equivalents based on the amount of compound (5a-2). The reaction temperature ranges from 0 ° C to reflux temperature, and the reaction time is from 10 minutes to 72 hours.

Compound (5a-1) can also be obtained from compound (5a-2) according to the method described below as an alternative method (1).

Alternative Method (1): Compound (5a-1) can be prepared by reacting compound (5a-2) with boron tribromide or boron trichloride. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction, but methylene chloride is preferably used. Boron tribromide or boron trichloride is used in an amount of 1 to 5 equivalents based on the amount of compound (5a-2). The reaction temperature ranges from -78 ° C to room temperature, and the reaction time is from 30 minutes to 24 hours.

[Production Method 6-1] Method 1 for the preparation of a halogen-modified product of compound (1a)

(where the ring A, Z, Hal, R ¹ and R ^{3 are as} defined above; R ³⁹ represents a hydrogen atom or a C _1-6 alkyl group).

Compound (6a-2) can be prepared according to the methods described in [Production Method 1].

[Stage 6-1]

This step is a step in which compound (6a-1) is obtained by substituting a hydrogen atom in the pyridine ring of compound (6a-2) with a halogen atom. The compound (6a-1) can be obtained according to methods similar to the methods of [Stage 1-11].

[Production Method 6-2] Method 2 for the preparation of a halogen-modified product of compound (1a)

(where the ring A, Z, Hal, R ² and R ^{3 are as} defined above; R ⁴⁰ represents a hydrogen atom or a C _1-6 alkyl group).

Compound (6a-4) can be prepared according to the methods described in [Production Method 1].

[Stage 6-2]

This step is a step in which compound (6a-3) is obtained by substituting a hydrogen atom in the pyridine ring of compound (6a-4) with a halogen atom. The compound (6a-3) can be obtained according to methods similar to the methods of [Stage 1-11].

[Production Method 7] Method 3 for the preparation of a halogen-modified product of compound (1a)

(where the ring A, Hal, R ³ , R ⁵ , R ⁶ and Z are as defined above).

Compound (7a-1), which is commercially available, can be used as it is. Compound (1c-1) can be obtained from commercially available products by known methods and can be obtained according to the methods described in the preparation example of the Examples section or [production method 1-3-1] and the like.

[Stage 7-1]

This step is a step in which compound (7a-2) is obtained by substituting a hydrogen atom in the pyridine ring of compound (7a-1) with a halogen atom. The compound (7a-2) can be obtained according to methods similar to the methods of [Step 1-11].

[Stage 7-2]

This step is a step in which compound (7a-3) is obtained by reacting compound (7a-2) with an ethynylsilane derivative. The compound (7a-3) can be obtained according to methods similar to the methods of [Step 1-1].

[Stage 7-3]

This step is a step in which a compound (7a-4) is obtained by reacting a compound (7a-3) with a base. The compound (7a-4) can be obtained according to methods similar to the methods of [Step 1-2].

[Stage 7-4]

This step is a step in which a compound (7a) is obtained by reacting a compound (7a-4) with a compound (1c-1) in the presence of a base. Compound (7a) can be obtained according to methods similar to the methods of [Step 1].

[Production Method 8] Method 1 for the preparation of a product of a compound with a modified amino group (1a)

(where the ring A, R ² , R ³ , R ⁴ , X, Y and Z are as defined above; R ³⁵ represents a hydrogen atom, a C _1-5 alkyl group, a hydroxy-C _1-5 alkyl group, a C _1-6 alkoxycarbonyl group or a C _1-6 alkoxy-C _1-5 alkyl group).

The compound (8a-1-1), which is a commercially available product, can be used as it is, or it can also be obtained from commercially available products by known methods. Compound (8a-1) can be prepared according to the methods described in [Production Method 1] and the like.

[Stage 8]

This step is a step in which a compound (8a) is obtained by reacting a compound (8a-1) with a compound (8a-1-1) in the presence of a reducing agent. This step can be performed by adding an acid, such as acetic acid or hydrochloric acid, in an amount from a catalytic amount to an amount of solvent. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; alcohol solvents such as methanol and ethanol; halogenated hydrocarbon solvents such as methylene chloride and chloroform, 1,2-dichloroethane; water, acetic acid, mixed solvents of the foregoing, and the like, a mixed solvent of N, N-dimethylformamide and acetic acid is preferred. Examples of the reducing agent used in this reaction include α-picoline borane, pyridinborane, sodium cyanoborohydride, sodium triacetoxyborohydride and the like, preferably α-picoline borane. Compound (8a-1-1) can be used in an amount of from 1 to 5 equivalents based on the amount of compound (8a-1), preferably from 1 to 1.5 equivalents. The reducing agent can be used in an amount of from 0.5 to 5 equivalents based on the amount of compound (8a-1), preferably from 1 to 1.5 equivalents. The reaction temperature ranges from 0 ° C to reflux, and the reaction time is from 10 minutes to 48 hours.

[Production Method 9] Method 2 for the production of a product of a compound with a modified amino group (1a)

(where the ring A, R ² , R ³ , R ⁴ , X, Y, and Z are as defined above; R ³⁶ is represented by a C _1-6 alkyl group or a C _1-6 alkoxyalkyl group).

Compound (8a-1-2), compound (8a-1-3) and compound (8a-1-4), which are commercially available products, can be used as they are, or they can also be prepared from commercially available products by known methods. Compound (8a-1) can be prepared according to the methods described in [production method 1] or the like.

[Stage 9-1]

This step is a step in which a compound (9a) is obtained by reacting a compound (8a-1-2) or a compound (8a-1-3) with a compound (8a-1) in the presence of a base. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include ethereal solvents such as tetrahydrofuran and diethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; halogenated hydrocarbon solvents such as methylene chloride and chloroform, mixed solvents of the foregoing, and the like. Examples of the base include triethylamine, pyridine, potassium carbonate and the like. A catalytic amount of 4-dimethylaminopyridine can also be added to accelerate the reaction. Compound (8a-1-2) or compound (8a-1-3) can be used in an amount of from 1 to 5 equivalents based on the amount of compound (8a-1), preferably from 1 to 1.5 equivalents. The base can be used in an amount of from 0.5 equivalents to the amount of solvent, based on the amount of compound (8a-1), preferably from 1 to 1.5 equivalents. The reaction temperature ranges from 0 ° C to reflux, and the reaction time is from 10 minutes to 48 hours.

[Stage 9-2]

This step is a step in which compound (9a) is obtained by reacting compound (8a-1) with compound (8a-1-4) in the presence of a condensing reagent. There are no particular restrictions on the solvent used in this reaction, provided that it can dissolve the starting materials to a certain extent without blocking the reaction. Examples of the solvent include halogenated hydrocarbon solvents such as methylene chloride and chloroform; ether solvents such as tetrahydrofuran and 1,4-dioxane; amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone; sulfoxide solvents such as dimethyl sulfoxide; ether solvents such as ethyl acetate, mixed solvents of the foregoing, and the like. Examples of a condensing reagent include Bop (1 H -1,2,3-benzotriazol-1-yloxy (tris (dimethylamino)) phosphonium hexafluorophosphate), WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride), DCC (N, N-dicyclohexylcarbodiimide) and the like. A catalytic amount of 4-dimethylaminopyridine can also be added to accelerate the reaction. In addition, this step can also be performed by adding a base, such as triethylamine, in an amount of from 1 to 5 equivalents. Compound (8a-1-4) can be used in an amount of from 1 to 3 equivalents based on the amount of compound (8a-1), preferably from 1 to 1.5 equivalents. The condensing reagent can be used in an amount of from 1 to 3 equivalents, based on the amount of compound (8a-1), preferably from 1 to 1.5 equivalents. The reaction temperature ranges from 0 ° C to reflux, and the reaction time is from 10 minutes to 48 hours.

[Production Method 10] Method 3 for the production of a product of a compound with a modified amino group (1a)

(where the ring A, R ³ , R ⁴ , X, Y, and Z are as defined above; R ³⁷ represents a hydrogen atom, a halogen atom, R ¹² - (CO) -NH- (R ¹² represents a C _1-6 alkyl group or C _1-6 alkoxy-C _1-6 alkyl group, C _1-6 alkyl group, hydroxy-C _1-6 alkyl group, cyano-C _1-6 alkyl group, C _1-6 alkoxy group or C _1-6 alkoxy-C _1-6 alkyl group; R ³⁸ represents a hydrogen atom and a C _1-5 alkyl group).

The compound (10a-1-1), which is a commercially available product, can be used as it is, or it can also be obtained from commercially available products by known methods. Compound (10a-1) can be prepared according to the methods described in [Production Method 1] and the like.

[Stage 10]

This step is a step in which a compound (10a) is obtained by reacting a compound (10a-1) with a compound (10a-1-1) in the presence of a reducing agent. Compound (10a) can be obtained according to methods similar to the methods of [Step 8].

[Examples]

Compounds of the present invention can be obtained, for example, according to the methods described in the following production examples and examples. However, they are solely examples, and the compounds of the present invention are in no way limited to the following specific examples.

[Example 1] 3- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a mixture of 4-benzyloxyphenylacetohydroximoyl chloride (1.2 g, 4.4 mmol) described in Production Example 1-1-3 and tetrahydrofuran (34 ml) at 0 ° C was added 3-ethynylpyridin-2-ylamine (260 mg, 2 , 2 mM), described in Production Example 1-2-3, and triethylamine (3.0 ml, 22 mmol) and stirred at room temperature for 1 hour. Water was added to the reaction mixture at room temperature, and then was extracted with ethyl acetate-tetrahydrofuran (2: 1). The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (240 mg, 15%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.00 (2H, s), 5.05 (2H, s), 5.41 (2H, s), 6.24 (1H, s ), 6.71 (1H, dd, J = 4.9, 7.6 Hz), 6.93-6.97 (2H, m), 7.18-7.22 (2H, m), 7, 31-7.44 (5H, m), 7.70 (1H, dd, J = 1.7, 7.6 Hz), 8.13 (1H, dd, J = 1.8, 4.9 Hz) .

The starting material, 4-benzyloxyphenylacetohydroximoyl chloride, was synthesized as follows.

[Production Example 1-1-1] 1-benzyloxy-4 - (( E ) -2-nitrovinyl) benzene

To a mixture of 4-benzyloxybenzaldehyde (1.0 g, 4.7 mmol), sodium methoxide (28% methanol solution, 150 μl, 0.74 mmol) and methanol (10 ml) at 0 ° C, nitromethane (330 μl, 6 , 1 mmol) and sodium methoxide (28% methanol solution, 1.0 ml, 4.9 mmol) and stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0 ° C and at the same temperature a 5N aqueous solution of hydrochloric acid (20 ml) was added thereto. Then the reaction mixture was stirred at room temperature for 15 minutes. The precipitated solid was filtered off to obtain the title compound (1.2 g, 100%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.20 (2H, s), 7.10-7.14 (2H, m), 7.32-7.38 (5H, m), 7.82-7.85 (2H, m), 8.12 (2H, dd, J = 13.5, 18.2 Hz).

[Production Example 1-1-2] 1-Benzyloxy-4- (2-nitroethyl) benzene

To a suitably cooled mixture of 1-benzyloxy-4 - (( E ) -2-nitrovinyl) benzene (1.0 g, 3.9 mmol) described in Production Example 1-1-1, acetic acid (1 ml) and dimethyl sulfoxide (17 ml), sodium borohydride (250 mg, 6.3 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 40 minutes. Water was added to this reaction mixture. The reaction mixture was partitioned into ethyl acetate and water. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (710 mg, 70%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.26 (2H, t, J = 7.2 Hz), 4.56 (2H, t, J = 7.2 Hz), 5, 04 (2H, s), 6.92 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.30-7.32 (5H, m )

[Production Example 1-1-3] 4-Benzyloxyphenyl-acetohydroximoyl chloride

To a mixture of 1-benzyloxy-4- (2-nitroethyl) benzene (340 mg, 1.3 mmol) described in Production Example 1-1-2 and methanol (5 ml), lithium methoxide (100 mg) was added at room temperature , 2.6 mmol) and stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. Methylene chloride (4 ml) and tetrahydrofuran (2 ml) were added to the residue. Titanium (IV) chloride was added to the reaction mixture at -78 ° C, then it was stirred at 0 ° C for 50 minutes and cooled to -78 ° C, and after adding water (5 ml), the reaction mixture was gradually heated to room temperature. The reaction mixture was partitioned into ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (310 mg, 84%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.83 (2H, s), 5.07 (2H, s), 6.94-6.98 (2H, m), 7.17 -7.21 (2H, m), 7.32-7.34 (5H, m).

The starting material, 3-ethynylpyridin-2-ylamine, was synthesized as follows.

[Production Example 1-2-1] 3-iodopyridin-2-ylamine

A mixture of N- (3-iodopyridin-2-yl) -2,2-dimethylpropionamide (66.2 g, 218 mmol) described in Production Example 39-1-2, 5N aqueous sodium hydroxide solution (200 ml) and methanol ( 200 ml) was stirred in a flask under reflux for 1 hour 20 minutes. The reaction mixture was allowed to cool to room temperature and then partitioned into water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the solvent was concentrated under reduced pressure to obtain the title compound (41.2 g, 85.9%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 6.00 (2H, br s), 6.32 (1H, dd, J = 4.8 Hz, 7.2 Hz), 7.87 (1H, d, J = 7.2 Hz); 7.92 (1H, d, J = 4.8 Hz).

[Production Example 1-2-2] 3-Trimethylsilanylethynylpyridin-2-ylamine

To the mixture of 3-iodopyridin-2-ylamine (40.2 g, 183 mmol) described in Production Example 1-2-1, trimethylsilylacetylene (51.7 ml, 366 mmol), copper (I) iodide (3.49 g , 18.3 mmol), N, N- diisopropylethylamine (63.7 ml, 366 mmol) and N-methylpyrrolidinone (200 ml) under nitrogen atmosphere were added tetrakis (triphenylphosphine) palladium (0) (10.6 g, 9.15 mm) and was stirred at room temperature for 3 hours 10 minutes. Water was added to the reaction mixture, and then extracted 4 times with ethyl acetate. The solvent was concentrated under reduced pressure. The residue was purified by NH silica gel chromatography (heptane: ethyl acetate = 4: 1). The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (heptane: ethyl acetate = 2: 1 then 1: 1) to obtain the title compound (28.1 g, 80.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.25 (9H, s), 6.09 (2H, br.s), 6.51-6.57 (1H, m) 7.50-7.55 (1H, m); 7.95-7.99 (1H, m).

[Production Example 1-2-3] 3-Ethynylpyridin-2-ylamine

To a solution of 3-trimethylsilanylethynylpyridin-2-ylamine (28.1 g, 148 mmol) described in Production Example 1-2-2, tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 20 ml, 20 mmol) was added in tetrahydrofuran (300 ml) and stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and then extracted 4 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (heptane: ethyl acetate = 1: 1 then 1: 2) to obtain the title compound (16.4 g, 93.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.33 (1H, s), 6.14 (2H, br s), 6.53 (1H, dd, J = 4, 8 Hz, 7.2 Hz), 7.53 (1H, d, J = 7.2 Hz), 7.96 (1H, d, J = 4.8 Hz).

[Production Method 1-3-1] 3-Trimethylsilanylethynylpyridin-2-ylamine (alternative method)

To a solution of 2-amino-3-bromopyridine (5.72 g, 33.1 mmol) in N- methylpyrrolidinone (120 ml) was added trimethylsilylacetylene (9.36 ml, 66.2 mmol), tetrakis (triphenylphosphine) palladium at room temperature (0) (1.91 g, 1.66 mmol), copper (I) iodide (630 mg, 3.31 mmol) and N, N-diisopropylethylamine (11.5 ml, 66.2 mmol) and stirred in atmosphere nitrogen at 70 ° C for 6 hours. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, 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 = 2: 1) to obtain the title compound (5.94 g, 94%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.23 (9H, s), 6.07 (2H, br s), 6.51 (1H, dd, J = 4, 9, 7.5 Hz), 7.39 (1H, dd, J = 1.8, 7.5 Hz), 7.94 (1H, dd, J = 1.8, 4.9 Hz).

[Example 2] 3- (3- (4- (Pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4- (pyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride (510 mg, 1.84 mmol) described in Production Example 2-1-5, and 3-ethynylpyridin-2-ylamine (150 mg, 1 , 27 mM) described in Production Example 1-2-3, triethylamine (708 μl, 5.08 mmol) was added in tetrahydrofuran (5 ml) at room temperature and stirred at room temperature for 95 minutes. Water was added to the reaction mixture at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 = 2: 1) to obtain the title compound (120 mg, 26%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.08 (2H, s), 5.37 (2H, s), 6.33 (1H, s), 6.35 (2H, br .c), 6.79-6.82 (2H, m), 6.88-6.91 (1H, m), 7.30 (2H, d, J = 8.1 Hz), 7.35 ( 2H, d, J = 8.1 Hz), 7.57-7.61 (1H, m), 7.85 (1H, d, J = 7.3 Hz), 8.03 (1H, d, J = 5.5 Hz), 8.17 (1H, m).

The starting material, (4- (pyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Method 2-1-1] (4- (pyridin-2-yloxymethyl) phenyl) methanol

To a mixture of 1,4-benzenedimethanol (5.5 g, 40 mmol), 2-fluoropyridine (1.3 g, 13 mmol) and N, N-dimethylformamide (15 ml) was added sodium hydride (1.4 g, 40 mM, 66% in oil) and stirred at room temperature for 20 minutes and at 70 ° C for 1 hour. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated 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, 66%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.71 (2H, s), 5.38 (2H, s), 6.81 (1H, td, J = 0.9, 8, 3 Hz), 6.89 (1H, ddd, J = 0.9, 5.1, 7.1 Hz), 7.37-7.37 (4H, m), 7.59 (1H, ddd, J = 2.0, 7.1, 8.3 Hz), 8.17 (1H, ddd, J = 0.7, 2.0, 5.1 Hz).

[Production Method 2-1-2] 4- (pyridin-2-yloxymethyl) benzaldehyde

To a mixture of (4- (pyridin-2-yloxymethyl) phenyl) methanol (1.9 g, 8.6 mmol) described in Production Example 2-1-1 and methylene chloride (30 ml), manganese dioxide was added at room temperature (15 g, 17 mmol) and at the same temperature was stirred overnight. The reaction mixture was filtered through a pad of celite and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (770 mg, 42%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.48 (2H, s), 6.85 (1H, d, J = 8.2 Hz), 6.90-6.93 (1H , m), 7.60-7.64 (3H, m), 7.89 (2H, d, J = 8.1 Hz), 8.16 (1H, dd, J = 1.3, 4.9 Hz), 10.0 (1H, s).

[Production Example 2-1-3] 2- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine

A mixture of 4- (pyridin-2-yloxymethyl) benzaldehyde (23.4 g, 110 mmol) described in Production Example 2-1-2, nitromethane (33.6 g, 550 mmol), ammonium acetate (17.0 g , 220 mmol) and acetic acid (200 ml) were stirred at 100 ° C for 1 hour 45 minutes. The reaction mixture was stirred in an ice bath while adding a small amount of water, and the precipitate was filtered off to obtain the title compound (21.0 g, 74.5%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.41 (2H, s), 6.91 (1H, dd, J = 0.8, 8.3 Hz), 6.99 -7.10 (1H, m), 7.53 (2H, d, J = 8.0 Hz), 7.72-7.79 (1H, m), 7.86 (2H, d, J = 8 , 0 Hz), 8.13 (1H, d, J = 10 Hz), 8.15-8.20 (1H, m), 8.23 (1H, d, J = 10 Hz).

[Production Example 2-1-4] 2- (4- (2-nitroethyl) benzyloxy) pyridine

In a suitably cooled solution of 2- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine (21.0 g, 81.9 mmol) described in Production Example 2-1-3, acetic acid (21 ml) in dimethyl sulfoxide (200 ml) was added sodium borohydride (4.96 g, 131 mmol) at room temperature. After adding sodium borohydride, the cooling bath was removed, then the mixture was stirred at room temperature for 15 minutes. The reaction mixture was partitioned into water and ethyl acetate. The ethyl acetate layer was washed twice with water and once with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (16.3 g, 77.1%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.23 (2H, t, J = 6.8 Hz), 4.85 (2H, t, J = 6.8 Hz), 5.32 (2H, s), 6.82-6.88 (1H, m), 6.96-7.01 (1H, m), 7.28 (2H, d, J = 8.0 Hz) 7.38 (2H, d, J = 8.0 Hz); 7.69-7.74 (1H, m); 8.15-8.19 (1H, m).

[Production Example 2-1-5] 4- (pyridin-2-yloxymethyl) -phenyl-acetohydroximoyl chloride

Lithium wire (323 mg, 46.6 mmol) was added and dissolved in methanol (75 ml). To the solution of the mixture was added 2- (4- (2-nitroethyl) -benzyloxy) -pyridine (6.0 g, 23.3 mmol), described in Production Example 2-1-4. The reaction solution was concentrated under reduced pressure. Toluene was added to the residue, and the solvent was concentrated under reduced pressure. A solution of the obtained residue in methylene chloride (90 ml) and tetrahydrofuran (45 ml) was cooled to -78 ° C and titanium (IV) chloride (8.15 ml, 74.4 mmol) was added with stirring. Immediately after the addition of titanium (IV) chloride, the reaction mixture was stirred at 0 ° C for 10 minutes and at room temperature for 30 minutes. The reaction solution was poured onto ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and magnesium sulfate was removed by filtration. The filtrate was passed through a neutral silica gel glass filter, washed with ethyl acetate. The resulting eluate was concentrated under reduced pressure. A small amount of ethyl acetate was added to the residue, and the precipitate formed was filtered off to obtain the title compound (1.86 g, 28.8%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.82 (2H, s), 5.33 (2H, s), 6.84-6.89 (1H, m), 6 97-7.01 (1H, m), 7.25 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.70-7, 76 (1H, m), 8.15-8.18 (1H, m), 11.7 (1H, s).

[Example 3] 3- (3- (4- (6-Methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (30 mg, 0.25 mmol) described in Production Example 1-2-3, in anhydrous tetrahydrofuran (5 ml) in a nitrogen atmosphere at room temperature was added (4- (6-methylpyridine -2-yloxymethyl) phenyl) -acetohydroximoyl chloride (222 mg, 0.76 mmol) described in Production Example 3-1-5. Triethylamine (142 μl, 1.0 mmol) was added dropwise to the reaction mixture and stirred at room temperature overnight. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 1) to obtain the title compound (10.5 mg, 11%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.39 (3H, s), 4.04 (2H, s), 5.29 (2H, s), 6.26 (2H , br.s), 6.61-6.64 (1H, m), 6.68-6.71 (1H, m), 6.81 (1H, s), 6.83 (1H, d, J = 7.2 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.57-7.61 (1H, dd , J = 7.2, 8.4 Hz), 7.87 (1H, dd, J = 2.0, 7.6 Hz), 8.08 (1H, dd, J = 2.4, 5.0 Hz).

The starting material, (4- (6-methylpyridin-2-yloxymethyl) benzene) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 3-1-1] 2- (4-bromobenzyloxy) -6-methylpyridine

Sodium hydride (999 mg, 25 mmol) was added to a solution of (4-bromophenyl) methanol (4.54 g, 24.3 mmol) in N, N-dimethylformamide (50 ml) in an ice bath under nitrogen (0 ° C). , 60% in oil) and stirred at room temperature for 30 minutes. Then, 2-fluoro-6-methylpyridine (1.8 g, 16.2 mmol) was added to the reaction mixture in an ice bath (0 ° C) and stirred at room temperature for 5 hours. The reaction mixture in an ice bath (0 ° C) was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 15) to obtain the title compound (3.65 g, 81%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.44 (3H, s), 5.32 (2H, s), 6.57-6.59 (1H, m), 6.71 -6.74 (1H, m), 7.26-7.35 (2H, m), 7.44-7.49 (3H, m).

[Production Example 3-1-2] 4- (6-methylpyridin-2-yloxymethyl) benzaldehyde

To a solution of 2- (4-bromobenzyloxy) -6-methylpyridine (7.30 g, 26.2 mmol) described in Production Example 3-1-1 in anhydrous tetrahydrofuran (200 ml) in a bath with a mixture of dry ice-ethanol (-78 ° C) n- butyllithium (2.67 M n- hexane solution, 11.8 ml, 31.4 mmol) was added dropwise under nitrogen atmosphere and stirred at -78 ° C for 30 minutes. N, N-dimethylformamide (4.04 ml, 52.4 mmol) was added to this mixture at -78 ° C and stirred for 5 minutes. Water and ethyl acetate were added to the reaction mixture and stirred at room temperature for 10 minutes, after which the organic layer was separated. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (4.19 g, 70%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.44 (3H, s), 5.46 (2H, s), 6.12-6.64 (1H, m), 6.74 -6.75 (1H, m), 7.44-7.50 (1H, m), 7.62 (2H, d, J = 8.0 Hz), 7.88 (2H, d, J = 8 , 0 Hz), 10.0 (1H, s).

[Production Example 3-1-3] 2-methyl-6- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine

To a solution of 4- (6-methylpyridin-2-yloxymethyl) benzaldehyde (4.19 g, 18.5 mmol) described in Production Example 3-1-2 in acetic acid (30 ml) under nitrogen atmosphere was added nitromethane ( 5.65 g, 92.6 mmol) and ammonium acetate (2.85 g, 37.0 mmol) and stirred at 110 ° C. for 3 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (5.50 g) as a crude product.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.45 (3H, s), 5.43 (2H, s), 6.05-6.28 (1H, m), 6.74 -6.76 (1H, m), 7.47-7.51 (1H, m), 7.55 (4H, s), 7.59 (1H, d, J = 13.6 Hz), 8, 01 (1H, d, J = 13.6 Hz).

[Production Example 3-1-4] 2-methyl-6- (4- (2-nitroethyl) benzyloxy) pyridine

To a suitably cooled solution of 2-methyl-6- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine (5.00 g, 18.5 mmol) described in Production Example 3-1-3, and acetic acid (5 ml) in dimethyl sulfoxide (50 ml) at room temperature under a nitrogen atmosphere was added sodium borohydride (1.2 g, 29.6 mmol) and stirred at room temperature for 10 minutes. Then water was added dropwise. The mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5 then 1: 2) to obtain the title compound (2.8 g, 56%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.39 (3H, s), 3.22 (2H, t, J = 6.8 Hz), 4.85 (2H, t , J = 6.8 Hz), 5.28 (2H, s), 6.64 (1H, d, J = 8.0 Hz), 7.84 (1H, d, J = 8.0 Hz), 7.28 (2H, d, J = 7.6 Hz), 7.39 (2H, d, J = 7.6 Hz), 7.59 (1H, t, J = 8.0 Hz).

[Production Example 3-1-5] (4- (6-methylpyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride

To a solution of 2-methyl-6- (4- (2-nitroethyl) benzyloxy) pyridine (500 mg, 1.84 mmol) described in Production Example 3-1-4 in methanol (10 ml) at room temperature in lithium methoxide (140 mg, 3.68 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Anhydrous methylene chloride (10 ml) and anhydrous tetrahydrofuran (5 ml) were added to the residue. Titanium (IV) chloride (667 μl, 6.07 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C), and the mixture was stirred at 0 ° C for 45 minutes. Then the reaction mixture was stirred at room temperature for another 60 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was separated. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (484 mg, 91%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.42 (3H, s), 3.82 (2H, s), 5.33 (2H, s), 6.76 (1H d, J = 7.6 Hz), 6.92 (1H, d, J = 7.6 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.44 (2H, d , J = 8.0 Hz), 7.70 (1H, t, J = 7.6 Hz), 11.8 (1H, br.s).

[Example 4] 3- (3- (4-Butoxymethyl-benzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of 4-butoxymethylphenylacetohydroximoyl chloride (28 mg, 0.11 mmol) described in Production Example 4-1-4, and 3-ethynylpyridin-2-ylamine (13 mg, 0.11 mmol) described in Example 1-2- 3 preparation, in tetrahydrofuran (1 ml) at room temperature was added triethylamine (31 μl, 0.22 mmol) and stirred at room temperature for 70 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 = 2: 1) and then further purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (2 , 3 mg, 5%) as a trifluoroacetic acid salt.

MS m / e (ESI) (MH ⁺ ) 338.14 (MH ⁺ )

The starting material, 4-butoxymethylphenyl-acetohydroximoyl chloride, was synthesized as follows.

[Production Example 4-1-1] 1-bromo-4-butoxymethylbenzene

To a solution of 4-bromobenzyl alcohol (10.0 g, 53.5 mmol) in N, N-dimethylformamide (200 ml) was added sodium hydride (3.08 g, 64.2 mmol, 50% in oil) at 0 ° C . This mixture was stirred at 0 ° C for 5 minutes, 1-bromobutane (7.47 ml, 69.3 mmol) was added to it at 0 ° C. The resulting mixture was stirred at room temperature for 40 minutes and then stirred at 70 ° C for 25 minutes. The reaction mixture at 0 ° C was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, 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 (11.5 g, 89%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.919 (3H, t, J = 7.3 Hz), 1.35-1.44 (2H, m), 1.56-1.63 (2H, m), 3.46 (2H, t, J = 6.6 Hz), 4.45 (2H, s), 7.21 (2H, d, J = 8.1 Hz), 7.45 -7.48 (2H, m).

[Production Example 4-1-2] 4-butoxymethylbenzaldehyde

To a solution of 1-bromo-4-butoxymethylbenzene (11.5 g, 47.3 mmol) described in Production Example 4-1-1 in tetrahydrofuran (200 ml) at -78 ° C was added n- butyllithium (32.5 ml, 1.6 M hexane solution, 52.0 mmol). This mixture was stirred at -78 ° C for 55 minutes and N, N-dimethylformamide (4.4 ml, 56.8 mmol) was added to it at -78 ° C. The resulting mixture was warmed to room temperature and stirred for 20 minutes. The reaction mixture at 0 ° C was partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 = 10: 1) to obtain the title compound (7.39 g, 81%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.936 (3H, t, J = 7.3 Hz), 1.37-1.47 (2H, m), 1.60-1.67 (2H, m), 3.52 (2H, t, J = 6.6 Hz), 4.58 (2H, s), 7.51 (2H, d, J = 7.9 Hz), 7.86 (2H, m), 10.0 (1H, s).

[Production Example 4-1-3] 1-butoxymethyl-4- (2-nitroethyl) benzene

To a solution of 4-butoxymethyl-benzaldehyde (7.39 g, 3.84 mmol) described in Production Example 4-1-2 in methanol (140 ml) at 0 ° C. was added nitromethane (2.70 ml, 49.9 mM) and then sodium methoxide (1.49 M methanol solution, 9.41 ml, 46.1 mmol). The reaction mixture was stirred at room temperature for 30 minutes and a 5N aqueous solution of hydrochloric acid (120 ml) was added thereto and stirred for another 25 minutes. This reaction solution at 0 ° C was separated into a saturated aqueous solution of sodium chloride and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a suitably cooled solution of the obtained residue in dimethyl sulfoxide (100 ml) and acetic acid (6 ml) was added sodium borohydride (1.84 g, 46.1 mmol) at room temperature. Then the solution was stirred at room temperature for 80 minutes. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 = 4: 1) to obtain the title compound (2.68 g, 29%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.918 (3H, t, J = 7.3 Hz), 1.37-1.42 (2H, m), 1.56-1.63 (2H, m), 3.31 (2H, t, J = 7.3 Hz), 3.47 (2H, t, J = 6.6 Hz), 4.47 (2H, s), 4.60 (2H, t, J = 7.3 Hz), 7.18 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz).

[Production Method 4-1-4] 4-butoxymethylphenyl-acetohydroximoyl chloride

To a solution of 1-butoxymethyl-4- (2-nitroethyl) benzene (55 mg, 0.23 mmol) described in Production Example 4-1-3, in methanol (2 ml) at 0 ° C was added sodium methoxide (1 , 49 M methanol solution, 47.3 μl, 0.23 mmol). The reaction mixture was stirred at room temperature for 35 minutes and concentrated under reduced pressure. Titanium (IV) chloride (28 μl, 0.23 mmol) was added to a solution of the residue in methylene chloride (2 ml) at -78 ° C under nitrogen atmosphere, then the solution was stirred at 0 ° C for 30 minutes. The reaction mixture at 0 ° C was partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration. The organic layer was filtered using silica gel, the filtrate was evaporated under reduced pressure to obtain the title compound (59 mg, 99%) as a crude product.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.90-0.94 (3H, m), 1.36-1.44 (2H, m), 1.56-1.64 ( 2H, m), 3.46-3.49 (2H, m), 3.79 (2H, s), 4.50 (2H, s), 7.23-7.26 (2H, m), 7 30-7.34 (2H, m); 8.29 (1H, s).

[Example 5] 3- (3- (4- (2-Fluorobenzyloxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a mixture of 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (4.2 mg, 0.016 mmol) described in Production Example 5-1-1 and methanol (0.4 ml) was added 1N aqueous sodium hydroxide solution (16 μl, 0.016 mm). The resulting mixture was concentrated under reduced pressure. To a mixture of the residue and N, N-dimethylformamide (0.5 ml) was added 2-fluorobenzyl bromide (2.3 μl, 0.019 mmol) and stirred at room temperature for 1 hour. The reaction mixture was then directly purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to give the title compound (3.3 mg, 43%) as a trifluoroacetic acid salt.

MS m / e (ESI) 376.14 (MH ⁺ )

The starting material, 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol, was synthesized as follows.

[Production Example 5-1-1] 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol

To a mixture of 3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine (32 mg, 0.090 mmol) described in Example 1 and trifluoroacetic acid (1 ml), thioanisole was added at room temperature (45 mg, 0.36 mmol) and stirred at the same temperature for 2 hours. This reaction mixture was added to a mixture of saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 4: 1) to obtain the title compound (24 mg, 100%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.90 (2H, s), 6.25 (2H, br s), 6.68-6.72 (3H, m) 6.76 (1H, s), 7.11 (2H, d, J = 8.6 Hz), 7.87 (1H, dd, J = 1.5, 7.7 Hz), 8.10 ( 1H, br s), 9.29 (1H, s).

[Example 6] 3- (3- (4- (3-Fluorobenzyloxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a mixture of 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (4.2 mg, 0.016 mmol) described in Production Example 5-1-1 and methanol (0.4 ml) was added a 1N aqueous sodium hydroxide solution (16 μl, 0.016 mmol) and then concentrated under reduced pressure. To a mixture of the residue and N, N-dimethylformamide (0.5 ml) was added 3-fluorobenzyl bromide (2.3 μl, 0.019 mmol) and stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to give the title compound (4.3 mg, 55%) as a trifluoroacetic acid salt.

MS m / e (ESI) 376.12 (MH ⁺ )

[Example 7] 3- (3- (4- (4-Fluorobenzyloxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a mixture of 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (4.2 mg, 0.016 mmol) described in Production Example 5-1-1 and methanol (0.4 ml) was added a 1N aqueous sodium hydroxide solution (16 μl, 0.016 mmol) and then concentrated under reduced pressure. To a mixture of the residue and N, N-dimethylformamide (0.5 ml) was added 4-fluorobenzyl bromide (2.3 μl, 0.019 mmol) and stirred at room temperature for 1 hour. The reaction mixture was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to give the title compound (3.1 mg, 39%) as a trifluoroacetic acid salt.

MS m / e (ESI) 376.12 (MH ⁺ )

[Example 8] 3- (3- (4-Cyclopropylmethoxybenzyl) -isoxazol-5-yl) pyridin-2-ylamine

To a mixture of 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (4.2 mg, 0.016 mmol) described in Production Example 5-1-1 and methanol (0.4 ml) was added a 1N aqueous sodium hydroxide solution (16 μl, 0.016 mmol) and then concentrated under reduced pressure. To a mixture of the residue and N, N-dimethylformamide (0.5 ml), cyclopropylmethyl bromide (2.3 μl, 0.019 mmol) and sodium iodide (1 mg, 7 μM) were added at room temperature and stirred at 60 ° C for 2 hours . The reaction mixture was cooled to room temperature and then purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid). The eluate was neutralized with triethylamine, while concentrating it. The solution was evaporated under reduced pressure. The residue was washed with water to obtain the title compound (1.6 mg, 30%).

MS m / e (ESI) 322.19 (MH ⁺ )

[Example 9] 3- (3- (4- (Pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a mixture of 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (4.2 mg, 0.016 mmol) described in Production Example 5-1-1 and methanol (0.4 ml) was added a 1N aqueous sodium hydroxide solution (16 μl, 0.016 mmol) and then concentrated under reduced pressure. To a mixture of the residue and N, N-dimethylformamide (0.5 ml) was added 2-picolyl chloride (3.1 mg, 0.019 mmol) and stirred at room temperature for 2 hours. The reaction mixture was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to give the title compound (3.6 mg, 39%) as a ditrifluoroacetic acid salt.

MS m / e (ESI) 359.16 (MH ⁺ )

[Example 10] 3- (3- (4- (6-Methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Methanol (3 ml) and a 1N aqueous sodium hydroxide solution (0.18 ml) were added to 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (50 mg, 0.19 mmol) described in Production Example 5-1-1, and then dissolved by sonication. The solution was concentrated under reduced pressure. To the resulting residue was added 2-chloromethyl-6-methylpyridine (31.8 mg, 0.22 mmol) described in Production Example 10-1-1 and N, N-dimethylformamide (2 ml) and stirred at 60 ° C. for 20 minutes. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was separated, and the solvent 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 (36 mg, 51.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.48 (3H, s), 3.96 (2H, s), 5.10 (2H, s), 6.25 (2H , br.s), 6.69 (1H, dd, J = 4.8, 8.0 Hz), 6.79 (1H, s), 6.97 (2H, d, J = 8.0 Hz) 7.18 (1H, d, J = 7.6 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.27 (1H, d, J = 7.6 Hz), 7 70 (1H, dd, J = 7.6, 7.6 Hz), 7.86 (1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 4.8 Hz) .

The starting material, 2-chloromethyl-6-methylpyridine, was prepared as follows.

[Production Example 10-1-1] 2-chloromethyl-6-methylpyridine

A solution of (6-methylpyridin-2-yl) methanol (1.44 g, 11.7 mmol), thionyl chloride (1.45 ml, 19.9 mmol) and methylene chloride (20 ml) were stirred under reflux for 40 minutes. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was separated into sodium bicarbonate solution and diethyl ether. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (1.42 g, 85.8%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.47 (3H, s), 4.72 (2H, s), 7.22 (1H, d, J = 7.6 Hz ), 7.33 (1H, d, J = 7.6 Hz), 7.72 (1H, dd, J = 7.6, 7.6 Hz).

[Example 11] 3- (3- (4- (4-Methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Methanol (3 ml) and a 1N aqueous sodium hydroxide solution (0.18 ml) were added to 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (50 mg, 0.19 mmol) described in Production Example 5-1-1, and then dissolved by sonication. The resulting solution was concentrated under reduced pressure. To the resulting residue was added 2-chloromethyl-4-methylpyridine (31.8 mg, 0.22 mmol) described in Production Example 11-1-4 and N, N-dimethylformamide (2 ml) and stirred at 60 ° C in for 10 minutes. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was separated and the solvent 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 (21 mg, 30.2%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.33 (3H, s), 3.96 (2H, s), 5.11 (2H, s), 6.25 (2H , br.s), 6.69 (1H, dd, J = 4.8, 8.0 Hz), 6.79 (1H, s), 6.98 (2H, d, J = 8.4 Hz) 7.17 (1H, d, J = 7.6 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.34 (1H, s), 7.87 (1H, d, J = 7.6 Hz), 8.09 (1H, d, J = 4.8 Hz), 8.41 (1H, d, J = 4.8 Hz).

The starting material, 2-chloromethyl-4-methylpyridine, was synthesized as follows.

[Production Example 11-1-1] 2,4-dimethylpyridin-1-oxide

To a solution of 2,4-lutidine (2.0 g, 18.7 mmol) in methylene chloride (100 ml) was added 3-chloroperoxybenzoic acid (5.07 g, 29.4 mmol) and stirred at room temperature for 20 minutes. A small amount of a saturated aqueous solution of sodium hydrogen sulfite was added to the reaction mixture, and the organic layer was separated after vigorous stirring. This organic layer was washed with 5N aqueous sodium hydroxide solution (5.9 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.54 g, 66.9%). The claimed compound was used in the reactions below without purification.

[Production Example 11-1-2] 4-methylpyridin-2-ylmethyl ester of acetic acid

Acetic anhydride (30 ml) was added to the 2,4-dimethylpyridin-1-oxide (1.93 g, 15.7 mmol) described in Production Example 11-1-1, and was stirred at 110 ° C for 10 minutes. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 2, then ethyl acetate) to obtain the title compound (774 mg, 29.8%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.11 (3H, s), 2.32 (3H, s), 5.09 (2H, s), 7.16 (1H d, J = 5.2 Hz), 7.23 (1H, s), 8.39 (1H, d, J = 5.2 Hz).

[Production Example 11-1-3] (4-methylpyridin-2-yl) -methanol

A 5N aqueous solution of sodium hydroxide (2 ml) and methanol (4 ml) was added to 4-methylpyridin-2-ylmethyl ester of acetic acid (774 mg, 4.69 mmol) described in Production Example 11-1-2, and this mixture stirred at 60 ° C for 10 minutes. The reaction mixture was partitioned into water and ethyl acetate. The separated aqueous layer was further extracted twice with ethyl acetate. The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (410 mg, 71.0%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.32 (3H, s), 4.52 (2H, br s), 5.35 (1H, br s), 7 06 (1H, d, J = 5.2 Hz), 7.29 (1H, s), 8.32 (1H, d, J = 5.2 Hz).

[Production Example 11-1-4] 2-chloromethyl-4-methylpyridine

A solution of a mixture of (4-methylpyridin-2-yl) methanol (410 mg, 3.33 mmol) described in Production Example 11-1-3, thionyl chloride (0.49 ml, 6.66 mmol) and methylene chloride (10 ml ) was stirred in a flask under reflux for 5 minutes. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The resulting residue was partitioned into diethyl ether and saturated sodium bicarbonate solution. The organic layer was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (340 mg, 72.1%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.37 (3H, s), 4.72 (2H, s), 7.20 (1H, d, J = 5.2 Hz ), 7.38 (1H, s), 8.30 (1H, d, J = 5.2 Hz).

[Example 12] 3- (3- (6-Benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (400 mg, 3.39 mmol) described in Production Example 1-2-3 in anhydrous tetrahydrofuran (20 ml) under nitrogen at room temperature was added (2-benzyloxypyridin-5- silt) -acetohydroximoyl chloride (2.50 g, 9.03 mmol). Then, triethylamine (1.89 ml, 13.6 mmol) was added dropwise thereto and stirred at room temperature for 1.5 hours. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 2) to obtain the title compound (315 mg, 26%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.00 (2H, s), 5.34 (2H, s), 6.27 (2H, br s), 6.70 (1H, dd, J = 4.8, 7.6 Hz), 6.84 (1H, s), 6.86 (1H, d, J = 8.8 Hz), 7.31-7.44 ( 5H, m), 7.69 (1H, dd, J = 2.4, 8.4 Hz), 7.87 (1H, dd, J = 2.0, 7.4 Hz), 8.09 (1H dd, J = 2.3, 4.8 Hz), 8.17 (1H, d, J = 2.4 Hz).

The starting material, (2-benzyloxypyridin-5-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 12-1-1] 2-Benzyloxy-5-bromopyridine

Sodium hydride (7.6 g, 190 mmol) was added to a solution of phenylmethanol (20.5 g, 190 mmol) in N, N-dimethylformamide (200 ml) in an ice bath (0 ° C) under nitrogen atmosphere and stirred at room temperature within 30 minutes. Then, 2,5-dibromopyridine was added in an ice bath (0 ° C) and stirred at room temperature for 60 minutes. The reaction mixture in an ice bath (0 ° C) was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 20 then 1:10) to obtain the title compound (15.1 g, 90%).

¹ H-NMR spectrum (CDC1 ₃ ) δ (ppm): 5.34 (2H, s), 6.71-6.73 (1H, m), 7.32-7.45 (5H, m) 7.64-7.67 (1H, m); 8.20-8.21 (1H, m).

[Production Example 12-1-2] 6-Benzyloxypyridin-3-carbaldehyde

To a solution of 2-benzyloxy-5-bromopyridine (15.1 g, 57.0 mmol) described in Production Example 12-1-1 in anhydrous tetrahydrofuran (250 ml) in a bath with a mixture of dry ice-ethanol (-78 ° C) n- butyllithium (2.67 M n- hexane solution, 25.6 ml, 68.4 mmol) was added dropwise under nitrogen atmosphere and stirred at -78 ° C for 30 minutes. Then, at -78 ° C, N, N-dimethylformamide (6.60 ml, 85.5 mmol) was added thereto and stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated after stirring at room temperature for 10 minutes. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 7 then 1: 5) to obtain the title compound (4.87 g, 40%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.49 (2H, s), 6.89-6.92 (1H, m), 7.34-7.48 (5H, m) 8.07-8.10 (1H, m); 8.64-8.65 (1H, m); 9.97 (1H, s).

[Production Example 12-1-3] 2-benzyloxy-5 - (( E ) -2-nitrovinyl) pyridine

To a solution of 6-benzyloxypyridin-3-carbaldehyde (4.87 g, 22.8 mmol), described in Production Example 12-1-2, in acetic acid (30 ml), nitromethane (6.96) was added at room temperature under a nitrogen atmosphere. g, 114 mmol) and ammonium acetate (3.51 g, 45.6 mmol) and stirred at 110 ° C for 2.5 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (5.60 g, 96%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.43 (2H, s), 7.01 (1H, d, J = 8.8 Hz), 7.34-7.47 (5H, m), 8.16 (1H, d, J = 13.6 Hz), 8.24 (1H, d, J = 13.6 Hz), 8.27 (1H, dd, J = 2, 4, 8.8 Hz), 8.64 (1H, d, J = 2.4 Hz).

[Production Example 12-1-4] 2-Benzyloxy-5- (2-nitroethyl) pyridine

In a suitably cooled solution of 2-benzyloxy-5 - (( E ) -2-nitrovinyl) -pyridine (5.80 g, 22.8 mmol) described in Production Example 12-1-3 and acetic acid (5, 80 ml) in dimethyl sulfoxide (70 ml) at room temperature under a nitrogen atmosphere was added sodium borohydride (1.44 g, 36.2 mmol) and stirred at room temperature for 10 minutes. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (2.50 g, 43%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.17 (2H, t, J = 6.8 Hz), 4.84 (2H, d, J = 6.8 Hz), 5.31 (2H, s), 6.84 (1H, d, J = 8.4 Hz), 7.31-7.42 (5H, m), 7.68 (1H, dd, J = 2, 4, 8.4 Hz), 8.06 (1H, d, J = 2.4 Hz).

[Production Example 12-1-5] (2-Benzyloxypyridin-5-yl) -acetohydroximoyl chloride

To a solution of 2-benzyloxy-5- (2-nitroethyl) pyridine (3.97 g, 15.4 mmol), described in Production Example 12-1-4, in methanol (25 ml), methoxide was added at room temperature under a nitrogen atmosphere. lithium (1.17 g, 30.8 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Anhydrous methylene chloride (30 ml) and anhydrous tetrahydrofuran (20 ml) were added to the residue. Titanium (IV) chloride (5.42 ml, 49.3 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at 0 ° C for 45 minutes. Water was added to the reaction mixture in an ice bath (0 ° C), ethyl acetate and tetrahydrofuran and the organic layer was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (3.3 g, 80%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.79 (2H, s), 5.34 (2H, s), 6.87 (1H, d, J = 8.4 Hz ), 7.30-7.62 (5H, m), 7.61 (1H, dd, J = 2.4, 8.4 Hz), 7.08 (1H, d, J = 2.4 Hz) 11.8 (1H, s).

[Example 13] 3- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the mixture of 4-benzyloxyphenyl-acetohydroximoyl chloride (140 mg, 0.51 mmol) described in Production Example 1-1-3 and tetrahydrofuran (10 ml) was added 3-ethynylpyridin-2,6-diamine (102 mg, 0.76 mM) described in Production Example 13-1-3 and triethylamine (0.71 ml, 5.1 mmol) and stirred at room temperature overnight. Then the reaction mixture was stirred at 55 ° C for another 1.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was filtered by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. The crude product was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid). The solution was evaporated under reduced pressure and the residue was filtered using NH silica gel to give the title compound (51 mg, 27%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.87 (2H, s), 5.07 (2H, s), 5.79 (2H, br.s), 5.82 (1H, d, J = 8.6 Hz), 6.10 (2H, br.s), 6.34 (1H, s), 6.94-6.98 (2H, m), 7.20- 7.24 (2H, m), 7.30-7.45 (5H, m), 7.51 (1H, d, J = 8.4 Hz).

The starting material, 3-ethynylpyridin-2,6-diamine, was synthesized as follows.

[Production Example 13-1-1] 3-iodopyridin-2,6-diamine

2,6-Diaminopyridine (100 g, 916 mmol) was dissolved in dimethyl sulfoxide (400 ml) and N-iodosuccinimide (100 g, 445 mmol) was added to one portion with stirring and at room temperature. The reaction mixture was stirred at room temperature for 10 minutes. Water (3.5 L) was added to this reaction mixture, and the precipitate was filtered off. The resulting aqueous layer was extracted 3 times with ethyl acetate (1.3 L). The ethyl acetate layers were combined, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (heptane: ethyl acetate = 2: 3) to obtain the title compound (23.8 g, 22.8%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.41 (2H, br s), 5.57 (1H, d, J = 8.0 Hz), 5.64 (2H , br.s), 7.37 (1H, d, J = 8.0 Hz).

[Production Example 13-1-2] 3-trimethylsilanylethynylpyridin-2,6-diamine

To the mixture of 3-iodopyridin-2,6-diamine (20.0 g, 85.2 mmol) described in Production Example 13-1-1, trimethylsilylacetylene (24.2 ml, 170 mmol), copper (I) iodide ( 3.25 g, 17.0 mmol), N, N- diisopropylethylamine (19.1 g, 148 mmol) and N- methylpyrrolidinone (286 ml) in an argon atmosphere was added tetrakis (triphenylphosphine) palladium (0) (9.81 g , 8.52 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was partitioned into water and ethyl acetate. The ethyl acetate layer was washed 4 times with water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel chromatography (heptane: ethyl acetate = 4: 1 then 1: 1). The solid obtained after the concentration of the eluate under reduced pressure was washed with heptane containing a small amount of ethyl acetate to obtain the title compound (10.5 g, 60.0%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.20 (9H, s), 5.53 (2H, br s), 5.66 (1H, d, J = 8, 0 Hz), 5.95 (2H, br.s), 7.11 (1H, d, J = 8.0 Hz).

[Production Example 13-1-3] 3-ethynylpyridin-2,6-diamine

To a solution of 3-trimethylsilanylethynylpyridin-2,6-diamine (7.0 g, 34.1 mmol) described in Production Example 13-1-2 in tetrahydrofuran (100 ml) in a ice bath was added a solution of tetrabutylammonium fluoride (1M tetrahydrofuran, 17 ml, 17 mmol) and stirred at room temperature for 10 minutes. Water was added to the reaction mixture, then the mixture was extracted 3 times with ethyl acetate. The extract was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (3.35 g, 73.8%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.08 (1H, s), 5.57 (2H, br s), 5.68 (1H, d, J = 8, 0 Hz), 5.89 (2H, br.s), 7.14 (1H, d, J = 8.0 Hz).

[Example 14] 3- (3- (4-Pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (120 mg, 0.90 mmol) described in Production Example 13-1-3 and 4- (pyridin-2-yloxymethyl) -phenyl-acetohydroximoyl chloride (390 mg, 1 , 41 mM) described in Production Example 2-1-5, triethylamine (502 μl, 3.6 mmol) was added in tetrahydrofuran (5.0 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour 30 minutes. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, and 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 = 1: 1, then ethyl acetate) to obtain the title compound (290 mg, 86.2%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.95 (2H, s), 5.31 (2H, s), 5.79 (2H, br.s), 5.82 (1H, d, J = 8.4 Hz), 6.11 (2H, br.s), 6.37 (1H, s), 6.84-6.86 (1H, m), 6.97- 7.00 (1H, m), 7.31 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.69-7.73 (1H, m), 8.16-8.18 (1H, m).

[Example 15] 3- (3- (4- (6-Methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (300 mg, 2.25 mmol) described in Production Example 13-1-3 in anhydrous tetrahydrofuran (30 ml) at room temperature under nitrogen atmosphere was added (4- (6 -methyl-pyridin-2-yloxymethyl) -phenyl) -acetohydroximoyl chloride (1.50 g, 5.16 mmol) described in Production Example 3-1-5. Then, triethylamine (1.25 ml, 9.00 mmol) was added dropwise at room temperature and stirred at room temperature for 1.5 hours. Water and ethyl acetate were added to the reaction mixture at room temperature, and the organic layer was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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 (637 mg, 73%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.39 (3H, s), 3.96 (2H, s), 5.29 (2H, s), 5.80 (2H , br.s), 5.83 (1H, d, J = 8.8 Hz), 6.11 (2H, br.s), 6.37 (1H, s), 6.63 (1H, dd, J = 0.4, 8.2 Hz), 6.83 (1H, dd, J = 0.4, 7.4 Hz), 7.31 (2H, d, J = 8.0 Hz), 7, 41 (2H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.58 (1H, t, J = 8.0 Hz).

[Example 16] 3- (3- (4-Butoxymethyl-benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (14.6 mg, 0.11 mmol) described in Production Example 13-1-3 and 4-butoxymethylphenyl-acetohydroximoyl chloride (28 mg, 0.11 mmol) described in Production Example 4-1-4, triethylamine (31 μl, 0.22 mmol) was added in tetrahydrofuran and stirred at room temperature for 4 hours. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 = 2: 1) and then again purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (6 , 7 mg, 13%) as a trifluoroacetic acid salt.

MS m / e (ESI) 353.34 (MH ⁺ )

[Example 17] 3- (3- (4-Phenoxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (170 mg, 28 mmol) described in Production Example 13-1-3 in anhydrous tetrahydrofuran (10 ml) at room temperature, (4-phenoxybenzene) -acetohydroximoyl chloride was added (652 mg, 2.49 mmol) described in Production Example 17-1-4. Then, triethylamine (714 μl, 5.12 mmol) was added dropwise and stirred at room temperature for 1 hour. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 2 then 2: 1) to obtain the title compound (314 mg, 68%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.00 (2H, s), 4.74 (2H, br s), 5.50 (2H, br s), 5 94 (1H, d, J = 8.8 Hz), 6.03 (1H, s), 6.96-7.02 (2H, m), 7.08-7.12 (1H, m), 7.22-7.26 (5H, m), 7.30-7.35 (1H, m), 7.52 (1H, d, J = 8.8 Hz).

The starting material, (4-phenoxybenzene) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 17-1-1] Sodium 2-nitro-1- (4-phenoxyphenyl) ethanolate

Sodium methoxide (1.49 M methanol solution, 0.19 ml, 0.91 mmol) was added dropwise to a solution of 4-phenoxybenzaldehyde (1.5 g, 7.56 mmol) in methanol (12 ml) at room temperature under a nitrogen atmosphere. ) Nitromethane (530 μl, 9.84 mmol) was added dropwise to the reaction mixture in an ice bath (0 ° C). There, sodium methoxide (1.49 M methanol solution, 1.66 ml, 8.16 mmol) was added dropwise at room temperature, the solution was stirred at room temperature for 30 minutes. The precipitate was filtered off and dried under reduced pressure, and the solid was azeotropically dried using toluene to give the title compound (1.17 g, 55%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.38 (1H, m), 5.73 (1H, d, J = 5.2 Hz), 6.58 (1H, d , J = 4.4 Hz), 6.91-7.00 (4H, m), 7.09-7.13 (1H, m), 7.34-7.39 (4H, m).

[Production Example 17-1-2] 1 - (( E ) -2-nitrovinyl) -4-phenoxybenzene

A solution of sodium 2-nitro-1- (4-phenoxyphenyl) ethanolate (1.17 g, 4.16 mmol), described in Production Example 17-1-1, acetic anhydride (510 mg, 4.99 mmol) and triethylamine (696 μl, 4.99 mmol) in anhydrous tetrahydrofuran (20 ml) was stirred at room temperature under nitrogen overnight. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.4 g, 70%, purity: about 50%) as a crude product.

[Production Example 17-1-3] 1- (2-nitroethyl) -4-phenoxybenzene

In a suitably cooled solution of 1 - (( E ) -2-nitrovinyl) -4-phenoxybenzene (1.40 g, 2.90 mmol, purity: 50%), described in Production Example 17-1-2, in methanol ( 15 ml), sodium borohydride (274 mg, 7.25 mmol) was added at room temperature under a nitrogen atmosphere and stirred at room temperature for 10 minutes. Then, by cooling appropriately, water was added dropwise at room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (199 mg, 28%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.21 (2H, t, J = 6.8 Hz), 4.84 (2H, t, J = 6.8 Hz), 6.94-7.00 (4H, m), 7.11-7.15 (1H, m), 7.28-7.30 (2H, m), 7.36-7.30 (2H, m) )

[Production Example 17-1-4] (4-Phenoxybenzene) -acetohydroximoyl chloride

To a solution of 1- (2-nitroethyl) -4-phenoxybenzene (100 mg, 0.41 mmol) described in Production Example 17-1-3, in methanol (3 ml) in a nitrogen atmosphere was added sodium methoxide (1.49 M methanol solution, 83.9 μl, 0.41 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Anhydrous methylene chloride (3 ml) was added to the residue. Titanium (IV) chloride (54.2 μl, 0.49 mmol) was added dropwise to the reaction mixture in an ice bath (0 ° C) and stirred at room temperature for 30 minutes. The reaction mixture in an ice bath (0 ° C) was separated by adding water, ethyl acetate and tetrahydrofuran. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (51 mg, 47%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.80 (2H, s), 6.96-7.03 (4H, m), 7.12-7.16 (1H, m), 7.26-7.28 (2H, m), 7.36-7.41 (2H, m), 11.7 (1H, s).

[Example 18] 3- (3- (4- (2-Fluorobenzyloxy) -benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (72.4 mg, 0.26 mmol) described in Production Example 18-1-1, in tetrahydrofuran (3 ml) was added a 5N aqueous sodium hydroxide solution (51.2 μl, 0.26 mmol) and was subjected to ultrasonic treatment for 5 minutes. Then, the reaction mixture was concentrated under reduced pressure to obtain a solid (77.9 mg). To a solution of the obtained solid (14.5 mg, 0.05 mmol) in N, N-dimethylformamide (1 ml) was added 2-fluorobenzyl bromide (11.5 μl, 0.10 mmol) and stirred at room temperature for 2 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and then further purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (6.7 mg, 36%) in the form of a salt of trifluoroacetic acid.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.96 (2H, s), 4.57 (2H, br s), 5.12 (2H, s), 5.90 (2H , br.s), 5.91 (1H, d, J = 8.4 Hz), 5.98 (1H, s), 6.95 (2H, d, J = 8.4 Hz), 7.05 -7.11 (1H, m), 7.14-7.24 (1H, m), 7.20 (2H, d, J = 8.4 Hz), 7.28-7.33 (1H, m ), 7.48 (1H, d, J = 8.4 Hz), 7.45-7.51 (1H, m).

MS m / e (ESI) 391.01 (MH ⁺ )

[Production Example 18-1-1] 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol

To a solution of 3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine (100 mg, 0.27 mmol) described in Example 13 in trifluoroacetic acid (3 ml) at thioanisole (126 μl) was added at room temperature and stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0 ° C. and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (72.3 mg, 95%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.82 (2H, s), 5.79 (2H, br s), 5.83 (1H, d, J = 8, 4 Hz), 6.10 (2H, br.s), 6.32 (1H, s), 6.70 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 9.27 (1H, s).

[Example 19] 3- (3- (4- (3-Fluorobenzyloxy) -benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (72.4 mg, 0.26 mmol) described in Production Example 18-1-1, in tetrahydrofuran (3 ml) was added a 5N aqueous sodium hydroxide solution (51.2 μl, 0.26 mmol) and was subjected to ultrasonic treatment for 5 minutes. Then, the reaction mixture was concentrated under reduced pressure to obtain a solid (77.9 mg). To a solution of the obtained solid (11.3 mg, 0.04 mmol) in N, N-dimethylformamide (1 ml) was added 3-fluorobenzyl bromide (9.1 μl, 0.07 mmol), which was stirred at room temperature for 2 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and further purified by reverse phase high performance liquid chromatography (using acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (6.7 mg, 36%) in as a trifluoroacetic acid salt.

MS m / e (ESI) 391.34 (MH ⁺ )

[Example 20] 3- (3- (4- (4-Fluorobenzyloxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (72.4 mg, 0.26 mmol) described in Production Example 18-1-1, in tetrahydrofuran (3 ml) was added a 5N aqueous sodium hydroxide solution (51.2 μl, 0.26 mmol) and was subjected to ultrasonic treatment for 5 minutes. Then, the reaction mixture was concentrated under reduced pressure to obtain a solid (77.9 mg). To a solution of the obtained solid (13.7 mg, 0.05 mmol) in N, N-dimethylformamide (1 ml) was added 4-fluorobenzyl bromide (11.2 μl, 0.09 mmol) and stirred at room temperature for 2 ,5 o'clock. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), the mixture was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) and then purified by preparative thin layer chromatography (ethyl acetate: hexane = 1: 1) s obtaining the title compound (4.0 mg, 18%).

¹ H-NMR spectrum (CDCl ₃ -d ₆ ) δ (ppm): 3.96 (2H, s), 4.53 (2H, br s), 5.00 (2H, s), 5, 30 (2H, br.s), 5.91 (1H, d, J = 8.0 Hz), 5.98 (1H, s), 6.92 (2H, dd, J = 2.0, 6, 8 Hz), 7.05-7.15 (2H, m), 7.20 (2H, d, J = 8.4 Hz), 7.26-7.46 (2H, m), 7.38 ( 1H, d, J = 8.0 Hz).

MS m / e (ESI) 391.04 (MH ⁺ )

[Example 21] 3- (3- (4-Cyclopropylmethoxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (72.4 mg, 0.26 mmol) described in Production Example 18-1-1, in tetrahydrofuran (3 ml) was added a 5N aqueous sodium hydroxide solution (51.2 μl, 0.26 mmol) and was subjected to ultrasonic treatment for 5 minutes. Then, the reaction mixture was concentrated under reduced pressure to obtain a solid (77.9 mg). To a solution of the obtained solid (8.3 mg, 0.03 mmol) in N, N-dimethylformamide (1 ml) was added cyclopropylmethyl bromide (5.3 μl, 0.06 mmol) and stirred at room temperature for 5 hours. The mixture was purified by reverse phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) and then further purified by preparative thin layer chromatography (ethyl acetate) to obtain the title compound (1.1 mg, 12%).

¹ H-NMR spectrum (CDCl ₃ -d ₆ ) δ ppm): 0.33-0.36 (2H, m), 0.63-0.66 (2H, m), 1.24-1, 29 (1H, s), 3.79 (2H, d, J = 4.8 Hz), 3.96 (2H, s), 4.57 (2H, br.s), 5.34 (2H, br .s), 5.92 (1H, d, J = 8.4 Hz), 5.99 (1H, s), 6.87 (2H, dd, J = 2.0, 6.8 Hz), 7 19 (2H, dd, J = 2.0, 6.8 Hz); 7.49 (1H, d, J = 8.4 Hz).

MS m / e (ESI) 337.11 (MH ⁺ )

[Example 22] 3- (3- (4- (Pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (49.7 mg, 0.18 mmol) described in Production Example 18-1-1, in tetrahydrofuran (3 ml) was added a 5N aqueous solution of sodium hydroxide (35.2 μl, 0.18 mmol) and was subjected to ultrasonic treatment for 5 minutes. Then the reaction mixture was concentrated under reduced pressure to obtain a solid (90.6 mg). A solution of N, N-dimethylformamide (3 ml) was prepared from the obtained solid. Tetrahydrofuran (390 μl) and a 1N aqueous sodium hydroxide solution (390 μl, 0.39 M) were added to 2-picolyl chloride hydrochloride (50 mg, 0.39 mmol), and then the organic layer was separated to obtain a solution of 2-picolyl chloride in tetrahydrofuran. A portion of this solution (0.30 ml) was added to the above solution of N, N-dimethylformamide and stirred at room temperature for 15 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (42.5 mg, 38%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.88 (2H, s), 5.15 (2H, s), 5.79 (2H, br.s), 5.83 (1H, dd, J = 1.2, 8.4 Hz), 6.11 (2H, br.s), 6.35 (1H, s), 6.97 (2H, d, J = 8.0 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.33 (1H, dd, J = 5.2, 8.0 Hz), 7.49 (1H, d, J = 8 , 0 Hz), 7.51 (1H, d, J = 8.0), 7.82 (1H, dd, J = 8.0, 8.0 Hz), 8.57 (1H, dd, J = 0.8, 4.8 Hz).

MS m / e (ESI) 374.28 (MH ⁺ ).

[Example 23] 3- (3- (4- (6-Methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (150 mg, 0.53 mmol) described in Production Example 18-1-1, methanol (3 ml) and 1N aqueous sodium hydroxide solution (0.53 ml) and then dissolved by ultrasonic treatment. This solution was concentrated under reduced pressure. To the obtained residue was added 2-chloromethyl-6-methylpyridine (90.2 mg, 0.64 M), described in Production Example 10-1-1, and N, N-dimethylformamide (2 ml) and stirred at 60 ° C. within 2 hours 50 minutes. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2, then ethyl acetate) to obtain the title compound (106 mg, 51.5%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.48 (3H, s), 3.88 (2H, s), 5.10 (2H, s), 5.78 (2H , br.s), 5.82 (1H, d, J = 8.4 Hz), 6.10 (2H, br.s), 6.34 (1H, s), 6.96 (2H, d, J = 8.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.27 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.70 (1H, dd, J = 8.0, 8.0 Hz).

[Example 24] 3- (3- (4- (4-Methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (80 mg, 0.28 mmol) described in Production Example 18-1-1, methanol (4 ml) and 1N aqueous sodium hydroxide solution (0.29 ml) and then dissolved by ultrasonic treatment. This solution was concentrated under reduced pressure. To the resulting residue was added 2-chloromethyl-4-methylpyridine (50.9 mg, 0.36 M), described in Production Example 11-1-4, and N, N-dimethylformamide (3 ml) and stirred at 60 ° C. for 10 minutes. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2, then ethyl acetate) to obtain the title compound (40 mg, 36.5%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.32 (3H, s), 3.88 (2H, s), 5.10 (2H, s), 5.79 (2H , br.s), 5.82 (1H, d, J = 8.4 Hz), 6.10 (2H, br.s), 6.35 (1H, s), 6.97 (2H, d, J = 8.0 Hz), 7.15 (1H, d, J = 5.2 Hz), 7.22 (2H, d, J = 8.0 Hz), 7.34 (1H, s), 7 50 (1H, d, J = 8.4 Hz), 8.41 (1H, d, J = 5.2 Hz).

[Example 25] 3- (3- (6-Benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (230 mg, 1.73 mmol) described in Production Example 13-1-3 in anhydrous tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere was added (2-benzyloxypyridine- 5-yl) -acetohydroximoyl chloride (1.00 g, 3.61 mmol) described in Production Example 12-1-5. Triethylamine (965 μl, 6.92 mmol) was added dropwise to the mixture and stirred at room temperature for 1.5 hours. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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 (470 mg, 73%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.92 (2H, s), 5.33 (2H, s), 5.81 (2H, br.s), 5.83 (1H, d, J = 8.4 Hz), 6.11 (2H, br.s), 6.40 (1H, s), 6.85 (1H, d, J = 8.8 Hz), 7 , 31-7.39 (3H, m), 7.42-7.44 (2H, m), 7.52 (1H, d, J = 8.4 Hz), 7.66 (1H, dd, J = 2.4, 8.4 Hz), 8.14 (1H, d, J = 2.4 Hz).

[Example 26] 3- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -6-methoxymethylpyridin-2-ylamine

To the mixture of (4-benzyloxyphenyl) -acetohydroximoyl chloride (19 mg, 0.069 mmol) described in Production Example 1-1-3 and tetrahydrofuran (1 ml) was added 3-ethynyl-6-methoxymethylpyridin-2-ylamine at room temperature (8 , 6 mg, 0.053 mmol), described in Production Example 26-1-7, and triethylamine (15 μl, 0.11 mmol) and stirred at room temperature for 5.5 hours. Water was added to the reaction mixture at room temperature, and then extracted with ethyl acetate-tetrahydrofuran (3: 2). The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 3) to obtain the title compound (8.8 mg, 41%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.47 (3H, s), 3.99 (2H, s), 4.42 (2H, s), 5.05 (2H, s ), 5.50 (2H, br.s), 6.23 (1H, s), 6.82 (1H, d, J = 7.9 Hz), 6.93-6.97 (2H, m) 7.18-7.22 (2H, m); 7.31-7.44 (5H, m); 7.72 (1H, d, J = 7.7 Hz).

The starting material, 3-ethynyl-6-methoxymethylpyridin-2-ylamine, was synthesized as follows.

[Production Example 26-1-1] 2-amino-6-chloro-nicotinic acid

A mixture of 2,6-dichloro-nicotinic acid (31 g, 0.14 M) and 28% aqueous ammonia (200 ml) was stirred in a hermetically sealed flask at 135 ° C for 10 hours. The resulting reaction solution was cooled to room temperature, and excess ammonia gas was removed under reduced pressure. Water was added to the residue to bring the total volume to 1000 ml, the mixture was cooled to 0 ° C and citric acid was added to adjust the pH to 6. The precipitate was filtered off to obtain the title compound (12 g, 49%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 6.63 (1H, d, J = 8.1 Hz), 7.55 (2H, br.s), 8.02 (1H d, J = 8.1 Hz).

[Production Example 26-1-2] 2-amino-6-chloro-nicotinic acid methyl ester

Concentrated sulfuric acid (25 ml) and 2-amino-6-chloronicotinic acid (4.3 g, 25 mmol) described in Production Example 26-1-1 were added to methanol (50 ml) in an ice bath and stirred at 70 ° C for 5 hours. The reaction mixture was cooled and then neutralized by the addition of an aqueous solution of sodium bicarbonate (90 g). The precipitate was filtered off to obtain the title compound (3.2 g, 17 mmol, 68%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.88 (3H, s), 6.62 (1H, d, J = 8.2 Hz), 8.05 (1H, d, J = 8.1 Hz).

[Production Example 26-1-3] Tributyl-methoxymethyl-tin

To a mixture of diisopropylamine (9.4 ml, 67 mmol) and tetrahydrofuran (150 ml) at -78 ° C, n- butyllithium (2.4 M n- hexane solution, 25 ml, 61 mmol) was added dropwise and stirred at the same temperature in within 30 minutes. Tributyltin hydride (16 ml, 61 mmol) was added dropwise to the reaction mixture at the same temperature, and stirred at 0 ° C for 30 minutes. The reaction mixture was cooled to −78 ° C. and chloromethyl methyl ether (4.6 ml, 61 mmol) was added dropwise thereto. The reaction mixture was gradually warmed to room temperature. Water was added to the reaction mixture, and then extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 30) to obtain the title compound (18 g, 86%).

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 = 6.8 Hz).

[Production Example 26-1-4] 2-amino-6-methoxymethyl-nicotinic acid methyl ester

A mixture of 2-amino-6-chloronicotinic acid methyl ester (1.4 g, 7.6 mmol) described in Production Example 26-1-2, tributylmethoxymethyltin (3.1 g, 9.1 mmol) described in Example 26 -1-3 preparation, tetrakis (triphenylphosphine) palladium (440 mg, 0.38 mmol) and N-methylpyrrolidinone (20 ml) were stirred at 130 ° C for 3.5 hours. The reaction mixture was cooled to room temperature, and an aqueous solution of potassium fluoride and ethyl acetate was added to this reaction mixture, then filtered through a pad of celite. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 2) to obtain the title compound (0.93 g, 63%).

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 = 7.9 Hz), 8.14 (1H, d, J = 7.9 Hz).

[Production Example 26-1-5] (2-amino-6-methoxymethylpyridin-3-yl) methanol

To a mixture of lithium aluminum hydride (80%, 220 mg, 4.6 mmol) and tetrahydrofuran (5 ml) at 2 ° C was added 2-amino-6-methoxymethyl-nicotinic acid methyl ester (300 mg, 1.5 mmol) described in Production Example 26-1-4, and stirred at the same temperature for 20 minutes. A 28% aqueous ammonia solution was added dropwise to the reaction mixture at 0 ° C. The mixture was warmed to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (260 mg, 100%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.45 (3H, s), 4.39 (2H, s), 4.62 (2H, s), 5.03 (2H, br .c), 6.70 (1H, d, J = 7.3 Hz), 7.31 (1H, d, J = 7.5 Hz).

[Production Example 26-1-6] 2-amino-6-methoxymethylpyridin-3-carbaldehyde

To a mixture of (2-amino-6-methoxymethylpyridin-3-yl) methanol (260 mg, 1.5 mmol) described in Production Example 26-1-5 and methylene chloride (15 ml) was added manganese dioxide (1.3 g , 15 mM) and stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 3: 2) to obtain the title compound (210 mg, 81%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.48 (3H, s), 4.44 (2H, s), 6.87 (1H, d, J = 7.9 Hz), 7.82 (1H, d, J = 7.7 Hz); 9.84 (1H, s).

[Production Example 26-1-7] 3-ethynyl-6-methoxymethylpyridin-2-ylamine

To a mixture of diisopropylamine (0.15 ml, 1.1 mmol) and tetrahydrofuran (2 ml) at -78 ° C was added dropwise n- butyllithium (1.6 M solution of n- hexane, 0.68 ml, 1.1 mmol) ) and stirred at the same temperature for 30 minutes. Trimethylsilyl diazomethane (2 M n- hexane solution, 0.50 ml, 0.99 mmol) was added to the reaction mixture at -78 ° C and stirred at the same temperature for 30 minutes. A mixture of 2-amino-6-methoxymethylpyridin-3-carbaldehyde (150 mg, 0.90 mmol) described in Preparation Example 26-1-6 and tetrahydrofuran (1.5 ml) was added dropwise to the reaction mixture at -78 ° C. ) and stirred at 0 ° C for 30 minutes. The reaction mixture was cooled to −78 ° C., and a mixture of acetic acid (0.10 ml) and tetrahydrofuran (1 ml) was added dropwise to this reaction mixture. The resulting reaction mixture was gradually cooled to 0 ° C and partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 2: 3) to obtain the title compound (73 mg, 50%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.40 (1H, s), 3.45 (3H, s), 4.39 (2H, s), 5.07 (2H, br .c), 6.72 (1H, d, J = 7.7 Hz), 7.58 (1H, d, J = 7.5 Hz).

[Example 27] 6-Methoxymethyl-3- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the mixture of 4- (pyridin-2-yloxymethyl) phenylacetohydroximoyl chloride (18 mg, 0.064 mmol) described in Production Example 2-1-5 and tetrahydrofuran (1 ml) was added 3-ethynyl-6-methoxymethylpyridin-2- ylamine (8.6 mg, 0.053 mmol), described in Production Example 26-1-7, and triethylamine (15 ul, 0.11 mmol) and stirred at room temperature for 2 hours. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 3) to obtain the title compound (10 mg, 48%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.47 (3H, s), 4.07 (2H, s), 4.44 (2H, s), 5.37 (2H, s ), 5.56 (2H, br s), 6.25 (1H, s), 6.79-6.84 (2H, m), 6.87-6.91 (1H, m), 7, 30 (2H, d, J = 7.9 Hz), 7.44 (2H, d, J = 7.9 Hz), 7.57-7.61 (1H, m), 7.73 (1H, d , J = 7.9 Hz), 8.18 (1H, d, J = 4.2 Hz).

[Example 28] 5- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 5-ethynylpyridin-2-ylamine (10 mg, 85 μM), described in Production Example 28-1-3, and 4-benzyloxyphenyl-acetohydroximoyl chloride (70 mg, 0.25 mmol) described in Example 1-1- 3 receiving, in tetrahydrofuran (2 ml) at room temperature was added triethylamine (35 μl, 0.25 mmol) and stirred at room temperature for 3 hours 40 minutes. The reaction mixture at 0 ° C was partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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% trifluoroacetic acid) to give the title compound (1 mg, 3%) as a trifluoroacetic acid salt.

MS m / e (ESI) 358.00 (MH ⁺ )

The starting material, 5-ethynylpyridin-2-ylamine, was synthesized as follows.

[Production Example 28-1-1] 2-nitro-5-trimethylsilanylethylenylpyridine

To a solution of 5-bromo-2-nitropyridine (1.00 g, 4.93 mmol) in N-methylpyrrolidinone (20 ml) was added trimethylsilylacetylene (1.39 ml, 9.85 mmol), tetrakis (triphenylphosphine) palladium at room temperature (0) (114 mg, 985 μM), copper (I) iodide (37.5 mg, 197 μM) and N, N-diisopropylethylamine (1.72 ml, 9.85 mmol) and stirred at 65 ° C. in atmosphere nitrogen for 4 hours. The reaction mixture at 0 ° C was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 6: 1) to obtain the title compound (490 mg, 45%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.298 (9H, s), 8.03-8.05 (1H, m), 8.22 (1H, J = 8.4 Hz), 8.66 (1H, d, J = 2.0 Hz).

[Production Example 28-1-2] 5-trimethylsilanylethynylpyridin-2-ylamine

To a solution of 2-nitro-5-trimethylsilanylethynylpyridine (405 mg, 1.84 mmol) described in Production Example 28-1-1 in tetrahydrofuran (10 ml) and water (5 ml), iron powder (514 mg) was added at room temperature , 9.21 mmol) and ammonium chloride (197 mg, 3.69 mmol) and stirred at 70 ° C for 75 minutes. The reaction mixture was cooled to room temperature and filtered through a pad of celite 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 (319 mg, 91%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.237 (9H, s), 4.73 (2H, br.s), 6.44 (1H, d, J = 8.6 Hz), 7.51 (1H, dd, J = 2.2, 8.4 Hz), 8.19 (1H, d, J = 2.2 Hz).

[Production Example 28-1-3] 5-ethynylpyridin-2-ylamine

To a solution of 5-trimethylsilanylethinylpyridin-2-ylamine (26 mg, 137 μM), described in Production Example 28-1-2, in tetrahydrofuran (1 ml) and methanol (1 ml), potassium carbonate (37.9 mg) was added at room temperature , 274 μM) and stirred at room temperature for 1 hour. The reaction mixture at 0 ° C was partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was concentrated 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, 99%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.07 (1H, s), 4.73 (2H, br.s), 6.46 (1H, d, J = 8.6 Hz ), 7.53 (1H, dd, J = 2.2, 8.6 Hz), 8.21 (1H, s).

[Example 29] 3- (5- (4-Benzyloxybenzyl) -isoxazol-3-yl) -pyridin-2-ylamine

To a solution of 3- (5- (4-benzyloxybenzyl) -isoxazol-3-yl) -5-chloropyridin-2-ylamine (50 mg, 0.13 mmol) described in Production Example 29-2-3, in N- methylpyrrolidinone (2 ml) at room temperature under nitrogen atmosphere was added formic acid (7.3 μl, 0.19 mmol), N, N-diisopropylethylamine (67 μl, 0.38 mmol) and tetrakis (triphenylphosphine) palladium (0) ( 15 mg, 13 μM) and stirred at 100 ° C for 2 hours 20 minutes. Water and ethyl acetate were added to the reaction mixture at room temperature, and then filtered through a pad of celite. The filtrate was partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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% trifluoroacetic acid) and then purified again by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (5 mg, 11%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.07 (2H, s), 5.07 (2H, s), 6.24 (1H, s), 6.34 (2H, br .c), 6.67 (1H, dd, J = 4.9, 7.5 Hz), 6.95-6.98 (2H, m), 7.20-7.23 (2H, m), 7.31-7.45 (5H, m), 7.66 (1H, dd, J = 1.7, 7.5 Hz), 8.11 (1H, dd, J = 1.7, 4.9 Hz).

MS m / e (ESI) 358.20 (MH ⁺ )

The starting material, 3- (5- (4-benzyloxybenzyl) -isoxazol-3-yl) -5-chloropyridin-2-ylamine, was synthesized as follows.

[Production Example 29-1-1] 2-aminopyridin-3-carbaldehyde oxime

Hydroxylamine hydrochloride (854 mg, 12.3 mmol) was added to a solution of 2-amino-3-formylpyridine (1.00 g, 8.19 mmol) in pyridine (20 ml) at room temperature and stirred at room temperature for 1 hour 40 minutes. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (951 mg, 85%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 6.60 (1H, dd, J = 4.8, 7.3 Hz), 6.94 (2H, s), 7.55 (1H, m), 7.96 (1H, dd, J = 1.7, 4.8 Hz), 8.22 (1H, s), 11.2 (1H, s).

[Production Example 29-1-2] 2-amino-5-chloro-N-hydroxypyridin-3-carboxyimidoyl chloride

To a solution of 2-aminopyridin-3-carbaldehyde oxime (951 mg, 6.93 mmol) described in Production Example 29-1-1 in N, N-dimethylformamide (20 ml) was added N-chlorosuccinimide at room temperature (2, 22 g, 16.6 mmol) and stirred at room temperature for 5 hours 30 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (249 mg, 17%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.24 (2H, br s), 7.91-7.92 (1H, m), 8.06-8.07 ( 1H, m), 12.6 (1H, s).

[Production Example 29-2-1] (3- (4-Benzyloxyphenyl) prop-1-ynyl) -trimethylsilane

Ethyl magnesium bromide (3 M diethyl ether solution, 1.86 ml, 5.59 mmol) was added to a solution of trimethylsilylacetylene (851 μl, 6.02 mmol) in tetrahydrofuran (20 ml) at room temperature under nitrogen atmosphere and stirred at 65 ° C for 40 minutes. The reaction mixture was cooled to room temperature, and copper (I) bromide (308 mg, 2.16 mmol) and 4-benzyloxybenzyl chloride (1.00 g, 4.30 mmol) were added to this reaction mixture and stirred at 65 ° C for 8 hours 45 minutes. A saturated solution of ammonium chloride was added to the reaction mixture at room temperature, and then was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 (911 mg, 72%).

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), 7.36-7.30 (2H, m), 7.42-7 44 (2H, m).

[Production Example 29-2-2] 1-Benzyloxy-4-prop-2-ynyl-benzene

To a solution of (3- (4-benzyloxyphenyl) -prop-1-ynyl) -trimethyl-silane (911 mg, 3.09 mmol) described in Production Example 29-2-1 in methanol (20 ml) at room temperature potassium carbonate (854 mg, 6.18 mmol) was added and stirred at room temperature for 4 hours 10 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 (618 mg, 90%).

¹ H-NMR spectrum (CDCl ₃ ) (ppm): δ 2.16 (1H, t, J = 2.4 Hz), 3.54 (2H, d, J = 2.4 Hz), 5, 05 (2H, s), 6.91-6.94 (2H, m), 7.24-7.26 (2H, m), 7.29-7.43 (5H, m).

[Production Example 29-2-3] 3- (5- (4-benzyloxybenzyl) -isoxazol-3-yl) -5-chloropyridin-2-ylamine

To a solution of 2-amino-5-chloro-N-hydroxypyridin-3-carboxymethyl chloride (100 mg, 485 μM) described in Production Example 29-1-2 in diethyl ether (2 ml) and tetrahydrofuran (1 ml) was added 1 the benzyloxy-4-prop-2-ynylbenzene (113 mg, 509 μM) described in Production Example 29-2-2 and triethylamine (81 μl, 582 μM) and stirred at room temperature for 4 hours 5 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain the title compound (59 mg, 31%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.11 (2H, s), 5.07 (2H, s), 6.97-6.99 (3H, m), 7 05 (2H, s), 7.24 (2H, d, J = 8.6 Hz), 7.29-7.32 (1H, m), 7.37 (2H, m), 7.42 ( 2H, m), 8.07 (1H, d, J = 2.6 Hz), 8.11 (1H, d, J = 2.6 Hz).

[Example 30] 3- (5- (4- (Pyridin-2-yloxymethyl) benzyl) isoxazol-3-yl) pyridin-2-ylamine

To a solution of 5-chloro-3- (5- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-3-yl) pyridin-2-ylamine (37 mg, 94 μM) described in Example 30- 1-3 preparation, in N-methyl-2-pyrrolidinone (2 ml) at room temperature was added formic acid (5.3 μl, 0.14 mmol), N, N-diisopropylethylamine (49 μl, 0.28 mmol) and bis ( t-tert- butylphosphine) palladium (0) (9.6 mg, 19 μM) and stirred at 100 ° C. under nitrogen for 1 hour 25 minutes. Water and ethyl acetate were added to the reaction mixture at room temperature, and then filtered through a pad of celite. The filtrate was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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% trifluoroacetic acid) and then further purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (0, 66 mg, 2.0%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.14 (2H, s), 5.39 (2H, s), 6.27 (1H, s), 6.49 (2H, br .c), 6.69 (1H, dd, J = 4.9, 7.5 Hz), 6.81 (1H, d, J = 8.4 Hz), 6.88-6.91 (1H, m), 7.31 (2H, d, J = 8.0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.57-7.62 (1H, m), 7, 68 (1H, dd, J = 1.8, 7.5 Hz), 8.09 (1H, dd, J = 1.8, 4.9 Hz), 8.17-8.19 (1H, m) .

MS m / e (ESI) 359.11 (MH ⁺ )

The starting material, 5-chloro-3- (5- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-3-yl) pyridin-2-ylamine, was synthesized as follows.

[Production Example 30-1-1] 2- (4-chloromethyl-benzyloxy) -pyridine

A mixture of (4- (pyridin-2-yloxymethyl) phenyl) methanol (540 mg, 2.51 mmol) described in Production Example 2-1-1, triphenylphosphine (856 mg, 3.27 mmol) and carbon tetrachloride (10 , 8 g, 10.2 mmol) were stirred in a flask under reflux for 2 hours 10 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: acetic acid = 8: 1) to obtain the title compound (300 mg, 51.1%).

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).

[Production Example 30-1-2] 2- (4-prop-2-ynyl-benzyloxy) -pyridine

Ethyl magnesium bromide (3 M diethyl ether solution, 1.09 ml, 3.28 mmol) was added to a solution of trimethylsilylacetylene (496 μl, 3.51 mmol) in tetrahydrofuran (15 ml) at room temperature under nitrogen atmosphere and stirred at 65 ° C within 30 minutes. The reaction mixture was cooled to room temperature and copper (I) bromide (168 mg, 1.17 mmol) and 2- (4-chloromethyl-benzyloxy) -pyridine (548 mg, 2.34 mmol) synthesized in Example 30 were added thereto. -1-1 receipt, and stirred at 65 ° C for 15 hours 10 minutes. The reaction mixture was separated at room temperature into a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in methanol (5 ml) and tetrahydrofuran (10 ml), potassium carbonate (647 mg, 4.68 mmol) was added and stirred at room temperature for 3 hours 25 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 a mixture of the title compound and 2- (4-chloromethyl-benzyloxy) -pyridine (448 mg, planned purity 20%, 17%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.04 (1H, m), 3.61 (2H, d, J = 2.6 Hz), 5.30 (2H, s ), 6.83-6.87 (1H, m), 6.95-6.99 (1H, m), 7.30-7.32 (2H, s), 7.36-7.40 (2H , m), 7.68-7.73 (1H, m), 8.14-8.16 (1H, m).

[Production Example 30-1-3] 5-chloro-3- (5- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-3-yl) pyridin-2-ylamine

To a solution of 2-amino-5-chloro-N-hydroxypyridin-3-carboximidoyl chloride (50 mg, 242 μM), described in Production Example 29-1-2, in tetrahydrofuran (5 ml) was added triethylamine (41 μl) at room temperature , 292 μM) and 2- (4-prop-2-ynyl-benzyloxy) -pyridine (271 mg, 243 μM, purity: 20%) described in Production Example 30-1-2, and stirred at room temperature for 30 minutes and then stirred in a flask under reflux for 2 hours 25 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain the title compound (37 mg, 39%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.22 (2H, s), 5.34 (2H, s), 6.86 (1H, d, J = 8.2 Hz ), 6.97-7.01 (1H, m), 7.04 (1H, s), 7.07 (2H, br.s), 7.34 (2H, d, J = 8.0 Hz) 7.44 (2H, d, J = 8.0 Hz), 7.70-7.74 (1H, m), 8.09 (1H, d, J = 2.6 Hz), 8.14 ( 1H, d, J = 2.6 Hz), 8.16-8.18 (1H, m).

[Example 31] 3- (1- (4-Benzyloxybenzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine

To a solution of 2-amino-3-bromopyridine (44.1 mg, 0.26 mmol) in anhydrous tetrahydrofuran (7 ml) in a nitrogen atmosphere was added 1- (4-benzyloxybenzyl) -4-tributylstannyl-1 H -pyrazole (141 mg 0.26 mM) described in Production Example 31-1-2, copper (I) iodide (19.4 mg, 0.10 mmol) and palladium (II) bis (triphenylphosphine) (35.8 mg, 0, 05 mM) and stirred at 70 ° C for 4 hours. Water was added to the reaction mixture at room temperature, and ethyl acetate was then filtered through a celite pad, and the filtrate was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1, then ethyl acetate) to obtain the title compound (1.8 mg, 2%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.09 (2H, s), 5.26 (2H, s), 5.87 (2H, br s), 6.61 (1H, dd, J = 4.8, 7.2 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7 32-7.44 (5H, m), 7.47-7.49 (1H, m), 7.74 (1H, s), 7.86 (1H, dd, J = 1.6, 5, 0 Hz), 8.13 (1H, s).

The starting material, 1- (4-benzyloxybenzyl) -4-tributylstannyl-1 H -pyrazole, was synthesized as follows.

Method 31-1-1 for the preparation of 1- (4-benzyloxybenzyl) -4-bromo-1 H -pyrazole

To a solution of 2-bromopyrazole (500 mg, 3.40 mmol) in N, N-dimethylformamide (10 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (196 mg, 4.08 mmol, 60% in oil) and stirred at room temperature for 30 minutes. Then 4-benzyloxybenzyl chloride (791 mg, 3.40 mmol) was added and stirred at room temperature for 60 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (1.1 g, 94%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.04 (2H, s), 5.17 (2H, s), 6.94 (2H, d, J = 8.8 Hz ), 7.17 (2H, d, J = 8.8 Hz), 7.31 (1H, s), 7.33-7.41 (5H, m), 7.47 (1H, m).

[Production Example 31-1-2] 1- (4-Benzyloxybenzyl) -4-tributylstannyl-1 H -pyrazole

To a solution of 1- (4-benzyloxybenzyl) -4-bromo- 1H- pyrazole (1.10 g, 3.20 mmol) described in Production Example 31-1-1 in xylene (20 ml) under nitrogen atmosphere was added tetrakis (triphenylphosphine) palladium (0) (370 mg, 0.32 mmol) and hexa -n -butyltin (5.57 g, 9.60 mmol) and stirred at 140 ° C for 2 hours. Water and ethyl acetate were added to the reaction mixture at room temperature, and then filtered through a celite pad, and the filtrate was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (141 mg, 8%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.87 (9H, t, J = 7.2 Hz), 0.92-1.00 (6H, m), 1.26-1 35 (6H, m), 1.46-1.54 (6H, m), 5.05 (2H, s), 5.27 (2H, s), 6.93-6.95 (2H, m ), 7.14-7.17 (2H, m), 7.23 (1H, s), 7.31-7.43 (5H, m), 7.46 (1H, s).

[Example 32] 3- (1- (4- (Pyridin-2-yloxymethyl) benzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2-ylamine (150 mg, 0.94 mmol) described in Production Example 32-1-4 in N, N-dimethylformamide (10 ml) in an ice bath (0 ° C), sodium hydride (48.7 mg, 1.22 mmol, 60% in oil) was added under nitrogen atmosphere. After stirring at room temperature for 40 minutes, 2- (4-chloromethylbenzyloxy) -pyridine (228 mg, 0.98 mmol) described in Production Example 30-1-1 was added and stirred at room temperature for 30 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1, then ethyl acetate) to obtain the title compound (307 mg, 92%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.33 (2H, s), 5.35 (2H, s), 5.60 (2H, br s), 6.61 (1H, dd, J = 4.8, 7.4 Hz), 6.84-6.87 (1H, m), 6.96-7.00 (1H, m), 7.30-7.43 (1H, m), 7.31 (2H, d, J = 8.4 Hz), 7.42 (1H, t, J = 8.4 Hz), 7.48 (1H, dd, J = 2, 0, 7.2 Hz), 7.69-7.73 (1H, m), 7.76 (1H, d, J = 1.2 Hz), 7.87 (1H, dd, J = 2.0 , 5.0 Hz), 8.15-8.17 (1H, m), 8.18 (1H, d, J = 0.8 Hz).

The starting material, 3- (1 H -pyrazol-4-yl) -pyridin-2-ylamine, was synthesized as follows.

[Production Example 32-1-1] 4-bromo-1-trityl-1 H -pyrazole

Triethylamine (23.7 ml, 170 mmol) was added dropwise to a solution of 4-bromopyrazole (10.0 g, 68.0 mmol) in N, N-dimethylformamide (100 ml) at room temperature under a nitrogen atmosphere. Trityl chloride (37.9 g, 136 mmol) was added to the reaction solution in an ice bath (0 ° C) and stirred at 70 ° C for 3 hours. Water (400 ml) was added to the reaction solution to precipitate a solid. The precipitated solid was filtered off and dried under reduced pressure. Then, the solid was dried azeotropically using toluene to give the title compound (22.9 g, 87%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.04-7.07 (6H, m), 7.35-7.38 (9H, m), 7.52 (1H, d, J = 0.4 Hz), 7.76 (1H, d, J = 0.8 Hz).

[Production Example 32-1-2] 4- (4,4,5,5-tetramethyl- (1,3,2) dioxaborolan-2-yl) -1-trityl-1 H -pyrazole

A mixture of 4-bromo-4-trityl- 1H- pyrazole (4.8 g, 12.3 mmol) described in Production Example 32-1-1, bis (pinacolyate) diborane (5.0 g, 19.7 mmol) ), potassium acetate (3.62 g, 36.9 mmol), 1,1 'bis (diphenylphosphino) ferrocene-dichloropalladium (II) (450 mg, 0.62 mmol) and dimethyl sulfoxide (50 ml) were stirred at 80 ° C in an argon atmosphere for 17 hours 10 minutes. The reaction solution was allowed to cool to room temperature and partitioned into water and ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (heptane: ethyl acetate = 4: 1). Heptane was added to the solid obtained by the concentration of the eluate under reduced pressure, then sonicated and filtered to give the title compound (1.51 g, 28.0%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.30 (12H, s), 7.10-7.16 (6H, m), 7.26-7.31 (9H, m) 7.75 (1H, s); 7.94 (1H, s).

[Production Example 32-1-3] 3- (1-trityl-1 H -pyrazol-4-yl) -pyridin-2-ylamine

4- (4,4,5,5-Tetramethyl- (1,3,2) dioxaborolan-2-yl) -1-trityl-1 H -pyrazole (3.2 g, 7.33 mmol) described in Example 32-1-2 preparation, 3-bromopyridin-2-ylamine (1.14 g, 6.60 mmol), tetrakis (triphenylphosphine) palladium (0) (424 mg, 0.37 mmol), toluene (40 ml), A 2 M aqueous solution of sodium carbonate (10 ml) and ethanol (20 ml) were stirred at 95 ° C for 1 hour. The reaction solution was allowed to cool to room temperature and partitioned into water and ethyl acetate. The ethyl acetate layer was washed once with water and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (heptane: ethyl acetate = 1: 2) to obtain the title compound (2.3 g, 78.0%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.52 (2H, br s), 6.57 (1H, dd, J = 7.2, 4.8 Hz), 7 10-7.16 (6H, m), 7.28-7.38 (9H, m), 7.42 (1H, d, J = 7.2 Hz), 7.66 (1H, s), 7.84 (1H, d, J = 4.8 Hz); 7.92 (1H, s).

[Production Example 32-1-4] 3- (1 H -pyrazol-4-yl) -pyridin-2-ylamine

3- (1-Trityl-1 H -pyrazol-4-yl) -pyridin-2-ylamine (2.3 g, 5.71 mmol) described in Production Example 32-1-3, 2H hydrochloric acid (15 ml ), methanol (15 ml) and tetrahydrofuran (10 ml) were stirred at 70 ° C for 30 minutes. The reaction solution was allowed to cool to room temperature and partitioned into water and ethyl acetate. Saturated sodium bicarbonate was added to the separated aqueous layer, and then extracted with ethyl acetate 6 times. The ethyl acetate layers were combined and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate, then with ethyl acetate: methanol = 10: 1) to obtain the title compound (625 mg, 68.3%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.59 (2H, br s), 6.62 (1H, dd, J = 4.8, 7.6 Hz), 7 49 (1H, d, J = 7.2 Hz), 7.88 (1H, d, J = 4.8 Hz), 7.72-8.15 (2H, br.s), 12.9 ( 1H, broad s).

[Example 33] 3- (1- (4-Butoxymethyl-benzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine

To a mixture of 3- (1 H- pyrazol-4-yl) -pyridin-2-ylamine (20 mg, 0.13 mmol) described in Production Example 32-1-4 and N, N-dimethylformamide (1 ml) was added sodium hydride (6.8 mg, 0.19 mmol, 66% in oil) and stirred at room temperature for 30 minutes. To the reaction mixture at room temperature was added 1-butoxymethyl-4-chloromethylbenzene (29 mg, 0.14 mmol), described in Production Example 33-1-4, and was stirred at 40 ° C. for 1.5 hours. The reaction mixture was cooled and partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent 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 (33 mg, 78%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.92 (3H, t, J = 7.4 Hz), 1.35-1.44 (2H, m), 1.56-1 , 62 (2H, m), 3.48 (2H, t, J = 6.6 Hz), 4.49 (2H, s), 4.61 (2H, br.s), 5.34 (2H, c), 6.70 (1H, dd, J = 5.0, 7.4 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8 , 1 Hz), 7.39 (1H, dd, J = 1.8, 7.3 Hz), 7.58 (1H, s), 7.73 (1H, d, J = 0.7 Hz), 8.00 (1H, dd, J = 1.8, 5.1 Hz).

The starting material, 1-butoxymethyl-4-chloromethylbenzene, was synthesized as follows.

[Production Example 33-1-1] 4-butoxymethyl-benzonitrile

To a mixture of sodium hydride (270 mg, 11 mmol, 66% in oil) and tetrahydrofuran (20 ml) was added n- butanol (1.1 ml, 12 mmol) at 0 ° C and 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, 7.4 mmol) and tetrahydrofuran (10 ml) was added dropwise at the same temperature. The reaction mixture was stirred at room temperature for 3 hours and N, N-dimethylformamide (10 ml) was added to the reaction mixture and stirred at the same temperature for another 4.5 hours. The reaction mixture was separated into water and diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent 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, 84%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.93 (3H, t, J = 7.3 Hz), 1.37-1.46 (2H, m), 1.59-1 66 (2H, m), 3.50 (2H, t, J = 6.6 Hz), 4.55 (2H, s), 7.43-7.46 (2H, m), 7.62- 7.65 (2H, m).

[Production Example 33-1-2] 4-butoxymethylbenzylamine

To a mixture of lithium aluminum hydride (600 mg, 13 mmol, purity: 80%) and tetrahydrofuran (10 ml) at 0 ° C was added a mixture of 4-butoxymethylbenzonitrile (600 mg, 3.2 mmol) as described in Example 33-1- 1 receipt, and tetrahydrofuran (10 ml) and was stirred at room temperature for 4 hours. A 28% aqueous ammonia solution was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was warmed to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (620 mg, 101%) as a crude product.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.92 (3H, t, J = 7.3 Hz), 1.37-1.44 (2H, m), 1.56-1 , 63 (2H, m), 3.47 (2H, t, J = 6.6 Hz), 3.86 (2H, s), 4.49 (2H, s), 7.27-7.32 ( 4H, m).

[Production Example 33-1-3] (4-butoxymethylphenyl) methanol

To a mixture of 4-butoxymethylbenzylamine (250 mg, 1.3 mmol) described in Production Example 33-1-2, acetic acid (2 ml) and water (2 ml) was added sodium nitrite (1.1 g, 16 mM) and stirred at room temperature for 40 minutes. The reaction mixture was partitioned into ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and the solvent was evaporated under reduced pressure. Methanol (2 ml) and potassium carbonate (360 mg, 2.6 mmol) were added to the residue, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated 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, 78%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.92 (3H, t, J = 7.3 Hz), 1.35-1.44 (2H, m), 1.57-1 64 (2H, m), 3.47 (2H, t, J = 6.6 Hz), 4.50 (2H, s), 4.69 (2H, s), 7.34 (4H, s) .

[Production Example 33-1-4] 1-butoxymethyl-4-chloromethyl-benzene

A mixture of (4-butoxymethylphenyl) methanol (190 mg, 0.98 mmol) described in Production Example 33-1-3, triphenylphosphine (310 mg, 1.2 mmol) and carbon tetrachloride (3 ml) was stirred in a flask with reverse refrigerator for 7 hours. The reaction mixture was cooled to room temperature and concentrated 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, 86%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.92 (3H, t, J = 7.3 Hz), 1.35-1.45 (2H, m), 1.57-1 64 (2H, m), 3.47 (2H, t, J = 6.6 Hz), 4.50 (2H, s), 4.59 (2H, s), 7.32-7.38 ( 4H, m).

[Example 34] 3- (1- (4-Phenoxybenzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2-ylamine (20 mg, 0.13 mmol) described in Production Example 32-1-4 in N, N-dimethylformamide (10 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (7.5 mg, 0.19 mm, 60% in oil) and stirred at room temperature for 30 minutes. Then, 1-chloromethyl-4-phenoxybenzene (32.8 mg, 0.15 mmol), described in Production Example 34-1-1, was added to the mixture, and stirred at room temperature for 30 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1, then only ethyl acetate) to obtain the title compound (41 mg, 86%, purity: 90%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.33 (2H, s), 5.60 (2H, br s), 6.61 (1H, dd, J = 4, 8, 7.4 Hz), 6.98-7.01 (2H, m), 7.12-7.16 (1H, m), 7.34-7.40 (2H, m), 7.48 -7.65 (5H, m), 7.77 (1H, s), 7.87 (1H, dd, J = 1.2, 5.0 Hz), 8.18 (1H, s).

The starting material, 1-chloromethyl-4-phenoxybenzene, was synthesized as follows.

[Production Example 34-1-1] 1-chloromethyl-4-phenoxybenzene

Triphenylphosphine (642 mg, 2.45 mmol) was added to a solution of (4-phenoxyphenyl) methanol (408 mg, 2.04 mmol) in carbon tetrachloride (8.2 ml) at room temperature under a nitrogen atmosphere, the reaction solution was stirred in a flask with reflux for 7 hours and 40 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1) to obtain the title compound (409 mg, 92%).

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 35] 3- (1- (3-Phenoxybenzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2-ylamine (20 mg, 0.13 mmol) described in Production Example 32-1-4 in N, N-dimethylformamide (10 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (7.5 mg, 0.19 mm, 60% in oil) and stirred at room temperature for 40 minutes. Then 1-chloromethyl-3-phenoxybenzene (32.8 mg, 0.15 mmol) was added, as described in Production Example 35-1-1, and was stirred at room temperature for 30 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1, then only ethyl acetate) to obtain the title compound (20 mg, 47%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.35 (2H, s), 5.59 (2H, br s), 6.62 (1H, dd, J = 1, 2, 7.4 Hz), 6.90-6.95 (2H, m), 6.99-7.06 (3H, m), 7.13-7.17 (1H, m), 7.34 -7.41 (3H, m), 7.48 (1H, dd, J = 2.0, 7.4 Hz), 7.70 (1H, d, J = 0.8 Hz), 7.87 ( 1H, dd, J = 2.0, 5.0 Hz), 8.18 (1H, d, J = 0.8 Hz).

The starting material, 1-chloromethyl-3-phenoxybenzene, was synthesized as follows.

[Production Example 35-1-1] 1-chloromethyl-3-phenoxybenzene

Triphenylphosphine (3.15 g, 12.0 mmol) was added to a solution of (3-phenoxyphenyl) methanol (2.00 g, 10.0 mmol) in carbon tetrachloride (40 ml) at room temperature. The reaction solution was stirred under nitrogen for 5 hours 40 minutes in a flask under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1) to obtain the title compound (2.05 g, 94%).

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 36] 3- (1- (4-Benzyloxybenzyl) -1 H -pyrazol-4-yl) pyridin-2,6-diamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2,6-diamine (25 mg, 0.14 mmol) described in Production Example 36-1-2 in N, N-dimethylformamide (10 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (8.6 mg, 0.22 mmol, 60% in oil) and stirred at room temperature for 30 minutes. Then 4-benzyloxybenzyl chloride (49.9 mg, 0.22 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1, then ethyl acetate only) to obtain the title compound (24.0 mg, 45%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.06 (2H, br s), 5.09 (2H, s), 5.21 (2H, s), 5.43 (2H, br.s), 5.77 (1H, d, J = 8.0 Hz), 6.97-7.00 (2H, m), 7.15 (1H, d, J = 8.0 Hz), 7.23-7.26 (2H, m), 7.30-7.34 (1H, m), 7.36-7.44 (4H, m), 7.56 (1H, d, J = 1.2 Hz), 7.90 (1H, d, J = 1.2 Hz).

The starting material, 3- (1 H -pyrazol-4-yl) -pyridin-2,6-diamine, was synthesized as follows.

[Production Example 36-1-1] 3- (1-trityl-1 H -pyrazol-4-yl) -pyridin-2,6-diamine

Ethanol (to a solution of 3-iodopyridin-2,6-diamine (3.3 g, 7.74 mmol, purity: 70%) described in Production Example 13-1-1 was added in toluene (50 ml) under nitrogen atmosphere ( 25 ml), 2N aqueous sodium carbonate solution (12.5 ml), 4- (4,4,5,5-tetramethyl- (1,3,2) dioxaborolan-2-yl) -1-trityl-1 H - pyrazole (3.3 g, 7.56 mmol) described in Production Example 32-1-2 and tetrakis (triphenylphosphine) palladium (0) (1.02 g, 0.88 mmol) and stirred at 95 ° C. within 2.5 hours. Water and ethyl acetate were added to the reaction mixture at room temperature, and then filtered through a pad of celite; the filtrate was separated into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 2, then 2: 1, then 5: 1) to obtain the title compound (2.4 g, 73%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.63 (2H, br s), 4.79 (2H, br s), 5.90 (1H, d, J = 8, 0 Hz), 7.16-7.20 (6H, m), 7.29-7.32 (10H, m), 7.45 (1H, s), 7.77 (1H, s).

[Production Example 36-1-2] 3- (1 H -pyrazol-4-yl) -pyridin-2,6-diamine

To a solution of 3- (1-trityl-1 H- pyrazol-4-yl) -pyridin-2,6-diamine (10.0 g, 25.7 mmol) described in Production Example 36-1-1 in methylene chloride (14 ml) under a nitrogen atmosphere was added trifluoroacetic acid (7 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate, then ethyl acetate: methanol = 10: 1) to obtain the title compound (600 mg, 60%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.04 (2H, br s), 5.41 (2H, br s), 5.78 (1H, d, J = 8.4 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.62 (1H, br.s), 7.78 (1H, br.s), 12.8 (1H, ears.s).

[Example 37] 3- (1- (4- (Pyridin-2-yloxymethyl) benzyl) -1 H -pyrazol-4-yl) pyridin-2,6-diamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2,6-diamine (25 mg, 0.14 mmol) described in Production Example 36-1-2 in N, N-dimethylformamide (3 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (8.6 mg, 0.22 mm, 60% in oil). After stirring at room temperature for 30 minutes, 2- (4-chloromethyl-benzyloxy) -pyridine (43.4 mg, 0.19 mmol), described in Production Example 30-1-1, was added and stirred at 60 ° C. within 30 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1, then ethyl acetate only) to obtain the title compound (22.8 mg, 43%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.07 (2H, br s), 5.30 (2H, s), 5.32 (2H, s), 5.43 (2H, br.s), 5.78 (1H, d, J = 8.0 Hz), 6.84-6.86 (1H, m), 6.96-7.00 (1H, m), 7.16 (1H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 7.6 Hz), 7, 58 (1H, s), 7.69-7.73 (1H, m), 7.94 (1H, s), 8.15-8.17 (1H, m).

[Example 38] 3- (1- (4-Butoxymethyl-benzyl) -1 H -pyrazol-4-yl) -pyridin-2,6-diamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2,6-diamine (20 mg, 0.11 mmol) described in Production Example 36-1-2 in N, N-dimethylformamide (4 ml) in an ice bath (0 ° C) in an atmosphere of nitrogen was added sodium hydride (5.9 mg, 0.15 mm, 60% in oil). After stirring at room temperature for 30 minutes, 1-butoxymethyl-4-chloromethylbenzene (26.7 mg, 0.13 mmol) was added, as described in Production Example 33-1-4, and was stirred at room temperature for 30 minutes. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1, then ethyl acetate) to obtain the title compound (29.0 mg, 72%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.864 (3H, d, J = 7.6 Hz), 1.30-1.35 (2H, m), 1.47-1 , 54 (2H, m), 3.40 (2H, d, J = 6.4 Hz), 4.42 (2H, s), 5.07 (2H, br.s), 5.29 (2H, c), 5.43 (2H, br.s), 5.78 (1H, d, J = 8.4 Hz), 7.16 (1H, t, J = 8.0 Hz), 7.24- 7.29 (4H, m), 7.58 (1H, s), 7.93 (1H, s).

[Example 39] 3- (4- (4-Benzyloxybenzyl) -pyrazol-1-yl) -pyridin-2-ylamine

To the mixture of 3- (4-bromo-pyrazol-1-yl) -pyridin-2-ylamine (34 mg, 0.14 mmol) described in Production Example 39-1-4, (4-benzyloxybenzyl) tributyltin (84 mg, 0.17 mmol) described in Production Example 39-2-1, and N-methylpyrrolidone (1.5 ml) at room temperature were added tri- o- tolylphosphine (17 mg, 0.057 mmol) and palladium (II) acetate (3.2 mg, 0.014 mmol) and stirred at 120 ° C for 5 hours. The reaction mixture was cooled to room temperature and filtered after adding an aqueous solution of potassium fluoride and ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to give the title compound (2.6 mg, 4%) as a trifluoroacetic acid salt.

MS m / e (ESI) 357.18 (MH ⁺ )

The starting material, 3- (4-bromopyrazol-1-yl) -pyridin-2-ylamine, was synthesized as follows.

[Production Example 39-1-1] 2,2-Dimethyl-N-pyridin-2-yl-propionamide

To a solution of 2-aminopyridine (50.0 g, 531 mmol) in methylene chloride (500 ml) at 0 ° C, triethylamine (81.4 ml, 584 mmol) and pivaloyl chloride (71.9 ml, 584 mmol) were added and stirred at room temperature for 4 hours 30 minutes. The reaction solution was separated into water and methylene chloride. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in methanol (300 ml) at 0 ° C was added potassium carbonate (73.4 g, 531 mmol) and stirred at room temperature for 90 minutes. The reaction solution at room temperature was partitioned into water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate; the solvent was evaporated under reduced pressure. Heptane (300 ml) was added to the residue, and the precipitated solid was filtered to obtain the title compound (80.2 g, 85%). The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (12.2 g, 13%).

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 39-1-2] N- (3-iodo-pyridin-2-yl) -2,2-dimethyl-propionamide

To the mixture of 2,2-dimethyl-N-pyridin-2-yl-propionamide (3.0 g, 17 mmol) described in Production Example 39-1-1, N, N, N ', N'-tetramethylethylenediamine (6 , 3 ml, 42 mmol) and tetrahydrofuran (60 ml) at -78 ° C, n- butyllithium (1.6 M n-hexane solution, 30 ml, 47 mmol) was added dropwise and stirred at 0 ° C overnight. Iodine (6.8 g, 27 mmol) was added to the reaction mixture at -78 ° C and stirred at 0 ° C for 1.5 hours. Water and an aqueous sodium thiosulfate solution were added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated 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, 57%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.38 (9H, s), 6.85 (1H, dd, J = 4.8, 7.9 Hz), 7.94 (1H , br.s), 8.11 (1H, dd, J = 1.7, 7.9 Hz), 8.46 (1H, dd, J = 1.7, 4.6 Hz).

[Production Example 39-1-3] N- (3- (4-bromopyrazol-1-yl) -pyridin-2-yl) -2,2-dimethylpropionamide

To the mixture of N- (3-iodopyridin-2-yl) -2,2-dimethylpropionamide (380 mg, 1.2 mmol) described in Production Example 39-1-2 and toluene (10 ml) was added at room temperature 4 β-bromopyrazole (160 mg, 1.1 mmol), copper (I) iodide (11 mg, 0.056 mmol), trans-1,2-cyclohexanediamine (26 mg, 0.22 mmol) and potassium carbonate (340 mg, 2 5 mM), then stirred at 110 ° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1) to obtain the title compound (190 mg, 52%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.10 (9H, s), 7.45 (1H, dd, J = 4.8, 8.1 Hz), 7.84 (1H, s), 8.00 (1H, dd, J = 1.7, 7.9 Hz), 8.23 (1H, s), 8.47 (1H, dd, J = 1.7, 4 8 Hz), 9.83 (1H, br s).

[Production Example 39-1-4] 3- (4-bromo-pyrazol-1-yl) -pyridin-2-ylamine

A mixture of N- (3- (4-bromopyrazol-1-yl) -pyridin-2-yl) -2,2-dimethylpropionamide (380 mg, 1.2 mmol) described in Production Example 39-1-3 and aqueous a solution of 2.5 N hydrochloric acid (2 ml) was stirred at 105 ° C. overnight. The reaction mixture was cooled to 0 ° C. and 5N sodium hydroxide solution (1 ml) was added. The resulting solid was filtered to give the title compound (100 mg, 72%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 6.34 (2H, br s), 6.69 (1H, dd, J = 4.8, 7.7 Hz), 7 62 (1H, dd, J = 1.7, 7.7 Hz), 7.90 (1H, s), 8.02 (1H, dd, J = 1.7, 4.8 Hz), 8, 45 (1H, s).

The starting material, (4-benzyloxybenzyl) tributyltin, was synthesized as follows.

[Production Example 39-2-1] (4-Benzyloxybenzyl) -tributyltin

To a mixture of diisopropylamine (1.1 ml, 7.7 mmol) and tetrahydrofuran (20 ml), n- butyllithium (1.6 M n- hexane solution, 4.5 ml, 7.1 mmol) was added dropwise at -78 ° C. ) and stirred at the same temperature for 30 minutes. Tributyltin hydride (1.7 ml, 6.5 mmol) was added dropwise to the reaction mixture at the same temperature, and then stirred at 0 ° C for 30 minutes. The reaction mixture was cooled to −78 ° C. and a mixture of 4-benzyloxybenzyl chloride (1.5 g, 6.5 mmol) and tetrahydrofuran (10 ml) was added dropwise at the same temperature. The reaction mixture was gradually warmed to room temperature. The reaction mixture was partitioned into water and n- heptane. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 30) to obtain the title compound (2.6 g, 83%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.77-0.81 (6H, m), 0.86 (9H, t, J = 7.3 Hz), 1.21-1 30 (6H, m), 1.38-1.46 (6H, m), 2.24 (2H, s), 5.01 (2H, s), 6.80-6.83 (2H, m ), 6.88-6.91 (2H, m), 7.29-7.44 (5H, m).

[Example 40] 3- (3- (6-Phenoxypyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (2-phenoxypyridin-5-yl) -acetohydroximoyl chloride (59.1 mg, 225 μM) described in Production Example 40-1-4, and 3-ethynylpyridin-2,6-diamine (20.0 mg, 150 μM) described in Production Example 13-1-3, triethylamine (41.8 μl, 300 μM) was added in tetrahydrofuran (1.3 ml) at room temperature and stirred at 50 ° C. for 65 minutes. The reaction solution was allowed to cool to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (52 mg, 97%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.93 (2H, s), 5.79 (2H, s), 5.81 (1H, d, J = 8.4 Hz ), 6.10 (2H, s), 6.40 (1H, s), 6.97 (1H, d, J = 8.4 Hz), 7.08-7.10 (2H, m), 7 , 16-7.20 (1H, m), 7.37-7.41 (2H, m), 7.50 (1H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 2.2, 8.4 Hz), 8.11 (1H, d, J = 2.4 Hz).

The starting material, (2-phenoxypyridin-5-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 40-1-1] 5-bromo-2-phenoxypyridine

To a solution of phenol (1.97 g, 20.9 mmol) in N, N-dimethylformamide (100 ml) at 0 ° C was added sodium hydride (1.00 g, 20.9 mmol) and stirred at 0 ° C for 5 minutes. Then, 2,5-dibromopyridine (4.50 g, 19.0 mmol) was added to this reaction solution at 0 ° C and stirred at room temperature for 40 minutes. Then this reaction solution was stirred at 120 ° C for another 3 hours. After cooling to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 6: 1) to obtain the title compound (3.85 g, 81%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.02 (1H, dd, J = 0.55, 8.8 Hz), 7.11-7.14 (2H, m) , 7.19-7.23 (1H, m), 7.38-7.43 (2H, m), 8.04 (1H, dd, J = 2.6, 8.8 Hz), 8.25 (1H, dd, J = 0.55, 2.6 Hz).

[Production Example 40-1-2] 6-Phenoxypyridin-3-carbaldehyde

To a solution of 5-bromo-2-phenoxypyridine (3.85 g, 15.4 mmol) described in Production Example 40-1-1 in tetrahydrofuran (60 ml) at -78 ° C under nitrogen atmosphere was added n- butyllithium ( 10.6 ml, 1.60 M hexane solution, 16.9 mmol) and stirred at -78 ° C for 35 minutes. Then, N, N-dimethylformamide (1.55 ml, 20.0 mmol) was added to this reaction solution at -78 ° C and stirred at room temperature for another 10 minutes. After cooling to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain the title compound (1.12 g, 37%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.04 (1H, d, J = 8.6 Hz), 7.17 (2H, d, J = 7.5 Hz), 7, 26-7.31 (1H, m), 7.44-7.48 (2H, m), 8.19 (1H, dd, J = 2.2, 8.6 Hz), 8.63 (1H, d, J = 2.2 Hz), 9.99 (1H, s).

[Production Example 40-1-3] 5- (2-nitroethyl) -2-phenoxypyridine

To a solution of 6-phenoxypyridin-3-carbaldehyde (1.12 g, 5.62 mmol), described in Production Example 40-1-2, in acetic acid (10 ml) under nitrogen atmosphere was added nitromethane (1.52 ml, 28 , 1 mmol) and ammonium acetate (866 mg, 11.2 mmol) and was stirred at 100 ° C for 3 hours. After cooling to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dimethyl sulfoxide (17 ml) and acetic acid (3 ml). Sodium borohydride (336 mg, 8.43 mmol) was added to this appropriately cooled solution at room temperature and stirred at room temperature for 30 minutes. The reaction solution was separated by adding sodium bicarbonate to water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (753 mg, 55%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.28 (2H, t, J = 7.1 Hz), 4.60 (2H, t, J = 7.1 Hz), 6, 88 (1H, d, J = 8.8 Hz), 7.11-7.14 (2H, m), 7.20-7.24 (1H, m), 7.39-7.43 (2H, m), 7.55 (1H, ddd, J = 0.37, 2.6, 8.4 Hz), 8.07 (1H, d, J = 2.4 Hz).

[Production Example 40-1-4] (2-Phoenosxypyridin-5-yl) -acetohydroximoyl chloride

To a solution of 5- (2-nitroethyl) -2-phenoxypyridine (753 mg, 3.08 mmol) described in Production Example 40-1-3, in methanol (10 ml) lithium methoxide (234 mg, 6.16 mmol) was added. ) and stirred at room temperature for 90 minutes. The reaction solution was concentrated under reduced pressure. The resulting residue was suspended in a solution of a mixture of tetrahydrofuran (10 ml) and methylene chloride (10 ml). Titanium (IV) chloride (745 μl, 6.87 mmol) was added to the suspension at -78 ° C in a nitrogen atmosphere and stirred at 0 ° C for 140 minutes. The reaction solution at 0 ° C was partitioned into water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (785 mg, 97%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.81 (2H, s), 6.99 (1H, dd, J = 0.73, 8.4 Hz), 7.09 -7.12 (2H, m), 7.17-7.21 (1H, m), 7.38-7.42 (2H, m), 7.72 (1H, dd, J = 2.6, 8.4 Hz), 8.03 (1H, dd, J = 0.55, 2.6 Hz), 11.8 (1H, s).

[Example 41] 3- (3- (4- (5-Fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (10 ml) and a 5N aqueous sodium hydroxide solution (448 μl, 2.24 mmol) were added to 4- (5- (2-aminopyridin-3-yl) -isoxazol-3-ylmethyl) -phenol (600 mg, 2 , 24 mmol) described in Production Example 5-1-1, and subjected to ultrasonic treatment for 1 minute. The reaction solution was then concentrated under reduced pressure to obtain a white solid. To the white solid obtained, 2-chloromethyl-5-fluoropyridine (359 mg, 2.46 M) described in Production Example 41-2 was added, and N, N-dimethylformamide (10 ml) was stirred at 60 ° C. for 1 hour After cooling to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (650 mg, 77%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.96 (2H, s), 5.15 (2H, s), 6.25 (2H, br s), 6.69 (1H, dd, J = 4.8, 8.0 Hz), 6.79 (1H, s), 6.99 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.59 (1H, dd, J = 4.8, 8.8 Hz), 7.76 (1H, ddd, J = 2.8, 8.8, 8.8 Hz ), 7.86 (1H, dd, J = 2.0, 7.6 Hz), 8.08 (1H, dd, J = 2.0, 4.8 Hz), 8.57 (1H, d, J = 3.2 Hz).

2-Chloromethyl-5-fluoropyridine was synthesized as follows.

[Production Example 41-1-1] (5-fluoropyridin-2-yl) -methanol

To a solution of 2-bromo-5-fluoropyridine (3.67 g, 20.8 mmol) in toluene (100 ml) at -78 ° C under nitrogen atmosphere was added dropwise n- butyllithium (15.6 ml, 1.6 M hexane solution, 25.0 mmol) and stirred for 30 minutes. N, N-dimethylformamide (8.05 ml, 104.0 mmol) was added dropwise to this solution at -78 ° C and stirred at 0 ° C for 20 minutes. After adding water and tetrahydrofuran, this reaction mixture was vigorously stirred. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Sodium borohydride (1.58 g, 41.8 mmol) was added to the filtrate at 0 ° C and stirred at room temperature for 1 hour. This reaction solution was separated by adding water and tetrahydrofuran. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (hexane: diethyl ether = 1: 2) to obtain the title compound (945 mg, 36%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.75 (2H, s), 7.29 (1H, dd, J = 4.4, 8.8 Hz), 7.43 (1H , ddd, J = 2.8, 8.4, 8.4 Hz), 8.42 (1H, d, J = 2.8 Hz).

[Production Example 41-1-2] 2-chloromethyl-5-fluoropyridine

To a solution of (5-fluoropyridin-2-yl) methanol (945 mg, 7.43 mmol) described in Production Example 41-1-1, in methylene chloride (70 ml), thionyl chloride (813 μl) was added dropwise at room temperature. , 11.1 mmol) and stirred for 30 minutes. This reaction solution was separated by adding water, sodium bicarbonate and methylene chloride. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane: diethyl ether = 1: 1) to obtain the title compound (761.1 mg, 70%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.67 (2H, s), 7.26-7.51 (2H, m), 8.43 (1H, d, J = 2, 8 Hz).

[Example 42] 3- (3- (4- (5-Methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To obtain the title compound (23 mg, 33%) according to methods similar to the methods of example 10, 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (50 mg, 0, 19 mM) described in Production Example 5-1-1 and 2-chloromethyl-5-methylpyridine (32 mg, 0.23 mmol) described in Production Example 42-1-2.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.29 (3H, s), 3.95 (2H, s), 5.11 (2H, s), 6.25 (2H , br.s), 6.69 (1H, dd, J = 4.8, 8.0 Hz), 6.79 (1H, s), 6.97 (2H, d, J = 8.4 Hz) , 7.24 (2H, d, J = 8.4 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.62 (1H, d, J = 8.0 Hz), 7 86 (1H, dd, J = 1.6, 8.0 Hz), 8.08 (1H, dd, J = 1.6, 4.8 Hz), 8.40 (1H, s).

The starting material, 2-chloromethyl-5-methylpyridine, was synthesized as follows.

[Production Example 42-1-1] (5-Methylpyridin-2-yl) -methanol

The title compound (1.1 g) was obtained according to the method described in Production Examples 11-1-1 to 11-1-3.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.27 (3H, s), 4.45 (2H, d, J = 5.6 Hz), 5.31 (1H, t , J = 5.6 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.59 (1H, dd, J = 1.6, 8.0 Hz), 8.31 (1H , d, J = 1.6 Hz).

[Production Example 42-1-2] 2-Chloromethyl-5-methylpyridine

A solution of a mixture of (5-methylpyridin-2-yl) methanol (500 mg, 4.1 mmol) described in Production Example 11-1-1, thionyl chloride (0.59 ml, 8.1 mmol) and methylene chloride (10 ml ) was stirred in a flask under reflux for 5 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was partitioned into diethyl ether and saturated sodium bicarbonate solution. The organic layer was separated and passed through a glass filter lined with silica gel (eluted with ethyl acetate). The eluate was concentrated to give the title compound (440 mg, 76%) as a crude product. The resulting compound was used in the subsequent reaction without further purification.

[Example 43] 3- (3- (4- (4-Methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4- (4-methylpyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride (270 mg, 0.930 mmol) described in Production Example 43-1-5, and 3-ethynylpyridin-2-ylamine (40.0 mg , 0.339 mM) described in Production Example 1-2-3, triethylamine (189 μl, 1.36 mmol) was added in tetrahydrofuran (7.00 ml) at room temperature and stirred at room temperature for 4 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 2) to obtain the title compound (28.9 mg, 20.6%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.26 (3H, s), 4.03 (2H, s), 5.30 (2H, s), 6.25 (2H , br.s), 6.68-6.70 (2H, m), 6.80 (1H, s), 6.81-6.82 (1H, m), 7.32 (2H, d, J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.86-7.88 (1H, m), 8.00-8.02 (1H, m), 8 08-8.09 (1H, m).

The starting material, (4- (4-methylpyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 43-1-1] 2- (4-bromobenzyloxy) -4-methylpyridine

Sodium hydride (1.00 g, 25.0 mmol) was added to a mixture of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) and N, N-dimethylformamide (50.0 ml) at 0 ° C under nitrogen atmosphere. 60% in oil) and stirred at room temperature for 50 minutes. Then, 2-fluoro-4-methylpyridine (1.80 g, 16.2 mmol) was added to it at 0 ° C and stirred at room temperature for 2 hours 30 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 15) to obtain the title compound (2.65 g, 58.8%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.28 (3H, s), 5.31 (2H, s), 6.60-6.61 (1H, m), 6.69 -6.71 (1H, m), 7.29-7.32 (2H, m), 7.46-7.48 (2H, m), 8.00-8.01 (1H, m).

[Production Example 43-1-2] 4- (4-methylpyridin-2-yloxymethyl) benzaldehyde

To a solution of 2- (4-bromobenzyloxy) -4-methylpyridine (5.70 g, 20.5 mmol) described in Production Example 43-1-1 in tetrahydrofuran (150 ml) in a bath with a mixture of dry ice-ethanol ( -78 ° C) n- butyllithium (2.67 M n- hexane solution, 9.21 ml, 24.6 mmol) was added dropwise under a nitrogen atmosphere and stirred at -78 ° C for 20 minutes. Then, N, N-dimethylformamide (3.16 ml, 41.0 mmol) was added dropwise thereto and stirred at -78 ° C for 10 minutes. The reaction solution was allowed to cool to room temperature, water was added, and then the solution was extracted with ethyl acetate. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (2.58 g, 55.4%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.31 (3H, s), 5.45 (2H, s), 6.66-6.67 (1H, m), 6.72 -6.74 (1H, m), 7.58-7.60 (2H, m), 7.85-7.88 (2H, m), 8.00-8.01 (1H, m), 10 , 0 (1H, s).

[Production Example 43-1-3] 4-methyl-2- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine

To a solution of 4- (4-methylpyridin-2-yloxymethyl) benzaldehyde (2.60 g, 11.5 mmol) described in Production Example 43-1-2 in acetic acid (20.0 ml) at room temperature in Nitromethane (3.50 g, 57.3 mmol) and ammonium acetate (1.76 g, 22.9 mmol) were added under nitrogen atmosphere and stirred at 100 ° C for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.40 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.28 (3H, s), 5.39 (2H, s), 6.75 (1H, m), 6.84-6 85 (1H, m), 7.50-7.53 (2H, m), 7.85-7.87 (2H, m), 8.00-8.02 (1H, m), 8.13 (1H, d, J = 13.6 Hz), 8.23 (1H, d, J = 13.6 Hz).

[Production Example 43-1-4] 4-methyl-2- (4- (2-nitroethyl) benzyloxy) pyridine

In a suitably cooled solution of 4-methyl-2- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine (3.10 g, 11.5 mmol) described in Production Example 43-1-3, and acetic acid (3.10 ml) in dimethyl sulfoxide (50 ml) was added sodium borohydride (733 mg, 18.4 mmol) at room temperature under nitrogen atmosphere, and was stirred for 10 minutes. Then, water was added dropwise into the appropriately cooled reaction solution at room temperature, and the reaction mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5 then 1: 2) to obtain the title compound (1.10 g, 35.1%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.27 (3H, s), 3.22 (2H, t, J = 6.8 Hz), 4.84 (2H, t , J = 6.8 Hz), 5.29 (2H, s), 6.69 (1H, s), 6.82 (1H, d, J = 5.2 Hz), 7.27 (2H, d , J = 8.0 Hz), 7.37 (2H, d, J = 8.0 Hz), 8.02 (1H, d, J = 5.2 Hz).

[Production Example 43-1-5] (4- (4-methylpyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride

To a solution of 4-methyl-2- (4- (2-nitroethyl) benzyloxy) pyridine (500 mg, 1.84 mmol), described in Production Example 43-1-4, in methanol (10.0 ml) at room temperature lithium methoxide (140 mg, 3.68 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (10.0 ml) and anhydrous tetrahydrofuran (5.00 ml) were added to the residue. Titanium (IV) chloride (667 μl, 6.07 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at 0 ° C for 45 minutes and then at room temperature in for 60 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (409 mg, 76.5%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.27 (3H, s), 3.82 (2H, s), 5.31 (2H, s), 6.70 (1H , c), 6.82-6.84 (1H, m), 7.24-7.28 (2H, m), 7.39-7.41 (2H, m), 8.01-8.03 (1H, m), 11.73 (1H, s).

[Example 44] 3- (3- (4- (5-Methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4- (5-methylpyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (246 mg, 0.846 mmol) described in Production Example 44-1-5, and 3-ethynylpyridin-2-ylamine (40.0 mg , 0.339 mM) described in Production Example 1-2-3, triethylamine (189 μl, 1.36 mmol) was added in tetrahydrofuran (7.00 ml) at room temperature and stirred at room temperature for 4 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 2) to obtain the title compound (21.3 mg, 16.9%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.20 (3H, s), 4.03 (2H, s), 5.28 (2H, s), 6.25 (2H , br.s), 6.68-6.71 (1H, m), 6.75-6.77 (1H, m), 6.81 (1H, s), 7.32 (2H, d, J = 8.0 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.52-7.55 (1H, m), 7.85-7.88 (1H, m), 7 96-7.97 (1H, m); 8.08-8.09 (1H, m).

The starting material, (4- (5-methylpyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 44-1-1] 2- (4-bromobenzyloxy) -5-methylpyridine

Sodium hydride (1.00 g, 25.0 mmol) was added to a solution of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) in N, N-dimethylformamide (50.0 ml) at 0 ° C under nitrogen atmosphere. 60% in oil) and stirred at room temperature for 30 minutes. Then, 2-fluoro-5-methylpyridine (1.80 g, 16.2 mmol) was added at 0 ° C and stirred at room temperature for 5 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 15) to obtain the title compound (2.67 g, 59.3%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.24 (3H, s), 5.30 (2H, s), 6.70-6.72 (1H, m), 7.31 -7.33 (2H, m), 7.38-7.41 (1H, m), 7.46-7.49 (2H, m), 7.95-7.96 (1H, m).

[Production Example 44-1-2] 4- (5-methylpyridin-2-yloxymethyl) benzaldehyde

To a solution of 2- (4-bromobenzyloxy) -5-methylpyridine (5.40 g, 19.4 mmol) described in Production Example 44-1-1 in tetrahydrofuran (150 ml) in a bath with a mixture of dry ice-ethanol ( -78 ° C) n- butyllithium (2.67 M n-hexane solution, 8.73 ml, 23.3 mmol) was added dropwise under a nitrogen atmosphere and stirred at -78 ° C for 30 minutes. Then, N, N-dimethylformamide (2.99 ml, 38.8 mmol) was added dropwise thereto and stirred at -78 ° C for 10 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 6 then 1: 4) to obtain the title compound (2.93 g, 66.5%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.21 (3H, s), 5.41 (2H, s), 6.72-6.74 (1H, m), 7.38 -7.41 (1H, m), 7.56-7.58 (2H, m), 7.83-7.85 (2H, m), 7.92-7.93 (1H, m), 9 97 (1H, s).

[Production Example 44-1-3] 5-methyl-2- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine

To a solution of 4- (5-methylpyridin-2-yloxymethyl) benzaldehyde (2.93 g, 12.9 mmol) described in Production Example 44-1-2 in acetic acid (20.0 ml) at room temperature in nitromethane (3.94 g, 64.5 mmol) and ammonium acetate (1.99 g, 25.8 mmol) were added under nitrogen atmosphere and stirred at 100 ° C for 2.5 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. Then the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.50 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.21 (3H, s), 5.38 (2H, s), 6.82-6.84 (1H, m), 7 52 (2H, d, J = 8.4 Hz), 7.55-7.58 (1H, m), 7.85 (2H, d, J = 8.4 Hz), 7.96-7, 97 (1H, m), 8.12 (1H, d, J = 13.6 Hz), 8.22 (1H, d, J = 13.6 Hz).

[Production Example 44-1-4] 5-methyl-2- (4- (2-nitroethyl) benzyloxy) pyridine

To a suitably cooled solution of 5-methyl-2- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine (3.50 g, 12.9 mmol) described in Production Example 44-1-3, and acetic acid (3.50 ml) in dimethyl sulfoxide (40.0 ml), sodium borohydride (822 mg, 20.6 mmol) was added at room temperature under nitrogen atmosphere and stirred for 10 minutes. Then, water was added dropwise to a solution cooled appropriately at room temperature. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (1.91 g, 54.3%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.20 (3H, s), 3.22 (2H, t, J = 6.8 Hz), 4.84 (2H, t , J = 6.8 Hz), 5.27 (2H, s), 6.76-6.78 (1H, m), 7.27 (2H, d, J = 8.0 Hz), 7.36 (2H, d, J = 8.0 Hz), 7.52-7.55 (1H, m), 7.97-7.98 (1H, m).

[Production Example 44-1-5] (4- (5-methylpyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride

To a solution of 5-methyl-2- (4- (2-nitroethyl) benzyloxy) pyridine (700 mg, 2.57 mmol) described in Production Example 44-1-4 in methanol (30 ml) at room temperature in lithium methoxide (195 mg, 5.14 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (15.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Then, titanium (IV) chloride (904 μl, 8.22 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C), and then stirred at room temperature for 45 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (569 mg, 76.1%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.02 (3H, s), 3.81 (2H, s), 5.29 (2H, s), 6.77-6 79 (1H, m), 7.25 (2H, d, J = 8.0 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.53-7.55 (1H, m), 7.97-7.98 (1H, m), 11.74 (1H, s).

[Example 45] 3- (3- (4- (6-Fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (3 ml) and a 5N aqueous sodium hydroxide solution (36.0 μl, 0.18 mmol) were added to 4- (5- (2-aminopyridin-3-yl) -isoxazol-3-ylmethyl) -phenol (48, 2 mg, 0.18 mmol) described in Production Example 5-1-1, and dissolved by sonication for 1 minute. Then the reaction mixture was concentrated under reduced pressure to obtain a white solid. This solid and 2-chloromethyl-6-fluoropyridine (63.2 mg, 0.43 mmol) described in Production Example 45-1-1 were added to N, N-dimethylformamide (3 ml) and stirred at room temperature in within 3 hours. This mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (47.9 mg, 59%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.00 (2H, s), 5.12 (2H, s), 5.40 (2H, br s), 6.24 (1H , c), 6.71 (1H, dd, J = 4.8, 7.6 Hz), 6.87 (1H, dd, J = 2.8, 8.4 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.40-7.42 (1H, m), 7.70 (1H, dd, J = 1 6, 7.6 Hz), 7.81 (1H, q, J = 8.0 Hz), 8.13 (1H, dd, J = 1.6, 4.8 Hz)

The starting material, 2-chloromethyl-6-fluoropyridine, was synthesized as follows.

[Production Example 45-1-1] 2-chloromethyl-6-fluoropyridine

A mixture of 2-fluoro-6-methylpyridine (420 mg, 3.78 mmol), N-chlorosuccinimide (757 mg, 5.67 mmol), 75% benzoyl peroxide (24.4 mg, 0.08 mmol), acetic acid (13 μl, 0.23 mmol) and acetonitrile (7 ml) were stirred at 85 ° C for 3 hours 30 minutes. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (370.7 mg, 67%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.75 (2H, s), 7.17-7.19 (1H, m), 7.50-7.52 (1H, m), 8.02-8.08 (1H, m).

[Example 46] 3- (3- (4- (5-Methylfuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a mixture of (4- (5-methylfuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride (11 mg, 0.043 mmol) described in Production Example 46-1-6 and tetrahydrofuran (1 ml) was added 3-ethynylpyridine at room temperature -2-ylamine (4.0 mg, 0.034 mmol) described in Production Example 1-2-3 and triethylamine (9.4 μl, 0.068 mmol) and stirred at 45 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 3) to obtain the title compound (5.1 mg, 41%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.24 (3H, s), 3.90 (2H, s), 4.03 (2H, s), 5.53 (2H, br .c), 5.85 (1H, d, J = 2.9 Hz), 5.87 (1H, d, J = 2.9 Hz), 6.26 (1H, s), 6.72 (1H dd, J = 5.0, 7.6 Hz), 7.21 (4H, s), 7.72 (1H, d, J = 7.7 Hz), 8.12 (1H, dd, J = 1.8, 4.9 Hz).

The starting material, (4- (5-methylfuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 46-1-1] 4- (hydroxy- (5-methylfuran-2-yl) methyl) benzaldehyde

To a mixture of 4-bromobenzaldehyde dimethyl acetal (2.0 ml, 12 mmol) and diethyl ether (30 ml) at -78 ° C was added dropwise n- butyllithium (1.6 M solution of n-hexane, 9.0 ml, 14 mmol) and at the same temperature was stirred for 20 minutes. 5-methylfurfural (1.3 ml, 13 mmol) was added dropwise to the reaction mixture at the same temperature, and stirred at 0 ° C for 50 minutes. Water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 2) to obtain the title compound (320 mg, 12%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.28 (3H, s), 5.86 (1H, s), 5.90-5.91 (1H, m), 5.98 (1H, d, J = 3.1 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = 7.9 Hz), 10.03 (1H , c).

[Production Example 46-1-2] (4- (5-methylfuran-2-ylmethyl) phenyl) methanol

To a mixture of lithium aluminum hydride (230 mg, 4.9 mmol) and tetrahydrofuran (15 ml) was added aluminum chloride (830 mg, 6.2 mmol) at 0 ° C and stirred at room temperature for 30 minutes. A mixture of 4- (hydroxy- (5-methylfuran-2-yl) methyl) benzaldehyde (320 mg, 1.5 mmol) described in Production Example 46-1-1 was added dropwise to this reaction mixture at 0 ° C. and tetrahydrofuran (5 ml) and stirred at the same temperature for 2 hours. To remove excess reagent, a 28% aqueous ammonia solution was added dropwise to the reaction mixture at the same temperature. The reaction mixture was cooled to room temperature and filtered, passing through a pad of celite. The filtrate was concentrated under reduced pressure to obtain the title compound (330 mg) as a crude product. The resulting compound was used in the subsequent reaction without further purification.

[Production Example 46-1-3] 4- (5-methylfuran-2-ylmethyl) benzaldehyde

To the mixture of (4- (5-methylfuran-2-ylmethyl) phenyl) methanol (350 mg, 1.7 mmol) obtained in Production Example 46-1-2 and dichloromethane (10 ml) was added at room temperature manganese (3.5 g, 4.7 mmol) and stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 6) to obtain the title compound (100 mg, 29%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.25 (3H, s), 3.99 (2H, s), 5.876-5.883 (1H, m), 5.92 (1H, d , J = 3.1 Hz), 7.39-7.41 (2H, m), 7.81-7.83 (2H, m), 9.99 (1H, s).

[Production Example 46-1-4] 2-methyl-5- (4 - (( E ) -2-nitrovinyl) benzyl) furan

To the mixture of 4- (5-methylfuran-2-ylmethyl) benzaldehyde (96 mg, 0.48 mmol) described in Production Example 46-1-3 and acetic acid (1 ml) was added nitromethane (190 μl at room temperature) , 3.6 mmol) and ammonium acetate (110 mg, 1.4 mmol) and stirred at 100 ° C for 3 hours. The reaction mixture was cooled to room temperature and extracted with water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain the title compound (120 mg) as a crude product. In the subsequent reaction, the resulting compound was used without further purification.

[Production Example 46-1-5] 2-methyl-5- (4- (2-nitroethyl) benzyl) furan

To a suitably cooled mixture of 2-methyl-5- (4 - (( E ) -2-nitrovinyl) benzyl) furan (120 mg) described in Production Example 46-1-4, acetic acid (0.2 ml ) and dimethyl sulfoxide (3.4 ml) was added sodium borohydride (29 mg, 0.77 mmol) at room temperature and stirred at room temperature for 20 minutes. Water was added to this reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (90 mg, 77%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.24 (3H, s), 3.30 (2H, t, J = 7.4 Hz), 3.89 (2H, s), 4.59 (2H, t, J = 7.4 Hz), 5.85-5.87 (2H, m), 7.14 (2H, d, J = 8.2 Hz), 7.20 (2H , d, J = 8.2 Hz).

[Production Example 46-1-6] (4- (5-methylfuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride

To a mixture of 2-methyl-5- (4- (2-nitroethyl) benzyl) furan (87 mg, 0.36 mmol) described in Production Example 46-1-5 and methanol (2 ml) at room temperature lithium methoxide (27 mg, 0.71 mmol) was added and stirred at room temperature for 15 minutes. The solvent from the reaction mixture was evaporated under reduced pressure. To the mixture of the obtained residue, methylene chloride (2 ml) and tetrahydrofuran (1 ml), titanium (IV) chloride (86 μl, 0.78 mmol) was added at -78 ° C and stirred at 0 ° C for 1 hour. The reaction mixture was cooled to −78 ° C., water (5 ml) was added, and the temperature was gradually raised to room temperature. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water until the pH was about 5. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After that, the organic layer was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (79 mg, 84%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.24 (3H, s), 3.78 (2H, s), 3.90 (2H, s), 5.85-5.87 (2H, m), 7.20 (4H, s).

[Example 47] 3- (3- (4- (2-Methylpyridin-4-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

(2-Methylpyridin-4-yl) methanol (40 mg, 0.33 mmol) described in Production Example 47-1-1, thionyl chloride (0.047 ml, 0.65 mmol) and methylene chloride (4.0 ml) were stirred at 60 ° C for 5 minutes. To separate the reaction solution, sodium bicarbonate solution and ethyl acetate were added, then the ethyl acetate layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloromethyl-2-methylpyridine as a crude product.

To dissolve 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (87 mg, 0.33 mmol) described in Production Example 5-1-1, 2N sodium hydroxide (0 , 16 ml, 0.32 mmol) and methanol (1.0 ml) and methanol was evaporated under reduced pressure. A solution of the above 4-chloromethyl-2-methylpyridine dissolved in dimethylformamide (1 ml) was added to the residue and stirred at 60 ° C for 10 minutes. Water and ethyl acetate were added to separate the reaction solution, the resulting ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 3) to obtain the title compound (47 mg, 39%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.47 (3H, s), 3.96 (2H, s), 5.11 (2H, s), 6.25 (2H , br.s), 6.68 (1H, dd, J = 4.8, 8.0 Hz), 6.79 (1H, s), 6.97 (2H, d, J = 8.8 Hz) 7.20 (1H, d, J = 5.2 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.29 (1H, s), 7.86 (1H, dd, J = 2.0, 8.0 Hz), 8.08 (1H, dd, J = 2.0, 4.8 Hz), 8.42 (1H, d, J = 5.2 Hz).

The starting material, (2-methylpyridin-4-yl) methanol, was synthesized as follows.

[Production Example 47-1-1] (2-methylpyridin-4-yl) methanol

The title compound (200 mg) was obtained according to methods similar to the methods described in Production Examples 11-1-1 to 11-1-3.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.45 (3H, s), 4.50 (2H, d, J = 5.2 Hz), 5.37 (1H, t , J = 5.2 Hz), 7.11 (1H, d, J = 5.2 Hz), 7.18 (1H, s), 8.36 (1H, d, J = 5.2 Hz).

[Example 48] 3- (3- (5- p- Tolyloxythiophen-2-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (5- p- tolyloxy-thiophen-2-yl) -acetohydroximoyl chloride (191 mg, 0.678 mmol) described in Production Example 48-1-5, and 3-ethynylpyridin-2-ylamine (40.0 mg, 0.339 mM) described in Production Example 1-2-3, triethylamine (189 μl, 1.36 mmol) was added in tetrahydrofuran (7.00 ml) at room temperature and stirred at room temperature for 4 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (2.03 mg, 1.65%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.32 (3H, s), 4.14 (2H, s), 5.54 (2H, br s), 6.34 -6.36 (1H, m), 6.40 (1H, s), 6.62-6.63 (1H, m), 6.73-6.77 (1H, m), 6.98-7 00 (2H, m), 7.11-7.13 (2H, m), 7.76-7.78 (1H, m), 8.14-8.15 (1H, m).

The starting material, (5- p- tolyloxythiophen-2-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 48-1-1] 5- p- tolyloxythiophene-2-carbonitrile

To a solution of 5-nitro-2-thiophenecarbonitrile (6.30 g, 40.9 mmol) in dimethyl sulfoxide (100 ml) in a nitrogen atmosphere was added p- cresol (8.85 g, 81.8 mmol) and potassium carbonate (11, 3 g, 81.8 mmol) and stirred at 60 ° C for 5 hours. The reaction solution was cooled to room temperature, and after adding water, it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 → 2: 1) to obtain the title compound (6.95 g, 78.9%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.36 (3H, s), 6.38-6.39 (1H, m), 7.03-7.05 (2H, m) 7.18-7.20 (2H, m); 7.33-7.35 (1H, m).

[Production Example 48-1-2] 5- p- tolyloxythiophene-2-carbaldehyde

To a solution of 5- p- tolyloxythiophene-2-carbonitrile (2.00 g, 9.29 mmol) described in Production Example 48-1-1 in tetrahydrofuran (70.0 ml) in a bath with a mixture of dry ice-ethanol ( -78 ° C) in a nitrogen atmosphere, diisobutylaluminum hydride (0.97 M n- hexane solution, 23.9 ml, 23.2 mmol) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was cooled to room temperature, and after adding water, it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (958 mg, 47.2%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.36 (3H, s), 6.47 (1H, d, J = 4.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 7.20 (2H, d, J = 8.0 Hz), 7.51 (1H, d, J = 4.0 Hz), 9.69 (1H, s).

[Production Example 48-1-3] 2 - (( E ) -2-nitrovinyl) -5- p- tolyloxythiophene

To a solution of 5- p- tolyloxythiophene-2-carbaldehyde (2.30 g, 10.5 mmol) described in Production Example 48-1-2, in acetic acid (20.0 ml), nitromethane was added at room temperature under a nitrogen atmosphere. (3.20 g, 52.5 mmol) and ammonium acetate (1.62 g, 21.0 mmol) and stirred at 100 ° C. for 2.5 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent from the filtrate was evaporated under reduced pressure to obtain the title compound (2.50 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.32 (3H, s), 6.70 (1H, d, J = 4.0 Hz), 7.18 (2H, d , J = 8.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.65 (1H, d, J = 4.0 Hz), 7.78 (1H, d, J = 12.8 Hz), 8.26 (1H, d, J = 12.8 Hz).

[Production Example 48-1-4] 2- (2-nitroethyl) -5- p- tolyloxythiophene

In a suitably cooled solution of 2 - ((E) -2-nitrovinyl) -5- p- tolyloxythiophene (2.50 g, 9.57 mmol) described in Production Example 48-1-3 and acetic acid (2, 50 ml) in dimethyl sulfoxide (30.0 ml) at room temperature under a nitrogen atmosphere was added sodium borohydride (610 mg, 20.6 mmol) and stirred at room temperature for 30 minutes. Then, water was added dropwise to a solution cooled appropriately at room temperature. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (1.20 g, 47.6%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.28 (3H, s), 3.33 (2H, t, J = 6.4 Hz), 4.81 (2H, t , J = 6.4 Hz), 6.45-6.46 (1H, m), 6.67-6.69 (1H, m), 6.98-7.00 (2H, m), 7, 17-7.20 (2H, m).

[Production Example 48-1-5] (5- p- tolyloxythiophen-2-yl) -acetohydroximoyl chloride

To a solution of 2- (2-nitroethyl) -5- p- tolyloxythiophene (500 mg, 1.90 mmol) described in Production Example 48-1-4, in methanol (10.0 ml) at room temperature under nitrogen atmosphere was added lithium methoxide (144 mg, 3.80 mmol) and stirred at room temperature for 30 minutes. The solvent from the reaction mixture was evaporated under reduced pressure, and anhydrous dichloromethane (15.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Then, titanium (IV) chloride (668 μl, 6.08 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 45 minutes. Thereafter, water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the title compound (530 mg, 99.0%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.28 (3H, s), 3.94 (2H, s), 6.48 (1H, d, J = 3.6 Hz ), 6.74 (1H, d, J = 3.6 Hz), 7.00-7.01 (2H, m), 7.18-7.20 (2H, m), 11.81 (1H, c)

[Example 49] 3- (3- (4- (Pyridin-4-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (3 ml) and 5N aqueous sodium hydroxide solution (22.4 μl, 0.11 mmol) were added to 4- (5- (2-aminopyridin-3-yl) -isoxazole-3-ylmethyl) -phenol (30 mg , 0.11 mm), described in Production Example 5-1-1, and dissolved by sonication for 1 minute. The reaction solution was then concentrated under reduced pressure to obtain a white solid. The resulting solid was suspended in N, N-dimethylformamide (1 ml). In this case, THF (390 μl) and a 1N aqueous sodium hydroxide solution (390 μl, 0.39 mmol) were added to 4- (chloromethyl) pyridine hydrochloride (50 mg, 0.39 mmol) and then the organic layer was separated to obtain a 4- solution (chloromethyl) pyridine in tetrahydrofuran. A portion of this solution in tetrahydrofuran (224 μl) was added to a previously prepared suspension of N, N-dimethylformamide and stirred at 60 ° C for 45 minutes. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (36 mg, 88%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.17 (2H, s), 6.26 (2H, br s), 6.68 -6.72 (1H, m), 6.79 (1H, s), 6.99 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.8 Hz) 7.43 (2H, d, J = 6.0 Hz), 7.87 (1H, dd, J = 2.0, 7.6 Hz), 8.09 (1H, dd, J = 1.6 , 4.8 Hz), 8.57 (2H, dd, J = 1.6, 4.4 Hz).

[Example 50] 3- (3- (4- (Pyridin-3-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (3 ml) and a 5N aqueous sodium hydroxide solution (22.4 μl, 0.11 mmol) were added to 4- (5- (2-aminopyridin-3-yl) -isoxazol-3-ylmethyl) -phenol (30 mg , 0.11 mm), described in Production Example 5-1-1, and dissolved by sonication for 1 minute. The reaction solution was then concentrated under reduced pressure to obtain a white solid. This solid was suspended in N, N-dimethylformamide (1 ml). At the same time, THF (390 μl) and a 1N aqueous sodium hydroxide solution (390 μl, 0.39 mmol) were added to 3- (chloromethyl) pyridine hydrochloride (50 mg, 0.39 mmol) and then the organic layer was separated to obtain a solution of 3- (chloromethyl) pyridine in tetrahydrofuran. A portion of this solution in tetrahydrofuran (224 μl) was added to the previously prepared suspension in N, N-dimethylformamide and stirred at 60 ° C. for 45 minutes. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (40.0 mg, 100%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.13 (2H, s), 6.25 (2H, br.s), 6.67 -6.74 (1H, m), 6.78 (1H, s), 7.00 (2H, d, J = 8.0 Hz), 7.26 (2H, d, J = 7.6 Hz) 7.40-7.46 (1H, m), 7.85-7.89 (2H, m), 8.09 (1H, d, J = 4.8 Hz), 8.54 (1H, d , J = 4.8 Hz), 8.65-8.68 (1H, m).

[Example 51] 3- (3- (4- (4-Chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (3 ml) and a 5N aqueous sodium hydroxide solution (22.4 μl, 0.11 mmol) were added to 4- (5- (2-aminopyridin-3-yl) -isoxazol-3-ylmethyl) -phenol (30 mg , 0.11 mm), described in Production Example 5-1-1, and dissolved by sonication for 1 minute. The reaction solution was then concentrated under reduced pressure to obtain a white solid. A solution of 4-chloro-2-chloromethylpyridine (36.3 mg, 0.22 mmol) described in Production Example 51-1-2 in N, N-dimethylformamide (1 ml) was added to a suspension of this solid and N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (36.6 mg, 83%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.17 (2H, s), 6.26 (2H, br s), 6.69 (1H, dd, J = 4.8, 8.0 Hz), 6.79 (1H, s), 7.01 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.51 (1H, dd, J = 2.0, 5.2 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.87 (1H, dd, J = 2.0, 8.0 Hz), 8.08 (1H, dd, J = 2.0, 4.8 Hz), 8.55 (1H, d, J = 5.2 Hz).

The starting material, 4-chloro-2-chloromethylpyridine, was synthesized as follows.

[Production Example 51-1-1] (4-chloropyridin-2-yl) -methanol

To a mixture of 4-chloro-2-pinocolin (1.0 g, 7.84 mmol) and dichloromethane (20 ml), m- chloroperbenzoic acid (3.5 g, 13.2 mmol) was added in an ice bath and stirred at room temperature within 1.5 hours. Water and sodium bicarbonate were added to this reaction mixture, followed by extraction with dichloromethane. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Acetic anhydride (20 ml) was added to the residue obtained by concentrating the filtrate under reduced pressure, and the mixture was stirred at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To a mixture of the obtained residue and methanol (20 ml) in an ice bath was added a 5N aqueous solution of sodium hydroxide (1.57 ml, 7.87 mmol) and stirred at room temperature for 1.5 hours. Water was added to this mixture and then extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 6: 1) to obtain the title compound (200 mg, 18%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.76 (2H, s), 7.23-7.25 (1H, m), 7.32-7.33 (1H, m) 8.46 (1H, d, J = 5.6 Hz).

[Production Example 51-1-2] 4-chloro-2-chloromethylpyridine

To the mixture of (4-chloropyridin-2-yl) methanol (146.8 mg, 1.0 mmol) described in Production Example 51-1-1 and toluene (3 ml) was added thionyl chloride (112 μl, 1.53 mmol) and stirred at room temperature for 1 hour 15 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (97 mg, 59%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.65 (2H, s), 7.26-7.28 (1H, m), 7.52-7.53 (1H, m) 8.48 (1H, d, J = 5.6 Hz).

[Example 52] 3- (3- (4- (6-Chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (3 ml) and a 5N aqueous sodium hydroxide solution (22.4 μl, 0.11 mmol) were added to 4- (5- (2-aminopyridin-3-yl) isoxazol-3-ylmethyl) phenol (30 mg, 0.11 mmol), described in Production Example 5-1-1, and dissolved by sonication for 1 minute. The reaction solution was then concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added a solution of 2-chloro-6-chloromethylpyridine (36.3 mg, 0.22 mmol), described in Production Example 52-1-2, in N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (39.5 mg, 90%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.15 (2H, s), 6.26 (2H, br s), 6.69 (1H, dd, J = 4.8, 8.0 Hz), 6.79 (1H, s), 6.99 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.46-7.52 (2H, m), 7.85-7.92 (2H, m), 8.08 (1H, dd, J = 2.0, 4, 8 Hz).

The starting material, 2-chloro-6-chloromethylpyridine, was synthesized as follows.

[Production Example 52-1-1] (6-chloropyridin-2-yl) -methanol

To a mixture of 2-chloro-6-methylpyridine (1.0 g, 7.84 mmol) and dichloromethane (20 ml) was added m- chloroperbenzoic acid (3.5 g, 13.2 mmol) in an ice bath and stirred at 40 ° C for 1.5 hours. Water and sodium bicarbonate were added to the reaction mixture, and then extracted with dichloromethane. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. Acetic anhydride (20 ml) was added to the obtained residue and stirred at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To a mixture of the obtained residue and methanol (20 ml) in an ice bath was added 5N aqueous sodium hydroxide solution (4 ml, 20.1 mmol) and stirred for 30 minutes. Water was added to this mixture and then extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (200.0 mg, 18%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.08 (1H, br s), 4.75 (2H, d, J = 5.2 Hz), 7.23-7.27 (2H, m), 7.64-7.69 (1H, m).

[Production Example 52-1-2] 2-chloro-6-chloromethylpyridine

To a mixture of (6-chloropyridin-2-yl) methanol (200 mg, 1.39 mmol) described in Production Example 52-1-1 and toluene (3 ml), thionyl chloride (152 μl, 2, 09 mM) and stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (163.2 mg, 73%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.64 (2H, s), 7.29 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 7.6 Hz), 7.70 (1H, dd, J = 7.6, 8.0 Hz).

[Example 53] 3- (3- (6-Phenoxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-ylamine

To the solution of (2-phenoxypyridin-5-yl) -acetohydroximoyl chloride (100 mg, 0.381 mmol) described in Production Example 40-1-4 and 3-ethynylpyridin-2-ylamine (30 mg, 0.25 mmol) described in Production Example 1-2-3, triethylamine (71 μl, 0.51 mmol) was added in tetrahydrofuran (2 ml) under nitrogen atmosphere and stirred at 50 ° C for 3 hours. Water was added to the reaction mixture at room temperature and then extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (27 mg, 31%).

¹ H-NMR Spectrum (DMSO-d ₆₎ δ (h / mn): 4,02 (2H, c) , 6,26 (2H, c), 6,68 (1H, dd, J = 4,8, 7.7 Hz), 6.83 (1H, s), 6.98 (1H, d, J = 8.6 Hz), 7.09 (2H, d, J = 7.5 Hz), 7.18 (1H, t, J = 7.3 Hz), 7.39 (2H, t, J = 7.5 Hz), 7.79 (1H, dd, J = 2.4, 8.6 Hz), 7 85 (1H, dd, J = 1.8, 7.7 Hz), 8.07 (1H, dd, J = 1.8, 4.8 Hz), 8.13 (1H, d, J = 2 , 2 Hz).

[Example 54] 3- (3- (6-Phenoxymethylpyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (6-phenoxymethylpyridin-3-yl) -acetohydroximoyl chloride (80.0 mg, 0.289 mmol) described in Production Example 54-1-6, and 3-ethynylpyridin-2-ylamine (20.0 mg, 0.169 mmol) described in Production Example 1-2-3, triethylamine (70.7 μl, 0.507 mmol) was added in tetrahydrofuran (3.00 ml) at room temperature and stirred at 60 ° C. for 4.5 hours. Water was added to the reaction solution at room temperature, then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 then 3: 1) to obtain the title compound (4.00 mg, 6.60%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.10 (2H, s), 5.16 (2H, s), 6.27 (2H, br s), 6.69 -6.72 (1H, m), 6.87 (1H, s), 6.92-7.02 (3H, m), 7.27-7.31 (2H, m), 7.48-7 50 (1H, m), 7.78-7.79 (1H, m), 7.86-7.88 (1H, m), 8.09-8.10 (1H, m), 8.58 -8.59 (1H, m).

The starting material, (6-phenoxymethylpyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 54-1-1] (5-bromopyridin-2-yl) -methanol

To a solution of 2,5-dibromopyridine (10.0 g, 42.2 mmol) in toluene (300 ml) in a bath with a mixture of dry ice-ethanol (-78 ° C) in a nitrogen atmosphere was added dropwise n- butyllithium (2, 55 M solution of n- hexane, 18.2 ml, 46.4 mmol) and stirred at -78 ° C for 2 hours. Then, N, N-dimethylformamide (3.7 g, 50.6 mmol) was added dropwise thereto and stirred at -78 ° C for 10 minutes. Then sodium borohydride (3.20 g, 84.4 mmol) and methanol (20.0 ml) were added and stirred at room temperature for 30 minutes. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 1 then 2: 1) to obtain the title compound (4.70 g, 59.2%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.54 (2H, d, J = 5.6 Hz), 5.28 (1H, t, J = 5.6 Hz), 7.44-7.47 (1H, m), 8.03-8.05 (1H, m), 8.59-8.60 (1H, m).

[Production Example 54-1-2] 5-bromo-2-chloromethylpyridine hydrochloride

To a solution of (5-bromopyridin-2-yl) methanol (4.70 g, 25.0 mmol) described in Production Example 54-1-1 in toluene (20.0 ml) in an ice bath (0 ° C ) thionyl chloride (3.65 ml, 50.1 mmol) was added dropwise under a nitrogen atmosphere and stirred at room temperature for 5 minutes. The solvent was evaporated under reduced pressure to obtain the title compound (4.2 g, 69.2%) as a hydrochloride.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.78 (2H, s), 7.55-7.57 (1H, m), 8.11-8.14 (1H, m), 8.70-8.72 (1H, m).

[Production Example 54-1-3] 5-bromo-2-phenoxymethylpyridine

To a solution of phenol (1.92 g, 20.4 mmol) in N, N-dimethylformamide (40.0 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (815 mg, 20.4 mmol, 60 % in oil) and stirred at room temperature for 20 minutes. Then, a mixture of 5-bromo-2-chloromethylpyridine hydrochloride (4.2 g, 20.4 mmol) described in Production Example 54-1-2 and triethylamine (28.0 ml, 20.4 mmol) was added to the reaction solution. stirred first at room temperature for 30 minutes and then at 70 ° C for 45 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 10) to obtain the title compound (4.40 g, 81.7%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.15 (2H, s), 6.95-6.99 (3H, m), 7.25-7.31 (2H, m) 7.42-7.45 (1H, m); 7.81-7.83 (1H, m); 8.64-8.65 (1H, m).

[Production Example 54-1-4] 6-phenoxymethylpyridin-3-carbaldehyde

To a solution of 5-bromo-2-phenoxymethylpyridine (4.40 g, 16.6 mmol), described in Production Example 54-1-3, in diethyl ether (250 ml) in a bath with a mixture of dry ice-ethanol (-78 ° C) n- butyllithium (2.55 M n- hexane solution, 8.46 ml, 21.6 mmol) was added under nitrogen atmosphere and stirred at -78 ° C for 40 minutes. Then, N, N-dimethylformamide (1.93 ml, 25.0 mmol) was added dropwise thereto, and stirred at -78 ° C for 20 minutes. The reaction solution was allowed to cool to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (1.00 g, 28.3%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.29 (2H, s), 6.97-7.01 (3H, m), 7.29-7.33 (2H, m) 7.73-7.75 (1H, m), 8.19-8.21 (1H, m), 9.05-9.06 (1H, m), 10.12 (1H, s).

[Production Example 54-1-5] 5- (2-nitroethyl) -2-phenoxymethylpyridine

To a solution of 6-phenoxymethylpyridin-3-carbaldehyde (1.00 g, 4.69 mmol) described in Production Example 54-1-4, in methanol (20.0 ml) at room temperature, lithium methoxide was added (21 4 mg, 0.56 mmol). This solution was cooled to 0 ° C, nitromethane (372 mg, 6.10 mmol) and lithium methoxide (193 mg, 5.07 mmol) were added and stirred at room temperature for 10 minutes. Then the reaction solution was concentrated under reduced pressure. Tetrahydrofuran (20.0 ml), then acetic anhydride (6.24 g, 61.1 mmol) and triethylamine (1.42 ml, 10.2 mmol) were added to the residue and stirred at 70 ° C for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure. Methanol (20.0 ml) was added to the residue, and then sodium borohydride (263 mg, 6.96 mmol) was added in an ice bath (0 ° C). After stirring at 0 ° C for 5 minutes, water was added dropwise at 0 ° C. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1) to obtain the title compound (170 mg, 14.2%).

¹ H-NMR Spectrum (DMSO-d ₆₎ δ (h / mn): 3,25 (2H, t, J = 6,8 Hz), 4,91 (2H, t, J = 6,8 Hz); 5.14 (2H, s), 6.93-6.97 (1H, m), 7.00-7.02 (2H, m), 7.27-7.31 (2H, m), 7, 46-7.48 (1H, m), 7.75-7.78 (1H, m), 8.49-8.50 (1H, m).

[Production Example 54-1-6] (6-phenoxymethylpyridin-3-yl) -acetohydroximoyl chloride

To a solution of 5- (2-nitroethyl) -2-phenoxymethylpyridine (170 mg, 0.658 mmol) described in Production Example 54-1-5, in methanol (7.00 ml) at room temperature, lithium methoxide (50 , 0 mg, 1.32 mmol) and stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (10.0 ml) and anhydrous tetrahydrofuran (5.00 ml) were added to the residue. Titanium (IV) chloride (231 μl, 2.11 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 30 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solution was evaporated from the filtrate under reduced pressure to obtain the title compound (169 mg, 92.8%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.90 (2H, s), 5.17 (2H, s), 6.93-6.97 (1H, m), 7 , 01-7.03 (2H, m), 7.27-7.30 (2H, m), 7.49-7.51 (1H, m), 7.72-7.74 (1H, m) 8.49-8.50 (1H, m); 11.83 (1H, s).

[Example 55] 3- (3- (4- (6-Fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4- (6-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Production Example 55-1-5, and 3-ethynylpyridin-2-ylamine (50 mg, 0.423 mmol) ) described in Production Example 1-2-3, triethylamine (237 μl, 1.7 mmol) was added in tetrahydrofuran (3 ml) at room temperature and stirred at 50 ° C for 2 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 = 4: 1 → 2: 1) to obtain the title compound (59 mg, 23%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.07 (2H, s), 5.32 (2H, s), 5.64 (2H, br s), 6.27 (1H , c), 6.47-6.50 (1H, m), 6.64-6.67 (1H, m), 6.71-6.74 (1H, m), 7.30 (2H, d , J = 8.4 Hz), 7.43 (2H, d, J = 8.4 Hz), 7.63-7.69 (1H, m), 7.72-7.75 (1H, m) 8.11-8.12 (1H, m).

The starting material, (4- (6-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride, was synthesized as follows.

[Production Example 55-1-1] 4- (6-fluoropyridin-2-yloxymethyl) benzonitrile

To a solution of 2,6-difluoropyridine (5 g, 43.4 mmol) and 4- (hydroxymethyl) benzonitrile (8.67 g, 65.1 mmol) was added sodium hydride (2.56 g, 65.1 mmol) at room temperature , 60% in oil). This mixture was stirred at 70 ° C for 4 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 10: 1-4: 1) to obtain the title compound (5.99 g, 61%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.41 (2H, s), 6.74-6.77 (1H, m), 6.87-6.89 (1H, m) 7.63-7.66 (2H, m); 7.85-7.88 (2H, m); 7.90-7.96 (1H, m).

[Production Example 55-1-2] 4- (6-fluoropyridin-2-yloxymethyl) benzaldehyde

To a solution of 4- (6-fluoropyridin-2-yloxymethyl) benzonitrile (5.99 g, 26.2 mmol) described in Production Example 55-1-1 in toluene (41 ml) at a temperature of from -70 ° C diisobutylaluminum hydride (1.01 M toluene solution, 39.3 mmol) was added to -78 ° C in a nitrogen atmosphere. This mixture was stirred at room temperature for 2 hours. This mixture was partitioned into ethyl acetate and a 20% aqueous Rochelle salt solution. After removal of the insoluble matter by filtration through a celite pad, the filtrate was separated. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1-4: 1) to obtain the title compound (4.57 g, 75%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.43 (2H, s), 6.50-6.53 (1H, m), 6.70-6.72 (1H, m) 7.60-7.62 (2H, m); 7.66-7.72 (1H, m); 7.88-7.91 (2H, m); 10.0 (1H, s).

[Production Example 55-1-3] 2-fluoro-6- (4- ( E ) -2-nitrovinyl) benzyloxy) pyridine

A mixture of 4- (6-fluoropyridin-2-yloxymethyl) benzaldehyde (4.57 g, 19.8 mmol) described in Production Example 55-1-2, nitromethane (2.13 ml, 39.6 mmol), acetate ammonium (2.29 g, 29.7 mmol) and acetic acid (45.7 ml) were stirred at 100 ° C for 19 hours. This mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (3.44 g, 63%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.39 (2H, s), 6.50-6.53 (1H, m), 6.68-6.71 (1H, m) 7.52-7.61 (5H, m); 7.66-7.72 (1H, m); 8.03-8.99 (1H, m).

[Production Example 55-1-4] 2-fluoro-6- (4- (2-nitroethyl) benzyloxy) pyridine

In a suitably cooled solution of 2-fluoro-6- (4- ( E ) -2-nitrovinyl) benzyloxy) pyridine (3.44 g, 12.5 mmol) described in Production Example 55-1-3, and acetic acid (3.44 ml) in dimethyl sulfoxide (58.5 ml) was added sodium borohydride (757 mg, 20 mmol) at room temperature. This mixture was stirred at room temperature for 4 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1-4: 1) to obtain the title compound (1.6 g, 46%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.31-3.35 (2H, m), 4.60-4.63 (2H, m), 5.31 (2H, s) 6.48-6.50 (1H, m), 6.64-6.67 (1H, m), 7.22-7.24 (2H, m), 7.41-7.43 (2H, m), 7.63-7.69 (1H, m).

[Production Example 55-1-5] (4- (6-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride

To a solution of 2-fluoro-6- (4- (2-nitroethyl) benzyloxy) pyridine (1.6 g, 5.79 mmol) described in Production Example 55-1-4, in methanol (20 ml) was added lithium methoxide (449 mg, 11.6 mmol). This mixture was stirred at room temperature for 1 hour. This mixture was concentrated under reduced pressure, the water in the residue was azeotropically distilled off with toluene, and the residue was diluted with methylene chloride (24 ml) and tetrahydrofuran (12 ml). The solution was cooled to −78 ° C. and titanium (IV) tetrachloride (2.04 ml, 18.5 mmol) was added dropwise to the suspension. The mixture was stirred at room temperature for 2 hours. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was pulverized in ethyl acetate. The solid was collected and dried under reduced pressure to obtain the title compound (1.36 g, 80%). This compound was used in the subsequent reaction without further purification.

[Example 56] 3- (3-4- (5-Fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of ((4- (5-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (800 mg, 2.72 mmol) described in Production Example 56-1-5, and 3-ethynylpyridin-2-ylamine (200 mg , 1.69 mM) described in Production Example 1-2-3, triethylamine (948 μl, 6.8 mmol) was added in tetrahydrofuran (5 ml) at room temperature, stirred at 50 ° C. for 4 hours. water was added to the solution at room temperature, then it was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and the booster was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (214 mg, 21%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.08 (2H, s), 5.08 (2H, s), 5.54 (2H, br s), 6.27 (1H , c), 6.71-6.74 (1H, m), 7.13-7.16 (1H, m), 7.31-7.39 (5H, m), 7.71-7.73 (1H, m), 8.11-8.14 (2H, m).

The starting material, (4- (5-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride, was synthesized as follows.

[Production Example 56-1-1] 4- (5-fluoropyridin-2-yloxymethyl) benzonitrile

To a solution of 2-bromo-5-fluoropyridine (5 g, 28.4 mmol) and 4- (hydroxymethyl) benzonitrile (5.67 g, 42.4 mmol) in N, N-dimethylformamide (50 ml) at room temperature sodium hydride (1.7 g, 42.4 mmol, 60% in oil) was added. The mixture was stirred at 70 ° C for 3 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1 - 1: 1 - ethyl acetate) to obtain the title compound (5.5 g, 85%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.15 (2H, s), 7.14-7.17 (1H, m), 7.39-7.41 (1H, m) 7.53-7.55 (2H, m); 7.70-7.72 (2H, m); 8.12-8.13 (1H, m).

[Production Example 56-1-2] 4- (5-Fluoropyridin-2-yloxymethyl) benzaldehyde

To a solution of 4- (5-fluoropyridin-2-yloxymethyl) benzonitrile (5.5 g, 24.1 mmol) described in Production Example 56-1-1 in toluene (37 ml) at a temperature of from -70 ° C diisobutylaluminum hydride (35.8 ml, 1.01 M toluene solution, 36.2 mmol) was added to -78 ° C in a nitrogen atmosphere. This solution was stirred at room temperature for 3 hours. This mixture was partitioned into ethyl acetate and a 20% aqueous Rochelle salt solution. After removal of the insoluble matter by filtration through a celite pad, the filtrate was separated. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (2.71 g, 49%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.31-5.33 (2H, m), 7.46-7.50 (1H, m), 7.57-7, 59 (1H, m), 7.64-7.69 (2H, m), 7.88-7.96 (2H, m), 8.21-8.22 (1H, m), 10.0 ( 1H, c).

[Production Example 56-1-3] 5-fluoro-2- (4 - (( E ) -nitrovinyl) benzyloxy) pyridine

A mixture of 4- (5-fluoropyridin-2-yloxymethyl) benzaldehyde (2.71 g, 11.7 mmol) described in Production Example 56-1-2, nitromethane (1.26 ml, 23.4 mmol), ammonium acetate (1.35 g, 17.6 mmol) and acetic acid (30 ml) were stirred at 100 ° C for 10 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2.9 g).

The resulting compound was used in the subsequent reaction without purification.

[Production Example 56-1-4] (5-fluoro-2- (4- (2-nitroethyl) -benzyloxy) -pyridine

In a suitably cooled solution of 5-fluoro-2- (4 - (( E ) -nitrovinyl) benzyloxy) pyridine (2.9 g, 10.6 mmol), described in Production Example 56-1-3, and acetic acid (2.9 ml) in dimethyl sulfoxide (49 ml) was added sodium borohydride (642 mg, 17 mmol) at room temperature. This mixture was stirred at room temperature for 1 hour. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 10: 1) to obtain the title compound (1.63 g, 56%).

¹ H-NMR Spectrum (DMSO-d ₆₎ δ (h / mn): 3,21-3,25 (2H, m), 4,83-4,87 (2H, m), 5,15 (2H, c), 7.31 (2H, d, J = 8 Hz), 7.40 (2H, d, J = 8 Hz), 7.44-7.48 (1H, m), 7.54-7, 57 (1H, m), 8.18-8.19 (1H, m).

[Production Example 56-1-5] (4- (5-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride

To a solution of (5-fluoro-2- (4- (2-nitroethyl) -benzyloxy) -pyridine (1.63 g, 5.9 mmol) described in Production Example 56-1-4, in methanol (20 ml) lithium methoxide (448 mg, 11.8 mmol) was added. This mixture was stirred at room temperature for 2 hours. This mixture was concentrated under reduced pressure, the residue in the residue was azeotroped using toluene, and the residue was diluted with methylene chloride (24 ml) and tetrahydrofuran (12 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (2.07 ml, 18.9 mmol) was added dropwise to the suspension, which was stirred at room temperature in t 2 hours. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was pulverized in ethyl acetate The solid was collected and dried under reduced pressure to obtain the title compound (1.75 g).

The resulting compound was used in the subsequent reaction without further purification.

[Example 57] 3- (3- (1-benzyl-1 H -pyrrol-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

The title compound (27 mg, 7.3%) was obtained according to methods similar to the methods of example 3 using 3-ethynylpyridin-2-ylamine (74 mg, 0.56 mmol) described in Production Example 1-2-3 , and (1-benzyl-1 H -pyrrol-3-yl) -acetohydroximoyl chloride (280 mg, 1.1 mmol) described in Production Example 57-1-3.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.78 (2H, s), 5.03 (2H, s), 5.99 (1H, d, J = 2.0 Hz ), 6.24 (2H, br.s), 6.68-6.80 (4H, m), 7.18 (2H, d, J = 8.4 Hz), 7.23-7.36 ( 3H, m), 7.87 (1H, dd, J = 2.0, 8.0 Hz), 8.08 (1H, dd, J = 2.0, 4.8 Hz).

The starting material, (1-benzyl-1 H -pyrrol-3-yl) acetohydroximoyl chloride, was synthesized as follows.

[Production Example 57-1-1] 1-benzyl-3 - (( E ) -2-nitrovinyl) -1 H- pyrrole

The title compound (3.0 g, 85%) was obtained according to methods similar to the methods of Production Example 3-1-3, using 1-benzyl-1 H -pyrrole-3-carbaldehyde (2.9 g, 15 mmol) .

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.16 (2H, s), 6.60-6.63 (1H, m), 6.99 (1H, dd, J = 2.0, 2.0 Hz), 7.22-7.40 (5H, m), 7.60 (1H, dd, J = 2.0, 2.0 Hz), 7.80 (1H, d , J = 13.2 Hz), 8.03 (1H, d, J = 13.2 Hz).

[Production Example 57-1-2] 1-benzyl-3- (2-nitroethyl) -1 H- pyrrole

The title compound (2.3 g, 75%) was obtained according to methods similar to the methods of Production Example 3-1-4, using 1-benzyl-3 - (( E ) -2-nitrovinyl) -1 H- pyrrole ( 3.0 g, 13 mmol) described in Production Example 57-1-1.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.00 (2H, d, J = 6.8 Hz), 4.67 (2H, d, J = 6.8 Hz), 5.01 (2H, s), 5.92 (1H, dd, J = 2.0, 2.0 Hz), 6.66 (1H, dd, J = 2.0, 2.0 Hz), 6 73 (1H, dd, J = 2.0, 2.0 Hz), 7.13-7.17 (2H, m), 7.23-7.35 (3H, m).

[Production Example 57-1-3] (1-benzyl-1 H -pyrrol-3-yl) acetohydroximoyl chloride

The title compound (550 mg, 51%) was obtained according to methods similar to the methods of Production Example 3-1-5, using 1-benzyl-3- (2-nitroethyl) -1H-pyrrole (280 mg, 1.1 mmol) ) described in Production Example 57-1-2.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.57 (2H, s), 5.03 (2H, s), 5.97 (1H, dd, J = 2.0, 2.0 Hz), 6.77 (1H, dd, J = 2.0, 2.0 Hz), 6.79 (1H, dd, J = 2.0, 2.0 Hz), 7.15- 7.22 (2H, m), 7.23-7.40 (3H, m), 11.46 (1H, s).

[Example 58] 3- (3- (6- (4-Fluorobenzyloxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (6- (4-fluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride (150 mg, 0.508 mmol) described in Production Example 58-1-5, and 3-ethynylpyridin-2-ylamine (30.0 mg , 0.254 mmol) described in Production Example 1-2-3, triethylamine (106 μl, 0.762 mmol) was added in tetrahydrofuran (10.0 ml) at room temperature and stirred at 60 ° C for 4 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 2) to obtain the title compound (21.2 mg, 22.2%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.00 (2H, s), 5.31 (2H, s), 6.27 (2H, br s), 6.68 -6.71 (1H, m), 6.83 (1H, s), 6.84-6.86 (1H, m), 7.17-7.22 (2H, m), 7.47-7 51 (2H, m), 7.67-7.70 (1H, m), 7.86-7.88 (1H, m), 8.08-8.10 (1H, m), 8.16 -8.17 (1H, m).

The starting material, (6- (4-fluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 58-1-1] 5-bromo-2- (4-fluorobenzyloxy) -pyridine

Sodium hydride (0.88 g, 22.2 mmol) was added to a solution of 4-fluorobenzyl alcohol (2.60 g, 20.6 mmol) in N, N-dimethylformamide (30.0 ml) at 0 ° C under nitrogen atmosphere. 60% in oil) and stirred at room temperature for 10 minutes. Then, 2.5-dibromopyridine (3.50 g, 14.8 mmol) was added at 0 ° C and stirred at room temperature for 19 hours. Water was added to the reaction solution at room temperature, and then the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (3.75 g, 89.8%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.29 (2H, s), 6.68-6.70 (1H, m), 7.02 -7.06 (2H, m) 7.38-7.42 (2H, m), 7.61-7.64 (1H, m), 8.19-8.20 (1H, m).

[Production Example 58-1-2] 6- (4-fluorobenzyloxy) -pyridin-3-carbaldehyde

To a solution of 5-bromo-2- (4-fluorobenzyloxy) -pyridine (3.75 g 13.3 mmol), described in Production Example 58-1-1, in diethyl ether (150 ml) in a bath with a mixture of dry ice- ethanol (-78 ° C) in a nitrogen atmosphere was added n- butyllithium (2.55 M n- hexane solution, 6.26 ml, 16.0 mmol) and stirred at -78 ° C for 30 minutes. Then, N, N-dimethylformamide (1.54 ml, 20.0 mmol) was added dropwise and stirred at -78 ° C for 5 minutes. The reaction solution was allowed to cool to room temperature, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (2.23 g, 72.5%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.45 (2H, s), 6.87-6.90 (1H, m), 7.05-7.09 (2H, m) 7.42-7.46 (2H, m), 8.07-8.10 (1H, m), 8.64-8.65 (1H, m), 9.96 (1H, s).

[Production Example 58-1-3] 2- (4-fluorobenzyloxy) -5 - (( E ) -2-nitrovinyl) pyridine

To a solution of 6- (4-fluorobenzyloxy) -pyridin-3-carbaldehyde (2.23 g, 9.64 mmol) described in Production Example 58-1-2, in acetic acid (20.0 ml) under nitrogen atmosphere was added nitromethane (2.94 g, 48.2 mmol) and ammonium acetate (1.49 g, 19.3 mmol) and was stirred at 105 ° C for 2.5 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the title compound (2.60 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.41 (2H, s), 7.00-7.02 (1H, m), 7.18-7.24 (2H, m), 7.50-7.54 (2H, m), 8.14-8.18 (1H, m), 8.22-8.26 (1H, m), 8.26-8.29 ( 1H, m), 8.64-8.65 (1H, m).

[Production Example 58-1-4] 2- (4-fluorobenzyloxy) -5- (2-nitroethyl) pyridine

In a suitably cooled solution of 2- (4-fluorobenzyloxy) -5 - (( E ) -2-nitrovinyl) pyridine (2.60 g, 9.48 mmol), described in Production Example 58-1-3, and acetic acid (3.00 ml) in dimethyl sulfoxide (20.0 ml) at room temperature under a nitrogen atmosphere was added sodium borohydride (574 mg, 15.2 mmol) and stirred for 20 minutes. Then, water was added dropwise at room temperature, cooling accordingly to remove sodium borohydride. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (785 mg, 30.0%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.18 (2H, t, J = 6.8 Hz), 4.85 (2H, t, J = 6.8 Hz), 5.31 (2H, s), 6.84-6.86 (1H, m), 7.18-7.23 (2H, m), 7.48-7.52 (2H, m), 7, 68-7.70 (1H, m), 8.07-8.08 (1H, m).

[Production Example 58-1-5] (6- (4-fluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride

To a solution of 2- (4-fluorobenzyloxy) -5- (2-nitroethyl) pyridine (785 mg, 2.84 mmol) described in Production Example 58-1-4, in methanol (20.0 ml) was added lithium methoxide (216 mg, 5.68 mmol) in a nitrogen atmosphere at room temperature and stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (5.00 ml) were added to the residue. Titanium (IV) chloride (998 μl, 9.09 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 45 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the title compound (801 mg, 95.7%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.79 (2H, s), 5.31 (2H, s), 6.85-6.87 (1H, m), 7 , 18-7.22 (2H, m), 7.48-7.52 (2H, m), 7.60-7.62 (1H, m), 8.07-8.08 (1H, m) 11.76 (1H, s).

[Production Example 59] 3- (3- (4- (4-fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4- (4-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Production Example 59-1-5, and 3-ethynylpyridin-2-ylamine (50 mg, 0.423 mM) described in Production Example 1-2-3, triethylamine (237 μl, 1.7 mmol) was added in tetrahydrofuran (3 ml) at room temperature and stirred at 50 ° C for 4 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and 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 = 4: 1 - 2: 1 - 1: 1) to obtain the title compound (57 mg, 22%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.09 (2H, s), 5.09 (2H, s), 5.84 (2H, br s), 6.30 (1H , c), 6.74-6.77 (1H, m), 6.80-6.82 (1H, m), 6.90-6.91 (1H, m), 7.33-7.42 (3H, m), 7.76-7.78 (1H, m), 8.09-8.11 (1H, m), 8.19-8.21 (2H, m).

The starting material, (4- (4-fluoropyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 59-1-1] 4- (4-fluoropyridin-2-yloxymethyl) benzonitrile

To a solution of 2-chloro-4-fluoropyridine (2.88 g, 21.9 mmol) and 4- (hydroxymethyl) benzonitrile (4.37 g, 32.9 mmol) in N, N-dimethylformamide (15 ml) at room sodium hydride (1.29 g, 32.9 mmol, 60% in oil) was added at temperature. This mixture was stirred at 70 ° C for 4 hours. Then this mixture was separated into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (4.08 g, 82%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.17 (2H, s), 6.81-6.83 (1H, m), 6.908-6.913 (1H, m), 7.52 -7.54 (2H, m), 7.70-7.73 (2H, m), 8.23-8.24 (1H, m).

[Production Example 59-1-2] 4- (4-fluoropyridin-2-yloxymethyl) benzaldehyde

To a solution of 4- (4-fluoropyridin-2-yloxymethyl) benzonitrile (4.08 g, 17.9 mmol) described in Production Example 59-1-1 in toluene (28 ml) at a temperature of from-70 ° C diisobutylaluminum hydride (26.6 ml, 1.01 M toluene solution, 26.9 mmol) was added to -78 ° C in a nitrogen atmosphere. This mixture was stirred at room temperature for 3 hours. Then this mixture was separated into ethyl acetate and a 20% aqueous Rochelle salt solution. The insoluble matter was then removed by filtration through a pad of celite and the filtrate was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (1.5 g, 36%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.20 (2H, s), 6.82-6.84 (1H, m), 6.92-6.93 (1H, m) 7.57-7.59 (2H, m), 7.93-7.95 (2H, m), 8.22-8.24 (1H, m), 10.0 (1H, s).

[Production Example 59-1-3] 4-fluoro-2- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine

A mixture of 4- (4-fluoropyridin-2-yloxymethyl) benzaldehyde (1.5 g, 6.49 mmol) described in Production Example 59-1-2, nitromethane (698 μl, 13 mmol), ammonium acetate (750 mg , 9.74 mmol) and acetic acid (15 ml) were stirred at 100 ° C for 6 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.72 g).

The resulting compound was used in the subsequent reaction without purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.16 (2H, s), 6.82-6.84 (1H, m), 6.917-6.923 (1H, m), 7.49 -7.51 (2H, m), 7.59-7.62 (3H, m), 8.00-8.04 (1H, m), 8.23-8.24 (1H, m).

[Production Example 59-1-4] 4-fluoro-2- (4- (2-nitroethyl) benzyloxy) pyridine

In a suitably cooled solution of 4-fluoro-2- (4 - (( E ) -2-nitrovinyl) benzyloxy) pyridine (1.72 g, 6.27 mmol) described in Production Example 59-1-3, in acetic acid (1.7 ml) and dimethyl sulfoxide (29 ml), sodium borohydride (380 mg, 10 mmol) was added at room temperature. This mixture was stirred at room temperature for 5 hours. Then this mixture was separated into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (960 mg, 55%).

¹ H-NMR spectrum (CDCl ₃₎ δ (h / mn): 3,33-3,37 (2H, m), 4,61-4,65 (2H, m), 5,09 (2H, c) 6.81-6.83 (1H, m), 6.91-6.92 (1H, m), 7.25-7.27 (3H, m), 7.36-7.38 (1H, m), 8.20-8.22 (1H, m).

[Production Example 59-1-5] (4- (4-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride

To a solution of 4-fluoro-2- (4- (2-nitroethyl) benzyloxy) pyridine (960 mg, 3.47 mmol) described in Production Example 59-1-4, in methanol (12 ml) was added lithium methoxide (264 mg, 6.94 mmol). This mixture was stirred at room temperature for 1 hour. This mixture was then concentrated under reduced pressure, the water in the residue was azeotropically distilled off with toluene, and then the precipitate was diluted with methylene chloride (14 ml) and tetrahydrofuran (7.2 ml). This mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (1.22 ml, 11.1 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 2 hours. The mixture was cooled to −78 ° C. and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was triturated with ethyl acetate. The solid was collected and dried under reduced pressure to obtain the title compound (969 mg).

The resulting compound was used in the subsequent reaction without further purification.

[Example 60] 3- (3- (3- (Pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of 3- (pyridin-2-ylmethoxy) -phenyl) -acetohydroximoyl chloride (200 mg, 0.723 mmol) described in Production Example 60-1-4 and 3-ethynylpyridin-2-ylamine (55 mg, 0.461 mmol), described in Production Example 1-2-3, triethylamine (252 μl, 1.81 mmol) was added in tetrahydrofuran (3 ml) at room temperature and stirred at 50 ° C for 2 hours. Water was added to the reaction mixture at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and 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 = 4: 1 - 2: 1 - 1: 1) to obtain the title compound (52 mg, 20%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.03 (2H, s), 5.20 (2H, s), 5.80 (2H, br s), 6.26 (1H , c), 6.73-6.76 (1H, m), 6.89-6.91 (4H, m), 7.19-7.24 (1H, m), 7.50-7.51 (1H, m), 7.68-7.77 (2H, m), 8.09-8.11 (1H, m), 8.57-8.59 (1H, m).

The starting material, 3- (pyridin-2-ylmethoxy) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 60-1-1] 3- (pyridin-2-ylmethoxy) benzaldehyde

3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N, N-dimethylformamide (60 ml). 2-picolyl chloride hydrochloride (4.44 g, 27.1 mmol) was added to this suspension and stirred at room temperature for 14 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1 - 1: 1) to obtain the title compound (2.98 g, 57%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.27 (2H, s), 7.24-7.29 (2H, m), 7.44-7.52 (4H, m) 7.71-7.76 (1H, m); 8.62-8.63 (1H, m); 9.98 (1H, s).

[Production Example 60-1-2] 2- (3 - (( E ) -2-nitrovinyl) phenoxymethyl) pyridine

A mixture of 3- (pyridin-2-ylmethoxy) benzaldehyde (2.98 g, 14 mmol) described in Production Example 60-1-1, nitromethane (1.51 ml, 28 mmol), ammonium acetate (1.62 g , 21 mmol) and acetic acid (30 ml) were stirred at 100 ° C for 6 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1 - 1: 1) to obtain the title compound (2.56 g, 71%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.27 (2H, s), 7.12-7.17 (3H, m), 7.28-7.30 (1H, m) 7.35-7.39 (1H, m), 7.52-7.58 (2H, m), 7.74-7.78 (1H, m), 7.94-7.97 (1H, m), 8.62-8.64 (1H, m).

[Production Example 60-1-3] 2- (3- (2-nitroethyl) phenoxymethyl) pyridine

In a suitably cooled solution of 2- (3 - (( E ) -2-nitrovinyl) phenoxymethyl) pyridine (2.56 g, 10 mmol) described in Production Example 60-1-2 in acetic acid (2, 5 ml) and dimethyl sulfoxide (43 ml) was added sodium borohydride (605 mg, 16 mmol) at room temperature. This mixture was stirred at room temperature for 1.5 hours, then partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1 - 4: 1 - 1: 1) to obtain the title compound (1.66 g, 64%).

¹ H-NMR Spectrum (DMSO-d ₆₎ δ (h / mn): 3,20-3,23 (2H, m), 4,83-4,87 (2H, m), 5,44 (2H, c), 6.86-6.89 (1H, m), 6.91-6.93 (1H, m), 7.00 (1H, m), 7.26-7.30 (1H, m) 7.64-7.67 (1H, m), 7.86-7.88 (1H, m), 8.21-8.24 (1H, m), 8.75-8.76 (1H, m).

[Production Example 60-1-4] 3- (Pyridin-2-ylmethoxy) phenyl) -acetohydroximoyl chloride

To a solution of 2- (3- (2-nitroethyl) phenoxymethyl) pyridine (1.66 g, 6.43 mmol) described in Production Example 60-1-3, lithium methoxide (488) was added in methanol (20 ml). mg, 12.9 mmol). This mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The water in the residue was azeotropically distilled off with toluene, and then the residue was diluted with methylene chloride (24 ml) and tetrahydrofuran (12 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (2.26 ml, 20.6 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 2 hours, then cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.25 g).

The resulting compound was used in the subsequent reaction without further purification.

[Example 61] 3- (3- (3-Benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (3-benzyloxyphenyl) -acetohydroximoyl chloride (200 mg, 0.724 mmol) described in Production Example 61-1-4 and 3-ethynylpyridin-2-ylamine (55 mg, 0.462 mmol) described in Example 1-2- 3 receiving, in tetrahydrofuran (3 ml) at room temperature was added triethylamine (252 μl, 1.81 mm) and stirred at 50 ° C for 4 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and 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 = 4: 1 - 2: 1) to obtain the title compound (58 mg, 22%).

¹ H-NMR spectrum (CDCl ₃₎ δ (h / mn): 4,03 (2H, c) , 5,05 (2H, c), 5,68 (2H, brs), 6,24 (1H , c), 6.72-6.75 (1H, m), 6.88-6.90 (3H, m), 7.30-7.43 (6H, m), 7.72-7.74 (1H, m), 8.10-8.12 (1H, m).

The starting material, (3-benzyloxyphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 61-1-1] 3-Benzyloxybenzaldehyde

3-hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N, N-dimethylformamide (60 ml). Benzyl bromide (3.21 ml, 27.1 mmol) was added to this suspension, and the suspension was stirred at room temperature for 14 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (5.16 g, 99%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.13 (2H, s), 7.24-7.25 (1H, m), 7.35-7.49 (8H, m) 9.98 (1H, s).

[Production Example 61-1-2] 1-benzyloxy-3 - (( E ) -2-nitrovinyl) benzene

A mixture of 3-benzyloxybenzaldehyde (5.16 g, 24.3 mmol), described in Production Example 61-1-1, nitromethane (2.16 ml, 48.6 mmol), ammonium acetate (2.81 g, 36.5 mM) and acetic acid (50 ml) were stirred at 100 ° C for 6 hours. This mixture was then cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1 - 1: 1) to obtain the title compound (5.50 g, 89%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.11 (2H, s), 7.10-7.16 (3H, m), 7.35-7.45 (6H, m) 7.53-7.57 (1H, m); 7.95-7.98 (1H, m).

[Production Example 61-1-3] 1-benzyloxy-3- (2-nitroethyl) benzene

In an appropriately cooled solution of 1-benzyloxy-3 - (( E ) -2-nitrovinyl) benzene (5.5 g, 21.5 mmol), described in Production Example 61-1-2, in acetic acid (5, 5 ml) and dimethyl sulfoxide (94 ml) was added sodium borohydride (1.3 g, 34.4 mmol) at room temperature. This mixture was then stirred at room temperature for 1.5 hours and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1-4: 1) to obtain the title compound (3.14 g, 57%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.17-3.21 (2H, m), 4.83-4.86 (2H, m), 5.07 (2H, s) 6.84-6.86 (1H, m), 6.88-6.90 (1H, m), 6.96-6.97 (1H, m), 7.20-7.24 (1H, m), 7.31-7.35 (1H, m), 7.37-7.41 (2H, m), 7.44-7.46 (2H, m).

[Production Example 61-1-4] (3-Benzyloxyphenyl) -acetohydroximoyl chloride

To a solution of 1-benzyloxy-3- (2-nitroethyl) benzene (3.14 g, 12.2 mmol) described in Production Example 61-1-3, in methanol (40 ml) was added lithium methoxide (927 mg, 24.4 mmol). This mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Water in the residue was azeotropically distilled off with toluene, and then the residue was diluted with methylene chloride (48 ml) and tetrahydrofuran (24 ml). This mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (2.95 ml, 26.8 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 2 hours, then cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.48 g).

The resulting compound was used in the subsequent reaction without further purification.

[Example 62] 3- (3- (4- (5-Chlorofuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the mixture of (4- (5-chlorofuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Production Example 62-1-6 and tetrahydrofuran (1 ml) was added 3-ethynylpyridine at room temperature -2-ylamine (8.0 mg, 0.068 mmol) described in Production Example 1-2-3 and triethylamine (19 μl, 0.14 mmol) and stirred at 55 ° C for 1 hour. This mixture was cooled to room temperature and water was added at the same temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent 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% trifluoroacetic acid) to obtain the title compound as a crude product, which was then purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1) to obtain the title compound (3.8 mg, 15%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.90 (2H, s), 4.04 (2H, s), 5.54 (2H, br s), 5.99 (1H , td, J = 0.9, 3.3 Hz), 6.04 (1H, d, J = 3.1 Hz), 6.27 (1H, s), 6.72 (1H, dd, J = 4.9, 7.7 Hz), 7.19-7.25 (4H, m), 7.73 (1H, dd, J = 1.8, 7.7 Hz), 8.12 (1H, dd , J = 1.8, 4.9 Hz).

The starting material, (4- (5-chlorofuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 62-1-1] 4 - ((5-chlorofuran-2-yl) hydroxymethyl) benzonitrile

To a mixture of 4-iodobenzonitrile (3.0 g, 13 mmol) and tetrahydrofuran (40 ml) at -78 ° C, isopropyl magnesium chloride (1-2 M diethyl ether solution, 11 ml, 11-22 mmol) was added dropwise and stirred at 0 ° C for 1 hour. The reaction mixture was cooled to −78 ° C., 5-chloro-2-furaldehyde (2.2 g, 17 mmol) was added to it at the same temperature, and the temperature was gradually raised to 0 ° C. After stirring at 0 ° C for 30 minutes, a saturated aqueous solution of ammonium chloride, water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, then the residue was filtered using NH silica gel. The filtrate was concentrated under reduced pressure to obtain the title compound (3.2 g) as a crude product. The resulting compound was used in the subsequent reaction without further purification.

[Production Example 62-1-2] 4- (5-chlorofuran-2-ylmethyl) benzylamine

To a mixture of lithium aluminum hydride (3.3 g, 69 mmol) and tetrahydrofuran (100 ml) at 0 ° C, aluminum chloride (13 g, 96 mmol) was added and stirred at room temperature for 1 hour. A mixture of 4 - ((5-chlorofuran-2-yl) -hydroxymethyl) -benzonitrile (3.2 g) described in Production Example 62-1-1 was added dropwise to the reaction mixture and tetrahydrofuran was stirred at room temperature for 1 hour To remove excess reagent, a 28% aqueous ammonia solution was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was allowed to cool to room temperature and was filtered through a pad of celite. The solvent was evaporated from the filtrate under reduced pressure, and the residue was filtered after diethyl ether was added. The filtrate was concentrated under reduced pressure to obtain the title compound (2.6 g) as a crude product.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.85 (2H, s), 3.90 (2H, s), 5.97 (1H, td, J = 0.9, 3, 1 Hz), 6.04 (1H, d, J = 3.1 Hz), 7.20 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 7.9 Hz )

[Production Example 62-1-3] (4- (5-chlorofuran-2-ylmethyl) phenyl) methanol

To a mixture of 4- (5-chlorofuran-2-ylmethyl) benzylamine (2.6 g) described in Production Example 62-1-2, acetic acid (25 ml) and water (25 ml) was added nitrite at 0 ° C. sodium (9.8 g, 140 mmol) and stirred at room temperature for 40 minutes. Water and ethyl acetate were added to the extract of the reaction mixture. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and the solvent was evaporated under reduced pressure. Methanol (25 ml) was added to the residue at 0 ° C, then potassium carbonate (3.3 g, 24 mmol) was added at the same temperature. This mixture was stirred at the same temperature for 1 hour. Water and ethyl acetate were added to the extract of the reaction mixture. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and the organic layer was concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 2) to obtain the title compound (1.2 mg, 44%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.91 (2H, s), 4.68 (2H, s), 5.97 (1H, d, J = 3.1 Hz), 6.04 (1H, d, J = 3.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz).

[Production Example 62-1-4] 4- (5-chlorofuran-2-ylmethyl) benzaldehyde

To the mixture of (4- (5-chlorofuran-2-ylmethyl) phenyl) methanol (650 mg, 2.9 mmol) described in Production Example 62-1-3 and dichloromethane (20 ml) was added dioxide at room temperature manganese (6.5 g, 75 mmol) and then stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure to obtain the title compound (530 mg, 83%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.00 (2H, s), 6.04-6.05 (1H, m), 6.07-6.08 (1H, m) 7.40 (2H, d, J = 7.9 Hz); 7.84 (2H, d, J = 7.9 Hz); 10.00 (1H, s).

[Production Example 62-1-5] 2-chloro-5- (4- (2-nitroethyl) benzyl) furan

To a mixture of 4- (5-chlorofuran-2-ylmethyl) benzaldehyde (270 mg, 1.2 mmol) described in Production Example 62-1-4 and acetic acid (3 ml) was added nitromethane (500 μl at room temperature) , 9.3 mmol) and ammonium acetate (290 mg, 3.7 mmol) and stirred at 100 ° C for 3 hours. The reaction mixture was cooled to room temperature and was extracted with water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a suitably cooled mixture of acetic acid (0.6 ml) and dimethyl sulfoxide (10 ml) was added sodium borohydride (76 mg, 2.0 mmol) at room temperature and stirred at room temperature for 10 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure, and the residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (210 mg, 62%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.30 (2H, t, J = 7.4 Hz), 3.89 (2H, s), 4.60 (2H, t, J = 7.4 Hz), 5.97 (1H, d, J = 3.1 Hz), 6.04 (1H, d, J = 3.1 Hz), 7.15 (2H, d, J = 8 , 2 Hz), 7.19 (2H, d, J = 8.2 Hz).

[Production Example 62-1-6] (4- (5-chlorofuran-2-ylmethyl) -phenyl) -acetohydroximoyl chloride

To a mixture of 2-chloro-5- (4- (2-nitroethyl) benzyl) furan (100 mg, 0.38 mmol) described in Production Example 62-1-5 and methanol (2 ml) was added at room temperature lithium methoxide (29 mg, 0.75 mmol) and stirred at room temperature for 10 minutes. The solvent was evaporated from the reaction mixture under reduced pressure. To the mixture of the obtained residue, methylene chloride (2 ml) and tetrahydrofuran (1 ml), titanium (IV) chloride (91 μl, 0.83 mmol) was added at -78 ° C and stirred at 0 ° C for 1 hour. The reaction mixture was cooled to −78 ° C., water (1 ml) was added, and the temperature was gradually raised to room temperature. Ethyl acetate and water were added to the extract of the reaction mixture. The organic layer was washed with water until the pH was about 5. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (110 mg, 84%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.78 (2H, s), 3.91 (2H, s), 5.97-5.99 (1H, m), 6.04 (1H, d, J = 3.3 Hz); 7.21 (4H, d, J = 1.7 Hz).

[Example 63] 3- (3- (4- (5-Chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (3 ml) and a 5N aqueous sodium hydroxide solution (22.4 μl, 0.11 mmol) were added to 4- (5- (2-aminopyridin-3-yl) -isoxazol-3-ylmethyl) -phenol (30 mg , 0.11 mm), described in Production Example 5-1-1, and dissolved by sonication for 1 minute. The reaction solution was then concentrated under reduced pressure to obtain a white solid. To a suspension of this solid and N, N-dimethylformamide (1 ml) was added a solution of 5-chloro-2-chloromethylpyridine (20 mg, 0.12 mmol) described in Production Example 63-1-2 in N, N-dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (41.1 mg, 93%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.17 (2H, s), 6.26 (2H, br s), 6.68 -6.72 (1H, m), 6.80 (1H, s), 6.99 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.8 Hz) 7.55 (1H, d, J = 8.4 Hz), 7.87 (1H, dd, J = 1.6, 8.0 Hz), 7.97 (1H, dd, J = 2.4 , 8.4 Hz), 8.09 (1H, d, J = 1.6, 4.8 Hz), 8.64 (1H, d, J = 2.4 Hz).

The starting material, 5-chloro-2-chloromethylpyridine, was synthesized as follows.

[Production Example 63-1-1] (5-chloropyridin-2-yl) methanol

To a mixture of 2-bromo-5-chloropyridine (2.0 g, 10.4 mmol) and toluene (50 ml) was added a 1.6 M solution of n- butyllithium in hexane (7.8 ml, 12, 5 mM) and the mixture was stirred for 1 hour. Then, N, N-dimethylformamide (4.0 ml, 52.0 mmol) was added dropwise to this mixture at the same temperature and stirred at room temperature for 15 minutes. Water and tetrahydrofuran were added to this reaction solution, and then stirred vigorously. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Sodium borohydride (1.18 g, 31.2 mmol) was added to the filtrate at 0 ° C and stirred at room temperature for 1 hour. This reaction solution was separated into water and tetrahydrofuran. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (hexane: diethyl ether = 1: 2) to obtain the title compound (706 mg, 47%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.75 (2H, s), 7.25 (1H, dd, J = 0.8, 8.4 Hz), 7.68 (1H dd, J = 2.4, 8.4 Hz), 8.53 (1H, d, J = 2.4 Hz).

[Production Example 63-1-2] 5-chloro-2-chloromethylpyridine

To the mixture of (5-chloropyridin-2-yl) methanol (706 mg, 4.92 mmol) described in Production Example 63-1-1 and dichloromethane (70 ml) was added thionyl chloride (539 μl, 7.38 mmol) and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, then the mixture was extracted with dichloromethane. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (620.0 mg, 78%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.66 (2H, s), 7.45 (1H, d, J = 8.0 Hz), 7.71 (1H, dd, J = 2.8, 8.0 Hz), 8.54 (1H, d, J = 2.8 Hz).

[Example 64] 3- (3- (3-Phenoxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (3-phenoxyphenyl) -acetohydroximoyl chloride (150 mg, 0.573 mmol) described in Production Example 64-1-3, and 3-ethynylpyridin-2-ylamine (30.0 mg, 0.254 mmol) described in Example 1- 2-3 preparation, triethylamine (106 μl, 0.762 mmol) was added in tetrahydrofuran (10.0 ml) at room temperature and stirred at 60 ° C for 2 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 2), then the mixture was further purified by reverse phase high performance liquid chromatography (using acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound ( 6.6 mg, 43%) as a trifluoroacetic acid salt.

MS m / e (ESI) 344.07 (MH ⁺ )

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 4.08 (2H, s), 6.81 (1H, s), 6.85-6.87 (1H, m), 6, 96-6.98 (3H, m), 7.03-7.12 (3H, m), 7.29-7.36 (3H, m), 8.03-8.04 (1H, m), 8.32-8.34 (1H, m).

The starting material, (3-phenoxyphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 64-1-1] 1 - (( E ) -2-nitrovinyl) -3-phenoxybenzene

To a solution of 3-phenoxybenzaldehyde (3.00 g, 15.1 mmol) in acetic acid (20.0 ml) at room temperature under nitrogen atmosphere was added nitromethane (4.61 g, 75.5 mmol) and ammonium acetate (2, 33 g, 30.2 mmol) and stirred at 100 ° C for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.60 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.03-7.06 (2H, m), 7.12-7.19 (2H, m), 7.39-7, 44 (2H, m), 7.47-7.51 (1H, m), 7.61-7.66 (2H, m), 8.13 (1H, d, J = 13.6 Hz), 8 25 (1H, d, J = 13.6 Hz).

[Production Example 64-1-2] 1- (2-nitroethyl) -3-phenoxybenzene

In an appropriately cooled solution of 1 - (( E ) -2-nitrovinyl) -3-phenoxybenzene (3.60 g, 14.9 mmol) described in Production Example 64-1-1 and acetic acid (3.00 ml ) in dimethyl sulfoxide (30.0 ml), sodium borohydride (902 mg, 23.8 mmol) was added at room temperature under a nitrogen atmosphere and stirred for 3 minutes. Then, by cooling appropriately, water was added dropwise at room temperature. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (2.47 g, 68.1%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.22 (2H, t, J = 6.8 Hz), 4.84 (2H, t, J = 6.8 Hz), 6.85-6.88 (1H, m), 6.98-7.00 (3H, m), 7.04-7.06 (1H, m), 7.12-7.16 (1H, m) ), 7.30-7.34 (1H, m), 7.37-7.41 (2H, m).

[Production Example 64-1-3] (3-phenoxyphenyl) -acetohydroximoyl chloride

To a solution of 1- (2-nitroethyl) -3-phenoxybenzene (800 mg, 3.29 mmol) described in Production Example 64-1-2, in methanol (10.0 ml) at room temperature, lithium methoxide was added (250 mg, 6.58 mmol) and stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Titanium (IV) chloride (1.08 ml, 9.87 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C), and then stirred at room temperature for 45 minutes. Water and ethyl acetate were added to this reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain the title compound (860 mg, 100%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.81 (2H, s), 6.90-6.91 (2H, m), 7.00-7.04 (3H, m), 7.13-7.17 (1H, m), 7.34-7.42 (3H, m), 11.75 (1H, s).

[Example 65 3- (3- (3-Butoxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (3-butoxyphenyl) -acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Production Example 65-1-4 and 3-ethynylpyridin-2-ylamine (47 mg, 0.396 mmol) described in Example 1-2- 3 preparation, triethylamine (216 μl, 1.55 mmol) was added in tetrahydrofuran (3 ml) at room temperature and stirred at 50 ° C for 2 hours. Water was added to this reaction solution at room temperature, then it was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (33 mg, 8%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.95-0.99 (3H, m), 1.46-1.51 (2H, m), 1.72-1.79 ( 2H, m), 3.93-3.96 (2H, m), 4.02 (2H, s), 5.51 (2H, br.s), 6.27 (1H, s), 6.70 -6.73 (1H, m), 6.79-6.86 (4H, m), 7.71-7.73 (1H, m), 8.12-8.13 (1H, m).

The starting material, (3-butoxyphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 65-1-1] 3-butoxybenzaldehyde

3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N, N-dimethylformamide (60 ml). To this suspension was added 1-bromobutane (3.17 ml, 29.5 mmol) and stirred at room temperature for 19 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (4.23 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.97-1.01 (3H, m), 1.48-1.56 (2H, m), 1.76-1.81 ( 2H, m), 4.01-4.04 (2H, m), 7.16-7.19 (1H, m), 7.384-7.390 (1H, m), 7.43-7.45 (2H, m), 9.97 (1H, s).

[Production Example 65-1-2] 1-butoxy-3 - ((E) -2-nitrovinyl) benzene

A mixture of 3-butoxybenzaldehyde (4.23 g, 23.7 mmol) described in Production Example 65-1-1, nitromethane (2.55 ml, 47.7 mmol), ammonium acetate (2.74 g, 35.6 mM) and acetic acid (40 ml) were stirred at 100 ° C for 5 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (3.92 g, 75%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.93-0.96 (3H, m), 1.42-1.47 (2H, m), 1.68-1, 75 (2H, m), 3.97-4.05 (2H, m), 7.07-7.10 (1H, m), 7.35-7.41 (2H, m), 7.458-7.462 ( 1H, m), 8.09 (1H, d, J = 13.6 Hz), 8.27 (1H, d, J = 13.6 Hz).

[Production Example 65-1-3] 1-butoxy-3- (2-nitroethyl) benzene

In an appropriately cooled solution of 1-butoxy-3 - ((E) -2-nitrovinyl) benzene (3.92 g, 17.7 mmol), described in [Production Example 65-1-2, in acetic acid (3 , 9 ml) and dimethyl sulfoxide (67 ml) was added sodium borohydride (1.07 g, 28.3 mmol) at room temperature. This mixture was stirred at room temperature for 4 hours, then partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1) to obtain the title compound (2.29 g, 58%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.91-0.95 (3H, m), 1.38-1.47 (2H, m), 1.65-1.70 ( 2H, m), 3.16-3.20 (2H, m), 3.92-3.95 (2H, m), 4.82-4.86 (2H, m), 6.78-6, 82 (2H, m), 6.85-6.86 (1H, m), 7.18-7.22 (1H, m).

[Production Example 65-1-4] (3-butoxyphenyl) -acetohydroximoyl chloride

To a solution of 1-butoxy-3- (2-nitroethyl) benzene (2.29 g, 10.3 mmol) described in Production Example 65-1-3, in methanol (28 ml) was added lithium methoxide (782 mg, 20.6 mmol). This mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The water in the residue was azeotropically distilled off with toluene, and the obtained residue was diluted with methylene chloride (33 ml) and tetrahydrofuran (16.5 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (2.49 ml, 22.7 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 2 hours, then cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2.85 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 66] 3- (3- (3-Cyclopropylmethoxybenzyl) -isoxazol-5-yl) pyridin-2-ylamine

To the solution of (3-cyclopropylmethoxyphenyl) -acetohydroximoyl chloride (150 mg, 0.624 mmol) described in Production Example 66-1-4 and 3-ethynylpyridin-2-ylamine (47 mg, 0.398 mmol) described in Example 1-2- 3 receiving, in tetrahydrofuran (3 ml) at room temperature was added triethylamine (220 μl, 1.56 mm) and stirred at 50 ° C for 2 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (26 mg, 13%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.32-0.36 (2H, m), 0.62-0.66 (2H, m), 1.24-1.28 ( 1H, m), 3.78-3.80 (2H, m), 4.02 (2H, s), 5.55 (2H, br.s), 6.27 (1H, s), 6.70 -6.74 (1H, m), 6.79-6.87 (3H, m), 7.22-7.24 (1H, m), 7.71-7.74 (1H, m), 8 11-8.13 (1H, m).

The starting material, (3-cyclopropylmethoxyphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 66-1-1] 3-cyclopropylmethoxybenzaldehyde

3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N, N-dimethylformamide (60 ml). Cyclopropylmethyl chloride (2.86 ml, 29.5 mmol) was added to this suspension and stirred at room temperature for 19 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (4.32 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.36-0.39 (2H, m), 0.65-0.69 (2H, m), 1.24-1.29 ( 1H, m), 3.86-3.88 (2H, m), 7.18-7.21 (1H, m), 7.37-7.38 (1H, m), 7.44-7, 45 (2H, m); 9.97 (1H, s).

[Production Example 66-1-2] 1-cyclopropylmethoxy-3 - ((E) -2-nitrovinyl) benzene

A mixture of 3-cyclopropylmethoxybenzaldehyde (4.32 g, 24.5 mmol) described in Production Example 66-1-1, nitromethane (2.64 ml, 49 mmol), ammonium acetate (2.83 g, 36.8 mmol) and acetic acid (40 ml) was stirred at 100 ° C for 5 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (3.73 g, 69%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.31-0.36 (2H, m), 0.56-0.61 (2H, m), 1.22-1, 26 (1H, m), 3.86-3.91 (2H, m), 7.08-7.11 (1H, m), 7.35-7.41 (2H, m), 7.45- 7.46 (1H, m), 8.08 (1H, d, J = 14 Hz), 8.27 (1H, d, J = 14 Hz).

[Production Example 66-1-3] 1-cyclopropylmethoxy-3- (2-nitroethyl) benzene

In a suitably cooled solution of 1-cyclopropylmethoxy-3 - ((E) -2-nitrovinyl) benzene (3.73 g, 17 mmol), described in Production Example 66-1-2, in acetic acid (3.7 ml ) and dimethyl sulfoxide (63 ml) was added sodium borohydride (1.03 g, 27.2 mmol) at room temperature. This mixture was stirred at room temperature for 4 hours and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1) to obtain the title compound (2.21 g, 59%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.30-0.32 (2H, m), 0.54-0.57 (2H, m), 1.17-1, 24 (1H, m), 3.17-3.19 (2H, m), 3.78-3.80 (2H, m), 4.82-4.85 (2H, m), 6.77- 6.82 (2H, m), 6.85-6.86 (1H, m), 7.17-7.21 (1H, m).

[Production Example 66-1-4] (3-Cyclopropylmethoxyphenyl) -acetohydroximoyl chloride

To a solution of 1-cyclopropylmethoxy-3- (2-nitroethyl) benzene (2.21 g, 10 mmol) described in Production Example 66-1-3, in methanol (27 ml) lithium methoxide (759 mg, 20 mmol) was added. ) This mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The water in the residue was azeotropically distilled off with toluene, and the obtained residue was diluted with methylene chloride (32 ml) and tetrahydrofuran (16 ml). The mixture was cooled to −78 ° C., and titanium (IV) tetrachloride (2.42 ml, 22 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 2 hours, then cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2.5 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 67] 3- (3- (4-Butoxybenzyl) -isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4-butoxyphenyl) -acetohydroximoyl chloride (150 mg, 0.619 mmol) described in Production Example 67-1-4 and 3-ethynylpyridin-2-ylamine (47 mg, 0.395 mmol) described in Example 1-2- 3 preparation, triethylamine (216 μl, 1.55 mmol) was added in tetrahydrofuran (3 ml) at room temperature and stirred at 50 ° C for 2 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (27 mg, 14%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.95-0.99 (3H, m), 1.44-1.53 (2H, m), 1.72-1.79 ( 2H, m), 3.93-3.96 (2H, m), 4.00 (2H, s), 5.65 (2H, br.s), 6.25 (1H, s), 6.71 -6.74 (1H, m), 6.86-6.88 (2H, m), 7.17-7.20 (2H, m), 7.72-7.75 (1H, m), 8 10-8.12 (1H, m).

The starting material, (4-butoxyphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 67-1-1] 4-butoxybenzaldehyde

4-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N, N-dimethylformamide (60 ml). To this suspension was added 1-bromobutane (3.17 ml, 29.5 mmol) and stirred at room temperature for 17 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (4.72 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.97-1.01 (3H, m), 1.48-1.54 (2H, m), 1.79-1.82 ( 2H, m), 4.03-4.07 (2H, m), 6.98-7.00 (2H, m), 7.82-7.84 (2H, m), 9.88 (1H, c)

[Production Example 67-1-2] 1-butoxy-4 - ((E) -2-nitrovinyl) benzene

A mixture of 4-butoxybenzaldehyde (4.72 g, 26.5 mmol) described in Production Example 67-1-1, nitromethane (2.85 ml, 53 mmol), ammonium acetate (3.06 g, 39.8 mmol) and acetic acid (40 ml) was stirred at 100 ° C for 13 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (4.44 g, 76%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.92-0.95 (3H, m), 1.41-1.46 (2H, m), 1.67-1, 74 (2H, m), 4.04-4.09 (2H, m), 7.13 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J = 8.8 Hz ), 8.09 (1H, d, J = 13.6 Hz), 8.13 (1H, d, J = 13.6 Hz).

[Production Example 67-1-3] 1-butoxy-4- (2-nitroethyl) benzene

In a suitably cooled solution of 1-butoxy-4 - ((E) -2-nitrovinyl) benzene (4.44 g, 20.1 mmol), described in Production Example 67-1-2, in acetic acid (4, 4 ml) and dimethyl sulfoxide (75 ml) was added sodium borohydride (1.22 g, 32.2 mmol) at room temperature. This mixture was stirred at room temperature for 4 hours, then partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1) to obtain the title compound (3.42 g, 76%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.90-0.95 (3H, m), 1.37-1.47 (2H, m), 1.63-1.70 ( 2H, m), 3.12-3.16 (2H, m), 3.91-3.94 (2H, m), 4.76-4.80 (2H, m), 6.83-6, 87 (2H, m), 7.14-7.18 (2H, m).

[Production Example 67-1-4] (4-butoxyphenyl) -acetohydroximoyl chloride

To a solution of 1-butoxy-4- (2-nitroethyl) benzene (3.42 g, 15.3 mmol) described in Production Example 67-1-3, in methanol (42 ml) was added lithium methoxide (1.16 g, 30.6 mmol). This mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. Water in the residue was azeotropically distilled off with toluene, and the obtained residue was diluted with methylene chloride (50 ml) and tetrahydrofuran (25 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (3.7 ml, 33.7 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 2 hours, then cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.5 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 68] 3- (3- (4-Benzylaminobenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (4-benzylaminophenyl) -acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Production Example 68-1-4 and 3-ethynylpyridin-2-ylamine (41 mg, 0.348 mmol) described in Example 1-2- 3 preparation, in tetrahydrofuran (3 ml) at room temperature was added triethylamine (190 μl, 1.37 mmol) and stirred at 50 ° C for 7 hours. Water was added to this reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (14 mg, 7%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.94 (2H, s), 4.32 (2H, s), 5.69 (2H, br s), 6.26 (1H , c), 6.59-6.62 (2H, m), 6.71-6.74 (1H, m), 7.06-7.09 (2H, m), 7.24-7.38 (4H, m), 7.73-7.75 (1H, m), 8.09-8.10 (1H, m).

(The presence of a proton in the amino group of NH-CH2Ph was not observed in the NMR diagram.)

The starting material, (4-benzylamino-phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 68-1-1] 4-benzylaminobenzaldehyde

To a solution of 4-benzylamino-benzonitrile (5 g, 24 mmol) in toluene (35 ml) at a temperature of from -70 ° C to -78 ° C in a nitrogen atmosphere was added diisobutylaluminum hydride (35.6 ml, a 1.01 M toluene solution 36 mM). This mixture was stirred at room temperature for 5 hours, partitioned into ethyl acetate and a 20% aqueous Rochelle salt solution. After removal of the insoluble matter by filtration through a layer of celite, the filtrate was separated. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5 g, 99%). The resulting compound was used in the subsequent reaction without further purification.

[Production Example 68-1-2] Benzyl- (4 - ((E) -2-nitrovinyl) phenyl) amine

A mixture of 4-benzylaminobenzaldehyde (5 g, 23.7 mmol) described in Production Example 68-1-1, nitromethane (2.55 ml, 47.7 mmol), ammonium acetate (2.74 g, 35.6 mmol) and acetic acid (50 ml) was stirred at 100 ° C for 6 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5.82 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.41-4.43 (2H, m), 4.68 (1H, br s), 6.62-6.67 (2H, m), 7.25-7.39 (6H, m), 7.47-7.50 (1H, m), 7.69-7.71 (1H, m), 7.93-7.96 ( 1H, m).

[Production Example 68-1-3] Benzyl- (4- (2-nitroethyl) phenyl) amine

In a suitably cooled solution of benzyl- (4 - ((E) -2-nitrovinyl) phenyl) amine (5.82 g, 22.9 mmol), described in Production Example 68-1-2, in acetic acid ( 5.8 ml) and dimethyl sulfoxide (100 ml) was added sodium borohydride (1.39 g, 36.6 mmol) at room temperature. This mixture was stirred at room temperature for 1 hour and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (2.79 g, 48%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.19-3.22 (2H, m), 4.32 (2H, s), 4.52-4.56 (3H, m) 6.60-6.62 (2H, m), 7.00-7.02 (2H, m), 7.27-7.37 (5H, m).

[Production Example 68-1-4] (4-benzylaminophenyl) -acetohydroximoyl chloride

To a solution of benzyl- (4- (2-nitroethyl) phenyl) amine (1 g, 3.91 mmol) described in Production Example 68-1-3, in methanol (12 ml) lithium methoxide (297 mg, 30.6 mmol). This mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The water in the residue was azeotropically distilled off using toluene, and the obtained residue was diluted with methylene chloride (15 ml) and tetrahydrofuran (7.6 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (945 μl, 8.6 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 1 hour, then cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.1 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 69] 3- (3- (4-phenylaminobenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (4-phenylaminophenyl) -acetohydroximoyl chloride (150 mg, 0.576 mmol) described in Production Example 69-1-4 and 3-ethynylpyridin-2-ylamine (43 mg, 0.367 mmol) described in Example 1-2- 3 receiving, in tetrahydrofuran (3 ml) at room temperature was added triethylamine (201 μl, 1.44 mmol) and stirred at 50 ° C for 7 hours. Water was added to this reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (48 mg, 24%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.00 (2H, s), 5.58 (2H, br s), 5.70 (1H, br s), 6.29 (1H, s), 6.71-6.74 (1H, m), 6.91-6.95 (1H, m), 7.03-7.07 (4H, m), 7.16-7 19 (2H, m), 7.24-7.28 (2H, m), 7.73-7.75 (1H, m), 8.11-8.13 (1H, m).

The starting material, (4-phenylaminophenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 69-1-1] 4-Phenylaminobenzaldehyde

To a solution of 4-phenylaminobenzonitrile (3 g, 15.4 mmol) in toluene (20 ml) at -78 ° C under nitrogen atmosphere was added diisobutylaluminum hydride (22.9 ml, a 1.01 M toluene solution, 23.1 mmol). This mixture was stirred at room temperature for 5 hours and partitioned into ethyl acetate and a 20% aqueous Rochelle salt solution. After removal of the insoluble matter by filtration through a celite pad, the filtrate was separated. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3 g, 98%). The resulting compound was used in the subsequent reaction without further purification.

[Production Example 69-1-2] (4 - ((E) -2-nitrovinyl) phenyl) phenylamine

A mixture of 4-phenylaminobenzaldehyde (3 g, 15.2 mmol) described in Production Example 69-1-1, nitromethane (1.63 ml, 30.4 mmol), ammonium acetate (1.76 g, 22.8 mmol) and acetic acid (30 ml) was stirred at 100 ° C for 6 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.2 g). The resulting compound was used in the subsequent reaction without purification.

[Production Example 69-1-3] (4- (2-nitroethyl) phenyl) phenylamine

In an appropriately cooled solution of (4 - ((E) -2-nitrovinyl) phenyl) phenylamine (3.2 g, 13.4 mmol) described in Production Example 69-1-2, in acetic acid (3, 2 ml) and dimethyl sulfoxide (54 ml) was added sodium borohydride (811 mg, 21.4 mmol) at room temperature. This mixture was stirred at room temperature for 1 hour and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (2.01 g, 62%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.24-3.28 (2H, m), 4.56-4.60 (2H, m), 5.81 (1H, br. s), 6.93-6.98 (1H, m), 7.00-7.12 (6H, m), 7.24-7.29 (2H, m).

[Production Example 69-1-4] (4-phenylaminophenyl) -acetohydroximoyl chloride

To a solution of (4- (2-nitroethyl) phenyl) phenylamine (1 g, 4.13 mmol) described in Production Example 69-1-3, in methanol (12 ml) lithium methoxide (314 mg, 8, 26 mM). This mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The water in the residue was azeotropically distilled off using toluene, and the obtained residue was diluted with methylene chloride (15 ml) and tetrahydrofuran (7.6 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (999 μl, 9.09 mmol) was added dropwise to the suspension. The mixture was stirred at room temperature for 1 hour. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.2 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 70] 3- (3- (4-Butylbenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (4-butylphenyl) -acetohydroximoyl chloride (150 mg, 0.665 mmol) described in Production Example 70-1-3, and 3-ethynylpyridin-2-ylamine (50 mg, 0.424 mmol) described in Example 1-2- 3 receiving, in tetrahydrofuran (3 ml) at room temperature was added triethylamine (232 μl, 1.66 mm) and stirred at 50 ° C for 8 hours. Water was added to this reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and 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 = 4: 1 - 2: 1) to obtain the title compound (55 mg, 18%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.91-0.94 (3H, m), 1.31-1.40 (2H, m), 1.55-1.63 ( 2H, m), 2.57-2.61 (2H, m), 4.03 (2H, s), 5.53 (2H, br.s), 6.26 (1H, s), 6.70 -6.73 (1H, m), 7.14-7.20 (4H, m), 7.71-7.73 (1H, m), 8.11-8.13 (1H, m).

The starting material, (4-butylphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 70-1-1] 1-butyl-4 - ((E) -2-nitrovinyl) benzene

A mixture of 4 -n- butylbenzaldehyde (5 g, 30.8 mmol), nitromethane (3.31 ml, 61.6 mmol), ammonium acetate (3.56 g, 46.2 mmol) and acetic acid (50 ml) was stirred at 100 ° C for 5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5.7 g). The resulting compound was used in the subsequent reaction without purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.92-0.95 (3H, m), 1.34-1.39 (2H, m), 1.58-1.65 ( 2H, m), 2.64-2.68 (2H, m), 7.25-7.27 (2H, m), 7.45-7.48 (2H, m), 7.56-7, 59 (1H, m), 7.98-8.02 (1H, m).

[Production Example 70-1-2] 1-butyl-4- (2-nitroethyl) benzene

To a suitably cooled solution of 1-butyl-4 - ((E) -2-nitrovinyl) benzene (5.7 g, 27.8 mmol), described in Production Example 70-1-1, in acetic acid (5, 7 ml) and dimethyl sulfoxide (95 ml) was added sodium borohydride (1.68 g, 44.5 mmol) at room temperature. This mixture was stirred at room temperature for 3 hours and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (1.48 g, 26%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.90-0.94 (3H, m), 1.31-1.37 (2H, m), 1.54-1.61 ( 2H, m), 2.56-2.60 (2H, m), 3.27-3.30 (2H, m), 4.57-4.61 (2H, m), 7.10-7, 15 (4H, m).

[Production Example 70-1-3] (4-butylphenyl) -acetohydroximoyl chloride

To a solution of 1-butyl-4- (2-nitroethyl) benzene (1.48 g, 7.14 mmol) described in Production Example 70-1-2, in methanol (18 ml) lithium methoxide (542 mg, 14.3 mmol). This mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The water in the residue was azeotropically distilled off with toluene, and the obtained residue was diluted with methylene chloride (22 ml) and tetrahydrofuran (11 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (1.7 ml, 15.7 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 1 hour, cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.5 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 71] 3- (3- (6- (3-Fluorophenoxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (20 mg, 0.17 mmol) described in Production Example 1-2-3, and (6- (3-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride (95 mg , 0.34 mmol) described in Production Example 71-1-4, triethylamine (47 μl, 0.34 mmol) was added in tetrahydrofuran (4 ml) and stirred at 50 ° C. under nitrogen for 3 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the filtrate was purified by NH silica gel column chromatography (ethyl acetate: methanol = 20: 1) and further purified by reverse phase high performance liquid chromatography (using acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the indicated in the title compound (33 mg, 33%) as a salt of ditrifluoroacetic acid.

MS m / e (ESI) (MH +) 363.01 (MH +)

The starting material, (6- (3-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 71-1-1] 5-bromo-2- (3-fluorophenoxy) pyridine

To a solution of 3-fluorophenol (3.30 g, 29.4 mmol) in N, N-dimethylformamide (100 ml) was added sodium hydride (1.41 g, 29.4 mmol, 50% in oil) and stirred at 0 ° C for 10 minutes. Then, 2,5-dibromopyridine (4.64 g, 19.6 mmol) was added to this mixture at 0 ° C and stirred at 110 ° C for 7 hours 45 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (5.81 g).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.00-7.02 (1H, m), 7.08-7.13 (3H, m), 7.43-7, 49 (1H, m), 8.09 (1H, dd, J = 2.8, 8.8 Hz), 8.31 (1H, d, J = 2.8 Hz).

[Production Example 71-1-2] 6- (3-Fluorophenoxy) -pyridin-3-carbaldehyde

To a solution of 5-bromo-2- (3-fluorophenoxy) -pyridine (5.81 g, 21.7 mmol) described in Production Example 71-1-1 in diethyl ether (100 ml) at -78 ° C in under nitrogen atmosphere n- butyllithium (13.8 ml, 1.57 M n- hexane solution, 21.7 mmol) was added and stirred at -78 ° C for 40 minutes. Then, N, N-dimethylformamide (2.02 ml, 26.0 mmol) was added to the mixture at -78 ° C and stirred for 25 minutes, gradually raising the temperature to 0 ° C. Water was added to the reaction solution at 0 ° C. and then extracted with ethyl acetate. The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain the title compound (2.47 g, 52%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 6.91-7.01 (3H, m), 7.06 (1H, d, J = 8.8 Hz), 7.37-7 42 (1H, m), 8.20 (1H, dd, J = 2.4, 8.4 Hz), 8.62 (1H, d, J = 2.4 Hz), 9.98 (1H, c)

[Production Example 71-1-3] 2- (3-fluorophenoxy) -5- (2-nitroethyl) pyridine

To a solution of 6- (3-fluorophenoxy) -pyridine-3-carbaldehyde (2.47 g, 11.4 mmol) described in Production Example 71-1-2, nitromethane (3.09) was added in acetic acid (20 ml). ml, 57.0 mmol) and ammonium acetate (1.76 g, 22.8 mmol) and stirred at 100 ° C for 6 hours. Water was added to this reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of the residue in dimethyl sulfoxide (35 ml) and acetic acid (5 ml) was added sodium borohydride (681 mg, 17.1 mmol) and stirred at room temperature for 40 minutes. Sodium hydrogen carbonate and water were added to the appropriately cooled reaction solution at room temperature, and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (1.96 g, 66%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.30 (2H, t, J = 7.1 Hz), 4.61 (2H, t, J = 7.1 Hz), 6, 86-6.94 (4H, m), 7.32-7.38 (1H, m), 7.58 (1H, dd, J = 2.6, 8.4 Hz), 8.07 (1H, d, J = 2.2 Hz).

[Production Example 71-1-4] (6- (3-Fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride

To a solution of 2- (3-fluorophenoxy) -5- (2-nitroethyl) pyridine (1.96 g, 7.47 mmol) described in Production Example 71-1-3, in methanol (20 ml) was added lithium methoxide (567 mg, 14.9 mmol) and stirred at room temperature for 35 minutes. The reaction mixture was concentrated under reduced pressure. Titanium (IV) tetrachloride (1.81 ml, 16.4 mmol) was added to a suspension of the residue in tetrahydrofuran (20 ml) and methylene chloride (20 ml) under nitrogen atmosphere and stirred at 0 ° C for 1 hour 15 minutes. Water was added to the reaction solution at 0 ° C. and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (in an amount of 2.1 g). The resulting compound was used in the subsequent reaction without further purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.77 (2H, s), 6.87-6.95 (4H, m), 7.31-7.38 (1H, m) 7.65 (1H, dd, J = 2.6, 8.4 Hz); 8.12 (1H, d, J = 2.6 Hz).

[Example 72] 3- (3- (6- (4-Fluorophenoxymethyl) -pyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-ylamine

To a solution of 2- (4-fluorophenoxymethyl) -5- (2-nitroethyl) pyridine (50.0 mg, 0.181 mmol) described in Production Example 72-1-3 in methanol (5.00 ml) at room temperature lithium methoxide (13.7 mg, 0.362 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (4.00 ml) and anhydrous tetrahydrofuran (2.00 ml) were added to the residue. Titanium (IV) chloride (63.7 μl, 0.579 mmol) was added dropwise to the reaction solution in a dry ice-ethanol bath (-78 ° C) and stirred at 0 ° C for 40 minutes. Water and ethyl acetate were added to this reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (43.0 mg). To a solution of this crude product (23.0 mg) and 3-ethynylpyridin-2-ylamine (3.44 mg, 0.029 mmol), described in Production Example 1-2-3, in tetrahydrofuran (5.00 ml) at room temperature triethylamine (12.2 μl, 0.083 mmol) was added and stirred at room temperature for 2 hours. Water was added to this reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 2), the mixture was further purified by reverse phase high performance liquid chromatography (using acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3 , 62 mg, 25.4%) as a salt of ditrifluoroacetic acid.

MS m / e (ESI) 377.18 (MH +)

The starting material, 2- (4-fluorophenoxymethyl) -5- (2-nitroethyl) pyridine, was synthesized as follows.

[Production Example 72-1-1] 5-bromo-2- (4-fluorophenoxymethyl) -pyridine

To a solution of 4-fluorophenol (3.00 g, 26.8 mmol) in N, N-dimethylformamide (40.0 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (1.00 g, 25, 0 mM, 60% in oil) and stirred at room temperature for 20 minutes. Then a mixture of 5-bromo-2-chloromethylpyridine hydrochloride (4.6 g, 22.3 mmol) described in Production Example 54-1-2 and triethylamine (30.6 ml, 20.4 mmol) was added to the reaction solution. stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (4.0 g, 63.6%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.10 (2H, s), 6.88-6.91 (2H, m), 6.95-6.99 (2H, m) 7.40-7.42 (1H, m); 7.81-7.84 (1H, m); 8.64-8.65 (1H, m).

[Production Example 72-1-2] 6- (4-fluorophenoxymethyl) -pyridin-3-carbaldehyde

To a solution of 5-bromo-2- (4-fluorophenoxymethyl) -pyridine (4.00 g, 14.2 mmol) described in Production Example 72-1-1 in diethyl ether (100 ml) in a bath with a mixture of dry ice -ethanol (-78 ° C) in a nitrogen atmosphere n- butyllithium (2.55 M n- hexane solution, 6.13 ml, 15.6 mmol) was added dropwise and stirred at -78 ° C for 40 minutes. Then, N, N-dimethylformamide (1.32 ml, 17.0 mmol) was added dropwise and stirred at -78 ° C for 5 minutes. The reaction solution was cooled to room temperature and water was added, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (1.00 g, 30.5%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.25 (2H, s), 6.91-7.02 (4H, m), 7.71-7.75 (1H, m) 8.19-8.22 (1H, m); 9.04-9.05 (1H, m); 10.12 (1H, s).

[Production Example 72-1-3] 2- (4-fluorophenoxymethyl) -5- (2-nitroethyl) pyridine

To a solution of 6- (4-fluorophenoxymethyl) -pyridin-3-carbaldehyde (500 mg, 1.30 mmol) described in Production Example 72-1-2 in nitric acid was added nitromethane (5.00 ml) under nitrogen atmosphere ( 923 mg, 15.1 mmol) and ammonium acetate (333 mg, 4.32 mmol) and stirred at 105 ° C. for 2 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure. Dimethyl sulfoxide (10.0 ml) and acetic acid (600 μl) were added to the residue, and then sodium borohydride (131 mg, 3.46 mmol) was added at room temperature, cooling accordingly. After stirring for 20 minutes at room temperature, water was added dropwise, cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1) to obtain the title compound (50 mg, 8.38%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.36 (2H, t, J = 6.8 Hz), 4.96 (2H, t, J = 6.8 Hz), 5.40 (2H, s), 7.01-7.05 (2H, m), 7.16-7.20 (2H, m), 7.84 (1H, d, J = 8.0 Hz) 8.17 (1H, dd, J = 2.0, 8.4 Hz); 8.75 (1H, s).

[Example 73] 3- (3- (4-Phenylaminomethylbenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (4-phenylaminomethylphenyl) -acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Production Example 73-1-6, and 3-ethynylpyridin-2-ylamine (41 mg, 0.348 mmol) described in Example 1-2- 3 receiving, in tetrahydrofuran (3 ml) was added triethylamine (104 μl, 0.748 mmol) and stirred at room temperature for 7 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1-1: 2) to obtain the title compound (11 mg, 6%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.05 (2H, s), 4.32 (2H, s), 5.39 (2H, br s), 6.26 (1H , c), 6.62-6.64 (2H, m), 6.69-6.74 (2H, m), 7.15-7.23 (5H, m), 7.34-7.36 (2H, m), 7.69-7.72 (1H, m), 8.13-8.15 (1H, m).

The starting material, (4-phenylaminomethylphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 73-1-1] 4- [1,3] dioxolan-2-ylbenzaldehyde

To a solution of 2- (4-bromophenyl) -1,3-dioxolane (8 g, 34.9 mmol) in tetrahydrofuran (100 ml) at -78 ° C was added dropwise n- butyllithium (19.6 ml, 2.67 M hexane solution, 52.4 mmol). After stirring at −78 ° C. for 1 hour, N-formylmorpholine (4.42 g, 38.4 mmol) was added to the mixture, and stirred at the same temperature for 3 hours. This mixture was partitioned into diethyl ether and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (6.3 g). The resulting compound was used in the subsequent reaction without purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.04-4.16 (4H, m), 5.89 (1H, s), 7.65-7.67 (2H, m) 7.90-7.92 (2H, m); 10.0 (1H, s).

[Production Example 73-1-2] (4- [1,3] dioxolan-2-yl-benzyl) -phenylamine

To the solution of 4- [1,3] dioxolan-2-yl-benzaldehyde (6.32 g, 35.5 mmol) described in Production Example 73-1-1, aniline (2.08 ml, 35.5 mmol) and acetic acid (10.2 ml, 178 mmol) in tetrahydrofuran (200 ml) sodium triacetoxyborohydride (15 g, 71 mmol) was added. This mixture was stirred at room temperature for 1 hour and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (4.16 g, 46%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.02-4.15 (5H, m), 4.35 (2H, s), 5.81 (1H, s), 6.61 -6.63 (2H, m), 6.69-6.73 (1H, m), 7.14-7.18 (2H, m), 7.38-7.40 (2H, m), 7 45-7.47 (2H, m).

[Production Example 73-1-3] 4-Phenylaminomethylbenzaldehyde

To a solution of a mixture of (4- [1,3] dioxolan-2-yl-benzyl) phenylamine (4.16 g, 16.3 mmol) described in Production Example 73-1-2 in methanol and tetrahydrofuran (1: 1, 20 ml) was added 5N hydrochloric acid (20 ml). This mixture was stirred at room temperature for 1 hour, then neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.5 g). The resulting compound was used in the subsequent reaction without purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.19 (1H, br s), 4.45 (2H, s), 6.59-6.62 (2H, m), 6 , 72-6.76 (1H, m), 7.15-7.20 (2H, m), 7.53-7.55 (2H, m), 7.84-7.87 (2H, m) 10.0 (1H, s).

[Production Example 73-1-4] (4 - ((E) -2-nitrovinyl) benzyl) phenylamine

A mixture of 4-phenylaminomethylbenzaldehyde (3.5 g, 16.6 mmol) described in Production Example 73-1-3, nitromethane (4.46 ml, 83 mmol), ammonium acetate (2.56 g, 33.2 mmol) and acetic acid (30 ml) was stirred at 100 ° C for 4 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 10: 1-4: 1) to obtain the title compound (1.53 g, 36%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.16 (1H, br s), 4.42 (2H, m), 6.60-6.62 (2H, m), 6 , 72-6.76 (1H, m), 7.15-7.19 (2H, m), 7.45-7.47 (2H, m), 7.51-7.53 (2H, m) 7.58 (1H, d, J = 13.6 Hz); 8.00 (1H, d, J = 13.6 Hz).

[Production Example 73-1-5] (4- (2-nitroethyl) benzyl) phenylamine

In an appropriately cooled solution of (4 - ((E) -2-nitrovinyl) benzyl) phenylamine (1.53 g, 6.02 mmol), described in Production Example 73-1-4, in acetic acid (1, 5 ml) and dimethyl sulfoxide (26 ml), sodium borohydride (364 mg, 9.63 mmol) was added at room temperature. This mixture was stirred at room temperature for 1.5 hours and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.5 g). The resulting compound was used in the subsequent reaction without purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.29-3.33 (2H, m), 4.32 (2H, s), 4.59-4.62 (2H, m) 6.61-6.63 (2H, m), 6.70-6.74 (1H, m), 7.15-7.20 (4H, m), 7.33-7.35 (2H, m).

[Production Example 73-1-6] (4-phenylaminomethylphenyl) -acetohydroximoyl chloride

To a solution of (4- (2-nitroethyl) benzyl) phenylamine (1.5 g, 5.66 mmol) described in Production Example 73-1-5, lithium methoxide (430 mg, 11.3 mmol). This mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The water in the residue was azeotropically distilled off using toluene, and the resulting residue was diluted with methylene chloride (25 ml) and tetrahydrofuran (12.5 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (1.99 ml, 18.1 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 1 hour, then cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.5 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 74] 3- (3- (6- (2-Fluorophenoxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (9.0 mg, 0.076 mmol), described in Production Example 1-2-3, and (6- (2-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride (28 mg ) described in Production Example 74-1-4, triethylamine (21 μl, 0.15 mmol) was added in tetrahydrofuran (1 ml) and stirred at 55 ° C for 5 hours. The mixture was cooled to room temperature and water was added at the same temperature, then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1) to obtain the title compound as a crude product. This product was then purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid). Triethylamine was added during the concentration of the mobile phase to make the solvent basic, and the eluate was concentrated under reduced pressure. The resulting residue was washed with water to obtain the title compound (1.0 mg, 4%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.01 (2H, s), 5.53 (2H, br s), 6.27 (1H, s), 6.73 (1H dd, J = 4.9, 7.7 Hz), 6.98 (1H, d, J = 8.4 Hz), 7.14-7.25 (4H, m), 7.63 (1H, dd, J = 2.4, 8.4 Hz), 7.72 (1H, dd, J = 1.8, 7.7 Hz), 8.09 (1H, d, J = 2.4 Hz), 8.14 (1H, dd, J = 1.9, 4.9 Hz).

The starting material, (6- (2-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 74-1-1] 5-bromo-2- (2-fluorophenoxy) pyridine

To a mixture of 2-fluorophenol (2.1 g, 19 mmol), 2,5-dibromopyridine (3.0 g, 13 mmol) and N, N-dimethylformamide (30 ml) was added sodium hydride (730 mg, 15 mM, 50% in oil) and stirred at room temperature for 10 minutes. Then this reaction mixture was stirred at 110 ° C for 5 hours. The reaction mixture was cooled to room temperature and water was added and then extracted with ethyl acetate. The organic layer was washed twice with water and then washed with a saturated aqueous solution of sodium chloride, concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 15: 1) to obtain the title compound (940 mg, 28%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 6.91-6.93 (1H, m), 7.16-7.24 (4H, m), 7.79 (1H, ddd, J = 0.6, 2.6, 8.6 Hz), 8.17 (1H, dd, J = 0.6, 2.6 Hz).

[Production Example 74-1-2] 6- (2-Fluorophenoxy) -pyridin-3-carbaldehyde

To a mixture of 5-bromo-2- (2-fluorophenoxy) -pyridine (500 mg, 1.9 mmol) described in Production Example 74-1-1 and tetrahydrofuran (7 ml) at -78 ° C under nitrogen atmosphere was added n- butyllithium (1.7 ml, 1.5 M n- hexane solution, 2.6 mmol). N, N-dimethylformamide (0.29 ml, 3.7 mmol) was added to the reaction solution at the same temperature, and then the temperature was gradually raised to 0 ° C. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (210 mg, 53%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.12-7.15 (1H, m), 7.20-7.31 (4H, m), 8.22 (1H, dd, J = 2.4, 8.6 Hz), 8.60 (1H, dd, J = 0.6, 2.4 Hz), 9.99 (1H, d, J = 0.6 Hz).

[Production Example 74-1-3] 2- (2-fluorophenoxy) -5- (2-nitroethyl) pyridine

To a mixture of 6- (2-fluorophenoxy) -pyridin-3-carbaldehyde (210 mg, 0.97 mmol) described in Production Example 74-1-2 and acetic acid (3 ml) was added nitromethane (0.39 ml, 7.3 mM) and ammonium acetate (220 mg, 2.9 mM) and stirred at 100 ° C for 3 hours. This reaction mixture was cooled to room temperature and water was added thereto, then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of dimethyl sulfoxide (3 ml) and acetic acid (0.2 ml) was added to the obtained residue, and sodium borohydride (58 mg, 1.5 mmol) was added to the reaction mixture, cooled accordingly at room temperature. The reaction mixture was stirred for 10 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (150 mg, 61%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.28 (2H, t, J = 7.1 Hz), 4.59 (2H, t, J = 7.1 Hz), 6, 97 (1H, d, J = 8.4 Hz), 7.15-7.24 (4H, m), 7.57 (1H, dd, J = 2.6, 8.4 Hz), 8.00 (1H, d, J = 2.6 Hz).

[Production Example 74-1-4] (6- (2-Fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride

To a mixture of 2- (2-fluorophenoxy) -5- (2-nitroethyl) -pyridine (150 mg, 0.59 mmol) described in Production Example 74-1-3 and methanol (1.5 ml) at room temperature lithium methoxide (45 mg, 1.2 mmol) was added and stirred at room temperature for 5 minutes. The solvent was evaporated from the reaction mixture under reduced pressure. To a mixture of the obtained residue, methylene chloride (2 ml) and tetrahydrofuran (1 ml), titanium (IV) chloride (140 μl, 1.3 mmol) was added at -78 ° C and stirred at 0 ° C for 80 minutes. The reaction mixture was cooled to −78 ° C., water (1 ml) was added, and the temperature was gradually raised to room temperature. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water until the pH was 5, and then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (160 mg) as a crude product. The resulting compound was used in the subsequent reaction without further purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.74 (2H, s), 6.97 (1H, d, J = 8.4 Hz), 7.15-7.25 (4H , m), 7.63 (1H, dd, J = 2.4, 8.4 Hz), 8.04 (1H, d, J = 2.0 Hz).

[Example 75] 3- (3- (6- (4-Fluorophenoxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine

To a mixture of (6- (4-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride (25 mg) described in Production Example 75-1-4 and tetrahydrofuran (1 ml) was added 3-ethynylpyridin-2-ylamine (6 , 0 mg, 0.051 mmol), described in Production Example 1-2-3, and triethylamine (21 μl, 0.15 mmol) and stirred at 55 ° C. for 5 hours. The reaction mixture was cooled to room temperature and water was added to it at the same temperature, then it was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1) to obtain the title compound (5.9 mg, 32%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.02 (2H, s), 5.41 (2H, br s), 6.27 (1H, s), 6.73 (1H dd, J = 4.8, 7.7 Hz), 6.90 (1H, d, J = 8.4 Hz), 7.06-7.12 (4H, m), 7.62 (1H, dd, J = 2.6, 8.4 Hz), 7.71 (1H, dd, J = 1.7, 7.6 Hz), 8.13 (1H, d, J = 2.6 Hz), 8.16 (1H, dd, J = 1.7, 4.9 Hz).

The starting material, (6- (4-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 75-1-1] 5-bromo-2- (4-fluorophenoxy) pyridine

To a mixture of 4-fluorophenol (2.1 g, 19 mmol), 2,5-dibromopyridine (3.0 g, 13 mmol) and N, N-dimethylformamide (30 ml) was added sodium hydride (730 mg, 15 mM, 50% in oil) and stirred at room temperature for 10 minutes. Then this reaction mixture was stirred at 110 ° C for 5 hours, cooled to room temperature and water was added, and then extracted with ethyl acetate. The organic layer was washed twice with water, then washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 15: 1) to obtain the title compound (2.6 g, 75%) .

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 6.83-6.85 (1H, m), 7.09 (4H, d, J = 6.4 Hz), 7.76-7 79 (1H, m), 8.20 (1H, dd, J = 0.6, 2.6 Hz).

[Production Example 75-1-2] 6- (4-fluorophenoxy) -pyridin-3-carbaldehyde

To a mixture of 5-bromo-2- (4-fluorophenoxy) -pyridine (940 mg, 3.5 mmol) described in Production Example 75-1-1 and tetrahydrofuran (10 ml) at -78 ° C under nitrogen atmosphere was added n- butyllithium (1.7 ml, 1.5 M n- hexane solution, 2.6 mmol) and stirred at the same temperature for 30 minutes. N, N-dimethylformamide (0.54 ml, 7.0 mmol) was added to the reaction solution at the same temperature, and the temperature was gradually raised to 0 ° C. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (280 mg, 36%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.04-7.06 (1H, m), 7.13-7.15 (4H, m), 8.20 (1H, ddd, J = 0.9, 2.4, 8.6 Hz), 8.61 (1H, dd, J = 0.6, 2.4 Hz), 9.99 (1H, d, J = 0.6 Hz )

[Production Example 75-1-3] 2- (4-fluorophenoxy) -5- (2-nitroethyl) pyridine

To a mixture of 6- (4-fluorophenoxy) -pyridine-3-carbaldehyde (150 mg, 0.69 mmol) described in Production Example 75-1-2 and acetic acid (2 ml) was added nitromethane (0.28 ml, 5.2 mM) and ammonium acetate (160 mg, 2.1 mM) and stirred at 100 ° C for 3 hours. The reaction mixture was cooled to room temperature and water was added thereto, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of dimethyl sulfoxide (3 ml) and acetic acid (0.2 ml) was added to the obtained residue, and sodium borohydride (42 mg, 1.1 mmol) was added at room temperature, cooling accordingly. The reaction mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (130 mg, 70%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.28 (2H, t, J = 7.1 Hz), 4.60 (2H, t, J = 7.1 Hz), 6, 89 (1H, dd, J = 0.4, 8.4 Hz), 7.09 (4H, d, J = 6.4 Hz), 7.55 (1H, dd, J = 2.6, 8, 4 Hz), 8.03 (1H, d, J = 2.2 Hz).

[Production Example 75-1-4] (6- (4-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride

To a mixture of 2- (4-fluorophenoxy) -5- (2-nitroethyl) pyridine (120 mg, 0.46 mmol) described in Production Example 75-1-3 and methanol (2 ml) was added methoxide at room temperature lithium (35 mg, 0.91 mmol) and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. A mixture of methylene chloride (2 ml) and tetrahydrofuran (1 ml) was added to the residue, and titanium (IV) chloride (110 μl, 1.0 mmol) was added to the reaction solution, the mixture was stirred at 0 ° C for 100 minutes . Then the reaction mixture was cooled to 0 ° C, water (1 ml) was added to it, and the temperature was gradually raised to room temperature. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with water until the pH was 5, then washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (130 mg) as a crude product. The resulting compound was used in the subsequent reaction without further purification.

[Example 76] 3- (3- (4- (pyridin-3-yloxy) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3- (4- (2-nitroethyl) -phenoxy) -pyridine (819 mg, 3.35 mmol) described in Production Example 76-1-3 in methanol (10.0 ml) at room temperature in the atmosphere lithium methoxide (254 mg, 6.70 mmol) was added, the solution was stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (15.0 ml) and anhydrous tetrahydrofuran (7.00 ml) were added to the residue. Titanium (IV) chloride (1.18 ml, 10.7 mmol) was added dropwise to the reaction solution in a dry ice-ethanol bath (-78 ° C), and stirred at room temperature for 30 minutes. Sodium carbonate solution and ethyl acetate were added to this reaction solution in an ice bath (0 ° C) and then filtered through a pad of celite. The organic layer of the filtrate was extracted with ethyl acetate, and this organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (400 mg). To a solution of this crude product (250 mg) and 3-ethynylpyridin-2-ylamine (40.0 mg, 0.339 mmol), described in Production Example 1-2-3, in tetrahydrofuran (5.00 ml) was added triethylamine at room temperature (142 μl, 1.02 mmol) and stirred at 60 ° C for 3 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1), additionally purified by reverse phase high performance liquid chromatography (using acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (11, 7 mg, 10.0%) as ditrifluoroacetic acid salt.

MS m / e (ESI) 345.13 (MH +)

¹ H-NMR spectrum (CD3OD) δ (ppm): 4.17 (2H, s), 6.89 (1H, s), 7.06-7.10 (1H, m), 7.19- 7.22 (2H, m), 7.48-8.50 (2H, m), 7.94-7.98 (1H, m), 8.04-8.06 (1H, m), 8, 08-8.11 (1H, m), 8.37-8.39 (1H, m), 8.55 (1H, d, J = 5.6 Hz), 8.60 (1H, d, J = 2.8 Hz).

The starting material, 3- (4- (2-nitroethyl) phenoxy) pyridine, was synthesized as follows.

[Production Example 76-1-1] 4- (pyridin-3-yloxy) benzaldehyde

To a solution of 3-hydroxypyridine (3.00 g, 31.5 mmol) and 4-fluorobenzaldehyde (5.08 g, 41.0 mmol) in N, N-dimethylformamide (30.0 ml) in a nitrogen atmosphere was added potassium carbonate ( 8.71 g, 63.0 mmol) and stirred at 70 ° C for 17 hours. Then the reaction mixture was cooled to room temperature, water was added thereto, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 1 then 3: 1) to obtain the title compound (1.70 g, 27.1%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.09-7.11 (2H, s), 7.35-7.39 (1H, m), 7.41-7.44 ( 1H, m), 7.88-7.91 (2H, m), 8.48-8.51 (2H, m), 9.96 (1H, s).

[Production Example 76-1-2] 3- (4 - ((E) -2-nitrovinyl) phenoxy) pyridine

To a solution of 4- (pyridin-3-yloxy) benzaldehyde (1.70 g, 8.53 mmol) described in Production Example 76-1-1 in acetic acid (17.0 ml) under nitrogen atmosphere was added nitromethane ( 2.60 g, 42.7 mmol) and ammonium acetate (1.32 g, 17.1 mmol) and stirred at 110 ° C. for 3 hours. Water and ethyl acetate were added to the reaction solution, and then the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2.00 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.12-7.14 (2H, m), 7.48-7.51 (1H, m), 7.57-7, 61 (1H, m), 7.91-7.94 (2H, m), 8.16-8.19 (2H, m), 8.46-8.47 (2H, m).

[Production Example 76-1-3] 3- (4- (2-nitroethyl) -phenoxy) -pyridine

In a suitably cooled solution of 3- (4 - ((E) -2-nitrovinyl) phenoxy) pyridine (2.00 g, 8.26 mmol) described in Production Example 76-1-2 and acetic acid ( 2.00 ml) in dimethyl sulfoxide (15.0 ml) at room temperature under a nitrogen atmosphere was added sodium borohydride (500 mg, 13.2 mmol) and stirred at room temperature for 30 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 2) to obtain the title compound (819 mg, 40.6%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.26 (2H, t, J = 6.8 Hz), 4.88 (2H, t, J = 6.8 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz), 7.68-7.76 (2H, m), 8.23 (1H c), 8.35 (1H, d, J = 5.2 Hz).

[Example 77] 3- (3- (4- (Thiophen-3-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4- (thiophen-3-ylmethoxy) phenyl) acetohydroximoyl chloride (150 mg, 0.532 mmol) described in Production Example 77-1-4 and 3-ethynylpyridin-2-ylamine (40 mg, 0.339 mmol) described in Production Example 1-2-3, triethylamine (185 μl, 1.33 mmol) was added in tetrahydrofuran (3 ml) and stirred at 50 ° C for 3 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1 - 1: 1) to obtain the title compound (46 mg, 24%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.00 (2H, s), 5.06 (2H, s), 5.41 (2H, br s), 6.24 (1H , c), 6.69-6.72 (1H, m), 6.93-6.95 (2H, m), 7.14-7.15 (1H, m), 7.19-7.22 (2H, m), 7.31-7.35 (2H, m), 7.69-7.71 (1H, m), 8.13-8.14 (1H, m).

The starting material, (4- (thiophen-3-ylmethoxy) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 77-1-1] 4- (thiophen-3-ylmethoxy) benzaldehyde

To a solution of diethyl azodicarboxylate (16.1 ml, 40.9 mmol) in tetrahydrofuran (250 ml) was added 4-hydroxybenzaldehyde (5 g, 40.9 mmol), 3-thiophenomethanol (3.86 ml, 40.9 mmol) and PS β-triphenylphosphine (29 g, 1.41 mmol / g, 40.9 mmol). This mixture was stirred at room temperature for 7 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (3.61 g, 40%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.17 (2H, s), 7.07-7.09 (2H, m), 7.15-7.17 (1H, m) 7.35-7.39 (2H, m); 7.84-7.86 (2H, m); 9.90 (1H, s).

[Production Example 77-1-2] 3- (4 - ((E) -2-nitrovinyl) phenoxymethyl) thiophene

A mixture of 4- (thiophen-3-ylmethoxy) benzaldehyde (3.61 g, 16.5 mmol) described in Production Example 77-1-1, nitromethane (4.44 ml, 82.5 mmol), ammonium acetate ( 2.54 g, 33 mmol) and acetic acid (36 ml) were stirred at 100 ° C for 5 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (4.1 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.14 (2H, s), 7.01-7.03 (2H, m), 7.14-7.16 (1H, m) 7.34-7.35 (1H, m), 7.37-7.39 (1H, m), 7.50-7.54 (3H, m), 7.96-8.00 (1H, m).

[Production Example 77-1-3] 3- (4- (2-nitroethyl) phenoxymethyl) thiophene

In an appropriately cooled solution of 3- (4 - ((E) -2-nitrovinyl) phenoxymethyl) thiophene (4.1 g, 15.7 mmol) described in Production Example 77-1-2 in acetic acid ( 4.1 ml) and dimethyl sulfoxide (70 ml) was added sodium borohydride (950 mg, 25.1 mmol) at room temperature. This mixture was stirred at room temperature for 1.5 hours, partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (1.93 g, 47%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.24-3.28 (2H, m), 4.55-4.59 (2H, m), 5.05 (2H, s) 6.91-6.93 (2H, m), 7.11-7.15 (3H, m), 7.31-7.32 (1H, m), 7.34-7.36 (1H, m).

[Production Example 77-1-4] (4- (thiophen-3-ylmethoxy) phenyl) -acetohydroximoyl chloride

To a solution of 3- (4- (2-nitroethyl) phenoxymethyl) thiophene (1 g, 3.8 mmol) described in Production Example 77-1-3, in methanol (12 ml) was added lithium methoxide (289 mg, 7.6 mmol). This mixture was stirred at room temperature for 1.5 hours, concentrated under reduced pressure. The water in the residue was azeotropically distilled off with toluene, and the resulting residue was diluted with methylene chloride (16 ml) and tetrahydrofuran (8 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (1.34 ml, 12.2 mmol) was added dropwise to the suspension. The suspension was stirred at room temperature for 1 hour. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.1 g). The resulting compound was used in the subsequent reaction without further purification.

[Production Example 78] 3- (3- (4-Cyclopentyloxybenzyl) -isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4-cyclopentyloxyphenyl) -acetohydroximoyl chloride (150 mg, 0.592 mmol) described in Production Example 78-1-4, and 3-ethynylpyridin-2-ylamine (45 mg, 0.378 mmol) described in Example 1-2- 3, triethylamine (206 μl, 1.48 mmol) was added in tetrahydrofuran (3 ml) and stirred at 50 ° C for 3 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (44 mg, 22%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.57-1.75 (2H, m), 1.75-1.92 (6H, m), 3.98 (2H, s) 4.71-4.75 (1H, m), 5.39 (2H, br s), 6.24 (1H, s), 6.69-6.72 (1H, m), 6.82 -6.85 (2H, m), 7.16-7.18 (2H, m), 7.69-7.71 (1H, m), 8.12-8.14 (1H, m).

The starting material, (4-cyclopentyloxyphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 78-1-1] 4-Cyclopentyloxybenzaldehyde

To a solution of diethyl azodicarboxylate (16.1 ml, 40.9 mmol) in tetrahydrofuran (250 ml) was added 4-hydroxybenzaldehyde (5 g, 40.9 mmol), cyclopentanol (3.71 ml, 40.9 mmol) and triphenylphosphine (10 7 g, 40.9 mmol). This mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (4.36 g, 56%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.61-1.70 (2H, m), 1.77-2.00 (6H, m), 4.84-4.87 ( 1H, m), 6.95-6.98 (2H, m), 7.80-7.83 (2H, m), 9.87 (1H, s).

[Production Example 78-1-2] 1-cyclopentyloxy-4 - ((E) -2-nitrovinylbenzene

A mixture of 4-cyclopentyloxybenzaldehyde (4.36 g, 22.9 mmol) described in Production Example 78-1-1, nitromethane (6.16 ml, 115 mmol), ammonium acetate (3.53 g, 33 mmol) and acetic acids (45 ml) were stirred at 100 ° C for 14 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (4.8 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.61-1.66 (2H, m), 1.78-1.97 (6H, m), 4.80-4.84 ( 1H, m), 6.90-6.93 (2H, m), 7.46-7.53 (3H, m), 7.96-7.99 (1H, m).

[Production Example 78-1-3] 1-cyclopentyloxy-4- (2-nitroethyl) benzene

In a suitably cooled solution of 1-cyclopentyloxy-4- (E) -2-nitrovinylbenzene (4.8 g, 20.4 mmol), described in Production Example 78-1-2, in acetic acid (4.8 ml) and dimethyl sulfoxide (82 ml) was added sodium borohydride (1.23 g, 32.6 mmol) at room temperature. The mixture was stirred at room temperature for 1.5 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (3.24 g, 68%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.59-1.65 (2H, m), 1.76-1.92 (6H, m), 3.23-3.27 ( 2H, m), 4.55-4.58 (2H, m), 4.70-4.74 (1H, m), 6.80-6.84 (2H, m), 7.07-7, 11 (2H, m).

[Production Example 78-1-4] (4-cyclopentyloxyphenyl) -acetohydroximoyl chloride

To a solution of 1-cyclopentyloxy-4- (2-nitroethyl) benzene (1 g, 4.26 mmol) described in Production Example 78-1-3, in methanol (12 ml) lithium methoxide (356 mg, 9, 37 mM). This mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The water in the residue was azeotropically distilled off with toluene, and the resulting residue was diluted with methylene chloride (16 ml) and tetrahydrofuran (8 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (1.03 ml, 9.37 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 1 hour, cooled to -78 ° C and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.1 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 79] 3- (3- (4-Cyclohexyloxybenzyl) -isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4-cyclohexyloxyphenyl) -acetohydroximoyl chloride (150 mg, 0.56 mmol) described in Production Example 79-1-4 and 3-ethynylpyridin-2-ylamine (42 mg, 0.357 mmol) described in Example 1- 2-3 preparation, triethylamine (195 μl, 1.4 mmol) was added in tetrahydrofuran (3 ml) and stirred at 50 ° C for 4 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (37 mg, 19%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.29-1.41 (3H, m), 1.47-1.56 (3H, m), 1.79-1.80 ( 2H, m), 1.96-1.99 (2H, m), 3.99 (2H, s), 4.18-4.24 (1H, m), 5.38 (2H, br.s) 6.25 (1H, s), 6.69-6.72 (1H, m), 6.85-6.88 (2H, m), 7.12-7.18 (2H, m), 7 69-7.71 (1H, m); 8.13-8.14 (1H, m).

The starting material, (4-cyclohexyloxyphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 79-1-1] 4-cyclohexyloxybenzaldehyde

To a solution of diethyl azodicarboxylate (16.1 ml, 40.9 mmol) in tetrahydrofuran (250 ml) was added 4-hydroxybenzaldehyde (5 g, 40.9 mmol), cyclohexanol (4.31 ml, 40.9 mmol) and triphenylphosphine (10 7 g, 40.9 mmol). This mixture was stirred at room temperature for 30 hours. The mixture 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 (2.84 g, 34%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.31-1.46 (4H, m), 1.53-1.63 (2H, m), 1.80-1.86 ( 2H, m), 1.98-2.02 (2H, m), 4.35-4.41 (1H, m), 6.97-7.00 (2H, m), 7.80-7, 84 (2H, m); 9.87 (1H, s).

[Production Example 79-1-2] 1-cyclohexyloxy-4 - ((E) -2-nitrovinyl) benzene

A mixture of 4-cyclohexyloxybenzaldehyde (2.84 g, 13.9 mmol) described in Production Example 79-1-1, nitromethane (3.74 ml, 69.5 mmol), ammonium acetate (2.14 g, 27.8 mM) and acetic acid (30 ml) were stirred at 100 ° C for 14 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.3 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.34-1.45 (3H, m), 1.51-1.61 (3H, m), 1.80-1.82 ( 2H, m), 1.98-2.00 (2H, m), 4.31-4.36 (1H, m), 6.91-6.95 (2H, m), 7.45-7, 50 (2H, m), 7.53-7.57 (1H, m), 7.96-7.99 (1H, m).

[Production Example 79-1-3] 1-cyclohexyloxy-4- (2-nitroethyl) benzene

In an appropriately cooled solution of 1-cyclohexyloxy-4 - ((E) -2-nitrovinyl) benzene (3.3 g, 13.1 mmol), described in Production Example 79-1-2, in acetic acid (3, 3 ml) and dimethyl sulfoxide (55 ml) was added sodium borohydride (793 mg, 21 mmol) at room temperature. This mixture was stirred at room temperature for 1 hour, partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (1.45 g, 44%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.26-1.43 (3H, m), 1.46-1.58 (3H, m), 1.79-1.81 ( 2H, m), 1.95-1.98 (2H, m), 3.23-3.27 (2H, m), 4.17-4.24 (1H, m), 4.55-4, 58 (2H, m), 6.83-6.87 (2H, m), 7.08-7.10 (2H, m).

[Production Example 79-1-4] (4-cyclohexyloxyphenyl) -acetohydroximoyl chloride

To a solution of 1-cyclohexyloxy-4- (2-nitroethyl) benzene (1.45 g, 5.82 mmol) described in Production Example 79-1-3, in methanol (17 ml) lithium methoxide (442 mg, 11.6 mmol). This mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. Water in the residue was azeotropically distilled off with toluene, and the obtained residue was diluted with methylene chloride (24 ml) and tetrahydrofuran (12 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (1.41 ml, 12.8 mmol) was added dropwise to the suspension. This mixture was stirred at room temperature for 1.5 hours. The mixture was cooled to −78 ° C. and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.5 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 80] 3- (3- (4- (2-Furan-2-yl-ethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (33.1 mg, 0.281 mmol) described in Production Example 1-2-3 in anhydrous tetrahydrofuran (5 ml) at room temperature under nitrogen atmosphere was added (4- (2-furan -2-yl-ethyl) phenyl) -acetohydroximoyl chloride (224 mg, 0.85 mmol) described in Production Example 80-1-7. Then, triethylamine (0.24 ml, 1.7 mmol) was added dropwise and stirred at 60 ° C for 1.5 hours. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 9 then 3: 7) to obtain the title compound (39.6 mg, 40.8%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.88-2.98 (4H, m), 4.03 (2H, s), 5.41 (2H, br.s), 5 97 (1H, d, J = 3.2 Hz), 6.25 (1H, s), 6.27 (1H, dd, J = 2.0, 3.2 Hz), 6.71 (1H, dd, J = 4.8, 8.0 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.31 ( 1H, d, J = 2.0 Hz), 7.70 (1H, dd, J = 2.0, 8.0 Hz), 8.13 (1H, dd, J = 2.0, 4.8 Hz )

The starting material, ((4- (2-furan-2-yl-ethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 80-1-1] 4 - ((E) -2-furan-2-yl-vinyl) -benzoic acid ethyl ester

60% Sodium hydride (0.48 g, 12 mmol) was suspended in anhydrous tetrahydrofuran (10 ml) in nitrogen atmosphere and diethyl 4-ethoxycarbonyl benzylphosphonate (3.6 g, 12 mmol) prepared from ethyl 4 was added at room temperature. β-bromomethyl benzoate and triethyl phosphite according to methods similar to the methods of production example 93-1-1, and stirred at room temperature for 30 minutes. Then, furfural (1 g, 10.4 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction mixture in an ice bath (0 ° C) was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 20) to obtain the title compound (1.07 g, 42%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40 (3H, t, J = 5.2 Hz), 4.38 (2H, q, J = 5.2 Hz), 6, 40-6.48 (2H, m), 6.99 (1H, d, J = 16 Hz), 7.05 (1H, d, J = 16 Hz), 7.43 (1H, m), 7, 50 (2H, dd, J = 2.0, 6.4 Hz), 8.01 (2H, dd, J = 2.0, 6.4 Hz).

[Production Example 80-1-2] 4- (2-furan-2-yl-ethyl) -benzoic acid ethyl ester

To a solution of 4 - ((E) -2-furan-2-yl-vinyl) -benzoic acid ethyl ester (1.07 g, 4.4 mmol) described in Production Example 80-1-1 in anhydrous tetrahydrofuran ( 25 ml) 10% palladium-on-carbon (50% hydrate, 500 mg) was added, the solution was stirred at room temperature in a hydrogen atmosphere for 2 hours. The reaction product was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( methyl tert-butyl ether: heptane = 5: 95) to obtain the title compound (706 mg, 65.4%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.39 (3H, t, J = 7.2 Hz), 2.90-3.08 (4H, m), 4.36 (2H q, J = 7.2 Hz), 5.94 (1H, m), 6.26 (1H, m), 7.21 (2H, d, J = 8.0 Hz), 7.32 (1H , m), 7.95 (2H, d, J = 8.0 Hz).

[Production Example 80-1-3] (4- (2-furan-2-yl-ethyl) -phenyl) -methanol

To a solution of ethyl 4- (2-furan-2-yl-ethyl) -benzoic acid ethyl ester (706 mg, 2.89 mmol), described in Production Example 80-1-2, in anhydrous tetrahydrofuran (10 ml) per a dry ice-ethanol mixture (-78 ° C) in a nitrogen atmosphere was added diisobutylaluminum hydride (0.97 M toluene solution, 7.45 ml, 7.23 mmol). After stirring for 30 minutes, a 15% aqueous potassium sodium tartrate solution (40 ml) was added to the reaction solution, and stirred at room temperature for 30 minutes. Ethyl acetate (100 ml) was added and the organic layer and the aqueous layer were separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (580 mg, 99%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.58 (1H, t, J = 6.0 Hz), 2.90-3.00 (4H, m), 4.66 (2H d, J = 6.0 Hz), 5.96 (1H, m), 6.27 (1H, m), 7.17 (2H, d, J = 8.0 Hz), 7.28 (2H d, J = 8.0 Hz), 7.32 (1H, m).

[Production Example 80-1-4] 4- (2-Furan-2-yl-ethyl) -benzaldehyde

To a solution of (4- (2-furan-2-yl-ethyl) phenyl) methanol (580 mg, 2.87 mmol) described in Production Example 80-1-3, activated dioxide was added in ethyl acetate (50 ml) manganese (8 g, 92 mmol) and stirred at room temperature for 12 hours. The reaction solution was filtered with a suction filter through a pad of celite, and the filtrate was washed with ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure to obtain the title compound (480 mg, 83.5%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.94-3.08 (4H, m), 5.96 (1H, m), 6.27 (1H, m), 7.32 (3H, d, J = 8.0 Hz), 7.80 (2H, d, J = 8.0 Hz), 9.98 (1H, s).

[Production Example 80-1-5] 4- (2-furan-2-yl-ethyl) - ((E) -2-nitrovinyl) benzene

To a solution of 4- (2-furan-2-yl-ethyl) -benzaldehyde (480 mg, 2.4 mmol) described in Production Example 80-1-4 in acetic acid (5 ml) at room temperature under a nitrogen atmosphere nitromethane (732 mg, 12 mmol) and ammonium acetate (370 mg, 4.8 mmol) were added and stirred at 120 ° C for 2 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (554 mg, 95%) as a crude product.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.90-3.08 (4H, m), 5.95 (1H, m), 6.27 (1H, m), 7.23 (2H, d, J = 8.0 Hz), 7.32 (1H, m), 7.46 (2H, d, J = 8.0 Hz), 7.57 (1H, d, J = 13, 6 Hz), 7.99 (1H, d, J = 13.6 Hz).

[Production Example 80-1-6] 4- (2-furan-2-yl-ethyl) - (2-nitroethyl) benzene

In a suitably cooled solution of 4- (2-furan-2-yl-ethyl) - ((E) -2-nitrovinyl) benzene (554 mg, 2.28 mmol) described in Production Example 80-1-5, and acetic acid (0.5 ml) in a tetrahydrofuran-dimethyl sulfoxide mixture (1: 1, 10 ml) was added sodium borohydride (129 mg, 3.42 mmol) at room temperature under nitrogen atmosphere and stirred at room temperature for 10 minutes. To this appropriately cooled reaction solution, water was added dropwise at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (methyl tert- butyl ether: heptane = 5: 95) to obtain the title compound (300 mg, 53%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.88-2.96 (4H, m), 3.29 (2H, t, J = 7.2 Hz), 4.59 (2H , t, J = 7.2 Hz), 5.95 (1H, m), 6.27 (1H, m), 7.10-7.16 (4H, m), 7.32 (1H, m) .

[Production Example 80-1-7] (4- (2-furan-2-yl-ethyl) phenyl) -acetohydroximoyl chloride

To a solution of 4- (2-furan-2-yl-ethyl) - (2-nitroethyl) benzene (300 mg, 1.22 mmol) described in Production Example 80-1-6 in methanol (5 ml) at lithium methoxide (92.7 mg, 2.44 mmol) was added at room temperature under a nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Anhydrous methylene chloride (7 ml) and anhydrous tetrahydrofuran (3 ml) were added to the residue. Titanium (IV) chloride (2.7 ml, 1 M 2.7 mmol dichloromethane solution) was added dropwise to the reaction solution in a dry ice-ethanol bath (-78 ° C) and stirred at 0 ° C for 45 minutes . Water and ethyl acetate were added to the reaction solution in an ice bath (0 ° C), and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (324 mg, 100%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.88-2.96 (4H, m), 3.77 (2H, s), 5.96 (1H, m), 6.27 (1H, m), 7.15 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.32 (1H, m), 7.36 (1H, s).

[Example 81] 3- (3- (4- (3-Fluorophenoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4- (3-fluorophenoxy) phenyl) -acetohydroximoyl chloride (290 mg, 1.04 mmol) described in Production Example 81-1-2, and 3-ethynylpyridin-2-ylamine (50.0 mg, 0.423 mM) described in Production Example 1-2-3, triethylamine (177 μl, 1.27 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at 60 ° C for 30 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (38.7 mg, 25.3%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.05 (2H, s), 6.27 (2H, br s), 6.70 (1H, dd, J = 3, 2, 8.0 Hz), 6.79-6.93 (2H, m), 6.84 (1H, s), 6.95 (1H, m), 7.04-7.06 (2H, m ), 7.37-7.43 (3H, m), 7.88 (1H, dd, J = 1.6, 8.0 Hz), 8.08-8.10 (1H, m).

The starting material, (4- (3-fluorophenoxy) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 81-1-1] 1- (3-fluorophenoxy) -4- (2-nitroethyl) benzene

To a solution of 3-fluorophenol (5.43 g, 48.4 mmol) and 4-fluorobenzaldehyde (3.00 g, 24.2 mmol) in N, N-dimethylformamide (30.0 ml) in a nitrogen atmosphere was added potassium carbonate ( 10.1 g, 72.5 mmol) and stirred at 80 ° C for 16 hours. The reaction mixture was cooled to room temperature and water was added and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 15 then 1:10) to obtain a mixture with the starting material (6.00 g). To a solution of this mixture (6.0 g) in acetic acid (50.0 ml), nitromethane (6.78 g, 111 mmol) and ammonium acetate (3.42 g, 44.4 mmol) were added at room temperature and stirred at 110 ° C for 4 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (5.5 g). To a suitably cooled solution of this crude product (5.5 g) and acetic acid (5.00 ml) in dimethyl sulfoxide (40.0 ml) was added sodium borohydride (1.28 g, 33.9 mmol) at room temperature and stirred at room temperature for 5 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (2.10 g, 37.9%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.24 (2H, t, J = 6.8 Hz), 4.86 (2H, t, J = 6.8 Hz), 6.78-6.85 (2H, m), 6.94-6.98 (1H, m), 7.03 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz), 7.40-7.42 (1H, m).

[Production Example 81-1-2] (4- (3-fluorophenoxy) phenyl) acetohydroximoyl chloride

To a solution of 1- (3-fluorophenoxy) -4- (2-nitroethyl) benzene (500 mg, 1.91 mmol) described in Production Example 81-1-1 in methanol (10.0 ml) at room temperature lithium methoxide (145 mg, 3.82 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The solvent was evaporated from the filtrate under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Titanium (IV) chloride (525 μl, 4.78 mmol) was added dropwise to the reaction solution in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 40 minutes. Water and ethyl acetate were added to the reaction solution in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (490 mg, 91.7%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.83 (2H, s), 6.80-6.89 (2H, m), 6.95-7.00 (1H, m), 7.05 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.38-7.45 (1H, m), 11, 75 (1H, s).

[Example 82] 3- (3- (4- (2- (Tetrahydrofuran-2-yl) ethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (43.7 mg, 0.37 mmol) described in Production Example 1-2-3 in anhydrous tetrahydrofuran (5 ml) at room temperature under nitrogen atmosphere was added (4- (2 -tetrahydrofuran-2-yl-ethyl) phenyl) -acetohydroximoyl chloride (300 mg, 1.12 mmol) described in Production Example 82-1-6. Then, triethylamine (0.31 ml, 2.24 mmol) was added dropwise and stirred at 60 ° C for 2 hours. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 9 then 3: 7) to obtain the title compound (68 mg, 53%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40-1.55 (1H, m), 1.70-2.00 (5H, m), 2.60-2.80 ( 2H, m), 3.70-3.90 (3H, m), 4.02 (2H, s), 5.41 (2H, br.s), 6.25 (1H, s), 6.70 (1H, dd, J = 4.8, 8.0 Hz), 7.16-7.24 (4H, m), 7.70 (1H, dd, J = 2.0, 8.0 Hz), 8.13 (1H, dd, J = 2.0, 4.8 Hz).

The starting material, (4- (2-tetrahydrofuran-2-yl-ethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 82-1-1] 4- (2- (tetrahydrofuran-2-yl) ethyl) benzoic acid ethyl ester

To a solution of 4 - ((E) -2-furan-2-yl-vinyl) -benzoic acid ethyl ester (2.2 g, 9.39 mmol) described in Production Example 80-1-1 in anhydrous tetrahydrofuran ( 25 ml) was added 10% palladium-on-charcoal (50% hydrate, 1 g) and stirred at room temperature in a hydrogen atmosphere for 6 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (2.2 g, 100%) as a crude product.

[Production Example 82-1-2] (4- (2- (tetrahydrofuran-2-yl) ethyl) phenyl) methanol

To a solution of ethyl 4- (2- (tetrahydrofuran-2-yl) ethyl) benzoic acid ethyl ester (2.2 g, 9.39 mmol) described in Production Example 82-1-1 in anhydrous tetrahydrofuran ( 20 ml) in a bath with a mixture of dry ice-ethanol (-78 ° C) in a nitrogen atmosphere was added diisobutylaluminum hydride (0.97 M toluene solution, 24.2 ml, 23.5 mmol). After stirring for 30 minutes, a 15% aqueous solution of potassium sodium tartrate (100 ml) was added to the reaction solution, and stirred at room temperature for 30 minutes. After adding ethyl acetate (200 ml), the organic layer and the aqueous layer were separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 9 then 2: 8) to obtain the title compound (600 mg, 31%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40-1.55 (1H, m), 1.63 (1H, t, J = 6.0 Hz), 1.70-2 00 (5H, m), 2.60-2.80 (2H, m), 3.70-3.90 (3H, m), 4.66 (2H, d, J = 6.0 Hz), 7.21 (2H, d, J = 8.0 Hz); 7.28 (2H, d, J = 8.0 Hz).

[Production Example 82-1-3] 4- (2- (tetrahydrofuran-2-yl) ethyl) benzaldehyde

To a solution of (4- (2- (tetrahydrofuran-2-yl) ethyl) phenyl) methanol (600 mg, 2.91 mmol) described in Production Example 82-1-2, in ethyl acetate (50 ml) was added active manganese dioxide (10 g, 115 mmol) and stirred at room temperature for 12 hours. The reaction solution was filtered with a suction filter through a pad of celite and washed with ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure to obtain the title compound (565 mg, 95%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40-1.55 (1H, m), 1.70-2.00 (5H, m), 2.60-2.80 ( 2H, m), 3.70-3.90 (3H, m), 7.37 (2H, d, J = 8.4 Hz), 7.80 (2H, d, J = 8.0 Hz), 9.97 (1H, s).

[Production Example 82-1-4] 4- (2- (tetrahydrofuran-2-yl) ethyl) - ((E) -2-nitrovinyl) benzene

To a solution of 4- (2- (tetrahydrofuran-2-yl) ethyl) benzaldehyde (565 mg, 2.77 mmol) described in Production Example 82-1-3 in acetic acid (10 ml) at room temperature in under nitrogen atmosphere, nitromethane (1.69 g, 27.7 mmol) and ammonium acetate (427 mg, 5.54 mmol) were added and stirred at 120 ° C. for 4 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (646 mg, 94%) as a crude product.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40-1.55 (1H, m), 1.70-2.00 (5H, m), 2.60-2.80 ( 2H, m), 3.70-3.90 (3H, m), 7.29 (2H, d, J = 8.0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.57 (1H, d, J = 13.6 Hz); 7.99 (1H, d, J = 13.6 Hz).

[Production Example 82-1-5] 4- (2- (tetrahydrofuran-2-yl) ethyl) - (2-nitroethyl) benzene

To a suitably cooled solution of 4- (2- (tetrahydrofuran-2-yl) ethyl) - ((E) -2-nitrovinyl) benzene (646 mg, 2.61 mmol) described in Example 82-1-4 of preparation, and acetic acid (0.6 ml) in a mixture of tetrahydrofuran-dimethyl sulfoxide (1: 1, 10 ml) was added sodium borohydride (148 mg, 3.92 mmol) at room temperature under nitrogen atmosphere and stirred at room temperature for 10 minutes. Water was added dropwise to a reaction cooled solution at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate: heptane = 2: 8) to obtain the title compound (421 mg, 65%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40-1.55 (1H, m), 1.70-2.00 (5H, m), 2.60-2.80 ( 2H, m), 3.29 (2H, t, J = 7.2 Hz), 3.70-3.90 (3H, m), 4.59 (2H, t, J = 7.2 Hz), 7.11 (2H, d, J = 8.4 Hz); 7.17 (2H, d, J = 8.4 Hz).

[Production Example 82-1-6] (4- (2- (tetrahydrofuran-2-yl) -ethyl) phenyl) -acetohydroximoyl chloride

To a solution of 4- (2- (tetrahydrofuran-2-yl) ethyl) - (2-nitroethyl) benzene (421 mg, 1.69 mmol) described in Production Example 82-1-5, in methanol (5 ml ) at room temperature in a nitrogen atmosphere, lithium methoxide (128 mg, 3.38 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Anhydrous methylene chloride (10 ml) and anhydrous tetrahydrofuran (5 ml) were added to the residue. Titanium (IV) chloride (1 M dichloromethane solution, 3.7 ml, 3.72 mmol) was added dropwise to the reaction solution in a bath of dry ice-ethanol (-78 ° C) and stirred at 0 ° C for 45 minutes. Water and ethyl acetate were added to the reaction solution in an ice bath (0 ° C), and the organic layer was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (445 mg, 98%) as a crude product.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40-1.55 (1H, m), 1.70-2.00 (5H, m), 2.60-2.80 ( 2H, m), 3.70-3.90 (3H, m), 3.77 (2H, s), 7.18 (4H, br.s), 7.51 (1H, br.s).

[Example 83] 3- (3- (4- (2-fluorophenoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (4- (2-fluorophenoxy) phenyl) -acetohydroximoyl chloride (290 mg, 1.04 mmol) described in Production Example 83-1-3, and 3-ethynylpyridin-2-ylamine (50.0 mg, 0.423 mM) described in Production Example 1-2-3, triethylamine (177 μl, 1.27 mmol) was added in tetrahydrofuran (10.0 ml) at room temperature and stirred at 60 ° C for 30 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (57.0 mg, 37.3%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.02 (2H, s), 6.27 (2H, br.s), 6.81-6.72 (1H, m) 6.82 (1H, s), 6.94 (2H, d, J = 8.4 Hz), 7.13-7.18 (1H, m), 7.20-7.25 (2H, m ), 7.33 (2H, d, J = 8.4 Hz), 7.36-7.41 (1H, m), 7.87-7.89 (1H, m), 8.08-8, 10 (1H, m).

The starting material, (4- (2-fluorophenoxy) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 83-1-1] 4- (2-Fluorophenoxy) benzaldehyde

To a solution of 2-fluorophenol (5.43 g, 48.4 mmol) and 4-fluorobenzaldehyde (3.00 g, 24.2 mmol) in N, N-dimethylformamide (30.0 ml) in a nitrogen atmosphere was added potassium carbonate ( 10.1 g, 72.5 mmol) and stirred at 80 ° C for 16 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 15 then 1:10) to obtain the title compound (5.20 g, 99.4%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.04 (2H, d, J = 8.8 Hz), 7.17-7.24 (4H, m), 7.85 (2H d, J = 8.8 Hz), 9.91 (1H, s).

[Production Example 83-1-2] 1- (2-fluorophenoxy) -4- (2-nitroethyl) benzene

Nitromethane was added to a solution of 4- (2-fluorophenoxy) benzaldehyde (3.00 g, 13.9 mmol) described in Production Example 83-1-1 in acetic acid (30.0 ml) under nitrogen atmosphere (4, 24 g, 69.5 mmol) and ammonium acetate (2.14 g, 27.8 mmol) and stirred at 110 ° C for 3 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (3.60 g). To a suitably cooled solution of this crude product (3.60 g) and acetic acid (3.00 ml) in dimethyl sulfoxide (50.0 ml) was added sodium borohydride (789 mg, 20.9 mmol) at room temperature and stirred at room temperature temperature for 20 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 10 then 1: 5) to obtain the title compound (1.80 g, 49.6%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.20 (2H, d, J = 7.2 Hz), 4.83 (2H, d, J = 7.2 Hz), 6.91-6.93 (2H, m), 7.13-7.17 (1H, m), 7.20-7.29 (4H, m), 7.36-7.41 (1H, m) )

[Production Example 83-1-3] (4- (2-fluorophenoxy) phenyl) acetohydroximoyl chloride

To a solution of 1- (2-fluorophenoxy) -4- (2-nitroethyl) benzene (1.80 g, 6.89 mmol) described in Production Example 83-1-2 in methanol (20.0 ml) at lithium methoxide (524 mg, 13.8 mmol) was added at room temperature under a nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (15.0 ml) and anhydrous tetrahydrofuran (5.00 ml) were added to the residue. Titanium (IV) chloride (1.74 ml, 15.8 mmol) was added dropwise to the reaction solution in a bath of dry ice-ethanol (-78 ° C) and stirred at room temperature for 30 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction solution in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2.00 g, 51.9%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.79 (2H, s), 6.93-6.95 (2H, m), 7.16-7.27 (5H, m), 7.28-7.42 (1H, m), 11.73 (1H, s).

[Example 84] 3- (3- (3-Pyridin-2-yl-benzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a mixture of (3- (pyridin-2-yl) phenyl) -acetohydroximoyl chloride (100 mg) described in Production Example 84-1-3 and tetrahydrofuran (2 ml) was added 3-ethynylpyridin-2-ylamine at room temperature ( 10 mg, 0.20 mmol), described in Production Example 1-2-3, and triethylamine (71 μl, 0.51 mmol) and stirred at 55 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature and water was added at the same temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1) to obtain the title compound as a crude product. Then, the resulting crude product was purified by reverse phase high performance liquid chromatography (using the acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to give the title compound (7.2 mg, 15%) as a ditrifluoroacetic acid salt.

MS m / e (ESI) 329.20 (MH +)

The starting material, (3- (pyridin-2-yl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 84-1-1] 3-pyridin-2-yl-benzaldehyde

To a mixture of 3-bromobenzaldehyde (930 mg, 5.0 mmol) and toluene (10 ml) was added tri-n-butyl (2-pyridyl) tin (2.1 g, 5.6 mmol) and palladium bis (triphenylphosphine) palladium chloride (II) (350 mg, 0.50 mmol); the reaction mixture was boiled under reflux for 5 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of potassium fluoride (1 ml) was added at the same temperature, and stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, and then filtered through a celite pad. The organic layer was separated from the filtrate and washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (530 mg, 58%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.28-7.32 (1H, m), 7.65 (1H, t, J = 7.7 Hz), 7.80-7 82 (2H, m), 7.93-7.95 (1H, m), 8.29-8.31 (1H, m), 8.50-8.51 (1H, m), 8.72 -8.74 (1H, m), 10.12 (1H, s).

[Production Example 84-1-2] 2- (3- (2-nitroethyl) phenyl) pyridine

To a mixture of 3-pyridin-2-yl-benzaldehyde (290 mg, 1.6 mmol) described in Production Example 84-1-1 and acetic acid (5 ml) was added nitromethane (0.65 ml, 12 mmol) and ammonium acetate (370 mg, 4.8 mmol) and stirred at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature and water was added and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of dimethyl sulfoxide (6 ml) and acetic acid (0.4 ml) was added to the obtained residue, and sodium borohydride (97 mg, 2.6 mmol) was added at room temperature, cooling accordingly. The reaction mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (260 mg, 71%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.41 (2H, t, J = 7.5 Hz), 4.67 (2H, t, J = 7.5 Hz), 7, 24-7.27 (2H, m), 7.44 (1H, t, J = 7.7 Hz), 7.70-7.79 (2H, m), 7.85 (1H, d, J = 7.9 Hz), 7.90 (1H, s), 8.68-8.70 (1H, m).

[Production Example 84-1-3] (3- (Pyridin-2-yl) phenyl) -acetohydroximoyl chloride

To a mixture of 2- (3- (2-nitroethyl) phenyl) pyridine (260 mg, 1.1 mmol) described in Production Example 84-1-2 and methanol (4 ml), lithium methoxide was added at room temperature ( 86 mg, 2.3 mmol) and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. A mixture of methylene chloride (6 ml) and tetrahydrofuran (3 ml) was added to the obtained residue, and titanium (IV) chloride (400 μl, 3.6 mmol) was added to the reaction solution at -78 ° C and stirred at 0 ° C for 60 minutes . The reaction mixture was cooled to 0 ° C and a saturated aqueous solution of sodium hydrogen carbonate was added at the same temperature, then water and ethyl acetate. The reaction mixture was filtered through a pad of celite and the organic layer was separated from the filtrate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (160 mg) as a crude product. The resulting compound was used in the subsequent reaction without further purification.

[Example 85] 3- (3-Biphenyl-3-ylmethyl-isoxazol-5-yl) -pyridin-2-ylamine

To a mixture of biphenyl-3-yl-acetohydroximoyl chloride (120 mg) described in Production Example 85-1-3 and tetrahydrofuran (6 ml) was added 3-ethynylpyridin-2-ylamine (28 mg, 0.24 mmol) at room temperature described in Production Example 1-2-3 and triethylamine (200 μl, 1.4 mmol) and stirred for 2.5 hours at 55 ° C. The reaction mixture was cooled to room temperature and water was added at the same temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1) to obtain the title compound (27 mg, 34%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.13 (2H, s), 5.41 (2H, br s), 6.28 (1H, s), 6.70 (1H dd, J = 4.9, 7.7 Hz), 7.27 (1H, d, J = 7.7 Hz), 7.33-7.37 (1H, m), 7.40-7, 46 (3H, m), 7.50 (2H, d, J = 6.8 Hz), 7.56-7.59 (2H, m), 7.70 (1H, dd, J = 1.8, 7.7 Hz), 8.13 (1H, dd, J = 1.7, 4.9 Hz).

The starting material, biphenyl-3-yl-acetohydroximoyl chloride, was synthesized as follows.

[Production Example 85-1-1] 3-phenyl-benzaldehyde

To a mixture of 3-bromobiphenyl (0.50 ml, 3.0 mmol) and tetrahydrofuran (8 ml) at -78 ° C under nitrogen atmosphere was added n- butyllithium (2.6 ml, 1.5 M solution of n- hexane, 3 , 9 mM) and stirred at the same temperature for 20 minutes. N, N-dimethylformamide (0.35 ml, 4.5 mmol) was added to the reaction solution at the same temperature, and the temperature was gradually raised to 0 ° C. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 6: 1) to obtain the title compound (430 mg, 79%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.38-7.42 (1H, m), 7.46-7.50 (2H, m), 7.60-7.64 ( 3H, m), 7.86 (2H, dd, J = 1.7, 7.9 Hz), 8.11 (1H, t, J = 1.8 Hz), 10.09 (1H, s).

[Production Example 85-1-2] 3- (2-nitroethyl) biphenyl

To a mixture of 3-phenyl-benzaldehyde (430 mg, 2.4 mmol) described in Production Example 85-1-1 and acetic acid (7 ml) was added nitromethane (0.95 ml, 18 mmol) and ammonium acetate (540 mg, 7.1 mmol) and stirred at 100 ° C for 2.5 hours. The reaction mixture was cooled to room temperature and water was added at the same temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of dimethyl sulfoxide (9.3 ml) and acetic acid (0.62 ml) was added to the obtained residue, and sodium borohydride (140 mg, 3.8 mmol) was added to a room-cooled reaction solution at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain the title compound (380 mg, 71%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.39 (2H, t, J = 7.4 Hz), 4.64-4.68 (2H, m), 7.18-7 20 (1H, m), 7.34-7.52 (6H, m), 7.55-7.57 (2H, m).

[Production Example 85-1-3] Biphenyl-3-yl-acetohydroximoyl chloride

To a mixture of 3- (2-nitroethyl) biphenyl (380 mg, 1.7 mmol) described in Production Example 85-1-2 and methanol (6 ml), lithium methoxide (130 mg, 3.4) was added at room temperature mM) and stirred at room temperature for 5 minutes. The solvent was evaporated from the reaction mixture under reduced pressure. A mixture of methylene chloride (7 ml) and tetrahydrofuran (3.5 ml) was added to the obtained residue at room temperature, and titanium (IV) chloride (410 μl, 3.7 mmol) was added to the reaction solution at -78 ° C and stirred at 0 ° C for 60 minutes. The reaction mixture was cooled to 0 ° C, water was added at the same temperature, and then ethyl acetate was added at room temperature to extract the mixture. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and the organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (420 mg) as a crude product. The resulting compound was used in the subsequent reaction without further purification.

[Example 86] 3- (3- (4-Phenoxymethylbenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (4-phenoxymethylphenyl) -acetohydroximoyl chloride (150 mg, 0.545 mmol) described in Production Example 86-1-5, and 3-ethynylpyridin-2-ylamine (41 mg, 0.348 mmol) described in Example 1-2- 3 receiving, in tetrahydrofuran (3 ml) was added triethylamine (104 μl, 0.747 mmol) and stirred at 50 ° C for 2 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 - 2: 1) to obtain the title compound (39 mg, 20%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.07 (2H, s), 5.05 (2H, s), 5.39 (2H, br s), 6.25 (1H , c), 6.70-6.73 (1H, m), 6.95-6.98 (3H, m), 7.29-7.32 (4H, m), 7.41-7.43 (2H, m), 7.69-7.72 (1H, m), 8.13-8.15 (1H, m).

The starting material, (4-phenoxymethylphenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 86-1-1] 1-bromo-4-phenoxymethyl-benzene

To a solution of 4-bromobenzyl bromide (5 g, 20 mmol) and phenol (2.26 g, 24 mmol) in N, N-dimethylformamide (50 ml) was added potassium carbonate (8.29 g, 60 mmol). This mixture was stirred at room temperature for 1 hour. Then the mixture was separated into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (4.69 g, 89%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.02 (2H, s), 6.94-6.99 (3H, m), 7.27-7.33 (4H, m) 7.49-7.52 (2H, m).

[Production Example 86-1-2] 4-Phenoxymethylbenzaldehyde

To a solution of 1-bromo-4-phenoxymethylbenzene (4.69 g, 17.8 mmol) described in Production Example 86-1-1 in tetrahydrofuran (50 ml) at -78 ° C was added dropwise n- butyllithium (16 , 8 ml, 1.59 M hexane solution, 26.7 mmol). After stirring at -78 ° C for 40 minutes, N-formylmorpholine (2.25 g, 19.6 mmol) was added to this mixture and then stirred at the same temperature for another 30 minutes. This mixture was partitioned into diethyl ether and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.8 g). In a subsequent reaction, this compound was used without purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.16 (2H, s), 6.96-6.99 (3H, m), 7.29-7.33 (2H, m) 7.60-7.62 (2H, m); 7.90-7.92 (2H, m); 10.0 (1H, s).

[Production Example 86-1-3] 1 - ((E) -2-nitrovinyl) -4-phenoxymethylbenzene

A mixture of 4-phenoxymethylbenzaldehyde (3.8 g, 17.8 mmol) described in Production Example 86-1-2, nitromethane (4.79 ml, 89 mmol), ammonium acetate (2.74 g, 35.6 mmol) and acetic acid (38 ml) was stirred at 100 ° C for 3 hours. This mixture was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (4.1 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.13 (2H, s), 6.96-7.01 (4H, m), 7.29-7.33 (2H, m) 7.52-7.62 (4H, m); 8.00-8.03 (1H, m).

[Production Example 86-1-4] 1- (2-nitroethyl) -4-phenoxymethyl-benzene

In a suitably cooled solution of 1 - ((E) -2-nitrovinyl) -4-phenoxymethylbenzene (4.1 g, 16.2 mmol), described in Production Example 86-1-3, in acetic acid (4.1 ml ) and dimethyl sulfoxide (70 ml) was added sodium borohydride (981 mg, 25.9 mmol) at room temperature. This mixture was stirred at room temperature for 1 hour. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (2.11 g, 51%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.21-3.24 (2H, m), 4.83-4.87 (2H, m), 5.06 (2H, c), 6.91-6.95 (1H, m), 6.98-7.01 (2H, m), 7.27-7.31 (4H, m), 7.38-7.40 ( 2H, m).

[Production Example 86-1-5] (4-phenoxymethylphenyl) -acetohydroximoyl chloride

To a solution of 1- (2-nitroethyl) -4-phenoxymethylbenzene (1 g, 3.89 mmol) described in Production Example 86-1-4, lithium methoxide (295 mg, 7.78 mmol) was added in methanol (12 ml) ) This mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The water in the residue was azeotropically distilled off with toluene, and the resulting residue was diluted with methylene chloride (16 ml) and tetrahydrofuran (8 ml). The mixture was cooled to −78 ° C. and titanium (IV) tetrachloride (940 μl, 8.56 mmol) was added dropwise to the suspension. The mixture was stirred at room temperature for 1.5 hours. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and ice water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1 g). The resulting compound was used in the subsequent reaction without further purification.

[Example 87] 3- (3- (3-Fluoro-4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 2- (2-fluoro-4- (2-nitroethyl) -phenoxy) pyridine (500 mg, 1.81 mmol) described in Production Example 87-1-3 in methanol (20.0 ml) at room temperature Under nitrogen atmosphere, lithium methoxide (137 mg, 3.61 mmol) was added and stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (15.0 ml) and anhydrous tetrahydrofuran (7.00 ml) were added to the residue. Titanium (IV) chloride (656 μl, 5.97 mmol) was added dropwise to the reaction solution in a bath of dry ice-ethanol (-78 ° C), and stirred at the same temperature for 30 minutes. Sodium bicarbonate and ethyl acetate were added to the reaction solution in an ice bath (0 ° C), then the solution was filtered through a celite pad. The organic layer of the filtrate was extracted with ethyl acetate, and this organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (300 mg). Triethylamine was added to a solution of this crude product (150 mg) and 3-ethynylpyridin-2-ylamine (30.0 mg, 0.254 mmol) described in Production Example 1-2-3 in tetrahydrofuran (5.00 ml) at room temperature. (106 μl, 0.762 mmol) and stirred at 50 ° C for 30 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1), the mixture was further purified by reverse phase high performance liquid chromatography (using acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (6 , 9 mg, 4.49%) as a salt of ditrifluoroacetic acid.

MS m / e (ESI) 377.15 (MH +)

The starting material, 2- (2-fluoro-4- (2-nitroethyl) phenoxy) pyridine, was synthesized as follows.

[Production Example 87-1-1] 3-fluoro-4- (pyridin-2-ylmethoxy) benzaldehyde

To a solution of 2- (hydroxymethyl) -pyridine (3.00 g, 27.5 mmol) in N, N-dimethylformamide (40.0 ml) at 0 ° C under nitrogen atmosphere was added sodium hydride (1.00 g, 25, 0 mM, 60% in oil) and stirred at room temperature for 20 minutes. Then, 3,4-difluorobenzaldehyde (4.69 g, 33.0 mmol) was added at 0 ° C and stirred at room temperature for 20 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 1 then 2: 1) to obtain the title compound (2.90 g, 45.6%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.36 (2H, s), 7.15 (1H, t, J = 8.0 Hz), 7.26-7.29 (1H , m), 7.55-7.67 (3H, m), 7.74-7.78 (1H, m), 8.61-8.63 (1H, m), 9.86-9.87 (1H, m).

[Production Example 87-1-2] 2- (2-Fluoro-4 - ((E) -2-nitrovinyl) phenoxymethyl) pyridine

To a solution of 3-fluoro-4- (pyridin-2-ylmethoxy) benzaldehyde (2.80 g, 12.1 mmol) described in Production Example 87-1-1 in acetic acid (25.0 ml) at room temperature Nitromethane (3.69 g, 60.5 mmol) and ammonium acetate (1.87 g, 24.2 mmol) were added under nitrogen atmosphere and stirred at 110 ° C for 2 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.00 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.35 (2H, s), 7.34-7.40 (2H, s), 7.54-6.84 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.85-7.92 (2H, m), 8.09 (1H, d, J = 13 4 Hz), 8.19 (1H, d, J = 13.4 Hz), 8.60 (1H, d, J = 4.0 Hz).

[Production Example 87-1-3] 2- (2-fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine

In a suitably cooled solution of 2- (2-fluoro-4 - ((E) -2-nitrovinyl) phenoxymethyl) pyridine (3.00 g, 10.9 mmol) described in Production Example 87-1-2, and acetic acid (3.00 ml) in dimethyl sulfoxide (30.0 ml) at room temperature in a nitrogen atmosphere was added sodium borohydride (660 mg, 17.4 mmol) and stirred at room temperature for 20 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was crystallized using a tetrahydrofuran-ethyl acetate-heptane system, and filtered to obtain the title compound (1.50 g, 49.8%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.18 (2H, t, J = 6.8 Hz), 4.84 (2H, t, J = 6.8 Hz), 5.50 (2H, s), 7.06-7.08 (2H, m), 7.28-7.31 (1H, m), 7.65-7.69 (1H, m), 7, 88 (1H, d, J = 8.0 Hz), 8.23-8.27 (1H, m), 8.76 (1H, J = 5.6 Hz).

[Example 88] 3- (3- (4- (Thiazol-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To 4- (5- (2-aminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (50.0 mg, 0.19 mmol) described in Production Example 5-1-1, tetrahydrofuran (3 ml) and a 5 N aqueous solution of sodium hydroxide (37.3 μl, 0.19 mmol) and dissolved by ultrasonic treatment for 1 minute. Then the reaction mixture was concentrated under reduced pressure to obtain a white solid. A solution of 2-chloromethyltriazole (29.8 mg, 0.22 mmol) described in Production Example 88-1-2 in N, N-dimethylformamide (1 ml) was added to a suspension of this solid and N, N-dimethylformamide (2 ml) and stirred at 60 ° C for 1 hour. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (53.0 mg, 78%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.42 (2H, s), 6.25 (2H, br.s), 6.68 -6.71 (1H, m), 6.79 (1H, s), 7.03 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz) 7.77 (1H, d, J = 3.2 Hz), 7.83 (1H, d, J = 3.2 Hz), 7.85-7.88 (1H, m), 8.08 ( 1H, dd, J = 2.0, 4.8 Hz).

The starting material, 2-chloromethyltriazole, was synthesized as follows.

[Production Example 88-1-1] Triazol-2-yl-methanol

Sodium borohydride (201.0 mg, 5.30 mmol) was added to a mixture of 2-formylthiazole (300 mg, 2.65 mmol) and methanol (30 ml) at 0 ° C and stirred at room temperature for 1 hour. Water was added to this reaction mixture, and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (diethyl ether) to obtain the title compound (251.2 mg, 82%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.74 (2H, d, J = 6.0 Hz), 6.04 (1H, t, J = 6.0 Hz), 7.63-7.65 (1H, m); 7.73-7.75 (1H, m).

[Production Example 88-1-2] 2-Chloromethyltriazole

To a mixture of triazol-2-yl-methanol (251 mg, 2.18 mmol) described in Production Example 88-1-1 and dichloromethane (10 ml), thionyl chloride (191 μl, 2.62 mmol) was added at room temperature and stirred for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and then extracted with dichloromethane. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (220.5 mg, 76%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.11 (2H, s), 7.81-7.83 (2H, m).

[Example 89] 3- (3- (6- (3, 4-Difluorobenzyloxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

The title compound (23 mg, 17%) was obtained according to methods similar to the methods of Example 3 using 3-ethynylpyridin-2-ylamine (40 mg, 0.34 mmol) described in Production Example 1-2-3, and (6- (3,4-difluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride (210 mg, 0.68 mmol) described in Production Example 89-1-1.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.01 (2H, s), 5.32 (2H, s), 6.27 (2H, br s), 6.70 (1H, ddd, J = 2.0, 4.8, 8.0 Hz), 6.83 (1H, d, J = 2.0 Hz), 6.88 (1H, d, J = 8.8 Hz), 7.28-7.34 (1H, m), 7.39-7.48 (1H, m), 7.49-7.56 (1H, m), 7.68-7.73 ( 1H, m), 7.85-7.89 (1H, m), 8.08-8.12 (1H, m), 8.17 (1H, s).

The starting material, (6- (3, 4-difluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 89-1-1] (6- (3,4-difluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride

The title compound (810 mg) was obtained according to methods similar to the methods of Production Examples 12-1-1 to 12-1-5, using 3,4-difluorobenzyl alcohol.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.80 (2H, s), 5.32 (2H, s), 6.89 (1H, d, J = 8.0 Hz ), 7.29-7.34 (1H, m), 7.40-7.49 (1H, m), 7.50-7.57 (1H, m), 7.62 (1H, d, J = 8.0 Hz), 8.08 (1H, s), 11.76 (1H, s).

[Example 90] 3- (3- (6- (2,4-Difluorobenzyloxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

The title compound (45 mg, 34%) was obtained according to methods similar to the methods of example 3, using 3-ethynylpyridin-2-ylamine (40 mg, 0.34 mmol) described in Production Example 1-2-3, and (6- (2,4-Difluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride (210 mg, 0.68 mmol) described in Production Example 90-1-1.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.01 (2H, s), 5.34 (2H, s), 6.27 (2H, br s), 6.70 (1H, dd, J = 4.8, 8.0 Hz), 6.84 (1H, s), 6.85 (1H, d, J = 8.0 Hz), 7.08-7.14 ( 1H, m), 7.26-7.33 (1H, m), 7.57-7.64 (1H, m), 7.69 (1H, dd, J = 2.4, 8.0 Hz) , 7.87 (1H, dd, J = 2.0, 8.0 Hz), 8.09 (1H, dd, J = 2.0, 4.8 Hz), 8.18 (1H, d, J = 2.4 Hz).

The starting material, (6- (2,4-difluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 90-1-1] (6- (2,4-difluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride

The title compound (600 mg) was obtained according to methods similar to the methods of Production Examples 12-1-1 to 12-1-5, using 2,4-difluorobenzyl alcohol.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.80 (2H, s), 5.34 (2H, s), 6.86 (1H, d, J = 8.0 Hz ), 7.08-7.14 (1H, m), 7.26-7.33 (1H, m), 7.58 (2H, m), 8.09 (1H, s), 11.75 ( 1H, c).

[Example 91] 3- (3- (5- (4-Fluorophenoxy) thiophen-2-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (5- (4-fluorophenoxy) -thiophen-2-yl) -acetohydroximoyl chloride (250 mg, 0.875 mmol) described in Production Example 91-1-4, and 3-ethynylpyridin-2-ylamine (50.0 mg , 0.423 mmol) described in Production Example 1-2-3, triethylamine (177 μl, 1.27 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at 60 ° C for 30 minutes. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 2 then 1: 1) to obtain the title compound (11.2 mg, 7.21%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.17 (2H, s), 6.28 (2H, br s), 6.53 (1H, d, J = 4, 0 Hz), 6.69-6.73 (1H, m), 6.78 (1H, d, J = 4.0 Hz), 6.88 (1H, s), 7.13-7.17 ( 2H, m), 7.20-7.25 (2H, m), 7.88-7.91 (1H, m), 8.09-8.11 (1H, m).

The starting material, (5- (4-fluorophenoxy) -thiophen-2-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 91-1-1] 5- (4-fluorophenoxy) thiophene-2-carbonitrile

To a solution of 5-nitro-2-thiophene carbonitrile (5.00 g, 32.4 mmol) in dimethyl sulfoxide (100 ml) under nitrogen atmosphere was added 4-fluorophenol (5.45 g, 48.6 mmol) and potassium carbonate (11 , 2 g, 81.0 mmol) and stirred at 60 ° C for 16 hours. The reaction solution was cooled to room temperature and water was added and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 10 then 1: 5) to obtain the title compound (6.10 g, 85.9%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 6.40 (1H, d, J = 4.4 Hz), 7.07-7.16 (4H, m), 7.36 (1H d, J = 4.4 Hz).

[Production Example 91-1-2] 5- (4-Fluorophenoxy) -thiophene-2-carbaldehyde

To a solution of 5- (4-fluorophenoxy) thiophene-2-carbonitrile (6.10 g, 27.8 mmol) described in Production Example 91-1-1 in tetrahydrofuran (150 ml) in a bath with a mixture of dry ice- ethanol (-78 ° C) in a nitrogen atmosphere diisobutylaluminum hydride (0.97 M n- hexane solution, 43.0 ml, 41.7 mmol) was added dropwise and stirred at room temperature for 2 hours. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (3.4 g, 55.0%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 6.48-6.49 (1H, m), 7.08-7.12 (2H, m), 7.16-7.19 ( 2H, m), 7.52-7.54 (1H, m), 9.71 (1H, s).

[Production Example 91-1-3] 2- (4-fluorophenoxy) -5- (2-nitroethyl) thiophene

To the solution of 5- (4-fluorophenoxy) thiophene-2-carbaldehyde (2.60 g, 11.7 mmol) described in Production Example 91-1-2 in acetic acid (20.0 ml) at room temperature in nitromethane (3.57 g, 58.5 mmol) and ammonium acetate (1.80 g, 23.4 mmol) were added under nitrogen atmosphere and stirred at 110 ° C for 4 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (3.00 g). To a suitably cooled solution of this crude product (3.00 g) and acetic acid (3.00 ml) in dimethyl sulfoxide (30.0 ml) was added sodium borohydride (684 g, 18.1 M) at room temperature and stirred at room temperature temperature for 20 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (1.38 g, 45.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.34 (2H, t, J = 6.8 Hz), 4.82 (2H, t, J = 6.4 Hz), 6.50 (1H, d, J = 3.6 Hz), 6.69-6.71 (1H, m), 7.12-7.16 (2H, m), 7.21-7.26 ( 2H, m).

[Production Example 91-1-4] (5- (4-Fluorophenoxy) -thiophen-2-yl) -acetohydroximoyl chloride

To a solution of 2- (4-fluorophenoxy) -5- (2-nitroethyl) thiophene (500 mg, 1.87 mmol) described in Production Example 91-1-3 in methanol (20.0 ml) at room temperature lithium methoxide (142 mg, 3.74 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (10.0 ml) and anhydrous tetrahydrofuran (5.00 ml) were added to the residue. Titanium (IV) chloride (514 μl, 4.68 mmol) was added dropwise to the reaction solution in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 30 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction solution in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the title compound (500 mg, 93.6%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.95 (2H, s), 6.52 (1H, d, J = 4.0 Hz), 6.76 (1H, d , J = 4.0 Hz), 7.14-7.26 (4H, m), 11.82 (1H, s).

[Example 92] 3- (3- (5- (4-Methylbenzyl) thiophen-2-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (5- (4-methylbenzyl) -thiophen-2-yl) -acetohydroximoyl chloride (250 mg, 0.894 mmol) described in Production Example 92-1-5, and 3-ethynylpyridin-2-ylamine (50.0 mg , 0.423 mmol) described in Production Example 1-2-3, triethylamine (177 μl, 1.27 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at 60 ° C for 2 hours. Water was added to the reaction solution at room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 2) to obtain the title compound (27.7 mg, 18.1%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.26 (3H, s), 4.02 (2H, s), 4.15 (2H, s), 6.26 (2H , broad s), 6.68-6.72 (2H, m), 6.80-6.81 (1H, m), 6.84 (1H, s), 7.08-7.14 (4H , m), 7.88 (1H, dd, J = 2.0, 7.6 Hz), 8.09 (1H, dd, J = 2.0, 4.8 Hz).

The starting material, (5- (4-methylbenzyl) -5-thiophen-2-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 92-1-1] (5-bromothiophen-2-yl) - p- tolyl-methanol

To a solution of 2,5-dibromothiophene (5.00 g, 19.6 mmol) in anhydrous tetrahydrofuran (70.0 ml) in a bath with a mixture of dry ice-ethanol (-78 ° C) in an atmosphere of nitrogen was added dropwise n- butyllithium (2.55 M n- hexane solution, 7.69 ml, 19.6 mmol) and stirred at -78 ° C for 20 minutes. Then p- tolylaldehyde (2.35 g, 19.6 mmol) was added dropwise and stirred at -78 ° C for 10 minutes. The reaction mixture was allowed to warm to room temperature and water was added and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5 → 1: 1) to obtain the title compound (4.30 g, 77.5%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.34 (3H, s), 2.62 (1H, br.s), 5.84 (1H, d, J = 4.0 Hz ), 6.56-6.57 (1H, m), 6.84 (1H, d, J = 4.0 Hz), 7.15-7.17 (2H, m), 7.25-7, 27 (2H, m).

[Production Example 92-1-2] 5- (4-methylbenzyl) thiophene-2-carbaldehyde

To a solution of sodium iodide (11.4 g, 76.0 mmol) in acetonitrile (50.0 ml) under nitrogen atmosphere was added dropwise chlorotrimethylsilane (9.65 ml, 76.0 mmol) and stirred at room temperature for 1, 5 o'clock. The reaction solution was cooled to -30 ° C, and added dropwise to a solution of (5-bromothiophene-2-yl) - p -tolil-methanol (4.30 g, 15.2 mmol) described in Example 1.1.92 obtain in acetonitrile (10.0 ml) and stirred at room temperature for 1.5 hours. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 10) to obtain a mixture (4.30 g). To a solution of this mixture (2.30 g) in tetrahydrofuran (40.0 ml) in a bath with a mixture of dry ice-ethanol (-78 ° C) n- butyllithium (1.57 M solution of n- hexane, 6, 03 ml, 9.47 mmol) and stirred at -78 ° C for 10 minutes. Then, N, N-dimethylformamide (864 μl, 11.2 mmol) was added dropwise at -78 ° C and stirred at -78 ° C for 5 minutes. The reaction solution was allowed to warm to room temperature and water was added and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 10) to obtain the title compound (1.05 g, 56.4%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.33 (3H, s), 4.14 (2H, s), 6.89 (1H, d, J = 3.6 Hz), 7.13 (4H, s), 7.59 (1H, d, J = 3.6 Hz), 9.79 (1H, s).

[Production Example 92-1-3] 2- (4-Methylbenzyl) -5 - ((E) -2-nitrovinyl) thiophene

To a solution of 5- (4-methylbenzyl) -thiophene-2-carbaldehyde (1.05 g, 4.85 mmol) described in Production Example 91-1-2 in acetic acid (10.0 ml) at room temperature in under nitrogen atmosphere, nitromethane (1.48 g, 24.3 mmol) and ammonium acetate (748 mg, 9.70 mmol) were added and stirred at 110 ° C for 4 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.20 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.27 (3H, s), 4.16 (2H, s), 7.04 (1H, d, J = 3.6 Hz ), 7.14-7.18 (4H, m), 7.66 (1H, d, J = 3.6 Hz), 7.83 (1H, d, J = 13.2 Hz), 8.27 (1H, d, J = 13.2 Hz).

[Production Example 92-1-4] 2- (4-methylbenzyl) -5- (2-nitroethyl) thiophene

In a suitably cooled solution of 2- (4-methylbenzyl) -5 - ((E) -2-nitrovinyl) thiophene (1.20 g, 4.63 mmol), described in Production Example 92-1-3, and acetic acid (1.20 ml) in dimethyl sulfoxide (20.0 ml) at room temperature in a nitrogen atmosphere was added sodium borohydride (280 mg, 7.41 mmol) and stirred at room temperature for 20 minutes. Then, water was added dropwise at room temperature, cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was crystallized using a tetrahydrofuran-ethyl acetate-heptane system, and filtered to obtain the title compound (525 mg, 43.4%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.26 (3H, s), 3.33 (2H, t, J = 6.4 Hz), 4.01 (2H, s ), 4.78 (2H, t, J = 6.4 Hz), 6.68-6.69 (1H, m), 6.72-6.73 (1H, m), 7.11 (4H, c)

[Production Example 92-1-5] (5- (4-methylbenzyl) -thiophen-2-yl) -acetohydroximoyl chloride

To a solution of 2- (4-methylbenzyl) -5- (2-nitroethyl) thiophene (525 mg, 2.01 mmol), described in Production Example 92-1-4, in methanol (20.0 ml) at room temperature lithium methoxide (153 mg, 4.02 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Titanium (IV) chloride (582 μl, 5.30 mmol) was added dropwise to the reaction solution in a dry ice-ethanol bath (-78 ° C), and then stirred at room temperature for 30 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction solution in an ice bath (0 ° C), and the organic layer was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (520 mg, 92.5%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.26 (3H, s), 3.93 (2H, s), 4.02 (2H, s), 6.71 (1H d, J = 3.2 Hz), 6.78 (1H, d, J = 3.2 Hz), 7.09-7.15 (4H, m), 11.76 (1H, s).

[Example 93] 3- (3- (4- (2-Pyridin-2-yl-ethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (39 mg, 0.33 mmol) described in Production Example 1-2-3 in anhydrous tetrahydrofuran (5 ml) at room temperature under nitrogen atmosphere was added (4- (2-pyridine -2-yl-ethyl) -phenyl) -acetohydroximoyl chloride hydrochloride (310 mg, 1.0 mmol) described in Production Example 93-1-8, then triethylamine (0.42 ml, 3.0 mmol) was added dropwise and stirred at 60 ° C for 2 hours. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 3: 7 then 4: 6) and the resulting crude product was further purified by thin layer chromatography (ethyl acetate) to obtain the title compound (21.2 mg, 18%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.00-3.16 (4H, m), 4.02 (2H, s), 5.42 (2H, br s), 6 25 (1H, s), 6.71 (1H, dd, J = 4.8, 8.0 Hz), 7.10-7.25 (6H, m), 7.55-7.60 (1H , m), 7.70 (1H, dd, J = 2.0, 8.0 Hz), 8.13 (1H, dd, J = 2.0, 4.8 Hz), 8.56 (1H, m).

The starting material, (4- (2-pyridin-2-yl-ethyl) phenyl) -acetohydroximoyl chloride hydrochloride, was synthesized as follows.

[Production Example 93-1-1] Diethyl 4-methoxycarbonyl benzylphosphonate

Methyl 4- (bromomethyl) benzoate (50 g, 218 mmol) and triethyl phosphite (43.5 g, 262 mmol) were mixed, stirring at 100 ° C for 30 minutes, and then stirred at 120 ° C for another 30 minutes . The reaction solution was evaporated under reduced pressure (165-175 ° C, 1 mmHg) to give the title compound (58.6 g, 94%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.24 (6H, t, J = 7.2 Hz), 3.20 (2H, d, J = 22 Hz), 3.91 ( 3H, s), 3.98-4.18 (4H, m), 7.38 (2H, dd, J = 2.4, 8.4 Hz), 7.99 (2H, J = 8.4 Hz )

[Production Example 93-1-2] methyl 4- (2-pyridin-2-yl-ethylenyl) benzoate

Sodium hydride (0.97 g, 24.2 mmol, 60% in oil) was suspended in anhydrous tetrahydrofuran (20 ml) under a nitrogen atmosphere, and diethyl 4-methoxycarbonyl benzylphosphonate (6.96 g, 24.2 mmol) was added at room temperature. ), described in Production Example 93-1-1, and methanol (0.5 ml) was added, followed by stirring at room temperature for 30 minutes. Then, 2-pyridinecarboxyaldehyde (2 g, 18.7 mmol) was added at room temperature and stirred at room temperature for 1 hour. The reaction mixture in an ice bath (0 ° C) was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 9) to obtain the title compound (3.71 g, 83%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.93 (3H, s), 7.19 (1H, dd, J = 4.8, 7.6 Hz), 7.27 (1H d, J = 16 Hz), 7.41 (1H, d, J = 7.6 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.66 (1H, d, J = 16 Hz), 7.69 (1H, t, J = 8.0 Hz), 8.05 (2H, d, J = 8.8 Hz), 8.63 (1H, d, J = 4.8 Hz).

[Production Example 93-1-3] methyl 4- (2-pyridin-2-yl-ethyl) benzoate

To a solution of methyl 4- (2-pyridin-2-yl-ethylenyl) benzoate (3.71 g, 15.5 mmol) described in Production Example 93-1-2 in anhydrous tetrahydrofuran (25 ml) was added 10% palladium-on-charcoal (50% hydrate, 1 g) and stirred at room temperature in a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (3.71 g, 99%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.11 (4H, m), 3.90 (3H, s), 7.04 (1H, d, J = 7.6 Hz), 7.12 (1H, dd, J = 6.0, 7.6 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.55 (1H, t, J = 7.6 Hz ), 7.94 (2H, d, J = 8.4 Hz), 8.56 (1H, d, J = 6.0 Hz).

[Production Example 93-1-4] 4- (2-pyridin-2-yl-ethyl) benzyl alcohol

To a solution of methyl 4- (2-pyridin-2-yl-ethyl) benzoate (3.71 g, 15.4 mmol) described in Production Example 93-1-3 in anhydrous tetrahydrofuran (50 ml) in a bath dry ice-ethanol mixture (-78 ° C) in a nitrogen atmosphere was added diisobutylaluminum hydrate (0.97 M solution in toluene, 39.7 ml, 38.5 mmol). After stirring for 30 minutes, a 15% aqueous potassium tartrate solution (100 ml) was added to the reaction mixture, and stirred at room temperature for 30 minutes. Ethyl acetate (100 ml) was added and the organic layer and the aqueous layer were separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (3.16 g, 96%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.79 (1H, br s), 3.07 (4H, m), 4.66 (2H, s), 7.07 (1H d, J = 7.6 Hz), 7.12 (1H, dd, J = 6.0, 7.6 Hz), 7.19 (2H, d, J = 8.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.57 (1H, t, J = 7.6 Hz), 8.56 (1H, d, J = 6.0 Hz).

[Production Example 93-1-5] 4- (2-Pyridin-2-yl-ethyl) benzaldehyde

To a solution of 4- (2-pyridin-2-yl-ethyl) benzyl alcohol (3.16 g, 14.8 mmol) described in Production Example 93-1-4, activated manganese dioxide (45 g) was added in ethyl acetate (100 ml). , 518 mmol) and stirred for 4 hours at room temperature. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (100 ml). The filtrate was concentrated under reduced pressure to obtain the title compound (2.57 g, 82%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.10-3.20 (4H, m), 7.07 (1H, d, J = 7.6 Hz), 7.12 (1H dd, J = 6.0, 7.6 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.57 (1H, t, J = 7.6 Hz), 7.79 (2H, d, J = 8.0 Hz), 8.56 (1H, d, J = 6.0 Hz), 9.97 (1H, s).

[Production Example 93-1-6] 4- (2-pyridin-2-yl-ethyl) - (( E ) -2-nitrovinyl) benzene

To a solution of 4- (2-pyridin-2-yl-ethyl) benzaldehyde (2.57 g, 12.2 mmol) described in Production Example 93-1-5 in acetic acid (30 ml) at room temperature in the atmosphere nitrogen was added nitromethane (7.45 g, 122 mmol) and ammonium acetate (1.88 g, 24.4 mmol) and stirred at 120 ° C for 3 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (2.83 g, 91%) as a crude product.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.10-3.20 (4H, m), 7.07 (1H, d, J = 7.6 Hz), 7.12 (1H dd, J = 6.0, 7.6 Hz), 7.26 (2H, d, J = 8.0 Hz), 7.45 (2H, d, J = 8.0 Hz), 7.56 (1H, d, J = 13.6 Hz), 7.57 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 13.6 Hz), 8.56 (1H d, J = 6.0 Hz).

[Production Example 93-1-7] 4- (2-pyridin-2-yl-ethyl) - (2-nitroethyl) -benzene

To a suitably cooled solution of 4- (2-pyridin-2-yl-ethyl) - (( E ) -2-nitrovinyl) benzene (2.83 g, 11.1 mmol) described in Example 93-1-6 of preparation and acetic acid (3 ml) in a tetrahydrofuran-dimethyl sulfoxide mixture (1: 1) at room temperature under nitrogen atmosphere was added sodium borohydride (630 mg, 16.7 mmol) and stirred at room temperature for 15 minutes. Water was added dropwise to a reaction cooled solution at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: getpan = 1: 9 then 2: 8) to obtain the title compound (2.11 g, 74%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.07 (2H, t, J = 7.6 Hz), 3.29 (2H, t, J = 7.2 Hz), 3, 47 (2H, t, J = 7.6 Hz), 4.60 (2H, t, J = 7.2 Hz), 7.13 (2H, d, J = 8.0 Hz), 7.19 ( 2H, d, J = 8.0 Hz), 7.19 (1H, d, J = 7.6 Hz), 7.30 (1H, dd, J = 6.0, 7.6 Hz), 7, 78 (1H, t, J = 7.6 Hz), 8.78 (1H, d, J = 7.6 Hz).

[Production Example 93-1-8] (4- (2-pyridin-2-yl-ethyl) -phenyl) -acetohydroximoyl hydrochloride

To a solution of 4- (2-pyridin-2-yl-ethyl) - (2-nitroethyl) benzene (1 g, 3.9 mmol) described in Production Example 93-1-7 in methanol (30 ml) at lithium methoxide (296 mg, 7.8 mmol) was added at room temperature under a nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Anhydrous methylene chloride (20 ml) and anhydrous tetrahydrofuran (10 ml) were added to the residue. Titanium (IV) chloride (1 M dichloromethane solution, 12.5 ml, 12.5 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at 0 ° C for 30 minutes. Water and ethyl acetate were added to the reaction mixture in an ice bath (0 ° C) and then neutralized by the addition of a 10% aqueous sodium hydrogen carbonate solution. The reaction liquid containing the precipitate was filtered through a pad of celite and washed with ethyl acetate. The organic layer was separated from the filtrate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and anhydrous magnesium sulfate was filtered off. A solution of 4N hydrochloric acid-ethyl acetate (4 ml) was added to the filtrate, and the solvent was evaporated under reduced pressure to obtain the title compound (324 mg, 100%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.08 (2H, t, J = 7.6 Hz), 3.32 (2H, t, J = 7.6 Hz), 3.78 (2H, s), 7.12-7.26 (4H, m), 7.80-7.94 (2H, m), 8.43 (1H, m), 8.80 (1H, m).

[Example 94] 3- (3- (3-Fluoro-4- (5-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (3-fluoro-4- (5-fluoropyridin-2-ylmethoxy) phenyl) -acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Production Example 94-1-3, and 3-ethynylpyridin-2-ylamine ( 40.0 mg, 0.339 mmol) described in Production Example 1-2-3, triethylamine (142 μl, 1.02 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at room temperature for 4 hours . Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 2) to obtain the title compound (18.0 mg, 13.5%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.98 (2H, s), 5.23 (2H, s), 6.27 (2H, br s), 6.70 (1H, dd, J = 0.8, 8.0 Hz), 6.82 (1H, s), 7.07 (1H, d, J = 8.0 Hz), 7.18-7.26 ( 2H, m), 7.61 (1H, dd, J = 0.8, 8.4 Hz), 7.76-7.81 (1H, m), 7.86-7.88 (1H, m) 8.09 (1H, dd, J = 1.6, 4.8 Hz); 8.58-8.59 (1H, m).

The starting material, (3-fluoro-4- (5-fluoropyridin-2-ylmethoxy) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 94-1-1] 3-fluoro-4- (5-fluoropyridin-2-ylmethoxy) benzaldehyde

To a solution of (5-fluoropyridin-2-yl) methanol (760 mg, 5.98 mmol) described in Production Example 41-1-1 in N, N-dimethylformamide (20.0 ml) at 0 ° C. sodium hydride (239 mg, 5.98 mmol, 60% in oil) was added under nitrogen atmosphere and stirred at room temperature for 10 minutes. Then, 3,4-difluorobenzaldehyde (935 mg, 6.58 mmol) was added at room temperature and stirred at room temperature for 30 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (629 mg, 42.2%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.33 (2H, s), 7.15 (1H, t, J = 8.0 Hz), 7.45-7.50 (1H , m), 7.57-7.66 (3H, m), 8.47 (1H, d, J = 3.2 Hz), 9.87 (1H, d, J = 2.0 Hz).

[Production Example 94-1-2] 5-fluoro-2- (2-fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine

To a solution of 3-fluoro-4- (5-fluoropyridin-2-ylmethoxy) benzaldehyde (629 mg, 2.52 mmol) described in Production Example 94-1-1 in acetic acid (8.00 ml) at room temperature At a temperature in a nitrogen atmosphere, nitromethane (769 mg, 12.6 mmol) and ammonium acetate (388 mg, 5.04 mmol) were added and stirred at 100 ° C for 6 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (736 mg). To a suitably cooled solution of this crude product (736 mg) and acetic acid (700 μl) in dimethyl sulfoxide (10.0 ml) was added sodium borohydride (153 mg, 4.03 mmol) at room temperature and stirred at room temperature for 30 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 5) to obtain the title compound (341 mg, 46.0%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.16 (2H, t, J = 6.8 Hz), 4.83 (2H, t, J = 6.8 Hz), 5.22 (2H, s), 7.01-7.03 (1H, m), 7.16-7.24 (2H, m), 7.59-7.63 (1H, m), 7, 77-7.82 (1H, m), 8.59 (1H, d, J = 2.8 Hz).

[Production Example] 94-1-3] (3-fluoro-4- (5-fluoropyridin-2-ylmethoxy) phenyl) -acetohydroximoyl chloride

To a solution of 5-fluoro-2- (2-fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine (341 mg, 1.16 mmol) described in Production Example 94-1-2, in methanol (20, 0 ml) at room temperature in a nitrogen atmosphere was added lithium methoxide (88.1 mg, 2.32 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Titanium (IV) chloride (408 μl, 3.71 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 60 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (340 mg, 93.7%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.77 (2H, s), 5.24 (2H, s), 7.01-7.02 (1H, m), 7 12-7.16 (1H, m), 7.20-7.24 (1H, m), 7.60-7.63 (1H, m), 7.77-7.82 (1H, m) 8.59 (1H, d, J = 2.8 Hz); 11.74 (1H, s).

[Example 95] 3- (3- (2-Fluoro-4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 2- (3-fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine (400 mg, 1.45 mmol) described in Production Example 95-1-3 in methanol (20.0 ml) at lithium methoxide (110 mg, 2.90 mmol) was added at room temperature under a nitrogen atmosphere and stirred at room temperature for 30 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Titanium (IV) chloride (510 μl, 4.64 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 60 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (360 mg). Triethylamine was added to a solution of this crude product (180 mg) and 3-ethynylpyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Production Example 1-2-3 in tetrahydrofuran (5.00 ml) at room temperature. (142 μl, 1.02 mmol) and stirred at 60 ° C for 1 hour. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 2) to obtain the title compound (25.2 mg, 19.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.98 (2H, s), 5.18 (2H, s), 6.26 (2H, br s), 6.68 -6.71 (1H, m), 6.77 (1H, s), 6.86 (1H, dd, J = 2.4, 8.4 Hz), 6.95 (1H, dd, J = 2 4, 12.0 Hz), 7.29-7.37 (2H, m), 7.51 (1H, d, J = 8.0 Hz), 7.82-7.88 (2H, m) 8.08-8.09 (1H, m); 8.57-8.59 (1H, m).

The starting material, 2- (3-fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine, was synthesized as follows.

[Production Example 95-1-1] 2-fluoro-4- (pyridin-2-ylmethoxy) benzaldehyde

To a solution of 2-fluoro-4-hydroxybenzaldehyde (1.60 g, 11.4 mmol) in N, N-dimethylformamide (10.0 ml) at 0 ° C under nitrogen atmosphere was added sodium hydride (547 mg, 13.7 mmol) , 60% in oil) and stirred at room temperature for 30 minutes. Then, 2-picolyl chloride (2.80 g, 17.1 mmol) was added at room temperature and stirred at 70 ° C for 1 hour. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 3) to obtain the title compound (1.07 g, 40.6%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.27 (2H, s), 6.74-6.77 (1H, m), 6.87-6.90 (1H, m) 7.26-7.29 (1H, m), 7.47-7.49 (1H, m), 7.73-7.85 (2H, m), 8.62-8.64 (1H, m) 10.21 (1H, s).

[Production Example 95-1-2] 2- (3-fluoro-4 - (( E ) -2-nitrovinyl) phenoxymethyl) pyridine

To a solution of 2-fluoro-4- (pyridin-2-ylmethoxy) benzaldehyde (1.07 g, 4.63 mmol) described in Production Example 95-1-1 in acetic acid (15.0 ml) at room temperature at a temperature in a nitrogen atmosphere, nitromethane (1.41 g, 23.2 mmol) and ammonium acetate (714 mg, 9.26 mmol) were added and stirred at 100 ° C for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.20 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.30 (2H, s), 7.02-7.05 (1H, m), 7.14-7.18 (1H, m), 7.36-7.39 (1H, m), 7.54 (1H, d, J = 7.6 Hz), 7.85-7.89 (1H, m), 7.93 (1H , t, J = 8.8 Hz), 8.06 (2H, s), 8.59-8.61 (1H, m).

[Production Example 95-1-3] 2- (3-Fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine

In a suitably cooled solution of 2- (3-fluoro-4 - (( E ) -2-nitrovinyl) phenoxymethyl) pyridine (1.20 g) described in Production Example 95-1-2 and acetic acid (1, 00 ml) in dimethyl sulfoxide (20.0 ml) at room temperature in a nitrogen atmosphere was added sodium borohydride (249 mg, 6.57 mmol) and stirred at room temperature for 30 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, then crystallized using an ethyl acetate-heptane system and filtered to obtain the title compound (614 mg, 50.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.21 (2H, t, J = 7.2 Hz), 4.79 (2H, t, J = 7.2 Hz), 5.46 (2H, s), 6.82 (1H, dd, J = 2.4, 8.4 Hz), 6.92 (1H, dd, J = 2.4, 8.4 Hz), 7 32 (1H, t, J = 8.8 Hz), 7.66 (1H, t, J = 6.4 Hz), 7.87 (1H, d, J = 8.0 Hz), 8.21 -8.25 (1H, m), 8.76 (1H, d, J = 5.6 Hz).

[Example 96] 3- (3- (2-Fluoro-4- (5-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the solution of (2-fluoro-4- (5-fluoropyridin-2-ylmethoxy) phenyl) -acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Production Example 96-1-4, and 3-ethynylpyridin-2-ylamine ( 40.0 mg, 0.339 mmol) described in Production Example 1-2-3, triethylamine (142 μl, 1.02 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at room temperature for 4 hours . Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 2) to obtain the title compound (32.0 mg, 23.9%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.99 (2H, s), 5.18 (2H, s), 6.26 (2H, br s), 6.68 -6.71 (1H, m), 6.77 (1H, s), 6.86 (1H, dd, J = 2.4, 8.4 Hz), 6.96 (1H, dd, J = 2 4, 12.0 Hz), 7.31 (1H, t, J = 8.8 Hz), 7.61 (1H, dd, J = 4.8, 8.8 Hz), 7.78 (1H , ddd, J = 2.8, 8.4, 17.2 Hz), 7.87 (1H, dd, J = 1.6, 7.6 Hz), 8.08 (1H, dd, J = 1 6, 7.6 Hz), 8.59 (1H, d, J = 2.8 Hz).

The starting material, (2-fluoro-4- (5-fluoropyridin-2-ylmethoxy) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 96-1-1] 2-fluoro-4- (5-fluoropyridin-2-ylmethoxy) benzaldehyde

To a solution of 2-fluoro-4-hydroxybenzaldehyde (1.48 g, 10.2 mmol) in N, N-dimethylformamide (20.0 ml) at 0 ° C under nitrogen atmosphere was added sodium hydride (411 mg, 10.3 mmol) , 60% in oil) and stirred at room temperature for 20 minutes. Then, 2-chloromethyl-5-fluoropyridine (1.20 g, 8.56 mmol), described in Production Example 41-1-2, was added at room temperature, and stirred at 80 ° C. for 30 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 5 then 1: 2) to obtain the title compound (901 mg, 42.2%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.24 (2H, s), 6.73-6.77 (1H, m), 6.87-6.89 (1H, m) 7.46-7.51 (2H, m), 7.84 (1H, t, J = 8.4 Hz), 8.48 (1H, d, J = 2.8 Hz), 10.22 ( 1H, c).

[Production Example 96-1-2] 5-fluoro-2- (3-fluoro-4 - (( E ) -2-nitrovinyl) phenoxymethyl) pyridine

To a solution of 2-fluoro-4- (5-fluoropyridin-2-ylmethoxy) benzaldehyde (901 mg, 3.62 mmol) described in Production Example 96-1-1 in acetic acid (20.0 ml) in an atmosphere Nitromethane (1.10 g, 18.1 mmol) and ammonium acetate (558 mg, 7.24 mmol) were added and stirred at 110 ° C for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.00 g) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.30 (2H, s), 7.04 (1H, dd, J = 2.4, 8.8 Hz), 7.17 (1H, dd, J = 2.4, 7.2 Hz), 7.63-7.66 (1H, m), 7.78-7.83 (1H, m), 7.93 (1H, d , J = 8.4 Hz), 8.06 (2H, s), 8.61 (1H, d, J = 2.8 Hz).

[Production Example 96-1-3] 5-fluoro-2- (3-fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine

To a suitably cooled solution of 5-fluoro-2- (3-fluoro-4 - (( E ) -2-nitrovinyl) phenoxymethyl) pyridine (1.00 g, 3.42 mmol) described in Preparation 96- 1-2, and acetic acid (1.00 ml) in a mixture of dimethyl sulfoxide (20.0 ml) -tetrahydrofuran (5.00 ml) at room temperature in a nitrogen atmosphere was added sodium borohydride (207 mg, 5.47 mmol) at room temperature for 10 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was crystallized using an ethyl acetate: heptane system and filtered to obtain the title compound (346 mg, 34.4%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.20 (2H, t, J = 6.8 Hz), 4.79 (2H, t, J = 6.8 Hz), 5.17 (2H, s), 6.84 (1H, dd, J = 2.4, 8.4 Hz), 6.94 (1H, dd, J = 2.4, 12.0 Hz), 7 , 27 (1H, t, J = 8.8 Hz), 7.61 (1H, dd, J = 4.4, 8.8 Hz), 8.78 (1H, ddd, J = 2.8, 8 8, 17.6 Hz), 8.58-8.59 (1H, m).

[Production Example 96-1-4] (2-fluoro-4- (5-fluoropyridin-2-ylmethoxy) phenyl) acetohydroximoyl chloride

To a solution of 5-fluoro-2- (3-fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine (346 mg, 1.18 mmol) described in Production Example 96-1-3, in methanol (20, 0 ml) at room temperature in a nitrogen atmosphere was added lithium methoxide (89.6 mg, 2.36 mmol) and stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Titanium (IV) chloride (584 μl, 5.30 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 60 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (300 mg, 81.3%) as a crude product.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.79 (2H, s), 5.19 (2H, s), 6.87 (1H, dd, J = 2.4, 8.4 Hz), 6.95 (1H, dd, J = 2.8, 12.0 Hz), 7.26 (1H, t, J = 8.8 Hz), 7.62 (1H, dd, J = 4.4, 8.8 Hz), 7.78 (1H, ddd, J = 3.2, 8.8, 13.6 Hz), 8.59 (1H, dd, J = 0.4, 2.8 Hz), 11.72 (1H, s).

[Example 97] 3- (3- (6-Phenylsulfanylpyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (6-phenylsulfanylpyridin-3-yl) -acetohydroximoyl chloride (149 mg, 0.54 mmol) described in Production Example 97-1-4 and 3-ethynylpyridin-2-ylamine (15 mg, 0.13 mmol) described in Production Example 1-2-3, triethylamine (80 μl, 0.57 mmol) was added in tetrahydrofuran (5 ml) and stirred at 50 ° C. under nitrogen for 4 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) and then further purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (11 mg, 23 %).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.99 (2H, s), 5.39 (2H, s), 6.24 (1H, s), 7.72 (1H, dd , J = 4.8, 7.7 Hz), 6.87 (1H, d, J = 8.2 Hz), 7.38 (1H, dd, J = 2.4, 8.2 Hz), 7 , 40-7.43 (3H, m), 7.58-7.60 (2H, m), 7.70 (1H, dd, J = 1.8, 7.7 Hz), 8.15 (1H dd, J = 1.8, 4.8 Hz), 8.40 (1H, d, J = 2.4 Hz).

The starting material, (6-phenylsulfanylpyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 97-1-1] 5-bromo-2-phenylsulfanylpyridine

To a solution of thiophenol (1.02 g, 9.28 mmol) in N, N-dimethylformamide (20 ml) was added sodium hydride (446 mg, 9.28 mmol, 50% in oil) and stirred at room temperature for 15 minutes . Then, 2,5-dibromopyridine (2.00 g, 8.44 mmol) was added to the reaction solution, and stirred at room temperature for 35 minutes and then at 55 ° C. for 45 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate: = 4: 1) to obtain the title compound (in an amount of 2.24 g).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 6.78 (1H, dd, J = 0.73, 8.4 Hz), 7.42-7.45 (3H, m), 7 56-7.60 (3H, m), 8.47 (1H, dd, J = 0.73, 2.6 Hz).

[Production Example 97-1-2] 6-phenylsulfanylpyridin-3-carbaldehyde

To a solution of 5-bromo-2-phenylsulfanylpyridine (2.24 g, 8.42 mmol) described in Production Example 97-1-1 in tetrahydrofuran (40 ml) at -78 ° C under nitrogen atmosphere was added n- butyllithium ( 6.35 ml, 1.6 M hexane solution, 10.1 mmol) and stirred at -78 ° for 45 minutes. Then, N, N-dimethylformamide (848 μl, 10.9 mmol) was added to this reaction mixture and stirred for 35 minutes, gradually raising the temperature to room temperature. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. 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 (583 mg, 32%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 6.94 (1H, d, J = 8.4 Hz), 7.48-7.52 (3H, m), 7.62-7 65 (2H, m), 7.89 (1H, dd, J = 2.4, 8.4 Hz), 8.82 (1H, dd, J = 0.73, 2.2 Hz), 9, 98 (1H, s).

[Production Example 97-1-3] 5- (2-Nitroethyl) -2-phenylsulfanylpyridine

To a solution of 6-phenylsulfanylpyridin-3-carbaldehyde (583 mg, 2.71 mmol) described in Production Example 97-1-2, nitromethane (734 μl, 13.6 mmol) and ammonium acetate were added in acetic acid (10 ml) (418 mg, 5.42 mmol) and stirred at 100 ° C. under nitrogen for 4 hours 35 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. Sodium borohydride (205 mg, 5.42 mmol) was added to a solution of the residue in dimethyl sulfoxide (10 ml) and acetic acid (1 ml) and stirred at room temperature for 55 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture, cooled appropriately at room temperature, and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (212 mg, 30%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.27 (2H, t, J = 6.6 Hz), 4.60 (2H, t, J = 6.6 Hz), 6, 71 (1H, d, J = 8.6 Hz), 7.39 (1H, d, J = 8.4 Hz), 7.50-7.58 (3H, m), 7.62-7.64 (2H, m), 8.57 (1H, s).

[Production Example 97-1-4] (6-phenylsulfanylpyridin-3-yl) -acetohydroximoyl chloride

To a solution of 5- (2-nitroethyl) -2-phenylsulfanylpyridine (212 mg, 0.814 mmol) described in Production Example 97-1-3, in methanol (5 ml) lithium methoxide (62 mg, 1.6 mmol) was added and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in tetrahydrofuran (3 ml) and methylene chloride (3 ml). Titanium (IV) tetrachloride (197 μl, 1.8 mmol) was added to this suspension at -78 ° C under nitrogen atmosphere and stirred at 0 ° C for 1 hour 30 minutes. The mixture was then further stirred at room temperature for 50 minutes, after which water was added to the reaction mixture at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (in an amount of 249 mg). This compound was used in the subsequent reaction without further purification.

[Example 98] 3- (3- (4- (3-Methoxybenzyloxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (3 ml) was added to the 4- (5- (2-aminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (30 mg, 0.11 mmol) described in Production Example 5-1-1. and 5N sodium hydroxide solution (22.4 μl, 0.11 mmol) and dissolved by sonication for 1 minute. Then, the reaction solution was concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added a solution of 3-methoxybenzyl chloride (21.0 mg, 0.13 mmol) in N, N-dimethylformamide (1 ml) and stirred at 60 ° C for 12 hours. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (35.1 mg, 81%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.75 (3H, s), 3.95 (2H, s), 5.05 (2H, s), 6.25 (2H , br.s), 6.67-6.71 (1H, m), 6.78 (1H, s), 6.86-6.90 (1H, m), 6.96 (2H, d, J = 8.4 Hz), 6.97-7.00 (2H, m), 7.24 (2H, d, J = 8.8 Hz), 7.29 (1H, t, J = 8.0 Hz ), 7.85-7.88 (1H, m), 8.07-8.10 (1H, m).

[Example 99] 3- (3- (4- (6-Methoxypyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

Tetrahydrofuran (3 ml) and a 5N sodium hydroxide solution (22.4 μl, 0.11 mmol) were added to 4- (5- (2-aminopyridin-3-yl) -isoxazol-3-ylmethyl) -phenol (30 mg, 0.11 mmol), described in Production Example 5-1-1, and dissolved by sonication for 1 minute. Then, the reaction solution was concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added a solution of 2-chloromethyl-6-methoxypyridine (21.2 mg, 0.13 mmol) described in Production Example 99-1-2, in N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 12 hours. The reaction mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (heptane: til acetate = 1: 1) to obtain the title compound (36.7 mg, 84%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.85 (3H, s), 3.96 (2H, s), 5.07 (2H, s), 6.25 (2H , br.s), 6.69 (1H, dd, J = 4.8, 7.6 Hz), 6.75 (1H, d, 8.0 Hz), 6.79 (1H, s), 6 99 (2H, d, J = 8.8 Hz), 7.07 (1H, d, J = 7.2 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.69 -7.74 (1H, m), 7.85-7.88 (1H, m), 8.08 (1H, dd, J = 2.0, 4.8 Hz).

The starting material, 2-chloromethyl-6-methoxypyridine, was synthesized as follows.

[Production Example 99-1-1] (6-methoxypyridin-2-yl) -methanol

N- Butyllithium (1.84 ml, 1.6 M hexane solution, 2, 93 mM) and stirred for 30 minutes. N, N-dimethylformamide (412 μl, 5.32 mmol) was added dropwise to this mixture at the same temperature and stirred at 0 ° C for 45 minutes. Water and tetrahydrofuran were added to the reaction solution and stirred vigorously. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. Sodium borohydride (201 mg, 5.31 mmol) was added to this filtrate at 0 ° C and stirred at room temperature for 2 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and then dried. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: diethyl ether = 2: 1) to obtain the title compound (104.8 mg, 28%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.81 (3H, s), 4.47 (2H, d, J = 6.0 Hz), 5.34 (1H, t , J = 5.6, 6.0 Hz), 6.65 (1H, dd, J = 0.8, 8.4 Hz), 7.03-7.05 (1H, m), 7.68 ( 1H, dd, J = 7.2, 8.0 Hz).

[Production Example 99-1-2] 2-chloromethyl-6-methoxypyridine

To the mixture of dichloromethane (5 ml) and (6-methoxypyridin-2-yl) methanol (105 mg, 0.75 mmol) described in Production Example 99-1-1, thionyl chloride (82.4 μl, 1.13 was added mM) and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to this reaction mixture and extracted with dichloromethane. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (105.8 mg, 89%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.85 (3H, s), 4.69 (2H, s), 7.79 (1H, dd, J = 0.4, 8.4 Hz), 7.12 (1H, dd, J = 0.4, 7.2 Hz), 7.73 (1H, dd, J = 7.2, 8.4 Hz).

[Example 100] 3- (3- (6- (Pyridin-3-yloxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a mixture of 5- (2-nitroethyl) -2- (pyridin-3-yloxy) pyridine (157.0 mg, 0.64 mmol) described in Production Example 100-1-2 and methanol (6 ml) was added methoxide lithium (48.7 mg, 1.28 mmol) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a solution of this solid in a mixture of dichloromethane (4 ml) and tetrahydrofuran (2 ml) at -78 ° C under nitrogen atmosphere was added titanium tetrachloride (155.0 μl, 1.41 mmol) and stirred at 0 ° C for another 3 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a mixture of the residue thus obtained (30.7 mg) and 3-ethynylpyridin-2-ylamine (13.7 mg, 0.12 mmol), described in Production Example 1-2-3, tetrahydrofuran (1 ml) and dimethyl sulfoxide ( 1 ml) triethylamine (32.4 μl, 0.23 mmol) was added at room temperature and stirred at 55 ° C for 1 hour. The reaction mixture was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by reverse phase high performance liquid chromatography (using the mobile phase acetonitrile: water containing 0.1% trifluoroacetic acid) and then further purified by preparative thin layer chromatography (NH silica gel, ethyl acetate) to obtain the title the title compound (1.41 mg, 4%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.03 (2H, s), 5.39 (2H, br s), 6.28 (1H, s), 6.73 (1H , ddd, J = 0.8, 4.8, 7.6 Hz), 6.98 (1H, d, J = 8.4 Hz), 7.35 (1H, dd, J = 4.8, 8 , 0 Hz), 7.51-7.54 (1H, m), 7.67 (1H, ddd, J = 0.2, 2.4, 8.4 Hz), 7.71 (1H, dd, J = 2.0, 7.6 Hz), 8.11 (1H, d, J = 2.8 Hz), 8.15-8.17 (1H, m), 8.46 (1H, d, J = 4.4 Hz), 8.50 (1H, d, J = 2.4 Hz).

The starting material, 5- (2-nitroethyl) -2- (pyridin-3-yloxy) pyridine, was synthesized as follows.

[Production Example 100-1-1] 6- (pyridin-3-yloxy) -pyridin-3-carbaldehyde

To a suspension of sodium hydride (407 mg, 8.48 mmol, 50% in oil) and N, N-dimethylformamide (45 ml) was added a solution of 3-hydroxypyridine (806 mg, 8.48 mmol) in N, N-dimethylformamide (5 ml) at 0 ° C and stirred for 30 minutes. A solution of 2-chloro-5-formylpyridine (1.0 g, 7.06 mmol) in N, N-dimethylformamide (5 ml) was added to this reaction mixture at the same temperature and stirred at 100 ° C for 5 hours. The reaction mixture was cooled to room temperature and water was added thereto and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (505.1 mg, 36%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.32-7.36 (1H, m), 7.53 (1H, ddd, J = 0.8, 4.8, 8 4 Hz), 7.72-7.75 (1H, m), 8.30-8.34 (1H, m), 8.50-8.54 (2H, m), 8.70-8, 72 (1H, m), 10.01 (1H, s).

[Production Example 100-1-2] 5- (2-nitroethyl) -2- (pyridin-3-yloxy) pyridine

A mixture of 6- (pyridin-3-yloxy) -pyridin-3-carbaldehyde (505.1 mg, 2.52 mmol) described in Production Example 100-1-1, nitromethane (680 μl, 12.6 mmol), acetate ammonium (388 mg, 5.04 mmol) and acetic acid (20 ml) were stirred at 140 ° C for 2.5 hours. The reaction mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. Sodium borohydride (114.0 mg, 3.02 mmol) was added to a mixture of the obtained residue in dimethyl sulfoxide (20 ml) and acetic acid (2 ml) at room temperature and stirred for 15 minutes. Water was added to this reaction mixture and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. 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 (157.3 mg, 26%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.23 (2H, t, J = 6.8 Hz), 4.88 (2H, t, J = 6.8 Hz), 7.18-7.22 (1H, m), 7.77 (1H, dd, J = 5.6, 8.4 Hz), 7.90 (1H, dd, J = 2.4, 8.4 Hz), 8.02-8.07 (1H, m), 8.07-8.10 (1H, m), 8.45 (1H, d, J = 6.0 Hz), 8.51 (1H , d, J = 2.8 Hz).

[Example 101] 3- (3- (4- (5-Methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

The title compound (120 mg, 57%) was obtained according to methods similar to the methods of Example 18 using 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (150 mg, 0.53 mmol) described in Production Example 18-1-1, and 2-chloromethyl-5-methylpyridine (90 mg, 0.64 mmol) described in Production Example 42-1-2.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.29 (3H, s), 3.87 (2H, s), 5.10 (2H, s), 5.78 (2H , br.s), 5.82 (1H, d, J = 8.0 Hz), 6.10 (2H, br.s), 6.34 (1H, s), 6.95 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.0 Hz), 7.62 (1H, d, J = 8.0 Hz), 8.40 (1H, s).

[Example 102] 3- (3- (4- (4-Methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (4-methylpyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride (130 mg, 0.447 mmol) described in Production Example 43-1-5 and 3-ethynylpyridin-2,6-diamine (30, 0 mg, 0.226 mmol) described in Production Example 13-1-3, triethylamine (126 μl, 0.903 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred for 1 hour at room temperature. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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 (37.4 mg, 42.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.26 (3H, s), 3.95 (2H, s), 5.30 (2H, s), 5.79 (2H , br.s), 5.83 (2H, d, J = 8.4 Hz), 6.11 (1H, br.s), 6.37 (1H, s), 6.67-6.68 ( 1H, m), 6.81-6.83 (1H, m), 7.30 (2H, d, J = 8.0 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.51 (1H, d, J = 8.4 Hz), 8.08-8.09 (1H, d, J = 5.2 Hz).

[Example 103] 3- (3- (4- (5-Methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (5-methylpyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (130 mg, 0.447 mmol) described in Production Example 44-1-5, and 3-ethynylpyridin-2,6-diamine (30, 0 mg, 0.226 mmol) described in Production Example 13-1-3, triethylamine (126 μl, 0.903 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at room temperature for 2 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent 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 (57.4 mg, 65.6%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.20 (3H, s), 3.95 (2H, s), 5.28 (2H, s), 5.79 (2H , br.s), 5.82 (1H, d, J = 8.4 Hz), 6.11 (2H, br.s), 6.36 (1H, s), 6.76 (1H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.53-7.55 (1H, m), 7.96-7.97 (1H, m).

[Example 104] 3- (3- (4- (6-Fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2, 6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (40 mg, 0.14 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N sodium hydroxide solution (28.3 μl, 0.14 mmol) and dissolved by sonication for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added a solution of 2-chloromethyl-6-fluoropyridine (52.7 mg, 0.36 mmol) described in Production Example 45-1-1, in N, N dimethylformamide (1 ml) and stirred at room temperature for 14 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2) and then further purified by reverse phase high performance liquid chromatography (using the mobile phase acetonitrile: water containing 0.1% trifluoroacetic acid) to obtain the title compound (7 , 8 mg, 11%) as a trifluoroacetic acid salt.

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 3.96 (2H, s), 5.08 (2H, s), 6.15 (1H, d, J = 8.8 Hz) 6.42 (1H, s), 6.96 (2H, d, J = 8.8 Hz), 6.96-7.00 (1H, m), 7.23 (2H, d, J = 8 4 Hz), 7.43-7.46 (1H, m), 7.90 (1H, d, J = 8.8 Hz), 7.94 (1H, q, J = 8.4, 7, 6 Hz).

MS m / e (ESI) 391.99 (MH ⁺ )

[Example 105] 3- (3- (4- (5-Methylfuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a mixture of (4- (5-methylfuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride (11 mg, 0.043 mmol) described in Production Example 46-1-6 and tetrahydrofuran (1 ml) was added 3-ethynylpyridin-2, 6-diamine (4.5 mg, 0.034 mmol) described in Production Example 13-1-3 and triethylamine (9.4 μl, 0.068 mmol) and stirred at 40 ° C. for 3 hours. Water was added to it at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 3: 2) to obtain the title compound (9.2 mg, 76%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.24 (3H, s), 3.89 (2H, s), 3.98 (2H, s), 4.53 (2H, br s), 5.31 (2H, broad s), 5.84-5.87 (2H, m), 5.91 (1H, d, J = 8.2 Hz), 5.99 (1H, c), 7.20 (4H, d, J = 2.4 Hz), 7.48 (1H, d, J = 8.2 Hz).

[Example 106] 3- (3- (5-p-Tolyloxythiophen-2-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (5- p- tolyloxythiophen-2-yl) -acetohydroximoyl chloride (130 mg, 0.461 mmol) described in Production Example 48-1-5, and 3-ethynylpyridin-2,6-diamine (30.0 mg, 0.226 mM) described in Production Example 13-1-3, triethylamine (126 μl, 0.903 mmol) was added in tetrahydrofuran (5.00 ml) and stirred at 60 ° C for 7 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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 (12.0 mg, 14.0%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.27 (3H, s), 4.08 (2H, s), 5.81 (2H, br s), 5.84 (1H d, J = 8.8 Hz), 6.13 (2H, br.s), 6.44 (1H, s), 6.47 (1H, d, J = 3.6 Hz), 6.73 (1H, d, J = 3.6 Hz), 6.98-7.01 (2H, m), 7.17-7.19 (2H, m), 7.54 (1H, d, J = 8 , 8 Hz).

[Example 107] 3- (3- (4- (Pyridin-4-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (50 mg, 0.18 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N sodium hydroxide solution (35.4 μl, 0.18 mmol) and dissolved by sonication for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. This solid was suspended in N, N-dimethylformamide (1 ml). Meanwhile, TFA (780 μl) and 1N sodium hydroxide solution (780 μl, 0.78 mmol) were added to 4- (chloromethyl) pyridine hydrochloride (100 mg, 0.78 mmol), then the organic layer was separated to obtain a solution of 4- ( chloromethyl) pyridine in tetrahydrofuran. A portion of this solution (354 μl) was added to the above suspension in N, N-dimethylformamide and stirred at room temperature for 14.5 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (64.6 mg, 98%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.88 (2H, s), 5.16 (2H, s), 5.79 (2H, br.s), 5.82 (1H, d, J = 8.4 Hz), 6.10 (2H, br.s), 6.34 (1H, s), 6.97 (2H, d, J = 8.4 Hz), 7 23 (2H, d, J = 8.8 Hz), 7.42 (2H, d, J = 5.2 Hz), 7.5 1 (1H, d, J = 8.4 Hz), 8, 56 (2H, d, J = 5.2 Hz).

[Example 108] 3- (3- (4- (pyridin-3-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2, 6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (50 mg, 0.18 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N sodium hydroxide solution (35.4 μl, 0.18 mmol) and dissolved by sonication for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. This solid was suspended in N, N-dimethylformamide (1 ml). Meanwhile, THF (780 μl) and a 1N sodium hydroxide solution (780 μl, 0.78 mmol) were added to 3- (chloromethyl) pyridine hydrochloride (100 mg, 0.78 mmol), then the organic layer was separated to obtain a solution of 3- ( chloromethyl) pyridine in tetrahydrofuran. A portion of this solution (354 μl) was added to the above suspension in N, N-dimethylformamide and stirred at room temperature for 15 hours. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (49.6 mg, 75%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.88 (2H, s), 5.13 (2H, s), 5.79 (2H, br.s), 5.83 (1H, d, J = 8.4 Hz), 6.11 (2H, br.s), 6.34 (1H, s), 6.98 (2H, d, J = 8.4 Hz), 7 23 (2H, d, J = 8.4 Hz), 7.42 (1H, dd, J = 4.8, 8.0 Hz), 7.51 (1H, d, J = 8.4 Hz) 7.85 (1H, d, J = 8.0 Hz), 8.54 (1H, d, J = 4.8 Hz), 8.55-8.58 (1H, m).

[Example 109] 3- (3- (4- (4-Chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (30 mg, 0.11 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N sodium hydroxide solution (21.2 μl, 0.11 mmol) and dissolved by ultrasonic treatment for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added a solution of 4-chloro-2-chloromethylpyridine (34.3 mg, 0.21 mmol), described in Production Example 51-1-2, in N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2) and then further purified by reverse phase high performance liquid chromatography (using acetonitrile: water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5 , 1 mg, 12%) as a trifluoroacetic acid salt.

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 3.94 (2H, s), 5.16 (2H, s), 5.95 (1H, d, J = 8.4 Hz) 6.21 (1H, s), 6.98 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.8 Hz), 7.35-7.45 ( 1H, m), 7.56 (1H, d, J = 8.4 Hz), 7.62-7.63 (1H, m), 8.47 (1H, d, J = 5.2 Hz).

MS m / e (ESI) 408.21 (MH ⁺ )

[Example 110] 3- (3- (4- (6-Chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (30 mg, 0.11 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N sodium hydroxide solution (21.2 μl, 0.11 mmol) and dissolved by ultrasonic treatment for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added a solution of 2-chloro-6-chloromethylpyridine (34.3 mg, 0.21 mmol), described in Production Example 52-1-2, in N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2) and then further purified by reverse phase high performance liquid chromatography (using the mobile phase acetonitrile: water containing 0.1% trifluoroacetic acid) to obtain the title compound (15 , 9 mg, 37%) as a trifluoroacetic acid salt.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.95 (2H, s), 4.56 (2H, br s), 5.15 (2H, s), 5.30 (2H , br.s), 5.90 (1H, d, J = 8.0 Hz), 5.99 (1H, s), 6.91 (2H, d, J = 8.8 Hz), 7.20 (2H, d, J = 8.0 Hz), 7.27-7.28 (1H, m), 7.45 (1H, d, J = 7.6 Hz), 7.46 (1H, d, J = 8.0 Hz), 7.67 (1H, dd, J = 7.6, 8.0 Hz).

MS m / e (ESI) 408.19 (MH ⁺ )

[Example 111] 3- (3- (6-Phenoxymethylpyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (6-phenoxymethylpyridin-3-yl) -acetohydroximoyl chloride (89.0 mg, 0.322 mmol) described in Production Example 54-1-6, and 3-ethynylpyridin-2,6-diamine (25.0 mg, 0.188 mM) described in Production Example 13-1-3, triethylamine (78.6 μl, 0.564 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at room temperature for 4.5 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1 then 3: 1) to obtain the title compound (21.0 mg, 29.9%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.02 (2H, s), 5.15 (2H, s), 5.81 (2H, br.s), 5.83 (1H, d, J = 8.4 Hz), 6.12 (2H, br.s), 6.43 (1H, s), 6.92-6.96 (1H, m), 7.01 ( 2H, d, J = 8.4 Hz), 7.27-7.31 (2H, m), 7.50 (2H, dd, J = 4.0, 16.4 Hz), 7.74-7 77 (1H, m); 8.56 (1H, d, J = 2.4 Hz).

[Example 112] 3- (3- (4- (5-Fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (25.5 mg, 0.09 mmol) described in Production Example 18-1-1, in tetrahydrofuran (3 ml) was added 5N sodium hydroxide solution (18.1 μl, 0.09 mm) and was dissolved by ultrasonic treatment for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added 2-chloromethyl-5-fluoropyridine (13.2 mg, 0.09 mmol), described in Production Example 41-1-2, in N, N- dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile: water containing 0.1% trifluoroacetic acid mobile phase) to give the title compound (23.6 mg, 67%) as a ditrifluoroacetic acid salt.

¹ H-NMR spectrum (DMSO-D ₆ ) δ (ppm): 3.93 (2H, s), 5.15 (2H, s), 6.04 (1H, d, J = 8.4 Hz ), 6.53 (1H, s), 6.98 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.57-7.61 (1H, m), 7.77 (1H, dt, J = 2.8, 8.8 Hz), 7.81-7.86 (1H, m), 8.57 (1H, d, J = 2 , 8 Hz).

MS m / e (ESI) 391.96 (MH ⁺ )

[Example 113] 3- (3- (4- (6-Fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (6-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (200 mg, 0.678 mmol) described in Production Example 55-1-5, and 3-ethynylpyridin-2,6-diamine (57, 6 mg, 0.433 mmol) described in Production Example 13-1-3, triethylamine (236 μl, 1.7 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 2 hours, partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (150 mg, 57%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.02 (2H, s), 4.57 (2H, br s), 5.32 (2H, s), 5.34 (2H , broad s), 5.91-5.93 (1H, m), 6.00 (1H, s), 6.47-6.50 (1H, m), 6.64-6.66 (1H , m), 7.30 (2H, d, J = 8.0 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.48-7.50 (1H, m), 7 62-7.68 (1H, m).

[Example 114] 3- (3- (4- (5-Fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (5-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Production Example 56-1-5, and 3-ethynylpyridin-2,6-diamine (57, 7 mg, 0.433 mmol) described in Production Example 13-1-3, triethylamine (237 μl, 1.7 mmol) was added in tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 4 hours, partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (86 mg, 32%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.03 (2H, s), 4.62 (2H, br s), 5.07 (2H, s), 5.39 (2H , br.s), 5.92-5.94 (1H, m), 6.00 (1H, s), 7.13-7.16 (1H, m), 7.31-7.33 (2H , m), 7.35-7.38 (3H, m), 7.49-7.51 (1H, m), 8.11-8.12 (1H, m).

[Example 115] 3- (3- (1-Benzyl-1 H -pyrrol-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

The title compound (7.6 mg, 2.0%) was obtained according to a similar manner to that of Example 3 using (1-benzyl-1 H -pyrrol-3-yl) acetohydroximoyl chloride (280 mg, 1.1 mmol), described in Production Example 57-1-3, and 3-ethynylpyridin-2,6-diamine (74 mg, 0.56 mmol) described in Production Example 13-1-3.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.70 (2H, s), 5.02 (2H, s), 5.77 (2H, br.s), 5.83 (1H, d, J = 8.0 Hz), 5.97 (1H, dd, J = 2.0, 2.0 Hz), 6.09 (2H, br.s), 6.35 (1H, c), 6.70 (1H, dd, J = 2.0, 2.0 Hz), 6.74 (1H, dd, J = 2.0, 2.0 Hz), 7.18 (2H, d , J = 7.6 Hz), 7.23-7.28 (1H, m), 7.30-7.35 (2H, m), 7.51 (1H, d, J = 8.0 Hz) .

[Example 116] 3- (3- (6- (4-Fluorobenzyloxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (6- (4-fluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride (133 mg, 0.450 mmol) described in Production Example 58-1-5, and 3-ethynylpyridin-2,6-diamine (30, 0 mg, 0.225 mmol) described in Production Example 13-1-3, triethylamine (94.1 μl, 0.675 mmol) was added in tetrahydrofuran (10.0 ml) and stirred at room temperature for 3 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 3: 1) to obtain the title compound (67.4 mg, 76.5%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.92 (2H, s), 5.31 (2H, s), 5.81 (2H, br.s), 5.83 (1H, d, J = 8.4 Hz), 6.12 (2H, br.s), 6.40 (1H, s), 6.84 (1H, d, 8.4 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.47-7.53 (3H, m), 7.65-7.67 (1H, m), 8.14 (1H, d, J = 2 , 0 Hz).

[Example 117] 3- (3- (4- (4-Fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (4-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Production Example 59-1-5, and 3-ethynylpyridin-2,6-diamine (57, 7 mg, 0.433 mmol) described in Production Example 13-1-3, triethylamine (237 μl, 1.7 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 4 hours, partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (113 mg, 43%).

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 4.02 (2H, s), 5.18 (2H, s), 5.94-5.96 (1H, m), 6, 23 (1H, s), 6.99-7.01 (1H, m), 7.097-7.103 (1H, m), 7.34-7.36 (2H, m), 7.40-7.42 ( 2H, m), 7.54-7.56 (1H, m), 8.14-8.15 (1H, m).

[Example 118] 3- (3- (3- (Pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of 3- (pyridin-2-ylmethoxy) -phenyl) -acetohydroximoyl chloride (200 mg, 0.723 mmol) described in Production Example 60-1-4 and 3-ethynylpyridin-2,6-diamine (61.4 mg, 0.461 mM) described in Production Example 13-1-3, triethylamine (252 μl, 1.81 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 2 hours and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (87 mg, 32%).

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 3.96 (2H, s), 5.16 (2H, s), 5.94-5.97 (1H, m), 6, 17 (1H, s), 6.87-6.92 (3H, m), 7.21-7.25 (1H, m), 7.29-7.32 (1H, m), 7.53- 7.57 (2H, m), 7.79-7.84 (1H, m), 8.48-8.50 (1H, m).

[Example 119] 3- (3- (3-Benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (3-benzyloxyphenyl) -acetohydroximoyl chloride (200 mg, 0.724 mmol) described in Production Example 61-1-4, and 3-ethynylpyridin-2,6-diamine (61.5 mg, 0.462 mmol) described in Example 13-1-3 preparation, triethylamine (252 μl, 1.81 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 4 hours and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (138 mg, 51%).

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 3.95 (2H, s), 5.07 (2H, s), 5.95-5.97 (1H, m), 6, 17 (1H, s), 6.86-6.88 (2H, m), 6.92 (1H, m), 7.20-7.27 (2H, m), 7.31-7.35 ( 2H, m), 7.39-7.41 (2H, m), 7.53-7.55 (1H, m).

[Example 120] 3- (3- (4- (5-Chlorfuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a mixture of (4- (5-chlorofuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Production Example 62-1-6 and tetrahydrofuran (1 ml) was added 3-ethynylpyridin-2, 6-diamine (9 mg, 0.068 mmol) described in Production Example 13-1-3 and triethylamine (19 μl, 0.14 mmol) and stirred for 1 hour at room temperature. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using the mobile phase acetonitrile: water containing 0.1% trifluoroacetic acid) to obtain the title compound as the trifluoroacetate salt (10 mg, 28%).

MS m / e (ESI) 381.13 (MH ⁺ )

[Example 121] 3- (3- (5-Phenoxypyridin-2-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine

The title compound (26 mg, 34%) was obtained according to a similar manner to that of Example 3 using (5-phenoxypyridin-2-yl) -acetohydroximoyl chloride (56 mg, 0.21 mmol) described in Example 121-1-5 preparation, and 3-ethynylpyridin-2,6-diamine (42 mg, 0.32 mmol) described in Production Example 13-1-3.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.11 (2H, s), 5.80 (2H, br s), 5.83 (1H, d, J = 8, 0 Hz), 6.12 (2H, br.s), 6.40 (1H, s), 7.05 (2H, d, J = 8.0 Hz), 7.15-7.21 (1H, m), 7.38-7.45 (4H, m), 7.52 (1H, d, J = 8.0 Hz), 8.31 (1H, s).

The starting material, (5-phenoxypyridin-2-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 121-1-1] 2-methyl-5-phenoxypyridine

Diphenyl iodide (5.8 g, 14 mmol), 3-hydroxy-6-methylpyridine (1.6 g, 14 mmol), potassium tert -butoxide (1.7 g, 15 mmol) and tetrahydrofuran (60 ml) were mixed with 60 ° C for 2.5 hours. Water was added to the reaction solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (1.5 g, 56%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.46 (3H, s), 7.00-7.04 (2H, m), 7.13-7.18 (1H, m), 7.28 (1H, d, J = 8.4 Hz), 7.37 (1H, dd, J = 2.8, 8.4 Hz), 7.37-7.43 (2H, m ), 8.24 (1H, d, J = 2.8 Hz).

[Production Example 121-1-2] (5-phenoxypyridin-2-yl) -methanol

A mixture of 2-methyl-5-phenoxypyridine (3.6 g, 19 mmol) described in Production Example 121-1-1, 3-chloroperoxybenzoic acid (5.6 g, 33 mmol) and methylene chloride (80 ml) was stirred at room temperature temperature for 45 minutes. An aqueous solution of sodium sulfite was added to the reaction solution, and the organic layer was separated and washed with a 5N aqueous solution of sodium hydroxide (7 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 2-methyl-5-phenoxypyridine 1-oxide (3.3 g). 2-Methyl-5-phenoxypyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 ml) were stirred at 115 ° C for 40 minutes. Acetic anhydride was evaporated under reduced pressure, an aqueous solution of sodium bicarbonate and ethyl acetate was added to the residue, and the organic layer was separated. The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain 5-phenoxypyridin-2-ylmethyl acetic acid ester (3.0 g). Acetic acid 5-phenoxypyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5N aqueous sodium hydroxide solution (8.0 ml) and methanol (20 ml) were stirred at 60 ° C. for 20 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain the title compound (2.6 g, 65%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.57 (2H, d, J = 6.0 Hz), 5.44 (1H, t, J = 6.0 Hz), 7.00-7.08 (2H, m), 7.15-7.20 (1H, m), 7.38-7.53 (4H, m), 8.29 (1H, d, J = 2 , 8 Hz).

[Production Example 121-1-3] 5-Phenoxypyridin-2-carbaldehyde

(5-Phenoxypyridin-2-yl) -methanol (300 mg, 1.5 mmol) described in Production Example 121-1-2, magnesium (IV) oxide (1.3 g, 15 mmol) and acetone (10 ml ) was stirred for 20 minutes in a flask under reflux. Then, magnesium (IV) oxide (1.5 g, 17 mmol) was additionally added, and the solution was again stirred for 20 minutes in a flask under reflux. The reaction solution was filtered through a pad of celite, and then the filtrate was concentrated under reduced pressure to obtain the title compound (220 mg, 74%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.20-7.25 (2H, m), 7.29-7.34 (1H, m), 7.47-7, 54 (3H, m), 7.95-8.00 (1H, m), 8.57-8.60 (1H, m), 9.94 (1H, s).

[Production Example 121-1-4] 2- (2-nitroethyl) -5-phenoxypyridine

A mixture of 5-phenoxypyridin-2-carbaldehyde (700 mg, 3.5 mmol) described in Production Example 121-1-3, lithium methoxide (170 mg, 4.6 mmol), nitromethane (280 mg, 4.6 mmol) and methanol (10 ml) was dissolved at room temperature, sonicated for 2 minutes, then the reaction solution was concentrated under reduced pressure. Acetic anhydride (30 ml) and triethylamine (1.1 g, 11 mmol) were added to the residue and stirred at room temperature for 10 minutes, then the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the organic layer was separated and washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, dimethyl sulfoxide (5.0 ml), acetic acid (0.50 ml) and sodium borohydride (270 mg, 7.0 mmol) were added to the residue and stirred for 5 minutes at room temperature. Water and ethyl acetate were added to the reaction solution, and then the ethyl acetate layer was separated and washed with an aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride. The solvent was evaporated under reduced pressure, and the residue was purified first by silica gel column chromatography (heptane: ethyl acetate = 2: 1) and then NH silica gel column chromatography (heptane: ethyl acetate = 4: 1 then 2: 1) to obtain the title compound (76 mg, 8.9%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.40 (2H, d, J = 6.4 Hz), 4.98 (2H, d, J = 6.4 Hz), 7.02-7.06 (2H, m), 7.16-7.21 (1H, m), 7.39-7.46 (4H, m), 8.28 (1H, d, J = 2 , 4 Hz).

[Production Example 121-1-5] (5-Phenoxypyridin-2-yl) -acetohydroximoyl chloride

To 2- (2-nitroethyl) -5-phenoxypyridine (76 mg, 0.31 mmol) described in Production Example 121-1-4, and methanol (6.0 ml) were added lithium methoxide (24 mg, 0.62 mM) at room temperature and was stirred for 3 minutes and then the solvent was evaporated under reduced pressure. Methylene chloride (10 ml) was added to the residue, then titanium (IV) chloride (0.11 ml, 1.0 mmol) was added at room temperature and stirred for 10 minutes. A cooled aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, filtered through a celite pad and the organic layer was separated. The organic layer was concentrated under reduced pressure to obtain the title compound (56 mg, 69%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.99 (2H, s), 7.00-7.10 (2H, m), 7.13-7.22 (1H, m), 7.34-7.48 (4H, m), 8.32 (1H, d, J = 2.4 Hz), 11.75 (1H, s).

[Example 122] 3- (3- (4- (5-Chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (30 mg, 0.11 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N sodium hydroxide solution (21.2 μl, 0.11 mmol) and dissolved by ultrasonic treatment for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added a solution of 5-chloro-2-chloromethylpyridine (18.9 mg, 0.12 mmol) described in Production Example 63-1-2, in N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (38.4 mg, 89%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.88 (2H, s), 5.16 (2H, s), 5.79 (2H, br.s), 5.82 (1H, d, J = 8.4 Hz), 6.11 (2H, br.s), 6.34 (1H, s), 6.97 (2H, d, J = 8.8 Hz), 7 23 (2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.96 (1H, dd, J = 2.4, 8.4 Hz), 8.63 (1H, d, J = 2.8 Hz).

[Example 123] 3- (3- (3-Phenoxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (3-phenoxyphenyl) -acetohydroximoyl chloride (133 mg, 0.508 mmol) described in Production Example 64-1-3 and 3-ethynylpyridin-2,6-diamine (30.0 mg, 0.254 mmol) described in Example 13-1-3 of preparation, triethylamine (94.1 μl, 0.675 mmol) was added in tetrahydrofuran (10.0 ml) at room temperature and stirred at room temperature for 14 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 3: 1) to obtain the title compound (26.1 mg, 80.6%).

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 3.95 (2H, s), 5.81 (2H, br s), 5.84 (1H, d, J = 8.4 Hz), 6.12 (2H, br.s), 6.38 (1H, s), 6.84-6.87 (1H, m), 6.98-7.02 (3H, m), 7 07 (1H, d, J = 8.0 Hz), 7.12-7.16 (1H, m), 7.31-7.41 (3H, m), 7.52 (1H, d, J = 8.4 Hz).

[Example 124] 3- (3- (3-Butoxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (3-butoxyphenyl) -acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Production Example 65-1-4 and 3-ethynylpyridin-2,6-diamine (52.8 mg, 0.396 mmol) described in Example 13-1-3, triethylamine (216 μl, 1.55 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 4 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1 ~ ethyl acetate) to obtain the title compound (43 mg, 21%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.95-0.98 (3H, m), 1.45-1.51 (2H, m), 1.72-1.77 ( 2H, m), 3.96-3.99 (2H, m), 3.98 (2H, s), 4.59 (2H, br.s), 5.36 (2H, br.s), 5 91-5.93 (1H, m); 6.01 (1H, s); 6.78-6.86 (4H, m); 7.21-7.24 (1H, m).

[Example 125] 3- (3- (3-Cyclopropylmethoxybenzyl) -isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (3-cyclopropylmethoxyphenyl) -acetohydroximoyl chloride (150 mg, 0.626 mmol) described in Production Example 66-1-4, and 3-ethynylpyridin-2,6-diamine (53.2 mg, 0.399 mmol) described in Example 13-1-3 preparation, triethylamine (218 μl, 1.57 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 4 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1 ~ ethyl acetate) to obtain the title compound (117 mg, 56%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.32-0.36 (2H, m), 0.61-0.66 (2H, m), 1.22-1.29 ( 1H, m), 3.77-3.79 (2H, m), 3.98 (2H, s), 4.58 (2H, br.s), 5.35 (2H, br.s), 5 , 91-5.93 (1H, m), 6.00 (1H, s), 6.78-6.87 (3H, m), 7.21-7.25 (1H, m), 7.48 7.50 (1H, m).

[Example 126] 3- (3- (4-Butoxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (4-butoxyphenyl) -acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Production Example 67-1-4 and 3-ethynylpyridin-2,6-diamine (52.8 mg, 0.396 mmol) described in Example 13-1-3, triethylamine (216 μl, 1.55 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 4 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1 ~ ethyl acetate) to obtain the title compound (155 mg, 74%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.95-0.99 (3H, m), 1.46-1.53 (2H, m), 1.72-1.79 ( 2H, m), 3.92-3.96 (4H, m), 4.60 (2H, br.s), 5.37 (2H, br.s), 5.91-5.92 (1H, m), 5.98 (1H, s), 6.84-6.86 (2H, m), 7.17-7.19 (2H, m), 7.48-7.50 (1H, m) .

[Example 127] 3- (3- (5-Benzyloxypyridin-2-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a mixture of 2- (5-benzyloxypyridin-2-yl) -N-hydroxyacetamide (50 mg, 0.19 mmol) described in Production Example 127-1-5 and a 5N aqueous solution of hydrochloric acid (1 ml) at 0 ° C sodium nitrite (20 mg, 0.29 mmol) was added and stirred at 0 ° C for 20 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of this residue in tetrahydrofuran (3 ml) was added 3-ethynylpyridin-2,6-diamine (10 mg, 0.39 mmol) described in Production Example 13-1-3 and triethylamine (27 μl, 0.19 mmol) ) and stirred at 50 ° C under nitrogen for 40 minutes. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1) and then further purified by reverse phase high performance liquid chromatography (using acetonitrile: water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (4 , 7 mg, 4.0%) as a salt of ditrifluoroacetic acid.

MS m / e (ESI) (MH ⁺ ) 374.01 (MH ⁺ )

The starting material, 2- (5-benzyloxypyridin-2-yl) -N-hydroxyacetamide, was synthesized as follows.

[Production Example 127-1-1] 5-Benzyloxy-2-methylpyridine

To a solution of 3-hydroxy-6-methylpyridine (5.00 g, 45.8 mmol) in N, N-dimethylformamide (50 ml) was added sodium hydride (2.02 g, 50.4 mmol, 60% in oil) and stirred at 0 ° C for 15 minutes. Then, benzyl bromide (5.99 ml, 50.4 mmol) was added to this reaction mixture at 0 ° C and stirred at room temperature for 3.5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. 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 (5.99 g, 66%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.49 (3H, s), 5.08 (2H, s), 7.05 (1H, d, J = 8.6 Hz), 7.17 (1H, dd, J = 2.9, 8.4 Hz), 7.31-7.44 (5H, m), 8.27 (1H, d, J = 2.9 Hz).

[Production Example 127-1-2] (5-benzyloxypyridin-2-yl) -methanol

To a solution of 5-benzyloxy-2-methylpyridine (5.99 g, 30.1 mmol) described in Production Example 127-1-1 in methylene chloride (100 ml) at 0 ° C was added m- chloroperbenzoic acid (8.79 g, 33.1 mmol, purity: 65%) and stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0 ° C. and extracted with methylene chloride. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 5-benzyloxy-2-methylpyridin-1-oxide (7.71 g). Acetic anhydride (77 ml) was added to the 5-benzyloxy-2-methylpyridin-1-oxide thus obtained (7.71 g) and stirred at 120 ° C. for 80 minutes. This mixture was cooled to room temperature and then concentrated under reduced pressure. To a solution of this residue in ethanol (50 ml) was added a 5N sodium hydroxide solution (7 ml) and stirred at room temperature for 50 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned into saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (4.17 g, 54%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.46 (2H, d, J = 5.9 Hz), 5.15 (2H, s), 5.26 (1H, t , J = 5.9 Hz), 7.29-7.40 (4H, m), 7.42-7.45 (3H, m), 8.22 (1H, d, J = 2.9 Hz) .

[Production Example 127-1-3] 5-benzyloxy-2-chloromethylpyridine

Triphenylphosphine (791 mg) was added to a solution of (5-benzyloxypyridin-2-yl) methanol (500 mg) described in Production Example 127-1-2 in carbon tetrachloride (10 ml) and refluxed in an atmosphere flask. nitrogen for 19 hours 35 minutes. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and 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 = 2.7 Hz).

[Production Example 127-1-4] (5-Benzyloxypyridin-2-yl) -acetonitrile

To a solution of 5-benzyloxy-2-chloromethylpyridine (2.13 g, 9.11 mmol) described in Production Example 127-1-3, in ethanol (30 ml) and water (10 ml) was added sodium cyanide (580 mg, 11.8 mmol) and stirred in a flask under reflux for 4 hours 25 minutes. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (1.77 g, 87%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.88 (2H, s), 5.12 (2H, s), 7.29 (1H, d, J = 2.7 Hz), 7.32-7.42 (6H, m); 8.33 (1H, d, J = 2.7 Hz).

[Production Example 127-1-5] 2- (5-Benzyloxypyridin-2-yl) -N-hydroxyacetamide

To the solution of (5-benzyloxypyridin-2-yl) -acetonitrile (1.77 g, 7.89 mmol) described in Production Example 127-1-4, hydroxylammonium chloride (848 mg, 11, 8 mM) and potassium carbonate (2.18 g, 15.8 mM) and stirred at 70 ° C for 11 hours 20 minutes. The mixture was then stirred in a flask under reflux for another 5 hours 45 minutes. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (550 mg, 27%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.61 (2H, s), 5.15 (2H, s), 7.21 (1H, d, J = 8.4 Hz ), 7.32-7.47 (6H, m), 8.08 (1H, s), 8.22 (1H, d, J = 3.1 Hz), 8.32 (1H, s), 9 49 (1H, s).

[Example 128] 3- (3- (4-Benzylaminobenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (4-benzylaminophenyl) -acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Production Example 68-1-4 and 3-ethynylpyridin-2,6-diamine (46.4 mg, 0.348 mmol) described in Example 13-1-3 preparation, triethylamine (190 μl, 1.37 mmol) was added in tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 6.5 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (17 mg, 8.4%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.89 (2H, s), 4.31 (2H, s), 4.52-4.58 (2H, m), 5.33 (2H, br.s), 5.90-5.92 (1H, m), 5.99 (1H, s), 6.58-6.62 (2H, m), 7.07-7.09 (2H, m), 7.25-7.38 (5H, m), 7.48-7.52 (1H, m).

The presence of a proton in the amino group NH-CH2Ph in the NMR diagram was not observed.

[Example 129] 3- (3- (4-Phenylaminobenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (4-phenylaminophenyl) -acetohydroximoyl chloride (150 mg, 0.576 mmol) described in Production Example 69-1-4, and 3-ethynylpyridin-2,6-diamine (48.9 mg, 0.367 mmol) described in Example 13-1-3 preparation, triethylamine (201 μl, 1.44 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 6.5 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (107 mg, 52%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.96 (2H, s), 4.55 (2H, br s), 5.34 (2H, br s), 5.69 (1H, br s), 5.91-5.94 (1H, m), 6.02 (1H, s), 6.91-6.94 (1H, m), 7.03-7.07 (4H, m), 7.16-7.18 (2H, m), 7.24-7.28 (2H, m), 7.49-7.51 (1H, m).

[Example 130] 3- (3- (4-Butylbenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (4-butylphenyl) -acetohydroximoyl chloride (150 mg, 0.665 mmol) described in Production Example 70-1-3, and 3-ethynylpyridin-2,6-diamine (56.5 mg, 0.424 mmol) described in Example 13-1-3, triethylamine (232 μl, 1.66 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 5 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (66 mg, 31%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 0.90-0.94 (3H, m), 1.30-1.40 (2H, m), 1.55-1.62 ( 2H, m), 2.57-2.61 (2H, m), 3.98 (2H, s), 4.55 (1H, br.s), 5.34 (2H, br.s), 5 , 91-5.93 (2H, m), 6.00 (1H, s), 7.14 (2H, d, J = 8.0 Hz), 7.19 (2H, d, J = 8.0 Hz), 7.48-7.50 (1H, m).

[Example 131] 3- (3- (6- (3-Fluorophenoxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (10 mg, 75 μM), described in Production Example 13-1-3, and (6- (3-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride (42 mg , 0.15 mmol) described in Production Example 71-1-4, triethylamine (21 μl, 0.15 mmol) was added in tetrahydrofuran (2 ml) and stirred under a nitrogen atmosphere for 1 hour at 50 ° C. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 20: 1) to obtain the title compound (27 mg, 95%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.98 (2H, s), 4.57 (2H, s), 5.33 (2H, s), 5.94 (1H, dd , J = 0.73, 8.2 Hz), 6.01 (1H, s), 6.86-6.94 (4H, m), 7.31-7.37 (1H, m), 7, 49 (1H, d, J = 8.4 Hz), 7.64 (1H, dd, J = 2.6, 8.4 Hz), 8.15 (1H, d, J = 2.6 Hz).

[Example 132] 3- (3- (6- (4-Fluorophenoxymethyl) -pyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 2- (4-fluorophenoxymethyl) -5- (2-nitrovinyl) pyridine (50.0 mg, 0.181 mmol) described in Production Example 72-1-3, methanol (5.00 ml) was added with lithium methoxide (13.7 mg, 0.362 mmol) in a nitrogen atmosphere, the solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (4.00 ml) and anhydrous tetrahydrofuran (2.00 ml) were added to the residue . Titanium (IV) tetrachloride (63.7 μl, 0.579 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C), then the system was stirred at 0 ° C for 40 minutes. Water and ethyl acetate were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (43.0 mg). To a solution of 3-ethynylpyridin-2,6-diamine (4.00 mg, 0.030 mmol) described in Production Example 13-1-3 and this crude product (20.0 mg) in tetrahydrofuran (5.00 ml) was added triethylamine (12.5 μl, 0.090 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile: water containing 0.1% trifluoroacetic acid mobile phase) to give the title compound (1.53 mg, 25.4%) as a ditrifluoroacetic acid salt.

MS m / e (ESI) 392.18 (MH ⁺ )

[Example 133] 3- (3- (4-Phenylaminomethyl-benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (4-phenylaminomethylphenyl) -acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Production Example 73-1-6, and 3-ethynylpyridin-2,6-diamine (46.4 mg, 0.348 mmol) described in Example 13-1-3 preparation, triethylamine (104 μl, 0.748 mmol) was added in tetrahydrofuran (3 ml). This mixture was stirred at room temperature for 7 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 then 1: 2 ~ ethyl acetate) to obtain the title compound (26 mg, 13%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.00 (2H, s), 4.31 (2H, br s), 4.46 (2H, br s), 5.25 (2H, broad s), 5.90-5.92 (1H, m), 5.99 (1H, s), 6.62-6.64 (2H, m), 6.69-6.73 (1H, m), 7.15-7.20 (2H, m), 7.25-7.27 (1H, m), 7.32-7.34 (2H, m), 7.47-7 49 (1H, m).

The presence of a proton in the amino group of PhNHCH2 in the NMR diagram was not observed.

[Example 134] 3- (3- (6- (2-Fluorophenoxy) pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine

To the mixture of (6- (2-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride (28 mg) described in Production Example 74-1-4 and tetrahydrofuran (1 ml) was added 3-ethynylpyridin-2,6-diamine (10 mg, 0.075 mmol) described in Production Example 13-1-3 and triethylamine (21 μl, 0.15 mmol) and stirred at room temperature for 5 hours. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate only) to obtain the title compound (13 mg, 45%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.96 (2H, s), 4.50 (2H, br s), 5.27 (2H, br s), 5.93 (1H, d, J = 8.4 Hz), 5.99 (1H, s), 6.96 (1H, d, J = 8.6 Hz), 7.16-7.23 (4H, m) 7.48 (1H, d, J = 8.2 Hz), 7.62 (1H, dd, J = 2.6, 8.4 Hz), 8.08 (1H, d, J = 2.6 Hz).

[Example 135] 3- (3- (6- (4-Fluorophenoxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a mixture of (6- (4-fluorophenoxy) -pyridin-3-yl) -acetohydroximoyl chloride (25 mg) described in Production Example 75-1-4 and tetrahydrofuran (1 ml) was added 3-ethynylpyridin-2,6-diamine (8 mg, 0.060 mmol) described in Production Example 13-1-3 and triethylamine (17 μl, 0.12 mmol) and stirred at room temperature for 5 hours. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (8.7 mg, 38%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.95 (2H, s), 5.81 (2H, br s), 5.83 (1H, d, J = 8, 4 Hz), 6.12 (2H, br.s), 6.41 (1H, s), 7.00 (1H, d, J = 8.4 Hz), 7.14-7.18 (2H, m), 7.21-7.26 (2H, m), 7.52 (1H, d, J = 8.4 Hz), 7.78 (1H, dd, J = 2.4, 8.4 Hz ), 8.12 (1H, d, J = 2.6 Hz).

[Example 136] 3- (3- (4- (Thiophen-3-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (thiophen-3-ylmethoxy) -phenyl) -acetohydroximoyl chloride (150 mg, 0.532 mmol) described in Production Example 77-1-4 and 3-ethynylpyridin-2,6-diamine (45.2 mg , 0.339 mmol) described in Production Example 13-1-3, triethylamine (185 μl, 1.33 mmol) was added in tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 1.5 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (73 mg, 36%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.87 (2H, s), 5.06 (2H, s), 5.79 (2H, br s), 5.81 -5.83 (1H, m), 6.11 (2H, br s), 6.34 (1H, s), 6.94-6.96 (2H, m), 7.15-7.17 (1H, m), 7.20-7.22 (2H, m), 7.50-5.56 (3H, m).

[Example 137] 3- (3- (4-Cyclopentyloxybenzyl) -isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4-cyclopentyloxyphenyl) -acetohydroximoyl chloride (150 mg, 0.592 mmol) described in Production Example 78-1-4, and 3-ethynylpyridin-2,6-diamine (50.3 mg, 0.378 mmol) described in Example 13-1-3 preparation, triethylamine (206 μl, 1.48 mmol) was added in tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 1.5 hours. This mixture was separated with ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (64 mg, 31%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 1.56-1.58 (2H, m), 1.67-1.68 (4H, m), 1.88-1, 89 (2H, m), 3.86 (2H, s), 4.76-4.77 (1H, m), 5.79 (2H, br.s), 5.81-5.84 (1H, m), 6.10 (2H, br.s), 6.34 (1H, s), 6.82-6.84 (2H, m), 7.17-7.19 (2H, m), 7 50-7.52 (1H, m).

[Example 138] 3- (3- (4- (Pyridin-3-yloxy) -benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3- (4- (2-nitroethyl) -phenoxy) -pyridine (819 mg, 3.35 mmol) described in Production Example 76-1-3, in methanol (10.0 ml) lithium methoxide (254 mg, 6.70 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (15.0 ml) and anhydrous tetrahydrofuran (7.00 ml) were added to the residue. Titanium (IV) chloride (1.18 ml, 10.7 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 30 minutes. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture in an ice bath (0 ° C) and filtered through a pad of celite. The organic layer of the filtrate was extracted with ethyl acetate, and this organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product (400 mg). To a solution of 3-ethynylpyridin-2,6-diamine (40.0 mg, 0.300 mmol) described in Production Example 13-1-3 and this crude product (150 mg) in tetrahydrofuran (5.00 ml) was added triethylamine ( 125 μl, 0.900 mM) and stirred at 60 ° C for 3 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 3: 1 → 5: 1) to obtain the title compound (17.0 mg, 15.8%).

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 3.96 (2H, s), 5.81 (2H, br s), 5.84 (1H, d, J = 8.4 Hz), 6.12 (2H, br.s), 6.40 (1H, s), 7.04 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8 8 Hz), 7.40-7.42 (2H, m), 7.53 (1H, d, J = 8.4 Hz), 8.35-8.38 (2H, m).

[Example 139] 3- (3- (4-Cyclohexyloxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (4-cyclohexyloxyphenyl) -acetohydroximoyl chloride (150 mg, 0.56 mmol) described in Production Example 79-1-4, and 3-ethynylpyridin-2,6-diamine (47.6 mg, 0.357 mmol) described in Production Example 13-1-3, triethylamine (195 μl, 1.4 mmol) was added in tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 4 hours. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 ~ ethyl acetate) to obtain the title compound (83 mg, 41%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.24-1.41 (3H, m), 1.46-1.52 (3H, m), 1.79-1.80 ( 2H, m), 1.97-1.99 (2H, m), 3.94 (2H, s), 4.18-4.24 (1H, br), 4.46 (2H, br.s ), 5.25 (2H, br.s), 5.90-5.93 (1H, m), 6.00 (1H, s), 6.84-6.86 (2H, m), 7, 16-7.18 (2H, m), 7.47-7.49 (1H, m).

[Example 140] 3- (3- (4- (2-Furan-2-yl-ethyl) -benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the mixture of (4- (2-furan-2-yl-ethyl) phenyl) -acetohydroximoyl chloride (100 mg, 0.38 mmol) described in Production Example 80-1-7 and tetrahydrofuran (3 ml) was added 3-ethynylpyridin-2 , 6-diamine (25.3 mg, 0.19 mmol) described in Production Example 13-1-3, and triethylamine (0.1 ml, 0.76 mmol), the solution was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. This organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1 then ethyl acetate) to obtain the title compound (50 mg, 72%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.88-2.98 (4H, m), 3.98 (2H, s), 4.47 (2H, br.s), 5 26 (2H, br.s), 5.91 (1H, d, J = 8.4 Hz), 5.97 (1H, d, J = 3.2 Hz), 5.99 (1H, s) 6.27 (1H, dd, J = 2.0, 3.2 Hz), 7.13 (2H, d, J = 8.0 Hz), 7.23 (2H, d, J = 8.0 Hz), 7.31 (1H, d, J = 2.0 Hz), 7.47 (1H, d, J = 8.4 Hz).

[Example 141] 3- (3- (4- (4-Fluorophenoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (4-fluorophenoxy) phenyl) -acetohydroximoyl chloride (290 mg, 1.04 mmol) described in Production Example 141-1-3 and 3-ethynylpyridin-2,6-diamine (40.0 mg , 0.300 mM) described in Production Example 13-1-3, in tetrahydrofuran (5.00 ml) at room temperature, triethylamine (105 μl, 0.750 mmol) was added and stirred at room temperature for 16 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 3: 1 then ethyl acetate) to obtain the title compound (38.1 mg, 33.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.94 (2H, s), 5.81 (2H, br s), 5.83 (1H, d, J = 8, 0 Hz), 6.12 (2H, br.s), 6.39 (1H, s), 6.95 (2H, d, J = 8.4 Hz), 7.03-7.06 (2H, m), 7.19-7.24 (2H, m), 7.31 (2H, d, J = 8.4 Hz), 7.52 (1H, d, J = 8.0 Hz).

The starting material, (4- (4-fluorophenoxy) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 141-1-1] 4- (4-fluorophenoxy) benzaldehyde

To a solution of 4-fluorophenol (5.00 g, 44.6 mmol) and 4-fluorobenzaldehyde (4.00 mg, 32.2 mmol) in N, N-dimethylformamide (40.0 ml) was added potassium carbonate (13.4 g, 96.6 mmol) and stirred at 80 ° C for 21 hours. Then the reaction solution was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 15 → 1: 10) to obtain the title compound (6.60 g, 90.1%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.02-7.11 (6H, m), 7.85 (2H, d, J = 8.8 Hz), 9.91 (1H , c).

[Production Example 141-1-2] 4- (4-fluorophenoxy) -1- (2-nitroethyl) benzene

To a solution of 4- (4-fluorophenoxy) benzaldehyde (3.00 g, 48.4 mmol) described in Production Example 141-1-1 in acetic acid (30.0 ml), nitromethane was added at room temperature under a nitrogen atmosphere. (4.03 g, 66.0 mmol) and ammonium acetate (2.03 g, 26.4 mmol) and stirred at 110 ° C. for 4 hours. Water and ethyl acetate were added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (3.4 g). To a suitably cooled solution of this crude product (3.4 g) and acetic acid (3.00 ml) in dimethyl sulfoxide (30.0 ml) was added sodium borohydride (793 mg, 21.0 mmol) at room temperature and stirred at room temperature temperature for 30 minutes. Then, water was added dropwise at room temperature, while cooling accordingly. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 3 then 1: 1) to obtain the title compound (1.80 g, 52.6%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.21 (2H, t, J = 6.8 Hz), 4.84 (2H, t, J = 6.8 Hz), 6.93 (2H, d, J = 8.4 Hz), 7.03-7.06 (2H, m), 7.22 (2H, t, J = 8.8 Hz), 7.29 (2H , d, J = 8.4 Hz).

[Production Example 141-1-3] (4- (4-fluorophenoxy) phenyl) acetohydroximoyl chloride

To a solution of 4- (4-fluorophenoxy) -1- (2-nitroethyl) benzene (500 mg, 1.91 mmol) described in Production Example 141-1-2 in methanol (20.0 ml) at room temperature lithium methoxide (145 mg, 3.82 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (5.00 ml) were added to the residue. Titanium (IV) chloride (525 μl, 4.78 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C), after which the system was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was separated. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (500 mg, 93.6%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.80 (2H, s), 6.95-6.97 (2H, m), 7.05-7.08 (2H, m), 7.21-7.27 (4H, m), 11.73 (1H, s).

[Example 142] 3- (3- (4- (3-Fluorophenoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (3-fluorophenoxy) phenyl) -acetohydroximoyl chloride (210 mg, 0.622 mmol) described in Production Example 81-1-2 and 3-ethynylpyridin-2,6-diamine (30.0 mg, 0.225 mM) described in Production Example 13-1-3, triethylamine (94.1 μl, 0.675 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at room temperature for 30 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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 (29.0 mg, 34.2%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.81 (2H, br s), 5.84 (1H, d, J = 8, 4 Hz), 6.12 (2H, br.s), 6.41 (1H, s), 6.79-6.81 (1H, m), 6.84-6.87 (1H, m), 6.93-6.98 (1H, m), 7.03 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.4 Hz), 7.39-7 43 (1H, m); 7.53 (1H, d, J = 8.4 Hz).

[Example 143] 3- (3- (4- (2- (Tetrahydrofuran-2-yl) ethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the mixture of (4- (2-tetrahydrofuran-2-yl-ethyl) -phenyl) -acetohydroximoyl chloride (145 mg, 0.54 mmol) described in Production Example 82-1-6 and 3-ethynylpyridine- was added The 2,6-diamine (36 mg, 0.27 mmol) described in Production Example 13-1-3 and triethylamine (0.15 ml, 1.08 mmol) were stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. This organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1 then ethyl acetate) to obtain the title compound (76 mg, 77%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.40-1.55 (1H, m), 1.70-2.00 (5H, m), 2.60-2.80 ( 2H, m), 3.70-3.90 (3H, m), 3.91 (2H, s), 4.47 (2H, br.s), 5.26 (2H, br.s), 5 91 (1H, d, J = 8.4 Hz), 5.99 (1H, s), 7.16 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.4 Hz).

[Example 144] 3- (3- (4- (2-Fluorophenoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (4- (2-fluorophenoxy) phenyl) -acetohydroximoyl chloride (210 mg, 0.622 mmol) described in Production Example 83-1-3, and 3-ethynylpyridin-2,6-diamine (30.0 mg, 0.225 mM) described in Production Example 13-1-3, triethylamine (94.1 μl, 0.675 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at room temperature for 16 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent 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 (41.7 mg, 49.2%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.94 (2H, s), 5.81 (2H, br s), 5.82-5.85 (1H, m) 6.12 (2H, br s), 6.39 (1H, s), 6.92-6.95 (2H, m), 7.13-7.24 (3H, m), 7.30 -7.32 (2H, m), 7.35-7.41 (1H, m), 7.51-7.54 (1H, m).

[Example 145] 3- (3- (5-Phenoxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 3- (2-nitroethyl) -5-phenoxypyridine (210 mg, 0.860 mmol) described in Production Example 145-1-4, lithium methoxide (65 mg, 1.72 mmol) was added in methanol (5 ml) and stirred at room temperature for 25 minutes. The reaction mixture was concentrated under reduced pressure. To a suspension of this residue in tetrahydrofuran (5 ml) and methylene chloride (5 ml) in a nitrogen atmosphere was added titanium (IV) tetrachloride (236 μl, 2.15 mmol) and stirred at 0 ° C for 50 minutes. Sodium hydrogen carbonate was added to the reaction mixture at 0 ° C and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of this residue in tetrahydrofuran (4 ml) was added 3-ethynylpyridin-2,6-diamine (15 mg, 0.11 mmol) described in Production Example 13-1-3 and triethylamine (240 μl, 1.72 mmol) ) and stirred at 50 ° C for 1 hour 15 minutes. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by reverse phase high performance liquid chromatography (using the mobile phase acetonitrile: water containing 0.1% trifluoroacetic acid) to obtain the title compound (5.6 mg, 1.1%) as a salt ditrifluoroacetic acid.

MS m / e (ESI) (MH ⁺ ) 360.02 (MH ⁺ )

The starting material, 3- (2-nitroethyl) -5-phenoxypyridine, was synthesized as follows.

[Production Example 145-1-1] 5-Phenoxynicotinic Acid Methyl Ester

To a solution of 5-hydroxynicotinic acid methyl ester (903 mg, 5.90 mmol) in tetrahydrofuran (10 ml) and N, N-dimethylformamide (10 ml) was added diphenyl iodide chloride (1.87 g, 5.90 mmol) at 0 ° C. ) and potassium tert -butoxide (662 mg, 5.90 mmol) and stirred at room temperature for 2 hours 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. 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 (1.11 g, 82%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.93 (3H, s), 7.04-7.06 (2H, m), 7.19-7.23 (1H, m) , 7.39-7.43 (2H, m), 7.83 (1H, dd, J = 1.7, 2.9 Hz), 8.57 (1H, d, J = 2.9 Hz), 8.95 (1H, d, J = 1.7 Hz).

[Production Example 145-1-2] (5-phenoxypyridin-3-yl) -methanol

To a suspension of lithium aluminum hydride (689 mg, 14.5 mmol, purity: 80%) in tetrahydrofuran (20 ml) at 0 ° C was added 5-phenoxynicotinic acid methyl ester (1.11 g, 4.84 mmol), described in Production Example 145-1-1, and stirred at room temperature for 20 minutes. Water (689 μl), 5N sodium hydroxide solution (689 μl) were added to the reaction mixture, and then water (2.07 ml) was added to the reaction mixture at 0 ° C and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (756 mg, 78%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.77 (1H, t, J = 5.9 Hz), 4.73 (2H, d, J = 5.9 Hz), 7, 03-7.06 (2H, m), 7.15-7.19 (1H, m), 7.32-7.33 (1H, m), 7.36-7.40 (2H, m), 8.33-8.34 (2H, m).

[Production Example 145-1-3] 5-Phenoxypyridin-3-carbaldehyde

Manganese (IV) dioxide (3.27 g) was added to a solution of (5-phenoxypyridin-3-yl) methanol (756 mg, 3.76 mmol) described in Production Example 145-1-2, in methylene chloride (20 ml). , 37.6 mmol) and stirred at room temperature for 2 hours. The insoluble matter was removed by filtration through a pad of celite, then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1 then 1: 1) to obtain the title compound (607 mg, 81%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.06-7.08 (2H, m), 7.22-7.26 (1H, m), 7.41-7.45 ( 2H, m), 7.64 (1H, dd, J = 1.7, 2.9 Hz), 8.66 (1H, d, J = 2.9 Hz), 8.79 (1H, d, J = 1.7 Hz), 10.1 (1H, s).

[Production Example 145-1-4] 3- (2-nitroethyl) -5-phenoxypyridine

To a solution of 5-phenoxypyridin-3-carbaldehyde (607 mg, 3.05 mmol) described in Production Example 145-1-3, nitromethane (826 μl, 15.3 mmol) and ammonium acetate were added in acetic acid (15 ml) (470 mg, 6.10 mmol) and stirred at 100 ° C. under nitrogen for 3 hours. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of this residue in dimethyl sulfoxide (10 ml) and acetic acid (1 ml) was added sodium borohydride (182 mg, 4.58 mmol) and stirred at room temperature for 20 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture, cooled appropriately at room temperature, and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (210 mg, 28%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.34 (2H, t, J = 6.8 Hz), 4.65 (2H, t, J = 6.8 Hz), 7, 05-7.07 (2H, m), 7.28-7.32 (1H, m), 7.38 (1H, s), 7.44-7.48 (2H, m), 8.23- 8.24 (2H, m).

[Example 146] 3- (3- (3-Pyridin-2-yl-benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a mixture of (3- (pyridin-2-yl) phenyl) -acetohydroximoyl chloride (50 mg) described in Production Example 84-1-3 and tetrahydrofuran (2 ml) was added 3-ethynylpyridin-2,6-diamine (6 , 0 mg, 0.045 mm), described in Production Example 13-1-3, and triethylamine (38 μl, 0.27 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound as a crude product. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile: water containing 0.1% trifluoroacetic acid mobile phase) to give the title compound (3.7 mg, 14%) as a ditrifluoroacetic acid salt.

MS m / e (ESI) 344.24 (MH ⁺ )

[Example 147] 3- (3-Biphenyl-3-ylmethylisoxazol-5-yl) -pyridin-2,6-diamine

To the mixture of biphenyl-3-yl-acetohydroximoyl chloride (60 mg) described in Production Example 85-1-3 and tetrahydrofuran (3 ml) was added 3-ethynylpyridin-2,6-diamine (15 mg, 0.11 mmol) described in Production Example 13-1-3, and triethylamine (94 μl, 0.68 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound as a crude product. The residue was purified by reverse phase high performance liquid chromatography (using acetonitrile: water containing 0.1% trifluoroacetic acid mobile phase) to give the title compound (32 mg, 62%) as a trifluoroacetic acid salt.

MS m / e (ESI) 343.18 (MH ⁺ )

[Example 148] 3- (3- (4-Phenoxymethylbenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (4-phenoxymethylphenyl) -acetohydroximoyl chloride (150 mg, 0.545 mmol) described in Production Example 86-1-5, and 3-ethynylpyridin-2,6-diamine (46.3 mg, 0.348 mmol) described in Example 13-1-3 of preparation, triethylamine (104 μl, 0.747 mmol) was added in tetrahydrofuran (3 ml) and stirred at room temperature for 1 hour. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (45 mg, 22%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.03 (2H, s), 4.46 (2H, br s), 5.05 (2H, s), 5.25 (2H , broad s), 5.91-5.93 (1H, m), 5.99 (1H, s), 6.97-6.99 (3H, m), 7.26-7.32 (4H , m), 7.40-7.42 (2H, m), 7.47-7.49 (1H, m).

[Example 149] 3- (3- (4- (3-Fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of (4- (3-fluoropyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride (33 mg, 0.11 mmol) described in Production Example 149-1-4, 3-ethynylpyridine- was added in tetrahydrofuran (2 ml) The 2,6-diamine (10 mg, 75 μM) described in Production Example 13-1-3 and triethylamine (21 μl, 0.15 mmol) were stirred at 50 ° C. and under nitrogen for 2 hours 25 minutes. . Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 20: 1) to obtain the title compound (27 mg, 92%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.23 (2H, s), 5.80 (2H, s), 5.83 (1H d, J = 8.4 Hz), 6.11 (2H, s), 6.39 (1H, s), 7.35 (2H, d, J = 8.2 Hz), 7.39 (1H dd, J = 4.6, 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.66 (1H, dd, J = 1.6, 8.4 Hz), 7.98 (1H, dd, J = 1.6, 4.8 Hz).

The starting material, (4- (3-fluoropyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 149-1-1] 2- (4-bromobenzyloxy) -3-fluoropyridine

To a solution of (4-bromophenyl) methanol (1.56 g, 8.34 mmol) in N, N-dimethylformamide (15 ml) was added sodium hydride (401 mg, 8.35 mmol, 50% in oil) and stirred at room temperature for 5 minutes. Then, 2-chloro-3-fluoropyridine (967 mg, 7.35 mmol) in N, N-dimethylformamide (5 ml) was added to this mixture, and stirred at room temperature for 1 hour 10 minutes. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (2.03 g, 98%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.13 (2H, s), 7.17 (1H, dd, J = 4.4, 8.1 Hz), 7.20 (1H dd, J = 2.0, 8.1 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 8.02 (1H, dd, J = 2.0, 4.4 Hz).

[Production Example 149-1-2] 4- (3-Fluoropyridin-2-yloxymethyl) benzaldehyde

To a solution of 2- (4-bromobenzyloxy) -3-fluoropyridine (2.03 g, 7.20 mmol) described in Production Example 149-1-1 in tetrahydrofuran (40 ml) at -78 ° C under nitrogen was added n- butyllithium (5.04 ml, 1.6 M hexane solution, 7.92 mmol) and stirred at -78 ° C for 45 minutes. Then, N, N-dimethylformamide (725 μl, 9.36 mmol) was added to the reaction mixture at -78 ° C and stirred for 1 hour 10 minutes, while raising the temperature to room temperature. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (887 mg, 53%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.26 (2H, s), 7.17-7.26 (2H, m), 7.64 (2H, d, J = 8, 1 Hz), 7.94 (2H, d, J = 8.0 Hz), 8.05 (1H, dd, J = 1.8, 4.4 Hz), 10.0 (1H, s).

[Production Example 149-1-3] 3-fluoro-2- (4- (2-nitroethyl) benzyloxy) pyridine

To a solution of 4- (3-fluoropyridin-2-yloxymethyl) benzaldehyde (887 mg, 3.84 mmol) described in Production Example 149-1-2, in the case of acetic acid (20 ml) was added nitromethane (1.04 ml, 19.2 mmol) and ammonium acetate (592 mg, 7.68 mmol) and stirred at 100 ° C. under nitrogen for 4 hours 30 minutes. Water was added to the reaction mixture at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of this residue in dimethyl sulfoxide (20 ml) and acetic acid (1 ml) was added sodium borohydride (291 mg, 7.68 mmol) and stirred at room temperature for 30 minutes. Sodium hydrogen carbonate and water were added to the appropriately cooled reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (674 mg, 64%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.33 (2H, t, J = 7.2 Hz), 4.62 (2H, t, J = 7.2 Hz), 5, 15 (2H, s), 7.16 (1H, dd, J = 4.8, 8.0 Hz), 7.20 (1H, dd, J = 2.0, 8.0 Hz), 7.23 -7.25 (2H, m), 7.41 (2H, d, J = 8.4 Hz), 8.00 (1H, dd, J = 1.6, 4.4 Hz).

[Production Example 149-1-4] (4- (3-fluoropyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride

To a solution of 3-fluoro-2- (4- (2-nitroethyl) benzyloxy) pyridine (674 mg, 2.44 mmol) described in Production Example 149-1-3, in methanol (10 ml) was added lithium methoxide (185 mg, 4.87 mmol) and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. Titanium (IV) tetrachloride (590 μl, 5.37 mmol) was added to a suspension of this residue in tetrahydrofuran (10 ml) and methylene chloride (10 ml) at -78 ° C under nitrogen atmosphere and stirred at 0 ° C for 1 hour. Water was added to the reaction mixture at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then filtered using neutral silica gel. The filtrate was concentrated under reduced pressure to obtain the title compound (629 mg, 88%). This compound was used in the subsequent reaction without further purification.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.82 (2H, s), 5.17 (2H, s), 7.17 (1H, ddd, J = 0.4, 4, 8, 8.0 Hz), 7.23 (1H, dd, J = 1.6, 8.0 Hz), 7.32 (2H, d, J = 7.9 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.64 (1H, s), 8.01 (1H, dd, J = 1.7, 4.6 Hz).

[Example 150] 3- (3- (3-Fluoro-4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 2- (2-Fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine (500 mg, 1.81 mmol) described in Production Example 87-1-3 in methanol (20.0 ml) in lithium methoxide (137 mg, 3.61 mmol) was added under nitrogen atmosphere and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and dichloromethane (15.0 ml) and anhydrous tetrahydrofuran (7.00 ml) were added to the residue. Titanium (IV) chloride (656 μl, 5.97 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 30 minutes. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture in an ice bath (0 ° C) and filtered through a pad of celite. The organic layer of the filtrate was extracted with ethyl acetate, and this organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (300 mg). To a solution of this crude product (150 mg) and 3-ethynylpyridin-2,6-diamine (30.0 mg, 0.225 mmol) described in Production Example 13-1-3 in tetrahydrofuran (5.00 ml) at room temperature triethylamine (94.1 μl, 0.675 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 then 10: 1) to obtain the title compound (35.0 mg, 39.7%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.90 (2H, s), 5.22 (2H, s), 5.80 (2H, br s), 5.83 (1H, d, J = 8.8 Hz), 6.12 (2H, br.s), 6.38 (1H, s), 7.04 (1H, d, J = 8.4 Hz), 7 , 15-7.23 (2H, m), 7.34-7.37 (1H, m), 7.52 (2H, d, J = 8.0 Hz), 7.85 (1H, t, J = 8.0 Hz), 8.58 (1H, d, J = 8.8 Hz).

[Example 151] 3- (3- (4- (Thiazol-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (50 mg, 0.18 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N sodium hydroxide solution (35.4 μl, 0.18 mmol) and dissolved by sonication for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a suspension of this solid in N, N-dimethylformamide (1 ml) was added a solution of 2-chloromethylthiazole (28.4 mg, 0.21 mmol), described in Production Example 88-1-2, in N, N-dimethylformamide (1 ml), the solution was stirred at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (43.0 mg, 64%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.89 (2H, s), 5.41 (2H, s), 5.79 (2H, br s), 5.82 (1H, d, J = 8.8 Hz), 6.11 (2H, br.s), 6.35 (1H, s), 7.01 (2H, d, J = 8.8 Hz), 7 24 (2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.77 (1H, d, J = 3.6 Hz), 7.83 (1H, d, J = 3.2 Hz).

[Example 152] 3- (3- (6- (3,4-Difluorobenzyloxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

The title compound (90 mg, 73%) was obtained according to a similar manner to that of Example 3 using 3-ethynylpyridin-2,6-diamine (40 mg, 0.30 mmol) described in Production Example 13-1-3, and (6- (3,4-difluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride (140 mg, 0.45 mmol) described in Production Example 89-1-1.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.92 (2H, s), 5.31 (2H, s), 5.81 (2H, br.s), 5.83 (1H, dd, J = 1.6, 8.0 Hz), 6.12 (2H, br.s), 6.40 (1H, d, J = 1.6 Hz), 6.86 (1H, d, J = 8.0 Hz), 7.28-7.34 (1H, m), 7.39-7.47 (1H, m), 7.48-7.56 (2H, m), 7 65-7.70 (1H, m); 8.14 (1H, s).

[Example 153] 3- (3- (6- (2,4-Difluorobenzyloxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

The title compound (62 mg, 67%) was obtained according to a similar manner to that of Example 12 using 3-ethynylpyridin-2,6-diamine (30 mg, 0.23 mmol) described in Production Example 13-1-3, and (6- (2,4-difluorobenzyloxy) -pyridin-3-yl) -acetohydroximoyl chloride (110 mg, 0.34 mmol), described in Production Example 90-1-1.

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.92 (2H, s), 5.34 (2H, s), 5.81 (2H, br.s), 5.83 (1H, d, J = 8.0 Hz), 6.12 (2H, br.s), 6.34 (1H, s), 6.83 (1H, d, J = 8.0 Hz), 7 , 07-7.14 (1H, m), 7.25-7.33 (1H, m), 7.51 (1H, d, J = 8.0 Hz), 7.56-7.64 (1H , m), 7.66 (1H, dd, J = 2.0, 8.0 Hz), 8.15 (1H, d, J = 2.0 Hz).

[Example 154] 3- (3- (6- (Pyridin-2-yloxymethyl) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of (6- (pyridin-2-yloxymethyl) -pyridin-3-yl) -acetohydroximoyl chloride (24 mg) described in Production Example 154-1-8, 3-ethynylpyridin-2,6 was added in tetrahydrofuran (2 ml) -diamine (5.0 mg, 38 μM), described in Production Example 13-1-3, and triethylamine (13 μl, 94 μM), and stirred at 50 ° C. for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 20: 1) to obtain the title compound (8.2 mg, 58%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.03 (2H, s), 4.53 (2H, s), 5.28 (2H, s), 5.50 (2H, s ), 5.92 (1H, d, J = 8.4 Hz), 6.00 (1H, s), 6.85-6.91 (2H, m), 7.43 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.58-7.62 (2H, m), 8.14-8.16 (1H, m), 8, 58 (1H, d, J = 2.4 Hz).

The starting material, (6- (pyridin-2-yloxymethyl) -pyridin-3-yl) acetohydroximoyl chloride, was synthesized as follows.

[Production Example 154-1-1] 6-bromopyridin-3-carbaldehyde

To a solution of 2,5-dibromopyridine (3.00 g, 12.7 mmol) in diethyl ether (60 ml) at -78 ° C under nitrogen atmosphere was added n- butyllithium (7.99 ml, 1.6 M hexane solution, 12.7 mmol) and stirred at -78 ° C for 50 minutes. Then, N, N-dimethylformamide (1.18 ml, 15.2 mmol) was added to the mixture and stirred for 35 minutes while raising the temperature to room temperature. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (1.56 g, 66%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 7.69 (1H, dd, J = 0.73, 8.2 Hz), 8.03 (1H, dd, J = 2.4, 8.2 Hz), 8.84 (1H, dd, J = 0.73, 2.4 Hz), 10.1 (1H, s).

[Production Example 154-1-2] 2-bromo-5- [1,3] dioxolan-2-yl-pyridine

Ethylene glycol (3.0 ml, 54 mmol) and p - monohydrate were added to the solution of 6-bromopyridin-3-carbaldehyde (5.0 g, 27 mmol) described in Production Example 154-1-1 in toluene (100 ml). toluenesulfonic acid (512 mg, 2.7 mmol) and refluxed under nitrogen for 3 hours and 40 minutes. Sodium bicarbonate and water were added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (6.0 g, 97%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.03-4.13 (4H, m), 5.83 (1H, s), 7.49-7.52 (1H, m) 7.64-7.67 (1H, m); 8.46 (1H, d, J = 2.4 Hz).

[Production Example 154-1-3] 5- [1,3] dioxolan-2-yl-pyridin-2-carbaldehyde

To a solution of 2-bromo-5- [1,3] dioxolan-2-yl-pyridine (4.77 g, 20.7 mmol) described in Production Example 154-1-2 in tetrahydrofuran (100 ml) with - 78 ° C under nitrogen atmosphere was added n- butyllithium (14.3 ml, 1.6 M hexane solution, 22.8 mmol) and stirred at -78 ° C for 20 minutes. Then, N, N-dimethylformamide (1.92 ml, 24.8 mmol) was added to the reaction mixture and stirred for 15 minutes while raising the temperature to room temperature. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. 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 (1.73 g, 47%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.07-4.16 (4H, m), 5.94 (1H, s), 7.98 (2H, s), 8.88 (1H, s), 10.1 (1H, s).

[Production Example 154-1-4] (5- [1,3] dioxolan-2-yl-pyridin-2-yl) -methanol

To a solution of 5- [1,3] dioxolan-2-yl-pyridin-2-carbaldehyde (1.73 g, 9.66 mmol) described in Production Example 154-1-3 in ethanol (20 ml) and tetrahydrofuran (20 ml) was added sodium borohydride (731 mg, 19.3 mmol), the solution was stirred at room temperature for 25 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 2) to obtain the title compound (1.37 g, 78%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.65 (1H, s), 4.05-4.16 (4H, m), 4.78 (2H, s), 5.87 (1H, s), 7.26-7.28 (1H, m), 7.80 (1H, dd, J = 2.0, 8.1 Hz), 8.65 (1H, d, J = 2 , 0 Hz).

[Production Example 154-1-5] 5- [1,3] dioxolan-2-yl-2- (pyridin-2-yloxymethyl) pyridine

To a solution of (5- [1,3] dioxolan-2-yl-pyridin-2-yl) -methanol (1.37 g, 7.56 mmol) described in Production Example 154-1-4, in N, N -dimethylformamide (40 ml) was added sodium hydride (333 mg, 8.32 mmol, 60% in oil), the solution was stirred at 0 ° C for 5 minutes. Then, 2-fluoropyridine (716 μl, 8.32 mmol) was added to the reaction mixture and stirred at 50 ° C for 45 minutes. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1 to 1: 1) to obtain the title compound (1.51 g, 77%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.04-4.15 (4H, m), 5.53 (2H, s), 5.87 (1H, s), 6.86 -6.91 (2H, m), 7.47 (1H, d, J = 8.1 Hz), 7.58-7.63 (1H, m), 7.79 (1H, dd, J = 2 , 0, 8.2 Hz), 8.14-8.16 (1H, m), 8.70 (1H, d, J = 2.0 Hz).

[Production Example 154-1-6] 6- (pyridin-2-yloxymethyl) -pyridin-3-carbaldehyde

To a solution of 5- [1,3] dioxolan-2-yl-2- (pyridin-2-yloxymethyl) pyridine (1.51 g, 5.85 mmol) described in Production Example 154-1-5, in tetrahydrofuran (15 ml) and dimethyl sulfoxide (10 ml) was added a 5N aqueous solution of hydrochloric acid (3 ml), stirred at room temperature for 25 minutes, and then at 60 ° C for another 1 hour 20 minutes. A 5N sodium hydroxide solution was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (603 mg, 48%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 5.61 (2H, s), 6.90-6.94 (2H, m), 7.26-7.66 (2H, m) 8.12-8.14 (1H, m), 8.17 (1H, dd, J = 2.0, 8.1 Hz), 9.05 (1H, d, J = 1.7 Hz), 10.1 (1H, s).

[Production Example 154-1-7] 5- (2-nitroethyl) -2- (pyridin-2-yloxymethyl) pyridine

To a solution of 6- (pyridin-2-yloxymethyl) -pyridin-3-carbaldehyde (504 mg, 2.35 mmol) described in Production Example 154-1-6, nitromethane (635 μl, was added in acetic acid (20 ml) 11.8 mmol) and ammonium acetate (363 mg, 4.71 mmol) and stirred at 100 ° C. under nitrogen for 4 hours. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of this residue in dimethyl sulfoxide (25 ml) and acetic acid (2.5 ml) was added sodium borohydride (178 mg, 4.71 mmol) and stirred at room temperature for 25 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (93 mg, 15%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.38 (2H, t, J = 6.8 Hz), 4.66 (2H, t, J = 6.8 Hz), 5, 83 (2H, s), 6.90-6.96 (2H, m), 7.63-7.70 (2H, m), 7.78 (1H, dd, J = 1.6, 8.0 Hz), 8.14 (1H, dd, J = 1.6, 4.8 Hz), 8.68 (1H, d, J = 1.2 Hz).

[Production Example 154-1-8] (6- (pyridin-2-yloxymethyl) -pyridin-3-yl) -acetohydroximoyl chloride

To a solution of 5- (2-nitroethyl) -2- (pyridin-2-yloxymethyl) pyridine (93 mg, 0.36 mmol) described in Production Example 154-1-7, lithium methoxide was added to methanol (5 ml) (27 mg, 0.72 mmol) and stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure. To a suspension of this residue in tetrahydrofuran (3 ml) and methylene chloride (3 ml) at -78 ° C under a nitrogen atmosphere was added titanium (IV) tetrachloride (87 μl, 0.79 mmol) and stirred at 0 ° C for 2 hours. At -78 ° C, titanium (IV) tetrachloride (50 μl, 0.46 mmol) was additionally added and stirred at 0 ° C for 3 hours. Water was added to the reaction mixture at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (24 mg). This compound was used in the subsequent reaction without further purification.

[Example 155] 3- (3- (5- (4-Fluorophenoxy-thiophen-2-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (5- (4-fluorophenoxy) -thiophen-2-yl) -acetohydroximoyl chloride (250 mg, 0.875 mmol) described in Production Example 91-1-4, and 3-ethynylpyridin-2,6-diamine (50, 0 mg, 0.376 mmol) described in Production Example 13-1-3, triethylamine (157 μl, 1.27 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at 60 ° C for 3 hours. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 → 3: 1) to obtain the title compound (20.9 mg, 14.5%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.09 (2H, s), 5.82 (2H, br s), 5.84 (1H, d, J = 8, 4 Hz), 6.14 (2H, br.s), 6.44 (1H, s), 6.51 (1H, d, J = 3.6 Hz), 6.75 (1H, d, J = 3.6 Hz), 7.13-7.16 (2H, m), 7.19-7.25 (2H, m), 7.54 (1H, d, J = 8.0 Hz).

[Example 156] 3- (3- (5- (4-Methylbenzyl) thiophen-2-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (5- (4-methylbenzyl) -thiophen-2-yl) acetohydroximoyl chloride (250 mg, 0.894 mmol) described in Production Example 92-1-5, and 3-ethynylpyridin-2,6-diamine (50.0 mg, 0.376 mmol) described in Production Example 13-1-3, triethylamine (157 μl, 1.13 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at 60 ° C for 30 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 then 3: 1) to obtain the title compound (49.8 mg, 35.2%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.25 (3H, s), 4.01 (2H, s), 4.07 (2H, s), 5.80 (2H , br.s), 5.83 (1H, d, J = 8.4 Hz), 6.13 (2H, br.s), 6.39 (1H, s), 6.69 (1H, d, J = 3.2 Hz), 7.78 (1H, d, J = 3.2 Hz), 7.08-7.13 (4H, m), 8.09 (1H, d, J = 8.4 Hz).

[Example 157] 3- (3- (3-Fluoro-4- (5-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To the solution of (3-fluoro-4- (5-fluoropyridin-2-ylmethoxy) phenyl) acetohydroximoyl chloride (170 mg, 0.554 mmol) described in Production Example 94-1-3, and 3-ethynylpyridin-2,6- diamine (40.0 mg, 0.300 mmol) described in Production Example 13-1-3, triethylamine (125 μl, 0.900 mmol) was added in tetrahydrofuran (5.00 ml) at room temperature and stirred at room temperature for 30 minutes . Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 then 3: 1) to obtain the title compound (59.0 mg, 48.0%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.90 (2H, s), 5.22 (2H, s), 5.80 (2H, br s), 5.83 (1H, d, J = 8.4 Hz), 6.11 (1H, br.s), 6.38 (1H, s), 7.05 (1H, d, J = 8.4 Hz), 7 , 19-7.22 (2H, m), 7.51 (2H, d, J = 8.4 Hz), 7.59-7.62 (1H, m), 7.76-7.81 (1H , m), 8.58 (1H, d, J = 2.8 Hz).

[Example 158] 3- (3- (2-Fluoro-4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 2- (3-fluoro-4- (2-nitroethyl) phenoxymethyl) pyridine (400 mg, 1.45 mmol) described in Production Example 95-1-3, in methanol (20.0 ml) was added lithium methoxide (110 mg, 2.90 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and anhydrous dichloromethane (20.0 ml) and anhydrous tetrahydrofuran (10.0 ml) were added to the residue. Titanium (IV) chloride (510 μl, 4.64 mmol) was added dropwise to the reaction mixture in a dry ice-ethanol bath (-78 ° C) and stirred at room temperature for 60 minutes. Water, ethyl acetate and tetrahydrofuran were added to the reaction mixture in an ice bath (0 ° C), and the organic layer was then extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (360 mg). To a solution of 3-ethynylpyridin-2,6-diamine (40.0 mg, 0.300 mmol) described in Production Example 13-1-3 and this crude product (180 mg) in tetrahydrofuran (5.00 ml) at room temperature triethylamine (125 μl, 0.900 mmol) was added and stirred at room temperature for 2 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 → 3: 1) and then further purified by reverse phase high performance liquid chromatography (using acetonitrile: water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.20 mg, 1.72%) as a salt of ditrifluoroacetic acid.

MS m / e (ESI) 392.19 (MH ⁺ )

[Example 159] 3- (3- (4- (2-Pyridin-2-yl-ethyl) -benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the mixture of (4- (2-pyridin-2-yl-ethyl) -phenyl) -acetohydroximoyl hydrochloride (780 mg, 2.51 mmol) described in Production Example 93-1-8 and dimethylformamide (10 ml) was added 3-ethynylpyridine -2,6-diamine (96 mg, 0.721 mmol) described in Production Example 13-1-3 and triethylamine (1.05 ml, 7.53 mmol) and stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. This organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 4: 6 then ethyl acetate) to obtain the title compound (80 mg, 30%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.00-3.10 (4H, m), 3.98 (2H, s), 4.46 (2H, br s), 5 , 25 (2H, br.s), 5.91 (1H, d, J = 8.4 Hz), 5.99 (1H, s), 7.07 (1H, d, J = 7.6 Hz) , 7.12 (1H, dd, J = 6.0, 7.6 Hz), 7.15 (2H, d, J = 8.0 Hz), 7.19 (2H, d, J = 8.0 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.57 (1H, t, J = 7.6 Hz), 8.56 (1H, d, J = 6.0 Hz) .

[Example 160] 3- (3- (1- (3-Fluorobenzyl) -1 H -pyrrol-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine

1- (3-fluorobenzyl) -1 H -pyrrol-3-yl) -acetohydroximoyl chloride (1.1 g) was obtained according to methods similar to the methods of Production Example 57-1-3 using 1- (3-fluorobenzyl) -3- (2-nitroethyl) -1 H -pyrrole (1.7 g, 6.9 mmol), described in Production Example 160-1-1. The title compound (4.7 mg, 4.3%) was obtained according to methods similar to the methods of Example 12 using 3-ethynylpyridin-2,6-diamine (40 mg, 0.30 mmol) described in Example 13-1. -3 preparation, and the aforementioned 1- (3-fluorobenzyl) -1 H -pyrrol-3-yl) -acetohydroximoyl chloride (400 mg, 1.5 mmol).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.71 (2H, s), 5.05 (2H, s), 5.77 (2H, br.s), 5.83 (1H, d, J = 8.0 Hz), 5.99 (1H, dd, J = 2.0, 2.0 Hz), 6.09 (2H, br.s), 6.35 (1H, c), 6.72 (1H, dd, J = 2.0, 2.0 Hz), 6.77 (1H, dd, J = 2.0, 2.0 Hz), 6.96-7.01 (1H, m), 7.02 (1H, d, J = 8.0 Hz), 7.06-7.12 (1H, m), 7.34-7.40 (1H, m), 7, 51 (1H, d, J = 8.0 Hz).

The starting material, 1- (3-fluorobenzyl) -3- (2-nitroethyl) -1 H -pyrrole, was synthesized as follows.

[Production Example 160-1-1] 1- (3-fluorobenzyl) -3- (2-nitroethyl) -1 H- pyrrole

The title compound (1.7 g, 48%) was obtained according to methods similar to the methods of Production Examples 57-1-1 to 57-1-2, using 1- (3-fluorobenzyl) -1 H -pyrrol-3- carbaldehyde (2.9 g, 14 mmol).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.00 (2H, t, J = 6.8 Hz), 4.67 (2H, t, J = 6.8 Hz), 5.05 (2H, s), 5.94 (1H, dd, J = 2.0, 2.0 Hz), 6.68 (1H, dd, J = 2.0, 2.0 Hz), 6 75 (1H, dd, J = 2.0, 2.0 Hz), 6.90-6.95 (1H, m), 6.98 (1H, d, J = 8.0 Hz), 7, 06-7.12 (1H, m), 7.33-7.49 (1H, m).

[Example 161] 3- (3- (6-Phenylsulfanylpyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To the solution of (6-phenylsulfanylpyridin-3-yl) -acetohydroximoyl chloride (100 mg, 0.359 mmol) described in Production Example 97-1-4 and 3-ethynylpyridin-2,6-diamine (15 mg, 0.13 mmol) described in Production Example 13-1-3, triethylamine (55 μl, 0.40 mmol) was added in tetrahydrofuran (4 ml) and stirred at 50 ° C. under nitrogen for 1 hour. To the reaction mixture was added and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (25 mg, 58%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.94 (2H, s), 4.51 (2H, s), 5.26 (2H, s), 5.92 (1H, d , J = 8.4 Hz), 5.97 (1H, s), 6.86 (1H, d, J = 8.4 Hz), 7.37 (1H, dd, J = 2.4, 8, 2 Hz), 7.40-7.43 (3H, m), 7.46 (1H, d, J = 8.2 Hz), 7.57-7.60 (2H, m), 8.39 ( 1H, d, J = 2.4 Hz).

[Example 162] 3- (3- (4- (3-Methoxybenzyloxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (30 mg, 0.11 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N aqueous solution of sodium hydroxide (21.2 μl, 0.11 mmol) and was dissolved by ultrasonic treatment for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a mixture of this solid and N, N-dimethylformamide (1 ml) was added a solution of 3-methoxybenzyl chloride (17.0 mg, 0.11 mmol) in N, N-dimethylformamide (1 ml) and stirred at 60 ° C for 12 hours. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (34.4 mg, 81%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.75 (3H, s), 3.87 (2H, s), 5.05 (2H, s), 5.89 (2H , br.s), 5.82 (1H, d, J = 8.4 Hz), 6.10 (2H, br.s), 6.34 (1H, s), 6.86-6.89 ( 1H, m), 6.95 (2H, d, J = 8.8 Hz), 6.98-7.02 (2H, m), 7.21 (2H, d, J = 8.8 Hz), 7.29 (1H, dd, J = 8.0, 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz).

[Example 163] 3- (3- (4- (6-Methoxypyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (30 mg, 0.11 mmol) described in Production Example 18-1-1 in tetrahydrofuran ( 3 ml) was added a 5N aqueous solution of sodium hydroxide (21.2 μl, 0.11 mmol) and was dissolved by ultrasonic treatment for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a mixture of this solid and N, N-dimethylformamide (1 ml) was added 2-chloromethyl-6-methoxypyridine (20.0 mg, 0.13 mmol), described in Production Example 99-1-2, in N, N- dimethylformamide (1 ml), the mixture was stirred at 60 ° C for 1 hour. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (26.1 mg, 61%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.85 (3H, s), 3.88 (2H, s), 5.06 (2H, s), 5.79 (2H , br.s), 5.82 (1H, d, J = 8.4 Hz), 6.11 (2H, br.s), 6.34 (1H, s), 6.75 (1H, dd, J = 0.8, 8.4 Hz), 6.98 (2H, d, J = 8.8 Hz), 7.05-7.08 (1H, m), 7.20-7.24 (2H , m), 7.51 (1H, d, J = 8.8 Hz), 7.69-7.74 (1H, m).

[Example 164] 3- (3- (6- (Pyridin-3-yloxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a mixture of 5- (2-nitroethyl) -2- (pyridin-3-yloxy) pyridine (157.0 mg, 0.64 mmol) described in Production Example 100-1-2 and methanol (6 ml) at room temperature lithium methoxide (48.7 mg, 1.28 mmol) was added and stirred for 1 hour. Then, the reaction mixture was concentrated under reduced pressure to obtain a white solid. To a mixture of this solid in dichloromethane (4 ml) and tetrahydrofuran (2 ml) at -78 ° C under nitrogen atmosphere was added titanium tetrachloride (155.0 μl, 1.41 mmol) and stirred at 0 ° C for 3 hours. Water was added to the reaction solution, then the solution was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To a mixture of the obtained residue (30.7 mg), 3-ethynylpyridin-2,6-diamine (15.4 mg, 0.12 mmol) described in Production Example 13-1-3, tetrahydrofuran (1 ml) and dimethyl sulfoxide ( 1 ml) triethylamine (32.4 μl, 0.23 mmol) was added at room temperature and stirred at 55 ° C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) and then further purified by preparative thin layer chromatography (NH silica gel, ethyl acetate) to obtain the title compound (3.6 mg, 9 %).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.98 (2H, s), 4.52 (2H, br s), 5.28 (2H, br s), 5.93 (1H, d, J = 8.4 Hz), 6.01 (1H, s), 6.96 (1H, dd, J = 0.4, 8.4 Hz), 7.34 (1H, ddd, J = 0.8, 4.4, 8.4 Hz), 7.50-7.53 (1H, m), 7.66 (1H, dd, 2.4, 8.4 Hz), 8.10 (1H, dd, J = 0.8, 2.4 Hz), 8.45 (1H, dd, J = 1.2, 1.6, 4.8, 5.2 Hz), 8.50 (1H , d, J = 2.8 Hz).

MS m / e (ESI) 361.05 (MH ⁺ )

[Example 165] 6-Methoxymethyl-3- (3- (4- (5-methylfuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the mixture of (4- (5-methylfuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride (11 mg, 0.043 mmol) described in Production Example 46-1-6 and tetrahydrofuran (1 ml) was added 3-ethynyl-6- methoxymethylpyridin-2-ylmethyl (6.5 mg, 0.035 mmol) described in Production Example 26-1-7 and triethylamine (9.6 μl, 0.069 mmol) and stirred at 40 ° C. for 3 hours. The reaction solution was allowed to cool to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 3) to obtain the title compound (9.2 mg, 58%, purity: 84%) as a mixture with the starting material 3-ethynyl-6-methoxymethylpyridine- 2-ylamine.

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.24 (3H, s), 3.46 (3H, s), 3.90 (2H, s), 4.02 (2H, s ), 4.42 (2H, s), 5.46 (2H, br s), 5.85-5.87 (2H, m), 6.23 (1H, s), 6.81 (1H, d, J = 7.9 Hz), 7.21 (4H, s), 7.71 (1H, d, J = 7.9 Hz).

[Example 166] 6-Methoxymethyl-3- (3- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 4- (5- (2-amino-6-methoxymethylpyridin-3-yl) isoxazol-3-ylmethyl) phenol (50 mg, 0.16 mmol) described in Production Example 166-1-1, in methanol (1.5 ml) was added a 1N aqueous sodium hydroxide solution (160 μl, 0.16 mmol) and concentrated under reduced pressure. N, N-dimethylformamide (1.5 ml) was added to the residue thus obtained at room temperature, and 2-picolyl chloride (29 mg, 0.23 mmol) was added to the reaction mixture at the same temperature; moreover, 2-picolyl chloride was obtained by adding 5N aqueous sodium hydroxide solution in 2-picolyl chloride hydrochloride). The reaction solution was stirred at the same temperature for 100 minutes. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 4: 1) to obtain the title compound (32 mg, 52%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.46 (3H, s), 3.99 (2H, s), 4.41 (2H, s), 5.20 (2H, s ), 5.43 (2H, br.s), 6.22 (1H, s), 6.81 (1H, d, J = 7.9 Hz), 6.95-6.97 (2H, m) , 7.19-7.24 (3H, m), 7.52 (1H, d, J = 7.9 Hz), 7.69-7.73 (2H, m), 8.60 (1H, d , J = 4.2 Hz).

The starting material, 4- (5- (2-amino-6-methoxymethylpyridin-3-yl) -isoxazol-3-ylmethyl) phenol, was synthesized as follows.

[Production Example 166-1-1] 4- (5- (2-amino-6-methoxymethylpyridin-3-yl) -isoxazol-3-ylmethyl) phenol

To a mixture of 3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -6-methoxymethylpyridin-2-ylamine (30 mg, 0.075 mmol) described in Example 26 and dichloromethane (1 ml) at -78 ° C was added boron tribromide (220 μl, 1 M dichloromethane solution, 0.22 mmol) and stirred at 0 ° C for 1 hour. The reaction solution was cooled to −78 ° C., methanol was added at the same temperature, and the excess was removed with boron tribromide. The reaction solution was gradually warmed to room temperature, an aqueous solution of sodium acetate was added to the reaction mixture at room temperature and neutralized, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 2: 1) to obtain the title compound (4.6 mg, 20%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.47 (3H, s), 3.98 (2H, s), 4.43 (2H, s), 5.50 (2H, br c), 6.22 (1H, s), 6.78-6.83 (3H, m), 7.13-7.16 (2H, m), 7.73 (1H, d, J = 7 9 Hz)

[Example 167] 6-methoxymethyl-3- (3- (6-Phenoxyxypyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (2-phenoxyxypyridin-5-yl) -acetohydroximoyl chloride (93 mg, 0.36 mmol) described in Production Example 40-1-4 and 3-ethynyl-6-methoxymethylpyridin-2-ylamine (32 mg, 0 , 20 mM) described in Production Example 26-1-7, triethylamine (55 μl, 0.39 mmol) was added in tetrahydrofuran (2 ml) and stirred at 50 ° C. under nitrogen for 5 hours 25 minutes. Water was added to the reaction solution at room temperature, and then extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (54 mg, 71%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.35 (3H, s), 4.03 (2H, s), 4.33 (2H, s), 6.31 (2H , c), 6.73 (1H, d, J = 7.7 Hz), 6.83 (1H, s), 7.00 (1H, d, J = 8.4 Hz), 7.10-7 12 (2H, m), 7.18-7.22 (1H, m), 7.38-7.44 (2H, m), 7.81 (1H, dd, J = 2.4, 8, 4 Hz), 7.89 (1H, d, J = 7.9 Hz), 8.15 (1H, d, J = 2.4 Hz).

[Example 168] 3- (3- (4- (5-chlorofuran-2-ylmethyl) benzyl) isoxazol-5-yl) -6-methoxymethylpyridin-2-ylamine

To a mixture of (4- (5-chlorofuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Production Example 62-1-6 and tetrahydrofuran (1 ml) was added 3-ethynyl-6- methoxymethylpyridin-2-ylamine (11 mg, 0.069 mmol) described in Production Example 26-1-7 and triethylamine (19 μl, 0.014 mmol) and stirred at 50 ° C. for 1 hour. The reaction solution was allowed to cool to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound as a crude product. This product was then purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1) to obtain the title compound (7.5 mg, 27%).

MS m / e (ESI) 410.10 (MH ⁺ )

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.46 (3H, s), 3.90 (2H, s), 4.03 (2H, s), 4.42 (2H, s ), 5.46 (2H, br s), 5.98-5.99 (1H, m), 6.04-6.05 (1H, m), 6.24 (1H, s), 6, 81 (1H, d, J = 7.9 Hz), 7.20 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.72 ( 1H, d, J = 7.9 Hz).

[Example 169] (6-amino-5- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -methanol

To the mixture of 4-benzyloxyphenyl-acetohydroximoyl chloride (9.8 mg, 0.043 mmol) described in Production Example 1-1-3 and tetrahydrofuran (1 ml) was added (6-amino-5-ethynylpyridin-2-yl) -methanol ( 6.1 mg, 0.024 mmol, purity: 57%) described in Production Example 169-1-2 and triethylamine (6.5 μl, 0.047 mmol) and stirred at 50 ° C. for 1 hour. The reaction solution was allowed to cool to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound as a crude product. This product was then purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (3.3 mg, 36%).

MS m / e (ESI) 388.01 (MH ⁺ )

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 4.00 (2H, s), 4.63 (2H, s), 5.05 (2H, s), 5.52 (2H, br .c), 6.22 (1H, s), 6.63 (1H, d, J = 7.9 Hz), 6.93-6.97 (2H, m), 7.19-7.22 ( 2H, m), 7.30-7.44 (5H, m), 7.70 (1H, d, J = 7.9 Hz).

The starting material, (6-amino-5-ethynylpyridin-2-yl) methanol, was synthesized as follows.

[Production Example 169-1-1] 2-amino-6-hydroxymethylpyridin-3-carbaldehyde

To a mixture of 2-amino-6-methoxymethylpyridin-3-carbaldehyde (57 mg, 0.34 mmol) described in Production Example 26-1-6 and dichloromethane (2 ml) at -78 ° C, boron tribromide was added (1, 0 ml, 1 M dichloromethane solution, 1.0 mM) and stirred at 0 ° C for 1 hour. The reaction solution was cooled to −78 ° C., methanol was added at the same temperature, and excess reagent was removed. The reaction solution was gradually warmed to room temperature and neutralized by adding aqueous ammonia solution (28%). Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 4: 1) to obtain the title compound (18 mg, 34%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.40 (2H, d, J = 5.9 Hz), 5.42 (1H, t, J = 5.9 Hz), 6.86 (1H, d, J = 7.7 Hz), 7.52 (2H, br.s), 8.00 (1H, d, J = 7.9 Hz), 9.81 (1H, s )

[Production Example 169-1-2] (6-amino-5-ethynylpyridin-2-yl) methanol

To the mixture of 2-amino-6-hydroxymethylpyridin-3-carbaldehyde (16 mg, 0.11 mmol) described in Production Example 169-1-1 and methanol (1.5 ml) at -10 ° C was added dimethyl- ( 1-diazo-2-oxopropyl) phosphonate (30 mg, 0.16 mmol) and potassium carbonate (23 mg, 0.17 mmol) and stirred at 0 ° C for 10 minutes and then additionally at room temperature for 6 hours . A saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride were added to the reaction mixture at the same temperature, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (13 mg, 47%, purity: 57%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.41 (1H, s), 4.60 (2H, s), 5.12 (2H, br s), 6.56 (1H d, J = 7.5 Hz), 7.56 (1H, d, J = 7.7 Hz).

[Example 170] 3- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -6-methylpyridin-2-ylamine

To a solution of 4-benzyloxyphenyl-acetohydroximoyl chloride (63 mg, 0.23 mmol) described in Production Example 1-1-3 and 3-ethynyl-6-methylpyridin-2-ylamine (20 mg, 0.15 mmol) described in Production Example 170-1-5, triethylamine (42 μl, 0.30 mmol) was added in tetrahydrofuran (2 ml) at room temperature and stirred at 50 ° C for 4 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1) and then further purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (26 mg, 34 %) in the form of a salt of trifluoroacetic acid.

MS m / e (ESI) (MH ⁺ ) 372.23 (MH ⁺ )

The starting material, 3-ethynyl-6-methylpyridin-2-ylamine, was synthesized as follows.

[Production Example 170-1-1] 2-amino-6-chloro-nicotinic acid ethyl ester

Concentrated sulfuric acid (10 ml) and 2-amino-6-chloronicotinic acid (6.3 g, 27 mmol, purity: 75%) described in Production Example 26-1-1 were added to ethanol (20 ml) in an ice bath. and stirred at 65 ° C overnight. The reaction solution was gradually cooled, after which an aqueous sodium hydrogen carbonate solution was added to neutralize the mixture. The precipitated solid was filtered to obtain the title compound (4.1 g, 74%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.38 (3H, t, J = 7.1 Hz), 4.34 (2H, q, J = 7.1 Hz), 6, 62 (1H, d, J = 8.1 Hz), 8.07 (1H, d, J = 8.1 Hz).

[Production Example 170-1-2] 2-amino-6-methyl-nicotinic acid ethyl ester

To a solution of 2-amino-6-chloro-nicotinic acid ethyl ester (2.00 g, 7.78 mmol) described in Production Example 170-1-1 in N- methylpyrrolidone (20 ml) was added tetramethyltin (1.62 ml, 11.7 mmol) and tetrakis (triphenylphosphine) palladium (0) (899 mg, 0.778 mmol) and stirred at 130 ° C. under nitrogen for 5 hours 40 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane: ethyl acetate = 3: 1) and then further purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (670 mg, 48%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 1.38 (3H, t, J = 7.1 Hz), 2.41 (3H, s), 4.33 (2H, q, J = 7.1 Hz), 6.49 (1H, d, J = 8.0 Hz), 8.03 (1H, d, J = 8.0 Hz).

[Production Example 170-1-3] (2-amino-6-methylpyridin-3-yl) methanol

To a solution of lithium aluminum hydride (706 mg, 14.9 mmol, purity: 80%) in tetrahydrofuran (12 ml) at 0 ° C was added 2-amino-6-methylnicotinic acid ethyl ester (670 mg, 3.72 mmol) described in Production Example 170-1-2, and stirred at room temperature for 30 minutes. Water (706 μl), 5N aqueous sodium hydroxide solution (706 μl) and water (2.12 ml) were added to the reaction mixture in the following order, the mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (379 mg, 74%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.38 (3H, s), 4.61 (2H, s), 5.08 (2H, s), 6.48 (1H, d , J = 7.2 Hz), 7.23 (1H, d, J = 7.2 Hz).

[Production Example 170-1-4] 2-amino-6-methylpyridin-3-carbaldehyde

To a solution of (2-amino-6-methylpyridin-3-yl) -methanol (379 mg, 2.74 mmol) described in Production Example 170-1-3, in methylene chloride (8 ml) was added manganese dioxide at room temperature ( IV) (1.19 mg, 13.7 mmol) and stirred at room temperature for 11 hours. The reaction solution was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 2) to obtain the title compound (328 mg, 88%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.44 (3H, s), 6.61 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.9 Hz), 9.80 (1H, s).

[Production Example 170-1-5] 3-ethynyl-6-methylpyridin-2-ylamine

To a solution of diisopropylamine (439 μl, 3.13 mmol) in tetrahydrofuran (5 ml) at -78 ° C under nitrogen atmosphere was added n- butyllithium (1.81 ml, 1.6 M hexane solution, 2.89 mmol) at 0 ° C for 15 minutes. Then, trimethylsilyldiazomethane (1.81 ml, 2 M tetrahydrofuran solution, 3.62 mmol) was added to the reaction mixture at -78 ° C and stirred at -78 ° C for 30 minutes. To the reaction mixture at -78 ° C was added 2-amino-6-methylpyridin-3-carbaldehyde (328 mg, 2.41 mmol), described in Production Example 170-1-4, in tetrahydrofuran (2 ml) and stirred for 25 minutes, slowly raising the temperature to -30 ° C. Acetic acid (414 ml, 7.23 mmol) was added to the reaction mixture at -78 ° C and the temperature was slowly raised, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (243 mg, 76%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 2.39 (3H, s), 3.38 (1H, s), 5.07 (2H, s), 6.49 (1H, d , J = 7.7 Hz), 7.47 (1H, d, J = 7.7 Hz).

[Example 171] 6-Methyl-3- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 3-ethynyl-6-methylpyridin-2-ylamine (20 mg, 0.15 mmol) described in Production Example 170-1-5, in tetrahydrofuran (2 ml), 4- (pyridin-2- iloxymethyl) phenylacetohydroximoyl chloride (63 mg, 0.23 mmol) described in Production Example 2-1-5 and triethylamine (42 μl, 0.30 mmol) and stirred at 50 ° C. for 2 hours 50 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1) and then further purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (29 mg, 32 %) in the form of a salt of trifluoroacetic acid.

MS m / e (ESI) (MH ⁺ ) 373.19 (MH ⁺ )

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.28 (3H, s), 4.00 (2H, s), 5.30 (2H, s), 6.17 (2H , c), 6.54 (1H, d, J = 7.9 Hz), 6.72 (1H, s), 6.83 (1H, d, J = 8.4 Hz), 6.95-6 98 (1H, m), 7.31 (2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.67-7.72 (1H, m), 7.75 (1H, d, J = 7.9 Hz), 8.14-8.15 (1H, m).

[Example 172] 5-Chloro-3- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a mixture of 3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine (10.0 mg, 0.03 mmol) described in Example 2 and N, N-dimethylformamide (1 ml) was added N-chlorosuccinimide (3.7 mg, 0.03 mmol) and stirred at room temperature for 2 hours. Then this mixture was stirred at 50 ° C for 1 hour and at room temperature for another 14 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (4.0 mg, 11%) as a ditrifluoroacetic acid salt .

¹ H-NMR spectrum (CD ₃ OD) δ (ppm): 4.08 (2H, s), 5.34 (2H, s), 6.69 (1H, s), 6.93 (1H, d, J = 8.4 Hz), 6.99-7.02 (1H, m), 7.33 (2H, d, J = 8.0 Hz), 7.42 (2H, d, J = 8 , 0 Hz), 7.75-7.79 (1H, m), 7.96 (1H, d, J = 2.4 Hz), 8.04 (1H, d, J = 2.8 Hz), 8.12-8.17 (1H, m).

MS m / e (ESI) 393.03 (MH ⁺ )

[Example 173] 3- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -5-fluoropyridin-2-ylamine

To a mixture of 3-ethynyl-5-fluoropyridin-2-ylamine (129 mg, 0.95 mmol) described in Production Example 173-1-2 and 4-benzyloxyphenyl acetohydroximoyl chloride (314 mg, 1.14 mmol) described in Production Example 1-1-3, in tetrahydrofuran (10 ml) triethylamine (264 μl, 1.90 mmol) was added at room temperature and stirred at 55 ° C for 1 hour and then at 60 ° C for one hour. This reaction mixture was cooled to room temperature and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (212 mg, 60%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.08 (2H, s), 6.24 (2H, br s), 6.90 (1H, s), 6.98 (2H, d, J = 8.0 Hz), 7.24 (2H, d, J = 8.8 Hz), 7.28-7.45 (5H, m) 7.83-7.90 (1H, m); 8.10-8.12 (1H, m).

The starting material, 3-ethynyl-5-fluoropyridin-2-ylamine, was synthesized as follows.

[Production Example 173-1-1] 5-fluoro-3-iodopyridin-2-ylamine

To a mixture of 2-amino-5-fluoropyridine (2.0 g, 17.8 mmol) and dimethyl sulfoxide (50 ml) was added N-iodosuccinimide (4.8 g, 21.4 mmol) and stirred at room temperature for 1 hour . The required amount of acetic acid was added to this mixture and stirred at the same temperature for 1 hour and then stirred at 55 ° C for another 3 hours. This reaction mixture was cooled to room temperature, after which a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (751 mg, 18%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.99 (2H, br s), 8.05 (1H, dt, J = 2.8, 8.0 Hz), 8 80-8.81 (1H, m).

[Production Example 173-1-2] 3-ethynyl-5-fluoropyridin-2-ylamine

To the mixture of 5-fluoro-3-iodopyridin-2-ylamine (751 mg, 3.16 mmol) described in Production Example 173-1-1, trimethylsilylacetylene (874 μl, 6.32 mmol), copper (I) iodide ( 60.2 mg, 0.32 mmol), N, N-diisopropylethylamine (1.07 ml, 6.32 mmol) and N-methylpyrrolidone (15 ml) were added tetrakis (triphenylphosphine) palladium (0) (183 mg, 0, 16 mM) and stirred at 70 ° C. under nitrogen for 3 hours. The resulting reaction solution was cooled to room temperature and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography and then silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (129 mg, 30%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.56 (1H, s), 6.13 (2H, br s), 7.56 (1H, dd, J = 3, 2, 8.8 Hz), 7.97 (1H, d, J = 3.2 Hz).

[Example 174] 5-Fluoro-3- (3- (4- (5-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To 4- (5- (2-amino-5-fluoropyridin-3-yl) -isoxazol-3-ylmethyl) -phenol (20.0 mg, 0.07 mmol) described in Production Example 174-1-1, tetrahydrofuran (3 ml) and a 5N aqueous sodium hydroxide solution (14.0 μl, 0.07 mmol) were added and dissolved by ultrasonic treatment for 1 minute. Then, the reaction solution was concentrated under reduced pressure to obtain a white solid. To a mixture of this solid and N, N-dimethylformamide (1 ml) was added a solution of 2-chloromethyl-5-fluoropyridine (11.2 mg, 0.08 mmol), described in Production Example 41-1-2, in N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. The reaction solution was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (24.7 mg, 89%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.98 (2H, s), 5.16 (2H, s), 6.25 (2H, br s), 6.91 (1H, s), 7.00 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.57-7.63 (1H, m) 7.77 (1H, dt, J = 2.8, 8.8 Hz), 7.87 (1H, dd, J = 2.8, 9.2 Hz), 8.12 (1H, d, J = 3.2 Hz), 8.58 (1H, d, J = 3.6 Hz).

The starting material, 4- (5- (2-amino-5-fluoropyridin-3-yl) -isoxazol-3-ylmethyl) phenol, was synthesized as follows.

[Production Example 174-1-1] 4- (5- (2-amino-5-fluoropyridin-3-yl) -isoxazol-3-ylmethyl) phenol

To a solution of 3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -5-fluoropyridin-2-ylamine (180 mg, 0.48 mmol) described in Example 173 in trifluoroacetic acid (5 ml) was added thioanisole (225 μl, 1.92 mmol) and stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to this reaction solution at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2 ~ ethyl acetate) to obtain the title compound (134.0 mg, 98%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.91 (2H, s), 6.24 (2H, br s), 6.71 (2H, d, J = 8, 8 Hz), 6.87 (1H, s), 7.10 (2H, d, J = 8.8 Hz), 7.86 (1H, dd, J = 2.8, 9.2 Hz), 8 11 (1H, d, J = 2.8 Hz); 9.32 (1H, br s).

[Example 175] 3- (3- (4- (4-Chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) -5-fluoropyridin-2-ylamine

Tetrahydrofuran (3 ml) and a 5N aqueous sodium hydroxide solution (14.0 μl, 0.07 mmol) were added to 4- (5- (2-amino-5-fluoropyridin-3-yl) -isoxazol-3-ylmethyl) - phenol (20.0 mg, 0.07 mmol), described in Production Example 174-1-1, and dissolved by sonication for 1 minute. Then, the reaction solution was concentrated under reduced pressure to obtain a white solid. To a mixture of this solid and N, N-dimethylformamide (1 ml) was added a solution of 4-chloromethyl-2-chloromethylpyridine (11.4 mg, 0.07 mmol), described in Production Example 51-1-2, in N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. The reaction solution was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (24.3 mg, 84%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.98 (2H, s), 5.18 (2H, s), 6.24 (2H, br s), 6.90 (1H, s), 7.01 (2H, d, J = 7.2 Hz), 7.26 (2H, d, J = 7.6 Hz), 7.50-7.54 (1H, m) 7.60-7.64 (1H, m), 7.85-7.89 (1H, m), 8.11-8.13 (1H, m), 8.55-8.57 (1H, m).

[Example 176] 5- (3- (4- (Pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 5-ethynylpyridin-2-ylamine (300 mg, 2.54 mmol) described in Production Example 28-1-3, tetrahydrofuran (2.0 ml) was added 4- (pyridin-2-yloxymethyl) phenylacetohydroximoyl chloride ( 1.05 g, 3.81 mmol) described in Production Example 2-1-5, and triethylamine (566 μl, 4.06 mmol) and stirred at 50 ° C. for 2 hours 40 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) and further purified by NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (196 mg, 22%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.96 (2H, s), 5.30 (2H, s), 6.47 (1H, dd, J = 0.73, 8.6 Hz), 6.50 (2H, s), 6.55 (1H, s), 6.83 (1H, d, J = 8.2 Hz), 6.95-6.98 (1H, m), 7.28 (2H, d, J = 8.1 Hz), 7.38 (2H, d, J = 8.1 Hz), 7.67-7.74 (2H, m), 8, 14-8.16 (1H, m), 8.36 (1H, d, J = 2.4 Hz).

[Example 177] 5- (3- (4- (Pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 4- (5- (6-aminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (150 mg, 0.561 mmol) described in Production Example 177-1-1 in tetrahydrofuran (3 ml) and acetone (3 ml) was added a 5N aqueous sodium hydroxide solution (112 μl, 0.561 mmol) and dissolved by ultrasonication for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a light brown sodium salt (in an amount of 162 mg). A solution of 2-picolyl chloride in tetrahydrofuran (obtained by adding a 5N aqueous solution of sodium hydroxide (13 μl, 62 μM) to a solution of 2-picolyl chloride (10 mg, 62 μM) and a saturated aqueous solution of sodium chloride (1 ml) in tetrahydrofuran (1 ml ), stirring for 1 minute and then separating the tetrahydrofuran layer) was added to a solution of the sodium salt obtained above (15 mg, 52 μM) in dimethyl sulfoxide (2 ml) and stirred at 65 ° C for 30 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 20: 1) to obtain the title compound (4.4 mg, 24%).

¹ H-NMR spectrum (CDCl ₃ ) δ (ppm): 3.97 (2H, s), 4.84 (2H, s), 5.20 (2H, s), 6.13 (1H, s ), 6.55 (1H, dd, J = 0.73, 8.6 Hz), 6.94-6.97 (2H, m), 7.19-7.24 (3H, m), 7, 52 (1H, d, J = 7.9 Hz), 7.71 (1H, dt, J = 1.8, 7.7 Hz), 7.78 (1H, dd, J = 2.4, 8, 6 Hz), 8.42 (1H, dd, J = 0.73, 2.4 Hz), 8.59-8.60 (1H, m).

The starting material, 4- (5- (6-aminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol, was synthesized as follows.

[Production Example 177-1-1] 4- (5- (6-aminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol

To a solution of 5- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine (270 mg, 0.755 mmol) described in Example 28 in trifluoroacetic acid (5 ml) at 0 ° C was added thioanisole (355 μl, 3.02 mmol) and stirred at room temperature for 1 hour 20 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (150 mg, 74%).

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.84 (2H, s), 6.51 (1H, d, J = 8.8 Hz), 6.53 (1H, s ), 6.57 (2H, s), 6.70 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz), 7.76 (1H, dd , J = 2.4, 8.8 Hz), 8.37 (1H, d, J = 2.4 Hz), 9.28 (1H, s).

[Example 178] 5- (3- (4- (5-Methylfuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the mixture of (4- (5-methylfuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride (38 mg, 0.14 mmol) described in Production Example 46-1-6 and tetrahydrofuran (1 ml) was added 5-ethynylpyridine- 2-ylamine (15 mg, 0.13 mmol), described in Production Example 28-1-3, and triethylamine (35 μl, 0.25 mmol), and stirred at 50 ° C. for 3.5 hours. The reaction solution was allowed to cool to room temperature and water was added to the system at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography on reverse phase HPLC (using a mobile phase containing 0.1% trifluoroacetic acid), whereupon the mixture obtained target product and the mobile phase was added triethylamine, thus making the mobile phase implicit Basic O and the eluate was concentrated under reduced pressure. The residue thus obtained was washed with water to obtain the title compound (5.1 mg, 12%).

MS m / e (ESI) 346.05 (MH ⁺ )

¹ H-NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.17 (3H, s), 3.86 (2H, s), 3.94 (2H, s), 5.93 (1H , c), 5.96 (1H, s), 6.49-6.57 (4H, m), 7.17 (2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.75 (1H, d, J = 7.1 Hz), 8.38 (1H, s).

[Example 179] 5- (3- (6-Benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

To the solution of (2-benzyloxypyridin-5-yl) -acetohydroximoyl chloride (191 mg, 0.690 mmol) described in Production Example 12-1-5, and 5-ethynylpyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Production Example 28-1-3, triethylamine (142 μl, 1.02 mmol) was added in tetrahydrofuran (7.00 ml) at room temperature under nitrogen atmosphere and stirred at 60 ° C for 3 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1 then 2: 1) to obtain the title compound (15.7 mg, 12.9%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.94 (2H, s), 5.33 (2H, s), 6.50 (1H, dd, J = 0.8, 8 8 Hz), 6.53 (2H, br.s), 6.61 (1H, s), 6.85 (1H, d, J = 8.4 Hz), 7.31-7.39 (3H , m), 7.42-7.45 (2H, m), 7.65 (1H, dd, J = 2.4, 8.4 Hz), 7.75 (1H, dd, J = 2.4 8.4 Hz), 8.14 (1H, d, J = 2.0 Hz), 8.38 (1H, d, J = 2.4 Hz).

[Example 180] 5- (3- (4- (Pyridin-4-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 4- (5- (6-aminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (150 mg, 0.561 mmol) described in Production Example 177-1-1 in tetrahydrofuran (3 ml) and acetone (3 ml) was added at room temperature a 5N aqueous sodium hydroxide solution (112 μl, 0.561 mmol) and dissolved by ultrasonication for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a light brown sodium salt (in an amount of 162 mg). A solution of 4-chloromethylpyridine in tetrahydrofuran (obtained by adding 5N aqueous sodium hydroxide solution (21 μl, 0.10 mmol) to a solution of 4-chloromethylpyridine hydrochloride (17 mg, 0.10 mmol) and a saturated aqueous solution of sodium chloride (1 ml) in tetrahydrofuran (1 ml), stirring for 1 minute and then separating the tetrahydrofuran layer) was added to a solution of the above sodium salt (15 mg, 52 μM) in dimethyl sulfoxide (1 ml) and stirred at room temperature for 2 hours and 15 minutes and then at 60 ° C for another hour. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (4.2 mg, 23%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.98 (2H, s), 4.88 (2H, s), 5.08 (2H, s), 6.13 (1H, s) 6.56 (1H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.4 Hz), 7 , 36 (2H, d, J = 5.5 Hz), 7.78 (1H, dd, J = 2.4, 9.0 Hz), 8.42 (1H, d, J = 2.4 Hz) 8.62 (2H, d, J = 6.0 Hz).

[Example 181] 5- (3- (6-Phenoxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-ylamine

To a solution of 5-ethynylpyridin-2-ylamine (30 mg, 0.25 mmol) described in Preparation Example 28-1-3, (2-phenoxyxypyridin-5-yl) -acetohydroximoyl chloride (100 mg) was added in tetrahydrofuran (2 ml) , 0.381 mmol) described in Production Example 40-1-4 and triethylamine (70.8 μl, 0.508 mmol) and stirred at 50 ° C. for 8 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (26 mg, 30%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 6.48 (1H, dd, J = 0.73, 8.6 Hz), 6.52 ( 2H, s), 6.61 (1H, s), 6.97 (1H, d, J = 8.4 Hz), 7.08-7.10 (2H, m), 7.16-7.20 (1H, m), 7.37-7.41 (2H, m), 7.72-7.77 (2H, m), 8.11 (1H, d, J = 2.2 Hz), 8, 37 (1H, dd, J = 0.73, 2.4 Hz).

[Example 182] 5- (3- (4- (5-Chlorofuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the mixture of (4- (5-chlorofuran-2-ylmethyl) phenyl) -acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Production Example 62-1-6 and tetrahydrofuran (1 ml) was added 5-ethynylpyridin-2- ylamine (8.0 mg, 0.068 mmol), described in Production Example 28-1-3, and triethylamine (19 μl, 0.14 mmol), and stirred at 50 ° C. for 1 hour. The reaction solution was allowed to cool to room temperature, and water was added to this system at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (1.6 mg, 4.9%) as a trifluoroacetic acid salt.

MS m / e (ESI) 366.09 (MH ⁺ )

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.93 (2H, s), 3.98 (2H, s), 6.24-6.25 (1H, m), 6, 34-6.35 (1H, m), 6.71 (1H, s), 6.76 (1H, d, J = 8.6 Hz), 7.20 (2H, d, J = 7.9 Hz ), 7.25 (2H, d, J = 7.9 Hz), 8.00 (1H, d, J = 8.6 Hz), 8.42 (1H, d, J = 2.4 Hz).

[Example 183] 5- (3- (4- (4-Chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To 4- (5-6-aminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (20.0 mg, 0.07 mmol) described in Production Example 177-1-1, tetrahydrofuran (3 ml) was added. ) and a 5N aqueous sodium hydroxide solution (14.9 μl, 0.07 mmol) and were dissolved by sonication for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a mixture of the solid obtained above and N, N-dimethylformamide (1 ml) was added a solution of 4-chloro-2-chloromethylpyridine (13.3 mg, 0.08 mmol), described in Production Example 51-1-2, in N, N-dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. The reaction solution was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (7.2 mg, 25%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.89 (2H, s), 5.15 (2H, s), 6.47 (1H, d, J = 8.8 Hz) 6.50 (2H, br s), 6.53 (1H, s), 6.85 (1H, s), 6.98 (2H, d, J = 8.4 Hz), 7.21 ( 2H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 2.4, 5.2 Hz), 7.72 (1H, dd, J = 2.4, 8.4 Hz ), 8.35 (1H, d, J = 2.4 Hz), 8.54 (1H, d, J = 5.2 Hz).

[Example 184] 5- (3- (4- (5-Fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To 4- (5- (6-aminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (20.0 mg, 0.07 mmol) described in Production Example 177-1-1, tetrahydrofuran (3 ml) and a 5N aqueous solution of sodium hydroxide (14.9 μl, 0.07 mmol) and were dissolved by sonication for 1 minute. The reaction solution was concentrated under reduced pressure to obtain a white solid. To a mixture of the solid obtained above and N, N-dimethylformamide (1 ml) was added 2-chloromethyl-5-fluoropyridine (12.0 mg, 0.08 mmol), described in Production Example 41-1-2, in N, N -dimethylformamide (1 ml) and stirred at 60 ° C for 1 hour. The reaction solution was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (3.0 mg, 11%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 3.96 (2H, s), 4.73 (2H, br s), 5.16 (2H, s), 6.12 (1H, c), 6.52 (1H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.20 (2H, d, J = 8.8 Hz) 7.42 (1H, dt, J = 2.8, 8.4 Hz), 7.49-7.55 (1H, m), 7.75 (1H, m), 8.42-8.44 (2H, m).

[Example 185] 5- (3- (6- (2-Fluorophenoxyxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine

To a mixture of (6- (2-fluorophenoxy) pyridin-3-yl) -acetohydroximoyl chloride (28 mg) described in Production Example 74-1-4 and tetrahydrofuran (1 ml) was added 5-ethynylpyridin-2-ylamine (9 , 0 mg, 0.076 mmol), described in Production Example 28-1-3, and triethylamine (21 μl, 0.15 mmol) and stirred at 50 ° C. for 5 hours. The reaction solution was allowed to cool to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (4.6 mg, 17%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.98 (2H, s), 4.73 (2H, br s), 6.14 (1H, s), 6.54 (1H, dd, J = 0.7, 8.6 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.14-7.26 (4H, m), 7.63 (1H, dd , J = 2.6, 8.4 Hz), 7.76 (1H, dd, J = 2.4, 8.6 Hz), 8.08 (1H, dd, J = 0.6, 2.5 Hz), 8.45 (1H, d, J = 2.4 Hz).

[Example 186] 5- (3- (6- (4-Fluorophenoxyxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine

To the mixture of (6- (4-fluorophenoxy) pyridin-3-yl) -acetohydroximoyl chloride (25 mg) described in Production Example 75-1-4 and tetrahydrofuran (1 ml) was added 5-ethynylpyridin-2-ylamine (6 , 0 mg, 0.051 mmol), described in Production Example 28-1-3, and triethylamine (14 μl, 0.10 mmol) and stirred at 50 ° C. for 5 hours. The reaction solution was allowed to cool to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (3.5 mg, 19%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.98 (2H, s), 4.72 (2H, br s), 6.15 (1H, s), 6.54 (1H, dd, J = 0.7, 8.6 Hz), 6.88 (1H, d, J = 8.6 Hz), 7.05-7.12 (4H, m), 7.62 (1H, dd , J = 2.6, 8.4 Hz), 7.77 (1H, dd, J = 2.2, 8.6 Hz), 8.12 (1H, d, J = 2.6 Hz), 8 45 (1H, d, J = 2.4 Hz).

[Example 187] 6-Methyl-5- (3- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To the mixture of (4- (pyridin-2-yloxymethyl) phenyl) -acetohydroximoyl chloride (55 mg, 0.20 mmol) described in Production Example 2-1-5 and tetrahydrofuran (1 ml) was added 5-ethynyl-6- methylpyridin-2-ylamine (20 mg, 0.15 mmol) described in Production Example 187-1-2 and triethylamine (43 μl, 0.31 mmol) and stirred for 2 hours at 50 ° C. The reaction solution was allowed to cool to room temperature and water was added to it at the same temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2) to obtain the title compound (35 mg, 61%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 2.52 (3H, s), 4.06 (2H, s), 4.64 (2H, br.s), 5.36 (2H, c), 6.05 (1H, s), 6.40 (1H, d, J = 8.4 Hz), 6.79-6.81 (1H, m), 6.87-6.90 (1H , m), 7.31 (2H, d, J = 8.1 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.56-7.60 (1H, m), 7 74 (1H, d, J = 8.4 Hz), 8.16-8.18 (1H, m).

The starting material, 5-ethynyl-6-methylpyridin-2-ylamine, was synthesized as follows.

[Production Example 187-1-1] 6-methyl-5-trimethylsilanylethynylpyridin-2-ylamine

To a mixture of 6-amino-3-bromo-2-methylpyridine (200 mg, 1.0 mmol), trimethylsilylacetylene (0.22 ml, 1.6 mmol), copper (I) iodide (9.9 mg, 0.052 mmol) and 1,4-dioxane (1.5 ml) was added bis (triphenylphosphine) palladium (II) chloride (73 mg, 0.10 mmol) and stirred under a nitrogen atmosphere for 3 hours and at 100 ° C for 30 minutes. The reaction solution was allowed to cool to room temperature, water, ethyl acetate were added to the reaction mixture at the same temperature, and the mixture was filtered through a celite pad. The organic layer of the filtrate was separated and washed with a saturated aqueous solution of sodium chloride, concentrated under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (140 mg, 57%, purity: 86%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 0.24 (9H, s), 2.50 (3H, s), 4.59 (2H, br s), 6.26 (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 8.4 Hz).

[Production Example 187-1-2] 5-ethynyl-6-methylpyridin-2-ylamine

To a mixture of 6-methyl-5-trimethylsilanylethinylpyridin-2-ylamine (450 mg, 1.9 mmol) described in Production Example 187-1-1 and methanol (5 ml) was added potassium carbonate (390 mg, 2.8 mmol) ) and stirred at the same temperature for 30 minutes. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (220 mg, 88%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 2.52 (3H, s), 3.24 (1H, s), 4.58 (2H, br.s), 6.29 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.4 Hz).

[Example 188] 5- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -6-methylpyridin-2-ylamine

To a mixture of 4-benzyloxyphenylacetohydroximoyl chloride (59 mg, 0.21 mmol) described in Production Example 1-1-3 and tetrahydrofuran (1 ml) was added 5-ethynyl-6-methylpyridin-2-ylamine (22 mg, 0.16 mM) described in Production Example 187-1-2 and triethylamine (46 μl, 0.33 mmol) and stirred at 50 ° C. for 2 hours. The reaction solution was allowed to cool to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2) to obtain the title compound (35 mg, 57%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 2.52 (3H, s), 3.99 (2H, s), 4.60 (2H, br s), 5.05 (2H, c), 6.04 (1H, s), 6.39-6.41 (1H, m), 6.92-6.96 (2H, m), 7.19-7.23 (2H, m) 7.30-7.44 (5H, m); 7.75 (1H, d, J = 8.4 Hz).

[Example 189] 3- (5- (4- (Pyridin-2-ylmethoxy) benzyl) isoxazol-3-yl) pyridin-2-ylamine

To a solution of 5-chloro-3- (5- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-3-yl) pyridin-2-ylamine (141 mg, 0.359 mmol) described in Example 189- 1-2 preparation, tetrakis (triphenylphosphine) palladium (0) (42 mg, 36 μM), formic acid (20 μl, 0.58 mmol) and N, N-diisopropylethylamine (193 μl) were added in N- methylpyrrolidone (4 ml) 1.08 mM) and stirred under nitrogen for 5 hours and at 100 ° C for 35 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) and then further purified by NH silica gel column chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound (8.3 mg , 6.5%).

MS m / e (ESI) (MH ⁺ ) 359.24 (MH ⁺ )

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.07 (2H, s), 5.21 (2H, s), 6.24 (1H, s), 6.25 (2H, s) 6.66 (1H, dd, J = 4.9, 7.7 Hz), 6.96-7.00 (2H, m), 7.20-7.25 (3H, m), 7.52 (1H, d, J = 7.9 Hz), 7.64 (1H, dd, J = 1.7, 7.5 Hz), 7.72 (1H, dt, J = 1.8, 7.7 Hz), 8.11 (1H, dd, J = 1.7, 4.8 Hz), 8.59-8.61 (1H, m).

The starting material, 5-chloro-3- (5- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-3-yl) pyridin-2-ylamine, was synthesized as follows.

[Production Example 189-1-1] 4- (3- (2-amino-5-chloropyridin-3-yl) -isoxazol-5-ylmethyl) phenol

To a solution of 3- (5- (4-benzyloxybenzyl) -isoxazol-3-yl) -5-chloropyridin-2-ylamine (304 mg, 0.776 mmol) described in Production Example 29-2-3 in trifluoroacetic acid (6 ml) at 0 ° C, thioanisole (364 ml, 3.10 mmol) was added and stirred at room temperature for 3 hours. Sodium hydrogen carbonate and water were added to this reaction mixture at 0 ° C. and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 20: 1) to obtain the title compound (146 mg, 62%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.07 (2H, s), 6.74 (2H, d, J = 8.4 Hz), 6.98 (1H, s) 7.07 (2H, s), 7.12 (2H, d, J = 8.4 Hz), 8.09 (1H, d, J = 2.6 Hz), 8.13 (1H, d, J = 2.6 Hz), 9.36 (1H, s).

[Production Example 189-1-2] 5-chloro-3- (5- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-3-yl) pyridin-2-ylamine

To a solution of 4- (3- (2-amino-5-chloropyridin-3-yl) -isoxazol-5-ylmethyl) phenol (146 mg, 0.484 mmol) described in Production Example 189-1-1 in tetrahydrofuran ( 4 ml), a 5N aqueous sodium hydroxide solution (96.8 μl, 0.484 mmol) was added at room temperature and dissolved by ultrasonic treatment for 1 minute. The reaction solution was concentrated under reduced pressure to obtain the sodium salt. A solution of 2-picolyl chloride in tetrahydrofuran (obtained by adding a 5N aqueous solution of sodium hydroxide (242 μl, 1.21 mmol) to a solution of 2-picolyl chloride (198 mg, 1.21 μM) in tetrahydrofuran (2 ml) and water (2 ml ), stirring for 1 minute and subsequent separation of the tetrahydrofuran layer) was added at room temperature to a solution of the sodium salt obtained above in N, N-dimethylformamide (5 ml) and stirred at 60 ° C for 2 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (141 mg, 74%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.08 (2H, s), 5.22 (2H, s), 6.22 (1H, s), 6.25 (2H, s) 6.99 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.26-7.31 (1H, m), 7.54 ( 1H, d, J = 6.4 Hz), 7.60 (1H, d, J = 2.4 Hz), 7.73 (1H, dt, J = 1.8, 7.9 Hz), 8, 07 (1H, d, J = 2.4 Hz), 8.61 (1H, d, J = 4.9 Hz).

[Example 190] 2-Methyl-5- (3- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridine

To a solution of 5-ethynyl-2-methylpyridine (10 mg, 85 μM) described in Production Example 190-1-1, 4- (pyridin-2-yloxymethyl) phenylacetohydroximoyl chloride (31 mg, 0) was added in tetrahydrofuran (2 ml). , 11 mM), described in Production Example 2-1-5, and triethylamine (18 μl, 0.13 mmol) and stirred at 50 ° C. for 2 hours and 30 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 1: 1) to obtain the title compound (14 mg, 46%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 2.52 (3H, s), 4.05 (2H, s), 5.32 (2H, s), 6.85 (1H, d, J = 8.2 Hz), 6.96 (1H, s), 6.98 (1H, dd, J = 5.1, 6.6 Hz), 7.33 (2H, d, J = 8 , 1 Hz), 7.39-7.43 (3H, m), 7.69-7.74 (1H, m), 8.10 (1H, dd, J = 2.2, 8.1 Hz) 8.17 (1H, dd, J = 2.0, 5.1 Hz); 8.91 (1H, d, J = 2.2 Hz).

The starting material, 5-ethynyl-2-methylpyridine, was synthesized as follows.

[Production Example 190-1-1] 5-ethynyl-2-methylpyridine

To a solution of 5-bromo-2-methylpyridine (1.00 g, 5.81 mmol) in N- methylpyrrolidone (20 ml) was added trimethylsilylacetylene (1.23 ml, 8.72 mmol), tetrakis (triphenylphosphine) palladium (0) (134 mg, 0.116 mmol), copper (I) iodide (44.3 mg, 0.232 mmol) and N, N-diisopropylethylamine (2.02 ml, 11.6 mmol) and stirred at room temperature under nitrogen for 13 hours. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 5: 1) to obtain a mixture (656 mg) of 5-bromo-2-methylpyridine and 2-methyl-5-trimethylsilanylethinylpyridine. To a solution of this mixture (656 mg) in methanol (10 ml) was added potassium carbonate (956 mg, 6.92 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction mixture at room temperature and extracted with diethyl ether. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. 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 (166 mg, 25%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 2.57 (3H, s), 3.17 (1H, s), 7.12 (1H, d, J = 8.1 Hz), 7 66 (1H, dd, J = 2.0, 8.1 Hz); 8.61 (1H, d, J = 1.8 Hz).

[Example 191] 3- (1- (6-Benzyloxypyridin-3-ylmethyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2-ylamine (20.0 mg, 0.125 mmol) described in Production Example 32-1-4 in N, N-dimethylformamide (5.00 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (5.50 g, 0.138 mmol, 60% in oil) and stirred at room temperature for 30 minutes. Then, 2-benzyloxy-5-chloromethylpyridine (49.7 mg, 0.213 mmol) described in Preparation Example 191-1-2 was added to this mixture, and stirred at room temperature for 30 minutes. This mixture was partitioned into ethyl acetate and water at room temperature. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 then ethyl acetate) to obtain the title compound (31.3 mg, 70.1%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.30 (2H, s), 5.34 (2H, s), 5.61 (2H, br s), 6.61 ( 1H, dd, J = 4.8, 7.2 Hz), 6.87 (1H, d, J = 8.0 Hz), 7.31-7.39 (3H, m), 7.42-7 44 (2H, m), 7.48 (1H, dd, J = 1.6, 7.2 Hz), 7.72 (1H, dd, J = 2.4, 8.4 Hz), 7, 75 (1H, d, J = 0.8 Hz), 8.87 (1H, dd, J = 2.0, 4.8 Hz), 8.18 (1H, d, J = 0.8 Hz), 8.20 (1H, d, J = 2.8 Hz).

The starting material, 2-benzyloxy-5-chloromethylpyridine, was synthesized as follows.

[Production Example 191-1-1] (6-Benzyloxypyridin-3-yl) -methanol

To a solution of 6-benzyloxypyridine-3-carbaldehyde (2.00 g, 9.38 mmol), described in Production Example 12-1-2, in methanol (20.0 ml) in an ice bath (0 ° C) in a nitrogen atmosphere sodium borohydride (426 mg, 11.3 mmol) was added and stirred at room temperature for 10 minutes. Water was added to the reaction solution at room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.84 g, 91.1%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 4.55 (2H, s), 5.39 (2H, s), 6.82 (1H, d, J = 8.4 Hz), 7 30-7.45 (5H, m), 7.63-7.66 (1H, m), 8.16 (1H, d, J = 2.4 Hz).

[Production Example 191-1-2] 2-Benzyloxy-5-chloromethylpyridine

To a solution of (6-benzyloxypyridin-3-yl) methanol (1.80 g, 8.36 mmol) described in Production Example 191-1-1 in dichloromethane (4.00 ml) in an ice bath (0 ° C ) thionyl chloride (732 μl, 10.0 mmol) was added dropwise under nitrogen atmosphere and stirred at room temperature for 5 minutes. An aqueous sodium bicarbonate solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.70 g, 87.0%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 4.60 (2H, s), 5.37 (2H, s), 6.80 (1H, d, J = 8.4 Hz), 7 31-7.46 (5H, m), 7.61-7.63 (1H, m), 8.11 (1H, d, J = 2.4 Hz).

[Example 192] 3- (1- (4- (Pyridin-2-ylmethoxy) benzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine

2- (4-Chloromethylphenoxymethyl) -pyridine was obtained according to methods similar to the methods of production example 199-1-1 and production example 199-1-2, using 4- (pyridine -2-ylmethoxy) benzaldehyde described in example 203-1 -1 receipt.

To a solution of 3- (1 H -pyrazol-4-yl) -pyridin-2-ylamine (20.0 mg, 0.125 mmol) described in Production Example 32-1-4 in N, N-dimethylformamide (5.00 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (5.50 mg, 0.138 mm, 60% in oil) and stirred at room temperature for 30 minutes. Then, 2- (4-chloromethylbenzyloxy) -pyridine (49.7 mg, 0.213 mmol) described in Production Example 30-1-1 was added to the above mixture, stirred at room temperature for 30 minutes and partitioned into ethyl acetate at room temperature and water. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 then ethyl acetate) to obtain the title compound (21.9 mg, 49.0%).

2- (4-Chloromethylphenoxymethyl) pyridine

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.56 (2H, s), 5.21 (2H, s), 6.95-6.99 (2H, m), 7.21- 7.23 (1H, m), 7.29-7.32 (2H, m), 7.49-7.51 (1H, m), 7.69-7.73 (1H, m), 8, 59-8.61 (1H, m).

Title Compound

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.16 (2H, s), 5.26 (2H, s), 5.59 (2H, br s), 6.61 ( 1H, dd, J = 5.2, 7.2 Hz), 6.99-7.02 (2H, m), 7.26-7.29 (2H, m), 7.32-7.35 ( 1H, m), 7.46-7.50 (2H, m), 7.74 (1H, s), 7.80-7.84 (1H, m), 7.84-7.87 (1H, m), 8.13 (1H, d, J = 1.2 Hz), 8.55-8.58 (1H, m).

[Example 193] 3- (1- (6-Phenoxypyridin-3-ylmethyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine

To a solution of 3- (1 H -pyrazol-4-yl) -pyridin-2-ylamine (20.0 mg, 0.125 mmol) described in Production Example 32-1-4 in N, N-dimethylformamide (5.00 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (5.50 mg, 0.138 mmol, 60% in oil) and stirred at room temperature for 10 minutes. Then, 5-chloromethyl-2-phenoxyxypyridine (49.7 mg, 0.226 mmol) described in Preparation Example 193-1-2 was added to the above mixture, and stirred at room temperature for 30 minutes. The reaction solution at room temperature was partitioned into ethyl acetate and water. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 then ethyl acetate) to obtain the title compound (25.0 mg, 58.2%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.34 (2H, s), 5.62 (2H, br s), 6.61 (1H, dd, J = 4.8 , 7.6 Hz), 7.01 (1H, d, J = 8.4 Hz), 7.10-7.12 (2H, m), 7.19-7.23 (1H, m), 7 , 39-7.43 (2H, m), 7.48 (1H, dd, J = 2.0, 7.2 Hz), 7.67 (1H, s), 7.83 (1H, dd, J = 2.4, 8.4 Hz), 7.87 (1H, dd, J = 2.0, 5.2 Hz), 8.16 (1H, d, J = 2.8 Hz), 8.19 (1H, s).

The starting material, 5-chloromethyl-2-phenoxyxypyridine, was synthesized as follows.

[Production Example 193-1-1] (6-phenoxypyridin-3-yl) -methanol

To a solution of 5-bromo-2-phenoxyxypyridine (1.02 g, 4.08 mmol) described in Production Example 40-1-1 in diethyl ether (30.0 ml) in a bath with a mixture of dry ice-ethanol (- 78 ° C) in a nitrogen atmosphere, n- butyllithium (2.55 M n -hexane solution, 1.92 ml, 4.90 mmol) was added dropwise and stirred at -78 ° C for 30 minutes. Then, N, N-dimethylformamide (378 μl, 4.90 mmol) was added dropwise thereto and stirred at -78 ° C for 10 minutes. Then sodium borohydride (309 mg, 8.16 mmol) and methanol (15.0 ml) were added and stirred at room temperature for 20 minutes. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 1) to obtain the title compound (2.93 g, 66.5%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 4.62 (2H, s), 6.88 (1H, d, J = 8.4 Hz), 7.10-7.13 (2H, m), 7.18-7.22 (1H, m), 7.37-7.41 (2H, m), 7.70-7.73 (1H, m), 8.12-8.13 ( 1H, m).

[Production Example 193-1-2] 5-chloromethyl-2-phenoxyxypyridine

To the solution of (6-phenoxyxypyridin-3-yl) methanol (458 mg, 2.28 mmol) described in Production Example 193-1-1 in dichloromethane (5.00 ml) in an ice bath (0 ° C) in thionyl chloride (333 μl, 4.56 mmol) was added dropwise under nitrogen atmosphere and stirred at room temperature for 5 minutes. An aqueous sodium bicarbonate solution was added to the reaction solution at room temperature and was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (450 mg, 89.8%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 4.55 (2H, s), 6.91 (1H, d, J = 8.8 Hz), 7.12-7.15 (2H, m), 7.20-7.24 (1H, m), 7.38-7.43 (2H, m), 7.72-7.75 (1H, m), 8.17 (1H, d, 2.4 Hz).

[Example 194] 3- (1- (4-Prop-2-yniloxymethylbenzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine

To a mixture of 3- (1 H- pyrazol-4-yl) -pyridin-2-ylamine (30 mg, 0.19 mmol) described in Production Example 32-1-4 and tetrahydrofuran (1 ml) at 0 ° C sodium hydride (12 mg, 0.24 mmol, 50% in oil) was added, and then N, N-dimethylformamide (1 ml) was added. The reaction solution was stirred at room temperature for 10 minutes, after which 1-chloromethyl-4-prop-2-yniloxymethylbenzene (47 mg, 0.24 mmol) was added to this mixture at 0 ° C, as described in Example 194-1-2 receiving, and stirred at room temperature for 2 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 4: 1) to obtain the title compound (37 mg, 62%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 2.47 (1H, t, J = 2.4 Hz), 4.18 (2H, d, J = 2.4 Hz), 4.56 (2H, br.s), 4.61 (2H, s), 5.35 (2H, s), 6.70 (1H, dd, J = 5.0, 7.4 Hz), 7.28 ( 2H, d, J = 8.2 Hz), 7.36-7.40 (3H, m), 7.58 (1H, d, J = 0.7 Hz), 7.74 (1H, d, J = 0.9 Hz), 8.01 (1H, dd, J = 1.8, 4.9 Hz).

The starting material, 1-chloromethyl-4-prop-2-yniloxymethylbenzene, was synthesized as follows.

[Production Example 194-1-1] (4-prop-2-yniloxymethylphenyl) methanol

To a mixture of sodium hydride (400 mg, 8.4 mmol, 50% in oil) and tetrahydrofuran (30 ml) at 0 ° C was added 1,4-benzenedimethanol (2.3 g, 17 mmol), and then N, N- dimethylformamide (30 ml). The reaction solution was stirred at room temperature for 10 minutes, after which propargyl bromide (1.0 g, 8.4 mmol) was added dropwise to the reaction mixture. The reaction solution was stirred at room temperature for 1 hour, after which water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by NH silica gel column chromatography (heptane: ethyl acetate = 3: 2) to obtain the title compound (860 mg, 58%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 1.64 (1H, t, J = 6.0 Hz), 2.47 (1H, t, J = 2.4 Hz), 4.18 (2H, d, J = 2.4 Hz), 4.62 (2H, s), 4.70 (2H, d, J = 5.9 Hz), 7.37 (4H, s).

[Production Example 194-1-2] 1-chloromethyl-4-prop-2-yniloxymethylbenzene

A mixture of (4-prop-2-yniloxymethylphenyl) methanol (190 mg, 1.1 mmol) described in Production Example 194-1-1, triphenylphosphine (340 mg, 1.3 mmol) and carbon tetrachloride (3 ml) was stirred for 6 hours in a flask with a reflux condenser. The reaction solution was cooled to room temperature, after which the reaction solution was concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate: heptane = 1: 10) to obtain the title compound (180 mg, 84%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 2.47 (1H, t, J = 2.4 Hz), 4.18 (2H, d, J = 2.4 Hz), 4.59 (2H, s), 4.62 (2H, s), 7.35-7.40 (4H, m).

[Example 195] 3- (1- (4-Cyclopropylmethoxymethylbenzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine

To a mixture of 3- (1- (4-bromobenzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine (24 mg, 0.073 mmol) described in Production Example 195-1-1, and 1.4 -dioxane (1.5 ml) was added at room temperature water (150 μl), cesium carbonate (95 mg, 0.29 mmol), cyclopropylmethoxymethyl trifluoroborate sodium (19 mg, 0.11 mmol) described in Production Example 195-2-2 palladium (II) acetate (1.6 mg, 0.0073 mmol) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (4.5 mg, 0,0073 mmol) and stirred at 100 ° C under nitrogen for 6 hours. The reaction solution was cooled to room temperature, after which water and ethyl acetate were added, and the mixture was filtered through a celite pad. The organic layer of the filtrate was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography on reverse phase HPLC (using a mobile phase containing 0.1% trifluoroacetic acid), whereupon the mixture obtained target product and the mobile phase was added triethylamine, thus making the mobile phase Basic O implicit, and the solvent was evaporated under reduced pressure. The residue thus obtained was filtered through NH silica gel (ethyl acetate) to obtain the title compound (1.6 mg, 6.6%).

MS m / e (ESI) 335.30 (MH ⁺ )

The starting material, 3- (1- (4-bromobenzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine, was synthesized as follows.

[Production Example 195-1-1] 3- (1- (4-bromobenzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine

To a mixture of 3- (1 H- pyrazol-4-yl) -pyridin-2-ylamine (150 mg, 0.94 mmol) described in Production Example 32-1-4 and tetrahydrofuran (2 ml) at 0 ° C sodium hydride (12 mg, 0.24 mmol, 50% in oil) was added and then N, N-dimethylformamide (2 ml) was added. The reaction solution was stirred at room temperature for 10 minutes, after which 4-bromobenzyl bromide (260 mg, 1.0 mmol) was added to this mixture at 0 ° C and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 4: 1) to obtain the title compound (270 mg, 86%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 4.55 (2H, br s), 5.30 (2H, s), 6.71 (1H, ddd, J = 0.7, 4 9, 7.3 Hz), 7.16 (2H, d, J = 8.6 Hz), 7.40 (1H, dd, J = 1.7, 7.3 Hz), 7.50 (2H d, J = 8.4 Hz), 7.60 (1H, s), 7.75 (1H, s), 8.02 (1H, dd, J = 1.7, 4.9 Hz).

The starting material, sodium cyclopropylmethoxymethyl trifluoroborate, was synthesized as follows.

[Production Example 195-2-1] 2- (Bromomethyl) -4,4,5,5-tetramethyl-1,3,2-dioxoborolan

To a mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 ml, 120 mmol) and tetrahydrofuran (150 ml) at -78 ° C was added dropwise n- butyllithium (2.6 M n -hexane solution, 39 ml , 100 mmol) for more than 1.5 hours and then the reaction mixture was stirred at the same temperature for 1.5 hours. This mixture was then stirred at room temperature for another 2 hours, after which it was cooled to 0 ° C, methanesulfonic acid (6.5 ml, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C, pinacol (12 g, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, after which the residue thus obtained was distilled under reduced pressure (74-76 ° C, 8 mmHg) to obtain the title compound (16 g).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 1.29 (12H, s), 2.59 (2H, s).

[Production Example 195-2-2] Sodium cyclopropylmethoxymethyl trifluoroborate

To a mixture of sodium hydride (430 mg, 12 mmol, 66% in oil) and tetrahydrofuran (20 ml) at 0 ° C cyclopropylmethanol (1.2 ml, 15 mmol) was added and stirred at room temperature for 30 minutes. To the reaction mixture at 0 ° C was added 2-bromomethyl) -4,4,5,5-tetramethyl-1,3,2-dioxoborolan (2.0 g, 9.1 mmol) described in Example 195-2-1 receiving, and stirred at room temperature for 1 hour, then at 45 ° C for another 4 hours. The reaction solution was cooled to 0 ° C, sodium hydrogen fluoride (2.2 g, 36 mmol) was added, then at the same temperature water (15 ml) was added dropwise to the reaction mixture. The reaction solution was warmed to room temperature, after which the solvent was evaporated under reduced pressure. To the thus obtained residue, acetone (100 ml) and methanol (1 m) were added, the mixture was heated and then gradually cooled to about 40 ° C and then filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain the title compound (1.2 g).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.05-0.09 (2H, m), 0.35-0.40 (2H, m), 0.86-0.96 (1H, m), 2.46 (2H, q, J = 5.6 Hz), 3.00 (2H, d, J = 6.8 Hz).

[Example 196] 3- (1- (4-Ethoxymethylbenzyl) -1 H -pyrazol-4-yl) pyridin-2-ylamine

To a mixture of 3- (1- (4-bromobenzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine (24 mg, 0.073 mmol) described in Production Example 195-1-1, and 1.4 -dioxane (1.5 ml) was added at room temperature water (150 μl), cesium carbonate (95 mg, 0.29 mmol), potassium ethoxymethyl trifluoroborate (18 mg, 0.11 mmol) described in Example 196-1-2 production, palladium (II) acetate (1.6 mg, 0.0073 mmol) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (4.5 mg, 0,0073 mmol) and stirred at 100 ° C. under nitrogen for 6 hours. The reaction solution was cooled to room temperature, after which water and ethyl acetate were added, then the mixture was filtered through a celite pad. The organic layer of the filtrate was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.2 mg, 17%) as a trifluoroacetic acid salt.

MS m / e (ESI) 309.29 (MH ⁺ )

The starting material, potassium ethoxymethyl trifluoroborate, was synthesized as follows.

[Production Example 196-1-1] Tributylethoxymethyltin

To a mixture of diisopropylamine (2.1 ml, 15 mmol) and tetrahydrofuran (30 ml) at -78 ° C was added dropwise n- butyllithium (2.4 M n -hexane solution, 5.0 ml, 12 mmol) and then the reaction the mixture was stirred for 30 minutes. Tributyltin hydride (3.3 ml, 12 mmol) was added dropwise to this mixture at -78 ° C, and then the reaction mixture was stirred at 0 ° C for 40 minutes. The reaction solution was cooled to -78 ° C, after which ethoxymethyl chloride (1.1 ml, 12 mmol) was added dropwise to the reaction mixture. The reaction solution was warmed to room temperature and diethyl ether and an aqueous solution of ammonium chloride were added to this reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride, after which the organic layer was concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane: diethyl ether = 30: 1) to obtain the title compound (2.8 g, 66%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 0.87-0.92 (15H, m), 1.16 (3H, t, J = 7.0 Hz), 1.26-1, 35 (6H, m), 1.43-1.55 (6H, m), 3.36 (2H, q, J = 7.0 Hz), 3.74 (2H, t, J = 6.5 Hz )

[Production Example 196-1-2] Potassium Ethoxymethyl Trifluoroborate

To a mixture of tributylethoxymethyltin (1.0 g, 2.9 mmol) described in Production Example 196-1-1 and tetrahydrofuran (10 ml) at -78 ° C was added n- butyllithium (1.5 M n solution) dropwise hexane, 2.0 ml, 3.2 mmol) and then the reaction mixture was stirred at the same temperature for 30 minutes. To the mixture of triisopropyl borate (0.73 ml, 3.2 mmol) and tetrahydrofuran (10 ml) at −78 ° C., the reaction mixture was added dropwise using a cannula. The reaction solution was stirred at room temperature for 30 minutes. Potassium hydrogen fluoride (1.3 g, 17 mmol) was added to this mixture at 0 ° C, and then water (10 ml) was added dropwise. The reaction solution was warmed to room temperature, after which the reaction mixture was concentrated under reduced pressure. The residue thus obtained was washed with diethyl ether (50 ml). Acetone (100 ml) was added to the residue, then the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from acetonitrile to obtain the title compound (150 mg, 32%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 0.99 (3H, t, J = 7.0 Hz), 2.42 (2H, q, J = 5.6 Hz), 3 18 (2H, q, J = 7.0 Hz).

[Example 197] 3- (1- (4-Cyclobutoxymethylbenzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine

To a mixture of 3- (1- (4-bromobenzyl) -1 H -pyrazol-4-yl) -pyridin-2-ylamine (24 mg, 0.073 mmol) described in Production Example 195-1-1, and 1.4 -dioxane (1.5 ml) was added at room temperature water (150 μl), cesium carbonate (95 mg, 0.29 mmol), potassium cyclobutoxymethyl trifluoroborate (21 mg, 0.11 mmol) described in Production Example 197-1-2 palladium (II) acetate (1.6 mg, 0.0073 mmol) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (4.5 mg, 0,0073 mmol) and stirred at 100 ° C under nitrogen for 6 hours. The reaction solution was cooled to room temperature, after which water and ethyl acetate were added, and the mixture was filtered through a celite pad. The organic layer of the filtrate was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.2 mg, 16%) as a trifluoroacetic acid salt.

MS m / e (ESI) 335.19 (MH ⁺ )

The starting material, potassium cyclobutoxymethyl trifluoroborate, was synthesized as follows.

[Production Example 197-1-1] Tributylcyclobutoxymethyltin

To a mixture of sodium hydride (250 mg, 7.0 mmol, 66% in oil) and tetrahydrofuran (20 ml) at 0 ° C were added cyclobutanol (0.55 ml, 7.0 mmol) and N, N-dimethylformamide (20 ml ) and then the reaction mixture was stirred at room temperature for 40 minutes. Tributyl-iodomethyl-tin (2.0 g, 4.6 mmol), described in Production Example 197-2-2, was added dropwise to the reaction mixture at 0 ° C., and then the reaction mixture was stirred at room temperature overnight. Heptane and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 20: 1) to obtain the title compound (1.6 g, 92%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 0.81-0.98 (15H, m), 1.26-1.35 (6H, m), 1.43-1.57 (7H , m), 1.65-1.70 (1H, m), 1.80-1.87 (2H, m), 2.14-2.21 (2H, m), 3.57 (2H, dd , J = 7.3, 7.0 Hz), 3.68-3.76 (1H, m).

[Production Example 197-1-2] Potassium Cyclobutoxymethyl Trifluoroborate

To the mixture of tributylcyclobutoxymethyl-tin (1.0 g, 2.7 mmol) described in Production Example 197-1-1 and tetrahydrofuran (10 ml) at -78 ° C was added n- butyllithium (1.5 M n solution of hexane, 1.7 ml, 2.7 mmol) and then the reaction solution was stirred at the same temperature for 60 minutes. A solution of triisopropyl borate (0.80 ml, 3.5 mmol) in tetrahydrofuran (10 ml) was added dropwise to this mixture at -78 ° C, and then the reaction mixture was stirred at room temperature for 5 minutes. Potassium acid fluoride (1.25 g, 16 mmol) was added to the reaction mixture at 0 ° C, and then the reaction mixture was stirred at room temperature for 50 minutes. Water (10 ml) was added dropwise to the compound at room temperature, and then the reaction mixture was stirred at the same temperature for another 50 minutes. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was washed with diethyl ether. Acetone was added to the residue and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (210 mg, 42%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 1.30-1.42 (1H, m), 1.48-1.58 (1H, m), 1.61-1.73 (2H, m), 1.99-2.08 (2H, m), 2.31 (2H, q, J = 5.6 Hz), 3.60 (1H, q, J = 6.8 Hz) .

The starting material, tributyl-iodomethyl-tin, was synthesized as follows.

[Production Example 197-2-1] Tritributyl Iodomethyltin Methanol

To a mixture of diisopropylamine (62 ml, 0.44 M) and tetrahydrofuran (1000 ml), n- butyllithium (2.6 M n -hexane solution, 100 ml, 0.26 M) was added dropwise at -78 ° C and n - butyllithium (1.6 M n -hexane solution, 95 ml, 0.15 M) and then the reaction mixture was stirred for 30 minutes. Tributyltin hydride (100 ml, 0.37 M) was added dropwise to this mixture at -78 ° C, and then the reaction mixture was stirred at 0 ° C for 60 minutes. The reaction solution was cooled to -78 ° C, after which parapharmaldehyde (13 g, 0.15 M) was added to the reaction mixture. The reaction solution was slowly warmed to room temperature, and then the reaction mixture was stirred at room temperature overnight. Water, an aqueous solution of ammonium chloride and diethyl ether were added to the reaction mixture, and the organic layer was separated. The organic layer was first washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. The organic layer was separated and concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography (heptane: diethyl ether = 4: 1) to obtain the title compound (95 g, 80%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 0.88-0.94 (15H, m), 1.27-1.36 (6H, m), 1.49-1.55 (6H , m), 4.02 (2H, dd, J = 1.8, 6.6 Hz).

[Production Example 197-2-2] Tributyl Iodomethyl Tin

To a mixture of triphenylphosphine (70 g, 0.27 M) and tetrahydrofuran (500 ml), a mixture of N-iodosuccinimide (60 g, 0.27 M) and tetrahydrofuran (500 ml) was added dropwise at 0 ° C, and then the reaction mixture was stirred at 0 ° C for 30 minutes. Tributylstannylmethanol (71 g, 0.22 M), described in Production Example 197-2-1, was added dropwise to this mixture at 0 ° C, and then the reaction mixture was stirred at 0 ° C for 20 minutes. The reaction solution was stirred at room temperature overnight. Diethyl ether and water were added to the reaction mixture, and the organic layer was separated. The organic layer was first washed with a saturated aqueous sodium thiosulfate solution and then with a saturated aqueous sodium chloride solution. The organic layer was separated and concentrated under reduced pressure. Heptane (400 ml) was added to the residue and filtered. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane) to obtain the title compound (90 g, 94%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 0.91 (9H, t, J = 7.2 Hz), 0.96-1.00 (6H, m), 1.28-1, 37 (6H, m), 1.49-1.56 (6H, m), 1.94 (2H, t, J = 8.9 Hz).

[Example 198] 3- (1- (6-Benzyloxypyridin-3-ylmethyl) -1 H -pyrazol-4-yl) pyridin-2,6-diamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2,6-diamine (30.0 mg, 0.171 mmol) described in Production Example 36-1-2 in N, N-dimethylformamide (5 , 00 ml) in an ice bath (0 ° C) was added sodium hydride (7.52 mg, 0.188 mmol, 60% in oil) and stirred at room temperature for 30 minutes. Then, 2-benzyloxy-5-chloromethylpyridine (59.9 mg, 0.257 mmol), described in Production Example 191-1-2, was added to the mixture, and stirred at room temperature for 30 minutes. The reaction solution was partitioned into ethyl acetate and water. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (27.4 mg, 43.0%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.09 (2H, br s), 5.26 (2H, s), 5.34 (2H, s), 5.44 ( 2H, br.s), 5.77 (1H, dd, J = 2.8, 8.0 Hz), 6.86 (1H, dd, J = 2.0, 8.8 Hz), 7.14 -7.16 (1H, m), 7.29-7.44 (5H, m), 7.57 (1H, d, J = 2.0 Hz), 7.68-7.71 (1H, m ), 7.94 (1H, d, J = 1.6 Hz), 8.17 (1H, s).

[Example 199] 3- (1- (4- (Pyridin-2-ylmethoxy) benzyl) -1 H -pyrazol-4-yl) pyridin-2,6-diamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2,6-diamine (30.0 mg, 0.171 mmol) described in Production Example 36-1-2 in N, N-dimethylformamide (5 , 00 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (7.52 mg, 0.188 mmol, 60% in oil) and stirred at room temperature for 30 minutes. Then, 2- (4-chloromethylphenoxymethyl) -pyridine (59.9 mg, 0.257 mmol) described in Example 192 was added to the mixture described above, and stirred at room temperature for 30 minutes. The reaction solution at room temperature was partitioned into ethyl acetate and water. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 2: 1 then ethyl acetate) to obtain the title compound (11.5 mg, 18.1%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.06 (2H, br s), 5.16 (2H, s), 5.21 (2H, s), 5.43 ( 2H, broad s), 5.77 (1H, d, J = 8.0 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.14 (1H, d, J = 8 4 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.32-7.35 (1H, m), 7.49 (1H, d, J = 7.6 Hz), 7.55 (1H, s), 7.80-7.84 (1H, m), 7.90 (1H, s), 8.56-8.57 (1H, m).

[Example 200] 3- (1- (6-Phenoxypyridin-3-ylmethyl) -1 H -pyrazol-4-yl) pyridin-2,6-diamine

To a solution of 3- (1 H- pyrazol-4-yl) -pyridin-2,6-diamine (30.0 mg, 0.171 mmol) described in Production Example 36-1-2 in N, N-dimethylformamide (5 , 00 ml) in an ice bath (0 ° C) in a nitrogen atmosphere was added sodium hydride (7.52 mg, 0.188 mmol, 60% in oil) and stirred at room temperature for 10 minutes. Then, 5-chloromethyl-2-phenoxyxypyridine (59.9 mg, 0.273 mmol) described in Preparation Example 193-1-2 was added to the mixture described above, and stirred at room temperature for 30 minutes. The reaction solution at room temperature was partitioned into ethyl acetate and water. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (15.4 mg, 25.2%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 5.09 (2H, br s), 5.29 (2H, s), 5.44 (2H, br s), 5, 77 (1H, dd, J = 0.8, 8.0 Hz), 7.01 (1H, d, J = 8.4 Hz), 7.10-7.23 (4H, m), 7.41 (2H, t, J = 7.6 Hz), 7.59 (1H, s), 7.79 (1H, dd, J = 2.0, 8.4 Hz), 7.96 (1H, s) 8.14 (1H, d, J = 2.8 Hz).

[Example 201] 3- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) pyridine

To a solution of 3-ethynylpyridine (50 mg, 0.485 mmol) and (4-benzyloxyphenyl) -acetohydroximoyl chloride (214 mg, 0.776 mmol) described in Production Example 1-1-3, triethylamine (270 μl, 1.94 mmol) and stirred at room temperature for 2.5 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4 then 1: 2) to obtain the title compound (80 mg, 48%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.02 (2H, s), 5.05 (2H, s), 5.37 (1H, s), 6.93-6.97 ( 2H, m), 7.19-7.22 (2H, m), 7.30-7.44 (6H, m), 8.04-8.06 (1H, m), 8.63-8, 65 (1H, m), 8.95-8.96 (1H, m).

[Example 202] 3- (3- (4- (Pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridine

To a solution of 3-ethynylpyridine (10 mg, 0.097 mmol) and (4- (pyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (42.9 mg, 0.155 mmol) described in Production Example 2-1-5, in tetrahydrofuran (3 ml) triethylamine (54.1 μl, 0.388 mmol) was added and stirred at room temperature for 2.5 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4 then 1: 2, then 1: 1) to obtain the title compound (8 mg, 24%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.09 (2H, s), 5.37 (2H, s), 6.38 (1H, s), 6.79-6.81 ( 1H, m), 6.87-6.90 (1H, m), 7.31 (2H, d, J = 8.4 Hz), 7.37-7.40 (1H, m), 7.45 (2H, d, J = 8.4 Hz), 7.56-7.61 (1H, m), 8.02-8.05 (1H, m), 8.16-8.18 (1H, m ), 8.64-8.65 (1H, m), 8.956-8.959 (1H, m).

[Example 203] 3- (3- (4- (Pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridine

To a solution of 3-ethynylpyridine (50 mg, 0.485 mmol) and (4- (pyridin-2-ylmethoxy) phenyl) acetohydroximoyl chloride (215 mg, 0.776 mmol) described in Production Example 203-1-4, in tetrahydrofuran (3 ml) triethylamine (270 μl, 1.94 mmol) was added and stirred at room temperature for 2.5 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4 - 1: 2, then 1: 1) to obtain the title compound (71 mg, 43%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.02 (2H, s), 5.20 (2H, s), 6.37 (1H, s), 7.47 (2H, d, J = 8.4 Hz), 7.20-7.24 (2H, m), 7.21 (1H, d, J = 8.4 Hz), 7.37-7.40 (1H, m), 7.51-7.53 (1H, m), 7.69-7.73 (1H, m), 8.02-8.05 (1H, m), 8.59-8.60 (1H, m ), 8.63-8.65 (1H, m), 8.95-8.96 (1H, m).

The starting material, (4- (pyridin-2-ylmethoxy) phenyl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 203-1-1] 4- (pyridin-2-ylmethoxy) benzaldehyde

To a solution of 4-hydroxybenzaldehyde (20 g, 164 mmol) and 2-picolyl chloride (27 g, 165 mmol) in N, N-dimethylformamide (250 ml) was added potassium carbonate (68 g, 492 mmol) and stirred at room temperature for 3 days. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (29 g, 83%). The title compound was used in the next reaction without purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 5.31 (2H, s), 7.21-7.25 (2H, m), 7.35-7.39 (1H, m ), 7.53-7.55 (1H, m), 7.83-7.90 (3H, m), 8.59-8.61 (1H, m), 9.88 (1H, s).

[Production Example 203-1-2] 2- (4 - (( E ) -nitrovinyl) phenoxymethyl) pyridine

A mixture of 4- (pyridin-2-ylmethoxy) benzaldehyde (29 g, 136 mmol) described in Production Example 203-1-1, nitromethane (36.6 ml, 680 mmol), ammonium acetate (21 g, 272 mmol) and acetic acid (300 ml) was stirred at 100 ° C for 21 hours. This mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (33.9 g, 97%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 5.27 (2H, s), 7.04-7.06 (2H, m), 7.25-7.28 (1H, m), 7.49-7.54 (4H, m), 7.72-7.76 (1H, m), 7.96-7.99 (1H, m), 8.62-8.63 (1H, m) )

[Production Example 203-1-3] 2- (4- (2-nitroethyl) phenoxymethyl) pyridine

In a suitably cooled solution of 2- (4 - (( E ) -nitrovinyl) phenoxymethyl) pyridine (33.9 g, 132 mmol) described in Production Example 203-1-2 in acetic acid (34 ml) and dimethyl sulfoxide (576 ml) was added sodium borohydride (7.99 g, 211 mmol) at room temperature. This mixture was stirred at room temperature for 5 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from heptane and ethyl acetate to obtain the title compound (6.81 g, 20%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 3.26-3.30 (2H, m), 4.57-4.61 (2H, m), 5.51 (2H, s), 6.97 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.41-7.44 (1H, m), 7.89-7 91 (1H, m), 7.96-8.00 (1H, m), 8.77-8.78 (1H, m).

[Production Example 203-1-4] (4- (pyridin-2-ylmethoxy) -phenyl) -acetohydroximoyl chloride

To a solution of 2- (4- (2-nitroethyl) phenoxymethyl) pyridine (3 g, 11.6 mmol) described in Production Example 203-1-3, methanol (36 ml) was added with lithium methoxide (881 mg, 23.2 mmol) and this mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the water in the residue was azeotropically distilled off, and the residue was diluted with methylene chloride (46 ml) and tetrahydrofuran (23 ml). The mixture was cooled to -78 ° C, after which titanium (IV) tetrachloride (4.08 ml, 37.1 mmol) was added dropwise to the resulting suspension. The mixture was stirred at room temperature for 1 hour. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and water. The thin organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.98 g).

The resulting compound was used in the subsequent reaction without further purification.

[Example 204] 3- (3- (2-Fluoro-4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (38.4 mg, 0.325 mmol) described in Production Example 1-2-3, and (2-fluoro-4- (pyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (150 mg, 0.509 mmol) described in Production Example 204-1-8, triethylamine (97.2 μl, 0.697 mmol) was added in tetrahydrofuran (3 ml) and stirred at 60 ° C for 2 hours. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4 - 1: 2, then 1: 1) to obtain the title compound (46 mg, 24%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.09 (2H, s), 5.37 (2H, s), 5.43 (2H, br s), 6.32 (1H, c), 6.70-6.73 (1H, m), 6.80-6.82 (1H, m), 6.88-6.92 (1H, m), 7.19-7.30 ( 3H, m), 7.58-7.62 (1H, m), 7.70-7.73 (1H, m), 8.13-8.18 (2H, m).

The starting material, (2-fluoro-4- (pyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride, was synthesized as follows.

[Production Example 204-1-1] 2- (4-bromo-2-fluoro-phenyl) - [1,3] dioxolane

A mixture of 4-bromo-2-fluorobenzaldehyde (10 g, 49.3 mmol), ethylene glycol (27.5 ml, 493 mmol), camphorsulfonic acid (115 mg, 0.493 mmol) and toluene (250 ml) were stirred for 5 hours in a flask with reflux condenser. The mixture was cooled to room temperature and a saturated aqueous sodium hydrogen carbonate solution was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (12.5 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 4.03-4.09 (2H, m), 4.10-4.16 (2H, m), 6.03 (1H, s), 7.25-7.28 (1H, m), 7.30-7.32 (1H, m), 7.40-7.44 (1H, m).

[Production Example 204-1-2] 4- [1,3] dioxolan-2-yl-3-fluorobenzaldehyde

To a solution of 2- (4-bromo-2-fluorophenyl) - [1,3] dioxolane (12.5 g, 50.7 mmol) described in Production Example 204-1-1, in tetrahydrofuran (600 ml), dropwise n- butyllithium (28.5 ml, 2.67 M hexane solution, 76.1 mmol) was added over 15 minutes. The mixture was stirred at -78 ° C for 5 minutes, after which a solution of N-formylmorpholine (5.61 ml, 55.8 mmol) in THF was added to this reaction solution and stirred at room temperature for another 2.5 hours. Water and ethyl acetate were added to this mixture, then the mixture was separated. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (9.99 g). The title compound was used in the subsequent reaction without further purification.

[Production Example 204-1-3] (4- [1,3] dioxolan-2-yl-3-fluorophenyl) methanol

To a solution of 4- [1,3] dioxolan-2-yl-3-fluorobenzaldehyde (10 g, 50.9 mmol) described in Production Example 204-1-2, sodium borohydride was added in methanol (200 ml) (2, 12 g, 56 mmol) and stirred at room temperature for 1 hour. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1) to obtain the title compound (2.44 g, 24%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 3.80 (1H, br s), 4.03-4.17 (4H, m), 6.21 (2H, d, J = 6 , 0 Hz), 6.08 (1H, s), 7.09-7.19 (1H, m), 7.38-7.54 (2H, m).

[Production Example 204-1-4] 2- (4- [1,3] dioxolan-2-yl-3-fluorobenzyloxy) pyridine

To a solution of (4- [1,3] dioxolan-2-yl-3-fluorophenyl) methanol (2.44 g, 12.3 mmol) described in Production Example 204-1-3 in N, N-dimethylformamide (20 ml) sodium hydride (537 mg, 14.8 mmol, 60% in oil) was added and cooled to 0 ° C, after which 2-fluoropyridine (1.27 ml, 14.8 mmol) was added to this suspension at 60 ° C for 2 hours. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (2.17 g, 64%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.05-4.17 (4H, m), 5.38 (2H, s), 6.09 (1H, s), 6.79- 6.83 (1H, m), 6.88-6.91 (1H, m), 7.16-7.25 (2H, m), 7.50-7.54 (1H, m), 7, 56-7.62 (1H, m), 8.14-8.16 (1H, m).

[Production Example 204-1-5] 2-fluoro-4- (pyridin-2-yloxymethyl) benzaldehyde

To a solution of 2- (4- [1,3] dioxolan-2-yl-3-fluorobenzyloxy) pyridine (2.17 g, 7.88 mmol) described in Production Example 204-1-4, in methanol (10 ml) and tetrahydrofuran (10 ml) was added 5N hydrochloric acid (8.43 ml, 8.43 mmol). The solution was stirred at room temperature for 15 minutes. This mixture was cooled to 0 ° C and neutralized with a saturated aqueous sodium hydrogen carbonate solution, after which it was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.81 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 5.46 (2H, s), 6.82-6.94 (3H, m), 7.29-7.34 (1H, m), 7.59-7.65 (1H, m), 7.85-7.89 (1H, m), 8.14-8.17 (1H, m), 10.35 (1H, s).

[Production Example 204-1-6] 2- (3-fluoro-4- ( E ) -2-nitrovinyl) benzyloxy) pyridine

A mixture of 2-fluoro-4- (pyridin-2-yloxymethyl) benzaldehyde (1.81 g 7.81 mmol) described in Production Example 204-1-5, nitromethane (2.12 ml, 39.1 mmol), ammonium acetate (1.2 g, 15.6 mmol) and acetic acid (20 ml) were stirred at 100 ° C for 5 hours. This mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (980 mg, 46%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 5.44 (2H, s), 6.84-6.87 (1H, s), 6.91-6.94 (1H, m), 7.24-7.32 (3H, m), 7.48-7.52 (1H, m), 7.61-7.65 (1H, m), 7.71-7.75 (1H, m ), 8.14-8.16 (1H, m).

[Production Example 204-1-7] 2- (3-fluoro-4- (2-nitroethyl) benzyloxy) pyridine

In a suitably cooled solution of 2- (3-fluoro-4- ( E ) -2-nitrovinyl) benzyloxy) pyridine (980 mg, 3.57 mmol) described in Production Example 204-1-6, in acetic acid (1 ml) and dimethyl sulfoxide (17 ml) was added sodium borohydride (203 mg, 5.36 mmol) at room temperature. This mixture was stirred at room temperature for 3 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (960 mg).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.34-3.39 (2H, m), 4.60-4.67 (2H, m), 5.36 (2H, s), 6.80-6.83 (1H, m), 6.89-6.92 (1H, m), 7.17-7.21 (3H, m), 7.58-7.62 (1H, m) ), 8.15-8.17 (1H, m).

[Production Example 204-1-8] (2-fluoro-4- (pyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride

To a solution of 2- (3-fluoro-4- (2-nitroethyl) benzyloxy) pyridine (960 mg, 3.47 mmol) described in Production Example 204-1-7, lithium methoxide was added to methanol (20 ml) (264 mg, 6.94 mmol) and this mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, the water in the residue was azeotropically distilled off with toluene, and the resulting residue was diluted with methylene chloride (15 ml) and tetrahydrofuran (5 ml). The mixture was cooled to −78 ° C., after which titanium (IV) tetrachloride (1.22 ml, 11.1 mmol) was added dropwise to this suspension. The mixture was stirred at 0 ° C for 2 hours. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (890 mg). The title compound was used in the subsequent reaction without further purification.

[Example 205] 3- (3- (4-Benzylsulfonylbenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (50 mg, 0.423 mmol) described in Production Example 1-2-3 and (4-phenylsulfanylmethylphenyl) acetohydroximoyl chloride (197 mg, 0.677 mmol) described in Example 205-1-6 of preparation, triethylamine (147 μl, 1.06 mmol) was added in tetrahydrofuran (3 ml) and stirred at room temperature for 18 hours. This mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4 to 1: 2) to obtain the title compound (29 mg, 18%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 3.98 (2H, s), 4.11 (2H, s), 5.38 (2H, br s), 6.22 (1H, c), 6.70-6.73 (1H, m), 7.16-7.18 (2H, m), 7.22-7.31 (7H, m), 7.69-7.71 ( 1H, m), 8.14-8.15 (1H, m).

The starting material, (4-benzylphenylsulfanylphenyl) acetohydroximoyl chloride, was synthesized as follows.

[Production Example 205-1-1] 2- (4-benzylsulfonylphenyl) - [1,3] dioxolane

To a solution of 2- (4-bromophenyl) -1,3-dioxane (5 g, 0.677 mmol) in tetrahydrofuran (100 ml) at -78 ° C was added n- butyllithium (14.9 ml, 2.64 M hexane solution, 39.2 mmol) and stirred for 15 minutes. Benzyl disulfide (5.91 g, 24 mmol) was added dropwise to the reaction mixture at -78 ° C and stirred for 5 hours. The mixture was heated to 0 ° C and separated into ethyl acetate and a water layer. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: heptane = 1: 4) to obtain the title compound (1.06 g, 18%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.90-4.04 (4H, m), 4.26 (2H, s), 5.67 (1H, s), 7, 23-7.37 (9H, m).

[Production Example 205-1-2] 4-Benzylsulfonylbenzaldehyde

To a solution of 2- (4-benzylsulfanylphenyl) - [1,3] dioxolane (1.06 g, 3.89 mmol) described in Production Example 205-1-1 in methanol (5 ml) and tetrahydrofuran (5 ml) 1N hydrochloric acid (4.16 ml) was added and stirred at room temperature for 30 minutes. The mixture was cooled to 0 ° C and neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (840 mg). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.40 (2H, s), 7.26-7.28 (1H, m), 7.31-7.35 (2H, m ), 7.43-7.45 (2H, m), 7.51-7.53 (2H, m), 7.79-7.81 (2H, m), 9.90 (1H, s).

[Production Example 205-1-3] 1-benzylsulfonyl-4 - (( E ) -2-nitrovinyl) benzene

A mixture of 4-benzylsulfanylbenzaldehyde (840 mg 3.68 mmol) described in Production Example 205-1-2, nitromethane (997 μl, 18.4 mmol), ammonium acetate (567 mg, 7.36 mmol) and acetic acid (10 ml) was stirred at 100 ° C for 2 hours. This mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (950 mg). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.37 (2H, s), 7.23-7.34 (3H, m), 7.40-7.45 (4H, m ), 7.76-7.81 (2H, m), 8.08 (1H, d, J = 14 Hz), 8.20 (1H, d, J = 14 Hz).

[Production Example 205-1-4] 1-benzylsulfonyl-4- (2-nitroethyl) benzene

To a solution of 1-benzylsulfanyl-4 - (( E ) -2-nitrovinyl) benzene (950 mg, 3.5 mmol), described in Production Example 205-1-3, in acetic acid (0.6 ml) and dimethyl sulfoxide (10 ml) was added sodium borohydride (212 mg, 5.6 mmol), while the temperature inside the mixture was maintained at 30 ° C or lower, the mixture was stirred at room temperature for 30 minutes. The mixture was cooled with ice water, water was added and stirred for another 30 minutes. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (936 mg). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.15-3.18 (2H, m), 4.21 (2H, s), 4.80-4.83 (2H, m ), 7.18-7.35 (9H, m).

[Production Example 205-1-5] (4-benzylphenylsulfanylphenyl) acetohydroximoyl chloride

To a solution of 1-benzylsulfanyl-4- (2-nitroethyl) -benzene (936 mg, 3.42 mmol) described in Production Example 205-1-4, lithium methoxide (260 mg, 6, 84 mM) and stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, the water in the residue was azeotroped off using toluene, and the resulting residue was diluted with methylene chloride (16 ml) and tetrahydrofuran (8 ml). The system was cooled to -78 ° C, after which titanium (IV) tetrachloride (825 μl, 7.52 mmol) was added dropwise to the resulting suspension. The mixture was stirred at 0 ° C for 1 hour. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.01 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.77 (2H, s), 4.23 (2H, s), 7.16-7.38 (9H, m), 11, 7 (1H, s).

[Example 206] 3- (3- (4-Phenylsulfanylmethylbenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (50 mg, 0.423 mmol) described in Production Example 1-2-3 and (4-phenylsulfanylmethylphenyl) acetohydroximoyl chloride (197 mg, 0.677 mmol) described in Example 206-1-6 of preparation, triethylamine (147 μl, 1.06 mmol) was added in tetrahydrofuran (3 ml) and stirred at room temperature for 18 hours. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4 to 1: 2) to obtain the title compound (41 mg, 26%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.03 (2H, s), 4.11 (2H, s), 5.42 (2H, br s), 6.23 (1H, c), 6.69-6.73 (1H, m), 7.16-7.35 (9H, m), 7.69-7.71 (1H, m), 8.13-8.15 ( 1H, m).

The starting material, (4-phenylsulfanylmethylphenyl) acetohydroximoyl chloride, was synthesized as follows.

[Production Example 206-1-1] 4-phenylsulfanylmethyl-benzoic acid

A mixture of 4- (bromomethyl) benzoic acid (10 g, 46.5 mmol), sodium thiophenoxide (6.15 g, 46.5 mmol) and ethanol (100 ml) was stirred for 1.5 hours in a flask under reflux. This mixture was cooled to room temperature and acidified with 1N hydrochloric acid. The precipitate thus obtained was collected, diluted with ethyl acetate and washed with water. The organic layer was concentrated under reduced pressure to obtain the title compound (10 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.31 (2H, s), 7.16-7.20 (1H, m), 7.26-7.34 (4H, m ), 7.45-7.47 (2H, m), 7.84-7.86 (2H, m), 12.9 (1H, br.s).

[Production Example 206-1-2] (4-phenylsulfanylmethylphenyl) methanol

To a suspension of lithium aluminum hydride (1.95 g, 51.3 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of 4-phenylsulfanylmethylbenzoic acid (5 g, 20.5 mmol) described in Production Example 206-1-1 in tetrahydrofuran and stirred at room temperature for 30 minutes. The mixture was cooled with ice water, while water was added carefully. The mixture was filtered through a pad of celite and the filtrate was combined. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2.01 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.22 (2H, s), 4.45 (2H, d, J = 5.6 Hz), 5.13 (1H, t, J = 5.6 Hz), 7.16-7.34 (9H, m).

[Production Example 206-1-3] 4-phenylsulfanylmethylbenzaldehyde

To a solution of (4-phenylsulfanylmethylphenyl) methanol (1 g, 4.34 mmol) described in Preparation Example 206-1-2, manganese dioxide (3.77 g, 43.4 mmol) was added in chloroform (10 ml) and stirred at room temperature for 15 hours. Manganese dioxide was removed by filtration through a celite pad, and the filtrate was concentrated under reduced pressure to obtain the title compound (990 mg). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.34 (2H, s), 7.16-7.20 (1H, m), 7.27-7.35 (4H, m ), 7.56 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.95 (1H, s).

[Production Example 206-1-4] 1 - (( E ) -2-nitrovinyl) -4-phenylsulfanylmethyl) benzene

A mixture of 4-phenylsulfanylmethylbenzaldehyde (990 mg, 4.34 mmol) described in Production Example 206-1-3, nitromethane (1.18 ml, 21.7 mmol), ammonium acetate (669 mg, 8.68 mmol) and acetic acids (5 ml) were stirred at 100 ° C for 6 hours. This mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.15 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.29 (2H, s), 7.16-7.20 (1H, m), 7.27-7.35 (4H, m ), 7.44 (2H, d, J = 6.8 Hz), 7.77 (2H, d, J = 6.8 Hz), 8.08 (1H, d, J = 13.6 Hz), 8.18 (1H, d, J = 13.6 Hz).

[Production Example 206-1-5] 1- (2-nitroethyl) -4-phenylsulfanylmethylbenzene

To a solution of 1 - (( E ) -2-nitrovinyl) -4-phenylsulfanylmethyl) benzene (1.15 g, 4.24 mmol) described in Production Example 206-1-4 in acetic acid (0.6 ml ) and dimethyl sulfoxide (10 ml) was added sodium borohydride (257 mg, 6.78 mmol) and stirred at room temperature for 30 minutes. The mixture was cooled with ice water and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.15 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.17-3.20 (2H, m), 4.21 (2H, s), 4.80-4.84 (2H, m ), 7.15-7.20 (3H, m), 7.27-7.33 (6H, m).

[Production Example 206-1-6] (4-phenylsulfanylmethylphenyl) acetohydroximoyl chloride

To a solution of 1- (2-nitroethyl) -4-phenylsulfanylmethyl-benzene (1.1 g, 4.03 mmol) described in Production Example 206-1-5, lithium methoxide (306 mg, 8.06 mmol) and stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, the water in the residue was azeotroped off using toluene, and the resulting residue was diluted with methylene chloride (16 ml) and tetrahydrofuran (8 ml). The system was cooled to -78 ° C, after which titanium (IV) tetrachloride (972 μl, 8.87 mmol) was added dropwise to the resulting suspension. The mixture was stirred at 0 ° C for 1 hour. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.15 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.78 (2H, s), 4.23 (2H, s), 7.15-7.19 (3H, m), 7, 27-7.34 (6H, m), 11.7 (1H, s).

[Example 207] 3- (3- (4-bromobenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (50 mg, 0.423 mmol) described in Production Example 1-2-3, and 4-bromophenyl acetohydroximoyl chloride (168 mg, 0.677 mmol) described in Production Example 207-1-3, in tetrahydrofuran (3 ml) triethylamine (147 μl, 1.06 mmol) was added and stirred at room temperature for 15 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4 to 1: 2) to obtain the title compound (33 mg, 24%).

¹ H NMR spectrum (CDCl ₃ ) δ (ppm): 4.02 (2H, s), 5.42 (2H, br s), 6.24 (1H, s), 6.70-6, 74 (1H, m), 7.16-7.18 (2H, m), 7.44-7.48 (2H, m), 7.70-7.72 (1H, m), 8.14- 8.16 (1H, m).

The starting material, 4-bromophenyl acetohydroximoyl chloride, was synthesized as follows.

[Production Example 207-1-1] 1-bromo-4 - (( E ) -2-nitrovinyl) benzene

A mixture of 4-bromobenzaldehyde (16.8 g, 91 mmol), nitromethane (24.6 ml, 455 mmol), ammonium acetate (14 g, 182 mmol) and acetic acid (160 ml) was stirred at 100 ° C for 4 hours . This mixture was cooled to room temperature and poured into water. The product thus precipitated was cooled, washed with water and dried under reduced pressure to obtain the title compound (17.4 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 7.71 (2H, d, J = 8.4 Hz), 7.82 (2H, d, J = 8.4 Hz), 8 13 (1H, d, J = 13.6 Hz), 8.27 (1H, d, J = 13.6 Hz).

[Production Example 207-1-2] 1-bromo-4- (2-nitroethyl) benzene

To a solution of 1-bromo-4 - (( E ) -2-nitrovinyl) benzene (1 g, 4.37 mmol) described in Production Example 207-1-1 in acetic acid (0.6 ml) and dimethyl sulfoxide (10 ml) sodium borohydride (265 mg, 6.99 mmol) was added and stirred at room temperature for 30 minutes. The mixture was cooled with ice water and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (948 mg). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.20 (2H, t, J = 6.8 Hz), 4.85 (2H, t, J = 6.8 Hz), 7 25 (2H, d, J = 8.2 Hz); 7.51 (2H, d, J = 8.2 Hz).

[Production Example 207-1-3] 4-bromophenylacetohydroximoyl chloride

To a solution of 1-bromo-4- (2-nitroethyl) benzene (948 mg, 4.12 mmol) described in Production Example 207-1-2, in methanol (12 ml) was added lithium methoxide (313 mg, 8, 24 mM) and stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, the water in the residue was azeotroped off using toluene, and the resulting residue was diluted with methylene chloride (16 ml) and tetrahydrofuran (8 ml). The system was cooled to -78 ° C, after which titanium (IV) tetrachloride (994 μl, 9.06 mmol) was added dropwise to this suspension. The mixture was stirred at 0 ° C for 1 hour. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (990 mg). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.82 (2H, s), 7.23 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 11.8 (1H, s).

[Example 208] 3- (3- (5- (4-Fluorobenzyl) -furan-2-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (50 mg, 0.423 mmol), described in Production Example 1-2-3, and (5- (4-fluorobenzyl) -furan-2-yl) acetohydroximoyl chloride (181 mg, 0.677 mmol) ) described in Production Example 208-1-5, triethylamine (147 μl, 1.06 mmol) was added in tetrahydrofuran (3 ml) and stirred at room temperature for 19 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 4 to 1: 2) to obtain the title compound (9 mg, 6%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.91 (2H, s), 4.04 (2H, s), 5.39 (2H, br s), 5.93 (1H, d, J = 3.0 Hz), 6.07 (1H, d, J = 3.0 Hz), 6.30 (1H, s), 6.72-6.75 (1H, m), 6, 96-7.01 (2H, m), 7.17-7.21 (2H, m), 7.66-7.68 (1H, m), 8.15-8.17 (1H, m).

The starting material, (5- (4-fluorobenzyl) -furan-2-yl) acetohydroximoyl chloride, was synthesized as follows.

[Production Example 208-1-1] 2- (5- (4-fluorobenzyl) -furan-2-yl) - [1,3] dioxolane

To a solution of 2- (1,3-dioxolan-2-ylfuran (5 g, 35.7 mmol) in tetrahydrofuran (50 ml) at -78 ° C was added n- butyllithium (15.6 ml, 2.64 M hexane solution , 41.1 mmol) and stirred at the same temperature for 1 hour, A solution of 4-fluorobenzyl bromide (6.9 g, 36.5 mmol) in tetrahydrofuran was added dropwise to this mixture and stirred at -78 ° C for another The mixture was warmed to room temperature and partitioned into ethyl acetate and a saturated aqueous solution of ammonium chloride.The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sulphate. magnesium atom and filtered The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel. (ethyl acetate: heptane = 1: 10 to 1: 3) to give the title compound (4.5 g, 51%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.86-3.90 (2H, m), 3.96-4.00 (4H, m), 5.78 (1H, s ), 6.07 (1H, d, J = 3.0 Hz), 6.42 (1H, d, J = 3.0 Hz), 7.12-7.16 (2H, m), 7.25 -7.29 (2H, m).

[Production Example 208-1-2] 5- (4-fluorobenzyl) -furan-2-carbaldehyde

To a solution of 2- (5- (4-fluorobenzyl) -furan-2-yl) - [1,3] dioxolane (4.51 g, 18.2 mmol) described in Production Example 208-1-1 in methanol (45 ml) was added a solution (45 ml) of citric acid (12.2 g, 63.7 mmol) and stirred vigorously at room temperature for 1 hour. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (4.51 g, 51%). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.11 (2H, s), 6.47-6.48 (1H, m), 7.15-7.19 (2H, m ), 7.30-7.34 (2H, m), 7.47-7.48 (1H, m), 9.49 (1H, s).

[Production Example 208-1-3] 2- (4-fluorobenzyl) -5 - (( E ) -2-nitrovinyl) furan

A mixture of 5- (4-fluorobenzyl) -furan-2-carbaldehyde (1 g, 4.89 mmol) described in Production Example 208-1-2, nitromethane (1.32 ml, 24.5 mmol), ammonium acetate ( 754 mg, 9.78 mmol) and acetic acid (10 ml) were stirred at 100 ° C for 3 hours. This mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.21 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.08 (2H, s), 6.42 (1H, d, J = 3.4 Hz), 7.08-7.19 ( 2H, m), 7.22 (1H, d, J = 3.4 Hz), 7.29-7.37 (2H, m), 7.64 (1H, d, J = 13.2 Hz), 7.96 (1H, d, J = 13.2 Hz).

[Production Example 208-1-4] 2- (4-fluorobenzyl) -5- (2-nitroethyl) furan

To a solution of 2- (4-fluorobenzyl) -5 - (( E ) -2-nitrovinyl) -furan (1.21 g, 4.89 mmol) described in Production Example 208-1-3 in acetic acid (0 , 6 ml) and dimethyl sulfoxide (10 ml) was added sodium borohydride (296 mg, 7.82 mmol) and stirred at room temperature for 30 minutes. The mixture was cooled with ice water and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.14 g). The title compound was used in the subsequent reaction without further purification.

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.20-3.24 (2H, m), 3.91 (2H, s), 4.77-4.80 (2H, m ), 6.00 (1H, d, J = 3.0 Hz), 6.10 (1H, d, J = 3.0 Hz), 7.08-7.15 (2H, m), 7.23 -7.28 (2H, m).

[Production Example 208-1-5] (5- (4-fluorobenzyl) -furan-2-yl) acetohydroximoyl chloride

To a solution of 2- (4-fluorobenzyl) -5- (2-nitroethyl) furan (1.14 g, 4.57 mmol) described in Production Example 208-1-4, lithium methoxide was added to methanol (12 ml) (347 mg, 9.14 mmol) and stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, the water in the residue was azeotroped off using toluene, and the resulting residue was diluted with methylene chloride (16 ml) and tetrahydrofuran (8 ml). The system was cooled to -78 ° C, after which titanium (IV) tetrachloride (1.1 ml, 10.1 mmol) was added dropwise to the resulting suspension. The mixture was stirred at 0 ° C for 1 hour. This mixture was cooled to −78 ° C. and partitioned into ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (940 mg). The title compound was used in the subsequent reaction without further purification.

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.82 (2H, s), 3.93 (2H, s), 6.03 (1H, d, J = 3.0 Hz) 6.20 (1H, d, J = 3.0 Hz), 7.11-7.15 (2H, m), 7.23-7.27 (2H, m), 11.8 (1H, s )

[Example 209] 3- (3- (4- (Pyridin-2-yloxy) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine

To a solution of 3-ethynylpyridin-2-ylamine (45 mg, 0.38 mmol) described in Production Example 1-2-3, and (4- (pyridin-2-yloxy) benzene) -acetohydroximoyl chloride (200 mg, 0, 76 mmol) described in Production Example 209-1-4, triethylamine (139 mg, 1.4 mmol) was added in tetrahydrofuran (5 ml) and stirred at 60 ° C for 10 minutes. The reaction solution was cooled to room temperature, NH silica gel was added, and the solvent was evaporated under reduced pressure. The crude product that was adsorbed on NH silica gel was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1, 1: 1) to obtain the title compound (40 mg, 30%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.05 (2H, s), 6.28 (2H, br.s), 6.68-6.72 (1H, m), 6.87 (1H, s), 7.00-7.03 (1H, m), 7.06-7.14 (3H, m), 7.37 (2H, d, J = 8.4 Hz) 7.81-87 (1H, m), 7.87-7.91 (1H, m), 8.08-8.11 (1H, m), 8.11-8.14 (1H, m) .

The starting material, (4- (pyridin-2-yloxy) benzene) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 209-1-1] 4- (pyridin-2-yloxy) benzaldehyde

To a solution of 4-hydroxybenzaldehyde (10 g, 82 mmol) and 2-fluoropyridine (8.0 g, 82 mmol) in N, N-dimethylformamide (100 ml) was added sodium hydride (3.3 g, 82 mmol, 60% in oil) and stirred at 120 ° C for 30 minutes, then at 140 ° C for 45 minutes and then at 160 ° C for another 2 hours. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water (three times) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (9.3 g, 57%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 7.15-7.20 (1H, m), 7.20-7.25 (1H, m), 7.33 (2H, d , J = 8.0 Hz), 7.40-8.00 (3H, m), 8.20-8.24 (1H, m), 9.98 (1H, s).

[Production Example 209-1-2] 2- (4 - (( E ) -2-nitrovinyl) phenoxyxy) pyridine

A mixture of 4- (pyridin-2-yloxy) benzaldehyde (9.3 g, 47 mmol) described in Production Example 209-1-1, nitromethane (14 g, 230 mmol), ammonium acetate (11 g, 140 mmol) and acetic acid (50 ml) was stirred at 100 ° C for 1 hour and 30 minutes. This mixture was cooled to room temperature and water was added to precipitate a solid. The solid was filtered to give the title compound (9.9 g, 87%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 7.11-7.14 (1H, m), 7.18-7.25 (3H, m), 7.89-7.94 (3H, m), 8.13-8.24 (3H, m).

[Production Example 209-1-3] 2- (4- (2-nitroethyl) phenoxyxy) pyridine

To a solution of 2-4 - (( E ) -2-nitrovinyl) -phenoxy) -pyridine (9.9 g, 41 mmol) described in Production Example 209-1-2, acetic acid (2.5 g) and dimethyl sulfoxide (60 ml) sodium borohydride (770 mg, 20 mmol) was added, while the temperature was maintained at 30 ° C or lower, the solution was stirred at room temperature for 15 minutes. This reaction solution was separated into ethyl acetate and water, while the temperature was maintained at 30 ° C or lower. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 3: 1) to obtain the title compound (4.5 g, 45%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.24 (2H, t, J = 7.2 Hz), 4.87 (2H, t, J = 7.2 Hz), 6 , 99-7.20 (1H, m), 7.07 (2H, d, J = 8.0 Hz), 7.09-7.14 (1H, m), 7.31 (2H, d, J = 8.0 Hz), 7.81-7.86 (1H, m), 8.12-8.16 (1H, m).

[Production Example 209-1-4] (4- (pyridin-2-yloxy) benzene) -acetohydroximoyl chloride

To a solution of 2- (4- (2-nitroethyl) -phenoxyxy) pyridine (2.0 g, 8.2 mmol) described in Production Example 209-1-3, lithium methoxide (470 was added in methanol (30 ml) mg, 12 mmol) and this mixture was concentrated under reduced pressure. Toluene was added to the residue, and the solvent was evaporated under reduced pressure. Titanium (IV) tetrachloride (2.3 ml, 21 mmol) was added to a solution of this residue in methylene chloride (40 ml) and tetrahydrofuran (20 ml), while stirring the solution at -76 ° C. The suspension was stirred at 0 ° C for 15 minutes and then at room temperature for another 20 minutes. The mixture was poured onto ice water and stirred for 30 minutes. Ethyl acetate was added and the organic layer was separated, washed with an aqueous solution of sodium chloride (once), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2.1 g, 98%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.84 (2H, s), 7.01-7.05 (1H, m), 7.07-7.15 (3H, m ), 7.29 (2H, d, J = 8.0 Hz), 7.82-7.88 (1H, m), 8.13-8.16 (1H, m), 11.75 (1H, c)

[Example 210] 3- (3- (6-Benzylpyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2-ylamine

A mixture of 3-ethynylpyridin-2-ylamine (30 mg, 0.25 mmol) described in Production Example 1-2-3, 2- (6-benzylpyridin-3-yl) -acetohydroximoyl chloride (88 mg, 0.34 mmol) described in Production Example 210-1-7, triethylamine (77 mg, 0.76 mmol) and tetrahydrofuran (5 ml) were stirred at 50 ° C for 25 minutes. The resulting reaction solution was partitioned into ethyl acetate and a water layer. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1, 1: 1, ethyl acetate) to obtain the title compound (4.6 mg, 5.3%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 4.03 (2H, s), 4.06 (2H, s), 6.26 (2H, br.s), 6.69 ( 1H, dd, J = 4.8, 7.6 Hz), 6.84 (1H, s), 7.15-7.22 (1H, m), 7.22-7.30 (5H, m) 7.65 (1H, dd, J = 2.0, 8.0 Hz), 7.86 (1H, dd, J = 2.0, 8.0 Hz), 8.08 (1H, dd, J = 2.4, 4.8 Hz), 8.48 (1H, d, J = 2.4 Hz).

The starting material, (6-benzyl-pyridin-3-yl) -acetohydroximoyl chloride, was synthesized as follows.

[Production Example 210-1-1] 6-bromopyridin-3-carbaldehyde

To a solution of 2,5-dibromopyridine (25 g, 110 mmol) in diethyl ether (500 ml) at -76 ° C n- butyllithium (2.67 M n -hexane solution, 45 ml, 120 mmol) was added dropwise and stirred for 25 minutes. N, N-dimethylformamide (9.0 ml, 120 mmol) was added dropwise to this solution at -76 ° C. After addition, the reaction solution was gradually cooled to room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 8: 1) to obtain the title compound (8.0 g, 41%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 7.89-7.92 (1H, m), 8.15-8.19 (1H, m), 8.89-8.92 (1H, m), 10.09 (1H, s).

[Production Example 210-1-2] 2-bromo-5- [1,3] dioxolan-2-yl-pyridine

A mixture of 6-bromopyridin-3-carbaldehyde (8.0 g, 43 mmol) described in Production Example 210-1-1, ethylene glycol (5.3 g, 86 mmol), p- toluenesulfoxylate (820 mg, 4.3 mmol) ) and toluene (110 ml) was stirred for 40 minutes in a flask under reflux. (The water obtained in this reaction was removed using a Dean-Stark trap.) The reaction solution was concentrated under reduced pressure and the residue was partitioned into ethyl acetate and water. The organic layer was separated and passed through a glass filter with NH silica gel (eluted with ethyl acetate). The eluate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate = 8: 1) to obtain the title compound (5.8 g, 59%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.93-4.11 (4H, m), 5.84 (1H, s), 7.68-7.72 (1H, m ), 7.77-7.82 (1H, m), 8.44-8.47 (1H, m).

[Production Example 210-1-3] 2-benzyl-5- [1,3] dioxolan-2-yl-pyridine

To a suspension of zinc (5.0 g, 77 mmol, a highly reactive Rieke metal, 100 ml of a suspension in tetrahydrofuran) and tetrahydrofuran (300 ml) at 0 ° C, benzyl bromide (7.9 ml, 66 mmol) was added dropwise and stirred at the same temperature for 4 hours. To this suspension was added bis (triphenylphosphine) nickel (II) chloride (5.8 g, 8.8 mmol) and 2-bromo-5- [1,3] dioxolan-2-yl-pyridine (11 g, 49 mmol) described in Production Example 210-1-2 and stirred at room temperature for another 2 hours. The reaction solution was partitioned into ethyl acetate and an aqueous solution of ammonium chloride. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1, 1: 1) to obtain the title compound (7.3 g, 62%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.92-4.06 (4H, m), 4.10 (2H, s), 5.78 (1H, s), 7, 16-7.22 (1H, m), 7.25-7.32 (5H, m), 7.74 (1H, dd, J = 2.0, 8.0 Hz), 8.55 (1H, d, J = 2.0 Hz).

[Production Example 210-1-4] 6-benzyl-pyridin-3-carbaldehyde

2-Benzyl-5- [1,3] dioxolan-2-yl-pyridine (7.3 g, 30 mmol) described in Production Example 210-1-3, and 2H hydrochloric acid (100 ml) was stirred at 100 ° C for 15 minutes. The reaction solution was cooled to room temperature and partitioned into ethyl acetate and 5N sodium hydroxide solution (40 ml). The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (4.7 g, 79%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.20 (2H, s), 7.18-7.25 (1H, m), 7.26-7.32 (4H, m ), 7.50 (1H, d, J = 8.0 Hz), 8.16 (1H, dd, J = 2.0, 8.0 Hz), 8.97-9.01 (1H, m) 10.06 (1H, s).

[Production Example 210-1-5] 2-benzyl-5 - (( E ) -2-nitrovinyl) pyridine

A mixture of 6-benzylpyridin-3-carbaldehyde (4.7 g, 24 mmol) described in Production Example 210-1-4, nitromethane (7.3 g, 120 mmol), ammonium acetate (5.6 g, 72 mmol) and acetic acid (40 ml) was stirred at 100 ° C for 90 minutes. The reaction solution was partitioned into ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 2: 1) to obtain the title compound (1.2 g, 21%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.11 (2H, s), 7.14-7.21 (1H, m), 7.23-7.29 (4H, m ), 7.38 (1H, d, J = 8.0 Hz), 8.12 (1H, d, J = 13.6 Hz), 8.18 (1H, dd, J = 2.0, 8, 0 Hz), 8.26 (1H, d, J = 13.6 Hz), 8.87 (1H, d, J = 2.0 Hz).

[Production Example 210-1-6] 2-benzyl-5- (2-nitroethyl) pyridine

To the mixture of 2-benzyl-5 - (( E ) -2-nitrovinyl) pyridine (1.2 g, 5.0 mmol) described in the preparation example 210-1-5, acetic acid (300 mg, 5.0 mM) and dimethyl sulfoxide (10 ml) sodium borohydride (94 mg, 2.5 mmol) was added and stirred at room temperature for 10 minutes. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and passed through a glass filter with NH silica gel (eluted with ethyl acetate). The eluate 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 (260 mg, 22%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.19 (2H, t, J = 6.8 Hz), 4.04 (2H, s), 4.86 (2H, t, J = 6.8 Hz), 7.16-7.30 (6H, m), 7.62 (1H, dd, J = 2.4, 8.0 Hz), 8.39 (1H, d, J = 2.4 Hz).

[Production Example 210-1-7] (6-benzylpyridin-3-yl) -acetohydroximoyl chloride

To 2-benzyl-5- (2-nitroethyl) pyridine (260 mg, 1.1 mmol) described in Production Example 210-1-6, and methanol (5 ml) were added lithium methoxide (81 mg, 2.1 mM) and concentrated under reduced pressure. To a suspension of the residue in methylene chloride (5 ml) and tetrahydrofuran (2.5 ml) at -76 ° C, titanium (IV) tetrachloride (0.38 ml, 3.4 mmol) was added dropwise and stirred at room temperature for 20 minutes . This reaction solution was added to ice water and extracted with ethyl acetate. The aqueous layer was again extracted with ethyl acetate (four times). The organic layers were combined, washed with an aqueous solution of sodium chloride (once), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and tetrahydrofuran was added to the residue. Insoluble materials thus obtained were filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (180 mg, 63%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.83 (2H, s), 4.07 (2H, s), 7.17-7.22 (1H, m), 7, 25-7.30 (5H, m), 7.60 (1H, dd, J = 2.0, 8.0 Hz), 8.39 (1H, d, J = 2.0 Hz), 11.77 (1H, s).

[Example 211] 3- (3- (2-fluoro-4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (43.2 mg, 0.325 mmol) described in Production Example 13-1-3 and (2-fluoro-4- (pyridin-2-yloxymethyl) phenyl) acetohydroximoyl chloride (150 mg, 0.509 mmol) described in Preparation Example 204-1-8, triethylamine (97.2 μl, 0.697 mmol) was added in tetrahydrofuran (3 ml) and stirred at room temperature for 2 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1, then ethyl acetate) to obtain the title compound (73 mg, 37%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 4.05 (2H, s), 4.49 (2H, br s), 5.26 (2H, br s), 5.37 ( 2H, s), 5.91-5.94 (1H, m), 6.06 (1H, s), 6.81-6.83 (1H, m), 6.89-6.92 (1H, m), 7.18-7.29 (3H, m), 7.48-7.51 (1H, m), 7.58-7.62 (1H, m), 8.16-8.18 ( 1H, m).

[Example 212] 3- (4- (5- (2,6-Diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenoxymethyl) benzonitrile

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (100 mg, 0.36 mmol) described in Production Example 18-1-1 in methanol ( 6.3 ml) was added a 2N aqueous sodium hydroxide solution (180 μl, 0.36 mmol). This mixture was concentrated under reduced pressure. N, N-dimethylformamide (1.3 ml) and 3-bromomethyl-benzonitrile (58 mg, 0.29 mmol) were added to the residue and stirred at 60 ° C for 15 minutes. This reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 2, then ethyl acetate) to obtain the title compound (24 mg, 17%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.88 (2H, s), 5.14 (2H, s), 5.79 (2H, br s), 5.82 ( 1H, d, J = 8.4 Hz), 6.11 (2H, br.s), 6.34 (1H, s), 6.98 (2H, d, J = 8.4 Hz), 7, 23 (2H, d, J = 8.4 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.61 (1H, dd, J = 8.0, 8.0 Hz), 7.76-7.82 (2H, m); 7.91 (1H, s).

[Example 213] 3- (4- (5- (2,6-Diaminopyridin-3-yl) -isoxazol-3-ylmethyl) -phenoxymethyl) -benzoic acid methyl ester

The title compound (48 mg, 16%) was obtained according to methods similar to the methods of Example 212 using 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (200 mg, 0.71 mmol) described in Production Example 18-1-1 and 3-bromomethyl benzoic acid methyl ester (160 mg, 0.71 mmol).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.86 (3H, s), 3.88 (2H, s), 5.17 (2H, s), 5.79 (2H, br.s), 5.82 (1H, d, J = 8.4 Hz), 6.11 (2H, br.s), 6.34 (1H, s), 6.97 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.55 (1H, dd, J = 8 , 0, 8.0 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.91 (1H, d, J = 8.0 Hz), 8.03 (1H, s).

[Example 214] 3- (3- (4- (3-Ethinylbenzyloxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (150 mg, 0.53 mmol) described in Production Example 18-1-1, (3- ethynylphenyl) methanol (91 mg, 0.69 mmol) described in Production Example 214-1-2, and triphenylphosphine (180 mg, 0.69 mmol) in tetrahydrofuran (10 ml) were added diethyl azodicarboxylate (300 mg, 0.69 mM, 40% toluene solution) and stirred at room temperature for 30 minutes. NH silica gel was added to the reaction solution, and the solvent was evaporated under reduced pressure. The crude product that was adsorbed on NH silica gel was purified by NH silica gel column chromatography (heptane: ethyl acetate = 2: 1, then 1: 1, then ethyl acetate) to obtain the title compound (110 mg, 51%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.88 (2H, s), 4.20 (1H, s), 5.09 (2H, s), 5.79 (2H, br.s), 5.82 (1H, d, J = 8.4 Hz), 6.10 (2H, br.s), 6.34 (1H, s), 6.96 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.38-7.54 (5H, m).

The starting material, (3-Ethynylphenyl) methanol, was synthesized as follows.

[Production Example 214-1-1] 1-bromo-3-methoxymethoxymethylbenzene

To a solution of 3-bromobenzyl alcohol (10 g, 54 mmol) in tetrahydrofuran (100 ml) was added sodium hydride (2.3 g, 98 mmol, 60% in oil) at room temperature. Then, chloromethyl methyl ether (5.2 g, 64 mmol) was added to this suspension and stirred at 60 ° C for 15 minutes. The mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 8: 1) to obtain the title compound (10 g, 83%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.30 (3H, s), 4.53 (2H, s), 4.66 (2H, s), 7.30-7, 38 (2H, m), 7.47-7.51 (1H, m), 7.54 (1H, m).

[Production Example 214-1-2] (3-ethynylphenyl) methanol

To the mixture of 1-bromo-3-methoxymethoxymethylbenzene (3.0 g, 13 mmol) described in Production Example 214-1-1, trimethylsilylacetylene (2.6 g, 26 mmol), N, N-diisopropylethylamine (3.4 g , 26 mM), copper (I) iodide (500 mg, 2.6 mM) and 1-methyl-2-pyrrolidone (30 ml) was added tetrakis (triphenylphosphine) palladium (0) (1.5 g, 1.3 mm ) and stirred at 60 ° C for 15 minutes. The mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 8: 1) to obtain a mixture of (3-methoxymethoxymethylphenylethynyl) -trimethylsilane and 1-bromo-3-methoxymethoxymethylbenzene (3.0 g of a mixture comprising approximately 30% (3-methoxymethoxymethylphenylethynyl) trimethylsilane). To a solution of this mixture in tetrahydrofuran (20 ml) was added tetrabutylammonium fluoride (2 ml, 1 M tetrahydrofuran solution) and stirred at room temperature for 15 minutes. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate = 20: 1) to obtain 1-ethynyl-3-methoxymethoxymethylbenzene (470 mg). To a solution of 1-ethynyl-3-methoxymethoxymethylbenzene (470 mg, 2.6 mmol) in methanol (10 ml) was added 5N hydrochloric acid and stirred at 70 ° C. for 25 minutes. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure to obtain the title compound (350 mg, 20%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.15 (1H, s), 4.49 (2H, d, J = 6.0 Hz), 5.25 (1H, t, J = 6.0 Hz), 7.31-7.35 (3H, m), 7.40-7.42 (1H, m).

[Example 215] 3- (3- (4- (6-Chloropyrazin-2-yloxy) -benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (50 mg, 0.18 mmol) described in Production Example 18-1-1 in methanol ( 1.5 ml) was added a 2N sodium hydroxide solution (89 μl) and concentrated under reduced pressure. The residue was added 2,6-dichloropyrazine (28 mg, 0.19 mmol) and N, N-dimethylformamide (0.75 ml) and stirred at 100 ° C for 10 minutes. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1, then ethyl acetate) to obtain the title compound (47 mg, 67%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 4.01 (2H, s), 5.82 (2H, br.s), 5.83 (1H, d, J = 8.4 Hz), 6.12 (2H, br.s), 6.44 (1H, s), 7.21 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8 4 Hz), 7.53 (1H, d, J = 8.4 Hz), 8.50 (1H, s), 8.53 (1H, s).

[Example 216] 3- (3- (4-Benzylsulfonylbenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (50 mg, 0.376 mmol) described in Production Example 13-1-3 and (4-benzylphenylsulfanylphenyl) acetohydroximoyl chloride (176 mg, 0.602 mmol) described in Example 205-1 -5 times, triethylamine (131 μl, 0.94 mmol) was added in tetrahydrofuran (3 ml) and stirred at room temperature for 2 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1, then ethyl acetate) to obtain the title compound (80 mg, 55%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.97 (2H, s), 4.10 (2H, s), 4.47 (2H, br s), 5.25 (2H, br.s), 5.92 (1H, d, J = 8.2 Hz), 5.96 (1H, s), 7.17 (2H, d, J = 8.8 Hz), 7.23- 7.29 (7H, m), 7.47 (1H, d, J = 8.2 Hz).

[Example 217] 3- (3- (4-Phenylsulfanylmethylbenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (50 mg, 0.376 mmol) described in Production Example 13-1-3 and (4-phenylsulfanylmethylphenyl) acetohydroximoyl chloride (176 mg, 0.602 mmol) described in Example 206-1 -6 preparation, triethylamine (131 μl, 0.94 mmol) was added in tetrahydrofuran (3 ml) and stirred at room temperature for 2 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1, then ethyl acetate) to obtain the title compound (98 mg, 67%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.98 (2H, s), 4.11 (2H, s), 4.46 (2H, br s), 5.25 (2H, br.s), 5.92 (1H, d, J = 8.4 Hz), 5.97 (1H, s), 7.18-7.32 (9H, m), 7.47 (1H, d , J = 8.4 Hz).

[Example 218] 3- (3- (4- (3-Methyl-2-but-2-enyloxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

The title compound (15 mg, 23%) was obtained according to methods similar to the methods of Example 212 using 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (50 mg, 0.18 mmol) described in Production Example 18-1-1, and 1-bromo-3-methyl-but-2-ene (32 mg, 0.21 mmol).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 1.69 (3H, s), 1.73 (3H, s), 3.87 (2H, s), 4.48 (2H, d, J = 6.4 Hz), 5.41 (1H, t, J = 6.4 Hz), 5.79 (2H, br.s), 5.82 (1H, d, J = 8.0 Hz), 6.10 (2H, br.s), 6.34 (1H, s), 6.86 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8 4 Hz), 7.50 (1H, d, J = 8.0 Hz).

[Example 219] 3- (3- (4-Prop-2-ynyloxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

The title compound (38 mg, 66%) was obtained according to methods similar to the methods of Example 212 using 4- (5- (2,6-diaminopyridin-3-yl) -isoxazol-3-ylmethyl) phenol (50 mg, 0.18 mmol) described in Production Example 18-1-1 and propargyl bromide (32 mg, 0.27 mmol).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.54 (1H, t, J = 2.0 Hz), 3.89 (2H, s), 4.76 (2H, d, J = 2.0 Hz), 5.79 (2H, br.s), 5.82 (1H, d, J = 8.4 Hz), 6.10 (2H, br.s), 6.35 ( 1H, s), 6.93 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.51 (1H, d, J = 8.4 Hz).

[Example 220] 3- (3- (4-Bromobenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (50 mg, 0.376 mmol) described in Production Example 13-1-3 and 4-bromophenylacetohydroximoyl chloride (150 mg, 0.602 mmol) described in Production Example 207-1-3 , in tetrahydrofuran (3 ml) triethylamine (131 μl, 0.94 mmol) was added and stirred at room temperature for 2 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1, then ethyl acetate) to obtain the title compound (85 mg, 66%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.97 (2H, s), 4.48 (2H, br s), 5.26 (2H, br s), 5.92 ( 1H, d, J = 8.4 Hz), 5.97 (1H, s), 7.15-7.13 (2H, m), 7.44-7.46 (2H, m), 7.48 (1H, d, J = 8.4 Hz).

[Example 221] 3- (3- (5- (4-Fluorobenzyl) -furan-2-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (50 mg, 0.376 mmol) described in Production Example 13-1-3 and (5- (4-fluorobenzyl) -furan-2-yl) acetohydroximoyl chloride (161 mg, 0.602 mmol) described in Preparation Example 208-1-5, triethylamine (131 μl, 0.94 mmol) was added in tetrahydrofuran (3 ml) and stirred at room temperature for 19 hours. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane = 1: 1, then ethyl acetate) to obtain the title compound (45 mg, 33%).

¹ H NMR Spectrum (CDCl ₃ ) δ (ppm): 3.91 (2H, s), 3.99 (2H, s), 4.49 (2H, br s), 5.25 (2H, br.s), 5.92 (1H, d, J = 2.8 Hz), 5.95 (1H, d, J = 8.4 Hz), 6.04 (1H, s), 6.06 ( 1H, d, J = 2.8 Hz), 6.96-7.01 (2H, m), 7.17-7.21 (2H, m), 7.45 (1H, d, J = 8, 4 Hz).

[Example 222] 3- (3- (4- (Pyridin-2-yloxy) -benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (45 mg, 0.34 mmol) described in Production Example 13-1-3 and (4- (pyridin-2-yloxy) benzene) -acetohydroximoyl chloride (300 mg, 1.1 mM) described in Production Example 209-1-4, triethylamine (120 mg, 1.1 mmol) was added in tetrahydrofuran (15 ml) and stirred at 60 ° C for 10 minutes. The reaction solution was cooled to room temperature, NH silica gel was added, and the solvent was evaporated under reduced pressure. The crude product that was adsorbed on NH silica gel was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1, then ethyl acetate) to obtain the title compound (57 mg, 14%).

¹ H NMR spectrum (DMSO-d ₆ ) δ (ppm): 3.97 (2H, s), 5.82 (2H, br s), 5.84 (1H, d, J = 8.0 Hz), 6.11 (2H, br.s), 6.42 (1H, s), 6.99-7.03 (1H, m), 7.05-7.13 (3H, m), 7 34 (2H, d, J = 8.0 Hz), 7.53 (1H, d, J = 8.0 Hz), 7.81-7.86 (1H, m), 8.12-8, 14 (1H, m).

[Example 223] 3- (3- (6-Benzyl-pyridin-3-ylmethyl) -isoxazol-5-yl) -pyridin-2,6-diamine

To a solution of 3-ethynylpyridin-2,6-diamine (20 mg, 0.15 mmol) described in Production Example 13-1-3 and 2- (6-benzylpyridin-3-yl) -acetohydroximoyl chloride (79 mg, 0 30 mM) described in Production Example 210-1-7, triethylamine (46 mg, 0.45 mmol) was added in tetrahydrofuran (5 ml) and stirred at 50 ° C for 30 minutes. The reaction solution was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate, then ethyl acetate: methanol = 20: 1) to obtain the title compound (43 mg, 80%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.95 (2H, s), 4.05 (2H, s), 5.80 (2H, br s), 5.82 ( 1H, d, J = 8.8 Hz), 6.11 (2H, br.s), 6.40 (1H, s), 7.15-7.30 (6H, m), 7.50 (1H d, J = 8.8 Hz), 7.62 (1H, dd, J = 2.0, 8.0 Hz), 8.46 (1H, d, J = 2.0 Hz).

[Example 224: 3- (3- (6-Benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) -N ^6- methylpyridin-2,6-diamine

To a mixture of 3- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine (50 mg, 0.13 mmol) described in Example 25 and N, N -dimethylformamide (0.5 ml) was added at room temperature an aqueous solution of formaldehyde (14 mg, 0.17 mmol, content: 37%), α-picolinborane (17 mg, 0.16 mmol) and acetic acid (50 μl) and stirred at the same temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the organic layer was concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain a crude product, and then purified by silica gel thin-layer chromatography (diethyl ether: hexane = 2: 1) to obtain the title compounds (2.3 mg, 4.4%).

1H NMR spectrum (DMSO-d ₆ ) δ (ppm): 2.76 (3H, d, J = 4.2 Hz), 3.91 (2H, s), 5.33 (2H, s), 5.83 (1H, d, J = 8.4 Hz), 5.87 (2H, br.s), 6.40 (1H, s), 6.68 (1H, br.s), 6.85 (1H, d, J = 8.6 Hz), 7.31-7.33 (1H, m), 7.35-7.39 (2H, m), 7.42-7.44 (2H, m ), 7.52 (1H, d, J = 8.6 Hz), 7.66 (1H, dd, J = 2.1, 8.3 Hz), 8.14 (1H, d, J = 2, 6 Hz).

[Example 225] 2- (6-amino-5- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-ylamino) ethanol

To a mixture of 3- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and N, N α-dimethylformamide (0.5 ml) was added at room temperature 2-hydroxyacetaldehyde (7.7 mg, 0.13 mmol), α-picolinborane (14 mg, 0.13 mmol) and acetic acid (40 μl) and stirred at that same temperature for 100 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the organic layer was concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain a crude product and then purified by NH silica gel column chromatography (ethyl acetate: methanol = 50: 1) to obtain the title compounds (4.5 mg, 10%).

1H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.31-3.34 (2H, m), 3.48-3.51 (2H, m), 3.91 (2H, s) , 5.33 (2H, s), 5.86 (2H, br.s), 5.89 (1H, d, J = 8.6 Hz), 6.39 (1H, s), 6.72 ( 1H, br.s), 6.85 (1H, d, J = 8.4 Hz), 7.29-7.33 (1H, m), 7.35-7.39 (2H, m), 7 , 42-7.44 (2H, m), 7.50 (1H, d, J = 8.6 Hz), 7.66 (1H, dd, J = 2.6, 8.6 Hz), 8, 14 (1H, d, J = 2.0 Hz).

[Example 226] N- (6-amino-5- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-yl) -2-methoxyacetamide

To a mixture of 3- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and dichloromethane (1 ml) at room temperature triethylamine (22 μl, 0.16 mmol) and methoxyacetyl chloride (15 mg, 0.14 mmol) were added and stirred at the same temperature for 2 hours. The solid precipitated in the reaction mixture was filtered. Tetrahydrofuran was added to the solid thus obtained, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (3.4 mg, 7%).

¹ H NMR Spectrum (DMSO-d ₆ ) δ (ppm): 3.37 (3H, m), 3.98 (2H, s), 4.05 (2H, s), 5.33 (2H, c), 6.23 (2H, br.s), 6.73 (1H, s), 6.86 (1H, d, J = 8.4 Hz), 7.29-7.33 (1H, m ), 7.35-7.44 (5H, m), 7.68 (1H, dd, J = 2.6, 8.4 Hz), 7.91 (1H, d, J = 8.4 Hz) 8.16 (1H, d, J = 2.4 Hz); 9.50 (1H, br s).

[Example 227] Ethyl ester of (6-amino-5- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-ylamino) -acetic acid

To a mixture of 3- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and N, N α-dimethylformamide (0.5 ml) was added the polymeric foam of glyoxylic acid ethyl ester (16 mg, 0.16 mmol), α-picoline borane (14 mg, 0.13 mmol) and acetic acid (40 μl) same temperature during the night. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which the organic layer was concentrated under reduced pressure. The residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (4.9 mg, 8%) as a trifluoroacetic acid salt.

MS m / e (ESI) 460.51 (MH ⁺ )

[Example 228] (3- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-yl) dimethylamine

To a mixture of 3- (3- (4-Benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine (50 mg, 0.14 mmol) described in Example 1, and N, N-dimethylformamide (0.5 ml) was added an aqueous solution of formaldehyde (34 mg, 0.42 mmol, content: 37%), α-picolinborane (37 mg, 0.35 mmol) and acetic acid (50 μl) and stirred at the same temperature overnight. Trifluoroacetic acid (50 μl) was added to the reaction mixture and stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue thus obtained was purified by reverse phase high performance liquid chromatography (using a mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (15 mg, 21%) as trifluoroacetate.

MS m / e (ESI) 386.30 (MH ⁺ )

Compounds (I) of the present invention or their salts exhibit excellent activity in inhibiting the transport of GPI-anchored proteins, based on the inhibition of biosynthesis of GPI fungus, activity against Candida and activity against Aspergillus , and are also exceptional in terms of their physical properties, safety and metabolic stability , which makes them extremely useful as prophylactic or therapeutic agents against fungal infections.

Pharmacological Testing Examples

To demonstrate the applicability of the compounds (I) of the present invention, the antifungal activity of the compounds (I) of the present invention was evaluated based on a measurement of 1) activity against Candida and against Aspergillus and 2) activity in an experimental systemic mouse model of Candida infection.

1. Activity against Candida and activity against Aspergillus

(1) Preparation of fungal suspension

For strain C. albicans CAF2-1 a fungal suspension from a stationary culture cultured at 30 ° C for 48 hours in Saburo's culture medium with liquid dextrose (SDB) was diluted with RPMI1640 medium to bring the concentration of the fungal suspension to 1.2 × 10 ³ cells / ml. As for the A. fumigiatus Tsukuba strain , the strain stored at -80 ° C was diluted with RPMI1640 medium, bringing the concentration of the fungal suspension to 4.5 × 10 ³ cells / ml.

(2) Preparation of Diluted Agent Tablets

Using a 96-well plate with a U-shaped bottom, 8 samples / plate (A-H) of solutions with a diluted sample were prepared. In the 2nd and 12th rows, 10 μl of dimethyl sulfoxide solution was added. The weighed sample was diluted in dimethyl sulfoxide to obtain a solution with a concentration of 2.5 mg / ml, 20 μl of this solution was added to the first row of the prepared plate, and 12 stages of double dilutions were performed on the tablet (10 μl of the solution + 10 μl of dimethyl sulfoxide solution). This diluted sample solution was added in an amount of 1 μl to a 96-well flat bottom MIC plate to prepare a diluted sample plate.

(3) Inoculation of fungal suspension and culture

The fungal suspension prepared according to the item (1) was used in an amount of 99 μl / well for adding to a 96-well flat-bottom plate containing 1 μl / well of a test dilution of the compound prepared according to (2), and the stationary culture was aerobically cultured at 35 ° C for 42-48 hours.

(4) MIC measurement

The minimum concentration that clearly inhibited the growth of the fungus compared to the visual inspection control was determined as the minimum inhibition concentration (MIC).

The following representative compounds obtained in the examples were measured for anti- Candida activity and anti- Aspergillus activity using the measurement method described in paragraph 1. As a result, as shown in Tables 1-6, it was found that the compounds of the present invention have obvious anti-activity Candida and against Aspergillus .

Table 1 Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) one 0.20 0.20 21 1,56 0.78 2 0.05 0.20 22 0.20 0.39 3 0.10 0.78 23 0.78 1,56 four 0.20 0.39 24 0.39 0.78 5 0.39 0.39 25 0.20 0.20 6 0.39 0.39 26 0.78 0.78 7 1,56 0.20 27 0.20 0.39 8 1,56 0.78 28 > 25 0.39 9 0.20 0.39 29th 0.39 0.20 10 0.39 0.78 thirty 0.10 0.20 eleven 0.10 0.39 31 0.20 0.39 12 0.10 0.10 32 0.20 0.78 13 0.20 0.10 33 0.39 0.78 fourteen 0.39 0.39 34 0.78 0.39 fifteen 0.20 0.39 35 0.20 1,56 16 0.39 0.39 36 0.39 0.78 17 0.78 0.20 37 0.39 1,56 eighteen 1,56 0.78 38 0.78 1,56 19 0.78 0.39 39 3.13 3.13 twenty 0.78 0.20 40 0.39 0.39

table 2 Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) 41 0.39 0.20 61 0.20 0.39 42 0.78 1,56 62 0.20 0.20 43 0.20 0.39 63 0.78 0.78 44 1,56 1,56 64 0.20 0.78 45 0.39 0.20 65 0.39 0.78 46 0.05 0.20 66 0.10 0.78 47 0.20 0.39 67 1,56 0.78 48 0.39 0.20 68 0.10 0.39 49 0.05 0.39 69 0.10 0.20 fifty 0.78 1,56 70 1,56 0.39 51 0.10 0.39 71 0.20 0.39 52 0.39 0.39 72 6.25 12.5 53 0.20 0.20 73 0.10 0.39 54 0.10 0.39 74 0.10 0.20 55 0.05 0.10 75 0.78 0.20 56 1,56 > 25 76 1,56 1,56 57 0.05 0.20 77 0.20 0.39 58 0.78 0.10 78 0.78 1,56 59 0.39 0.39 79 1,56 6.25 60 0.20 1,56 80 0.20 0.78

Table 3 Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) 81 0.20 0.39 101 1,56 1,56 82 0.20 0.39 102 0.20 0.39 83 0.20 0.20 103 1,56 0.78 84 3.13 > 25 104 0.78 0.78 85 1,56 3.13 105 0.20 0.20 86 0.05 0.20 106 0.78 0.20 87 0.20 0.78 107 0.78 0.78 88 0.20 0.20 108 1,56 3.13 89 0.39 0.20 109 0.39 0.78 90 1,56 0.39 110 0.78 0.78 91 0.20 0.10 111 0.39 0.78 92 0.39 0.39 112 0.78 0.39 93 0.20 1,56 113 0.10 0.20 94 0.78 0.39 114 6.25 6.25 95 0.39 1,56 115 0.10 0.20 96 3.13 0.78 116 0.78 0.20 97 0.39 0.20 117 1,56 0.78 98 0.39 0.39 118 0.78 3.13 99 3.13 0.78 119 0.39 0.78 one hundred 3.13 6.25 120 0.39 0.20

Table 4 Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) 121 0.39 0.78 141 0.39 0.20 122 1,56 0.78 142 0.39 0.39 123 0.20 0.39 143 0.39 0.78 124 0.20 0.39 144 0.39 0.20 125 0.10 0.39 145 6.25 12.5 126 1,56 0.39 146 6.25 > 25 127 0.78 1,56 147 1,56 1,56 128 0.20 0.39 148 0.20 0.20 129 0.20 0.20 149 6.25 1,56 130 1,56 0.20 150 0.39 0.78 131 0.20 0.20 151 0.78 0.39 132 3.13 3.13 152 0.78 0.39 133 0.20 0.39 153 1,56 0.39 134 0.39 0.78 154 0.78 1,56 135 0.78 0.39 155 0.10 0.10 136 0.20 0.20 156 0.20 0.20 137 0.78 1,56 157 3.13 0.78 138 0.78 0.78 158 1,56 3.13 139 1,56 > 25 159 0.78 3.13 140 0.20 0.78 160 0.39 0.78

Table 5 Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) 161 0.39 0.39 181 1,56 0.39 162 0.78 0.39 182 > 25 0.20 163 3.13 1,56 183 0.20 0.78 164 6.25 6.25 184 > 25 0.39 165 0.78 1,56 185 0.78 0.78 166 0.39 0.78 186 3.13 0.78 167 1,56 0.78 187 1,56 0.78 168 0.78 0.78 188 1,56 0.78 169 0.39 0.39 189 0.05 0.20 170 0.78 0.39 190 0.78 0.78 171 0.20 0.39 191 0.20 0.39 172 6.25 12.5 192 0.39 1,56 173 1,56 0.78 193 0.78 0.78 174 6.25 1,56 194 1,56 3.13 175 0.78 1,56 195 0.39 0.78 176 0.20 0.20 196 6.25 6.25 177 0.39 0.78 197 3.13 1,56 178 0.39 0.20 198 0.78 1,56 179 0.78 0.39 199 3.13 6.25 180 0.39 1,56 200 3.13 3.13

Table 6 Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) Example No. Activity against Candida (mcg / ml) Activity against Aspergillus (mcg / ml) 201 0.78 0.39 215 0.39 0.78 202 0.05 0.20 216 0.39 0.39 203 0.20 1,56 217 0.10 0.20 204 0.20 0.39 218 0.20 0.10 205 0.39 0.78 219 3.13 3.13 206 0.10 0.39 220 6.25 6.25 207 25 6.25 221 1,56 0.39 208 6.25 0.78 222 0.39 0.39 209 0.20 0.39 223 0.39 0.39 210 0.10 0.20 224 0.39 0.20 211 0.39 0.39 225 0.78 3.13 212 0.78 0.78 226 0.39 0.39 213 6.25 1,56 227 1,56 1,56 214 0.39 0.39 228 0.78 0.78

Experimental systemic mouse model of Candida infection

(1) Preparation of the fungal inoculant

A static culture of C. albicans strain E81022 was cultured at 30 ° C for 48 hours in Saburo dextrose (SDA) agar medium, and the reconstituted fungal cells were suspended in sterilized physiological saline. By counting the number of fungal cells on a cytometric plate, the suspension was diluted to 2 × 10 ⁷ cells / ml with sterilized saline to inoculate the fungus.

(2) Infection

The fungal inoculum was used in amounts of 0.2 ml for inoculation (4 × 10 ⁶ cells / mouse) into the tail vein of female ICR mice of 4.5-5.5 weeks old.

(3) Processing

0.5-1 hours after inoculation of the fungus, 0.2 ml of a solution containing an agent (dissolved or suspended in a sterilized saline solution containing 6.5% dimethyl sulfoxide and 3.5% tween 80) was injected into the stomach using an oral probe, 3 times every 4 hours. The concentration of the agent was 2.5 mg / kg, and the number of animals in one group was 5.

(4) Effect assessment

The protective effect was determined by analyzing the life / death ratio within 14 days after infection and the average number of days of survival was calculated.

As a result, as shown in Tables 7 and 8, mice with the administered compounds of the present invention remained alive for a longer time than the untreated group, and it was found that the compounds of the present invention exhibit in vivo activity against Candida.

Table 7 Example No. The average number of days of survival Untreated group (control) 2.5 mg / kg 10 mg / kg one 4.0 12,2 14.0 2 4.0 13,2 14.0 9 3.4 12.8 14.0 eleven 2.6 8.2 13.6 12 2.6 10.8 14.0 13 6.0 13.8 14.0 fourteen 4.0 13,4 14.0 fifteen 2.6 10.8 12.6 16 4.0 4.8 12.8 17 4.0 8.2 13.0 24 2.6 7.4 14.0 25 2.6 12,2 - 27 2.6 3.0 10.0 29th 3.2 - 11,4 thirty 6.0 13.0 - 31 6.0 - 13.0 32 6.0 10,2 12,2 33 6.0 2,4 8.4 36 6.0 9,4 14.0 37 6.0 5,4 14.0 38 6.0 4.8 10.0 40 4.0 11.6 14.0 41 4.0 11,4 11.8

Table 8 Example No. The average number of days of survival Untreated group (control) 2.5 mg / kg 10 mg / kg 43 3.2 10.6 14.0 45 3.2 10.6 10.8 51 4.0 13.5 14.0 52 4.0 10.6 13,4 54 2,8 13.0 13.6 55 2,8 13.8 14.0 58 2,8 3.8 12.0 62 1.4 10,2 - 73 2.2 4.4 12.6 102 3.2 13,2 13.0 104 3.2 8.2 13,2 105 3.2 5,4 12.8 109 2,8 11.0 11.8 110 2,8 12.0 - 111 2,8 13.6 - 112 4.0 - 12,2 113 2,8 13.0 14.0 115 2,8 10.8 13,2 116 2,8 4.6 12.6 120 2,8 3.2 13,4 131 1.4 12.6 12.8 133 2.2 7.0 13,4 135 2.2 11.0 13,4 151 2,4 7.0 14.0 155 2,4 10,4 13.0 166 2,8 3.4 12,4 171 2,8 8.4 12.6 176 4.2 12.6 13,4 192 1,0 3.2 9,4 202 1,0 2,4 10.0

Industrial applicability

According to the present invention, the compound (I) of the present invention or its salt 1) acts against the appearance, progression and persistence of infections by inhibiting the biosynthesis of fungal GPI, thereby inhibiting the expression of cell wall proteins and blocking the assembly of the cell wall, preventing pathogens from adhering to the cells so that pathogens cannot become pathogenic, and 2) are exceptional in terms of their physical properties, safe and metabolically stable, and extremely useful as a prophylactic and a therapeutic agent for fungal infections.

Claims (36)

1. The compound represented by the following formula (I), or a salt thereof:

where R ¹ represents a hydrogen atom, an amino group, R ¹¹ —NH— (where R ¹¹ represents a C _1-6 alkyl group, a hydroxy-C _1-6 alkyl group, a C _1-6 alkoxycarbonyl-C _1-6 alkyl group) R ¹² - (CO) -NH- (where R ¹² represents a C _1-6 alkyl group or a C _1-6 alkoxy-C _1-6 alkyl group), a C _1-6 alkyl group, a hydroxy-C _1-6 an 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, a C _1-6 alkyl group, an amino group or a di-C _1-6 alkylamino group;
one of X and Y represents a nitrogen atom, while the other represents a nitrogen atom or an oxygen atom;
ring A represents a 5- or 6-membered heteroaryl ring or a benzene ring which may have 1 or 2 halogen atoms;
Z represents a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, —CH ₂ O—, —OCH ₂ -, —NH—, —CH ₂ NH—, —NHCH ₂ -, —CH ₂ S— or
-SCH ₂ -;
R ³ represents a hydrogen atom or a halogen atom, or a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _6-10 aryl group, a 5- or 6-membered heteroaryl group, where these groups can have 1 or 2 substituents selected from group a substituents: and
[group of α substituents]
the substituent group α represents a group consisting of a halogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group and a C _{3- 6} alkynyl groups;
R ⁴ represents a hydrogen atom or a halogen atom;
with the exception of compounds in which all of R ¹ , R ^2, and R ⁴ represent a hydrogen atom at the same time that Z represents a single bond or R ³ represents a hydrogen atom. 2. The compound according to claim 1 or its salt, in which part of the structure represented by formula (II):

in the compound represented by formula (I):

,
represents a part of a structure selected from the group consisting of:

,

,

and

; 3. The compound according to claim 1 or its salt, in which one of X and Y represents a nitrogen atom, and the other represents an oxygen atom. 4. The compound according to claim 3 or its salt, in which part of the structure represented by formula (II):

in the compound represented by formula (I):

represents a part of the structure represented by the following formula (III):

or a part of the structure represented by the following formula (IV):

5. The compound according to claim 1 or its salt, in which both X and Y are nitrogen atoms. 6. The compound according to claim 5 or its salt, in which part of the structure represented by formula (II):

in the compound represented by formula (I):

represents the part of the structure represented by the following formula (V):

or a part of the structure represented by the following formula (VI):

7. The compound according to any one of claims 1 to 6 or its salt, in which R ² represents an amino group. 8. The compound according to claim 7 or its salt, in which R ¹ represents a hydrogen atom, an amino group or a C _1-6 alkoxy-C _1-6 alkyl group. 9. The compound according to any one of claims 1 to 6, or a salt thereof, in which R ¹ represents an amino group and R ² represents a hydrogen atom. 10. The compound according to any one of claims 1 to 6 or a salt thereof, in which ring A is a pyridine ring, a benzene ring, a furan ring, a thiophene ring or a pyrrole ring. 11. The compound of claim 10 or a salt thereof, wherein ring A is a pyridine ring or a benzene ring. 12. The compound according to any one of claims 1 to 6, or a salt thereof, in which Z represents an oxygen atom, —CH ₂ O— or —OCH ₂ -. 13. The compound and its pharmaceutically acceptable salt, and the compound is selected from the group consisting of:
3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine;
3- (3- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (4-benzyloxybenzyl) -isoxazole-5-yl) -pyridin-2,6-diamine;
3- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (6-benzyloxypyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (5- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-3-yl) pyridin-2-ylamine;
3- (1- (4- (pyridin-2-yloxymethyl) benzyl) -1H-pyrazol-4-yl) pyridin-2-ylamine;
3- (3- (6-phenoxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (4- (5-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (4- (6-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-yl amine;
3- (3- (4- (4-chloropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-yl amine;
3- (3- (6-phenoxymethylpyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (4- (5-chlorofuran-2-ylmethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (4-phenylaminomethylbenzyl) -isoxazol-5-yl) -pyridin-2-ylamine;
3- (3- (4- (4-methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (6-phenoxymethylpyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (4- (6-fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (1-benzyl-1H-pyrrol-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (6- (3-fluorophenoxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (6- (4-fluorophenoxy) -pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine;
5- (3- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (6-benzyloxypyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (4- (6-methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (4-butoxymethyl-benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine;
3- (3- (4-phenoxybenzyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (3- (4- (4-methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine;
3- (1- (4-benzyloxybenzyl) -1H-pyrazol-4-yl) pyridin-2,6-diamine;
3- (3- (4- (4-methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (4- (6-fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine;
3- (3- (4- (6-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine; and
3- (3- (6- (4-fluorobenzyloxy) pyridin-3-ylmethyl) isoxazol-5-yl) pyridin-2,6-diamine. 14. The compound representing 3- (3- (4-benzyloxybenzyl) -isoxazol-5-yl) -pyridin-2-ylamine

or a pharmaceutically acceptable salt thereof. 15. The compound representing 3- (3- (4- (pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

or a pharmaceutically acceptable salt thereof. 16. The compound representing
3- (3- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2-ylamine

or a pharmaceutically acceptable salt thereof. 17. The compound representing
3- (3- (4-pyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 18. The compound representing 3- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 19. The compound representing
3- (1- (4- (pyridin-2-yloxymethyl) benzyl) -1H-pyrazol-4-yl) pyridin-2-ylamine

or a pharmaceutically acceptable salt thereof. 20. The compound representing
3- (3- (6-phenoxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition having antifungal activity, comprising a compound according to any one of claims 1 to 6, or a salt thereof. 22. A drug having antifungal activity, comprising a compound according to any one of claims 1 to 6, or a salt thereof. 23. An antifungal agent comprising, as an active component, a compound according to any one of claims 1 to 6 or a salt thereof. 24. A method of preventing and / or treating a fungal infection, comprising administering a pharmacologically effective dose of a compound according to any one of claims 1 to 6 or a salt thereof. 25. The use of the compound according to any one of claims 1 to 6 or its salt to obtain an antifungal agent. 26. A compound representing
3- (3- (6-benzyloxypyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2-yl amine:

or a pharmaceutically acceptable salt thereof. 27. The compound representing
3- (3- (4- (6-methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 28. The compound is a
3- (3- (4-butoxymethyl-benzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 29. The compound representing
3- (3- (4-phenoxybenzyl) -isoxazol-5-yl) -pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 30. A compound representing
3- (3- (4- (pyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 31. A compound representing
3- (3- (4- (4-methylpyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 32. A compound representing
3- (1- (4-benzyloxybenzyl) -1H-pyrazol-4-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 33. A compound representing
3- (3- (4- (4-methylpyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

or a pharmaceutically acceptable salt thereof. 34. The compound representing
3- (3- (4- (6-fluoropyridin-2-yloxymethyl) benzyl) isoxazol-5-yl) pyridin-2-ylamine

or a pharmaceutically acceptable salt thereof. 35. The compound is a
3- (3- (4- (6-fluoropyridin-2-ylmethoxy) benzyl) isoxazol-5-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof. 36. The compound is a
3- (3- (6- (4-fluorobenzyloxy) -pyridin-3-ylmethyl) -isoxazol-5-yl) pyridin-2,6-diamine

or a pharmaceutically acceptable salt thereof.