JP2020059651A - Pyrazole derivative and pharmaceutical containing the same - Google Patents

Abstract

To provide a novel compound having retinoic acid receptor related orphan receptor γt inhibitory effect and useful as prevention or treatment agent of autoimmune diseases or allergic diseases.SOLUTION: There is provided a pyrazole derivative represented by the following formula, such as 1-(tert-butyl)-4-chloro-5-((3,5-dichloropyridine-2-yl)oxy)-N-(4-sulfamoylbenzyl)-1H-pyrazole-3-carboxamide or 1-(tert-butyl)-4-ethyl-N-((5-(ethylsulfonyl)pyridine-2-yl)methyl)-5-((3-(trifluoromethyl)pyridine-2-yl)oxy)-1H-pyrazole-3-carboxamide, or a salt thereof.SELECTED DRAWING: None

Description

  The present invention contains a novel pyrazole derivative or salt thereof having a retinoic acid receptor-related orphan receptor γt (retinoic acid receptor-related orphan receptor-γt: RORγt) inhibitory action, and the pyrazole derivative or salt thereof as an active ingredient. Related medicine.

  The retinoic acid receptor-related orphan receptor (ROR) is one of the orphan nuclear receptor subfamilies, and there are three subtypes of RORα, RORβ and RORγ. RORγt is a splicing variant of RORγ and is mainly expressed in cells of the immune system. Recently, it was revealed that RORγt functions as an important regulator of Th17 cell differentiation (Non-Patent Document 1). Regarding the importance of RORγt in the differentiation of Th17 cells and its involvement in the disease of Th17 cells, the differentiation of Th17 cells and the production of IL-17 in T cells of RORγt knockout mice are suppressed, and a model of multiple sclerosis pathology. It is shown by suppressing the pathological condition of Experimental Autoimmune encephalomyelitis, which is a non-patent document 2).

  Th17 cells are one of the helper T cell subsets that produce inflammatory cytocans such as IL-17A, IL-17F, IL-21 and IL-22. Th17 cells or inflammatory cytokines such as IL-17A and IL-17F are used in various types including psoriasis, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), rheumatoid arthritis, systemic lupus erythematosus, etc. The relationship has been shown in autoimmune diseases and allergic diseases (Non-Patent Document 3). Therefore, a drug that inhibits the action of RORγt suppresses the differentiation and activation of Th17 cells and exerts a therapeutic or prophylactic effect in various diseases involving Th17 cells or inflammatory cytokines such as IL-17A and IL-17F. It is expected.

（式中、Ｘは酸素又は窒素を示す。詳細は当該文献を参照のこと。） For example, compounds represented by the following formulas have been known as RORγt inhibitors (Patent Documents 1 to 6).
(Patent Document 1)

(In the formula, X represents oxygen or nitrogen. For details, refer to the document.)

（式中、Ｒ³は６〜１０員環の１又は２環性の芳香環、若しくは、５〜１４員環の１，２又は３環性のヘテロ芳香環で、Ｎ，Ｏ又はＳのいずれかのヘテロ原子を１〜５個含む。詳細は当該文献を参照のこと。） (Patent Document 2)

(In the formula, R ³ is a 6- to 10-membered 1- or 2-cyclic aromatic ring, or a 5- to 14-membered 1, 2 or 3-cyclic heteroaromatic ring, and is either N, O or S. 1 to 5 heteroatoms, see the literature for details.)

（式中、Ｘ、Ｙ及びＺは窒素原子若しくはＲ^eが置換した炭素原子を示す。詳細は当該文献を参照のこと。） (Patent Document 3)

(In the formula, X, Y and Z represent a nitrogen atom or a carbon atom substituted with R ^e . For details, refer to the literature.)

（式中、Ｘは−Ｃ（＝Ｏ）ＮＨ−又はＮＨＣ（＝Ｏ）−を示す。詳細は当該文献を参照のこと。） (Patent Document 4)

(In the formula, X represents -C (= O) NH- or NHC (= O)-. For details, refer to the document.)

（式中、Ｒ³はΗ, Ｆ, Ｃｌ, ＣＨ₃又はＣＦ₃を示す。詳細は当該文献を参照のこと。） (Patent Document 5)

(In the formula, R ³ represents Η, F, Cl, CH ₃ or CF _3. For details, refer to the literature.)

（式中、Ｒ³及びＲ⁴はΗ又はＣＨ₃を示す。詳細は当該文献を参照のこと。） (Patent Document 6)

(In the formula, R ³ and R ⁴ represent Η or CH _3. For details, refer to the literature.)

International publication WO2012 / 100734 pamphlet International publication WO2014 / 023367 Pamphlet International publication WO2015 / 017335 pamphlet International publication WO2015 / 116904 pamphlet International publication WO2015 / 129926 pamphlet International publication WO2016 / 061160 Pamphlet

Jetten, Nuclear Receptor Signaling, 2009, Volume 7, e003 Ivanov et al., Cell, 2006, Volume 126, p.1121-1133. Maddur et al., Am. J. Pathol, 2012, Volume 181, p.8-18

An object of the present invention is to provide a novel compound or a salt thereof having a RORγt inhibitory action and useful as a preventive or therapeutic agent for autoimmune diseases, allergic diseases and the like.
Another object of the present invention is to provide a medicament containing the novel compound or salt thereof as an active ingredient and useful for preventing or treating autoimmune diseases, allergic diseases and the like.

As a result of intensive studies to solve the above problems, the present inventors have found that the pyrazole derivative represented by the following general formula (I) has an excellent RORγt inhibitory action, and the present invention is based on this finding. Was completed.
Hereinafter, the present invention will be described in detail. In the following description, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is generically referred to as "pyrazole derivative of the present invention".

［式中、
Ｒ^１は、Ｃ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６ハロアルキル基又はＣ_３〜Ｃ_６シクロアルキル基、
Ｒ^２は、水素原子、ハロゲン原子、Ｃ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６ハロアルキル基またはＣ_３〜Ｃ_６シクロアルキル基、
Ｒ^３及びＲ^４は、それぞれ独立して水素原子、Ｃ_１〜Ｃ_６アルコキシ基で置換されていても良いＣ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６ヒドロキシアルキル基、ＣＯＲ^ａ（ここでＲ^ａは、ＯＨ、Ｃ_１〜Ｃ_６アルコキシ基若しくはＮＨ_２を示す）、Ｃ_３〜Ｃ_６シクロアルキル基又は４〜６員のオキサシクロアルキル基を示すか、あるいはＲ^３とＲ^４が結合する炭素原子と一体となって３〜６員のシクロアルキル若しくは４〜６員のオキサシクロアルキルを形成していてもよく、
Ｒ^５は、Ｒ^ｋで置換されていても良いＣ_１〜Ｃ_６アルキル基（ここで、Ｒ^ｋは、Ｃ_３〜Ｃ_６シクロアルキル基若しくは４〜６員のオキサシクロアルキル基を示す）、Ｃ_１〜Ｃ_６ハロアルキル基又はＮＨＲ^ｂ（ここでＲ^ｂは、水素原子、Ｃ_１〜Ｃ_６アルキル基、Ｃ_３〜Ｃ_６シクロアルキル基若しくは４〜６員のオキサシクロアルキル基を示す）、
Ｙ^１、Ｙ^２、Ｙ^３及びＹ^４は、それぞれ独立して、Ｎ又はＣＲ^ｃ１、ＣＲ^ｃ２、ＣＲ^ｃ３若しくはＣＲ^ｃ４（ここで、Ｒ^ｃ１、Ｒ^ｃ２、Ｒ^ｃ３及びＲ^ｃ４は、それぞれ独立して、水素原子、ハロゲン原子、Ｃ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６アルコキシ基若しくはＣ_１〜Ｃ_６ハロアルキル基を示す）、
Ｒ^７は、水素原子；ハロゲン原子；シアノ基；Ｒ^ｄで置換されていても良いＣ_１〜Ｃ_６アルキル基（ここで、Ｒ^ｄは、Ｃ_１〜Ｃ_６アルコキシ基若しくはジＣ_１〜Ｃ_６アルキルアミノ基を示す）；Ｃ_２〜Ｃ_６アルケニル基；Ｃ_１〜Ｃ_６アルコキシ基；水酸基で置換されていても良いＣ_１〜Ｃ_６ハロアルキル基；水酸基で置換されても良いＣ_２〜Ｃ_６アルキニル基；Ｃ_１〜Ｃ_６ハロアルコキシ基；Ｃ_１〜Ｃ_６ハロアルキル基若しくはＣ_３〜Ｃ_６シクロアルキル基で置換されていても良いＣ_１〜Ｃ_６ヒドロキシアルキル基；ＯＲ^ｅ（ここでＲ^ｅは、Ｃ_１〜Ｃ_６ハロアルキル基、Ｃ_１〜Ｃ_６ヒドロキシアルキル基、Ｃ_３〜Ｃ_６シクロアルキルＣ_１〜Ｃ_６アルキル基若しくは４〜６員のオキサシクロアルキル基を示す）；ＮＲ^ｆＲ^ｇ（ここで、Ｒ^ｆ及びＲ^ｇは、それぞれ独立して、水素原子、Ｃ_１〜Ｃ_６ハロアルコキシ基で置換されていても良いＣ_１〜Ｃ_６アルキル基、水酸基で置換されていても良いＣ_３〜Ｃ_６シクロアルキル基、Ｃ_１〜Ｃ_６ヒドロキシアルキル基又はＲ^ｆとＲ^ｇが隣接する窒素原子と一体となって４〜６員の含窒素複素環を形成していてもよく、また当該含窒素複素環は、水酸基、Ｃ_１〜Ｃ_６アルキル基若しくはＣ_１〜Ｃ_６ヒドロキシアルキル基で置換されていても良い）；ＮＲ^ｈＲ^ｉで置換されたＣ_１〜Ｃ_６アルキル基（ここで、Ｒ^ｈ及びＲ^ｉは、それぞれ独立して、水素原子、Ｃ_１〜Ｃ_６ハロアルコキシ基で置換されていても良いＣ_１〜Ｃ_６アルキル基、Ｃ_３〜Ｃ_６シクロアルキル基、Ｃ_１〜Ｃ_６ヒドロキシアルキル基又はＲ^ｈとＲ^ｉが隣接する窒素原子と一体となって４〜６員の含窒素複素環を形成していてもよく、また当該含窒素複素環は、水酸基、Ｃ_１〜Ｃ_６アルキル基若しくはＣ_１〜Ｃ_６ヒドロキシアルキル基で置換されていても良い）；又はＣ_１〜Ｃ_６アルキルカルボニル基、
Ｒ^８は、水素原子、ハロゲン原子、シアノ基、Ｃ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６アルコキシ基、Ｃ_１〜Ｃ_６ハロアルキル基、Ｃ_１〜Ｃ_６ハロアルコキシ基又はＣ_１〜Ｃ_６ヒドロキシアルキル基、
Ｒ^９は、ハロゲン原子、Ｃ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６アルコキシ基又はＣ_１〜Ｃ_６ハロアルキル基、
Ｘ^ａは、酸素原子又はＮＲ^ｊ（ここで、Ｒ^ｊは、水素原子若しくはＣ_１〜Ｃ_６アルキル基を示す）であり、
Ｘ^ｂは、酸素原子又はＮＨ、
ｎは０〜３のいずれかの整数、
環Ａは、６〜１０員のアリール又は５〜１０員のヘテロアリールを示す］
で表される化合物若しくは薬学的に許容されるその塩。 Aspects of the present invention are as follows.
(1) General formula (I):

[In the formula,
R ¹ is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group or a C ₃ -C ₆ cycloalkyl group,
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group or a C ₃ -C ₆ cycloalkyl group,
R ³ and R ⁴ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ hydroxyalkyl group, COR ^a (wherein R ^a represents OH, C ₁ -C ₆ alkoxy group or NH ₂ ), C ₃ -C ₆ cycloalkyl group or 4-6 membered oxacycloalkyl group, or R ³ and R ⁴ are bonded to each other. May form a 3- to 6-membered cycloalkyl or a 4- to 6-membered oxacycloalkyl together with the carbon atom
R ⁵ is a C ₁ -C ₆ alkyl group which may be substituted with R ^k (wherein R ^k is a C ₃ -C ₆ cycloalkyl group or a 4-6 membered oxacycloalkyl group), A C ₁ -C ₆ haloalkyl group or NHR ^b (where R ^b represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a 4-6 membered oxacycloalkyl group),
Y ¹ , Y ² , Y ³ and Y ⁴ are each independently N or CR ^c1 , CR ^c2 , CR ^c3 or CR ^c4 (wherein R ^c1 , R ^c2 , R ^c3 and R ^c4 are each independent. And represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ haloalkyl group),
R ⁷ is a hydrogen atom; a halogen atom; a cyano group; a C ₁ -C ₆ alkyl group which may be substituted with R ^d (wherein R ^d is a C ₁ -C ₆ alkoxy group or di C ₁ -C). ₆ shows the alkylamino _group); C 2 -C ₆ alkenyl _group; C 1 -C ₆ alkoxy group; is a good _C 2 be ~ substituted with a hydroxyl group; a hydroxyl group in an optionally substituted _C 1 -C ₆ haloalkyl group C _{6 alkynyl;} C 1 -C ₆ haloalkoxy _group; C 1 -C ₆ haloalkyl group or _C 3 -C ₆ optionally substituted with a cycloalkyl group _C 1 -C ₆ hydroxyalkyl group; oR ^e (wherein in ^{R e} _is shown a C 1 -C ₆ haloalkyl _group, C 1 -C ₆ hydroxyalkyl _group, C 3 -C ₆ cycloalkyl _C 1 -C ₆ alkyl or 4-6 membered oxacycloalkyl group ); In ^NR f ^{R g} (wherein, ^{R f} and ^{R g} each independently represents a hydrogen _atom, C 1 -C ₆ haloalkoxy optionally substituted _C 1 -C ₆ alkyl group with a group, a hydroxyl group An optionally substituted C ₃ -C ₆ cycloalkyl group, C ₁ -C ₆ hydroxyalkyl group, or R ^f and R ^g are united with the adjacent nitrogen atom to form a 4- to 6-membered nitrogen-containing heterocycle. And the nitrogen-containing heterocycle may be substituted with a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ hydroxyalkyl group); C substituted with NR ^h R ⁱ ₁ -C ₆ alkyl group (wherein, ^{R h} and ^{R i} are each independently hydrogen _atom, C 1 -C ₆ haloalkoxy group optionally substituted _C 1 -C ₆ alkyl group, _{C 3} -C ₆ cycloalkyl _group, C 1 -C ₆ Mud alkoxyalkyl group or R ^h and R ⁱ is may form a nitrogen-containing heterocyclic ring having 4 to 6 membered together with the adjacent nitrogen atom, also those nitrogen-containing heterocycles, hydroxyl, C ₁ ~ C ₆ alkyl or _C 1 -C ₆ optionally substituted by a hydroxy group); or _C 1 -C ₆ alkylcarbonyl group,
R ⁸ is a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ haloalkoxy group or C ₁ -C. ₆ -hydroxyalkyl group,
R ⁹ is a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ haloalkyl group,
X ^a is an oxygen atom or NR ^j (where R ^j is a hydrogen atom or a C ₁ -C ₆ alkyl group),
X ^b is an oxygen atom or NH,
n is an integer from 0 to 3,
Ring A represents 6-10 membered aryl or 5-10 membered heteroaryl]
A compound represented by or a pharmaceutically acceptable salt thereof.

(2) The compound or a pharmaceutically acceptable salt thereof according to (1), wherein in the general formula (I), R ⁵ is a C ₁ -C ₆ alkyl group and X ^b is an oxygen atom.
(3) In the general formula (I), R ¹ is a C ₁ -C ₆ alkyl group, and R ² is a C ₁ -C ₆ alkyl group, or the compound or pharmaceutical agent according to (2). Its salt acceptable to.
(4) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein in the general formula (I), ring A is phenyl or pyridyl.
(5) In the general formula (I),
R ¹ is a C ₁ -C ₆ alkyl group, R ² is a C ₁ -C ₆ alkyl group, R ³ and R ⁴ are each independently a hydrogen atom or a hydroxymethyl group, and R ⁵ is C a ₁ -C ₆ alkyl group, ^{R 8} is _C 1 -C ₆ haloalkyl group, ^{X a} is an oxygen atom, a compound or a pharmaceutically acceptable according to the ring a is phenyl or pyridyl (1) That salt that will be.
(6) The compound or a pharmaceutically acceptable salt thereof according to (1) to (5), wherein in the general formula (I), R ⁵ is a methyl group or an ethyl group, and X ^b is an oxygen atom.
(7) The compound or pharmaceutically acceptable according to any one of (1) to (6), wherein in the general formula (I), R ¹ is a tert-butyl group and R ² is a methyl group or an ethyl group. That salt that will be.

である（９）に記載の化合物若しくは薬学的に許容されるその塩。
（１１）前記一般式（Ｉ）中、Ｒ^８がトリフルオロメチル基である（１）〜（１０）のいずれかに記載の化合物若しくは薬学的に許容されるその塩。
（１２）前記一般式（Ｉ）中、Ｒ^７がヒドロキシメチル基、１−ヒドロキシエチル基、１−ヒドロキシプロピル基、シクロプロピル（ヒドロキシ）メチル基、２，２−ジフルオロ−１−ヒドロキシエチル基又は２，２，２−トリフルオロ−１−ヒドロキシエチル基である（１）〜（１１）のいずれかに記載の化合物若しくは薬学的に許容されるその塩。 (8) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein in the general formula (I), ring A is pyridyl.
(9) The compound or the pharmaceutically acceptable salt thereof according to (8), wherein ring A is 2-pyridyl or 3-pyridyl.
(10) In ring A which is 2-pyridyl or 3-pyridyl, the substitution positions of R ⁷ and R ⁸ are

The compound according to (9) or a pharmaceutically acceptable salt thereof.
(11) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (10), wherein in the general formula (I), R ⁸ is a trifluoromethyl group.
(12) In the general formula (I), R ⁷ is a hydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxypropyl group, a cyclopropyl (hydroxy) methyl group, a 2,2-difluoro-1-hydroxyethyl group or The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (11), which is a 2,2,2-trifluoro-1-hydroxyethyl group.

のいずれかである（１）に記載の化合物若しくは薬学的に許容されるその塩。 (13) The compound represented by the general formula (I) is

The compound or the pharmaceutically acceptable salt thereof according to (1), which is any of the above.

(14) A medicament comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
(15) The medicine according to (14), which is a RORγt inhibitor.
(16) The medicine according to (15), which suppresses the differentiation and / or activation of Th17 cells.
(17) The medicine according to any one of (14) to (16), for preventing and / or treating a disease involving Th17 cells.
(18) The medicament according to (14) or (15) for preventing and / or treating a disease involving an inflammatory cytokine.
(19) The medicament according to (18), wherein the inflammatory cytokine is IL-17A and / or IL-17F.
(20) Psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, multiple sclerosis, scleroderma, uveitis, asthma, ankylosing spondylitis, systemic lupus erythematosus, atopy The drug according to any one of (14) to (19), for treating and / or preventing one or more diseases selected from the group consisting of dermatitis and chronic obstructive pulmonary disease.

(21) Use of the compound according to (1) or a pharmaceutically acceptable salt thereof for the manufacture of the medicament according to any of (14) to (20) above.
(22) A method of inhibiting RORγt in the body of a mammal including human, which comprises the step of administering to the mammal an effective amount of the compound according to (1) or a pharmaceutically acceptable salt thereof.
(23) A method for suppressing the differentiation and / or activation of Th17 cells in the body of mammals including humans, which comprises administering an effective amount of the compound or the pharmaceutically acceptable salt thereof according to (1) to mammals. A method comprising the step of administering to.
(24) A method for preventing and / or treating a disease involving Th17 cells in mammals including human, which is effective for treating and / or preventing the compound according to (1) or a pharmaceutically acceptable salt thereof. A method comprising the step of administering an amount to a mammal in need of treatment or prevention.
(25) A method for preventing and / or treating a disease involving inflammatory cytokines, preferably IL-17A and / or IL-17F in mammals including human, wherein the compound or the pharmaceutical agent according to (1) A method comprising the step of administering a therapeutically and / or prophylactically effective amount of a pharmaceutically acceptable salt thereof to a mammal in need of treatment or prevention.
(27) Psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, multiple sclerosis, scleroderma, uveitis, asthma, ankylosing spondylitis in mammals including humans A method for treating or preventing one or more diseases selected from the group consisting of systemic lupus erythematosus, atopic dermatitis and chronic obstructive pulmonary disease, wherein the compound or the pharmaceutically acceptable according to (1) A method comprising the step of administering a therapeutically and / or prophylactically effective amount of a salt thereof to a mammal in need of treatment or prevention.

  The pyrazole derivative or a salt thereof of the present invention has an excellent RORγt inhibitory action, suppresses differentiation and / or activation of Th17 cells, and produces inflammatory cytokines such as IL-17A and / or IL-17F. Can be suppressed. Therefore, a drug containing the pyrazole derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is, for example, rheumatoid arthritis, psoriasis, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), multiple sclerosis. , Systemic lupus erythematosus, ankylosing spondylitis, various autoimmune diseases such as uveitis and allergic diseases (asthma, atopic dermatitis, chronic obstructive pulmonary disease, etc.), Th17 cells or IL-17A or IL-17F It is useful as an active ingredient of a medicament for the prevention and / or treatment of diseases involving inflammatory cytokines such as Furthermore, the pyrazole derivative of the present invention or a salt thereof has excellent properties such as solubility, safety and pharmacokinetics.

Next, the present invention will be described in more detail.
First, each substituent in the general formula (I) will be described.
The meanings of the terms used in the definition of each substitution are as follows.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The “C ₁ -C ₆ alkyl group” represents a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and n. -Butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, n-pentan-3-yl group, tert-pentyl group, 3-methylbutyl group (isopentyl group), neopentyl group, n- A hexyl group and the like can be mentioned.

The “C ₁ -C ₆ haloalkyl group” means a group in which one or more halogen atoms can be substituted at any position of the C ₁ -C ₆ alkyl group, and specific examples include: Trifluoromethyl group, difluoromethyl group, 1,1,1-trifluoroethyl group, pentafluoroethyl group, trichloromethyl group, 3-chloropropyl group, 1,1,1-trifluoropropyl group, 2,2- Examples thereof include a difluoropropyl group, a 4-bromobutyl group and a 1,1,1,3,3,3-hexafluoropropan-2-yl group.
The “C ₁ -C ₆ hydroxyalkyl group” means a group in which the C ₁ -C ₆ alkyl group is substituted at any position where a hydroxy group can be substituted, and specific examples thereof include a hydroxymethyl group and 1- Hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-1-methylethyl group, 1-hydroxybutyl group, 4-hydroxybutyl group, etc. Is mentioned.

The “C ₁ -C ₆ alkoxy group” represents an alkoxy group whose alkyl part has the same meaning as the above C ₁ -C ₆ alkyl group, and specific examples include a methoxy group, an ethoxy group, an n-propoxy group, and isopropoxy. Group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentyloxy group, tert-amyloxy group, 3-methylbutoxy group, neopentyloxy group, n-hexyloxy group and the like. To be

The “C ₁ -C ₆ haloalkoxy group” means a group in which the above C ₁ -C ₆ alkoxy group is substituted at any position capable of substituting one or more halogen atoms, and specific examples include: Examples include a trifluoromethoxy group, a difluoromethoxy group, a fluoromethoxy group, a 2,2,2-trifluoroethoxy group, a trichloromethoxy group, and a 1,1,1,3,3,3-hexafluoro-2-propoxy group. To be
The “C ₁ -C ₆ alkylcarbonyl group” represents a group in which the C ₁ -C ₆ alkyl group is bonded to a carbonyl group, and specific examples thereof include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, and a valeryl group. , Isovaleryl group, pivaloyl group and the like.

The “di C ₁ -C ₆ alkylamino group” represents a group in which two C ₁ -C ₆ alkyl groups are bound to an amino group, and specific examples thereof include a dimethylamino group, a diethylamino group and a dipropylamino group. , Diisopropylamino group, dibutylamino group, diisobutylamino group, dipentylamino group and the like.
The "C ₃ -C ₆ cycloalkyl" represents a cycloalkyl monocyclic 3 to 6 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The “C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl group” represents a group in which the C ₁ -C ₆ alkyl group is substituted with the C ₃ -C ₆ cycloalkyl group, and specific examples include cyclo. Examples thereof include a propylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a 2-cyclopentylethyl group and a 3-cyclohexylpropyl group.

The “C ₂ -C ₆ alkenyl group” represents a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an allyl group, an isopropenyl group, 1-butenyl. Group, 2-butenyl group, 2-methyl-2-propenyl group, 1-methyl-2-propenyl group, 2-methyl-1-propenyl group, 1-pentenyl group, 1-hexenyl group and the like.
The "C ₂ -C ₆ alkynyl group" represents a straight chain or branched chain of carbon atoms 2 to 6 alkynyl group, specifically, ethynyl group, 1-propynyl, 2-propynyl, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-butynyl group, 2-methyl-3-butynyl group, 1-pentynyl group, 1-hexynyl group and the like can be mentioned.

The "6- to 10-membered aryl" represents a monocyclic or bicyclic aromatic carbocyclic ring, and specifically means phenyl, 1-naphthyl or 2-naphthyl.
The "4- to 6-membered oxacycloalkyl" represents a 4- to 6-membered saturated monocyclic ring having carbon atoms and oxygen atoms as ring-constituting atoms, and specific examples thereof include oxetanyl, tetrahydrofuranyl, and tetrahydro. Pyranyl and the like can be mentioned.
The “4- to 6-membered nitrogen-containing heterocycle” represents a 4- to 6-membered saturated monocyclic ring containing at least one or more nitrogen atoms as ring-constituting atoms, and specific examples thereof include an azetidine ring and a pyrrolidine. Ring, piperidine ring, piperazine ring, morpholine ring and the like.

  The "5- to 10-membered heteroaryl" is a 5- to 10-membered monocyclic or bicyclic compound having at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring-constituting atoms. Represents an aromatic ring of, as specific examples, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, indazolyl, benzo. Examples include oxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, tetrazolyl and the like.

  In the compound of the present invention represented by the general formula (I), when an asymmetric carbon atom is present, it may be in any form of a racemate, a mixture of diastereoisomers or an individual optically active substance. When geometric isomers are present, they may be in any form of (E) form, (Z) form or a mixture thereof. Further, among one or more hydrogen atoms present in a substituent such as an alkyl group or an alkoxy group, any hydrogen atom may be replaced with a deuterium atom.

  The pharmaceutically acceptable salt of the compound represented by the general formula (I) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include a salt with an organic acid and a salt with an inorganic acid. Examples thereof include salts with amino acids. Examples of salts with organic acids include formate, acetate, tartrate, fumaric acid, maleate, succinate, lactate, citric acid, malate, ascorbate, oxalate, glycolic acid. Examples thereof include salts, phenylacetates, benzoates, methanesulfonates and benzenesulfonates. Examples of the salt with an inorganic acid include hydrochloride, hydrobromide, phosphate, sulfamate, nitrate, sulfate and the like. Examples of salts with amino acids include aspartic acid and glutamic acid.

Next, a preferred embodiment of the present invention will be described.
R ¹ is preferably a C ₁ -C ₆ alkyl group, and more preferably a tert-butyl group.
R ² is preferably a C ₁ -C ₆ alkyl group, more preferably a methyl group or an ethyl group, and even more preferably a methyl group.
R ³ and R ⁴ are preferably both R ³ and R ⁴ are hydrogen atoms, or one of R ³ and R ⁴ is a hydrogen atom, and the other is a C ₁ -C ₆ hydroxyalkyl group, and more preferably R ³ and R ⁴ are both hydrogen atoms, or one of R ³ and R ⁴ is a hydrogen atom and the other is a hydroxymethyl group.

R ⁵ is preferably a C ₁ -C ₆ alkyl group, more preferably a methyl group or an ethyl group.
Y ¹ , Y ² , Y ³ and Y ⁴ are preferably Y ¹ , Y ² , Y ³ and Y ⁴ all being CH, or Y ¹ is N and Y ² , Y ³ and Y 4. ^{All 4} are CH.
R ⁷ is preferably a hydrogen atom, a halogen _atom, C 1 -C ₆ haloalkyl group or _C 3 ~C _{6 C} 1 may be substituted with a cycloalkyl group -C ₆ hydroxyalkyl _group, C 1 -C ₆ an alkoxy group or _C 1 -C ₆ haloalkoxy group, more _preferably, at C 1 -C ₆ haloalkyl group or _C 3 -C ₆ cycloalkyl group substituted by _C 1 may also be -C ₆ hydroxyalkyl group Yes, and even more preferably, hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxypropyl group, cyclopropyl (hydroxy) methyl group, 2,2-difluoro-1-hydroxyethyl group, 2,2,2-tri It is a fluoro-1-hydroxyethyl group.

R ⁸ is preferably a cyano group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ haloalkyl group, and more preferably a trifluoromethyl group or a difluoromethyl group.
X ^a is preferably an oxygen atom or NH, more preferably an oxygen atom.
X ^b is preferably an oxygen atom.

が好ましく、

がより好ましい。 Ring A is preferably phenyl or pyridyl, more preferably 2-pyridyl or 3-pyridyl.
When the ring A is phenyl or pyridyl, the substitution positions of the substituents R ⁷ and R ⁸ are

Is preferred,

Is more preferable.

Further, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , X ^a , X ^b , Y ¹ , Y ² , Y ³ , Y ⁴ in the general formula (I), For rings A and n, the following combinations are preferred.
Those in which R ¹ is a C ₁ -C ₆ alkyl group and R ² is a C ₁ -C ₆ alkyl group are preferred, R ¹ is a tert-butyl group, and R ² is a methyl group or ethyl. A group is more preferable.
It is preferable that R ⁵ is a C ₁ -C ₆ alkyl group and X ^b is an oxygen atom, and it is more preferable that R ⁵ is a methyl group or an ethyl group and X ^b is an oxygen atom.
It is preferable that Y ¹ , Y ² , Y ³ and Y ⁴ are all CH, R ⁵ is a methyl group or an ethyl group, and X ^b is an oxygen atom.
It is preferable that Y ¹ is N, Y ² , Y ³ and Y ⁴ are all CH, R ⁵ is a methyl group or an ethyl group, and X ^b is an oxygen atom.

R ³ and R ⁴ are both hydrogen atoms, Y ¹ , Y ² , Y ³ and Y ⁴ are all CH, R ⁵ is a methyl group or an ethyl group, and X ^b is an oxygen atom. Is preferred.
R ³ and R ⁴ are both hydrogen atoms, Y ¹ is N, Y ² , Y ³ and Y ⁴ are all CH, R ⁵ is a methyl group or an ethyl group, and X ^b is oxygen. Those that are atoms are preferred.
One of R ³ and R ⁴ is a hydrogen atom, the other is a hydroxymethyl group, all of Y ¹ , Y ² , Y ³ and Y ⁴ are CH, R ⁵ is a methyl group or an ethyl group, and X is Those in which ^b is an oxygen atom are preferred.
X ^a is an oxygen atom, ring A is phenyl or pyridyl, ^{R 7} is _C 1 -C ₆ haloalkyl group or _C 3 -C ₆ cycloalkyl _C 1 -C ₆ hydroxyalkyl optionally substituted with a group A group, R ⁸ is a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ haloalkyl group, and n is 0, X ^a is an oxygen atom, and ring A is 2-pyridyl or 3 -Pyridyl and R ⁷ is a hydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxypropyl group, a cyclopropyl (hydroxy) methyl group, a 2,2-difluoro-1-hydroxyethyl group or a 2,2,2- More preferred is a trifluoro-1-hydroxyethyl group, R ⁸ is a difluoromethyl group or a trifluoromethyl group, and n is 0.

Furthermore, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , X ^a , X ^b , Y ¹ , Y ² , Y ³ , Y ⁴ in the general formula (I), For rings A and n, the following combinations of compounds are preferred.
R ¹ is a C ₁ -C ₆ alkyl group;
R ² is a C ₁ -C ₆ alkyl group;
R ³ and R ⁴ are both hydrogen atoms, or one of R ³ and R ⁴ is a hydrogen atom and the other is a C ₁ -C ₆ hydroxyalkyl group;
R ⁵ is a C ₁ -C ₆ alkyl group;
R ⁷ is located in _C 1 -C ₆ haloalkyl group or _C 3 ~C _{6 C} 1 may be substituted with a cycloalkyl group -C ₆ hydroxyalkyl group;
R ⁸ is a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ haloalkyl group;
X ^a is an oxygen atom;
X ^b is an oxygen atom;
n is 0;
A compound wherein Ring A is pyridyl.

<Method for producing pyrazole derivative of the present invention>
The compound represented by the general formula (I) can be produced by various methods. For example, it can be produced by the method shown in the following reaction formula-1 (step 1-1 to step 1-5).

［式中、環Ａ、ｎ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^７、Ｒ^８、Ｒ^９、Ｘ^ａ、Ｘ^ｂ、Ｙ^１、Ｙ^２、Ｙ^３及びＹ^４は前述の一般式（Ｉ）の定義と同じ；Ｒ^２ａは水素原子、Ｃ_１〜Ｃ_６アルキル基、Ｃ_１〜Ｃ_６ハロアルキル基又はＣ_３〜Ｃ_６シクロアルキル基を表し、Ｒ^２ｂはハロゲン原子を表し、Ｒ^６はメチル基又はエチル基であり、Ｘ^ｃは、フッ素原子又は塩素原子であり、ｍは０〜２を表す。］ <Reaction formula-1>

[In the formula, rings A, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , X ^a , X ^b , Y ¹ , Y ² , Y ³ and Y ⁴ Is the same as the above-mentioned definition of the general formula (I); R ^2a represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group or a C ₃ -C ₆ cycloalkyl group, and R ^2b is halogen. Represents an atom, R ⁶ represents a methyl group or an ethyl group, X ^c represents a fluorine atom or a chlorine atom, and m represents 0 to 2. ]

(Step 1-1)
In step 1-1, the compound represented by the general formula (II) is reacted with the compound represented by the general formula (III) in the presence or absence of an acid or a base to give a compound represented by the general formula (IV) A compound represented by can be produced. When an acid is used, examples of the acid used include formic acid, acetic acid, hydrochloric acid, sulfuric acid, and toluene-4-sulfonic acid. When using a base, as the base to be used, potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, Examples thereof include lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium hexamethyldisilazane, and sodium hydride. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, methanol, ethanol, 1-propanol, 2 -Propanol, 1-butanol, benzene, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, 2-methoxyethanol, water or a mixed solvent thereof or the like can be mentioned. The reaction temperature is not particularly limited and is usually room temperature to 150 ° C. The reaction time is not particularly limited and is preferably 1 hour to 24 hours.

(Process 1-2)
In step 1-2, the compound represented by the general formula (IV) and the compound represented by the general formula (V) are subjected to an S _N aryl reaction in the presence of a base to form the compound represented by the general formula (VI-1). The compound can be prepared. As the base used, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium Inorganic base such as hexamethyldisilazane or sodium hydride, or trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) Or 1,8-diaza Cyclo [5.4.0] -7-undecene (DBU) organic amines, and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, acetonitrile, tetrahydrofuran, 1,4 -Dioxane, benzene, toluene, xylene, pyridine, dichloromethane, chloroform, a mixed solvent thereof or the like can be mentioned, and water can be added to the reaction solvent. The reaction temperature is not particularly limited and is usually room temperature to 150 ° C. The reaction time is not particularly limited and is preferably 1 hour to 24 hours.

(Process 1-3)
Step 1-3 uses a compound (R ^2a is a hydrogen atom) represented by the general formula (VI-1-1) among the compounds produced in Step 1-2, and converts it into R ² moiety. It is a step of producing a compound represented by the general formula (VI-2) in which a halogen atom is introduced. Specifically, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoro) is added to the compound represented by the general formula (VI-1-1). It can be converted to a compound represented by the general formula (VI-2) by reacting borate), N-chlorosuccinimide, N-bromosuccinimide, or the like. The reaction solvent is not particularly limited as long as it is an inert solvent, aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; diethyl ether, tetrahydrofuran Ethers such as 1,4-dioxane; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethylsulfoxide; nitriles such as acetonitrile and propionitrile. The reaction temperature is not particularly limited and is usually room temperature to 150 ° C. The reaction time is not particularly limited, and 1 hour to 24 hours is preferable.

  Further, the obtained compound represented by the general formula (VI-1) or the general formula (VI-2) is, for example, a condensation reaction, an addition reaction, an oxidation reaction, a reduction reaction, a substitution reaction, a coupling reaction, a halogenation. A compound represented by another general formula (VI-1) or general formula (VI-2) by subjecting it to a general reaction for those skilled in the art such as reaction, dehydration reaction or hydrolysis, or by appropriately combining these reactions. It can also be converted into the compound.

(Process 1-4)
In the step 1-4, the compound represented by the general formula (VI) (the compound represented by the general formula (VI-1) produced in the step 1-2 and the general formula (VI- produced in the step 1-3) The compound represented by the general formula (VII) can be produced by hydrolyzing (the compound represented by 2)) in the presence of a base. Examples of the base used include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and the base may be used as an aqueous solution. Examples of the reaction solvent include methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, acetonitrile and the like. The reaction temperature is not particularly limited and is usually room temperature to 90 ° C. The reaction time is not particularly limited and is preferably 1 hour to 24 hours.

(Step 1-5)
Step 1-5 is a step of reacting the compound represented by the general formula (VII) with the compound represented by the general formula (VIII) to produce the compound represented by the general formula (I). Specifically, the compound represented by the general formula (VII) and the compound represented by the general formula (VIII) are subjected to a condensation reaction using a condensing agent in an inert solvent in the presence or absence of a base. By doing so, the compound represented by the general formula (I) can be produced. As the condensing agent, N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), 1,1-carbonyldiimidazole (CDI), 2-chloro -1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride (PPA), N, N'-dicyclohexylcarbodiimide, O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -Tetramethyluronium hexafluorophosphate (HATU) and the like. Examples of the base include trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, triisopropylamine, tributylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), or 1,8-diazabicyclo [5.4]. .0] -7-undecene (DBU) and other organic amines. Examples of the solvent include halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate; ethers such as tetrahydrofuran; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; ketones such as acetone and methyl ethyl ketone. Examples: aromatic hydrocarbons such as toluene, mixed solvents thereof, and the like. A reaction reagent such as 1-hydroxybenzotriazole (HOBt) may be added if necessary. The reaction temperature is not particularly limited and is preferably 0 ° C. to 80 ° C., for example. The reaction time is not particularly limited, and 1 hour to 24 hours is preferable.

  Alternatively, the compound represented by the general formula (VII) may be introduced into a reaction intermediate by using an activator for a carboxyl group, and then reacted with the compound represented by the general formula (VIII) ( The compounds represented by I) can be prepared. Examples of the activator for the carboxyl group include thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosgene, triphosgene, 1,1'-carbonyldiimidazole, ethyl chlorocarbonate and the like. Examples of the solvent include aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, nitrobenzene, and xylene; halogenated hydrocarbon solvents such as chloroform and dichloromethane; ethers such as tetrahydrofuran; ketones such as acetone and methyl ethyl ketone; acetonitrile and propio Examples thereof include nitrile solvents such as nitrile, and mixed solvents thereof. If necessary, a catalytic amount of amides such as N, N-dimethylformamide may be added. The reaction temperature is not particularly limited and is preferably 0 ° C. to 80 ° C., for example. The reaction time is not particularly limited, and 1 hour to 24 hours is preferable.

［式中、Ｒ^１は前述の一般式（Ｉ）の定義と同じ；Ｒ^６はメチル基またはエチル基であり、ｍは０〜２を表す。］ Among the compounds represented by the general formula (IV) in the reaction formula-1, the compound (IV-1) in which R ^2a is a hydrogen atom is produced by the following reaction formula-2 (step 2-1). You can also
<Reaction formula-2>

[In the formula, R ¹ is the same as the above-mentioned definition of the general formula (I); R ⁶ is a methyl group or an ethyl group, and m represents 0 to 2. ]

(Step 2-1)
In step 2-1, the compound represented by the general formula (IV-1) is reacted with the compound represented by the general formula (II) and dimethyl acetylenedicarboxylate or diethyl acetylenedicarboxylate in the presence or absence of an acid or a base. ). The compound represented by these can be manufactured. When an acid is used, examples of the acid used include formic acid, acetic acid, hydrochloric acid, sulfuric acid, and toluene-4-sulfonic acid. When a base is used, examples of the base used include potassium carbonate, potassium hydrogen carbonate, potassium acetate, sodium acetate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, lithium carbonate, tripotassium phosphate, potassium hydroxide, sodium hydroxide. , Lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, potassium hexamethyldisilazane, sodium hydride and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methanol, ethanol, 1-propanol, 2 -Propanol, 1-butanol, benzene, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 2-methoxyethanol, or a mixed solvent thereof or the like can be illustrated. The reaction temperature is not particularly limited and is usually room temperature to 150 ° C. The reaction time is not particularly limited, and 1 hour to 24 hours is preferable.

  The compounds represented by the general formula (I) thus obtained are, for example, condensation reaction, addition reaction, oxidation reaction, reduction reaction, substitution reaction, coupling reaction, halogenation reaction, dehydration reaction or hydrolysis. It is also possible to induce another compound represented by the general formula (I) by subjecting it to a general reaction for those skilled in the art, or by appropriately combining these reactions.

  The compound represented by the general formula (I) produced by the above-described method is isolated and purified as a free compound, a salt thereof, various solvates such as hydrates or ethanol solvates, or crystalline polymorphic substances. . The pharmaceutically acceptable salt of the compound of the present invention can be produced by a conventional salt formation reaction. Isolation and purification are performed by applying chemical operations such as extraction fractionation, crystallization and various fractionation chromatography. The optically active substance can be obtained as a stereochemically pure isomer by selecting an appropriate starting material compound or by a conventional optical resolution from a racemate. For example, in the case of optically resolving a racemate using a chiral column, a method known to those skilled in the art (for example, “Separation of optical isomers” (Quarterly Chemistry Review No. 6, 1989, Chemical Society of Japan, Publishing Center), etc.) Refer to)). In addition, various chiral columns are commercially available, and an appropriate one may be appropriately selected, and preferred examples include CHIRALPAK IA and CHIRALFLASH IA manufactured by Daicel Corporation.

  Since the pyrazole derivative of the present invention exhibits excellent RORγt inhibitory activity, the drug containing the pyrazole derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is also useful as a drug based on this action. Without being bound to any particular theory, the drug of the present invention containing the pyrazole derivative of the present invention as an active ingredient can suppress differentiation into Th17 cells and activation of Th17 cells by RORγt inhibitory activity, It is useful for the prevention and / or treatment of various diseases involving Th17 cells or various diseases involving inflammatory cytokines such as IL-17A and IL-17F. Examples of such diseases include psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease (Crohn's disease and ulcerative colitis, etc.), multiple sclerosis, scleroderma, uveitis, asthma, ankylosing Spondylitis, systemic lupus erythematosus, atopic dermatitis, chronic obstructive pulmonary disease, type I diabetes, alopecia areata, glomerulonephritis, neuromyelitis optica, Sjogren's syndrome, celiac disease, dry eye and graft-versus-host disease Examples include, but are not limited to:

  The medicament of the present invention is preferably psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, multiple sclerosis, scleroderma, uveitis, asthma, ankylosing spondylitis. , Systemic lupus erythematosus, atopic dermatitis, chronic obstructive pulmonary disease, etc. can be used as a preventive or therapeutic agent.

  The drug containing the pyrazole derivative of the present invention can be administered systemically or locally. The administration route is also not particularly limited, and it may be administered orally or parenterally, for example, transdermally, nasally, respiratory tract, transpulmonary, eye drop, intravenous injection, subcutaneous injection, or rectal administration. it can. The dosage form can be appropriately selected depending on the administration route, and examples thereof include tablets, troches, sublingual tablets, dragees, capsule tablets, pills, powders, granules, solutions, emulsions, creams, and ointments. Agents, lotions, jellies, suspensions, syrups, eye drops, nasal drops, inhalants, suppositories, injections and the like. Further, the pharmaceutical containing the pyrazole derivative of the present invention is a pharmaceutically acceptable carrier, that is, an excipient, and further, if necessary, a binder, a disintegrating agent, a coating agent, a lubricant, a preservative, a wetting agent. It may contain various commonly used additives such as an agent, an emulsifier, a stabilizer, a preservative, a coloring agent, a sweetener, a solubilizing agent, etc., and can be prepared according to a conventional method in the art. .

  The dose of the drug containing the pyrazole derivative of the present invention may be appropriately determined depending on the conditions of administration subject, administration route, symptoms, etc. For example, when orally administered to an adult patient, the present compound which is an active ingredient Is usually in the range of about 0.01 to 1000 mg, preferably 0.1 to 500 mg, and is preferably administered 1 to 3 times a day.

Hereinafter, the features of the present invention will be described more specifically with reference to Examples and Test Examples.
Materials, usage amounts, ratios, processing contents, processing procedures, and the like shown in the following examples can be appropriately changed without departing from the spirit of the present invention.
Therefore, the scope of the present invention should not be limitedly interpreted by the following specific examples.

The ¹ H-NMR spectrum shown below is a JNM-ECA400 type spectrometer (400 MHz, using a heavy chloroform (CDCl ₃ ) or heavy dimethyl sulfoxide (DMSO-d ₆ ) as a solvent and tetramethylsilane (TMS) as an internal standard. It was measured with JEOL Ltd.) or AVANCE III HD400 type (400 MHz, Bruker BioSpin Ltd.). As for the measurement results of the chemical shift, the δ value is shown in ppm, and the J value of the binding constant is shown in Hz. The abbreviations s means singlet, d means doublet, t means triplet, q means quartet, m means multiplet, and br means broad. The mass spectrum (ESI-MS) was measured by Excitive (made by Thermo Fisher Scientific Co., Ltd.) by the electrospray ionization method. The chemical structural formulas and physical property values of the compound (I-1) to the compound (I-353) in each example are shown in Tables 1 to 46.

In each example, each abbreviation has the following meaning.
HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate
m-CPBA: Metachloroperbenzoic acid
sec: secondary
tert: tertiary
n: normal

Example 1
1- (tert-butyl) -4-chloro-5-((3,5-dichloropyridin-2-yl) oxy) -N- (4-sulfamoylbenzyl) -1H-pyrazole-3-carboxamide (I -1) Manufacturing process 1
Dimethyl acetylenedicarboxylate (983 μL, 8.02 mmol) was added to a suspension of tert-butylhydrazine hydrochloride (1.00 g, 8.03 mmol) and potassium carbonate (1.11 g, 8.03 mmol) in methanol (8.0 mL) and heated for 5 hours. Refluxed. The reaction solution was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 40: 60), and 1- (tert-butyl) -5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester ( Yield 821 mg, yield 52%).

Process 2
To a suspension of 1- (tert-butyl) -5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester (300 mg, 1.51 mmol) and cesium carbonate (740 mg, 2.27 mmol) in dimethyl sulfoxide (3.0 mL). , 3,5-Dichloro-2-fluoropyridine (502 mg, 3.02 mmol) were added, and the mixture was stirred at 80 ° C. for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25 → 40: 60), and 1- (tert-butyl) -5-((3 , 5-Dichloropyridin-2-yl) oxy) -1H-pyrazole-3-carboxylic acid methyl ester (yield 485 mg, yield 93%) was obtained.

Process 3
A solution of 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -1H-pyrazole-3-carboxylic acid methyl ester (600 mg, 1.74 mmol) in acetonitrile (17.4 mL). N-chlorosuccinimide (1.16 g, 8.69 mmol) was added to and stirred at 80 ° C. for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20 → 50: 50), and 1- (tert-butyl) -4-chloro-5 was used. -((3,5-Dichloropyridin-2-yl) oxy) -1H-pyrazole-3-carboxylic acid methyl ester (yield 646 mg, yield 98%) was obtained.

Step 4
1- (tert-Butyl) -4-chloro-5-((3,5-dichloropyridin-2-yl) oxy) -1H-pyrazole-3-carboxylic acid methyl ester (385 mg, 1.21 mmol) in ethanol ( 5.6 mL) and 4 mol / L sodium hydroxide aqueous solution (840 μL, 3.36 mmol) were added, and the mixture was stirred at room temperature for 6 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1- (tert-butyl) -4-chloro-5-((3,5-dichloropyridin-2-yl) oxy) -1H-pyrazole-3-carboxylic acid (yield 355 mg, 96% yield) was obtained as a crude product.

Step 5
1- (tert-Butyl) -4-chloro-5-((3,5-dichloropyridin-2-yl) oxy) -1H-pyrazole-3-carboxylic acid (49 mg, 0.15 mmol) in N, N- In a dimethylformamide (0.68 mL) solution, 4- (aminomethyl) benzenesulfonamide hydrochloride (30 mg, 0.13 mmol), N, N-diisopropylethylamine (58 μL, 0.34 mmol) and HATU (61 mg, 0.16 mmol) were added. Were sequentially added, and the mixture was stirred at room temperature for 17 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 50:50 → 0: 100) to give the title compound (I-1) (yield 67 mg, yield 99%) was obtained.

Example 2
1- (tert-butyl) -4-chloro-N- (4-sulfamoylbenzyl) -5-((4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide Production of (I-2) In the same manner as in Example 1, using 3-fluoro-4- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in Step 2, the compound (I -2) was obtained.

Example 3
4-chloro-5-((3,5-dichloropyridin-2-yl) oxy) -1-isobutyl-N- (4- (methylsulfonyl) benzyl) -1H-pyrazole-3-carboxamide (I-3) Preparation of Example 1 Using isobutylhydrazine hydrochloride instead of tert-butylhydrazine hydrochloride in step 1 of Example 1 and replacing Step 4 of Example 1 with 4- (aminomethyl) benzenesulfonamide hydrochloride. , 4- (methanesulfonyl) benzylamine hydrochloride was used to obtain compound (I-3) in the same manner as in Example 1.

Example 4
1- (tert-butyl) -4-chloro-N- (4-sulfamoylbenzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide Production of (I-4) In the same manner as in Example 1, using 2-fluoro-3- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in step 2, the compound (I -4) was obtained.

Example 5
1- (tert-butyl) -4-chloro-N- (4- (methylsulfonyl) benzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3- Preparation of carboxamide (I-5) In Step 2 of Example 1, 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and in Example 1 Compound (I-5) was obtained in the same manner as in Example 1 by using 4- (methanesulfonyl) benzylamine hydrochloride instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 5. Obtained.

Example 6
4-Bromo-1- (tert-butyl) -N- (4- (methylsulfonyl) benzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3- Production of carboxamide (I-6) Using 2-fluoro-3- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 1, Step 3 of Example 1 N-bromosuccinimide in place of N-chlorosuccinimide in Example 1, and 4- (methanesulfonyl) benzylamine in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 5 of Example 1. Compound (I-6) was obtained in the same manner as in Example 1 by using the hydrochloride.

Reference example 1
(5- (Methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) production step 1
N-Methylpyrrolidone (60 mL), sodium methanethiolate (22.9 g, 327.9 mmol) and potassium carbonate (60.3 g, 437.2 mmol) were added to 5-bromopyridine-2-carbonitrile (40.0 g, 218.6 mmol) and sealed. Stir in tube for 20 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5- (methylthio) picolinonitrile (yield 18.0 g, yield 55%).

Process 2
Dichloromethane (400 mL) was added to 5- (methylthio) picolinonitrile (18.0 g, 120 mmol), and the mixture was cooled to -15 ° C. After adding m-CPBA (61.9 g, 360 mmol) at the same temperature, the mixture was stirred at room temperature for 2 hours. After pouring the reaction solution into an aqueous solution of sodium sulfite, the mixture was stirred for 30 minutes and extracted with dichloromethane. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5- (methylsulfonyl) pyridine-2-carbonitrile (yield 19.0 g, yield 87%).

Process 3
Methanol (200 mL), hydrogen chloride tert-butyl methyl ether solution (22 mL) and 10% palladium carbon (2 g) were added to 5- (methylsulfonyl) pyridine-2-carbonitrile (11.0 g, 60.1 mmol), The mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure. After adding water, it was dried to obtain (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) (6.5 g, 50% yield).

Example 7
1- (tert-butyl) -4-chloro-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-7) 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 1. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 5 of Example 1, (5- (methylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 1 Compound (I-7) was obtained in the same manner as in Example 1 by using hydrochloride (VIII-1).

Reference example 2
Process 1 for producing 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2)
To a suspension of 2-amino-2- (4-bromophenyl) acetic acid methyl ester (10.0 g, 41.0 mmol) in tetrahydrofuran (164 mL) was added ditert-butyl dicarbonate (9.88 mL, 43.9 mmol) at room temperature. Stir for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80:20 → 50:50), and 2- (4-bromophenyl) -2-(( tert-Butoxycarbonyl) amino) acetic acid methyl ester (yield 9.01 g, yield 64%) was obtained.

Process 2
2- (4-Bromophenyl) -2-((tert-butoxycarbonyl) amino) acetic acid methyl ester (9.01 g, 26.2 mmol), sodium ethylsulfinate (15.2 g, 131 mmol) and copper iodide (24.9 g, A suspension of 131 mmol) in dimethyl sulfoxide (131 mL) was stirred at 110 ° C. for 19 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 30: 70) to give 2-((tert-butoxycarbonyl) amino) -2. -(4- (Ethylsulfonyl) phenyl) acetic acid methyl ester (yield 5.32 g, yield 57%) was obtained.

Process 3
2-((tert-Butoxycarbonyl) amino) -2- (4- (ethylsulfonyl) phenyl) acetic acid methyl ester (513 mg, 26.2 mmol) in tetrahydrofuran (7.2 mL) was added to 3 mol / L lithium borohydride. A tetrahydrofuran solution (1.4 mL, 4.2 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50:50 → 0: 100), and tert-butyl (1- (4- (ethylsulfonyl)) Phenyl) -2-hydroxymethyl) carbamate (220 mg, 47% yield) was obtained.

Step 4
A solution of tert-butyl (1- (4- (ethylsulfonyl) phenyl) -2-hydroxymethyl) carbamate (220 mg, 0.668 mmol) in chloroform (3.3 mL) was added to a solution of 4 mol / L hydrogen chloride in ethyl acetate (3.3 mL). ) Was added and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to give 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) (yield 174 mg, yield 98%).

Example 8
1- (tert-butyl) -4-chloro-5-((3,5-dichloropyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) Preparation of -1H-pyrazole-3-carboxamide (I-8) In the same manner as in Example 1, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 5, it was synthesized by the method described in Reference Example 2. 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) was used to give compound (I-8).

Example 9
1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-N- (4-sulfamoylbenzyl) -1H-pyrazole-3-carboxamide (I -9) Manufacturing process 1
To a suspension of tert-butylhydrazine hydrochloride (4.70 g, 37.7 mmol) and potassium carbonate (10.4 g, 75.2 mmol) in ethanol (75.5 mL), diethyl 2-methyl-3-oxosuccinate (7.00 mL, 37.7 mmol) was added. Was added and the mixture was heated under reflux for 22 hours. The precipitate was filtered and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 70: 30) to give 1- (tert-butyl)- 5-Hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 6.10 g, yield 71%) was obtained.

Process 2
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (400 mg, 1.77 mmol) and cesium carbonate (864 mg, 2.56 mmol) in dimethyl sulfoxide (3.5 mL) 3,5-Dichloro-2-fluoropyridine (440 mg, 2.65 mmol) was added to the suspension, and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 80: 20), and 1- (tert-butyl) -5-((3 , 5-Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 658 mg, quantitative) was obtained.

Process 3
1- (tert-Butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (658 mg, 1.77 mmol) in ethanol (8.8 mL) and 4 mol / L sodium hydroxide aqueous solution (1.33 mL, 5.32 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (yield 621 mg, quantitative) was obtained as a crude product.

Step 4
1- (tert-Butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (46 mg, 0.13 mmol) in tetrahydrofuran (1.3 mL), 4- (aminomethyl) benzenesulfonamide hydrochloride (30 mg, 0.13 mmol), N, N-diisopropylethylamine (56 μL, 0.33 mmol) and HATU (60 mg, 0.16 mmol) were added at room temperature to 16 Stir for hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, chloroform: methanol = 99: 1 → 90:10) to give the title compound (I-9) (yield 69 mg, quantitative Target).

Example 10
1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-N- (4- (methylsulfonyl) benzyl) -1H-pyrazole-3-carboxamide ( Preparation of I-10) In the same manner as in Example 9, using 4- (methanesulfonyl) benzylamine hydrochloride instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4, the compound (I-10 ) Got.

Example 11
1- (tert-butyl) -4-methyl-N- (4-sulfamoylbenzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide Production of (I-11) In the same manner as in Example 9, using 2-fluoro-3- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in Step 2, the compound (I -11) was obtained.

Example 12
1- (tert-butyl) -4-methyl-N- (4- (methylsulfonyl) benzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3- Preparation of carboxamide (I-12) In Step 2 of Example 9, 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and in Example 9 Compound (I-12) was obtained in the same manner as in Example 9 by using 4- (methanesulfonyl) benzylamine hydrochloride instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4. Obtained.

Example 13
1-isobutyl-4-methyl-N- (4-sulfamoylbenzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide (I-13 ) In step 9 of Example 9 isobutylhydrazine hydrochloride was used in place of tert-butylhydrazine hydrochloride, and in step 2 of Example 9 instead of 3,5-dichloro-2-fluoropyridine. Compound (I-13) was obtained in the same manner as in Example 9 by using 2-fluoro-3- (trifluoromethyl) pyridine.

Example 14
1-isobutyl-4-methyl-N- (4- (methylsulfonyl) benzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide (I- Preparation of 14) Using isobutylhydrazine hydrochloride instead of tert-butylhydrazine hydrochloride in Step 1 of Example 9 and replacing 2 of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 with 2 -Fluoro-3- (trifluoromethyl) pyridine was used, and 4- (methanesulfonyl) benzylamine hydrochloride was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9. By using the compound, the compound (I-14) was obtained in the same manner as in Example 9.

Reference example 3
Process 1 for producing 4- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride (VIII-3)
Benzylamine (2.00 g, 18.7 mmol) was added to a solution of phthalic anhydride (2.76 g, 18.6 mmol) in acetic acid (18.7 mL), and the mixture was heated under reflux for 4 hours. The precipitate was collected by filtration and washed with water to obtain N-benzylphthalimide as a crude product.

Process 2
Chlorosulfonic acid (7.3 mL) was cooled to 0 ° C. and N-benzylphthalimide was added. The reaction solution was heated to 60 ° C. and stirred for 1 hour. The reaction solution was poured into ice and the precipitate was collected by filtration. The obtained solid was washed with water to give 4-((1,3-dioxoisoindoline-2-yl) methyl) benzene-1-sulfonyl chloride as a crude product.

Process 3
Tetrahydrofuran (36.3 mL) was added to 4-((1,3-dioxoisoindoline-2-yl) methyl) benzene-1-sulfonyl chloride, and the temperature was adjusted to 0 ° C. A methanol solution of methylamine (5.56 mmol, 54.5 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The precipitate was collected by filtration to obtain 4-((1,3-dioxoisoindoline-2-yl) methyl) -N-methylbenzenesulfonamide as a crude product.

Step 4
Ethanol (36.3 mL) and hydrazine monohydrate (885 µL, 18.2 mmol) were added to 4-((1,3-dioxoisoindoline-2-yl) methyl) -N-methylbenzenesulfonamide and heated for 3 hours. Refluxed. After cooling the reaction solution, it was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, chloroform: methanol = 99: 1 → 80:20). A 4 mol / L ethyl acetate solution of hydrogen chloride (10 mL) was added, and the precipitate was collected by filtration to give 4- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride (VIII-3) (yield 2.86 g, A four-step yield of 67%) was obtained.

Example 15
1- (tert-butyl) -4-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole Preparation of -3-carboxamide (I-15) In the step 2 of Example 9, 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 4- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride (VIII- was synthesized by the method described in Reference Example 3). Compound (I-15) was obtained in the same manner as in Example 9 by using 3).

Example 16
Of 1- (tert-butyl) -5- (4-chloro-2-cyanophenoxy) -4-methyl-N- (4- (methylsulfonyl) benzyl) -1H-pyrazole-3-carboxamide (I-16) Preparation 5-Chloro-2-fluorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and 4- (aminomethyl) in Step 4 of Example 9 was used. Compound (I-16) was obtained in the same manner as in Example 9 by using 4- (methanesulfonyl) benzylamine hydrochloride instead of benzenesulfonamide hydrochloride.

Example 17
1- (tert-butyl) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-17) 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (methylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 1 Compound (I-17) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-1).

Example 18
1- (tert-butyl) -5-((3-cyano-4-ethoxypyridin-2-yl) oxy) -4-methyl-N- (4- (N-methylsulfamoyl) benzyl) -1H- Preparation of pyrazole-3-carboxamide (I-18) 2-chloro-3-cyano-4-methoxypyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 4- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride (VIII was synthesized by the method described in Reference Example 3). Compound (I-18) was obtained in the same manner as in Example 9 by using -3).

Example 19
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-N- (4-sulfamoylbenzyl) -1H-pyrazole Preparation of 3--3-carboxamide (I-19) In the same manner as in Example 9, 2,5-dichloro-3- (trifluoromethyl) pyridine was used instead of 3,5-dichloro-2-fluoropyridine in Step 2. Was used to obtain the compound (I-19).

Example 20
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridine-2- Preparation of (yl) methyl) -1H-pyrazole-3-carboxamide (I-20) 2,5-dichloro-3- (tri) instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. Fluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 1 (5- (methylsulfonyl) pyridine. By using 2--2-yl) methanamine hydrochloride (VIII-1), compound (I-20) was obtained in the same manner as in Example 9.

Example 21
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-N- (4- (N-methylsulfamoyl) benzyl ) -1H-Pyrazole-3-carboxamide (I-21) 2,5-dichloro-3- (trifluoromethyl) in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Pyridine was used, and 4- (aminomethyl) -N-methylbenzene synthesized by the method described in Reference Example 3 was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-21) was obtained in the same manner as in Example 9 by using sulfonamide hydrochloride (VIII-3).

Reference example 4
Production of diethyl 2-ethyl-3-oxosuccinate (III-1) To a solution of ethyl butyrate (1.82 mL, 13.7 mmol) and diethyl oxalate (2.00 g, 13.7 mmol) in N, N-dimethylformamide (13.7 mL), Sodium hydride (657 mg, 16.4 mmol) was added at room temperature, and the mixture was stirred at 100 ° C for 2 hr. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80:20 → 60:40), and diethyl 2-ethyl-3-oxosuccinate (III-1 ) (Yield 2.45 g, 83% yield).

Example 22
1- (tert-butyl) -4-ethyl-N- (4-sulfamoylbenzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide Production of (I-22) Instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9, diethyl 2-ethyl-3-oxosuccinate (III- synthesized by the method described in Reference Example 4). 1) was used, and in the same manner as in Example 9, except that 2-fluoro-3- (trifluoromethyl) pyridine was used instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Compound (I-22) was obtained by the method described in 1.

Example 23
1- (tert-butyl) -4-ethyl-N- (4- (N-methylsulfamoyl) benzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H- Production of Pyrazole-3-carboxamide (I-23) 2-Ethyl-3-oxosuccinate synthesized by the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Diethyl (III-1) acid was used, 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 4, 4- (aminomethyl) -N-methylbenzenesulfonamido synthesized by the method described in Reference Example 3 was used. By using hydrochloride salt (VIII-3), to give compound (I-23) in the same manner as in Example 9.

Example 24
1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-ethyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H -Preparation of pyrazole-3-carboxamide (I-24) 2-Ethyl-3-synthesized by the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Diethyl oxosuccinate (III-1) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, it was synthesized by the method described in Reference Example 1 (5- ( Compound (I-24) was obtained in the same manner as in Example 9 by using methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1).

Example 25
1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-ethyl-N- (4- (N-methylsulfamoyl) benzyl) -1H-pyrazole- Production of 3-carboxamide (I-25) Instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9, diethyl 2-ethyl-3-oxosuccinate synthesized by the method described in Reference Example 4. (III-1) was used, and 4- (aminomethyl)-was synthesized by the method described in Reference Example 3 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-25) was obtained in the same manner as in Example 9 by using N-methylbenzenesulfonamide hydrochloride (VIII-3).

Example 26
1- (tert-butyl) -4-methyl-N- (4-sulfamoylbenzyl) -5-((3- (trifluoromethoxy) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide Production of (I-26) In the same manner as in Example 9, except that 2-fluoro-3- (trifluoromethoxy) pyridine was used instead of 3,5-dichloro-2-fluoropyridine in Step 2, the compound (I -26) was obtained.

Example 27
1- (tert-butyl) -4-methyl-N- (4- (N-methylsulfamoyl) benzyl) -5-((3- (trifluoromethoxy) pyridin-2-yl) oxy) -1H- Preparation of Pyrazole-3-carboxamide (I-27) In Step 2 of Example 9, 2-fluoro-3- (trifluoromethoxy) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 4- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride (VIII was synthesized by the method described in Reference Example 3). Compound (I-27) was obtained in the same manner as in Example 9 by using -3).

Reference example 5
Production Step 1 of (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4)
Dimethyl sulfoxide (24.6 mL) was added to 5-bromopicolinonitrile (4.50 g, 24.6 mmol) and sodium ethanesulfinate (4.28 g, 36.9 mmol), and the mixture was stirred at 110 ° C for 19 hours. Water (75 mL) was added to the reaction solution and the precipitate was collected by filtration to give 5- (ethylsulfonyl) picolinonitrile (yield 3.66 g, yield 76%).

Process 2
5- (Ethylsulfonyl) picolinonitrile (3.66 g, 18.7 mmol), 10% Palladium on carbon (366 mg) Methanol (93.3 mL) and concentrated hydrochloric acid (3.11 mL, 18.7 mmol) were placed in a pressure resistant container, and 0.3 MPa hydrogen was added. The mixture was stirred under an atmosphere at room temperature for 18 hours. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The obtained solid was washed with chloroform to obtain (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) (yield 2.91 g, yield 66%).

Example 28
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-28) 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 5. Compound (I-28) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-4).

Example 29
1- (tert-butyl) -5-((3-chloro-4- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-N- (4-sulfamoylbenzyl) -1H-pyrazole Production of 3--3-carboxamide (I-29) In the same manner as in Example 9, 2,3-dichloro-4- (trifluoromethyl) pyridine was used instead of 3,5-dichloro-2-fluoropyridine in Step 2. Was used to obtain the compound (I-29).

Example 30
1- (tert-butyl) -5-((3-chloro-4- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridine-2- Preparation of (yl) methyl) -1H-pyrazole-3-carboxamide (I-30) 2,3-dichloro-4- (tri) instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. Fluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 1 (5- (methylsulfonyl) pyridine. By using 2--2-yl) methanamine hydrochloride (VIII-1), compound (I-30) was obtained in the same manner as in Example 9.

Example 31
1- (tert-butyl) -5-((3-chloro-4- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-N- (4- (N-methylsulfamoyl) benzyl ) -1H-Pyrazole-3-carboxamide (I-31) 2,3-dichloro-4- (trifluoromethyl) in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Pyridine was used, and 4- (aminomethyl) -N-methylbenzene synthesized by the method described in Reference Example 3 was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-31) was obtained in the same manner as in Example 9 by using sulfonamide hydrochloride (VIII-3).

Example 32
1- (tert-butyl) -5- (2-cyano-3- (difluoromethoxy) phenoxy) -4-methyl-N- (4-sulfamoylbenzyl) -1H-pyrazole-3-carboxamide (I-32 In the same manner as in Example 9, compound (I-32) was prepared by substituting 2- (difluoromethoxy) -6-fluorobenzonitrile for 3,5-dichloro-2-fluoropyridine in Step 2. Obtained.

Example 33
1- (tert-butyl) -5- (2-cyano-3- (difluoromethoxy) phenoxy) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole -3-carboxamide (I-33)
2- (difluoromethoxy) -6-fluorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and 4- (amino) in Step 4 of Example 9 was used. Example 9 by using (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Reference Example 1 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-33) was obtained in the same manner as in.

Example 34
1- (tert-butyl) -5- (2-cyano-3- (difluoromethoxy) phenoxy) -4-methyl-N- (4- (N-methylsulfamoyl) benzyl) -1H-pyrazole-3- Preparation of carboxamide (I-34) In Step 2 of Example 9, 2- (difluoromethoxy) -6-fluorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine, and Example 9 was used. Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4, 4- (aminomethyl) -N-methylbenzenesulfonamide hydrochloride (VIII-3) synthesized by the method described in Reference Example 3 was used. By using the same compound (I-34) was obtained in the same manner as in Example 9.

Example 35
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-35) 2-fluoro-3- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 Was used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl) synthesized by the method described in Reference Example 2 was used. ) Phenyl) ethanol hydrochloride (VIII-2) was used to obtain compound (I-35) in the same manner as in Example 9.

Example 36
1- (tert-butyl) -4-ethyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Production of -1H-pyrazole-3-carboxamide (I-36) 2-Ethyl-synthesized by the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using diethyl 3-oxosuccinate (III-1), substituting 2-fluoro-3- (trifluoromethyl) pyridine for 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (methylsulfonyl) pyridine-2 synthesized by the method described in Reference Example 1 By using yl) methanamine hydrochloride (VIII-1), to give compound (I-36) in the same manner as in Example 9.

Example 37
1- (tert-butyl) -4-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-37) 2-Ethyl-synthesized by the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using diethyl 3-oxosuccinate (III-1), substituting 2-fluoro-3- (trifluoromethyl) pyridine for 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridine-2 was synthesized by the method described in Reference Example 5. By using yl) methanamine hydrochloride (VIII-4), to give compound (I-37) in the same manner as in Example 9.

Example 38
1- (tert-butyl) -5- (2-cyano-3- (difluoromethoxy) phenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole Preparation of 3-carboxamide (I-38) In Step 2 of Example 9, 2- (difluoromethoxy) -6-fluorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine, and the preparation was carried out. Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII was synthesized by the method described in Reference Example 5. Compound (I-38) was obtained in the same manner as in Example 9 by using -4).

Reference example 6
Production Step 1 of (5- (ethylsulfonyl) pyrimidin-2-yl) methanamine hydrochloride (VIII-5)
To a solution of 5-bromopyrimidine-2-carbonitrile (1.00 g, 5.44 mmol) in N, N-dimethylformamide (10.9 mL) was added potassium carbonate (2.25 g, 16.3 mmol) and ethanethiol (380 μL, 5.13 mmol). The mixture was added sequentially and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80:20 → 70:30), and 5- (ethylthio) pyrimidine-2-carbonitrile (yield 885 mg, yield 99%) was obtained.

Process 2
Oxone (registered trademark) (7.57 g, 12.3 mmol) was added to a solution of 5- (ethylthio) pyrimidine-2-carbonitrile (885 mg, 5.36 mmol) in acetone (5.4 mL) and water (5.4 mL) at 40 ° C. Stir for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5- (ethylsulfonyl) pyrimidine-2-carbonitrile (yield 990 mg, yield 94%).

Process 3
5- (ethylsulfonyl) pyrimidine-2-carbonitrile (490 mg, 2.48 mmol), 10% palladium carbon (49.0 mg), methanol (25.0 mL) and concentrated hydrochloric acid (207 μL, 2.48 mmol) were placed in a pressure resistant container, The mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere of 0.3 MPa. After filtering the reaction solution, the solvent was distilled off under reduced pressure to obtain (5- (ethylsulfonyl) pyrimidin-2-yl) methanamine hydrochloride (VIII-5) (yield 569 mg, yield 96%). .

Example 39
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyrimidin-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-Pyrazole-3-carboxamide (I-39) In Step 2 of Example 9, 2-fluoro-3- (trifluoromethyl) pyridine was used instead of 3,5-dichloro-2-fluoropyridine. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyrimidin-2-yl) methanamine synthesized by the method described in Reference Example 6. Compound (I-39) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-5).

Example 40
1- (tert-butyl) -4-ethyl-N-((5- (ethylsulfonyl) pyrimidin-2-yl) methyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-40) In place of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9, 2-ethyl-synthesized by the method described in Reference Example 4. Using diethyl 3-oxosuccinate (III-1), substituting 2-fluoro-3- (trifluoromethyl) pyridine for 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyrimidine was synthesized by the method described in Reference Example 6. The 2-yl) be used methanamine hydrochloride (VIII-5), to give compound (I-40) in the same manner as in Example 9.

Example 41
1- (tert-butyl) -5- (4-cyano-2- (trifluoromethyl) phenoxy) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H- Preparation of pyrazole-3-carboxamide (I-41) 4-fluoro-3- (trifluoromethyl) benzonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 1 Compound (I-41) was obtained in the same manner as in Example 9 by using (VIII-1).

Example 42
1- (tert-butyl) -5- (4-cyano-2- (trifluoromethyl) phenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H- Preparation of pyrazole-3-carboxamide (I-42) In Step 2 of Example 9, 4-fluoro-3- (trifluoromethyl) benzonitrile was used in place of 3,5-dichloro-2-fluoropyridine, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 5. Compound (I-42) was obtained in the same manner as in Example 9 by using (VIII-4).

Example 43
1- (tert-butyl) -5- (4-cyano-2- (trifluoromethyl) phenoxy) -N-((5- (ethylsulfonyl) pyrimidin-2-yl) methyl) -4-methyl-1H- Preparation of pyrazole-3-carboxamide (I-43) 4-fluoro-3- (trifluoromethyl) benzonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyrimidin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 6 Compound (I-43) was obtained in the same manner as in Example 9 by using (VIII-5).

Example 44
2- (1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide) -2- (4- ( Preparation of ethylsulfonyl) phenyl) ethyl acetate (I-44) 1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5- ( Acetic anhydride (8 μL) was added to a solution of (3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide (I-35) (40 mg, 0.072 mmol) in tetrahydrofuran (1.4 mL). , 0.080 mmol), triethylamine (12 μL, 0.086 mmol) and 4-dimethylaminopyridine (1.8 mg, 0.015 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50:50 → 20:80) to give compound (I-44) (yield 37 mg, yield 86%).

Example 45
1- (tert-butyl) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -5-((4- (trifluoromethyl) pyridin-3-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-45) 3-Fluoro-4- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (methylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 1 Compound (I-45) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-1).

Example 46
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((4- (trifluoromethyl) pyridin-3-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-46) 3-Fluoro-4- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 5. Compound (I-46) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-4).

Example 47
1- (tert-butyl) -4-ethyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -5-((4- (trifluoromethyl) pyridin-3-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-47) 2-Ethyl-synthesized by the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using diethyl 3-oxosuccinate (III-1), substituting 3-fluoro-4- (trifluoromethyl) pyridine for 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, the compound was synthesized by the method described in Reference Example 1 (5- (methylsulfonyl) pyridine-2- By using the Le) methanamine hydrochloride (VIII-1), to give compound (I-47) in the same manner as in Example 9.

Example 48
1- (tert-butyl) -4-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((4- (trifluoromethyl) pyridin-3-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-48) 2-Ethyl-synthesized by the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using diethyl 3-oxosuccinate (III-1), substituting 3-fluoro-4- (trifluoromethyl) pyridine for 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridine-2 was synthesized by the method described in Reference Example 5. By using yl) methanamine hydrochloride (VIII-4), to give compound (I-48) in the same manner as in Example 9.

Example 49
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Preparation of -4-methyl-1H-pyrazole-3-carboxamide (I-49) 2,5-dichloro-3- (tri) was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Fluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl) pyridine. By using 2--2-yl) methanamine hydrochloride (VIII-4), compound (I-49) was obtained in the same manner as in Example 9.

Example 50
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxy Preparation of ethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-50) 2,5-dichloro-3-in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Using 2- (trifluoromethyl) pyridine, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2-synthesized by the method described in Reference Example 2. The compound (I-50) was obtained in the same manner as in Example 9 by using (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 51
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((4- (trifluoromethyl) pyridin-3-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-51) 3-fluoro-4- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 Was used, and 2-amino-2- (4- (ethylsulfonyl) synthesized by the method described in Reference Example 2 was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. ) Phenyl) ethanol hydrochloride (VIII-2) was used to obtain compound (I-51) in the same manner as in Example 9.

Example 52
1- (tert-butyl) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((4- (trifluoromethyl) pyridin-3-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-52) In place of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9, 2-synthesized by the method described in Reference Example 4 Using ethyl-3-oxosuccinate diethyl (III-1), using 3-fluoro-4- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2- (4- (ethyl) was synthesized by the method described in Reference Example 2. The use of sulfonyl) phenyl) ethanol hydrochloride (VIII-2), to give compound (I-52) in the same manner as in Example 9.

Example 53
1- (tert-butyl) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-53) 2-Synthesis by the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9 Diethyl ethyl-3-oxosuccinate (III-1) was used, and 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2- (4- (ethyl) was synthesized by the method described in Reference Example 2. The use of sulfonyl) phenyl) ethanol hydrochloride (VIII-2), to give compound (I-53) in the same manner as in Example 9.

Example 54
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-54) 2,3-difluoro-5-in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Using 2- (trifluoromethyl) pyridine, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- synthesized by the method described in Reference Example 2. Compound (I-54) was obtained in the same manner as in Example 9 by using (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 55
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-55) 1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl- 5-((3- (Trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide (I-35) (0.10 g, 0.18 mmol) in N, N-dimethylformamide (1.8 mL) Cesium carbonate (0.18 g, 0.55 mmol) and iodomethane (34 μL, 0.55 mmol) were added to the solution, and the mixture was stirred at 70 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 20: 80) to give compound (I-55) (yield 33 mg, yield 32%).

Reference example 7
Production Step 1 of ethyl 2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) acetate hydrochloride (VIII-6)
2-Bromo-5-ethylsulfonylpyridine (1.00 g, 4.00 mmol) was added to ethyl (diphenylmethyleneamino) acetate (1.60 g, 5.99 mmol), tert-butoxylithium (0.512 g, 6.40 mmol), n-butyldi-1. -Adamantylphosphine (0.287 g, 0.801 mmol), palladium acetate (0.180 g, 0.802 mmol) and 1,4-dioxane (13.3 mL) were added, and the mixture was stirred at 110 ° C for 5 hr under microwave irradiation. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20 → 40: 60), and 2-((diphenylmethylene) amino) -2- ( Ethyl 5- (ethylsulfonyl) pyridin-2-yl) acetate (yield 0.832 g, yield 48%) was obtained.

Process 2
2-((Diphenylmethylene) amino) -2- (5- (ethylsulfonyl) pyridin-2-yl) ethyl acetate (0.832 g, 1.91 mmol) in 2.0 mol / L hydrogen chloride ethanol solution (2.9 mL, 5.8 mmol) Was added, and the mixture was stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 0: 100). To the purified product, 2.0 mol / L hydrogen chloride ethanol solution (1.0 mL, 2.1 mmol) was added, and the mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to remove 2-amino-2- (5- (ethyl Sulfonyl) pyridin-2-yl) ethyl acetate hydrochloride (VIII-6) (yield 0.521 g, yield 89%) was obtained.

Example 56
1- (tert-butyl) -N- (1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -4-methyl-5-((3- (trifluoromethyl) pyridine- 2-yl) oxy) -1H-pyrazole-3-carboxamide (I-56) production step 1
2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and 4- (amino) in Step 4 of Example 9 was used. Instead of methyl) benzenesulfonamide hydrochloride, 2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethyl acetate hydrochloride (VIII-6) synthesized by the method described in Reference Example 7 was used. By using 2- (1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H- in the same manner as in Example 9. Obtained ethyl pyrazole-3-carboxamido) -2- (5- (ethylsulfonyl) pyridin-2-yl) acetate.

Process 2
2- (1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide) -2- (5- ( Ethylsulfonyl) pyridin-2-yl) ethyl acetate (22.5 mg, 0.0377 mmol) in ethanol (0.50 mL) was added with sodium borohydride (4.3 mg, 0.11 mmol) at 0 ° C and stirred at room temperature for 3 hours. . A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40 → 0: 100) to give compound (I-56) (yield 10.0 mg, yield 48). %).

Example 57
1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-57) In the same manner as in Example 9, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4, it was synthesized by the method described in Reference Example 2. Compound (I-57) was obtained using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 58
1- (tert-butyl) -5-((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Preparation of -4-methyl-1H-pyrazole-3-carboxamide (I-58) 2,3-dichloro-5- (tri) instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. Fluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl) pyridine. By using 2--2-yl) methanamine hydrochloride (VIII-4), compound (I-58) was obtained in the same manner as in Example 9.

Example 59
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((2- (trifluoromethyl) pyridin-3-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-59) 3-Fluoro-2- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 5. Compound (I-59) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-4).

Example 60
1- (tert-butyl) -5-((3-chloropyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H -Preparation of pyrazole-3-carboxamide (I-60) 3-chloro-2-fluoropyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Example 9 2-Amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII synthesized by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of -2) was used to obtain the compound (I-60) in the same manner as in Example 9.

Example 61
1- (tert-butyl) -5-((3- (difluoromethyl) pyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- Preparation of Methyl-1H-pyrazole-3-carboxamide (I-61) 3-difluoromethyl-2-fluoropyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol synthesized by the method described in Reference Example 2. Compound (I-61) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-2).

Reference example 8
Process 1 for producing 3-amino-3- (4- (ethylsulfonyl) phenyl) propanoic acid methyl ester hydrochloride (VIII-7)
To 3-amino-3- (4-bromophenyl) propanoic acid methyl ester (500 mg, 1.94 mmol), tetrahydrofuran (10 mL), triethylamine (0.30 mL, 2.2 mmol) and ditert-butyl dicarbonate (0.47 mL, 0.20 mmol) was added and the mixture was stirred at room temperature for 60 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85:15 → 70:30), and 3- (4-bromophenyl) -3-(( tert-Butoxycarbonyl) amino) propanoic acid methyl ester (yield 594 mg, yield 86%) was obtained.

Process 2
3- (4-Bromophenyl) -3-((tert-butoxycarbonyl) amino) propanoic acid methyl ester (594 mg, 1.66 mmol) was added to sodium ethylsulfinate (963 mg, 8.29 mmol) and copper iodide (1.58). g, 8.30 mmol) and dimethyl sulfoxide (8.0 mL) were added, and the mixture was stirred at 110 ° C. for 18 hr. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was stirred for 20 minutes and then filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80:20 → 40:60), and 3-((tert-butoxycarbonyl) amino) -3 was used. -(4- (Ethylsulfonyl) phenyl) propanoic acid methyl ester (yield 297 mg, yield 48%) was obtained.

Process 3
To a solution of 3-((tert-butoxycarbonyl) amino) -3- (4- (ethylsulfonyl) phenyl) propanoic acid methyl ester (297 mg, 0.800 mmol) in ethyl acetate (2.0 mL), 4 mol / L hydrochloric acid ( 2.0 mL) was added, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure to give 3-amino-3- (4- (ethylsulfonyl) phenyl) propanoic acid methyl ester hydrochloride (VIII-7) (yield 240 mg, yield 98%).

Example 62
3- (1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide) -3- (4- ( Preparation of ethylsulfonyl) phenyl) propanoic acid methyl ester (I-62) 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 3-amino-3- (4- (ethylsulfonyl)) synthesized by the method described in Reference Example 8 Compound (I-62) was obtained in the same manner as in Example 9 by using phenyl) propanoic acid methyl ester hydrochloride (VIII-7).

Example 63
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -3-hydroxypropyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-63) 3- (1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy ) -1H-Pyrazole-3-carboxamide) -3- (4- (ethylsulfonyl) phenyl) propanoic acid methyl ester (I-62) (60.0 mg, 0.101 mmol) in tetrahydrofuran (1.0 mL) solution under ice cooling. A 3 mol / L lithium borohydride tetrahydrofuran solution (0.10 mL, 0.30 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -3-hydroxypropyl) -4-methyl-5-((3- ( Trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide (I-63) (yield 56.8 mg, yield 99%) was obtained.

Reference example 9
Preparation of 1- (tert-butyl) -5-((3- (1,1-difluoroethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-1) Process 1
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.33 mmol) was added to dimethyl sulfoxide (2.0 mL), 1- (2-chloropyridine- 3-yl) ethanone (309 mg, 1.99 mmol) and cesium carbonate (864 mg, 2.65 mmol) were added, and the mixture was stirred at 100 ° C for 16 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 70:30) to give 5-((3-acetylpyridine-2 -Yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 53.8 mg, yield 12%) was obtained.

Process 2
5-((3-Acetylpyridin-2-yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (150 mg, 0.434 mmol) in dichloromethane (1.5 mL) ) Solution, N, N-diethylaminosulfur trifluoride (0.56 mL, 4.2 mmol) was added, and the mixture was stirred at 45 ° C for 20 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was directly purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 75: 25), and 1- (tert-butyl) -5-((3- (1,1-difluoroethyl)) Pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 26.7 mg, yield 17%) was obtained.

Process 3
1- (tert-butyl) -5-((3- (1,1-difluoroethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (5.0 mg, 0.014 (0.50 mL) and 4 mol / L sodium hydroxide aqueous solution (0.10 mL, 0.40 mmol) were added to (mmol), and the mixture was stirred at room temperature for 4 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1- (tert-butyl) -5-((3- (1,1-difluoroethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3. -Carboxylic acid (VII-1) (4.2 mg, 91% yield) was obtained.

Example 64
1- (tert-butyl) -5-((3- (1,1-difluoroethyl) pyridin-2-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl)- Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-64) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy in step 4 of Example 9 ) -4-Methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((3- (1,1-difluoroethyl)) synthesized by the method described in Reference Example 9. Pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-1) was used, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. In place of Compound (I-64) was obtained in the same manner as in Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method.

Example 65
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-ethyl-N-((5- (ethylsulfonyl) pyridine-2- Preparation of (yl) methyl) -1H-pyrazole-3-carboxamide (I-65) In place of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9, it was synthesized by the method described in Reference Example 4. Diethyl 2-ethyl-3-oxosuccinate (III-1) was used, and 2,5-dichloro-3- (trifluoromethyl) was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. ) Pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfoni ) The use of pyridin-2-yl) methanamine hydrochloride (VIII-4), to give compound (I-65) in the same manner as in Example 9.

Example 66
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) Preparation of 2-hydroxyethyl) -1H-pyrazole-3-carboxamide (I-66) By the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using the synthesized 2-ethyl-3-oxosuccinate diethyl (III-1), 2,5-dichloro-3- (triethyl was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Fluoromethyl) pyridine was used, and 2-amino-synthesized by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. - The use of (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2), to give compound (I-66) in the same manner as in Example 9.

Reference example 10
Process 1 for producing 2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8)
A solution of sodium sulfite (5.65 g, 44.8 mmol) and sodium hydrogen carbonate (3.96 g, 47.1 mmol) in water (118 mL) was stirred at 75 ° C for 1 hour. 6-Chloropyridine-3-sulfonyl chloride (5.00 g, 23.6 mmol) was added to the reaction solution, the mixture was stirred for 1 hour, and the solvent was evaporated under reduced pressure. Sodium hydrogen carbonate (3.96 g, 47.1 mmol), ethyl iodide (2.09 mL, 25.9 mmol) and N, N-dimethylformamide (42.9 mL) were added to the residue, and the mixture was stirred at 75 ° C for 3 hr. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80:20 → 30:70), and 2-chloro-5- (ethylsulfonyl) pyridine (yield 2.56 g, yield 53%) was obtained.

Process 2
2-Chloro-5- (ethylsulfonyl) pyridine (2.56 g, 12.4 mmol) in (diphenylmethyleneamino) ethyl acetate (4.99 g, 18.7 mmol), tert-butoxy lithium (1.59 g, 19.9 mmol) and dimethyl sulfoxide (41.5 mL) was added and the mixture was stirred at 150 ° C. for 0.5 hours under microwave irradiation. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20 → 40: 60), and 2-((diphenylmethylene) amino) -2- ( Ethyl 5- (ethylsulfonyl) pyridin-2-yl) acetate (amount 3.25 g, yield 60%) was obtained.

Process 3
2-((Diphenylmethylene) amino) -2- (5- (ethylsulfonyl) pyridin-2-yl) ethyl acetate (3.25 g, 7.45 mmol) in 2.0 mol / L hydrogen chloride ethanol solution (11 mL, 22 mmol) Was added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure to obtain ethyl 2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) acetate hydrochloride (VIII-6) as a crude product.

Step 4
Ethyl 2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) acetate hydrochloride (VIII-6) obtained in Step 3 was added to ditert-butyl dicarbonate (1.79 g, 8.20 mmol), Triethylamine (1.66 g, 16.4 mmol) and dichloromethane (24.8 mL) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 2-((tert-butoxycarbonyl) amino) -2- (5- (ethylsulfonyl) pyridin-2-yl) acetate as a crude product.

Step 5
To a solution of ice-cooled ethyl 2-((tert-butoxycarbonyl) amino) -2- (5- (ethylsulfonyl) pyridin-2-yl) acetate in ethanol (24.8 mL) was added sodium borohydride (0.563 g, 14.9 mL). mmol) was added and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40 → 0: 100), and tert-butyl (1- (5- (ethylsulfonyl)) Pyridin-2-yl) -2-hydroxyethyl) carbamate (yield 1.22 g, 3 step yield 50%) was obtained.

Process 6
To a solution of tert-butyl (1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) carbamate (1.22 g, 3.69 mmol) in ethyl acetate (3.69 mL), 4.0 mol / L hydrogen chloride acetic acid was added. An ethyl solution (1.9 mL, 7.6 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure to obtain 2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8) (yield 0.981 g, quantitative).

Example 67
1- (tert-butyl) -4-ethyl-N- (1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -5-((3- (trifluoromethyl) pyridine- Preparation of 2-yl) oxy) -1H-pyrazole-3-carboxamide (I-67) By the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using synthesized 2-ethyl-3-oxosuccinate diethyl (III-1), 2-fluoro-3- (trifluoromethyl) was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. ) Pyridine was used, and 2-amino-2-synthesized by the method described in Reference Example 10 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. By using 5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8), to give compound (I-67) in the same manner as in Example 9.

Example 68
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -N- (1- (5- (ethylsulfonyl) pyridin-2-yl) Preparation of 2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-68) 2,5-dichloro-2-fluoropyridine instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 Using dichloro-3- (trifluoromethyl) pyridine, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, synthesized by the method described in Reference Example 10 Compound (I-68) was obtained in the same manner as in Example 9 by using amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8).

Example 69
1- (tert-butyl) -5-((5-chloro-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-ethyl-N- (1- (5- (ethylsulfonyl) pyridine- Preparation of 2-yl) -2-hydroxyethyl) -1H-pyrazole-3-carboxamide (I-69) Refer to Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using 2-ethyl-3-oxosuccinate diethyl (III-1) synthesized by the described method, 2,5-dichloro-in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Using 3- (trifluoromethyl) pyridine, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, the method described in Reference Example 10 was used. - The use of amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8), to give compound (I-69) in the same manner as in Example 9.

Example 70
1- (tert-butyl) -N- (1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -4-methyl-5-((4- (trifluoromethyl) pyridine- Preparation of 3-yl) oxy) -1H-pyrazole-3-carboxamide (I-70) 3-fluoro-4- (tri) in place of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. 2-Amino-2- (5) synthesized by the method described in Reference Example 10 using fluoromethyl) pyridine, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-70) was obtained in the same manner as in Example 9 by using-(ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8).

Example 71
1- (tert-butyl) -4-ethyl-N- (1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -5-((4- (trifluoromethyl) pyridine- Preparation of 3-yl) oxy) -1H-pyrazole-3-carboxamide (I-71) By the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using synthesized 2-ethyl-3-oxosuccinate diethyl (III-1), 3-fluoro-4- (trifluoromethyl) was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. ) Pyridine was used, and 2-amino-2-synthesized by the method described in Reference Example 10 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. By using 5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8), to give compound (I-71) in the same manner as in Example 9.

Example 72
1- (tert-butyl) -5-((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxy Preparation of ethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-72) 2,3-dichloro-5-in place of 3,5-dichloro-2-fluoropyridine in step 9 of Example 9. Using 2- (trifluoromethyl) pyridine, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2-synthesized by the method described in Reference Example 2. Compound (I-72) was obtained in the same manner as in Example 9 by using (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 73
5-((3-Bromopyridin-2-yl) oxy) -1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H -Preparation of pyrazole-3-carboxamide (I-73) In step 2 of Example 9, 3-bromo-2-fluoropyridine was used in place of 3,5-dichloro-2-fluoropyridine, and Example 9 was used. 2-Amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII synthesized by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of -2) was used to obtain compound (I-73) in the same manner as in Example 9.

Example 74
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((2- (trifluoromethyl) pyridin-3-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-74) 3-fluoro-2- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Was used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl) synthesized by the method described in Reference Example 2 was used. ) Phenyl) ethanol hydrochloride (VIII-2) was used to obtain compound (I-74) in the same manner as in Example 9.

Example 75
1- (tert-butyl) -5-((3-cyano-2-ethoxypyridin-4-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-75) 2,4-dichloro-3-cyanopyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 5. Compound (I-75) was obtained in the same manner as in Example 9 by using (VIII-4).

Example 76
1- (tert-butyl) -5-((3-cyano-2-ethoxypyridin-4-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4 Preparation of -Methyl-1H-pyrazole-3-carboxamide (I-76) 2,4-dichloro-3-cyanopyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl) phenyl synthesized by the method described in Reference Example 2. ) Compound (I-76) was obtained in the same manner as in Example 9 by using ethanol hydrochloride (VIII-2).

Example 77
1- (tert-butyl) -5- (2-cyanophenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide ( Preparation of I-77) 2-fluorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and 4- (aminomethyl) in Step 4 of Example 9 was used. ) By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of benzenesulfonamide hydrochloride, Compound (I-77) was obtained in the same manner as in No. 9.

Example 78
1- (tert-butyl) -5- (3-chloro-2-cyanophenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole-3- Preparation of carboxamide (I-78) 2,6-dichlorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and 4 in Step 4 of Example 9 was used. By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of-(aminomethyl) benzenesulfonamide hydrochloride, Compound (I-78) was obtained in the same manner as in Example 9.

Example 79
1- (tert-butyl) -5- (3-chloro-2-cyanophenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H-pyrazole- Preparation of 3-carboxamide (I-79) 2,6-dichlorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and in Step 4 of Example 9. Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 was used. By using it, a compound (I-79) was obtained in the same manner as in Example 9.

Example 80
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-4-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-80) 4-chloro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 5. Compound (I-80) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-4).

Example 81
1- (tert-butyl) -5- (2-cyano-3-ethoxyphenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole-3- Preparation of carboxamide (I-81) 2-ethoxy-6-fluorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 and in Step 4 of Example 9. , (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used in place of 4- (aminomethyl) benzenesulfonamide hydrochloride. Thus, the compound (I-81) was obtained in the same manner as in Example 9.

Reference example 11
Production Step 1 of (5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-9)
N, N-Dimethylformamide (50 mL) and sodium sulfide (21.6 g, 90.2 mmol) were added to 5-fluoropicolinonitrile (10.0 g, 82.0 mmol), and the mixture was stirred at room temperature for 1 hr under a nitrogen atmosphere. A 1 mol / L sodium hydroxide aqueous solution (500 mL) was added, and the mixture was extracted with dichloromethane. 6 mol / L hydrochloric acid was added to the aqueous layer until the pH became 1-2, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5-mercaptopicolinonitrile (yield 5.0 g, yield 45%).

Process 2
N, N-Dimethylformamide (30 mL) and bromomethylcyclopropane (2.0 g, 14.7 mmol) were added to 5-mercaptopicolinonitrile (2.0 g, 14.7 mmol), and the mixture was cooled to 0 ° C. Sodium hydride (0.9 g, 22.1 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5-((cyclopropylmethyl) thio) picolinonitrile (yield 2.0 g, yield 72%).

Process 3
Dichloromethane (30 mL) was added to 5-((cyclopropylmethyl) thio) picolinonitrile (2.0 g, 10.5 mmol), and the mixture was cooled to 0 ° C. m-CPBA (5.4 g, 31.6 mmol) was added, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen sulfite solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5-((cyclopropylmethyl) sulfonyl) picolinonitrile (amount 1.5 g, yield 64%).

Step 4
Methanol (30 mL) and 10% palladium carbon (150 mg) were added to 5-((cyclopropylmethyl) sulfonyl) picolinonitrile (1.5 g, 6.7 mmol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours. After filtering the reaction solution, a 4 mol / L hydrogen chloride ethyl acetate solution (2 mL) was added. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-9) (yield 300 mg, Yield 20%) was obtained.

Example 82
1- (tert-butyl) -N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridine-2- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-82) 2-fluoro-3- (trifluoromethyl) instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. ) Pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 11 (5-((cyclopropylmethyl) sulfonyl). ) Pyridin-2-yl) methanamine hydrochloride (VIII-9) was used to obtain compound (I-82) in the same manner as in Example 9.

Reference example 12
Production of 1- (tert-butyl) -5- (2- (difluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-2) In the same manner as in Reference Example 9, Step 1 2-fluorobenzaldehyde in place of 3-acetyl-2-chloropyridine of 1- (tert-butyl) -5- (2- (difluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic The acid (VII-2) was obtained.

Example 83
1- (tert-butyl) -5- (2- (difluoromethyl) phenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide Preparation of (I-83) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3 in step 4 of Example 9 -In place of the carboxylic acid, 1- (tert-butyl) -5- (2- (difluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (synthesized by the method described in Reference Example 12 ( VII-2) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl) pyridine. -2 By using yl) methanamine hydrochloride (VIII-4), to give compound (I-83) in the same manner as in Example 9.

Reference example 13
Production of 2-amino-2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride (VIII-10) In the same manner as in Reference Example 2, sodium methylsulfinate was used instead of sodium ethylsulfinate in step 2. To give 2-amino-2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride (VIII-10).

Example 84
1- (tert-butyl) -N- (2-hydroxy-1- (4- (methylsulfonyl) phenyl) ethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Oxy) -1H-pyrazole-3-carboxamide (I-84) 2-fluoro-3- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 Was used in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, and 2-amino-2- (4- (methylsulfonyl) was synthesized by the method described in Reference Example 13. ) Phenyl) ethanol hydrochloride (VIII-10) was used to obtain compound (I-84) in the same manner as in Example 9.

Example 85
1- (tert-butyl) -4-ethyl-N- (2-hydroxy-1- (4- (methylsulfonyl) phenyl) ethyl) -5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-85) In place of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9, 2-synthesized by the method described in Reference Example 4 Diethyl ethyl-3-oxosuccinate (III-1) was used, and 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2- (4- (meth By using Rusuruhoniru) phenyl) ethanol hydrochloride (VIII-10), to give compound (I-85) in the same manner as in Example 9.

Example 86
1-cyclobutyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H -Preparation of pyrazole-3-carboxamide (I-86) Cyclobutylhydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9, and 3,5 in Step 2 of Example 9 was used. 2-fluoro-3- (trifluoromethyl) pyridine was used in place of dichloro-2-fluoropyridine, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 Using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 Ri, to give compound (I-86) in the same manner as in Example 9.

Reference Example 14
Preparation of 2-fluoro-6- (2,2,2-trifluoroethoxy) benzonitrile (V-1) 2-Fluoro-6-hydroxy-benzonitrile (500 mg, 3.65 mmol) in N, N-dimethylformamide To the (12 mL) solution, potassium carbonate (756 mg, 5.47 mmol), 2,2,2-trifluoroethyl methanesulfonate (0.79 mL, 5.5 mmol) and potassium iodide (60.5 mg, 0.364 mmol) were added, The mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with a mixed solution of ethyl acetate / hexane. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 70:30) and 2-fluoro-6- (2,2,2- Trifluoroethoxy) benzonitrile (V-1) (yield 740 mg, 93% yield) was obtained.

Example 87
1- (tert-butyl) -5- (2-cyano-3- (2,2,2-trifluoroethoxy) phenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl)- Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-87) Instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, it was synthesized by the method described in Reference Example 14. Using 2-fluoro-6- (2,2,2-trifluoroethoxy) benzonitrile (V-1) and replacing 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 In the same manner as in Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 in the same manner as in Example 9. − 87) was obtained.

Example 88
1- (tert-butyl) -5- (2-cyano-3-ethoxyphenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H-pyrazole- Preparation of 3-carboxamide (I-88) In the step 2 of Example 9, 2-ethoxy-6-fluorobenzonitrile was used in place of 3,5-dichloro-2-fluoropyridine, and the step of Example 9 was used. 4 in place of 4- (aminomethyl) benzenesulfonamide hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 Compound (I-88) was obtained in the same manner as in Example 9 by using).

Example 89
1- (tert-butyl) -5- (2-cyano-3- (2,2,2-trifluoroethoxy) phenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl ) -4-Methyl-1H-pyrazole-3-carboxamide (I-89) By the method described in Reference Example 14, instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, Using the synthesized 2-fluoro-6- (2,2,2-trifluoroethoxy) benzonitrile (V-1), 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. In the same manner as in Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of To give compound (I-89).

Example 90
1- (tert-butyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Production of -4-methyl-1H-pyrazole-3-carboxamide (I-90) 3,5-difluoro-4- (instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 was used. Trifluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl)). The compound (I-90) was obtained in the same manner as in Example 9 by using pyridin-2-yl) methanamine hydrochloride (VIII-4).

Example 91
1- (tert-butyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxy Preparation of ethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-91) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4 was used. Using 2- (trifluoromethyl) pyridine, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2 synthesized by the method described in Reference Example 2. Compound (I-91) was obtained in the same manner as in Example 9 by using-(4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 92
N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1-neopentyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole Preparation of 3-carboxamide (I-92) 2,3-Dimethylpropylhydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9, 3 in Step 2 of Example 9. , 5-Dichloro-2-fluoropyridine was replaced by 2-fluoro-3- (trifluoromethyl) pyridine, and the replacement of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 In addition, by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5, To give compound (I-92) in the same manner as in Example 9.

Example 93
N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1-neopentyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H Preparation of -Pyrazole-3-carboxamide (I-93) 2,2-Dimethylpropylhydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9, in Step 2 of Example 9. , 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 was used. 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of By have to give compound (I-93) in the same manner as in Example 9.

Reference example 15
Process 1 for producing 2-amino-2- (4- (ethylsulfonyl) phenyl) acetamide hydrochloride (VIII-11)
Methanol (4.0 mL) was added to 2-((tert-butoxycarbonyl) amino) -2- (4- (ethylsulfonyl) phenyl) acetic acid methyl ester (300 mg, 0.839 mmol) produced in Step 2 of Reference Example 2. And 4 mol / L sodium hydroxide aqueous solution (0.63 mL, 2.5 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 2-((tert-butoxycarbonyl) amino) -2- (4- (ethylsulfonyl) phenyl) acetic acid (yield 280 mg, 97% yield).

Process 2
2-((tert-Butoxycarbonyl) amino) -2- (4- (ethylsulfonyl) phenyl) acetic acid (100 mg, 0.291 mmol) in tetrahydrofuran (3.0 mL), N, N-diisopropylethylamine (0.25 mL, 1.4 mmol), ammonium chloride (46.7 mg, 0.873 mmol) and HATU (166 mg, 0.437 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was directly purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40 → 0: 100) and tert-butyl-N- (2-amino-1- (4- (ethylsulfonyl) phenyl). 2-oxo-ethyl) carbamate (yield 76.6 mg, yield 77%) was obtained.

Process 3
tert-Butyl-N- (2-amino-1- (4- (ethylsulfonyl) phenyl) -2-oxo-ethyl) carbamate (74.5 mg, 0.218 mmol), ethyl acetate (1.0 mL), methanol (1.0 mL) ) And 4 mol / L hydrochloric acid (1.0 mL) were added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure to obtain 2-amino-2- (4- (ethylsulfonyl) phenyl) acetamide hydrochloride (VIII-11) (yield 41.3 mg, yield 68%).

Example 94
N- (2-amino-1- (4- (ethylsulfonyl) phenyl) -2-oxoethyl) -1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) pyridine-2 Preparation of -yl) oxy) -1H-pyrazole-3-carboxamide (I-94) 2-fluoro-3- (trifluoro) instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. 2-amino-2- (4-) synthesized by the method described in Reference Example 15 was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 using methyl) pyridine. Compound (I-94) was obtained in the same manner as in Example 9 by using (ethylsulfonyl) phenyl) acetamide hydrochloride (VIII-11).

Example 95
N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1-propyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole Preparation of 3-carboxamide (I-95) 3,5-Dichloro- 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 2-fluoropyridine, and Reference Example 5 was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9. By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in 1. To give Compound (I-95) in law.

Example 96
N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1-propyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H -Preparation of pyrazole-3-carboxamide (I-96) propylhydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9, and 3,5-, in Step 2 of Example 9. 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of dichloro-2-fluoropyridine, and reference was made in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Example 2, In the same manner as in Example 9 to give the compound (I-96).

Example 97
1- (sec-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-97) sec-butylhydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride in step 1 of example 9, step 2 of example 9, 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and the 4- (aminomethyl) benzenesulfonamide hydrochloride salt in Step 4 of Example 9 was used. Instead of Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5. To give compound (I-97) in the same manner.

Example 98
1- (sec-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-98) sec-butylhydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9, Step 2 of Example 9. 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Example 1, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. Using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of the salt Ri, to give compound (I-98) in the same manner as in Example 9.

Example 99
N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1-isobutyl-4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole Preparation of 3-carboxamide (I-99) Using isobutylhydrazine hydrochloride in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9, 3,5-dichloro-2 in Step 2 of Example 9 2-fluoro-3- (trifluoromethyl) pyridine was used in place of -fluoropyridine, and in Reference Example 5 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9. Similar to Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described. To give Compound (I-99) by the method.

Example 100
N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1-isobutyl-4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H -Preparation of pyrazole-3-carboxamide (I-100) Using isobutylhydrazine hydrochloride instead of tert-butylhydrazine hydrochloride in step 1 of Example 9, 3,5-dichloro in step 2 of Example 9. 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 2-fluoropyridine, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, Reference Example By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in 2. In the same manner as in Example 9 to give the compound (I-100).

Example 101
1- (tert-butyl) -5-((3-chloropyridin-2-yl) oxy) -N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-101) In the step 2 of Example 9, 2-fluoro-3-chloropyridine was used instead of 3,5-dichloro-2-fluoropyridine, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 11 Compound (I-101) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-9).

Example 102
1- (tert-butyl) -N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((2- (trifluoromethyl) pyridine-3- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-102) 3-fluoro-2- (trifluoromethyl) instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. ) Pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 11 (5-((cyclopropylmethyl) sulfonyl). ) Pyridin-2-yl) methanamine hydrochloride (VIII-9) was used to obtain compound (I-102) in the same manner as in Example 9.

Example 103
1- (tert-butyl) -N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) -4-ethyl-5-((3- (trifluoromethyl) pyridine-2- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-103) In place of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9, it was synthesized by the method described in Reference Example 4. Using 2-ethyl-3-oxosuccinate diethyl (III-1), in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 2-fluoro-3- (trifluoromethyl) pyridine. Was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, it was synthesized by the method described in Reference Example 11 (5-((cyclo By using Ropirumechiru) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-9), to give compound (I-103) in the same manner as in Example 9.

Example 104
1- (tert-butyl) -N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((4- (trifluoromethyl) pyridine-3- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-104) 3-fluoro-4- (trifluoromethyl) in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 ) Pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 11 (5-((cyclopropylmethyl) sulfonyl). ) Pyridin-2-yl) methanamine hydrochloride (VIII-9) was used to obtain compound (I-104) in the same manner as in Example 9.

Example 105
1- (tert-butyl) -5- (2- (difluoromethyl) phenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H-pyrazole-3 -Preparation of carboxamide (I-105) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole in step 4 of Example 9 Instead of -3-carboxylic acid, 1- (tert-butyl) -5- (2- (difluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid synthesized by the method described in Reference Example 12 Acid (VII-2) was used, and 2-amino-2-synthesized by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. (4- ( Compound (I-105) was obtained in the same manner as in Example 9 by using ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 106
1- (tert-butyl) -5-((3-cyano-2-ethoxypyridin-4-yl) oxy) -N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-106) 2,4-dichloro-3-cyanopyridine instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. Was used in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 (5-((cyclopropylmethyl) sulfonyl) pyridine synthesized by the method described in Reference Example 11. By using 2--2-yl) methanamine hydrochloride (VIII-9), compound (I-106) was obtained in the same manner as in Example 9.

Example 107
N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) -4-methyl-1-propyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-107) Using propylhydrazine dihydrochloride in place of tert-butylhydrazine hydrochloride in step 1 of Example 9, step 2 of Example 9, 3, 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 5-dichloro-2-fluoropyridine, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 , (5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-) synthesized by the method described in Reference Example 11. ) Is used, to give the compound (I-107) in the same manner as in Example 9.

Example 108
1- (cyclopropylmethyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-Pyrazole-3-carboxamide (I-108) Substituting (cyclopropylmethyl) hydrazine dihydrochloride for tert-butylhydrazine hydrochloride in Step 1 of Example 9, Step 2 of Example 9. 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Example 4, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. Instead of the salt, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used. By you have to give compound (I-108) in the same manner as in Example 9.

Example 109
1- (cyclopropylmethyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Oxy) -1H-pyrazole-3-carboxamide (I-109) Preparation of Example 9 using (cyclopropylmethyl) hydrazine dihydrochloride instead of tert-butylhydrazine hydrochloride in step 1 of Example 9. 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2, and 4- (aminomethyl) benzenesulfone in Step 4 of Example 9 was used. 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloric acid synthesized by the method described in Reference Example 2 instead of amide hydrochloride The use of (VIII-2), to give compound (I-109) in the same manner as in Example 9.

Example 110
N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1- (pentan-3-yl) -5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-110) In the step 1 of Example 9, the pentan-3-ylhydrazine hydrochloride was used in place of the tert-butylhydrazine hydrochloride. 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in 2, and 4- (aminomethyl) benzenesulfonamide in step 4 of Example 9 Use (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of the hydrochloride. More, to give compound (I-110) in the same manner as in Example 9.

Example 111
N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1- (pentan-3-yl) -5-((3- (trifluoromethyl) pyridin-2- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-111) Example 9 using pentan-3-ylhydrazine hydrochloride instead of tert-butylhydrazine hydrochloride in step 1 of Example 9. 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 1, and 4- (aminomethyl) benzene in Step 4 of Example 9 was used. Instead of sulfonamide hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2 synthesized by the method described in Reference Example 2 was used. By using, to give compound (I-111) in the same manner as in Example 9.

Example 112
1,4-diethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3 -Preparation of carboxamide (I-112) 2-methyl-3-oxosuccinic acid in step 1 of Example 9 using ethylhydrazine dihydrochloride in place of tert-butylhydrazine hydrochloride in step 1 of example 9. In place of diethyl, diethyl 2-ethyl-3-oxosuccinate (III-1) synthesized by the method described in Reference Example 4 was used, and 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 was used. 2-fluoro-3- (trifluoromethyl) pyridine was used in place of, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. In the same manner as in Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of (I-112) was obtained.

Example 113
1,4-diethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole Preparation of 3-carboxamide (I-113) 2-Methyl-3-, in Step 1 of Example 9, using ethylhydrazine dihydrochloride in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9. In place of diethyl oxosuccinate, diethyl 2-ethyl-3-oxosuccinate (III-1) synthesized by the method described in Reference Example 4 was used, and 3,5-dichloro-2- in Step 2 of Example 9 was used. 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of fluoropyridine, and 4- (aminomethyl) benzenesulfone in Step 4 of Example 9 was used. Similar to Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of the amide hydrochloride. Compound (I-113) was obtained by the method of.

Example 114
4-Ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -1-propyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole Preparation of 3-carboxamide (I-114) In the step 1 of Example 9, propylhydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride, and 2-methyl-3- in the step 1 of Example 9 was used. In place of diethyl oxosuccinate, diethyl 2-ethyl-3-oxosuccinate (III-1) synthesized by the method described in Reference Example 4 was used, and 3,5-dichloro-2- in Step 2 of Example 9 was used. 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of fluoropyridine, and 4- (aminomethyl) benzenesulfone in Step 4 of Example 9 was used. A method similar to that in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of the amide hydrochloride. To obtain the compound (I-114).

Example 115
4-Ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1-propyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H -Preparation of pyrazole-3-carboxamide (I-115) 2-methyl- in Step 1 of Example 9 using propylhydrazine dihydrochloride instead of tert-butylhydrazine hydrochloride in Step 1 of Example 9. In place of diethyl 3-oxosuccinate, diethyl 2-ethyl-3-oxosuccinate (III-1) synthesized by the method described in Reference Example 4 was used, and 3,5-dichloro- in Step 2 of Example 9 was used. 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 2-fluoropyridine, and 4- (aminomethyl) benze in Step 4 of Example 9 was used. Example 9 was obtained by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of sulfonamide hydrochloride. Compound (I-115) was obtained by the same method.

Reference example 16
Production Step 1 of (5- (ethylsulfonyl) -3-methylpyridin-2-yl) methanamine hydrochloride (VIII-12)
To 5-bromo-3-methylpicolinonitrile (10.0 g, 50.8 mmol), N, N-dimethylformamide (100 mL), ethyl mercaptan (3.8 g, 60.9 mmol), copper iodide (0.97 g, 5.1 mmol), Tetrabutylammonium bromide (5.9 g, 5.1 mmol) and tripotassium phosphate (21.6 g, 101.5 mmol) were added, and the mixture was stirred at 130 ° C for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 5- (ethylthio) -3-methylpicolinonitrile (yield 8.0 g, yield 89%).

Process 2
Dichloromethane (120 mL) and m-CPBA (19.3 g, 112.3 mmol) were added to 5- (ethylthio) -3-methylpicolinonitrile (8.0 g, 44.9 mmol), and the mixture was stirred at room temperature for 1 hour. An aqueous sodium sulfite solution and an aqueous sodium carbonate solution were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with petroleum ether to give 5- (ethylsulfonyl) -3-methylpicolinonitrile (yield 9.0 g, yield 95%).

Process 3
Palladium carbon (200 mg) and methanol (40 mL) were added to 5- (ethylsulfonyl) -3-methylpicolinonitrile (2.0 g, 9.5 mol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hr. The reaction solution was filtered and the solvent was evaporated under reduced pressure to give (5- (ethylsulfonyl) -3-methylpyridin-2-yl) methanamine (2.0 g) as a crude product.

Step 4
To (5- (ethylsulfonyl) -3-methylpyridin-2-yl) methanamine (2.0 g), dichloromethane (40 mL), sodium hydrogen carbonate (2.0 g, 23.8 mol) and ditert-butyl dicarbonate (3.1 g). , 14.3 mol) was added, and the mixture was stirred at room temperature for 4 hours. The organic layer was washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give tert-butyl ((5- (ethylsulfonyl) -3-methylpyridin-2-yl) methyl) carbamate (yield 2.0 g, Yield 67%) was obtained.

Step 5
tert-Butyl ((5- (ethylsulfonyl) -3-methylpyridin-2-yl) methyl) carbamate (2.0 g, 6.4 mmol) in ethyl acetate (20 mL) and 4 mol / L hydrogen chloride ethyl acetate solution ( 1.6 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and washed with ethyl acetate to give (5- (ethylsulfonyl) -3-methylpyridin-2-yl) methanamine hydrochloride (VIII-12) (yield 1.5 g, yield 88%). Obtained.

Example 116
1- (tert-butyl) -N-((5- (ethylsulfonyl) -3-methylpyridin-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridine-2- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-116) 2-fluoro-3- (trifluoromethyl) in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 ) Pyridine was used, and it was synthesized by the method described in Reference Example 16 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 (5- (ethylsulfonyl) -3- Compound (I-116) was obtained in the same manner as in Example 9 by using methylpyridin-2-yl) methanamine hydrochloride (VIII-12).

Reference Example 17
Production Step 1 of 3- (4- (ethylsulfonyl) phenyl) oxetane-3-amine (VIII-13)
To a solution of 1,2-diethyldisulfane (10.6 g, 87.2 mmol) and tert-butyl nitrite (8.9 g, 87.2 mmol) in dichloroethane (100 mL) was added 4-bromoaniline (10.0 g, 58.1 mmol) in dichloroethane. (100 mL) solution was added dropwise at 40 ° C. over 1 hour. The reaction solution was stirred at room temperature for 16 hours, water was added, and the mixture was stirred for 10 minutes. The organic layer was separated, the organic layer was washed successively with 1 mol / L hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1), (4-bromophenyl) (ethyl) sulfane (yield 7.0 g, yield 58%) ) Got.

Process 2
Tetraisopropyl orthotitanate (45 mL, 208 mmol) was added to a solution of 2-methyl-2-propanesulfinamide (7.5 g, 104 mmol) and 3-oxetanone (12.6 g, 104 mmol) in tetrahydrofuran (123 mL). It was added dropwise at room temperature over 15 minutes. The reaction solution was stirred at 50 ° C. for 4 hours, and saturated brine was added. After filtering the suspension, the solid was washed with ethyl acetate. The filtrate was washed successively with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2-methyl-N- (oxetane-3-ylidene) propane-2-sulfinamide (yield 13.0 g) as a crude product.

Process 3
A n-butyllithium hexane solution (13 mL, 32.3 mmol) was added dropwise to a tetrahydrofuran (150 mL) solution of (4-bromophenyl) (ethyl) sulfane (7.0 g, 32.3 mmol) at -78 ° C. After stirring the reaction solution at the same temperature for 1 hour, a solution of 2-methyl-N- (oxetane-3-ylidene) propane-2-sulfinamide (4.7 g, 26.9 mmol) in tetrahydrofuran (25 mL) was added dropwise at the same temperature. did. The reaction solution was stirred at −78 ° C. for another 30 minutes and then warmed to room temperature. After stirring the reaction solution at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 0: 100, then methanol: ethyl acetate = 5: 95), and N- (3- (4- (ethylthio) phenyl). ) Oxetan-3-yl) -2-methylpropane-2-sulfinamide (yield 3.1 g, yield 37%) was obtained.

Step 4
A solution of N- (3- (4- (ethylthio) phenyl) oxetane-3-yl) -2-methylpropane-2-sulfinamide (0.9 g, 2.9 mmol) in ethyl acetate (3 mL) was added at 0 ° C. Hydrogen tert-butyl methyl ether solution (3 mL) was added, and the mixture was stirred for 10 minutes. The precipitate was collected by filtration and washed with ethyl acetate to give 3- (4- (ethylthio) phenyl) oxetane-3-amine hydrochloride (yield 0.6 g, yield 86%).

Step 5
Tetrahydrofuran (60 mL) and saturated aqueous sodium carbonate solution (60 mL) were added to 3- (4- (ethylthio) phenyl) oxetane-3-amine hydrochloride (2.8 g, 11.5 mmol), and then ditert-butyl dicarbonate. A solution of (3.8 g, 17.3 mmol) in tetrahydrofuran (30 mL) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give tert-butyl (3- (4- (ethylthio) phenyl) oxetane-3-yl) carbamate (yield 3.4 g, yield 63%). ) Got.

Process 6
m-CPBA (4.7 g, 27.5 mmol) was added to a solution of tert-butyl (3- (4- (ethylthio) phenyl) oxetan-3-yl) carbamate (2.8 g, 11.5 mmol) in dichloromethane (60 mL) at 0 ° C. And stirred at the same temperature for 1 hour. Aqueous sodium sulfite solution (20 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give tert-butyl (3- (4- (ethylsulfonyl) phenyl) oxetane-3-yl) carbamate (yield 1.8 g, yield 49 %) Was obtained.

Process 7
Trifluoroacetic acid (10 mL) was added to a dichloromethane (40 mL) solution of tert-butyl (3- (4- (ethylsulfonyl) phenyl) oxetan-3-yl) carbamate (1.8 g, 5.3 mmol) at 0 ° C. After that, the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and then saturated aqueous sodium carbonate solution was added until the reaction solution became basic. After extraction with dichloromethane, the organic layer was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3- (4- (ethylsulfonyl) phenyl) oxetane-3-amine (VIII-13) (yield 0.7 g, yield 54%). ) Got.

Example 117
1- (tert-butyl) -N- (3- (4- (ethylsulfonyl) phenyl) oxetane-3-yl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-117) 2-fluoro-3- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 Was used, and 3- (4- (ethylsulfonyl) phenyl) oxetane synthesized by the method described in Reference Example 17 was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-117) was obtained in the same manner as in Example 9 by using -3-amine (VIII-13).

Example 118
1- (tert-butyl) -5-((3-cyano-2-propoxypyridin-4-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-118) Using 2,4-dichloro-3-cyanopyridine instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. 1-Propanol was used in place of ethanol in Step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was replaced by the method described in Reference Example 5. Compound (I-118) was obtained in the same manner as in Example 9 by using the synthesized (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4). It was.

Reference Example 18
Production of 1- (tert-butyl) -5-((4- (difluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-3) Reference Example 9 and In a similar manner, substituting 3-fluoro-4-pyridinecarboxaldehyde for 3-acetyl-2-chloropyridine in step 1, 1- (tert-butyl) -5-((4- (difluoromethyl) pyridine -3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-3) was obtained.

Example 119
1- (tert-butyl) -N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) -5-((4- (difluoromethyl) pyridin-3-yl) oxy)- Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-119) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy in step 4 of Example 9 ) -4-Methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((4- (difluoromethyl) pyridine-3-) synthesized by the method described in Reference Example 18. Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-3) and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 Reference example 11 By using (5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-9) synthesized by the method described in 1., the compound (I- 119) was obtained.

Example 120
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-methoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-120) 3,5-difluoro-4- (instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Trifluoromethyl) pyridine was used, methanol was used in place of ethanol in step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 was used as a reference. By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Example 5, the same procedure as in Example 9 was performed. To give the compound in (I-120).

Example 121
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-methoxy-4- (trifluoromethyl) pyridin-3-yl) Preparation of (oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-121) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4 was used. -(Trifluoromethyl) pyridine was used, methanol was used in place of ethanol in step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride was replaced in step 4 of Example 9 By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2. To give compound (I-121) in the same manner as 9.

Reference example 19
Production Step 1 of (4- (ethylsulfonyl) -2-fluorophenyl) methanamine hydrochloride (VIII-14)
Dichloromethane (10 mL) and 1,2-diethyldisulfane (1.16 g, 9.56 mmol) were added to 4-amino-2-fluorobenzonitrile (1.00 g, 7.35 mmol), and tert-butyl nitrite (1.00 g, A dichloromethane solution (10 mL) of 9.71 mmol) was added dropwise at 60 ° C under a nitrogen atmosphere. The reaction mixture was stirred at 60 ° C for 2 hours, water was added, and the mixture was extracted. The organic layer was washed successively with saturated brine and 2 mol / L hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 0: 100, then methanol: ethyl acetate = 20: 1), and 4- (ethylthio) -2-fluorobenzonitrile ( Yield 860 mg, yield 65%).

Process 2
m-CPBA (19.0 g, 110.5 mmol) was added to a solution of 4- (ethylthio) -2-fluorobenzonitrile (5.0 g, 27.6 mmol) in dichloromethane (150 mL). The reaction solution was stirred at room temperature for 5 hours, and the precipitate was filtered. The filtrate was washed successively with saturated sodium hydrogen carbonate, water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 4- (ethylsulfonyl) -2-fluorobenzonitrile (yield 3.8 g, yield 65%).

Process 3
Palladium carbon (0.5 g) and methanol (20 mL) were added to 4- (ethylsulfonyl) -2-fluorobenzonitrile (2.0 g, 9.38 mmol), and the mixture was stirred in a sealed tube under a hydrogen atmosphere at room temperature for 12 hours. . After the reaction solution was filtered, a hydrogen chloride methanol solution was added to the filtrate, and the solvent was distilled off under reduced pressure. By recrystallizing the residue with ethanol, (4- (ethylsulfonyl) -2-fluorophenyl) methanamine hydrochloride (VIII-14) (yield 0.8 g, yield 34%) was obtained.

Example 122
1- (tert-butyl) -N- (4- (ethylsulfonyl) -2-fluorobenzyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H- Preparation of pyrazole-3-carboxamide (I-122) In Step 2 of Example 9, 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (4- (ethylsulfonyl) -2-fluorophenyl) methanamine hydrochloride ( Compound (I-122) was obtained in the same manner as in Example 9 by using VIII-14).

Example 123
5-((3-chloro-4- (trifluoromethyl) pyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1 Preparation of -Propyl-1H-pyrazole-3-carboxamide (I-123) Using propylhydrazine dihydrochloride in place of tert-butylhydrazine hydrochloride in step 1 of example 9, step 2 of example 9, 2,3-dichloro-5- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 was used. Instead of the salt, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 was used. The Rukoto to give compound (I-123) in the same manner as in Example 9.

Reference example 20
Preparation of 2-amino-2- (4- (propylsulfonyl) phenyl) ethanol hydrochloride (VIII-15) In the same manner as in Example 2, instead of sodium ethylsulfinate in step 2, sodium n-propylsulfinate was used. To give 2-amino-2- (4- (propylsulfonyl) phenyl) ethanol hydrochloride (VIII-15).

Example 124
1- (tert-butyl) -N- (2-hydroxy-1- (4- (propylsulfonyl) phenyl) ethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-124) 2-fluoro-3- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Was used in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, and 2-amino-2- (4- (propylsulfonyl) was synthesized by the method described in Reference Example 20. ) Phenyl) ethanol hydrochloride (VIII-15) was used to obtain compound (I-124) in the same manner as in Example 9.

Example 125
1- (tert-butyl) -N-((5-((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridine-3- Preparation of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-125) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro -4- (trifluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, it was synthesized by the method described in Reference Example 11 (5- By using ((cyclopropylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-9), the compound (I-125) was prepared in the same manner as in Example 9. Obtained.

Example 126
1- (tert-butyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridine-2- Production of (yl) methyl) -1H-pyrazole-3-carboxamide (I-126) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4- ( Trifluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 1 (5- (methylsulfonyl)). Compound (I-126) was obtained in the same manner as in Example 9 by using pyridin-2-yl) methanamine hydrochloride (VIII-1).

Example 127
1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Production of 4-methyl-1H-pyrazole-3-carboxamide (I-127) 3,5-dichloro-4- (instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 was used. Trifluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl)). The compound (I-127) was obtained in the same manner as in Example 9 by using pyridin-2-yl) methanamine hydrochloride (VIII-4).

Example 128
1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxy Preparation of ethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-128) 3,5-dichloro-4 was used instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Using 2- (trifluoromethyl) pyridine, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2 synthesized by the method described in Reference Example 2. Compound (I-128) was obtained in the same manner as in Example 9 by using-(4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 129
1- (tert-butyl) -5-((5-methoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridine-2- Preparation of (yl) methyl) -1H-pyrazole-3-carboxamide (I-129) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4- ( Trifluoromethyl) pyridine was used, methanol was used in place of ethanol in step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 was used as a reference. By using (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Example 1, the same procedure as in Example 9 was performed. To give the compound in (I-129).

Example 130
1- (tert-butyl) -5-((3-chloro-2-ethoxypyridin-4-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-130) 2,3,4-trichloropyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and carried out. Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII was synthesized by the method described in Reference Example 5. -4) was used to obtain a compound (I-130) in the same manner as in Example 9.

Example 131
1- (tert-butyl) -5-((2,3-dichloropyridin-4-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H Preparation of -Pyrazole-3-carboxamide (I-131) 2,3,4-trichloropyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of (5), (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4 was synthesized by the method described in Reference Example 5. Compound (I-131) was obtained in the same manner as in Example 9 by using).

Reference example 21
Of 1- (tert-butyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-4) Manufacturing process 1
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.00 g, 4.42 mmol) was added to dimethyl sulfoxide (9.0 mL), 3,5-dichloro-4-. (Trifluoromethyl) pyridine (1.43 g, 6.62 mmol) and cesium carbonate (2.16 g, 6.63 mmol) were added, and the mixture was stirred at 110 ° C. for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl)) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 517 mg, yield 29%) was obtained.

Process 2
1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (50.0 mg, 0.123 mmol), potassium vinyltrifluoroborate (82.5 mg, 0.616 mmol), cesium carbonate (201 mg, 0.617 mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) ( 8.7 mg, 0.012 mmol) and 1,4-dioxane (1.0 mL) were added, and the mixture was stirred at 120 ° C. for 30 min under microwave irradiation. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -4-methyl-5 was used. -((4- (Trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 34.8 mg, 71% yield) was obtained.

Process 3
1- (tert-butyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (34.8 mg, Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.13 mL, 0.52 mmol) were added to 0.0876 mmol), and the mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole- 3-Carboxylic acid (VII-4) (yield 27.7 mg, 86% yield) was obtained.

Example 132
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridine-3- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-132) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 Instead of (oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-methyl-5-((4- (trifluoro Methyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-4) was used, and 4- (aminomethyl) benzenesulfonamide in step 4 of Example 9 was used. Instead of hydrochloride, By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5, the compound (I-132) was prepared in the same manner as in Example 9. ) Got.

Example 133
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridine- Preparation of 3-yl) oxy) -1H-pyrazole-3-carboxamide (I-133) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5-dichloropyridine-2- Instead of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-methyl-5-((4- (was synthesized by the method described in Reference Example 21. Trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-4) was used, and 4- (aminomethyl) benzene in step 4 of Example 9 was used. Of sulfonamide hydrochloride Instead of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2, in the same manner as in Example 9. The compound (I-133) was obtained.

Example 134
1- (tert-butyl) -5-((3-chloro-2-ethoxypyridin-4-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4 Preparation of -Methyl-1H-pyrazole-3-carboxamide (I-134) 2,3,4-trichloropyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol synthesized by the method described in Reference Example 2. Compound (I-134) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-2).

Example 135
1- (tert-butyl) -5-((2,3-dichloropyridin-4-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-135) 2,3,4-trichloropyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and carried out. 2-Amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride prepared by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 Compound (I-135) was obtained in the same manner as in Example 9 by using (VIII-2).

Example 136
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-136) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4- ( Trifluoromethyl) pyridine was used, tetrahydrofuran was used instead of ethanol in Step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Example 5, It was obtained like the compound by the method of (I-136).

Example 137
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5- (2,2,2-trifluoroethoxy) -4 Preparation of-(trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-137) Instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 , 3,5-difluoro-4- (trifluoromethyl) pyridine, 2,2,2-trifluoroethanol was used in place of ethanol in Step 3 of Example 9, and Step 4 of Example 9 was used. In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 5. Compound (I-137) was obtained in the same manner as in Example 9 by using (VIII-4).

Example 138
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) Preparation of (oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-138) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4 was used. -(Trifluoromethyl) pyridine was used, tetrahydrofuran was used in place of ethanol in step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride was replaced in step 4 of Example 9 By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2. To give compound (I-138) in the same manner as in Example 9.

Example 139
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((5- (2,2,2-trifluoroethoxy) Preparation of -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-139) Of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 Instead, 3,5-difluoro-4- (trifluoromethyl) pyridine was used, in step 3 of Example 9 2,2,2-trifluoroethanol was used instead of ethanol, and in Example 9 Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethene synthesized by the method described in Reference Example 2 was used. Compound (I-139) was obtained in the same manner as in Example 9 by using tanol hydrochloride (VIII-2).

Example 140
1- (tert-butyl) -5-((5-ethyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-140) 1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl- 5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-132) (12.6 mg, 0.0228 mmol) in methanol (1.5 mL) And palladium carbon (3.0 mg) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40 → 20: 80) to obtain compound (I-140) (yield 9.8 mg, yield 77%).

Example 141
1- (tert-butyl) -5-((5-ethyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxy Preparation of ethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-141) In the same manner as in Example 140, 1- (tert-butyl) -N-((5- (ethylsulfonyl) ) Pyridin-2-yl) methyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-132) Instead of 1- (tert-butyl) -N- (1- (4- (ethyl ester) phenyl) -2-hydroxyethyl) -4-methyl-5-((4- (trifluoromethyl) -5- Vinyl pyridine-3- Compound (I-141) was obtained using (yl) oxy) -1H-pyrazole-3-carboxamide (I-133).

Example 142
1-Ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-methoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-142) In step 1 of Example 9, ethyl hydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride, and in step 2 of Example 9, 3, 3,5-difluoro-4- (trifluoromethyl) pyridine was used in place of 5-dichloro-2-fluoropyridine, methanol was used in place of ethanol in step 3 of Example 9, and Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 1, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl)). The use of lysine-2-yl) methanamine hydrochloride (VIII-4), to give compound (I-142) in the same manner as in Example 9.

Example 143
1-Ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-methoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4 Preparation of -Methyl-1H-pyrazole-3-carboxamide (I-143) In step 1 of Example 9, ethyl hydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride, in step 2 of Example 9, 3,5-dichloro-2-fluoropyridine was used in place of 3,5-difluoro-4- (trifluoromethyl) pyridine, methanol was used in place of ethanol in Step 3 of Example 9, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2-synthesized by the method described in Reference Example 2. By using 4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2), to give compound (I-143) in the same manner as in Example 9.

Example 144
5-((5-Ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -1-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-144) In Step 1 of Example 9, ethyl hydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride, and Step 2 of Example 9, 3, 3,5-Difluoro-4- (trifluoromethyl) pyridine was used in place of 5-dichloro-2-fluoropyridine, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. In place of (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5. To give compound (I-144) in the same manner as in Example 9.

Example 145
5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -1-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4 Preparation of -Methyl-1H-pyrazole-3-carboxamide (I-145) In step 1 of Example 9, ethyl hydrazine dihydrochloride was used in place of tert-butylhydrazine hydrochloride, in step 2 of Example 9, 3,5-Difluoro-4- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and 4- (aminomethyl) benzenesulfonamide in Step 4 of Example 9 was used. Instead of the hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 was used. By you have to give compound (I-145) in the same manner as in Example 9.

Reference example 22
Process 1 for producing 5- (propylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-16)
Dimethylsulfoxide (2.7 mL), sodium n-propylsulfinate (355 mg, 2.73 mmol) and copper iodide (520 mg, 2.73 mmol) were added to 5-bromopyridine-2-carbonitrile (100 mg, 0.546 mmol). The mixture was stirred at 110 ° C for 16 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 5-propylsulfonylpyridine-2-carbonitrile (yield 88 mg, yield 77%).

Process 2
5-Propylsulfonylpyridine-2-carbonitrile (88 mg, 0.42 mmol), platinum carbon (5 mg), methanol (2.1 mL) and concentrated hydrochloric acid (0.08 mL) were placed in a pressure resistant container, and under a hydrogen atmosphere of 0.3 MPa, The mixture was stirred at room temperature for 4 hours. After the reaction solution was filtered, the solvent was distilled off under reduced pressure to obtain 5- (propylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-16) (yield 97 mg, yield 92%).

Example 146
1- (tert-butyl) -4-methyl-N-((5- (propylsulfonyl) pyridin-2-yl) methyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-146) 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 5- (propylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 22. Compound (I-146) was obtained in the same manner as in Example 9 by using salt (VIII-16).

Reference Example 23
Preparation of 1- (tert-butyl) -5- (2- (difluoromethyl) -3-fluorophenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-5) Method similar to Reference Example 9 Then, using 2-6-difluorobenzaldehyde instead of 3-acetyl-2-chloropyridine in Step 1, 1- (tert-butyl) -5- (2- (difluoromethyl) -3-fluorophenoxy) -4 -Methyl-1H-pyrazole-3-carboxylic acid (VII-5) was obtained.

Example 147
1- (tert-butyl) -5- (2- (difluoromethyl) -3-fluorophenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole Preparation of -3-carboxamide (I-147) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H in step 4 of Example 9 1- (tert-butyl) -5- (2- (difluoromethyl) -3-fluorophenoxy) -4-methyl-1H synthesized by the method described in Reference Example 23 instead of pyrazole-3-carboxylic acid -Pyrazole-3-carboxylic acid (VII-5) was used, and it was synthesized by the method described in Reference Example 5 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. (5- Compound (I-147) was obtained in the same manner as in Example 9 by using (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4).

Example 148
1- (tert-butyl) -5- (2- (difluoromethyl) -3-fluorophenoxy) -N- (1-
Preparation of (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-148) 1- (tert-butyl) -in Step 4 of Example 9 Instead of 5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl synthesized by the method described in Reference Example 23. ) -5- (2- (Difluoromethyl) -3-fluorophenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-5) was used, and in step 4 of Example 9, 4- 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 was used in place of (aminomethyl) benzenesulfonamide hydrochloride. Thus, the compound (I-148) was obtained in the same manner as in Example 9.

Reference Example 24
Production of 1- (tert-butyl) -5- (2- (difluoromethyl) -4-fluorophenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-6) Method similar to Reference Example 9 And using 2,6-difluorobenzaldehyde in place of 3-acetyl-2-chloropyridine in Step 1- (tert-butyl) -5- (2- (difluoromethyl) -4-fluorophenoxy) -4 -Methyl-1H-pyrazole-3-carboxylic acid (VII-6) was obtained.

Example 149
1- (tert-butyl) -5- (2- (difluoromethyl) -4-fluorophenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole Preparation of -3-carboxamide (I-149) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H in step 4 of Example 9 -1- (tert-butyl) -5- (2- (difluoromethyl) -4-fluorophenoxy) -4-methyl-1H synthesized by the method described in Reference Example 24 instead of pyrazole-3-carboxylic acid -Pyrazole-3-carboxylic acid (VII-6) was used, and it was synthesized by the method described in Reference Example 5 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. (5- ( By using Chirusuruhoniru) pyridin-2-yl) methanamine hydrochloride (VIII-4), to give compound (I-149) in the same manner as in Example 9.

Example 150
1- (tert-butyl) -5- (2- (difluoromethyl) -4-fluorophenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H -Preparation of pyrazole-3-carboxamide (I-150) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl in step 4 of Example 9 Instead of -1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5- (2- (difluoromethyl) -4-fluorophenoxy) -4-methyl synthesized by the method described in Reference Example 24. -1H-pyrazole-3-carboxylic acid (VII-6) was used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, the procedure described in Reference Example 2 was used. Synthesis 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) was used to give compound (I-150) in the same manner as in Example 9.

Example 151
N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1- (3 Preparation of 3,3-trifluoropropyl) -1H-pyrazole-3-carboxamide (I-151) (3,3,3-trifluoropropyl) in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9 ) Using hydrazine dihydrochloride, substituting 2-fluoro-3- (trifluoromethyl) pyridine for 3,5-dichloro-2-fluoropyridine in step 2 of Example 9, and In place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4, 2-amino-2- (4- (ethylsulfonyl)) synthesized by the method described in Reference Example 2 By using Eniru) ethanol Hydrochloride (VIII-2), to give compound (I-151) in the same manner as in Example 9.

Example 152
N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((4- (trifluoromethyl) pyridin-3-yl) oxy) -1- (3 Preparation of 3,3-trifluoropropyl) -1H-pyrazole-3-carboxamide (I-152) Instead of tert-butylhydrazine hydrochloride in Step 1 of Example 9, (3,3,3-trifluoropropyl) ) Using hydrazine dihydrochloride, substituting 3-fluoro-4- (trifluoromethyl) pyridine for 3,5-dichloro-2-fluoropyridine in step 2 of Example 9, and In place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4, 2-amino-2- (4- (ethylsulfonyl)) synthesized by the method described in Reference Example 2 By using Eniru) ethanol hydrochloride (VIII-2), to give compound (I-152) in the same manner as in Example 9.

Reference Example 25
Preparation of 4- (aminomethyl) -N- (oxetane-3-yl) benzenesulfonamide hydrochloride (VIII-17) In the same manner as in Reference Example 3, instead of the methanol solution of methylamine in Step 3, 3- 4- (Aminomethyl) -N- (oxetane-3-yl) benzenesulfonamide hydrochloride (VIII-17) was obtained using oxetanamin.

Example 153
1- (tert-butyl) -4-methyl-N- (4- (N- (oxetan-3-yl) sulfamoyl) benzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy ) -1H-Pyrazole-3-carboxamide (I-153) 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 4- (aminomethyl) -N- (oxetane-3) synthesized by the method described in Reference Example 25 -Yl) benzenesulfonamide hydrochloride (VIII-17) was used to obtain compound (I-153) in the same manner as in Example 9.

Reference example 26
Production of 4- (aminomethyl) -N-cyclopropylbenzenesulfonamide hydrochloride (VIII-18) In the same manner as in Reference Example 3, cyclopropylamine was used in place of the methylamine methanol solution in Step 3, 4- (Aminomethyl) -N-cyclopropylbenzenesulfonamide hydrochloride (VIII-18) was obtained.

Example 154
1- (tert-butyl) -N- (4- (N-cyclopropylsulfamoyl) benzyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H -Preparation of pyrazole-3-carboxamide (I-154) In the step 2 of Example 9, 2-fluoro-3- (trifluoromethyl) pyridine was used instead of 3,5-dichloro-2-fluoropyridine, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 4- (aminomethyl) -N-cyclopropylbenzenesulfonamide hydrochloride synthesized by the method described in Reference Example 26. Compound (I-154) was obtained in the same manner as in Example 9 by using (VIII-18).

Example 155
1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridine-2- Preparation of (yl) methyl) -1H-pyrazole-3-carboxamide (I-155) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-dichloro-4- ( Trifluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 1 (5- (methylsulfonyl)). The compound (I-155) was obtained in the same manner as in Example 9 by using pyridin-2-yl) methanamine hydrochloride (VIII-1).

Reference example 27
1- (tert-butyl) -5-((5- (ethylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 7) Manufacturing process 1
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (600 mg, 2.65 mmol) was added to dimethyl sulfoxide (5.0 mL), 3,5-difluoro-4-. (Trifluoromethyl) pyridine (583 mg, 3.18 mmol) and cesium carbonate (1.30 g, 3.99 mmol) were added, and the mixture was stirred at 120 ° C for 16 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was directly purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 70: 30), and 1- (tert-butyl) -5-((5-fluoro-4- (trifluoromethyl ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 418 mg, yield 41%) was obtained.

Process 2
1- (tert-butyl) -5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (50.0 mg, Tetrahydrofuran (0.50 mL) and water (0.50 mL) were added to 0.128 mmol), then ethylamine hydrochloride (26.2 mg, 0.321 mmol) and lithium hydroxide (15.4 mg, 0.643 mmol) were added, and the mixture was stirred at room temperature for 18 hours. . Then, lithium hydroxide (15.4 mg, 0.643 mmol) was added, and the mixture was stirred at 60 ° C for 24 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (ethylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H was obtained by distilling off the solvent under reduced pressure. -Pyrazole-3-carboxylic acid (VII-7) (yield 49.6 mg, yield 99%) was obtained.

Example 156
1- (tert-butyl) -5-((5- (ethylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl ) Methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-156) 1- (tert-butyl) -5-((3,5-dichloropyridine-2) in step 4 of Example 9 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5- (ethylamino)) synthesized by the method described in Reference Example 27. -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-7) was used, and 4- (in Step 4 of Example 9 was used. Aminomethyl) benzenesulfonami By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of the hydrochloride, a method similar to that in Example 9 was obtained. To give the compound (I-156).

Example 157
1- (tert-butyl) -5-((5- (ethylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl)- Preparation of 2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-157) 1- (tert-butyl) -5-((3,5-dichloropyridine in step 4 of Example 9) 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (ethyl Amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-7) was used, and in step 4 of Example 9, 4 -(Aminomethyl) benzenes Similar to Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of rufonamide hydrochloride. Compound (I-157) was obtained by the method of.

Example 158
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5-propoxy-4- (trifluoromethyl) pyridine-3- Production of (yl) oxy) -1H-pyrazole-3-carboxamide (I-158) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4- ( Trifluoromethyl) pyridine was used, 1-propanol was used in place of ethanol in step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride was replaced in step 4 of Example 9 Example 9 was obtained by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5. It was obtained like the compound by the method of (I-158).

Example 159
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((5-propoxy-4- (trifluoromethyl) pyridine- Preparation of 3-yl) oxy) -1H-pyrazole-3-carboxamide (I-159) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4 was used. -(Trifluoromethyl) pyridine was used, 1-propanol was used in place of ethanol in Step 3 of Example 9, and the 4- (aminomethyl) benzenesulfonamide hydrochloride salt in Step 4 of Example 9 was used. Instead, by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2. To give compound (I-159) in the same manner as in Example 9.

Reference example 28
(4-((Difluoromethyl) sulfonyl) phenyl) methanamine (VIII-19) Production Step 1
1- (chloromethyl) -4-((difluoromethyl) sulfonyl) benzene (100 mg, 0.416 mmol) in N, N-dimethylformamide (4.1 mL), and (1,3-dioxoisoindoline-2-yl) ) Potassium (154 mg, 0.831 mmol) was added, and the mixture was stirred at 50 ° C for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 2- (4-((difluoromethyl) sulfonyl) benzyl) isoindoline-1,3-dione (yield 88 mg, yield 77%).

Process 2
Ethanol (3 mL) and hydrazine monohydrate (0.14 mL) were added to 2- (4-((difluoromethyl) sulfonyl) benzyl) isoindoline-1,3-dione (110 mg, 0.313 mmol) at room temperature. Stir for 3 hours. After the reaction solution was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (4-((difluoromethyl) sulfonyl) phenyl) methanamine (VIII-19) (yield 66 mg, yield Rate 95%).

Example 160
1- (tert-butyl) -N- (4-((difluoromethyl) sulfonyl) benzyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole Preparation of 3--3-carboxamide (I-160) In Step 2 of Example 9, 2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (4-((difluoromethyl) sulfonyl) phenyl) methanamine (VIII-19) synthesized by the method described in Reference Example 28. Compound (I-160) was obtained in the same manner as in Example 9 by using

Example 161
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5- (methyl (3- (trifluoromethyl) pyridin-2-yl) amino ) -1H-Pyrazole-3-carboxamide (I-161)
N, N-Dimethylformamide (34.2 mL), propionitrile (2.41 mL, 34.2 mmol) and sodium hydride (1.64 g, 41.0 mmol) were added to diethyl oxalate (5.00 g, 34.2 mmol), and the mixture was added at 100 ° C for 2 Stir for hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60:40 → 20:80) to give 3-cyano-2-oxobutyric acid ethyl ester (yield 3.50 g, yield 66%) was obtained.

Process 2
To tert-butylhydrazine hydrochloride (2.81 g, 22.6 mmol), ethanol (45.1 mL), potassium carbonate (3.12 g, 22.6 mmol), and 3-cyano-2-oxobutyric acid ethyl ester (3.50 g, 22.6 mmol) were added. In addition, the mixture was heated under reflux for 17 hours. After filtering the reaction solution, the solvent was distilled off under reduced pressure. 1 mol / L hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 30: 70) to give 5-amino-1- (tert-butyl) -4. -Methyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 3.40 g, yield 67%) was obtained.

Process 3
5-Amino-1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (200 mg, 0.888 mmol) was added to toluene (3.0 mL), 2-bromo-3-trifluoromethyl. Pyridine (241 mg, 1.07 mmol), (R)-(+)-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (55.3 mg, 0.0888 mmol), cesium carbonate (434 mg, 1.33) mmol) and tris (dibenzylideneacetone) dipalladium (0) (40.6 mg, 0.0443 mmol) were added, and the mixture was stirred at 100 ° C. for 16 hours. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, 1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) amino) pyrazole-3-carboxylic acid ethyl ester (Yield 119 mg, yield 36%) was obtained.

Step 4
1- (tert-Butyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) amino) pyrazole-3-carboxylic acid ethyl ester (35.0 mg, 0.0945 mmol) in N, N -Dimethylformamide (1.0 mL) and sodium hydride (5.7 mg, 0.14 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 20 minutes. Then, iodomethane (7.1 μL, 0.11 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 1- (tert-butyl) -4-methyl-5- (methyl- (3- (trifluoromethyl) pyridine-2- Ilyl) amino) pyrazole-3-carboxylic acid ethyl ester (yield 13.2 mg, yield 36%) was obtained.

Step 5
1- (tert-Butyl) -4-methyl-5- (methyl- (3- (trifluoromethyl) pyridin-2-yl) amino) pyrazole-3-carboxylic acid ethyl ester (13.2 mg, 0.0343 mmol) in ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (52 μL, 0.208 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 6 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1- (tert-butyl) -4-methyl-5- (methyl- (3- (trifluoromethyl) pyridin-2-yl) amino) pyrazole-3-carboxylic acid ( Yield 10.2 mg, yield 83%).

Process 6
1- (tert-Butyl) -4-methyl-5- (methyl- (3- (trifluoromethyl) pyridin-2-yl) amino) pyrazole-3-carboxylic acid (5.0 mg, 0.014 mmol) in tetrahydrofuran (0.50 mL), N, N-diisopropylethylamine (7.3 μL, 0.042 mmol), (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) (5.0 mg, 0.021 mmol), and HATU (8.0). mg, 0.021 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was directly purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40 → 20: 80), and 1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridine-2- Iyl) methyl) -4-methyl-5- (methyl (3- (trifluoromethyl) pyridin-2-yl) amino) -1H-pyrazole-3-carboxamide (I-161) (yield 6.5 mg, yield 86 %) Was obtained.

Example 162
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5- (methyl (3- (trifluoromethyl) pyridin-2-yl) ) Amino) -1H-pyrazole-3-carboxamide (I-162) In the same manner as in Example 161, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) in Step 6 was used. In the same manner as in Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of To obtain the compound (I-162).

Reference Example 29
Production of 1- (tert-butyl) -5-((2- (difluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-8) Reference Example 9 and In a similar manner, substituting 3-fluoro-2-pyridinecarboxaldehyde for 3-acetyl-2-chloropyridine in step 1, 1- (tert-butyl) -5-((2- (difluoromethyl) pyridine -3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-8) was obtained.

Example 163
1- (tert-butyl) -5-((2- (difluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl- Preparation of 1H-pyrazole-3-carboxamide (I-163) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4- in step 4 of Example 9 Instead of methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((2- (difluoromethyl) pyridin-3-yl) oxy) synthesized by the method described in Reference Example 29. -4-Methyl-1H-pyrazole-3-carboxylic acid (VII-8) was used, and in Reference Example 5 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Synthesized by the described method Compound (I-163) was obtained in the same manner as in Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4).

Example 164
1- (tert-butyl) -5-((2- (difluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- Preparation of Methyl-1H-pyrazole-3-carboxamide (I-164) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy)-in step 4 of Example 9 Instead of 4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((2- (difluoromethyl) pyridin-3-yl) synthesized by the method described in Reference Example 29. Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-8) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, reference example Person described in 2 The compound (I-164) was obtained in the same manner as in Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method. .

Reference Example 30
Of 1- (tert-butyl) -4-methyl-5-((5-methyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-9) In the same manner as in Production Reference Example 21, 1- (tert-butyl) -4-methyl-5-((5-methyl-4- (tri- Fluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-9) was obtained.

Example 165
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5-methyl-4- (trifluoromethyl) pyridine-3- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-165) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 Instead of (oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-methyl-5-((5-methyl-4) was synthesized by the method described in Reference Example 30. -(Trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-9) was used, and 4- (aminomethyl) benzenesulfonamide in Step 4 of Example 9 was used. Instead of hydrochloride, By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5, the compound (I-165) was prepared in the same manner as in Example 9. ) Got.

Example 166
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((5-methyl-4- (trifluoromethyl) pyridine- Preparation of 3-yl) oxy) -1H-pyrazole-3-carboxamide (I-166) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5-dichloropyridine-2- Instead of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-methyl-5-((5-methyl -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-9) was used, and 4- (aminomethyl) benzene in step 4 of Example 9 was used. Of sulfonamide hydrochloride Instead of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2, in the same manner as in Example 9. Compound (I-166) was obtained.

Reference example 31
1- (tert-butyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- Manufacturing process 1 of 10)
1- (tert-butyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (53.0 mg, 0.133 mmol), 1,4-dioxane (1.8 mL), water (0.30 mL), 2,6-dimethylpyridine (31 μL, 0.267 mmol), sodium periodate (114 mg, 0.533 mmol), and 2.5% An osmium tetroxide tert-butanol solution (68 μL, 0.0067 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl). Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 42.8 mg, 80% yield) was obtained.

Process 2
1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (42.8 mg, Tetrahydrofuran (1.0 mL) and sodium borohydride (4.1 mg, 0.11 mmol) were added to 0.107 mmol) under ice cooling, and the mixture was stirred at 0 ° C for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 20: 80), and 1- (tert-butyl) -5-((5 -(Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 21.6 mg, yield 50%) was obtained.

Process 3
1- (tert-butyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester ( Ethanol (1.0 mL) and 4 mol / L sodium hydroxide (40 μL, 0.16 mmol) were added to 10.8 mg, 0.0269 mmol) under ice cooling, and the mixture was stirred at room temperature for 6 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H was obtained by distilling off the solvent under reduced pressure. -Pyrazole-3-carboxylic acid (VII-10) (yield 10.0 mg, quantitative) was obtained.

Example 167
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl ) Oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-167) 1- (tert-butyl) -5-((3,5-dichloropyridine-2) in step 4 of Example 9 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (hydroxymethyl)) synthesized by the method described in Reference Example 31. -4- (Trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used, and 4- (in Step 4 of Example 9 was used. Aminomethyl) benzenes A method similar to that in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of rufonamide hydrochloride. To obtain the compound (I-167).

Example 168
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-168) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (hydroxy Methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used, and in step 4 of Example 9, 4 -(Aminomethyl) Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of benzenesulfonamide hydrochloride Compound (I-168) was obtained in the same manner as in.

Example 169
1- (tert-butyl) -4-methyl-N- (4- (N- (oxetan-3-yl) sulfamoyl) benzyl) -5-((4- (trifluoromethyl) pyridin-3-yl) oxy ) -1H-Pyrazole-3-carboxamide (I-169) 3-fluoro-4- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 4- (aminomethyl) -N- (oxetane-3) synthesized by the method described in Reference Example 25 -Yl) benzenesulfonamide hydrochloride (VIII-17) was used to obtain compound (I-169) in the same manner as in Example 9.

Example 170
1- (tert-butyl) -N- (4- (N-cyclopropylsulfamoyl) benzyl) -4-methyl-5-((4- (trifluoromethyl) pyridin-3-yl) oxy) -1H -Preparation of pyrazole-3-carboxamide (I-170) In the step 2 of Example 9, 3-fluoro-4- (trifluoromethyl) pyridine was used instead of 3,5-dichloro-2-fluoropyridine, and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 4- (aminomethyl) -N-cyclopropylbenzenesulfonamide hydrochloride synthesized by the method described in Reference Example 26. Compound (I-170) was obtained in the same manner as in Example 9 by using (VIII-18).

Example 171
1,4-diethyl-N- (4- (N- (oxetane-3-yl) sulfamoyl) benzyl) -5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole- Preparation of 3-carboxamide (I-171) Using 2-ethyl-3-oxosuccinic acid in Step 1 of Example 9 using ethylhydrazine dihydrochloride instead of tert-butylhydrazine hydrochloride in Step 1 of Example 9. Instead of diethyl acid, diethyl 2-ethyl-3-oxosuccinate (III-1) synthesized by the method described in Reference Example 4 was used, and 3,5-dichloro-2-fluoro in Step 2 of Example 9 was used. 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of pyridine, and 4- (aminomethyl) benzenesulfonamimine in step 4 of Example 9 was used. Example 9 by using 4- (aminomethyl) -N- (oxetane-3-yl) benzenesulfonamide hydrochloride (VIII-17) synthesized by the method described in Reference Example 25 instead of the hydrochloride. Compound (I-171) was obtained by a method similar to.

Example 172
N- (4- (N-cyclopropylsulfamoyl) benzyl) -1,4-diethyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide Preparation of (I-172) Using ethylhydrazine dihydrochloride in place of tert-butylhydrazine hydrochloride in Step 1 of Example 9 to give diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Instead, diethyl 2-ethyl-3-oxosuccinate (III-1) synthesized by the method described in Reference Example 4 was used, and instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. 2-fluoro-3- (trifluoromethyl) pyridine was used as the compound, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. Instead, by using 4- (aminomethyl) -N-cyclopropylbenzenesulfonamide hydrochloride (VIII-18) synthesized by the method described in Reference Example 26, the compound (I -172) was obtained.

Reference Example 32
Production Step 1 of (5- (ethylsulfonyl) -3-fluoropyridin-2-yl) methanamine hydrochloride (VIII-20)
5-Bromo-3-fluoropicolinonitrile (869 mg, 4.98 mmol), tris (dibenzylideneacetone) dipalladium (0) (95.1 mg, 0.199 mmol) and 4,5-bis (diphenylphosphino) -9, To 9-dimethylxanthene (230 mg, 0.398 mmol) was added toluene (8.5 mL) and N, N-diisopropylethylamine (1.85 mL, 10.8 mmol) under a nitrogen atmosphere, and then ethanethiol (368 μL, 4.98 mmol) was added. The mixture was stirred at 80 ° C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 80: 20) to give 5- (ethylthio) -3-fluoropicolinonitrile (yield 682. mg, yield 87%) was obtained.

Process 2
To a solution of 5- (ethylthio) -3-fluoropicolinonitrile (779 mg, 4.28 mmol) in acetic acid (0.44 mL), potassium permanganate (1.01 g, 6.41 mmol) dissolved in water (30 mL) was added dropwise. And stirred at room temperature for 17 hours. Acetic acid (0.44 mL) and potassium permanganate (1.01 g, 6.41 mmol) dissolved in water (30 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction solution, the mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40) to give 5- (ethylsulfonyl) -3-fluoropicolinonitrile (yield 640 mg, yield 70%).

Process 3
Methanol (64 mL) and 10% palladium carbon (130 mg) were added to 5- (ethylsulfonyl) -3-fluoropicolinonitrile (640 mg, 2.99 mmol), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure to give (5- (ethylsulfonyl) -3-fluoropyridin-2-yl) methanamine (amount 636 mg, yield 97%).

Step 4
Ethyl acetate (60 mL) and 4 mol / l hydrogen chloride ethyl acetate solution (3 mL) were added to (5- (ethylsulfonyl) -3-fluoropyridin-2-yl) methanamine (536 mg, 2.45 mmol), The mixture was stirred at room temperature for 5 minutes. The precipitate was collected by filtration and washed with ethyl acetate to obtain (5- (ethylsulfonyl) -3-fluoropyridin-2-yl) methanamine hydrochloride (VIII-20) (yield 474 mg, yield 76%). It was

Example 173
1- (tert-butyl) -N-((5- (ethylsulfonyl) -3-fluoropyridin-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridine-2- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-173) 2-fluoro-3- (trifluoromethyl) instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 ) Pyridine was used, and it was synthesized by the method described in Reference Example 32 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 (5- (ethylsulfonyl) -3- The compound (I-173) was obtained in the same manner as in Example 9 by using fluoropyridin-2-yl) methanamine hydrochloride (VIII-20).

Reference Example 33
1- (tert-butyl) -5-((5- (2-hydroxyethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-11) In the same manner as in Reference Example 27, 1- (tert-butyl) -5-((5- (2-hydroxyethoxy)-was used, except that ethylene glycol was used instead of ethylamine hydrochloride in step 2. 4- (Trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-11) was obtained.

Example 174
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2-hydroxyethyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-174) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (2 -Hydroxyethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-11) and also in step 4 of Example 9. , 4- (aminomethyl) Similar to Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of benzenesulfonamide hydrochloride. Compound (I-174) was obtained by the method described in 1.

Example 175
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (2-hydroxyethoxy) -4- (trifluoromethyl) pyridine Preparation of -3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-175) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (2-Hydroxyethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-11) was used and the process of Example 9 4- (a) By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of minomethyl) benzenesulfonamide hydrochloride. Compound (I-175) was obtained in the same manner as in Example 9.

Reference Example 34
Of 1- (tert-butyl) -5-((5-ethoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-12) Manufacturing process 1
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (400 mg, 1.77 mmol) was added to dimethyl sulfoxide (3.0 mL), 5-bromo-2-chloro-. 3- (Trifluoromethyl) pyridine (691 mg, 2.65 mmol) and cesium carbonate (864 mg, 2.65 mmol) were added, and the mixture was stirred at 120 ° C for 16 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was directly purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 70: 30), and 5-((5-bromo-3- (trifluoromethyl) pyridin-2-yl) oxy was obtained. ) -1- (tert-Butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 536 mg, 67%) was obtained.

Process 2
5-((5-Bromo-3- (trifluoromethyl) pyridin-2-yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (180 mg, To a tetrahydrofuran (0.80 mL) solution of 0.400 mmol), 1.3 mol / L isopropyl magnesium chloride lithium chloride complex tetrahydrofuran solution (0.37 mL, 0.48 mmol) was added at -78 ° C, and the mixture was stirred at the same temperature for 1 hour. Then, 1.3 mol / L isopropyl magnesium chloride lithium chloride complex tetrahydrofuran solution (0.37 mL, 0.48 mmol) was added at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Then, triisopropyl borate (0.28 mL, 1.2 mmol) was added at -78 ° C, the temperature was raised to room temperature, and the mixture was stirred for 16 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a boronic acid intermediate as a crude product.

  A 0.3 mol / L potassium peroxymonosulfate (295 mg, 0.480 mmol) aqueous solution (1.6 mL) was added to a solution of the boronic acid intermediate in acetone (2.0 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. A 20% sodium sulfite solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium sulfite solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 1- (tert-butyl) -5-((5-hydroxy-3- (trifluoromethyl) pyridin-2-yl). Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid isopropyl ester (yield 73.8 mg, yield 46%) was obtained.

Process 3
1- (tert-butyl) -5-((5-hydroxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid isopropyl ester (73.8 mg, 0.184 mmol), N, N-dimethylformamide (1.0 mL), potassium carbonate (50.8 mg, 0.368 mmol) and iodoethane (22 μL, 0.274 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 1- (tert-butyl) -5-((5-ethoxy-3- (trifluoromethyl) pyridin-2-yl). Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid isopropyl ester (yield 65.1 mg, yield 83%) was obtained.

Step 4
1- (tert-butyl) -5-((5-ethoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid isopropyl ester (65.1 mg, Tetrahydrofuran (0.80 mL), ethanol (0.80 mL), and 8 mol / L potassium hydroxide aqueous solution (0.19 mL, 1.5 mmol) were added to 0.152 mmol), and it stirred at 50 degreeC for 30 minutes. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -5-((5-ethoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole- 3-Carboxylic acid (VII-12) (yield 58.7 mg, quantitative) was obtained.

Example 176
1- (tert-butyl) -5-((5-ethoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-176) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 Instead of (oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5-ethoxy-3- (trifluoro) was synthesized by the method described in Reference Example 34. Methyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-12) was used, and 4- (aminomethyl) benzenesulfonamide in step 4 of Example 9 was used. Instead of hydrochloride In addition, by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5, a compound ( I-176) was obtained.

Example 177
1- (tert-butyl) -5-((5-ethoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxy Preparation of ethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-177) 1- (tert-butyl) -5-((3,5-dichloropyridine-2- Instead of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5-ethoxy-3- (was synthesized by the method described in Reference Example 34. Trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-12) was used, and 4- (aminomethyl) benzene in step 4 of Example 9 was used. Sulfonamide salt Similar to Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of the acid salt. Compound (I-177) was obtained by the method.

Reference Example 35
1- (tert-butyl) -5-((5- (difluoromethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 13) Manufacturing process 1
1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (44.0 mg, Dichloromethane (1.0 mL) and N, N-diethylaminosulfur trifluoride (44 μL, 0.33 mmol) were added to 0.110 mmol), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -5-((5 -(Difluoromethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 29.9 mg, yield 64%) was obtained.

Process 2
1- (tert-butyl) -5-((5- (difluoromethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester ( Ethanol (1.0 mL) and a 4 mol / L sodium hydroxide aqueous solution (0.11 mL, 0.44 mmol) were added to 29.9 mg, 0.0710 mmol) under ice cooling, and the mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (difluoromethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H was obtained by distilling off the solvent under reduced pressure. -Pyrazole-3-carboxylic acid (VII-13) (yield 27.9 mg, quantitative) was obtained.

Example 178
1- (tert-butyl) -5-((5- (difluoromethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl ) Methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-178) 1- (tert-butyl) -5-((3,5-dichloropyridine-2) in step 4 of Example 9 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (difluoromethyl)) synthesized by the method described in Reference Example 35 -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-13) was used, and 4- (in Step 4 of Example 9 was used. Aminomethyl) benzenes A method similar to that in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of rufonamide hydrochloride. To obtain the compound (I-178).

Example 179
1- (tert-butyl) -5-((5- (difluoromethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl)- Preparation of 2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-179) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (difluoro Methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-13) was used, and in step 4 of Example 9 at 4 -(Aminomethyl) Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of benzenesulfonamide hydrochloride Compound (I-179) was obtained by a method similar to.

Example 180
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-isopropoxy-4- (trifluoromethyl) pyridin-3-yl) oxy ) -4-Methyl-1H-pyrazole-3-carboxamide (I-180) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4-. Using (trifluoromethyl) pyridine, substituting 2-propanol for ethanol in step 3 of Example 9, and substituting 4- (aminomethyl) benzenesulfonamide hydrochloride for step 4 of Example 9. To (Example 5) by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5. To give compound (I-180) in the same manner as.

Example 181
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-isopropoxy-4- (trifluoromethyl) pyridin-3-yl) ) Oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-181) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro- 4- (trifluoromethyl) pyridine was used, 2-propanol was used in place of ethanol in Step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. In place of 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2. More, to give compound (I-181) in the same manner as in Example 9.

Example 182
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (methoxy-D3) -4- (trifluoromethyl) pyridine-3- Preparation of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-182) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro 4- (trifluoromethyl) pyridine was used, deuterated methanol was used in place of ethanol in Step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of To give compound (I-182) in the same manner as.

Example 183
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (methoxy-D3) -4- (trifluoromethyl) pyridine- Preparation of 3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-183) In place of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9, 3,5 -Difluoro-4- (trifluoromethyl) pyridine was used, deuterated methanol was used in place of ethanol in step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide in step 4 of Example 9 Use 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of the hydrochloride. More, to give compound (I-183) in the same manner as in Example 9.

Reference Example 36
1- (tert-butyl) -5-((5- (methoxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 14) Manufacturing process 1
1- (tert-butyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester ( Dichloromethane (1.0 mL), triethylamine (31 μL, 0.22 mmol) and methanesulfonyl chloride (8.7 μL, 0.11 mmol) were added to 14.9 mg, 0.0371 mmol), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. By distilling the solvent off under reduced pressure, 1- (tert-butyl) -4-methyl-5-((5-(((methylsulfonyl) oxy) methyl) -4- (trifluoromethyl) pyridine-3- (Yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 17.8 mg, quantitative) was obtained.

Process 2
1- (tert-butyl) -4-methyl-5-((5-(((methylsulfonyl) oxy) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3 -Carboxylic acid ethyl ester (17.8 mg, 0.0371 mmol) was added tetrahydrofuran (0.50 mL), methanol (0.50 mL) and 4 mol / L aqueous sodium hydroxide solution (0.10 mL, 0.40 mmol) under ice cooling, and the mixture was stirred at room temperature for 4 hours. Stir for hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (methoxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H was obtained by distilling off the solvent under reduced pressure. -Pyrazole-3-carboxylic acid (VII-14) (yield 14.4 mg, quantitative) was obtained.

Example 184
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (methoxymethyl) -4- (trifluoromethyl) pyridin-3-yl) ) Oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-184) 1- (tert-butyl) -5-((3,5-dichloropyridine-2) in step 4 of Example 9 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (methoxymethyl)) synthesized by the method described in Reference Example 36 -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-14) was used, and 4- (in Step 4 of Example 9 was used. Aminomethyl) benzenesulfo In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of the amide hydrochloride. To obtain the compound (I-184).

Example 185
1- (tert-butyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (2-hydroxy-1- (4- (methylsulfonyl) phenyl) Production of ethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-185) 3,5-difluoro-4 was used instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Using 2- (trifluoromethyl) pyridine, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2 synthesized by the method described in Reference Example 13. Compound (I-185) was obtained in the same manner as in Example 9 by using-(4- (methylsulfonyl) phenyl) ethanol hydrochloride (VIII-10).

Example 186
1- (tert-butyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyrimidin-2-yl) methyl) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-186) 3,5-difluoro-4- (instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Trifluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, it was synthesized by the method described in Reference Example 6 (5- (ethylsulfonyl)). Compound (I-186) was obtained in the same manner as in Example 9 by using pyrimidin-2-yl) methanamine hydrochloride (VIII-5).

Reference Example 37
Production Step 1 of (4- (S-methylsulfonimidoyl) phenyl) methanamine (VIII-21)
To a solution of 4- (methylthio) benzaldehyde (50 g, 0.33 mol) in methanol (500 mL) was added sodium borohydride (25 g, 0.66 mol) at 0 ° C, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain (4- (methylthio) phenyl) methanol (yield 45 g, yield 90%).

Process 2
Under a nitrogen atmosphere, diisopropyl azodicarboxylate (67 g, 0.33 mol) was added to (4- (methylthio) phenyl) methanol (45 g, 0.3 mol), phthalimide (44 g, 0.3 mol) and triphenylphosphine (78.6 g, 0.3 mol) of tetrahydrofuran (500 mL) was added dropwise. The reaction was stirred at room temperature for 18 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2- (4- (methylthio) benzyl) isoindoline-1,3-dione (yield 69 g, yield 84%) as a crude product.

Process 3
M-CPBA (42 g, 0.24 mol) was added to a solution of 2- (4- (methylthio) benzyl) isoindoline-1,3-dione (69 g, 0.24 mol) in dichloromethane (700 mL) at 0 ° C. The reaction was stirred at room temperature for 16 hours. The reaction solution was poured into an aqueous sodium sulfite solution, stirred for 30 minutes, and extracted with dichloromethane. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 2- (4- (methylsulfinyl) benzyl) isoindoline-1,3-dione (yield 45 g, yield 62%). Got

Step 4
2- (4- (Methylsulfinyl) benzyl) isoindoline-1,3-dione (45 g, 0.15 mol) was added with dichloromethane (500 mL) and O- (mesitylsulfonyl) hydroxylamine (107 g, 0.5 mol). In addition, the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure to obtain 2- (4- (S-methylsulfonimidoyl) benzyl) isoindoline-1,3-dione as a mixture.

Step 5
Ethanol (200 mL) and hydrazine monohydrate (40 mL) were added to 2- (4- (S-methylsulfonimidoyl) benzyl) isoindoline-1,3-dione (20 g, 0.06 mol) to give 20 Heated to reflux for hours. After filtering the reaction solution, the solvent was distilled off under reduced pressure to obtain (4- (S-methylsulfonimidoyl) phenyl) methanamine (VIII-21) (yield 6 g, yield 51%).

Example 187
1- (tert-butyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N- (4- (S-methylsulfonimidoyl) benzyl ) -1H-Pyrazole-3-carboxamide (I-187) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4- (trifluoromethyl) was used. ) Pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 37 (4- (S-methylsulfonimideyl). ) Phenyl) methanamine (VIII-21) was used to obtain compound (I-187) in the same manner as in Example 9.

Example 188
1- (tert-butyl) -5-((4-ethoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-188) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 2-chloro-4-ethoxy-3 was used. -(Trifluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethyl The compound (I-188) was obtained in the same manner as in Example 9 by using sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4).

Example 189
1- (tert-butyl) -5-((4-ethoxy-3- (trifluoromethyl) pyridin-2-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxy Preparation of ethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-189) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 2-chloro-4-ethoxy was used. Using 2- (trifluoromethyl) pyridine, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino synthesized by the method described in Reference Example 2. Compound (I-189) was obtained in the same manner as in Example 9 by using 2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 190
1- (tert-butyl) -5-((5-chloro-4- (difluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl)- Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-190) In place of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9, 3,5-dichloro-4- (difluoro) was used. Methyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl) pyridine- Compound (I-190) was obtained in the same manner as in Example 9 by using 2-yl) methanamine hydrochloride (VIII-4).

Example 191
1- (tert-butyl) -5-((5-chloro-4- (difluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl ) -4-Methyl-1H-pyrazole-3-carboxamide (I-191) In place of 3,5-dichloro-2-fluoropyridine in Step 9 of Example 9, 3,5-dichloro-4- was used. (Difluoromethyl) pyridine was used. Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (synthesized by the method described in Reference Example 2 was used. Compound (I-191) was obtained in the same manner as in Example 9 by using 4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 192
1- (tert-butyl) -5-((5- (2,2-difluoroethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine Preparation of 2-yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-192) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-dichloro-2-fluoropyridine was used. 5-difluoro-4- (trifluoromethyl) pyridine was used, 2,2-difluoroethanol was used in place of ethanol in step 3 of Example 9, and 4- (amino) in step 4 of Example 9 was used. (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-192) was obtained by using the same method as in Example 9.

Example 193
1- (tert-butyl) -5-((5- (2,2-difluoroethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) ) Phenyl) -2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-193) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4- (trifluoromethyl) pyridine was used, 2,2-difluoroethanol was used in place of ethanol in step 3 of Example 9, and in step 4 of Example 9, 4- 2-Amino-2- (4- (ethylsulfonyl) phenyl) ethanol salt synthesized by the method described in Reference Example 2 instead of (aminomethyl) benzenesulfonamide hydrochloride The use of salt (VIII-2), to give compound (I-193) in the same manner as in Example 9.

Example 194
1- (tert-butyl) -5-((5- (cyclopropylmethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine-2- Preparation of (yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-194) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro 4- (trifluoromethyl) pyridine was used, cyclopropanemethanol was used in place of ethanol in Step 3 of Example 9, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. Instead of the salt, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used. By to give compound (I-194) in the same manner as in Example 9.

Example 195
1- (tert-butyl) -5-((5- (cyclopropylmethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) Preparation of 2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-195) 3,5 instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 -Difluoro-4- (trifluoromethyl) pyridine was used, cyclopropanemethanol was used in place of ethanol in step 3 of Example 9, and 4- (aminomethyl) benzenesulfone in step 4 of Example 9 was used. Instead of amide hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VI was synthesized by the method described in Reference Example 2). Compound (I-195) was obtained in the same manner as in Example 9 by using II-2).

Reference Example 38
1- (tert-butyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-15) manufacturing process 1
1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (50.0 mg, 0.125 mmol) in tetrahydrofuran (1.0 mL) was added with 3 mol / L methylmagnesium bromide tetrahydrofuran solution (50 μL, 0.15 mmol) at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. Then, a 3 mol / L methylmagnesium bromide tetrahydrofuran solution (25 μL, 0.075 mmol) was added at −78 ° C., and the mixture was stirred at the same temperature for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 60: 40), and 1- (tert-butyl) -5-((5 -(1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 39.2 mg, yield 75%) was obtained. It was

Process 2
Ethyl 1- (tert-butyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylate Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.14 mL, 0.56 mmol) were added to the ester (39.2 mg, 0.0944 mmol), and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1- (tert-butyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl. -1H-pyrazole-3-carboxylic acid (VII-15) was obtained (yield 36.6 mg, quantitative).

Example 196
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-196) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5- (1 -Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-15) and also in step 4 of Example 9. , 4- (aminomethyl) be In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of benzenesulfonamide hydrochloride. Compound (I-196) was obtained by the method described in 1.

Example 197
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine Preparation of 3--3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-197) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-15) was used and the process of Example 9 4- (amino) in 4 By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-197) was obtained in the same manner as in Example 9.

Reference Example 39
1- (tert-butyl) -4-methyl-5-((5- (oxetan-3-yloxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid Production of (VII-16) In the same manner as in Reference Example 27, oxetane-3-ol was used instead of ethylamine hydrochloride in step 2, and 1- (tert-butyl) -4-methyl-5-((5 -(Oxetan-3-yloxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-16) was obtained.

Example 198
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5- (oxetan-3-yloxy) -4- (trifluoro Methyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-198) 1- (tert-butyl) -5-((3,5-dichloro) in Step 4 of Example 9 Pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -4-methyl-5- (synthesized by the method described in Reference Example 39. (5- (oxetan-3-yloxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-16) was used, and also the process of Example 9 4- (ami) in 4 Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of (nomethyl) benzenesulfonamide hydrochloride. Compound (I-198) was obtained in the same manner as in.

Example 199
1- (tert-butyl) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -5-((5- (oxetan-3-yloxy) -4- (trifluoro Methyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-199) 1- (tert-butyl) -5-((3,5-dichloro) in Step 4 of Example 9 Instead of pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-methyl-5- (synthesized by the method described in Reference Example 39. (5- (oxetan-3-yloxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-16) was used, and also the process of Example 9 4- (ami) in 4 Example 9 by using (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Reference Example 1 instead of (nomethyl) benzenesulfonamide hydrochloride. Compound (I-199) was obtained in the same manner as in.

Reference Example 40
1- (tert-butyl) -5-((5- (cyclopropylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII Preparation of -17) In the same manner as in Reference Example 27, 1- (tert-butyl) -5-((5- (cyclopropylamino) -4 was used, using cyclopropylamine instead of ethylamine hydrochloride in step 2. -(Trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-17) was obtained.

Example 200
1- (tert-butyl) -5-((5- (cyclopropylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2- Preparation of (yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-200) 1- (tert-butyl) -5-((3,5-dichloropyridine- Instead of 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (cyclopropyl) was synthesized by the method described in Reference Example 40. Amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-17) was used, and in step 4 of Example 9, 4 -(Aminomethyl) In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of benzenesulfonamide hydrochloride. Compound (I-200) was obtained by the method of.

Example 201
1- (tert-butyl) -5-((5- (cyclopropylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) Preparation of 2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-201) 1- (tert-butyl) -5-((3,5-dichloro) in Step 4 of Example 9 Instead of pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (was synthesized by the method described in Reference Example 40. Cyclopropylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-17) was used and also in step 4 of Example 9. , 4- (amino By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-201) was obtained in the same manner as in Example 9.

Reference Example 41
1- (tert-butyl) -5-((5-((dimethylamino) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid Manufacturing process 1 of (VII-18)
1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (50.0 mg, Dimethylamine hydrochloride (20.4 mg, 0.250 mmol) and sodium triacetoxyborohydride (79.6 mg, 0.376 mmol) were added to a solution of 0.125 mmol) in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was directly purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -5-((5-((dimethylamino) methyl)- 4- (Trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 23.9 mg, yield 45%) was obtained.

Process 2
1- (tert-butyl) -5-((5-((dimethylamino) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid Ethanol (1.0 mL) and a 4 mol / L sodium hydroxide aqueous solution (84 μL, 0.34 mmol) were added to ethyl ester (23.9 mg, 0.0558 mmol), and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -5-((5-((dimethylamino) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4- Methyl-1H-pyrazole-3-carboxylic acid (VII-18) (yield 19.0 mg, yield 85%) was obtained.

Example 202
1- (tert-butyl) -5-((5-((dimethylamino) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine- Preparation of 2-yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-202) 1- (tert-butyl) -5-((3,5-dichloro) in Step 4 of Example 9 Instead of pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (was synthesized by the method described in Reference Example 41. (Dimethylamino) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-18) was used and the process of Example 9 4- (aminome Example 9 by substituting (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 in place of tyl) benzenesulfonamide hydrochloride. Compound (I-202) was obtained in the same manner as in.

Example 203
1- (tert-butyl) -5-((5-((dimethylamino) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl)) Production of phenyl) -2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-203) 1- (tert-butyl) -5-((3,5 -Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5 -((Dimethylamino) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-18) was used and also in Example 9. 4-in Step 4 of By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of (aminomethyl) benzenesulfonamide hydrochloride A compound (I-203) was obtained in the same manner as in Example 9.

Reference Example 42
Of 1- (tert-butyl) -4-methyl-5-((5-morpholino-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-19) 1- (tert-Butyl) -4-methyl-5-((5-morpholino-4- (trifluoromethyl)) using morpholine instead of the ethylamine hydrochloride in step 2 in the same manner as in Production Reference Example 27. Pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-19) was obtained.

Example 204
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5-morpholino-4- (trifluoromethyl) pyridine-3- Preparation of (yl) oxy) -1H-pyrazole-3-carboxamide (I-204) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 Instead of (oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-methyl-5-((5-morpholino-4 was synthesized by the method described in Reference Example 42. -(Trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-19) was used, and 4- (aminomethyl) benzenesulfonamide in step 4 of Example 9 was used. Of hydrochloride Instead of (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5, a compound ( I-204) was obtained.

Example 205
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((5-morpholino-4- (trifluoromethyl) pyridine- Preparation of 3-yl) oxy) -1H-pyrazole-3-carboxamide (I-205) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5-dichloropyridine-2- 1- (tert-butyl) -4-methyl-5-((5-morpholino) synthesized by the method described in Reference Example 42 instead of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid. 4-((trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-19) was used, and 4- (aminomethyl) benzene in step 4 of Example 9 was used. Sulfonami As in Example 9, except that 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 was used instead of dohydrochloride. Compound (I-205) was obtained by the method of.

Reference Example 43
1- (tert-butyl) -5-((5- (3-hydroxyazetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole- Process 1 for producing 3-carboxylic acid (VII-20)
1- (tert-butyl) -5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (50.0 mg, 0.128 mmol), 1-methyl-2-pyrrolidinone (0.60 mL), N, N-diisopropylethylamine (0.22 mL, 1.3 mmol) and 3-hydroxyazetidine hydrochloride (42.2 mg, 0.385 mmol) were added, and microwaved. Under irradiation, the mixture was stirred at 160 ° C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -5-((5 -(3-Hydroxyazetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 29.6 mg, yield 52%).

Process 2
1- (tert-butyl) -5-((5- (3-hydroxyazetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole- Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.10 mL, 0.40 mmol) were added to 3-carboxylic acid ethyl ester (29.6 mg, 0.0669 mmol), and the mixture was stirred at room temperature for 4 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (3-hydroxyazetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy was obtained by distilling off the solvent under reduced pressure. ) -4-Methyl-1H-pyrazole-3-carboxylic acid (VII-20) (yield 27.7 mg, quantitative) was obtained.

Example 206
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (3-hydroxyazetidin-1-yl) -4- (trifluoro Preparation of Methyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-206) 1- (tert-butyl) -5-((3 , 5-Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was synthesized by the method described in Reference Example 43 1- (tert-butyl) -5- (. (5- (3-Hydroxyazetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-20) was used. Also, in Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 is used. Thus, the compound (I-206) was obtained in the same manner as in Example 9.

Example 207
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (3-hydroxyazetidin-1-yl) -4- ( Preparation of trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-207) 1- (tert-butyl) -5- (in Step 4 of Example 9 Instead of (3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5 synthesized by the method described in Reference Example 43. -((5- (3-Hydroxyazetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-20) Of Example 9 Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII- was synthesized by the method described in Reference Example 2). Compound (I-207) was obtained in the same manner as in Example 9 by using 2).

Example 208
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2-methoxyethoxy) -4- (trifluoromethyl) pyridine-3 Preparation of -yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-208) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5- Difluoro-4- (trifluoromethyl) pyridine was used, 2-methoxyethanol and tetrahydrofuran were used in place of ethanol in Step 3 of Example 9, and 4- (aminomethyl) in Step 4 of Example 9 was used. Instead of benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine salt synthesized by the method described in Reference Example 5 The use of salt (VIII-4), to give compound (I-208) in the same manner as in Example 9.

Example 209
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (2-methoxyethoxy) -4- (trifluoromethyl) pyridine Preparation of 3--3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-209) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-dichloro-2-fluoropyridine was used. 5-difluoro-4- (trifluoromethyl) pyridine was used, 2-methoxyethanol and tetrahydrofuran were used in place of ethanol in step 3 of Example 9, and 4- (amino) in step 4 of Example 9 was used. 2-amino-2- (4- (ethylsulfonyl) phenyl synthesized by the method described in Reference Example 2 instead of methyl) benzenesulfonamide hydrochloride. The use of ethanol hydrochloride (VIII-2), to give compound (I-209) in the same manner as in Example 9.

Reference Example 44
1- (tert-butyl) -5-((5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3- Production of Carboxylic Acid (VII-21) In the same manner as in Reference Example 43, 1- (tert-butyl) -5-((5- ((2-Hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-21) was obtained.

Example 210
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) Preparation of pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-210) 1- (tert-butyl) -5-((3,5 -Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5 Using-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-21), 4 in Step 4 of Example 9 By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of-(aminomethyl) benzenesulfonamide hydrochloride, Compound (I-210) was obtained in the same manner as in Example 9.

Example 211
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-((2-hydroxyethyl) amino) -4- (trifluoro Preparation of (methyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-211) 1- (tert-butyl) -5-((3 , 5-Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5- (synthesized by the method described in Reference Example 44. (5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-21) was used, , Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 Compound (I-211) was obtained in the same manner as in Example 9 by using

Reference Example 45
Preparation of 1- (tert-butyl) -5-((4- (difluoromethyl) -5-ethoxypyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-22) In the same manner as in Reference Example 34, using 3-bromo-4- (difluoromethyl) -5-fluoropyridine instead of 5-bromo-2-chloro-3- (trifluoromethyl) pyridine in Step 1 -(Tert-Butyl) -5-((4- (difluoromethyl) -5-ethoxypyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-22) was obtained. .

Example 212
1- (tert-butyl) -5-((4- (difluoromethyl) -5-ethoxypyridin-3-yl) oxy-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4 Preparation of -methyl-1H-pyrazole-3-carboxamide (I-212) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) in step 4 of Example 9 Instead of -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((4- (difluoromethyl) -5-ethoxypyridine) synthesized by the method described in Reference Example 45. -3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-22) was used, and the 4- (aminomethyl) benzenesulfonamide hydrochloride salt in step 4 of Example 9 was used. instead of, By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5, a compound (I-212 ) Got.

Example 213
1- (tert-butyl) -5-((4- (difluoromethyl) -5-ethoxypyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl ) -4-Methyl-1H-pyrazole-3-carboxamide (I-213) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 ) Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((4- (difluoromethyl) -5) synthesized by the method described in Reference Example 45. -Ethoxypyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-22) was used and 4- (aminomethyl) benzenesulfonamide in step 4 of Example 9 was used. Hydrochloride In the same manner as in Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of To give the compound (I-213).

Reference Example 46
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxypropyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII -23) Manufacturing process 1
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.10 g, 4.86 mmol) was added to dimethyl sulfoxide (9.0 mL) and cesium carbonate (2.38 g, 7.30 mmol). ) And 3-bromo-4- (difluoromethyl) -5-fluoropyridine (1.43 g, 6.33 mmol) were added, and the mixture was stirred at 100 ° C for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25 → 40: 60), and 5-((5-bromo-4- (difluoromethyl) pyridine) -3-yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 1.37 g, yield 65%) was obtained.

Process 2
5-((5-Bromo-4- (difluoromethyl) pyridin-3-yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (40.0 mg, 0.0925 1.3 mol / L isopropylmagnesium chloride lithium chloride complex tetrahydrofuran solution (0.21 mL, 0.27 mmol) was added to a tetrahydrofuran (0.50 mL) solution of (mmol) at -40 ° C, and the mixture was stirred at the same temperature for 30 minutes. Then, propionaldehyde (10 μL, 0.19 mmol) was added at −40 ° C., and the mixture was stirred at the same temperature for 1 hour. Then, propionaldehyde (10 μL, 0.19 mmol) was added, and the mixture was stirred at -25 ° C for 1 hr. Then, propionaldehyde (10 μL, 0.19 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50), and 1- (tert-butyl) -5-((4 -(Difluoromethyl) -5- (1-hydroxypropyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 6.8 mg, yield 18%) was obtained. .

Process 3
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxypropyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester Ethanol (0.50 mL), tetrahydrofuran (0.50 mL), and 4 mol / L sodium hydroxide aqueous solution (30 μL, 0.12 mmol) were added to (6.8 mg, 0.017 mmol), and the mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. By distilling the solvent off under reduced pressure, 1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxypropyl) pyridin-3-yl) oxy) -4-methyl- 1H-pyrazole-3-carboxylic acid (VII-23) (6.3 mg, 99% yield) was obtained.

Example 214
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxypropyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine-2- Preparation of (yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-214) 1- (tert-butyl) -5-((3,5-dichloropyridine- 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((4- (difluoromethyl) synthesized by the method described in Reference Example 46. ) -5- (1-Hydroxypropyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-23) and also in step 4 of Example 9 at 4 -(Aminomethyl) In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of benzenesulfonamide hydrochloride. The compound (I-214) was obtained by the method of.

Example 215
1- (tert-butyl) -5-((4-cyano-5-ethoxypyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-215) 3,5-difluoropyridine-4-carbonitrile was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 5. The compound (I-215) was obtained in the same manner as in Example 9 by using the hydrochloride (VIII-4).

Reference Example 47
Production of 2- (2,2-difluoroethoxy) -6-fluorobenzonitrile (V-2) 2-Fluoro-6-hydroxybenzonitrile (200 mg, 1.46 mmol) was added to N, N-dimethylformamide (4.9 mL). ), 2,2,2-trifluoroethyl trifluoromethanesulfonate (468 mg, 2.19 mmol), potassium carbonate (302 mg, 2.19 mmol) and potassium iodide (24.3 mg, 0.146 mmol) were added, and the mixture was stirred at room temperature for 3 hours. It was stirred. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 65: 35), and 2- (2,2-difluoroethoxy) -6- Fluorobenzonitrile (V-2) (yield 258 mg, yield 88%) was obtained.

Example 216
1- (tert-butyl) -5- (2-cyano-3- (2,2-difluoroethoxy) phenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl Production of -1H-pyrazole-3-carboxamide (I-216) 2- () was synthesized by the method described in Reference Example 47 instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. 2,2-difluoroethoxy) -6-fluorobenzonitrile (V-2) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, referential example 5 was used. Compound (I-216) was obtained in the same manner as in Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described. Obtained.

Example 217
1- (tert-butyl) -5- (2-cyano-3- (2,2-difluoroethoxy) phenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4 -Methyl-1H-pyrazole-3-carboxamide (I-217) was prepared by the method described in Reference Example 47 instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 2 -(2,2-difluoroethoxy) -6-fluorobenzonitrile (V-2) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, reference example In the same manner as in Example 9, by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in 2, I-217) was obtained.

Reference Example 48
1- (tert-butyl) -4-ethyl-5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII- 24) Manufacturing process 1
In tert-butylhydrazine hydrochloride (824 mg, 6.61 mmol), ethanol (20 mL), diethyl 2-ethyl-3-oxosuccinate (III-1) (1.43 g, 6.61 mmol) and potassium carbonate (1.83 g, 13.2). mmol) was added and the mixture was stirred with heating under reflux for 20 hours. The reaction solution was filtered and washed with ethanol. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 50: 50), and 1- (tert-butyl) -4-ethyl-5 was used. -Hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (yield 780 mg, yield 49%) was obtained.

Process 2
1- (tert-Butyl) -4-ethyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (800 mg, 3.33 mmol) was added to dimethyl sulfoxide (6.5 mL) and cesium carbonate (1.63 g, 5.00 mmol). ) And 3,5-dichloro-4- (trifluoromethyl) pyridine (1.08 g, 5.00 mmol) were added, and the mixture was stirred at 100 ° C for 16 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25 → 40: 60) to give 1- (tert-butyl) -5-((5-chloro- 4- (Trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 684 mg, yield 49%) was obtained.

Process 3
1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 0.715 mmol), potassium vinyltrifluoroborate (479 mg, 3.58 mmol), cesium carbonate (1.16 g, 3.56 mmol), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (25.3 mg, 0.0357 mmol) and 1,4-dioxane (7.0 mL) were added, and the mixture was stirred at 120 ° C. for 1 hr in a sealed tube. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 70: 30), and 1- (tert-butyl) -4- Ethyl-5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 270 mg, yield 92%) was obtained.

Step 4
1- (tert-butyl) -4-ethyl-5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (53.4 mg, To a solution of 0.130 mmol) in 1,4-dioxane (2.0 mL) and water (0.20 mL), 2,6-dimethylpyridine (30 μL, 0.26 mmol), sodium periodate (111 mg, 0.519 mmol) and 2.5% An osmium tetroxide tert-butanol solution (66 μL, 0.0065 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50) and 1- (tert-butyl) -4-ethyl-5- ((5-Formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 37.9 mg, yield 71%) was obtained.

Step 5
1- (tert-butyl) -4-ethyl-5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (18.9 mg, Sodium borohydride (2.6 mg, 0.069 mmol) was added to a tetrahydrofuran (1.0 mL) solution of 0.0457 mmol) under ice cooling, and the mixture was stirred at 0 ° C for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 50: 50), and 1- (tert-butyl) -4-ethyl-5 was used. -((5- (Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 7.9 mg, yield 42%) was obtained.

Process 6
1- (tert-butyl) -4-ethyl-5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester ( Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (29 μL, 0.12 mmol) were added to 7.9 mg, 0.019 mmol), and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 1- (tert-butyl) -4-ethyl-5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole was obtained. -3-Carboxylic acid (VII-24) (yield 7.4 mg, quantitative) was obtained.

Example 218
1- (tert-butyl) -4-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridine Preparation of 3--3-yl) oxy) -1H-pyrazole-3-carboxamide (I-218) 1- (tert-butyl) -5-((3,5-dichloropyridine-2) in Step 4 of Example 9 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -4-ethyl-5-((5- (Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-24) was used, and 4- (in Step 4 of Example 9 was used. Aminomethyl) benzenes A method similar to that in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of rufonamide hydrochloride. To obtain the compound (I-218).

Reference Example 49
1- (tert-butyl) -4-ethyl-5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ( VII-25) Production of 1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-in the step 1 of Reference Example 38. 1- (tert-Butyl) -4-ethyl-5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H instead of 1H-pyrazole-3-carboxylic acid ethyl ester By using -pyrazole-3-carboxylic acid ethyl ester, 1- (tert-butyl) -4-ethyl-5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine-3- Ill) Oki )-1H-pyrazol-3-carboxylic acid (VII-25).

Example 219
1- (tert-butyl) -4-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-219) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -4-ethyl-5-((synthesized by the method described in Reference Example 49). 5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-25) was used and also in step 4 of Example 9. , 4- (aminomethyl) be In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of benzenesulfonamide hydrochloride. Compound (I-219) was obtained by the method described in 1.

Reference Example 50
(5-((oxetane-3-ylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-22) production step 1
N, N-Dimethylformamide (45 mL) and sodium sulfide (6.33 g, 81.1 mmol) were added to 5-fluoropicolinonitrile (9.00 g, 73.7 mmol), and the mixture was stirred at room temperature for 3 hours. A 1 mol / L sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was extracted with dichloromethane. 6 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 10% Hydrochloric acid (360 mL) and zinc powder (36.1 g) were added to the residue, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was filtered, the organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5-mercaptopicolinonitrile (yield 4.35 g, yield 43%).

Process 2
After adding N, N-dimethylformamide (12 mL) and potassium carbonate (1.66 mg, 12.0 mmol) to 5-mercaptopicolinonitrile (817 mg, 5.99 mmol), 3- (bromomethyl) oxetane ( 929 mg, 6.29 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 30: 70), and 5-((oxetane-3-ylmethyl) thio) picolinonitrile (yield 939 mg , Yield 84%) was obtained.

Process 3
A solution of 5-((oxetane-3-ylmethyl) thio) picolinonitrile (939 mg, 4.55 mmol) in acetic acid (864 μL) was dissolved in water (60 mL) potassium permanganate (1.99 g, 12.6 mmol). ) Was added and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction solution, and filtered through Celite. The filtrate was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 50: 50), and 5-((oxetane-3-ylmethyl) sulfonyl) picolinonitrile (yield 635 mg, Yield 59%) was obtained.

Step 4
To 5-((oxetane-3-ylmethyl) sulfonyl) picolinonitrile (635 mg, 2.67 mmol) was added methanol (60 mL) and 10% palladium carbon (133 mg), and the mixture was stirred at room temperature for 26 hours under a hydrogen atmosphere. did. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure to give (5-((oxetan-3-ylmethyl) sulfonyl) pyridin-2-yl) methanamine (yield 0.64 g, 99% yield).

Step 5
(5-((oxetane-3-ylmethyl) sulfonyl) pyridin-2-yl) methanamine (544 mg, 2.24 mmol) was added with methanol (13 mL) and 4 mol / L hydrogen chloride ethyl acetate solution (2 mL), The mixture was stirred at room temperature for 5 minutes. The precipitate was collected by filtration and washed with ethyl acetate to give (5-((oxetan-3-ylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-22) (yield 413 mg, yield 66 %).

Example 220
1- (tert-butyl) -4-methyl-N-((5-((oxetan-3-ylmethyl) sulfonyl) pyridin-2-yl) methyl) -5-((3- (trifluoromethyl) pyridine- Preparation of 2-yl) oxy) -1H-pyrazole-3-carboxamide (I-220) 2-fluoro-3- (tri) instead of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9. (Fluoromethyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, it was synthesized by the method described in Reference Example 50 (5-((oxetane-3 By using -ylmethyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-22), compound (I-220) was obtained in the same manner as in Example 9.

Reference Example 51
Production Step 1 of 3- (4- (ethylsulfonyl) phenyl) tetrahydrofuran-3-amine (VIII-23)
Tetrahydrofuran-3-one (2 g, 23 mmol) was charged with tetrahydrofuran (30 mL), 2-methylpropane-2-sulfinamide (2.8 g, 23 mmol) and tetraisopropyl orthotitanate (14 mL, 47 mmol). The mixture was added and stirred at 70 ° C for 16 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was stirred for 30 minutes and then filtered through Celite. The filtrate was extracted with chloroform, the organic layer was washed with saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain (Z) -N- (dihydrofuran-3 (2H) -ylidene) -2-methylpropane-2-sulfinamide (yield 2.4 g, yield 55%) was obtained.

Process 2
A solution of (Z) -N- (dihydrofuran-3 (2H) -ylidene) -2-methylpropane-2-sulfinamide (1.05 g, 5.55 mmol) in tetrahydrofuran (9.2 mL) was added at -78 ° C to give 2.6 mol / L-normal butyllithium normal-hexane solution (1.9 mL, 4.9 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. A solution of 1-bromo-4-ethylsulfanyl-benzene (1.00 g, 4.61 mmol) in toluene (4.0 mL) was added at −78 ° C., the mixture was stirred at the same temperature for 30 minutes, and then heated to 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give N- (3- (4- (ethylthio) phenyl) tetrahydrofuran-3-yl) -2-methylpropane-2-sulfinamide. (Yield 540 mg, yield 36%) was obtained.

Process 3
N- (3- (4- (ethylthio) phenyl) tetrahydrofuran-3-yl) -2-methylpropane-2-sulfinamide (540 mg, 1.65 mmol) was added to dichloromethane (60 mL) and 4 mol / L hydrochloric acid ( 1 mL, 0.004 mol) was added, and the mixture was stirred at room temperature for 30 minutes. N-Hexane was added to the reaction solution, and the precipitate was collected by filtration to give 3- (4- (ethylthio) phenyl) tetrahydrofuran-3-amine hydrochloride (amount 380 mg, yield 89%).

Step 4
To 3- (4- (ethylthio) phenyl) tetrahydrofuran-3-amine hydrochloride (380 mg, 1.46 mmol), tetrahydrofuran (4.9 mL), sodium carbonate (465 mg, 4.39 mmol) and ditert-butyl dicarbonate (0.40). (mL, 1.7 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give tert-butyl (3- (4- (ethylthio) phenyl) tetrahydrofuran-3-yl) carbamate (yield 288 mg, yield 61 %) Was obtained.

Step 5
tert-Butyl (3- (4- (ethylthio) phenyl) tetrahydrofuran-3-yl) carbamate (288 mg, 0.891 mmol) in dichloromethane (8.9 mL), disodium hydrogen phosphate (506 mg, 3.56 mmol) and m -CPBA (473 mg, 1.78 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography, and tert-butyl (3- (4- (ethylsulfonyl) phenyl) tetrahydrofuran-3-yl) carbamate (yield 145 mg, yield 46%).

Process 6
A solution of tert-butyl (3- (4- (ethylsulfonyl) phenyl) tetrahydrofuran-3-yl) carbamate (144 mg, 0.405 mmol) in dichloromethane (4 mL) was added at 0 ° C to 2,2,2-trifluoroacetic acid. (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. Aqueous sodium carbonate solution was added to the reaction solution, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 3- (4- (ethylsulfonyl) phenyl) tetrahydrofuran-3-amine (VIII-23) (yield 69.3 mg, yield 67%).

Example 221
1- (tert-butyl) -N- (3- (4- (ethylsulfonyl) phenyl) tetrahydrofuran-3-yl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Preparation of (oxy) -1H-pyrazole-3-carboxamide (I-221) 2-fluoro-3- (trifluoromethyl) pyridine instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9 Was used, and 3- (4- (ethylsulfonyl) phenyl) tetrahydrofuran synthesized by the method described in Reference Example 51 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-221) was obtained in the same manner as in Example 9 by using -3-amine (VIII-23).

Example 222
1- (tert-butyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-N-((5- (ethylsulfonyl) pyridine-2- Preparation of (yl) methyl) -1H-pyrazole-3-carboxamide (I-222) In place of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9, it was synthesized by the method described in Reference Example 4. Using diethyl 2-ethyl-3-oxosuccinate (III-1), in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 3,5-difluoro-4- (trifluoro) was used. Methyl) pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethyl By using Ruhoniru) pyridin-2-yl) methanamine hydrochloride (VIII-4), to give compound (I-222) in the same manner as in Example 9.

Example 223
1- (tert-butyl) -5-((5-ethoxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) Preparation of 2-hydroxyethyl) -1H-pyrazole-3-carboxamide (I-223) By the method described in Reference Example 4 instead of diethyl 2-methyl-3-oxosuccinate in Step 1 of Example 9. Using the synthesized diethyl 2-ethyl-3-oxosuccinate (III-1), 3,5-difluoro-4- (was used instead of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. 2- (aminomethyl) benzenesulfonamide hydrochloride was used instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in the step 4 of Example 9 using trifluoromethyl) pyridine. By using the amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2), to give compound (I-223) in the same manner as in Example 9.

Example 224
5-((5-acetyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-224) 1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-(( 5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-196) (63.0 mg, 0.111 mmol), Dichloromethane (1.1 mL) and Dess-Martin periodinane (93.8 mg, 0.221 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80:20 → 20:80) to give compound (I-224) (yield 17.3 mg, yield 28%).

Reference Example 52
1- (tert-butyl) -5-((5- (2-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-26) manufacturing process 1
1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (200 mg, 0.493 mmol), 1,4-dioxane (5.0 mL), (E) -1-ethoxyethene-2-boronic acid pinacol ester (488 mg, 2.46 mmol), cesium carbonate (803 mg, 2.46 mmol) and bis ( Di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (17.4 mg, 0.0246 mmol) was added, and the mixture was stirred at 120 ° C for 2.5 hr in a sealed tube. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and (E) -1- (tert-butyl) -5 -((5- (2-Ethoxyvinyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (Yield 198 mg, Yield 91 %) Was obtained.

Process 2
(E) -1- (tert-Butyl) -5-((5- (2-ethoxyvinyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Carboxylic acid ethyl ester (150 mg, 0.340 mmol) was added with ethyl acetate (1.0 mL) and 4 mol / L hydrogen chloride ethyl acetate solution (1.0 mL, 4.0 mmol), and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, which was washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -4-methyl-5-((5- (2-oxoethyl)) -4- (Trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 97.6 mg, 70% yield) was obtained.

Process 3
1- (tert-butyl) -4-methyl-5-((5- (2-oxoethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester Sodium borohydride (8.2 mg, 0.22 mmol) was added to a tetrahydrofuran (1.0 mL) solution of (60.0 mg, 0.145 mmol) under ice cooling, and the mixture was stirred at 0 ° C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 0: 100), and 1- (tert-butyl) -5-((5 -(2-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 30.1 mg, yield 50%) was obtained. It was

Step 4
Ethyl 1- (tert-butyl) -5-((5- (2-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylate Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.11 mL, 0.44 mmol) were added to the ester (30.1 mg, 0.0725 mmol), and the mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1- (tert-butyl) -5-((5- (2-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl. -1H-pyrazole-3-carboxylic acid (VII-26) was obtained (yield 28.1 mg, quantitative).

Example 225
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2-hydroxyethyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-225) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (2 -Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-26) was used and also in step 4 of Example 9. , 4- (aminomethyl) be As in Example 9, except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of benzenesulfonamide hydrochloride. The compound (I-225) was obtained by the method of.

Example 226
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (2-hydroxyethyl) -4- (trifluoromethyl) pyridine Preparation of 3--3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-226) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (2-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-26) was used, and also the process of Example 9 4- (amino) in 4 By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-226) was obtained in the same manner as in Example 9.

Reference Example 53
1- (tert-butyl) -5-((5- (2-ethoxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-27) manufacturing process 1
(E) -1- (tert-Butyl) -5-((5- (2-ethoxyvinyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Carboxylic acid ethyl ester (48.0 mg, 0.109 mmol) was added with ethyl acetate (1 mL) and palladium carbon (10.0 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. Then, methanol (1.0 mL) and palladium hydroxide carbon (10.0 mg) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction solution was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50), and 1- (tert-butyl) -5-((5- (2-ethoxyethyl) -4- (Trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 32.7 mg, yield 68%) was obtained.

Process 2
Ethyl 1- (tert-butyl) -5-((5- (2-ethoxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylate Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.11 mL, 0.44 mmol) were added to the ester (32.7 mg, 0.0737 mmol), and the mixture was stirred at room temperature for 5 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (2-ethoxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl was obtained by distilling off the solvent under reduced pressure. -1H-pyrazole-3-carboxylic acid (VII-27) was obtained (yield 30.6 mg, quantitative).

Example 227
1- (tert-butyl) -5-((5- (2-ethoxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine-2 -Yl) Methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-227) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (2 -Ethoxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-27) and also in step 4 of Example 9. , 4- (aminomethyl) benze In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used in place of the sulfonamide hydrochloride. Compound (I-227) was obtained by the method of.

Example 228
1- (tert-butyl) -5-((5- (2-ethoxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl) ) -2-Hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-228) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (2-Ethoxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-27) was used and the process of Example 9 4- (aminomethyi in 4 And) 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of benzenesulfonamide hydrochloride. Compound (I-228) was obtained in the same manner as in Example 9.

Reference Example 54
1- (tert-butyl) -5-((5- (2-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-28) manufacturing process 1
1- (tert-butyl) -4-methyl-5-((5- (2-oxoethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester To a tetrahydrofuran (0.80 mL) solution of (35.0 mg, 0.0847 mmol), 3 mol / L methylmagnesium bromide tetrahydrofuran solution (50 μL, 0.15 mmol) was added at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50), and 1- (tert-butyl) -5-((5 -(2-Hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 12.5 mg, yield 34%) was obtained. It was

Process 2
Ethyl 1- (tert-butyl) -5-((5- (2-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylate Ethanol (0.50 mL) and 4 mol / L sodium hydroxide aqueous solution (44 μL, 0.176 mmol) were added to the ester (12.5 mg, 0.0291 mmol), and the mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1- (tert-butyl) -5-((5- (2-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl. -1H-pyrazole-3-carboxylic acid (VII-28) (yield 11.7 mg, quantitative) was obtained.

Example 229
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2-hydroxypropyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-229) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5- (2 -Hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-28) and also in step 4 of Example 9. , 4- (aminomethyl ) By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of benzenesulfonamide hydrochloride, Compound (I-229) was obtained by the same method.

Reference Example 55
1- (tert-butyl) -5-((5- (3-hydroxypyrrolidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Production of carboxylic acid (VII-29) In the same manner as in Reference Example 43, 3-pyrrolidinol was used instead of 3-hydroxyazetidine hydrochloride in step 1, and 1- (tert-butyl) -5-(( 5- (3-Hydroxypyrrolidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-29) was obtained.

Example 230
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (3-hydroxypyrrolidin-1-yl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-230) 1- (tert-butyl) -5-((3, Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 55). 5- (3-hydroxypyrrolidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-29) was used, , Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 is used. Thus, the compound (I-230) was obtained in the same manner as in Example 9.

Example 231
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (3-hydroxypyrrolidin-1-yl) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-231) 1- (tert-butyl) -5-((in Step 4 of Example 9 Instead of 3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-synthesized by the method described in Reference Example 55. ((5- (3-Hydroxypyrrolidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-29) was used. In addition, in Example 9 Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII- was synthesized by the method described in Reference Example 2). Compound (I-231) was obtained in the same manner as in Example 9 by using 2).

Reference Example 56
Production Step 1 of 3- (5- (ethylsulfonyl) pyridin-2-yl) tetrahydrofuran-3-amine (VIII-24)
In the same manner as in Step 2 of Reference Example 51, N- (3- (5-bromopyridin-2-yl) tetrahydrofuran was prepared by using 2,5-dibromopyridine instead of 1-bromo-4-ethylsulfanyl-benzene. -3-yl) -2-methylpropane-2-sulfinamide was obtained.

Process 2
N- (3- (5-Bromopyridin-2-yl) tetrahydrofuran-3-yl) -2-methylpropane-2-sulfinamide (886 mg, 2.55 mmol) in dichloromethane (60 mL) and 4 mol / L Hydrochloric acid (1.5 mL, 6.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. N-Hexane was added to the reaction solution, and the precipitate was collected by filtration to obtain 3- (5-bromopyridin-2-yl) tetrahydrofuran-3-amine hydrochloride (yield 802 mg) as a crude product.

Process 3
Pyridine (8.4 mL) and benzyl chloroformate (0.08 mL) were added to 3- (5-bromopyridin-2-yl) tetrahydrofuran-3-amine hydrochloride (120 mg, 0.429 mmol), and the mixture was stirred at room temperature for 12 hours. . Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give benzyl (3- (5-bromopyridin-2-yl) tetrahydrofuran-3-yl) carbamate (yield 140 mg, yield 86 %) Was obtained.

Step 4
Benzyl (3- (5-bromopyridin-2-yl) tetrahydrofuran-3-yl) carbamate (140 mg, 0.371 mmol) in dimethyl sulfoxide (6.5 mL), sodium ethanesulfinate (216 mg, 1.86 mmol) and iodine. Copper chloride (354 mg, 1.86 mmol) was added, and the mixture was stirred at 100 ° C for 2 hr under microwave irradiation. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography, and benzyl (3- (5- (ethylsulfonyl) pyridin-2-yl) tetrahydrofuran-3-yl) carbamate (yield 78 mg, Yield 54%).

Step 5
To benzyl (3- (5- (ethylsulfonyl) pyridin-2-yl) tetrahydrofuran-3-yl) carbamate (78 mg, 0.200 mmol), methanol (2 mL) and palladium hydroxide on carbon (8 mg) were added, The mixture was stirred under a hydrogen atmosphere at room temperature for 30 minutes. After filtering the reaction solution, the solvent was distilled off under reduced pressure to give 3- (5- (ethylsulfonyl) pyridin-2-yl) tetrahydrofuran-3-amine (VIII-24) (yield 36 mg, 70% yield). ) Got.

Example 232
1- (tert-butyl) -N- (3- (5- (ethylsulfonyl) pyridin-2-yl) tetrahydrofuran-3-yl) -4-methyl-5-((3- (trifluoromethyl) pyridine- Preparation of 2-yl) oxy) -1H-pyrazole-3-carboxamide (I-232) In Step 2 of Example 9, instead of 3,5-dichloro-2-fluoropyridine, 2-fluoro-3- (tri) was used. Fluoromethyl) pyridine was used, and 3- (5- (ethylsulfonyl) was synthesized by the method described in Reference Example 56 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. ) Pyridin-2-yl) tetrahydrofuran-3-amine (VIII-24) was used to give compound (I-232) in the same manner as in Example 9.

Reference Example 57
Production Step 1 of 3-amino-3- (5- (ethylsulfonyl) pyridin-2-yl) propan-1-ol hydrochloride (VIII-25)
5-Bromopicolinaldehyde (5.0 g, 27 mmol) in N, N-dimethylformamide (50 mL) solution, ethanethiol (2.0 g, 32.4 mmol), tetrabutylammonium bromide (0.8 g, 2.7 mmol), iodinated Copper (0.3 g, 27 mmol) and tripotassium phosphate (11.5 g, 54 mmol) were added, and the mixture was stirred at 100 ° C for 2 hr under a nitrogen atmosphere. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- (ethylthio) picolinaldehyde (yield 2.6 g, yield 58%).

Process 2
5- (Ethylthio) picolinaldehyde (2.6 g, 15.6 mmol) in dichloromethane (40 mL), 2-methyl-2-propanesulfinamide (3.8 g, 31.2 mmol) and copper (II) sulfide pentahydrate (7.8 g, 31.2 mmol) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours. The reaction solution was filtered through Celite and washed with ethyl acetate. The organic layer was poured into water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and N-((5- (ethylthio) pyridin-2-yl) methylene) -2-methylpropane-2-sulfinamide (yield 4.0 g, yield Got 95%)

Process 3
To a solution of acetonitrile (1.3 g, 31.2 mmol) in tetrahydrofuran (84 mL) was added n-butyllithium (12.5 mL, 31.2 mmol) at -78 ° C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. A solution of N-((5- (ethylthio) pyridin-2-yl) methylene) -2-methylpropane-2-sulfinamide (4.2 g, 15.6 mmol) in tetrahydrofuran (84 mL) was added to the reaction solution at the same temperature. After stirring for 1 hour, the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and N- (2-cyano-1- (5- (ethylthio) pyridin-2-yl) ethyl) -2-methylpropane-2- Sulfinamide (yield 3.3 g, yield 69%) was obtained.

Step 4
N- (2-cyano-1- (5- (ethylthio) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide (3.0 g, 9.6 mmol) in hydrogen chloride methanol solution (30 mL) Was added and the mixture was stirred at 80 ° C. for 3 hours. The solvent was distilled off under reduced pressure to give 3-amino-3- (5- (ethylthio) pyridin-2-yl) propanoic acid methyl ester hydrochloride (amount 2.0 g, yield 87%).

Step 5
3-Amino-3- (5- (ethylthio) pyridin-2-yl) propanoic acid methyl ester hydrochloride (9.0 g, 32.5 mmol) in dichloromethane (200 mL), triethylamine (8.2 g, 81.3 mmol) and dicarbonic acid. Di-tert-butyl (7.8 g, 35.7 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and 3-((tert-butoxycarbonyl) amino) -3- (5- (ethylthio) pyridin-2-yl) propanoic acid methyl ester ( Yield 11 g, quantitative).

Process 6
3-((tert-Butoxycarbonyl) amino) -3- (5- (ethylthio) pyridin-2-yl) propanoic acid methyl ester (10.0 g, 29.3 mmol) in dichloromethane (50 mL) was added at 0 ° C to m. -CPBA (10.1 g, 58.6 mmol) was added, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-((tert-butoxycarbonyl) amino) -3- (5- (ethylsulfonyl) pyridin-2-yl) propanoic acid methyl ester. (Yield 9.0 g, yield 83%) was obtained.

Process 7
A solution of 3-((tert-butoxycarbonyl) amino) -3- (5- (ethylsulfonyl) pyridin-2-yl) propanoic acid methyl ester (1.50 g, 4.02 mmol) in tetrahydrofuran (30 mL) was added at 0 ° C. Lithium borohydride (0.13 g, 6.03 mmol) and ethanol (0.18 g, 4.02 mmol) were added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and tert-butyl (1- (5- (ethylsulfonyl) pyridin-2-yl) -3-hydroxypropyl) carbamate (yield 0.8 g, Yield 58%) was obtained.

Process 8
To tert-butyl (1- (5- (ethylsulfonyl) pyridin-2-yl) -3-hydroxypropyl) carbamate (0.8 g, 2.3 mmol) was added hydrogen chloride methanol solution (10 mL), and the mixture was stirred at room temperature for 1 hour. It was stirred. The solvent was distilled off under reduced pressure, and 3-amino-3- (5- (ethylsulfonyl) pyridin-2-yl) propan-1-ol hydrochloride (VIII-25) (yield 0.36 g, yield 56%) was obtained. Obtained.

Example 233
1- (tert-butyl) -N- (1- (5- (ethylsulfonyl) pyridin-2-yl) -3-hydroxypropyl) -4-methyl-5-((3- (trifluoromethyl) pyridine- Preparation of 2-yl) oxy) -1H-pyrazole-3-carboxamide (I-233) 2-fluoro-3- (tri) in place of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 Fluoromethyl) pyridine was used, and 3-amino-3- (5 was synthesized by the method described in Reference Example 57 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-233) was obtained in the same manner as in Example 9 by using-(ethylsulfonyl) pyridin-2-yl) propan-1-ol hydrochloride (VIII-25).

Reference Example 58
(5-(((1-methylcyclopropyl) methyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-26) Production Step 1
A solution of 5-mercaptopicolinonitrile (5.0 g, 36.8 mmol) in tetrahydrofuran (100 mL) was charged with (1-methylcyclopropyl) methanol (3.16 g, 36.8 mmol), triphenylphosphine (12.5 g, 47.8 mmol) and azo. Diethyl dicarboxylate (8.3 g, 47.8 mol) was added, and the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(((1-methylcyclopropyl) methyl) thio) picolinonitrile (amount 2.0 g, yield 27%).

Process 2
M-CPBA (5.1 g, 29.4 mmol) was added at room temperature to a solution of 5-(((1-methylcyclopropyl) methyl) thio) picolinonitrile (2.0 g, 9.8 mmol) in dichloromethane (30 mL) at room temperature. It was stirred for 4 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-(((1-methylcyclopropyl) methyl) sulfonyl) picolinonitrile (amount 1.5 g, yield 65%).

Process 3
Ethyl acetate (30 mL) and 10% palladium-carbon (100 mg) were added to 5-(((1-methylcyclopropyl) methyl) sulfonyl) picolinonitrile (800 g, 3.4 mmol), and the mixture was heated under a hydrogen atmosphere at room temperature. It was stirred for 4 hours. After filtering the reaction solution, 4 mol / L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the precipitate was collected by filtration (5-(((1-methylcyclopropyl) methyl) sulfonyl) pyridine-2- Il) methanamine hydrochloride (VIII-26) (yield 400 mg, 50% yield) was obtained.

Example 234
1- (tert-butyl) -4-methyl-N-((5-(((1-methylcyclopropyl) methyl) sulfonyl) pyridin-2-yl) methyl) -5-((3- (trifluoromethyl ) Preparation of pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide (I-234)

  2-fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, and 4- (amino) in Step 4 of Example 9 was used. (5-(((1-methylcyclopropyl) methyl) sulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-26) synthesized by the method described in Reference Example 58 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-234) was obtained in the same manner as in Example 9 by using

Reference Example 59
1- (tert-butyl) -4-ethyl-5-((5- (2-hydroxyethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ( VII-30) manufacturing process 1
1- (tert-Butyl) -4-ethyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.25 mmol) was added to dimethyl sulfoxide (2.5 mL), 3,5-difluoro-4-. (Trifluoromethyl) pyridine (343 mg, 1.87 mmol) and cesium carbonate (610 mg, 1.87 mmol) were added, and the mixture was stirred at 100 ° C for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -4-ethyl-5 was used. -((5-Fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 373 mg, yield 74%) was obtained.

Process 2
1- (tert-butyl) -4-ethyl-5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (50.0 mg, Tetrahydrofuran (0.50 mL), water (0.50 mL), ethylene glycol (76.9 mg, 1.24 mmol) and lithium hydroxide (29.7 mg, 1.24 mmol) were added to 0.124 mmol), and the mixture was stirred at 60 ° C. for 18 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, ethylene glycol (1.0 mL) was added to the residue, and the mixture was stirred at 120 ° C for 6 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and 1- (tert-butyl) -4-ethyl-5-((5- (2-hydroxyethoxy) -4- (trifluoro). Methyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-30) was obtained (yield 51.7 mg, quantitative).

Example 235
1- (tert-butyl) -4-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2-hydroxyethoxy) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-235) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -4-ethyl-5-((synthesized by the method described in Reference Example 59. 5- (2-Hydroxyethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-30) was used and also in step 4 of Example 9. , 4- (aminomethyl ) By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of benzenesulfonamide hydrochloride, Compound (I-235) was obtained by the same method.

Example 236
1- (tert-butyl) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (2-hydroxyethoxy) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-236) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-ethyl-5-synthesized by the method described in Reference Example 59. ((5- (2-Hydroxyethoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-30) was used and the process of Example 9 4- (a) By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of minomethyl) benzenesulfonamide hydrochloride. Compound (I-236) was obtained in the same manner as in Example 9.

Reference Example 60
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-31 ) Manufacturing process 1
5-((5-Bromo-4- (difluoromethyl) pyridin-3-yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (250 mg, 0.578 mmol), 1,4-dioxane (5.5 mL), potassium vinyltrifluoroborate (387 mg, 2.89 mmol), cesium carbonate (942 mg, 2.89 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl). ) Phosphine) dichloropalladium (II) (20.5 mg, 0.0290 mmol) was added, and the mixture was stirred at 120 ° C for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -5-((4 -(Difluoromethyl) -5-vinylpyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 142 mg, yield 65%) was obtained.

Process 2
1- (tert-butyl) -5-((4- (difluoromethyl) -5-vinylpyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (142 mg, 0.374 1,4-dioxane (5.0 mL) and water (0.50 mL) solution of 2,6-dimethylpyridine (87 μL, 0.75 mmol), sodium periodate (320 mg, 1.50 mmol) and 2.5%. An osmium tetroxide tert-butanol solution (0.19 mL, 0.019 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50), and 1- (tert-butyl) -5-((4 -(Difluoromethyl) -5-formylpyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 137 mg, yield 96%) was obtained.

Process 3
1- (tert-butyl) -5-((4- (difluoromethyl) -5-formylpyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (25 mg, 0.0656 Sodium borohydride (37.2 mg, 0.983 mmol) was added to a tetrahydrofuran (1.3 mL) solution of (mmol) at 0 ° C, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 40: 60), and 1- (tert-butyl) -5-((4- ( Difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 11.2 mg, yield 45%) was obtained.

Step 4
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (10.5 Ethanol (0.170 mL) and a 4 mol / L sodium hydroxide aqueous solution (40 μL, 0.16 mmol) were added to (mg, 0.0274 mmol), and the mixture was stirred at room temperature for 30 minutes. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-methyl-1H- Pyrazole-3-carboxylic acid (VII-31) (yield 8.5 mg, yield 87%) was obtained.

Example 237
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) Preparation of Methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-237) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5-dichloropyridine-2- Instead of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((4- (difluoromethyl)-was synthesized by the method described in Reference Example 60. 5- (hydroxymethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-31) was used, and 4- (aminomethyl) in step 4 of Example 9 was used. ) Benzenesulfo In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used in place of the amide hydrochloride. To obtain the compound (I-237).

Reference Example 61
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxyethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII In the same manner as in Reference Example 38, 1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4 in step 1 was prepared. -Methyl-1H-pyrazole-3-carboxylic acid ethyl ester instead of 1- (tert-butyl) -5-((4- (difluoromethyl) -5-formylpyridin-3-yl) oxy) -4- By using methyl-1H-pyrazole-3-carboxylic acid ethyl ester, 1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxyethyl) pyridin-3-yl) Oxy)- - give methyl -1H- pyrazole-3-carboxylic acid (VII-32).

Example 238
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxyethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine-2- Preparation of (yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-238) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5-dichloropyridine- Instead of 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((4- (difluoromethyl) was synthesized by the method described in Reference Example 61. ) -5- (1-Hydroxyethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-32) and also in step 4 of Example 9 at 4 -(Aminomethyl) benze In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used in place of the sulfonamide hydrochloride. The compound (I-238) was obtained by the method of.

Example 239
1- (tert-butyl) -N- (3- (4- (ethylsulfonyl) phenyl) tetrahydrofuran-3-yl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-239) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (hydroxy Methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used, and in step 4 of Example 9, 4 -(Aminome Example 9 by substituting 3- (4- (ethylsulfonyl) phenyl) tetrahydrofuran-3-amine (VIII-23) synthesized by the method described in Reference Example 51 in place of (tyl) benzenesulfonamide hydrochloride. Compound (I-239) was obtained in the same manner as in.

Example 240
1- (tert-butyl) -N- (3- (5- (ethylsulfonyl) pyridin-2-yl) tetrahydrofuran-3-yl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-240) 1- (tert-butyl) -5-((3, Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 31). 5- (Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used and the process of Example 9 4-in 4- 3- (5- (ethylsulfonyl) pyridin-2-yl) tetrahydrofuran-3-amine (VIII-24) synthesized by the method described in Reference Example 56 is used instead of (aminomethyl) benzenesulfonamide hydrochloride. Thus, the compound (I-240) was obtained in the same manner as in Example 9.

Reference Example 62
Production Step 1 of (5- (ethylsulfonyl) thiazol-2-yl) methanamine hydrochloride (VIII-27)
tert-Butyl ((5-bromothiazol-2-yl) methyl) carbamate (1.21 g, 4.09 mmol) in toluene (81.8 mL), tris (dibenzylideneacetone) dipalladium (0) (197 mg, 0.205 mmol) , 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (214 mg, 0.344 mmol), (2R) -1-((1R) -1- (dicyclohexylphosphino) ethyl) -2- ( Diphenylphosphino) ferrocene (69.0 mg, 0.115 mmol) and triethylamine (649 μL, 4.66 mmol) were added, and the mixture was stirred at 120 ° C. for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, ethanethiol (363 μL, 4.91 mmol) was added, and the mixture was stirred at 120 ° C. for 3 hours. After filtering the reaction solution, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 80: 20), and tert-butyl ((5- (ethylthio) thiazole-2 -Yl) methyl) carbamate (yield 1.12 g, quantitative) was obtained.

Process 2
A solution of tert-butyl ((5- (ethylthio) thiazol-2-yl) methyl) carbamate (1.12 g, 4.07 mmol) in acetone (78 mL) was added to Oxone® (5.50 g, 8.95 mmol) in water ( 39 mL) solution was added and stirred for 17 hours. Acetone was distilled off under reduced pressure, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate only), and tert-butyl ((5- (ethylsulfonyl) thiazol-2-yl) methyl) carbamate (yield 1.15 g, yield 92%).

Process 3
tert-Butyl ((5- (ethylsulfonyl) thiazol-2-yl) methyl) carbamate (1.15 g, 3.76 mmol) in dichloromethane (21 mL) and 4 mol / L hydrogen chloride 1,4-dioxane solution (9.5 mL) ) Was added and the mixture was stirred at room temperature for 3 hours. A 4 mol / L hydrogen chloride 1,4-dioxane solution (4.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration and washed with dichloromethane to obtain (5- (ethylsulfonyl) thiazol-2-yl) methanamine hydrochloride (VIII-27) (yield 871 mg, yield 95%).

Example 241
1- (tert-butyl) -N-((5- (ethylsulfonyl) thiazol-2-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) oxy) Preparation of -1H-pyrazole-3-carboxamide (I-241) 2-Fluoro-3- (trifluoromethyl) pyridine was used in place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9. Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) thiazol-2-yl) methanamine synthesized by the method described in Reference Example 62. Compound (I-241) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-27).

Reference Example 63
Production Step 1 of (4- (ethylsulfonyl) phenyl) (oxetan-3-yl) methanamine (VIII-28)
To a solution of 1-bromo-4-ethylsulfanylbenzene (908 mg, 4.18 mmol) in tetrahydrofuran (14 mL) was added a 2.6 mol / L n-butyllithium n-hexane solution (1.5 mL, 3.9 mmol) at -78 ° C, and the same. Stir for 10 minutes at warm temperature. A solution of oxetane-3-carbaldehyde (300 mg, 3.49 mmol) in toluene (4 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. The temperature was raised to 0 ° C., saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain (4- (ethylthio) phenyl) (oxetane-3-yl) methanol (yield 566 mg, yield 72%). .

Process 2
(4- (Ethylthio) phenyl) (oxetane-3-yl) methanol (97 mg, 0.433 mmol), dichloromethane (4.4 mL), disodium hydrogen phosphate (250 mg, 1.76 mmol) and m-CPBA (344 mg). , 1.30 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain (4- (ethylsulfonyl) phenyl) (oxetane-3-yl) methanol (yield 78.9 mg, yield 71%). It was

Process 3
Acetic anhydride (1 mL) and dimethyl sulfoxide (2 mL) were added to (4- (ethylsulfonyl) phenyl) (oxetane-3-yl) methanol (35 mg, 0.137 mmol), and the mixture was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain (4- (ethylsulfonyl) phenyl) (oxetan-3-yl) methanone (yield 19.2 mg, yield 55%). It was

Step 4
(4- (Ethylsulfonyl) phenyl) (oxetan-3-yl) methanone (63.8 mg, 0.251 mmol) in methanol (1 mL), ammonium acetate (193 mg, 2.50 mmol) and sodium cyanoborohydride (44.8 mg, 0.713 mmol) was added and the mixture was stirred at 70 ° C. for 38 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain (4- (ethylsulfonyl) phenyl) (oxetan-3-yl) methanamine (VIII-28) (yield 28.8 mg, yield 45%).

Example 242
1- (tert-butyl) -N-((4- (ethylsulfonyl) phenyl) (oxetan-3-yl) methyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl ) Oxy) -1H-pyrazole-3-carboxamide (I-242) 2-fluoro-3- (trifluoromethyl) in place of 3,5-dichloro-2-fluoropyridine in step 2 of Example 9 Pyridine was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (4- (ethylsulfonyl) phenyl) (oxetane) synthesized by the method described in Reference Example 63. Compound (I-242) was obtained in the same manner as in Example 9 by using -3-yl) methanamine (VIII-28).

Reference Example 64
1- (tert-butyl) -5-((5- (4-hydroxypiperidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Production of carboxylic acid (VII-33) In the same manner as in Reference Example 43, using 4-hydroxypiperidine instead of 3-hydroxyazetidine hydrochloride in step 1, 1- (tert-butyl) -5- ( (5- (4-Hydroxypiperidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-33) was obtained. .

Example 243
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (4-hydroxypiperidin-1-yl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-243) 1- (tert-butyl) -5-((3, in step 4 of Example 9 Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 64). 5- (4-hydroxypiperidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-33) was used, and , Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 is used. Thus, the compound (I-243) was obtained in the same manner as in Example 9.

Example 244
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (4-hydroxypiperidin-1-yl) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-244) 1- (tert-butyl) -5-((in the step 4 of Example 9) Instead of 3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-synthesized by the method described in Reference Example 64. ((5- (4-Hydroxypiperidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-33) was used. In addition, in Example 9 Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII- was synthesized by the method described in Reference Example 2). Compound (I-244) was obtained in the same manner as in Example 9 by using 2).

Reference Example 65
(S) -1- (tert-Butyl) -5-((5- (2- (hydroxymethyl) azetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4- Production of methyl-1H-pyrazole-3-carboxylic acid (VII-34) In the same manner as in Reference Example 43, (S) -azetidin-2-ylmethanol was used in place of 3-hydroxyazetidine hydrochloride in step 1. Using (S) -1- (tert-butyl) -5-((5- (2- (hydroxymethyl) azetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy)- 4-Methyl-1H-pyrazole-3-carboxylic acid (VII-34) was obtained.

Example 245
(S) -1- (tert-Butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2- (hydroxymethyl) azetidin-1-yl) Preparation of 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-245) 1- (tert-butyl) in Step 4 of Example 9 Instead of -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, it was synthesized by the method described in Reference Example 65 (S) -1. -(Tert-Butyl) -5-((5- (2- (hydroxymethyl) azetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole -3-carboxylic acid (VII-34 ) Was used in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 (5- (ethylsulfonyl) pyridine-2-). (Il) Methanamine hydrochloride (VIII-4) was used to obtain compound (I-245) in the same manner as in Example 9.

Example 246
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-((S) -2- (hydroxymethyl) azetidine-1- Preparation of (yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-246) 1- (tert- in Step 4 of Example 9 Butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was synthesized by the method described in Reference Example 65 (S). -1- (tert-Butyl) -5-((5- (2- (hydroxymethyl) azetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H -Pyrazole-3-carboxylic acid (VII-34) was used, and 2-amino-2- (synthesized by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-246) was obtained in the same manner as in Example 9 by using 4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Reference Example 66
1- (tert-butyl) -5-((5-((2-hydroxy-2-methylpropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H- Production of pyrazole-3-carboxylic acid (VII-35) In the same manner as in Reference Example 43, 1-amino-2-methyl-propan-2-ol was used in place of 3-hydroxyazetidine hydrochloride in step 1. 1- (tert-butyl) -5-((5-((2-hydroxy-2-methylpropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H -Pyrazole-3-carboxylic acid (VII-35) was obtained.

Example 247
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-((2-hydroxy-2-methylpropyl) amino) -4 Preparation of-(trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-247) 1- (tert-butyl) -5 in Step 4 of Example 9 1- (tert-butyl) synthesized by the method described in Reference Example 66 instead of-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid -5-((5-((2-hydroxy-2-methylpropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-35) Further, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl)) synthesized by the method described in Reference Example 2. Compound (I-247) was obtained in the same manner as in Example 9 by using phenyl) ethanol hydrochloride (VIII-2).

Reference Example 67
1- (tert-butyl) -4-methyl-5-((5-((2- (2,2,2-trifluoroethoxy) ethyl) amino) -4- (trifluoromethyl) pyridin-3-yl ) Oxy) -1H-pyrazole-3-carboxylic acid (VII-36) In the same manner as in Reference Example 43, 2- (2,2,2- instead of 3-hydroxyazetidine hydrochloride in step 1 was used. 1- (tert-butyl) -4-methyl-5-((5-((2- (2,2,2-trifluoroethoxy) ethyl) amino) -4- (trifluorotriethoxy) ethanamine Fluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-36) was obtained.

Example 248
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5-((2- (2,2,2-trifluoro Preparation of ethoxy) ethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-248) 1- (tert- in Step 4 of Example 9 Butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was synthesized by the method described in Reference Example 67 1- ( tert-butyl) -4-methyl-5-((5-((2- (2,2,2-trifluoroethoxy) ethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ( VII-36) and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 and synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl) pyridine. By using 2--2-yl) methanamine hydrochloride (VIII-4), compound (I-248) was obtained in the same manner as in Example 9.

Example 249
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((5-((2- (2,2,2- Preparation of trifluoroethoxy) ethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-249) 1- (in Step 4 of Example 9 tert-Butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was synthesized by the method described in Reference Example 67 in place of 1 -(Tert-Butyl) -4-methyl-5-((5-((2- (2,2,2-trifluoroethoxy) ethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) Oxy) -1H-pyrazole-3-ca Ruminoic acid (VII-36) was used, and 2-amino-2 synthesized by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. Compound (I-249) was obtained in the same manner as in Example 9 by using-(4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Reference Example 68
1- (tert-butyl) -5-((5-((1-hydroxy-2-methylpropan-2-yl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4- Production of Methyl-1H-pyrazole-3-carboxylic acid (VII-37) In the same manner as in Reference Example 43, 2-amino-2-methyl-propane-1 was used instead of 3-hydroxyazetidine hydrochloride in step 1. 1- (tert-butyl) -5-((5-((1-hydroxy-2-methylpropan-2-yl) amino) -4- (trifluoromethyl) pyridin-3-yl) using Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-37) was obtained.

Example 250
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((1-hydroxy-2-methylpropan-2-yl) amino)) Preparation of 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-250) 1- (tert-butyl) in Step 4 of Example 9 Instead of -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert- was synthesized by the method described in Reference Example 68. Butyl) -5-((5-((1-hydroxy-2-methylpropan-2-yl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole -3-carboxylic acid (VII- 37) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl) pyridine-2. -Yl) Methanamine hydrochloride (VIII-4) was used to obtain compound (I-250) in the same manner as in Example 9.

Example 251
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((2-hydroxy-2-methylpropyl) amino) -4- ( Preparation of trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-251) 1- (tert-butyl) -5- (in Step 4 of Example 9 Instead of (3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5 synthesized by the method described in Reference Example 66. -((5-((2-hydroxy-2-methylpropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 35), and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride ( Compound (I-251) was obtained in the same manner as in Example 9 by using VIII-4).

Reference Example 69
1- (tert-butyl) -5-((5-((1-hydroxypropan-2-yl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H- Production of pyrazole-3-carboxylic acid (VII-38) In the same manner as in Reference Example 43, 2-aminopropan-1-ol was used instead of 3-hydroxyazetidine hydrochloride in step 1, and 1- (tert. -Butyl) -5-((5-((1-hydroxypropan-2-yl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3- A carboxylic acid (VII-38) was obtained.

Example 252
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((1-hydroxypropan-2-yl) amino) -4- ( Preparation of trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-252) 1- (tert-butyl) -5- (in Step 4 of Example 9 Instead of (3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5 synthesized by the method described in Reference Example 69. -((5-((1-Hydroxypropan-2-yl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 38) and also performed Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII was synthesized by the method described in Reference Example 5. Compound (I-252) was obtained in the same manner as in Example 9 by using -4).

Reference Example 70
1- (tert-butyl) -5-((5- (tert-butylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-39) In the same manner as in Reference Example 43, using tert-butylamine instead of 3-hydroxyazetidine hydrochloride in step 1, 1- (tert-butyl) -5-((5- (tert -Butylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-39) was obtained.

Example 253
1- (tert-butyl) -5-((5- (tert-butylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine-2 -Yl) Methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-253) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (tert -Butylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-39) and also in step 4 of Example 9. , 4- (aminomethyl) benzene A method similar to that in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of rufonamide hydrochloride. To obtain the compound (I-253).

Reference Example 71
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid (VII-40 ) Manufacturing process 1
1- (tert-Butyl) -4-ethyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.25 mmol) was added to dimethyl sulfoxide (2.5 mL) and cesium carbonate (610 mg, 1.87 mmol). ) And 3-bromo-4- (difluoromethyl) -5-fluoropyridine (339 mg, 1.50 mmol) were added, and the mixture was stirred at 100 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25 → 40: 60) to give 5-((5-bromo-4- (difluoromethyl) pyridine). 3-yl) oxy) -1- (tert-butyl) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 187 mg, yield 34%) was obtained.

Process 2
5-((5-Bromo-4- (difluoromethyl) pyridin-3-yl) oxy) -1- (tert-butyl) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (187 mg, 0.419 mmol), 1,4-dioxane (4.0 mL), potassium vinyltrifluoroborate (281 mg, 2.10 mmol), cesium carbonate (683 mg, 2.10 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl). ) Phosphine) dichloropalladium (II) (14.8 mg, 0.0209 mmol) was added, and the mixture was stirred at 120 ° C. for 30 minutes under microwave irradiation. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -5-((4 -(Difluoromethyl) -5-vinylpyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 101 mg, yield 61%) was obtained.

Process 3
1- (tert-butyl) -5-((4- (difluoromethyl) -5-vinylpyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (101 mg, 0.257 mmol) in 1,4-dioxane (3.5 mL) and water (0.35 mL), 2,6-dimethylpyridine (60 μL, 0.52 mmol), sodium periodate (220 mg, 1.03 mmol) and 2.5% tetrasodium. An osmium oxide tert-butanol solution (0.13 mL, 0.013 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50), and 1- (tert-butyl) -5-((4 -(Difluoromethyl) -5-formylpyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 100 mg, yield 99%) was obtained.

Step 4
1- (tert-butyl) -5-((4- (difluoromethyl) -5-formylpyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (60.0 mg, 0.152 Sodium borohydride (8.6 mg, 0.23 mmol) was added to a tetrahydrofuran (1.5 mL) solution of (mmol) at 0 ° C, and the mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 50: 50), and 1- (tert-butyl) -5-((4 -(Difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 22.7 mg, 38% yield) was obtained.

Step 5
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester (22.7 Ethanol (0.50 mL), tetrahydrofuran (0.50 mL) and 4 mol / L sodium hydroxide aqueous solution (86 μL, 0.344 mmol) were added to mg, 0.0571 mmol), and the mixture was stirred at room temperature for 4 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-ethyl-1H-. Pyrazole-3-carboxylic acid (VII-40) was obtained (yield 21.1 mg, quantitative).

Example 254
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -4-ethyl-N-((5- (ethylsulfonyl) pyridine- Preparation of 2-yl) methyl) -1H-pyrazole-3-carboxamide (I-254) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5-dichloropyridine-2- Instead of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((4- (difluoromethyl)-was synthesized by the method described in Reference Example 71. 5- (hydroxymethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid (VII-40) was used, and 4- (aminomethyl) in step 4 of Example 9 was used. ) Benzenesulfo In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of the amide hydrochloride. To obtain the compound (I-254).

Reference Example 72
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxyethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid (VII In the same manner as in Reference Example 38, 1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy)-in Step 1 was produced. 4-Methyl-1H-pyrazole-3-carboxylic acid ethyl ester instead of 1- (tert-butyl) -5-((4- (difluoromethyl) -5-formylpyridin-3-yl) oxy) -4 By using ethyl-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester, 1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxyethyl) pyridin-3-yl) ) Oxy -4-ethyl--1H- pyrazole-3-carboxylic acid (VII-41).

Example 255
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxyethyl) pyridin-3-yl) oxy) -4-ethyl-N-((5- (ethylsulfonyl)) Preparation of pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-255) 1- (tert-butyl) -5-((3,5-dichloropyridine-in step 4 of Example 9 Instead of 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((4- (difluoromethyl) was synthesized by the method described in Reference Example 72. ) -5- (1-Hydroxyethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid (VII-41) and also in step 4 of Example 9 at 4 -(Aminomethyl) benze In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of the sulfone amide hydrochloride. The compound (I-255) was obtained by the method of.

Example 256
1- (tert-butyl) -4-ethyl-5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (methylsulfonyl) pyridine Preparation of 2--2-yl) methyl) -1H-pyrazole-3-carboxamide (I-256) 1- (tert-butyl) -5-((3,5-dichloropyridine-2) in Step 4 of Example 9 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -4-ethyl-5-((5- (Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-24) was used, and 4- (in Step 4 of Example 9 was used. Aminomethyl) benzenes A method similar to that in Example 9 by using (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Reference Example 1 instead of the rufonamide hydrochloride. To obtain the compound (I-256).

Example 257
1- (tert-butyl) -N-((4- (ethylsulfonyl) phenyl) (oxetan-3-yl) methyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridine- Preparation of 3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-257) 1- (tert-butyl) -5-((3,5-dichloro) in Step 4 of Example 9 Instead of pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (was synthesized by the method described in Reference Example 31. Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used, and in step 4 of Example 9, 4- (aminometh Example 1) By using (4- (ethylsulfonyl) phenyl) (oxetane-3-yl) methanamine (VIII-28) synthesized by the method described in Reference Example 63 instead of benzenesulfonamide hydrochloride. Compound (I-257) was obtained in the same manner as in 9.

Example 258
1- (tert-butyl) -5-((5- (tert-butylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (1- (4- (ethylsulfonyl) phenyl ) -2-Hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-258) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (Tert-Butylamino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-39) was used and the process of Example 9 4- (aminomethyl in 4 Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of benzenesulfonamide hydrochloride Compound (I-258) was obtained by a method similar to.

Reference Example 73
1- (tert-butyl) -4-methyl-5-((5- (pyrrolidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid Production of (VII-42) In the same manner as in Reference Example 43, 1- (tert-butyl) -4-methyl-5-((5 -(Pyrrolidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-42) was obtained.

Example 259
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5- (pyrrolidin-1-yl) -4- (trifluoro) Methyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-259) 1- (tert-butyl) -5-((3,5-dichloro) in Step 4 of Example 9 Pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced with 1- (tert-butyl) -4-methyl-5- (synthesized by the method described in Reference Example 73. (5- (Pyrrolidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-42) was used and the process of Example 9 4- (aminomethyl) beta in 4 In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of benzenesulfonamide hydrochloride. Compound (I-259) was obtained by the method described in 1.

Example 260
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((5- (pyrrolidin-1-yl) -4- ( Preparation of trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-260) 1- (tert-butyl) -5-((3,5 -Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -4-methyl-5 synthesized by the method described in Reference Example 73. -((5- (Pyrrolidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-42) was used, and Example 9 4- (amino) in step 4 of By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-260) was obtained in the same manner as in Example 9.

Reference Example 74
1- (tert-butyl) -5-((5-((2-hydroxyethyl) (methyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole Production of 3-carboxylic acid (VII-43) In the same manner as in Reference Example 43, 2- (methylamino) ethanol was used instead of 3-hydroxyazetidine hydrochloride in step 1, and 1- (tert-butyl) was used. ) -5-((5-((2-hydroxyethyl) (methyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-43) was obtained.

Example 261
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((2-hydroxyethyl) (methyl) amino) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-261) 1- (tert-butyl) -5-((in step 9 of Example 9 Instead of 3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-synthesized by the method described in Reference Example 74. ((5-((2-hydroxyethyl) (methyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-43) Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of (5), (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4 was synthesized by the method described in Reference Example 5. Compound (I-261) was obtained in the same manner as in Example 9 by using

Example 262
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-((2-hydroxyethyl) (methyl) amino) -4- Preparation of (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-262) 1- (tert-butyl) -5-in Step 4 of Example 9 Instead of ((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl)-synthesized by the method described in Reference Example 74. 5-((5-((2-hydroxyethyl) (methyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 43), and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol synthesized by the method described in Reference Example 2. Compound (I-262) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-2).

Reference Example 75
1- (tert-butyl) -5-((5- (3-hydroxypiperidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Production of Carboxylic Acid (VII-44) In the same manner as in Reference Example 43, using piperidin-3-ol hydrochloride instead of 3-hydroxyazetidine hydrochloride in step 1, 1- (tert-butyl)- 5-((5- (3-Hydroxypiperidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-44) Got

Example 263
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (3-hydroxypiperidin-1-yl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-263) 1- (tert-butyl) -5-((3, in step 4 of Example 9 Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 75). 5- (3-hydroxypiperidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-44) was used, , Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 is used. Thus, the compound (I-263) was obtained in the same manner as in Example 9.

Reference Example 76
1- (tert-butyl) -4-ethyl-5-((5- (2-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ( Preparation of VII-45) In the same manner as in Reference Example 52, 1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl) pyridin-3-yl) oxy) in step 1 was used. -4-Methyl-1H-pyrazole-3-carboxylic acid ethyl ester instead of 1- (tert-butyl) -5-((5-chloro-4- (trifluoromethyl) pyridin-3-yl) oxy) By using -4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester, 1- (tert-butyl) -4-ethyl-5-((5- (2-hydroxyethyl) -4- (trifluoro Methyl) pyridine-3- Le) oxy)-1H-pyrazole-3-carboxylic acid (VII-45).

Example 264
1- (tert-butyl) -4-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2-hydroxyethyl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-264) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -4-ethyl-5-((synthesized by the method described in Reference Example 76). 5- (2-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-45) was used and also in step 4 of Example 9. , 4- (aminomethyl) be In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of benzenesulfonamide hydrochloride. Compound (I-264) was obtained by the method described in 1.

Reference Example 77
1- (tert-butyl) -5-((5- (1-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-46) manufacturing process 1
1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (500 mg, To a solution of 1.25 mmol) in tetrahydrofuran (6.0 mL) was added vinylmagnesium bromide 14% tetrahydrofuran solution (1.9 mL, 1.9 mmol) at -50 ° C, and the mixture was stirred at the same temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 90: 10 → 50: 50), and 1- (tert-butyl) -5- ((5- (1-Hydroxyallyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 435 mg, yield 81% ) Got.
Process 2
Ethyl 1- (tert-butyl) -5-((5- (1-hydroxyallyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylate 10% Palladium on carbon (15.1 mg) was added to a solution of the ester (75.7 mg, 0.177 mmol) in methanol (1.5 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtering the reaction solution, the solvent was distilled off under reduced pressure to give 1- (tert-butyl) -5-((5- (1-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl). Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 71.8 mg, yield 94%) was obtained.
Process 3
Ethyl 1- (tert-butyl) -5-((5- (1-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylate Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.12 mL, 0.48 mmol) were added to the ester (35 mg, 0.082 mmol), and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1- (tert-butyl) -5-((5- (1-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl. -1H-pyrazole-3-carboxylic acid (VII-46) (yield 33 mg, quantitative) was obtained.

Example 265
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (1-hydroxypropyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-265) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5- (1 -Hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-46) and also in step 4 of Example 9. , 4- (aminomethyl ) By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of benzenesulfonamide hydrochloride, Compound (I-265) was obtained by the same method.

Reference Example 78
1- (tert-butyl) -4-ethyl-5-((5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3- Process 1 for producing carboxylic acid (VII-47)
1- (tert-Butyl) -4-ethyl-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.25 mmol) was added to dimethyl sulfoxide (2.5 mL), 3,5-difluoro-4-. (Trifluoromethyl) pyridine (343 mg, 1.87 mmol) and cesium carbonate (610 mg, 1.87 mmol) were added, and the mixture was stirred at 100 ° C for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -4-ethyl-5 was used. -((5-Fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 373 mg, yield 74%) was obtained.

Process 2
1- (tert-butyl) -4-ethyl-5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (53.0 mg, To a solution of 0.131 mmol) in 1-methyl-2-pyrrolidone (0.70 mL) was added N, N-diisopropylethylamine (0.11 mL, 0.64 mmol) and ethanolamine (24 μL, 0.40 mmol), and microwave irradiation was performed to The mixture was stirred at 0 ° C for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 50: 50), and 1- (tert-butyl) -4-ethyl-5 was used. -((5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 27.2 mg, 47% yield) ) Got.

Process 3
1- (tert-butyl) -4-ethyl-5-((5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3- Ethanol (1.0 mL, 17 mmol) and 4 mol / L sodium hydroxide aqueous solution (0.10 mL, 0.40 mmol) were added to carboxylic acid ethyl ester (27.2 mg, 0.0612 mmol), and the mixture was stirred at room temperature for 16 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 1- (tert-butyl) -4-ethyl-5-((5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy was obtained. ) -1H-Pyrazole-3-carboxylic acid (VII-47) (yield 22.9 mg, yield 90%) was obtained.

Example 266
1- (tert-butyl) -4-ethyl-N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((2-hydroxyethyl) amino) -4- ( Preparation of trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-266) 1- (tert-butyl) -5-((3,5 -Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -4-ethyl-5 synthesized by the method described in Reference Example 78. -((5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-47) was also used and 4 in Step 4 of Example 9 By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of-(aminomethyl) benzenesulfonamide hydrochloride, Compound (I-266) was obtained in the same manner as in Example 9.

Example 267
1- (tert-butyl) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-((2-hydroxyethyl) amino) -4 Preparation of-(trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-267) 1- (tert-butyl) -5-((3 , 5-Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -4-ethyl synthesized by the method described in Reference Example 78. -5-((5-((2-hydroxyethyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-47) was used, , Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 Compound (I-267) was obtained by using the same method as in Example 9.

Reference Example 79
Production Step 1 of 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (hydroxymethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-48)
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (500 mg, 2.21 mmol) was added to dimethyl sulfoxide (4.0 mL), 2-bromo-6-fluorobenzaldehyde. (673 mg, 3.32 mmol) and cesium carbonate (1.44 g, 4.42 mmol) were added, and the mixture was stirred at 150 ° C for 1 hr under microwave irradiation. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 5- (3-bromo-2-formylphenoxy)- 1- (tert-Butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 360 mg, yield 40%) was obtained.

Process 2
5- (3-Bromo-2-formylphenoxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (360 mg, 0.880 mmol) in dichloromethane (5.0 mL) solution. , Bis (2-methoxyethyl) aminosulfur trifluoride (0.57 mL, 2.7 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 95: 5 → 70: 30), and 5- (3-bromo-2- ( Difluoromethyl) phenoxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 298 mg, yield 79%) was obtained.

Process 3
5- (3-Bromo-2- (difluoromethyl) phenoxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (298 mg, 0.691 mmol), 1,4 -Dioxane (4.0 mL), potassium vinyltrifluoroborate (463 mg, 3.46 mmol), cesium carbonate (1.13 g, 3.47 mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II ) (24.5 mg, 0.0346 mmol) was added, and the mixture was stirred at 120 ° C. for 2 hours in a sealed tube. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -5- (2- (Difluoromethyl) -3-vinylphenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 206 mg, yield 79%) was obtained.

Step 4
1,4- (tert-Butyl) -5- (2- (difluoromethyl) -3-vinylphenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (206 mg, 0.544 mmol) To a solution of dioxane (5.0 mL) and water (0.50 mL), 2,6-dimethylpyridine (0.13 mL, 1.1 mmol), sodium periodate (466 mg, 2.18 mmol) and 2.5% osmium tetroxide tert-butanol solution ( 0.28 mL, 0.028 mmol) was sequentially added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50), and 1- (tert-butyl) -5- (2- (Difluoromethyl) -3-formylphenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 141 mg, yield 68%) was obtained.

Step 5
1- (tert-Butyl) -5- (2- (difluoromethyl) -3-formylphenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (80.0 mg, 0.210 mmol) in tetrahydrofuran (2.0 mL) ) Sodium borohydride (11.9 mg, 0.315 mmol) was added to the solution at 0 ° C, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous solution of ammonium chloride and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (hydroxymethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylate. An ester (yield 80.4 mg, quantitative) was obtained.

Process 6
1- (tert-butyl) -5- (2- (difluoromethyl) -3- (hydroxymethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (80.4 mg, 0.210 mmol), Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.32 mL, 1.3 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (hydroxymethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 48) (yield 74.2 mg, quantitative).

Example 268
1- (tert-butyl) -5- (2- (difluoromethyl) -3- (hydroxymethyl) phenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl- Preparation of 1H-pyrazole-3-carboxamide (I-268) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4- in Step 4 of Example 9 Instead of methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (hydroxymethyl) phenoxy) synthesized by the method described in Reference Example 79. -4-Methyl-1H-pyrazole-3-carboxylic acid (VII-48) was used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, referential example 5 was used. The compound (I-268) was obtained in the same manner as in Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the described method. .

Example 269
1- (tert-butyl) -5- (2- (difluoromethyl) -3- (hydroxymethyl) phenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- Preparation of Methyl-1H-pyrazole-3-carboxamide (I-269) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy)-in step 4 of Example 9 Instead of 4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (hydroxymethyl) synthesized by the method described in Reference Example 79 was used. Phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-48) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, Using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 in the same manner as in Example 9, -269) was obtained.

Reference Example 80
Preparation of 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (1-hydroxyethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-49) Reference example 1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-in Step 1 by a method similar to that of 38. Instead of 3-carboxylic acid ethyl ester, 1- (tert-butyl) -5- (2- (difluoromethyl) -3-formylphenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester is used. Thus, 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (1-hydroxyethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII 49) was obtained.

Example 270
1- (tert-butyl) -5- (2- (difluoromethyl) -3- (1-hydroxyethyl) phenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4- Preparation of Methyl-1H-pyrazole-3-carboxamide (I-270) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy)-in step 4 of Example 9 Instead of 4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (1-hydroxy) synthesized by the method described in Reference Example 80 was used. Ethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-49) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, three Using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Consideration 5 in the same manner as in Example 9, the compound (I-270 ) Got.

Example 271
1- (tert-butyl) -5- (2- (difluoromethyl) -3- (1-hydroxyethyl) phenoxy) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl)- Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-271) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy in step 4 of Example 9 ) -4-Methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5- (2- (difluoromethyl) -3- (1) synthesized by the method described in Reference Example 80. -Hydroxyethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-49) and the substitution of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 Instead, by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2, the compound was prepared in the same manner as in Example 9. (I-271) was obtained.

Reference Example 81
Process 1 for producing 1- (tert-butyl) -5-((6-ethoxy-5-formylpyrimidin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-50)
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg, 0.442 mmol) was added to dimethyl sulfoxide (0.88 mL) and 4,6-dichloropyrimidine-5. -Carbaldehyde (93.9 mg, 0.531 mmol) and cesium carbonate (288 mg, 0.884 mmol) were added, and the mixture was stirred at 120 ° C for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 70: 30) and 1- (tert-butyl) -5-((6- Chloro-5-formylpyrimidin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 76.8 mg, yield 47%) was obtained.

Process 2
1- (tert-Butyl) -5-((6-chloro-5-formylpyrimidin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (72.0 mg, 0.196 mmol) Bis (2-methoxyethyl) aminosulfur trifluoride (126 μL, 0.587 mmol) was added to a dichloromethane (0.65 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 10: 90), and 1- (tert-butyl) -5-((6-chloro -5- (Difluoromethyl) pyrimidin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 59.8 mg, yield 78%) was obtained.

Process 3
1- (tert-butyl) -5-((6-chloro-5- (difluoromethyl) pyrimidin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (55.0 mg, 0.141 (0.82 mL) and 4 mol / L sodium hydroxide aqueous solution (212 μL, 0.848 mmol) were added to (mmol), and the mixture was stirred at room temperature for 3 hours. 2 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and 1- (tert-butyl) -5-((6-ethoxy-5-formylpyrimidin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 50) (56.5 mg, quantitative).

Example 272
1- (tert-butyl) -5-((5- (difluoromethyl) -6-ethoxypyrimidin-4-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl)- Process 1 for producing 4-methyl-1H-pyrazole-3-carboxamide (I-272)
In place of 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid in step 4 of Example 9, 1- (tert-butyl) -5-((6-ethoxy-5-formylpyrimidin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid synthesized by the method described in Reference Example 81 (VII-50) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl)). By using pyridin-2-yl) methanamine hydrochloride (VIII-4) in the same manner as in Example 9, 1- (tert-butyl) -5-((6-ethoxy-5-formylpyrimidine-4). -Yl) oxy)- N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide was obtained.

Process 2
1- (tert-butyl) -5-((6-ethoxy-5-formylpyrimidin-4-yl) oxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl To a solution of -1H-pyrazole-3-carboxamide (24.0 mg, 0.0452 mmol) in dichloromethane (0.45 mL) was added bis (2-methoxyethyl) aminosulfur trifluoride (29 µL, 0.14 mmol) at 0 ° C, and the mixture was stirred at room temperature. Stir for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30 → 10: 90) to give compound (I-272) (yield 20.1 mg, 80% yield). ) Got.

Example 273
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((6- (trifluoromethoxy) benzo [d] thiazole- Preparation of 2-yl) oxy) -1H-pyrazole-3-carboxamide (I-273) In place of 3,5-dichloro-2-fluoropyridine in Step 2 of Example 9, 2-chloro-6- ( Trifluoromethoxy) -1,3-benzothiazole was used, and 2 was synthesized by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. The compound (I-273) was obtained in the same manner as in Example 9 by using -amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Reference Example 82
1- (tert-butyl) -5-((5-((1- (hydroxymethyl) cyclopropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H- Production of pyrazole-3-carboxylic acid (VII-51) In the same manner as in Reference Example 43, 1- (tert. -Butyl) -5-((5-((1- (hydroxymethyl) cyclopropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3- A carboxylic acid (VII-51) was obtained.

Example 274
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((1- (hydroxymethyl) cyclopropyl) amino) -4- ( Preparation of trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-274) 1- (tert-butyl) -5- (in Step 4 of Example 9 Instead of (3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5 synthesized by the method described in Reference Example 82. -((5-((1- (Hydroxymethyl) cyclopropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 51) Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 5. Compound (I-274) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-4).

Example 275
1- (tert-butyl) -4-ethyl-N- (2-hydroxy-1- (4- (methylsulfonyl) phenyl) ethyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-275) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced with 1- (tert-butyl) -4-ethyl-5-((synthesized by the method described in Reference Example 48). 5- (Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-24) was used and in step 4 of Example 9 at 4 -(Aminomethyl) Example 9 by using 2-amino-2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride (VIII-10) synthesized by the method described in Reference Example 13 instead of benzenesulfonamide hydrochloride Compound (I-275) was obtained by a method similar to.

Example 276
1- (tert-butyl) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (1-hydroxyethyl) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-276) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-ethyl-5-synthesized by the method described in Reference Example 49. ((5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-25) was used and the process of Example 9 4- (amino) in 4 By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-276) was obtained in the same manner as in Example 9.

Example 277
1- (tert-butyl) -4-ethyl-N- (2-hydroxy-1- (4- (methylsulfonyl) phenyl) ethyl) -5-((5- (1-hydroxyethyl) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-277) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -4-ethyl-5-synthesized by the method described in Reference Example 49. ((5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-25) was used and the process of Example 9 4- (amino) in 4 By using 2-amino-2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride (VIII-10) synthesized by the method described in Reference Example 13 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-277) was obtained in the same manner as in Example 9.

Reference Example 83
1- (tert-butyl) -5-((5- (3- (hydroxymethyl) azetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H- Production of Pyrazole-3-carboxylic acid (VII-52) In the same manner as in Reference Example 43, 1- (tert. -Butyl) -5-((5- (3- (hydroxymethyl) azetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3- A carboxylic acid (VII-52) was obtained.

Example 278
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (3- (hydroxymethyl) azetidin-1-yl) -4- ( Preparation of trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-278) 1- (tert-butyl) -5- (in Step 4 of Example 9 Instead of (3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5 synthesized by the method described in Reference Example 83. -((5- (3- (Hydroxymethyl) azetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 52) and also Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride ((5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (synthesized by the method described in Reference Example 5) Compound (I-278) was obtained in the same manner as in Example 9 by using VIII-4).

Example 279
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (3- (hydroxymethyl) azetidin-1-yl) -4 Preparation of-(trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-279) 1- (tert-butyl) -5 in Step 4 of Example 9 1- (tert-butyl) synthesized by the method described in Reference Example 83 instead of-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid -5-((5- (3- (Hydroxymethyl) azetidin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-52) Further, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl)) synthesized by the method described in Reference Example 2. Compound (I-279) was obtained in the same manner as in Example 9 by using phenyl) ethanol hydrochloride (VIII-2).

Example 280
1- (tert-butyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N- (4- (methylsulfonyl) benzyl) Preparation of 1H-pyrazole-3-carboxamide (I-280) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4 in step 4 of Example 9 1- (tert-butyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) synthesized by the method described in Reference Example 31 instead of -methyl-1H-pyrazole-3-carboxylic acid ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used, and 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 was used. Salt Instead of using (4- (methylsulfonyl) phenyl) methanamine hydrochloride, compound (I-280) was obtained in the same manner as in Example 9.

Reference Example 84
1- (tert-butyl) -5-((5-((1R, 2R) -2-hydroxycyclopentyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl- Production of 1H-pyrazole-3-carboxylic acid (VII-53) In the same manner as in Reference Example 43, instead of 3-hydroxyazetidine hydrochloride in step 1, (1R, 2R) -2-aminocyclopentanol hydrochloride was used. 1- (tert-butyl) -5-((5-(((1R, 2R) -2-hydroxycyclopentyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy)-using the salt 4-Methyl-1H-pyrazole-3-carboxylic acid (VII-53) was obtained.

Example 281
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((1R, 2R) -2-hydroxycyclopentyl) amino) -4 Preparation of-(trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-281) 1- (tert-butyl) -5 in Step 4 of Example 9 1- (tert-butyl) synthesized by the method described in Reference Example 84 instead of-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid -5-((5-(((1R, 2R) -2-hydroxycyclopentyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic Acid (VII- 53) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- (ethylsulfonyl) pyridine-2. -Yl) Methanamine hydrochloride (VIII-4) was used to obtain compound (I-281) in the same manner as in Example 9.

Example 282
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-(((1R, 2R) -2-hydroxycyclopentyl) amino) Preparation of 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-282) 1- (tert-butyl) in step 4 of Example 9 Instead of -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert- was synthesized by the method described in Reference Example 84. Butyl) -5-((5-((1R, 2R) -2-hydroxycyclopentyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Carbo Acid (VII-53) was used, and 2-amino-2 synthesized by the method described in Reference Example 2 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9. By using-(4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2), compound (I-282) was obtained in the same manner as in Example 9.

Reference Example 85
1- (tert-butyl) -5-((5- (2-hydroxypropan-2-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Process 1 for producing carboxylic acid (VII-54)
Ethyl 1- (tert-butyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylate Dichloromethane (1.5 mL) and Dess-Martin periodinane (167 mg, 0.394 mmol) were added to the ester (81.6 mg, 0.196 mmol), and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 5-((5-acetyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -1- (tert-butyl. ) -4-Methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 67.4 mg, yield 83%) was obtained.

Process 2
5-((5-acetyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (67.4 mg, To a tetrahydrofuran (4 mL) solution of 0.163 mmol) was added 1.13 mol / L methyllithium diethyl ether solution (0.15 mL, 0.17 mmol) at -78 ° C, and then the mixture was stirred at -60 ° C for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give 1- (tert-butyl) -5-((5- (2-hydroxypropan-2-yl) -4- (trifluoro). Methyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 41.5 mg, 59% yield) was obtained.

Process 3
1- (tert-butyl) -5-((5- (2-hydroxypropan-2-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Methanol (1 mL) and 1 mol / L sodium hydroxide aqueous solution (0.48 mL, 0.48 mmol) were added to carboxylic acid ethyl ester (41.5 mg, 0.0966 mmol), and it stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate. 1 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (2-hydroxypropan-2-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) was obtained by distilling off the solvent under reduced pressure. -4-Methyl-1H-pyrazole-3-carboxylic acid (VII-54) (yield 32.2 mg, 83% yield) was obtained.

Example 283
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2-hydroxypropan-2-yl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-283) In step 4 of Example 9, 1- (tert-butyl) -5-((3, Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 85). 5- (2-hydroxypropan-2-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-54) was used, , In step 4 of Example 9 , (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used in place of 4- (aminomethyl) benzenesulfonamide hydrochloride. Thus, the compound (I-283) was obtained in the same manner as in Example 9.

Reference Example 86
1- (tert-butyl) -5-((5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Production of carboxylic acid (VII-55) In the same manner as in Reference Example 43, using 3-aminocyclobutanol hydrochloride in place of 3-hydroxyazetidine hydrochloride in Step 1, 1- (tert-butyl)- 5-((5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-55) Got

Example 284
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-284) In the step 4 of Example 9, 1- (tert-butyl) -5-((3, Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 86). 5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-55) was used, Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, the (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 is used. Thus, the compound (I-284) was obtained in the same manner as in Example 9.

Example 285
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-((3-hydroxycyclobutyl) amino) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-285) In step 4 of Example 9, 1- (tert-butyl) -5-(( Instead of 3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-synthesized by the method described in Reference Example 86. Using ((5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-55) , Example In place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of 9, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (synthesized by the method described in Reference Example 2 Compound (I-285) was obtained in the same manner as in Example 9 by using VIII-2).

Example 286
1- (tert-butyl) -4-ethyl-5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (4- (methylsulfonyl) benzyl) Preparation of 1H-pyrazole-3-carboxamide (I-286) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4 in step 4 of Example 9 1- (tert-butyl) -4-ethyl-5-((5- (hydroxymethyl) -4-) synthesized by the method described in Reference Example 48 instead of -methyl-1H-pyrazole-3-carboxylic acid. (Trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-24) was used, and 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 was used. Salt Instead of using (4- (methylsulfonyl) phenyl) methanamine hydrochloride, Compound (I-286) was obtained in the same manner as in Example 9.

Reference Example 87
1- (tert-butyl) -5-((5- (4- (2-hydroxyethyl) piperazin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl- Production of 1H-pyrazole-3-carboxylic acid (VII-56) In the same manner as in Reference Example 43, 2-piperazin-1-ylethanol was used in place of 3-hydroxyazetidine hydrochloride in Step 1- (Tert-Butyl) -5-((5- (4- (2-hydroxyethyl) piperazin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H- Pyrazole-3-carboxylic acid (VII-56) was obtained.

Example 287
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (4- (2-hydroxyethyl) piperazin-1-yl) -4 Preparation of-(trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-287) 1- (tert-butyl) -5 in Step 4 of Example 9 1- (tert-butyl) synthesized by the method described in Reference Example 87 instead of-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid -5-((5- (4- (2-hydroxyethyl) piperazin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic With acid (VII-56) Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 5. Compound (I-287) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-4).

Example 288
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (4- (2-hydroxyethyl) piperazin-1-yl) Preparation of 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-288) 1- (tert-butyl) in Step 4 of Example 9 Instead of 5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert- was synthesized by the method described in Reference Example 87. Butyl) -5-((5- (4- (2-hydroxyethyl) piperazin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Carboxylic acid (VII-5 6) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2- (4- (was prepared by the method described in Reference Example 2). Compound (I-288) was obtained in the same manner as in Example 9 by using ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Reference Example 88
1- (tert-butyl) -4-methyl-5-((5- (3-oxopiperazin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3 -Preparation of carboxylic acid (VII-57) In the same manner as in Reference Example 43, using piperazin-2-one in place of 3-hydroxyazetidine hydrochloride in Step 1, 1- (tert-butyl) -4- Methyl-5-((5- (3-oxopiperazin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-57) was obtained. It was

Example 289
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5- (3-oxopiperazin-1-yl) -4- Preparation of (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-289) In step 4 of Example 9, 1- (tert-butyl) -5-((3, 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -4-methyl-synthesized by the method described in Reference Example 88. 5-((5- (3-oxopiperazin-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-57) was used, and 4 in Step 4 of Example 9 Examples were obtained by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of aminomethyl) benzenesulfonamide hydrochloride. Compound (I-289) was obtained in the same manner as in No. 9.

Example 290
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (2-hydroxypropan-2-yl) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-290) 1- (tert-butyl) -5-((in Step 4 of Example 9 Instead of 3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-synthesized by the method described in Reference Example 85. ((5- (2-Hydroxypropan-2-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-54) was used. Also, the process of Example 9 4 in place of 4- (aminomethyl) benzenesulfonamide hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2 Compound (I-290) was obtained in the same manner as in Example 9 by using

Example 291
1- (tert-butyl) -N- (2-hydroxy-1- (4- (methylsulfonyl) phenyl) ethyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine Preparation of -3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-291) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-15) was used and the process of Example 9 4- (amino) in 4 By using 2-amino-2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride (VIII-10) synthesized by the method described in Reference Example 13 instead of methyl) benzenesulfonamide hydrochloride. Compound (I-291) was obtained in the same manner as in Example 9.

Reference Example 89
1- (tert-butyl) -5-((5-((3-hydroxypropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3- Production of Carboxylic Acid (VII-58) 1- (tert-Butyl) -5 was used in the same manner as in Reference Example 43, except that 3-amino-1-propanol was used instead of 3-hydroxyazetidine hydrochloride in Step 1. -((5-((3-Hydroxypropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-58) was obtained. It was

Example 292
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((3-hydroxypropyl) amino) -4- (trifluoromethyl) Preparation of pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-292) 1- (tert-butyl) -5-((3,5 -Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5 -((3-Hydroxypropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-58) was also used and carried out. In Step 4 of Example 9 , (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used in place of 4- (aminomethyl) benzenesulfonamide hydrochloride. Thus, the compound (I-292) was obtained in the same manner as in Example 9.

Example 293
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-((3-hydroxypropyl) amino) -4- (trifluoro Preparation of Methyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-293) 1- (tert-butyl) -5-((3 , 5-Dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was synthesized by the method described in Reference Example 89 1- (tert-butyl) -5- (. (5-((3-hydroxypropyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-58) was used, Process of Example 9 4 in place of 4- (aminomethyl) benzenesulfonamide hydrochloride, 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 Compound (I-293) was obtained in the same manner as in Example 9 by using

Reference Example 90
1- (tert-butyl) -5-((5- (3-hydroxy-1-propyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H- Process 1 for producing pyrazole-3-carboxylic acid (VII-59)
1- (tert-butyl) -5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, To a solution of 0.771 mmol) in 1-methyl-2-pyrrolidone (3.5 mL), N, N-diisopropylethylamine (1.3 mL, 7.5 mmol) and ammonium chloride (206 mg, 3.85 mmol) were added, and microwave irradiation was performed to The mixture was stirred at 0 ° C for 1 hour. Then, the mixture was stirred at 200 ° C. for 1 hour under microwave irradiation. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85:15 → 60:40), and 5-((5-amino-4- (trifluoro) Methyl) pyridin-3-yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 238 mg, yield 80%) was obtained.

Process 2
5-((5-amino-4- (trifluoromethyl) pyridin-3-yl) oxy) -1- (tert-butyl) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (238 mg, To a solution of 0.616 mmol) in tetrahydrofuran (5.0 mL), amyl nitrite (0.25 mL, 1.9 mmol), diiodomethane (0.50 mL, 6.2 mmol) and copper iodide (58.7 mg, 0.308 mmol) were sequentially added, and the mixture was heated at 60 ° C for 16 ° C. Stir for hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 50: 50), and 1- (tert-butyl) -5-((5 -Iodo-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 58.0 mg, yield 19%) was obtained.

Process 3
1- (tert-butyl) -5-((5-iodo-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (58.0 mg, Propargyl alcohol (41 mL, 0.69 mmol), triethylamine (0.10 mL, 0.72 mmol) and copper iodide (4.4 mg, 0.023 mmol) were sequentially added to a solution of 0.117 mmol) in acetonitrile (0.5 mL), and the mixture was heated at 80 ° C for 6 hours. It was stirred. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 50:50), and 1- (tert-butyl) -5-((5 -(3-Hydroxy-1-propyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 36.1 mg, Yield 73%) was obtained.

Step 4
1- (tert-butyl) -5-((5- (3-hydroxy-1-propyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H- To a solution of pyrazole-3-carboxylic acid ethyl ester (36.1 mg, 0.0849 mmol) in ethanol (1.0 mL), 4 mol / L sodium hydroxide aqueous solution (0.13 mL, 0.52 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (3-hydroxy-1-propyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl was obtained by distilling the solvent off under reduced pressure. ) Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-59) (yield 33.7 mg, quantitative) was obtained.

Example 294
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (3-hydroxypropyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-294) production step 1
Instead of 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid in step 4 of Example 9, 1- (tert-butyl) -5-((5- (3-hydroxy-1-propyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) synthesized by the method described in Reference Example 90 ) Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-59) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, reference By using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Example 5, 1- (tert-butyl) was obtained in the same manner as in Example 9. ) -N-((5- (ethyl Sulfonyl) pyridin-2-yl) methyl) -5-((5- (3-hydroxy-1-propyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl -1H-pyrazole-3-carboxamide was obtained.

Process 2
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (3-hydroxy-1-propyn-1-yl) -4- ( Trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (5.9 mg, 0.010 mmol) was added with ethanol (0.50 mL) and palladium carbon (1.0 mg), and hydrogen atmosphere was added. The mixture was stirred under room temperature for 16 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was directly purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 60: 40 → 0: 100) to obtain the compound (I-294).

Example 295
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (3-hydroxypropyl) -4- (trifluoromethyl) pyridine Preparation of (3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-295) In the same manner as in Example 294, (5- (ethylsulfonyl) pyridin-2-yl of step 1 was used. ) A compound (2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 was used in place of the methanamine hydrochloride (VIII-4). I-295) was obtained.

Reference example 91
1- (tert-butyl) -4-methyl-5-((5- (2,2,2-trifluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy)- Process 1 for producing 1H-pyrazole-3-carboxylic acid (VII-60)
1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg, 0.250 mmol) in tetrahydrofuran (2.0 mL) solution, trimethyl (trifluoromethyl) silane (0.11 mL, 0.74 mmol) and 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (0.73 mL, 0.73 mmol) under ice cooling. The mixture was added sequentially and stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 60: 40), and 1- (tert-butyl) -4-methyl-5 was used. -((5- (2,2,2-Trifluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 87.4 mg, yield 74%) was obtained.

Process 2
1- (tert-butyl) -4-methyl-5-((5- (2,2,2-trifluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy)- Ethanol (2.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.28 mL, 1.1 mmol) were added to 1H-pyrazole-3-carboxylic acid ethyl ester (87.4 mg, 0.186 mmol), and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -4-methyl-5-((5- (2,2,2-trifluoro-1-hydroxyethyl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-60) (yield 82.2 mg, quantitative) was obtained.

Example 296
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5- (2,2,2-trifluoro-1-hydroxy Preparation of ethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-296) 1- (tert-butyl) -5 in Step 4 of Example 9 1- (tert-butyl) synthesized by the method described in Reference Example 91 instead of-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid -4-Methyl-5-((5- (2,2,2-trifluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic Acid (VII-60) Further, in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 5 was used. Compound (I-296) was obtained in the same manner as in Example 9 by using salt (VIII-4).

Example 297
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((5- (2,2,2-trifluoro-1 -Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-297) 1- (tert-butyl) in step 4 of example 9 Instead of -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert- was synthesized by the method described in Reference Example 91. Butyl) -4-methyl-5-((5- (2,2,2-trifluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3 -Carboxylic acid (VII-60) Was used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl) synthesized by the method described in Reference Example 2 was used. ) Phenyl) ethanol hydrochloride (VIII-2) was used to obtain compound (I-297) in the same manner as in Example 9.

Reference example 92
1- (tert-butyl) -5-((2- (1-hydroxyethyl) -3- (trifluoromethyl) pyridin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-61) manufacturing process 1
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (200 mg, 0.884 mmol) was added to dimethyl sulfoxide (1.8 mL) and cesium carbonate (432 mg, 1.33 mmol). ) And 2,4-dichloro-3- (trifluoromethyl) pyridine (286 mg, 1.32 mmol) were added, and the mixture was stirred at 100 ° C for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 80: 20), and 1- (tert-butyl) -5-((2-chloro -3- (Trifluoromethyl) pyridin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (amount 316 mg, yield 88%) was obtained.

Process 2
1- (tert-butyl) -5-((2-chloro-3- (trifluoromethyl) pyridin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (316 mg, 0.779 mmol), 1,4-dioxane (11.6 mL), potassium vinyltrifluoroborate (522 mg, 3.89 mmol), cesium carbonate (1.27 g, 3.90 mmol) and bis (di-tert-butyl (4-dimethylamino). Phenyl) phosphine) dichloropalladium (II) (27.6 mg, 0.0390 mmol) was added, and the mixture was stirred at 120 ° C for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and 1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) -2-vinylpyridine-4- Yield) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 421 mg) was obtained as a crude product.

Process 3
1- (tert-butyl) -4-methyl-5-((3- (trifluoromethyl) -2-vinylpyridin-4-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (201 mg, To a solution of 0.507 mmol) in 1,4-dioxane (5.0 mL) and water (0.50 mL), 2,6-dimethylpyridine (0.117 mL, 1.01 mmol), sodium periodate (434 mg, 2.03 mmol) and 2.5% An osmium tetroxide tert-butanol solution (0.26 mL, 0.026 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 1- (tert-butyl) -5-((2-formyl-3- (trifluoromethyl) pyridin-4-yl) oxy). -4-Methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 149 mg, 73%) was obtained.

Step 4
1- (tert-butyl) -5-((2-formyl-3- (trifluoromethyl) pyridin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (41.3 mg, 0.103 mmol) in tetrahydrofuran (1.0 mL) was added with 0.97 mol / L methylmagnesium bromide tetrahydrofuran solution (0.13 mL, 0.13 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 1- (tert-butyl) -5-((2- (1-hydroxyethyl) -3- (trifluoromethyl) pyridine-4. -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 36.6 mg, yield 85%) was obtained.

Step 5
Ethyl 1- (tert-butyl) -5-((2- (1-hydroxyethyl) -3- (trifluoromethyl) pyridin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylate Ethanol (0.9 mL) and 4 mol / L sodium hydroxide aqueous solution (0.235 mL, 0.940 mmol) were added to the ester (36.6 mg, 0.0881 mmol), and the mixture was stirred at room temperature for 12 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure,
1- (tert-butyl) -5-((2- (1-hydroxyethyl) -3- (trifluoromethyl) pyridin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-61) (yield 32.2 mg, yield 94%).

Example 298
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((2- (1-hydroxyethyl) -3- (trifluoromethyl) pyridine-4 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-298) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((2- (1 -Hydroxyethyl) -3- (trifluoromethyl) pyridin-4-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-61) and also in step 4 of Example 9. , 4- (aminomethyl) be In the same manner as in Example 9 except that (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 was used instead of benzenesulfonamide hydrochloride. The compound (I-298) was obtained by the method of.

Reference Example 93
Of 1- (tert-butyl) -5-((5-hydroxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-62) Production 1- (tert-butyl) -5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (149 mg , 0.383 mmol), tetrahydrofuran (3.8 mL) and 4 mol / L sodium hydroxide aqueous solution (574 μL, 2.30 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -5-((5-hydroxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole- 3-Carboxylic acid (VII-62) (yield 138 mg, quantitative) was obtained.

Example 299
1- (tert-butyl) -5-((5- (3-cyanopropoxy) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine-2 -Yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-299) production step 1
In place of 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid in step 4 of Example 9, 1- (tert-butyl) -5-((5-hydroxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole- synthesized by the method described in Reference Example 93 Using 3-carboxylic acid (VII-62), and synthesizing by the method described in Reference Example 5 instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9 (5- By using (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) in the same manner as in Example 9, 1- (tert-butyl) -N-((5- (ethylsulfonyl)). Pyridin-2-yl) Methyl) -5-((5-hydroxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide was obtained.

Process 2
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-hydroxy-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-Methyl-1H-pyrazole-3-carboxamide (16.0 mg, 0.0295 mmol), N, N-dimethylformamide (0.3 mL), 4-bromobutanenitrile (4 μL, 0.0403 mmol), potassium carbonate (8.2 mg) , 0.059 mmol) and potassium iodide (2.5 mg, 0.015 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 70: 30 → 15: 85) to give compound (I-299) (yield 12.6 mg , Yield 70%) was obtained.

Example 300
1- (tert-butyl) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-300) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced with 1- (tert-butyl) -4-ethyl-5-((synthesized by the method described in Reference Example 48). 5- (Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-24) was used and in step 4 of Example 9 at 4 -(Aminomethyl) Example 9 by using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of benzenesulfonamide hydrochloride Compound (I-300) was obtained in the same manner as in.

Example 301
1- (tert-butyl) -4-ethyl-5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (methylsulfonyl ) Pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-301) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -4-ethyl-5-((synthesized by the method described in Reference Example 49. 5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-25) was used and also in step 4 of Example 9. , 4- (aminomethyl) be In the same manner as in Example 9 except that (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Reference Example 1 was used instead of benzenesulfonamide hydrochloride. Compound (I-301) was obtained by the method of.

Reference Example 94
1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic Acid (VII-63) production process 1
1- (tert-butyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (97.4 mg, 0.245 mmol), 1,4-dioxane (2.0 mL), water (0.2 mL), 4-methylmorpholine-N-oxide (86.1 mg, 0.735 mmol) and 2.5% osmium tetroxide tert-butanol solution (0.12 mL, 0.012 mmol) was sequentially added, and the mixture was stirred at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 40: 60 → 0: 100), and 1- (tert-butyl) -5-((5 -(1,2-Dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 97.0 mg, 92% yield) Got

Process 2
1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (0.34 mL, 1.4 mmol) were added to acid ethyl ester (97.0 mg, 0.225 mmol), and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4. -Methyl-1H-pyrazole-3-carboxylic acid (VII-63) (yield 87.5 mg, yield 97%) was obtained.

Example 302
1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine Preparation of 2-yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-302) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (1,2-Dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-63) was used, and Example 9 4- (ami) in step 4 of Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of (nomethyl) benzenesulfonamide hydrochloride. Compound (I-302) was obtained in the same manner as in.

Reference Example 95
1- (tert-butyl) -5-((5- (3-hydroxy-3-methyl-1-butyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4- Production of Methyl-1H-pyrazole-3-carboxylic acid (VII-64) By using 2-methyl-3-butyn-2-ol instead of propargyl alcohol in Step 3 of Reference Example 90, Reference Example 90 And 1- (tert-butyl) -5-((5- (3-hydroxy-3-methyl-1-butyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) ) Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-64) was obtained.

Example 303
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (3-hydroxy-3-methyl-1-butyn-1-yl) Preparation of 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-303) 1- (tert-butyl) in Step 4 of Example 9 Instead of -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert- was synthesized by the method described in Reference Example 95. Butyl) -5-((5- (3-hydroxy-3-methyl-1-butyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole Using 3-carboxylic acid (VII-64) Also, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine synthesized by the method described in Reference Example 5. Compound (I-303) was obtained in the same manner as in Example 9 by using hydrochloride (VIII-4).

Example 304
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (3-hydroxy-3-methyl-1-butyne-1- Preparation of (yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-304) 1- (tert- in Step 4 of Example 9 Butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was synthesized by the method described in Reference Example 95 1- (. tert-Butyl) -5-((5- (3-hydroxy-3-methyl-1-butyn-1-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H -Pyrazole-3-carboxylic acid (VII-6 4) was used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (4- (was prepared by the method described in Reference Example 2). Compound (I-304) was obtained in the same manner as in Example 9 by using ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Reference Example 96
1- (tert-butyl) -5-((5- (3-hydroxyoxetan-3-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Process 1 for producing carboxylic acid (VII-65)
1- (tert-butyl) -5-((5-iodo-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (30.0 mg, To a suspension of 0.0603 mmol) in tetrahydrofuran (0.50 mL, 6.2 mmol), 1.3 mol / L isopropyl magnesium chloride lithium chloride complex tetrahydrofuran solution (0.10 mL, 0.13 mmol) was added at -60 ° C and stirred for 15 minutes. Then, 3-oxetanone (10 μL, 0.16 mmol) was added at −60 ° C., the temperature was raised to −40 ° C., and the mixture was stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 50: 50), and 1- (tert-butyl) -5-((5 -(3-Hydroxyoxetan-3-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (Yield 2.1 mg, Yield 8 %).

Process 2
1- (tert-butyl) -5-((5- (3-hydroxyoxetan-3-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -To carboxylic acid ethyl ester (2.1 mg, 0.0047 mmol), ethanol (0.5 mL) and 4 mol / L sodium hydroxide aqueous solution (0.030 mL, 0.12 mmol) were added, and the mixture was stirred at room temperature for 5 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. 1- (tert-butyl) -5-((5- (3-hydroxyoxetan-3-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) was obtained by distilling off the solvent under reduced pressure. -4-Methyl-1H-pyrazole-3-carboxylic acid (VII-65) (yield 2.0 mg, quantitative) was obtained.

Example 305
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (3-hydroxyoxetan-3-yl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-305) 1- (tert-butyl) -5-((3, Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 96). 5- (3-hydroxyoxetan-3-yl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-65) was used, , Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 is used. Thus, the compound (I-305) was obtained in the same manner as in Example 9.

Reference Example 97
Production of (4- (ethylsulfonyl) phenyl) methanamine hydrochloride (VIII-29) Reference Example 5 by using 4-fluorobenzonitrile instead of 5-bromopicolinonitrile in Step 1 of Reference Example 5. (4- (Ethylsulfonyl) phenyl) methanamine hydrochloride (VIII-29) was obtained in the same manner as in.

Example 306
1- (tert-butyl) -N- (4- (ethylsulfonyl) benzyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl Preparation of -1H-pyrazole-3-carboxamide (I-306) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4 in step 4 of Example 9 1- (tert-butyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) synthesized by the method described in Reference Example 31 instead of -methyl-1H-pyrazole-3-carboxylic acid ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used, and 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9 was used. Salt Instead of (4- (ethylsulfonyl) phenyl) methanamine hydrochloride (VIII-29) synthesized by the method described in Reference Example 97, the compound (I-306) was prepared in the same manner as in Example 9. Got

Reference Example 98
1- (tert-butyl) -4-methyl-5-((5-((3-methylenecyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3 -Preparation of carboxylic acid (VII-66) 1- (tert-butyl) in the same manner as in Reference Example 43, using 3-methylenecyclobutanamine hydrochloride in place of 3-hydroxyazetidine hydrochloride in Step 1. -4-Methyl-5-((5-((3-methylenecyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-66 ) Got.

Example 307
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5-((3-methylenecyclobutyl) amino) -4- Preparation of (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-307) In step 4 of Example 9, 1- (tert-butyl) -5-((3, 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -4-methyl-synthesized by the method described in Reference Example 98. 5-((5-((3-methylenecyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-66) was used, and , Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 is used. Thus, the compound (I-307) was obtained in the same manner as in Example 9.

Example 308
1- (tert-butyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl ) Pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-308) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5- (1 -Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-15) and also in step 4 of Example 9. , 4- (aminomethyl) be In the same manner as in Example 9 except that (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Reference Example 1 was used instead of benzenesulfonamide hydrochloride. Compound (I-308) was obtained by the method described in 1.

Example 309
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5-(((2,2,2-trifluoroethyl) Amino) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-309) production step 1
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl ) Oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-167) (300 mg, 0.540 mmol), dichloromethane (3.0 mL) and tetrahydrofuran (3.0 mL) were added, and the mixture was cooled to 0 ° C. After Dess-Martin periodinane (458 mg, 1.08 mmol) was added at a temperature, the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 60: 40 → 20: 80), and 1- (tert-butyl) -N-((5 -(Ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide ( Yield 192 mg, yield 64%).

Process 2
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-Methyl-1H-pyrazole-3-carboxamide (30.0 mg, 0.0542 mmol), dichloromethane (0.50 mL), 2,2,2-trifluoroethylamine hydrochloride (14.6 mg, 0.108 mmol), sodium triacetoxyboro Hydride (22.9 mg, 0.108 mmol) and acetic acid (1 drop) were sequentially added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was directly purified by silica gel column chromatography (NH silica gel, n-hexane: ethyl acetate = 60: 40 → 20: 80) to obtain compound (I-309) (yield 2.7 mg, yield 8%). .

Example 310
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((3-hydroxyazetidin-1-yl) methyl) -4- Preparation of (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-310) In the same manner as in Example 309, 2,2,2- of Step 2 was used. Compound (I-310) was obtained by using 3-hydroxyazetidine hydrochloride instead of trifluoroethylamine hydrochloride.

Example 311
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-5-((5- (morpholinomethyl) -4- (trifluoromethyl) pyridine Preparation of 3--3-yl) oxy) -1H-pyrazole-3-carboxamide (I-311) In the same manner as in Example 309, morpholine was used in place of 2,2,2-trifluoroethylamine hydrochloride in step 2. It was used to obtain the compound (I-311).

Reference Example 99
1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic Production of Acid (VII-67) In the same manner as in Reference Example 94, 1- (tert-butyl) -4-methyl-5-((4- (trifluoromethyl) -5-vinylpyridine-3 of step 1 was used. -Yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester was synthesized by the method described in Step 2 of Reference Example 48, 1- (tert-butyl) -4-ethyl-5-((4 Using (-(trifluoromethyl) -5-vinylpyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester, 1- (tert-butyl) -5-((5- (1, 2-dihydroxyethyl) -4- (trif Oromechiru) pyridin-3-yl) oxy) -4-ethyl -1H- pyrazole-3-carboxylic acid (VII-67).

Example 312
1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-N-((5- ( Preparation of ethylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-312) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- Using (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid (VII-67), Example 9 4- (ami) in step 4 of Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of (nomethyl) benzenesulfonamide hydrochloride. Compound (I-312) was obtained in the same manner as in.

Example 313
1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-N- (4- (ethyl Preparation of (sulfonyl) benzyl) -1H-pyrazole-3-carboxamide (I-313) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 Instead of (oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) was synthesized by the method described in Reference Example 99. ) -4- (Trifluoromethyl) pyridin-3-yl) oxy) -4-ethyl-1H-pyrazole-3-carboxylic acid (VII-67) and also in step 4 of Example 9, 4- (Aminomethyl) benzene By using (4- (ethylsulfonyl) phenyl) methanamine hydrochloride (VIII-29) synthesized by the method described in Reference Example 97 instead of rufonamide hydrochloride, a compound ( I-313) was obtained.

Example 314
1- (tert-butyl) -N- (3- (4- (ethylsulfonyl) phenyl) oxetan-3-yl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-314) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (hydroxy Methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used and in step 4 of Example 9 at 4 -(Aminomethyl) In the same manner as in Example 9 except that 3- (4- (ethylsulfonyl) phenyl) oxetane-3-amine (VIII-13) synthesized by the method described in Reference Example 17 was used instead of benzenesulfonamide hydrochloride. The compound (I-314) was obtained by the method of.

Reference example 100
Production of (4- (ethylsulfonimidoyl) phenyl) methanamine hydrochloride (VIII-30) In the same manner as in Reference Example 37, 4- (ethylthio) benzaldehyde was replaced with 4- (ethylthio) benzaldehyde instead of 4- (methylthio) benzaldehyde in step 1. By using, (4- (ethylsulfonimidoyl) phenyl) methanamine hydrochloride (VIII-30) was obtained.

Example 315
1- (tert-butyl) -N- (4- (ethylsulfonimidoyl) benzyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4 Preparation of -Methyl-1H-pyrazole-3-carboxamide (I-315) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) in step 4 of Example 9 Instead of -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (hydroxymethyl) -4- (tri) was synthesized by the method described in Reference Example 31. Fluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used, and 4- (aminomethyl) benzenesulfone in step 4 of Example 9 was used. Amide A compound was prepared in the same manner as in Example 9 by using (4- (ethylsulfonimidoyl) phenyl) methanamine hydrochloride (VIII-30) synthesized by the method described in Reference Example 100 instead of the hydrochloride. (I-315) was obtained.

Reference example 101
1- (tert-butyl) -5-((5-((3-hydroxy-3- (hydroxymethyl) cyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl -1H-Pyrazole-3-carboxylic acid (VII-68) production process 1
1- (tert-butyl) -5-((5-fluoro-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg, 0.257 mmol) in 1-methyl-2-pyrrolidinone (1.3 mL) was added with N, N-diisopropylethylamine (444 μL, 2.57 mmol) and 3-methylenecyclobutanamine hydrochloride (65.2 mg, 0.545 mmol), and micro The mixture was stirred at 160 ° C for 1 hour under wave irradiation. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -4-methyl-5 was used. -((5-((3-Methylenecyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 106 mg, yield 91 %).

Process 2
1- (tert-butyl) -4-methyl-5-((5-((3-methylenecyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3 In a solution of carboxylic acid ethyl ester (50.0 mg, 0.110 mmol) in 1,4-dioxane (1.1 mL) and water (0.11 mL) was added 4-methylmorpholine-N-oxide (38.8 mg, 0.331 mmol) and 2.5% tetracarboxylic acid. Osmium oxide tert-butanol solution (56 μL, 0.0055 mmol) was sequentially added, and the mixture was stirred at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 40: 60 → 0: 100), and 1- (tert-butyl) -5-((5 -((3-Hydroxy-3- (hydroxymethyl) cyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 54.3 mg, quantitative) was obtained.

Process 3
1- (tert-butyl) -5-((5-((3-hydroxy-3- (hydroxymethyl) cyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl Ethanol (1.0 mL) and a 4 mol / L sodium hydroxide aqueous solution (154 μL, 0.616 mmol) were added to -1H-pyrazole-3-carboxylic acid ethyl ester (50.0 mg, 0.103 mmol), and the mixture was stirred at room temperature for 2 hours. . 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -5-((5-((3-hydroxy-3- (hydroxymethyl) cyclobutyl) amino) -4- (trifluoromethyl) pyridine- 3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-68) (yield 49.0 mg, quantitative) was obtained.

Example 316
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-((3-hydroxy-3- (hydroxymethyl) cyclobutyl) amino)- Preparation of 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-316) 1- (tert-butyl) -in Step 4 of Example 9 Instead of 5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl synthesized by the method described in Reference Example 101. ) -5-((5-((3-Hydroxy-3- (hydroxymethyl) cyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3 -Carboxylic acid (VII-68) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, it was synthesized by the method described in Reference Example 5 (5- ( Compound (I-316) was obtained in the same manner as in Example 9 by using ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4).

Reference example 102
1- (tert-butyl) -5-((5-(((cis) -3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H -Preparation of pyrazole-3-carboxylic acid (VII-69) Using (cis) -3-aminocyclobutanol hydrochloride instead of 3-hydroxyazetidine hydrochloride in step 1 in the same manner as in Reference Example 43. Thus, 1- (tert-butyl) -5-((5-(((cis) -3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl -1H-pyrazole-3-carboxylic acid (VII-69) was obtained.

Example 317
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-(((cis) -3-hydroxycyclobutyl) amino) -4- Preparation of (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-317) 1- (tert-butyl) -5-in Step 4 of Example 9 Instead of ((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl)-synthesized by the method described in Reference Example 102. 5-((5-(((cis) -3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-69), and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 5. Compound (I-317) was obtained in the same manner as in Example 9 by using (VIII-4).

Example 318
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-(((cis) -3-hydroxycyclobutyl) amino)- Preparation of 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-318) 1- (tert-butyl) -in Step 4 of Example 9 Instead of 5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl synthesized by the method described in Reference Example 102. ) -5-((5-(((cis) -3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic Acid (VII-69) Used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl)) synthesized by the method described in Reference Example 2 Compound (I-318) was obtained in the same manner as in Example 9 by using phenyl) ethanol hydrochloride (VIII-2).

Example 319
1- (tert-butyl) -5-((5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N- (4- Preparation of (methylsulfonyl) benzyl) -1H-pyrazole-3-carboxamide (I-319) In Step 4 of Example 9, 1- (tert-butyl) -5-((3,5-dichloropyridine-2- In place of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5-((3-hydroxy Cyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-55) was used, and also step 4 of Example 9 In 4- (ami Compound (I-319) was obtained in the same manner as in Example 9 by using (4- (methylsulfonyl) phenyl) methanamine hydrochloride instead of nomethyl) benzenesulfonamide hydrochloride.

Example 320
1- (tert-butyl) -N- (4- (ethylsulfonyl) benzyl) -5-((5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) Preparation of (oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-320) 1- (tert-butyl) -5-((3,5-dichloropyridine-2-in Step 4 of Example 9 Instead of (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5-((3-hydroxy Cyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-55) was used, and also step 4 of Example 9 was used. In 4- (ami A method similar to that in Example 9 by using (4- (ethylsulfonyl) phenyl) methanamine hydrochloride (VIII-29) synthesized by the method described in Reference Example 97 instead of (nomethyl) benzenesulfonamide hydrochloride. To obtain the compound (I-320).

Example 321
1- (tert-butyl) -5-((5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5 Preparation of-(methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-321) In step 4 of Example 9, 1- (tert-butyl) -5-((3, Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 86). 5-((3-hydroxycyclobutyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-55) was used, Step 4 of Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Reference Example 1 is used. Thus, the compound (I-321) was obtained in the same manner as in Example 9.

Reference example 103
1- (tert-butyl) -5-((5-(((cis) -4-hydroxycyclohexyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H- Production of pyrazole-3-carboxylic acid (VII-70) By a method similar to that in Reference Example 43 and using (cis) -4-aminocyclohexanol hydrochloride in place of 3-hydroxyazetidine hydrochloride in Step 1. , 1- (tert-butyl) -5-((5-(((cis) -4-hydroxycyclohexyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H -Pyrazole-3-carboxylic acid (VII-70) was obtained.

Example 322
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5-(((cis) -4-hydroxycyclohexyl) amino) -4- ( Preparation of trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-322) 1- (tert-butyl) -5- (in Step 4 of Example 9 Instead of (3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5 synthesized by the method described in Reference Example 103. -((5-(((cis) -4-hydroxycyclohexyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 70), Further, instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 5. Compound (I-322) was obtained in the same manner as in Example 9 by using salt (VIII-4).

Example 323
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5-(((cis) -4-hydroxycyclohexyl) amino) -4 Preparation of-(trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-323) 1- (tert-butyl) -5 in Step 4 of Example 9 1- (tert-butyl) synthesized by the method described in Reference Example 103 instead of-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid -5-((5-(((cis) -4-hydroxycyclohexyl) amino) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-70 ) Was used in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, and 2-amino-2- (4- (ethyl) was synthesized by the method described in Reference Example 2. Compound (I-323) was obtained in the same manner as in Example 9 by using sulfonyl) phenyl) ethanol hydrochloride (VIII-2).

Example 324
1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N- (4- (ethylsulfonyl) benzyl) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-324) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 Instead of (oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (1,2-dihydroxyethyl) was synthesized by the method described in Reference Example 94. ) -4- (Trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-63) was used, and 4- (Aminomethyl) benzene By using (4- (ethylsulfonyl) phenyl) methanamine hydrochloride (VIII-29) synthesized by the method described in Reference Example 97 instead of rufonamide hydrochloride, a compound ( I-324) was obtained.

Example 325
1- (tert-butyl) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -5-((5- (2,2,2-trifluoro-1-hydroxy Preparation of ethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-325) 1- (tert-butyl) -5 in step 4 of Example 9 1- (tert-butyl) synthesized by the method described in Reference Example 91 in place of-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid -4-Methyl-5-((5- (2,2,2-trifluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic Acid (VII-60) Further, in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 1 Compound (I-325) was obtained in the same manner as in Example 9 by using salt (VIII-1).

Reference Example 104
Production Step 1 of 1- (tert-butyl) -5- (3- (hydroxymethyl) -2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-71)
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (450 mg, 1.99 mmol), dimethyl sulfoxide (4.0 mL), cesium carbonate (972 mg, 2.98 mmol) ) And 3-fluoro-2- (trifluoromethyl) benzaldehyde (495 mg, 2.58 mmol) were added, and the mixture was stirred at 110 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25 → 40: 60), and 1- (tert-butyl) -5- (3-formyl- 2- (Trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (62.1 mg, 8% yield) was obtained.

Process 2
1- (tert-Butyl) -5- (3-formyl-2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (10.6 mg, 0.0266 mmol) in tetrahydrofuran (0.50 (mL) solution, sodium borohydride (1.5 mg, 0.040 mmol) was added at 0 ° C, and the mixture was stirred at the same temperature for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous solution of ammonium chloride and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 1- (tert-butyl) -5- (3- (hydroxymethyl) -2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid was obtained. Ethyl ester (yield 10.7 mg, quantitative) was obtained.

Process 3
To 1- (tert-butyl) -5- (3- (hydroxymethyl) -2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (10.7 mg, 0.0267 mmol) , Ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (40 μL, 0.16 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 1- (tert-butyl) -5- (3- (hydroxymethyl) -2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII -71) (yield 8.8 mg, yield 88%) was obtained.

Example 326
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5- (3- (hydroxymethyl) -2- (trifluoromethyl) phenoxy) -4-methyl Preparation of 1H-pyrazole-3-carboxamide (I-326) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4 in step 4 of Example 9 1- (tert-butyl) -5- (3- (hydroxymethyl) -2- (trifluoromethyl) synthesized by the method described in Reference Example 104 instead of -methyl-1H-pyrazole-3-carboxylic acid Phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-71) was used, and instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of Example 9, reference Compound (I-326) was synthesized in the same manner as in Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Example 5. Got

Reference example 105
1- (tert-butyl) -5-((5- (2,2-difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole Step of producing 3-carboxylic acid (VII-72) 1
1- (tert-butyl) -5-((5-formyl-4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (37.5 mg, (Difluoromethyl) trimethylsilane (27 μL, 0.19 mmol) and cesium fluoride (2.9 mg, 0.019 mmol) were added to a solution of 0.0939 mmol) of N, N-dimethylformamide (1.0 mL), and the mixture was stirred at room temperature for 20 hours. . A 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (1.0 mL, 1.0 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 → 50: 50), and 1- (tert-butyl) -5-((5 -(2,2-Difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 8.9 mg, yield 21%).

Process 2
1- (tert-butyl) -5-((5- (2,2-difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole Ethanol (0.50 mL) and 4 mol / L sodium hydroxide aqueous solution (30 μL, 0.12 mmol) were added to -3-carboxylic acid ethyl ester (8.9 mg, 0.020 mmol), and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 1- (tert-butyl) -5-((5- (2,2-difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-Methyl-1H-pyrazole-3-carboxylic acid (VII-72) (yield 6.8 mg, yield 81%) was obtained.

Example 327
1- (tert-butyl) -5-((5- (2,2-difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- ( Preparation of ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-327) 1- (tert-butyl) -5-((in Step 4 of Example 9) Instead of 3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-synthesized by the method described in Reference Example 105. ((5- (2,2-Difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-72) Example Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of 9, the (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII- was synthesized by the method described in Reference Example 5). Compound (I-327) was obtained in the same manner as in Example 9 by using 4).

Example 328
1- (tert-butyl) -N- (4- (ethylsulfonimidoyl) benzyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-328) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 Instead of (oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (1-hydroxyethyl)-was synthesized by the method described in Reference Example 38. 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-15) was used, and 4- (amino) in Step 4 of Example 9 was used. Methyl) benzenesulfo In the same manner as in Example 9, except that (4- (ethylsulfonimidoyl) phenyl) methanamine hydrochloride (VIII-30) synthesized by the method described in Reference Example 100 was used instead of the amide hydrochloride. Compound (I-328) was obtained.

Example 329
1- (tert-butyl) -N- (3- (4- (ethylsulfonyl) phenyl) oxetane-3-yl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine Preparation of 3--3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-329) In step 4 of Example 9, 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-15) was used and the process of Example 9 4- (aminome Example 9 by substituting 3- (4- (ethylsulfonyl) phenyl) oxetane-3-amine (VIII-13) synthesized by the method described in Reference Example 17 in place of (tyl) benzenesulfonamide hydrochloride. Compound (I-329) was obtained in the same manner as in.

Reference Example 106
Production Step 1 of 1- (4- (ethylsulfonyl) phenyl) -2-methoxyethanamine hydrochloride (VIII-31)
tert-Butyl (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) carbamate (1.12 g, 3.40 mmol), n-hexane (34 mL), tetrabutylammonium hydrogen sulfate (23 mg, 0.068 mmol) ), 50% aqueous sodium hydroxide solution (0.82 mL) and dimethyl sulfate (0.77 mL) were added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give tert-butyl (1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) carbamate (yield 897 mg, yield 77%).

Process 2
A solution of tert-butyl (1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) carbamate (897 mg, 2.61 mmol) in dichloromethane (20 mL) was added at 0 ° C to a 4 mol / L hydrogen chloride ethyl acetate solution. (2.5 mL, 10 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure to give 1- (4- (ethylsulfonyl) phenyl) -2-methoxyethanamine hydrochloride (VIII-31) (yield 778 mg, quantitative).

Example 330
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine Preparation of 3--3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-330) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-15) was used and the process of Example 9 4- (aminome By using 1- (4- (ethylsulfonyl) phenyl) -2-methoxyethanamine hydrochloride (VIII-31) synthesized by the method described in Reference Example 106, instead of (tyl) benzenesulfonamide hydrochloride, Compound (I-330) was obtained in the same manner as in Example 9.

Reference example 107
1- (tert-butyl) -5-((5- (hydroxymethyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII- 73) Manufacturing process 1
1- (tert-Butyl) -5-hydroxy-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.33 mmol), cesium carbonate (648 mg, 1.99 mmol), dimethyl sulfoxide (2.7 mL) ) And 6-chloro-5- (trifluoromethyl) nicotinic acid (449 mg, 1.99 mmol) were added, and the mixture was stirred at 100 ° C for 4 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. 1 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Tetrahydrofuran (6.6 mL) and 1 mol / L borane tetrahydrofuran complex tetrahydrofuran solution (6.63 mL, 6.63 mmol) were added to the residue, and the mixture was stirred at room temperature for 22 hours. Methanol was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 0: 100), and 1- (tert-butyl) -5-((5- (hydroxymethyl) -3- (triethyl)). Fluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 193 mg, yield 36%) was obtained.

Process 2
1- (tert-butyl) -5-((5- (hydroxymethyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester ( To 193 mg, 0.481 mmol), ethanol (2.4 mL) and 4 mol / L sodium hydroxide aqueous solution (361 μL, 1.44 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 0: 100), and 1- (tert-butyl) -5-((5- ( Hydroxymethyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-73) (yield 61.1 mg, 34% yield) was obtained. ..

Example 331
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (hydroxymethyl) -3- (trifluoromethyl) pyridin-2-yl ) Oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-331) 1- (tert-butyl) -5-((3,5-dichloropyridine-2) in step 4 of Example 9 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (hydroxymethyl)) synthesized by the method described in Reference Example 107 -3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-73) was used, and 4- (in Step 4 of Example 9 was used. Aminomethyl) benzene Similar to Example 9 by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of sulfonamide hydrochloride. Compound (I-331) was obtained by the method.

Example 332
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((5- (hydroxymethyl) -3- (trifluoromethyl) pyridine-2 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-332) 1- (tert-butyl) -5-((3,5-dichloropyridine) in Step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (hydroxy Methyl) -3- (trifluoromethyl) pyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-73) was used, and in step 4 of Example 9 at 4 -(Aminomethyl ) By using 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (VIII-2) synthesized by the method described in Reference Example 2 instead of benzenesulfonamide hydrochloride, Compound (I-332) was obtained in the same manner as in No. 9.

Example 333
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridin-3-yl) oxy) -N- (4- (ethylsulfonyl) benzyl) -4-methyl- Preparation of 1H-pyrazole-3-carboxamide (I-333) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy) -4- in Step 4 of Example 9 Instead of methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((4- (difluoromethyl) -5- (hydroxymethyl) pyridine) synthesized by the method described in Reference Example 60. -3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-31) was used, and the 4- (aminomethyl) benzenesulfonamide hydrochloride salt in Step 4 of Example 9 was used. Instead In addition, by using (4- (ethylsulfonyl) phenyl) methanamine hydrochloride (VIII-29) synthesized by the method described in Reference Example 97, the compound (I-333) was prepared in the same manner as in Example 9. Got

Example 334
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1-hydroxyethyl) pyridin-3-yl) oxy) -N- (4- (ethylsulfonyl) benzyl) -4- Preparation of methyl-1H-pyrazole-3-carboxamide (I-334) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) oxy)-in step 4 of Example 9 Instead of 4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((4- (difluoromethyl) -5- (1- Hydroxyethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-32) was used, and 4- (aminomethyl) benzenesulfone in step 4 of Example 9 was used. Amido hydrochloric acid By using (4- (ethylsulfonyl) phenyl) methanamine hydrochloride (VIII-29) synthesized by the method described in Reference Example 97 instead of the salt, the compound (I- 334) was obtained.

Reference example 108
Of 1- (tert-butyl) -5- (3- (1,2-dihydroxyethyl) -2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-74) Manufacturing process 1
To a suspension of methyl (triphenyl) phosphonium bromide (143 mg, 0.400 mmol) in tetrahydrofuran (1.0 mL) was added potassium tert-butoxide (47.4 mg, 0.401 mmol) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. 1- (tert-butyl) -5- (3-formyl-2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (32.0 mg, 0.0803 mmol) was added to the reaction solution. Tetrahydrofuran (1.0 mL) solution was added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 → 60: 40), and 1- (tert-butyl) -4-methyl-5 was used. -(2- (Trifluoromethyl) -3-vinylphenoxy) -1H-pyrazole-3-carboxylic acid ethyl ester (yield 20.1 mg, yield 63%) was obtained.

Process 2
1,4- (tert-butyl) -4-methyl-5- (2- (trifluoromethyl) -3-vinylphenoxy) -1H-pyrazole-3-carboxylic acid ethyl ester (28.0 mg, 0.0706 mmol) 1,4 -To a solution of dioxane (1.0 mL) and water (0.1 mL), 4-methylmorpholine-N-oxide (24.8 mg, 0.212 mmol) and 2.5% osmium tetroxide tert-butanol solution (36 μL, 0.0035 mmol) were added, The mixture was stirred at room temperature for 20 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 50: 50), and 1- (tert-butyl) -5- (3- (1,2-Dihydroxyethyl) -2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 22.7 mg, yield 75%) was obtained.

Process 3
1- (tert-butyl) -5- (3- (1,2-dihydroxyethyl) -2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (22.7 mg, To 0.0527 mmol), ethanol (1.0 mL) and 4 mol / L sodium hydroxide aqueous solution (79 μL, 0.32 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 1- (tert-butyl) -5- (3- (1,2-dihydroxyethyl) -2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3- Obtained carboxylic acid (VII-74) (yield 21.2 mg, quantitative).

Example 335
1- (tert-butyl) -5- (3- (1,2-dihydroxyethyl) -2- (trifluoromethyl) phenoxy) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) Preparation of 4-methyl-1H-pyrazole-3-carboxamide (I-335) 1- (tert-butyl) -5-((3,5-dichloropyridin-2-yl) in step 4 of Example 9 Instead of (oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5- (3- (1,2-dihydroxyethyl)) synthesized by the method described in Reference Example 108. 2- (trifluoromethyl) phenoxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-74) was used, and 4- (aminomethyl) benzenesulfonamide in step 4 of Example 9 was used. salt A similar method to that in Example 9 was obtained by using (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 instead of the acid salt. To give the compound (I-335).

Reference example 109
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-3-yl) oxy) -4-methyl-1H -Production step 1 of pyrazole-3-carboxylic acid (VII-75)
1- (tert-butyl) -5-((4- (difluoromethyl) -5-vinylpyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (337 mg, 0.888 mmol) in 1,4-dioxane (8.5 mL) and water (0.85 mL), 2,6-dimethylpyridine (0.21 mL, 1.8 mmol), sodium periodate (760 mg, 3.55 mmol) and 2.5% tetrahydrofuran. An osmium oxide tert-butanol solution (0.45 mL, 0.044 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography, and 1- (tert-butyl) -5-((4- (difluoromethyl) -5-formylpyridin-3-yl) oxy)- 4-Methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 313 mg, yield 92%) was obtained.

Process 2
1- (tert-butyl) -5-((4- (difluoromethyl) -5-formylpyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (156 mg, 0.409 trimethyl (trifluoromethyl) silane (0.18 mL, 1.2 mmol) and 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution (1.2 mL, 1.2 mmol) to a tetrahydrofuran (4.0 mL) solution of Stir for 30 minutes at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 85: 15 → 50: 50), and 1- (tert-butyl) -5-((4 -(Difluoromethyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield 76.4 mg , Yield 41%) was obtained.

Process 3
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-3-yl) oxy) -4-methyl-1H To ethanol-pyrazole-3-carboxylic acid ethyl ester (76.4 mg, 0.169 mmol), ethanol (1.7 mL) and a 4 mol / L sodium hydroxide aqueous solution (0.25 mL, 1.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 1- (tert-butyl) -5-((4- (difluoromethyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-3-yl) Oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-75) (yield 71.6 mg, quantitative) was obtained.

Example 336
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-3-yl) oxy) -N-((5 Preparation of-(ethylsulfonyl) pyridin-2-yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-336) 1- (tert-butyl) -5-in Step 4 of Example 9 Instead of ((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl)-synthesized by the method described in Reference Example 109. 5-((4- (difluoromethyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-75), and Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride synthesized by the method described in Reference Example 5. Compound (I-336) was obtained in the same manner as in Example 9 by using (VIII-4).

Example 337
1- (tert-butyl) -5-((4- (difluoromethyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-3-yl) oxy) -N- (1- Preparation of (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-1H-pyrazole-3-carboxamide (I-337) 1- (tert-butyl) -in Step 4 of Example 9 Instead of 5-((3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl was synthesized by the method described in Reference Example 109. ) -5-((4- (Difluoromethyl) -5- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic Acid (VII-75) Used, and in place of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of Example 9, 2-amino-2- (4- (ethylsulfonyl)) synthesized by the method described in Reference Example 2. Compound (I-337) was obtained in the same manner as in Example 9 by using phenyl) ethanol hydrochloride (VIII-2).

Example 338
1- (tert-butyl) -N- (4- (ethylsulfonimidoyl) benzyl) -4-methyl-5-((5- (2,2,2-trifluoro-1-hydroxyethyl) -4- Preparation of (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-338) In step 4 of Example 9, 1- (tert-butyl) -5-((3, 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -4-methyl-synthesized by the method described in Reference Example 91. 5-((5- (2,2,2-trifluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxylic acid (VII-60 ) Is used, and in Example 9 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride in step 4 of (4), (4- (ethylsulfonimidoyl) phenyl) methanamine hydrochloride (VIII-30) synthesized by the method described in Reference Example 100 was used. By using the compound, the compound (I-338) was obtained in the same manner as in Example 9.

Example 339
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-339) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2- (yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid instead of 1- (tert-butyl) -5-((5- (hydroxy Methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used and in step 4 of Example 9 at 4 -(Aminomethyl) Example 1- (4- (ethylsulfonyl) phenyl) -2-methoxyethanamine hydrochloride (VIII-31) synthesized by the method described in Reference Example 106 was used instead of benzenesulfonamide hydrochloride. Compound (I-339) was obtained in the same manner as in No. 9.

Example 340
1- (tert-butyl) -N- (1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -5-((5- (hydroxymethyl) -4- (trifluoromethyl) ) Pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-340) Preparation of 1- (tert-butyl) -5-((3, Instead of 5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((synthesized by the method described in Reference Example 31). 5- (Hydroxymethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-10) was used and the process of Example 9 4- (ami) in 4 2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8) synthesized by the method described in Reference Example 10 is used in place of (nomethyl) benzenesulfonamide hydrochloride. Thus, the compound (I-340) was obtained in the same manner as in Example 9.

Example 341
1- (tert-butyl) -N- (1- (5- (ethylsulfonyl) pyridin-2-yl) -2-hydroxyethyl) -5-((5- (1-hydroxyethyl) -4- (tri Preparation of fluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-341) 1- (tert-butyl) -5-((in step 4 of Example 9 Instead of 3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-synthesized by the method described in Reference Example 38 was used. ((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-15) was used and 4 in Step 4 of Example 9 2-Amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethanol hydrochloride (VIII-8 synthesized by the method described in Reference Example 10 instead of-(aminomethyl) benzenesulfonamide hydrochloride Compound (I-341) was obtained by the same method as in Example 9 by using

Example 342
1- (tert-butyl) -5-((5- (2,2-difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N- ( Preparation of (5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-342) In step 4 of Example 9, 1- (tert-butyl) -5-(( Instead of 3,5-dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-synthesized by the method described in Reference Example 105. ((5- (2,2-Difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-72) Example Instead of 4- (aminomethyl) benzenesulfonamide hydrochloride in Step 4 of 9, the (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII- was synthesized by the method described in Reference Example 1). Compound (I-342) was obtained in the same manner as in Example 9 by using 1).

Reference example 110
1- (tert-butyl) -5-((5- (cyclopropyl (hydroxy) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic Production of Acid (VII-76) In the same manner as in Reference Example 38, by using 0.7 mol / L cyclopropyl magnesium bromide tetrahydrofuran solution in place of the 3 mol / L methyl magnesium bromide tetrahydrofuran solution in Step 1, 1- (Tert-Butyl) -5-((5- (cyclopropyl (hydroxy) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid ( VII-76) was obtained.

Example 343
1- (tert-butyl) -5-((5- (cyclopropyl (hydroxy) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -N-((5- (ethylsulfonyl) pyridine Preparation of 2-yl) methyl) -4-methyl-1H-pyrazole-3-carboxamide (I-343) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (Cyclopropyl (hydroxy) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-76) was used, and Example 9 To step 4 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-4) synthesized by the method described in Reference Example 5 is used. Thus, the compound (I-343) was obtained in the same manner as in Example 9.

Example 344
1- (tert-butyl) -5-((5- (cyclopropyl (hydroxy) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- ( Preparation of methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-344) 1- (tert-butyl) -5-((3,5- Instead of dichloropyridin-2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid, 1- (tert-butyl) -5-((5- (Cyclopropyl (hydroxy) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-76) was used, and Example 9 To step 4 In place of 4- (aminomethyl) benzenesulfonamide hydrochloride, (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Reference Example 1 is used. Thus, the compound (I-344) was obtained in the same manner as in Example 9.

Example 345
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((3- (trifluoromethyl) pyridin-2-yl) Oxy) -1H-pyrazole-3-carboxamide (I-35) optical resolution 1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl -5-((3- (Trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide (I-35) (811 mg) was added to ethanol (20 mL) and n-hexane (20 mL). ) Dissolved in a mixed solution of HPLC) (HPLC: column: CHIRALPAK IA 2 cm x 25 cm, developing solvent: n-hexane / ethanol = 50/50, flow rate: 5 mL / min, injection amount: 2 mL, room temperature) Isomer A (I-345-A) (elution time About 15 minutes) (yield 343 mg, 42% yield) and isomer B (I-345-B) (elution time: to obtain about 22 minutes) (yield 365 mg, 45% yield).

Example 346
1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl-5-((4- (trifluoromethyl) pyridin-3-yl) Oxy) -1H-pyrazole-3-carboxamide (I-51) optical resolution 1- (tert-butyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4-methyl -5-((4- (Trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrazole-3-carboxamide (I-51) (93.6 mg) was added to ethanol (5 mL) and n-hexane (5 mL). ) Dissolved in a mixed solution of HPLC) (HPLC: column: CHIRALPAK IA 2 cm x 25 cm, developing solvent: n-hexane / ethanol = 50/50, flow rate: 5 mL / min, injection amount: 2 mL, room temperature) Isomer A (I-346-A) (elution time: About 22 minutes) (amount 43.1 mg, yield 46%) and isomer B (I-346-B) (elution time: about 26 minutes) (amount 43.3 mg, yield 46%) were obtained.

Example 347
1- (tert-butyl) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((3- (trifluoromethyl) pyridin-2-yl) Oxy) -1H-pyrazole-3-carboxamide (I-53) optical resolution 1- (tert-butyl) -4-ethyl-N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -5-((3- (Trifluoromethyl) pyridin-2-yl) oxy) -1H-pyrazole-3-carboxamide (I-53) (116 mg) was added to ethanol (6 mL) and n-hexane (6 mL). ) Dissolved in a mixed solution of HPLC) (HPLC: column: CHIRALPAK IA 2 cm x 25 cm, developing solvent: n-hexane / ethanol = 50/50, flow rate: 5 mL / min, injection amount: 2 mL, room temperature) Isomer A (I-347-A) (elution time: 14 min) (yield 55.0 mg, 47% yield) and isomer B (I-347-B) (elution time: to obtain about 18 minutes) (yield 55.4 mg, 48% yield).

Example 348
1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridine-3 -Yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-196) optical resolution 1- (tert-butyl) -N-((5- (ethylsulfonyl) pyridin-2-yl) methyl ) -5-((5- (1-Hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxamide (I-196) (36.1 mg) ) Is dissolved in ethanol (4 mL), and HPLC fractionation (column: CHIRALPAK IA 2 cm x 25 cm, developing solvent: n-hexane / ethanol = 30/70, flow rate: 10 mL / min, injection amount: 2 mL) , Room temperature), and isomer A (I-348-A) Elution time: about 6 minutes) (yield 14.6 mg, 41% yield) and isomer B (I-348-B) (elution time: to obtain about 11 minutes) (yield 15.1 mg, 42% yield).

Example 349
1- (tert-butyl) -5-((5- (1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl ) Pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-308) optical resolution 1- (tert-butyl) -5-((5- (1-hydroxyethyl) -4- (tri Fluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-308) (150 mg. ) Is dissolved in ethanol (6 mL) and preparative by HPLC (column: CHIRALPAK IA 2 cm x 25 cm, developing solvent: n-hexane / ethanol = 30/70, flow rate: 10 mL / min, injection rate: 2 mL). , Room temperature), isomer A (I-349-A) Elution time: about 13 minutes) (yield 70.1 mg, 47% yield) and isomer B (I-349-B) (elution time: to obtain about 20 minutes) (yield 69.8 mg, 47% yield).

Example 350
1- (tert-butyl) -5-((5- (2,2-difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N- ( Optical resolution of (5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-342) 1- (tert-butyl) -5-((5- (2,2- Difluoro-1-hydroxyethyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole -3-Carboxamide (I-342) (24.0 mg) was dissolved in ethanol (5 mL), and HPLC fractionation (column: CHIRALPAK IA 2 cm x 25 cm, developing solvent: n-hexane / ethanol = 30/70, Flow rate: 10 mL / min, injection volume: 1 mL , Isomer A (I-350-A) (elution time: about 11 minutes) (11.7 mg, 49% yield) and isomer B (I-350-B) (elution time: about 20 minutes). Min) (yield 11.4 mg, yield 48%).

Example 351
1- (tert-butyl) -5-((5- (cyclopropyl (hydroxy) methyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- ( Optical resolution of methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-344) 1- (tert-butyl) -5-((5- (cyclopropyl (hydroxy) methyl)- 4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-344 ) (22.0 mg) is dissolved in a mixed solvent of ethanol (3 mL) and n-hexane (1 mL), and the medium pressure fractionation (column: CHIRALFLASH IA 3 cm x 10 cm, developing solvent: n-hexane / ethanol = 30/70, Velocity: 12 mL / min, injection rate: 4 mL, room temperature), isomer A (I-351-A) (elution time: about 11 minutes) (yield 9.2 mg, 42%) and isomer B ( I-351-B) (elution time: about 22 minutes) (yield 9.0 mg, yield 41%) was obtained.

Example 352
1- (tert-butyl) -5-((5- (1-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl ) Pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-352) 1- (tert-butyl) -5-((3,5-dichloropyridine) in step 4 of Example 9 2-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid was replaced by 1- (tert-butyl) -5-((5- (1 -Hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-1H-pyrazole-3-carboxylic acid (VII-46) was used and also in step 4 of Example 9. , 4- (aminomethyl Similar to Example 9 by using (5- (methylsulfonyl) pyridin-2-yl) methanamine hydrochloride (VIII-1) synthesized by the method described in Reference Example 1 instead of benzenesulfonamide hydrochloride. The compound (I-352) was obtained by the method of.

Example 353
1- (tert-butyl) -5-((5- (1-hydroxypropyl) -4- (trifluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl ) Pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-352) optical resolution 1- (tert-butyl) -5-((5- (1-hydroxypropyl) -4- (tri Fluoromethyl) pyridin-3-yl) oxy) -4-methyl-N-((5- (methylsulfonyl) pyridin-2-yl) methyl) -1H-pyrazole-3-carboxamide (I-352) (79.3 mg ) Is dissolved in ethanol (1 mL), and the medium pressure fractionation (column: CHIRALFLASH IA 3 cm x 10 cm, developing solvent: n-hexane / ethanol = 30/70, flow rate: 12 mL / min, injection rate: 1) mL, room temperature), isomer A (I-353 -A) (elution time: about 11 minutes) (yield 35.8 mg, yield 45%) and isomer B (I-353-B) (elution time: about 25 minutes) (yield 31.7 mg, yield 40%) Obtained.

  Tables 1 to 46 below show the chemical structural formulas and instrumental analysis data of the compounds synthesized in Examples 1 to 353. In Tables 44 to 46, an asterisk (*) in the structural formula means an optically pure form.

Test Example 1: Evaluation of RORγt inhibitory action The RORγt inhibitory action of a test compound was evaluated using the following reporter gene assay.
Jurkat cells used in the assay were cultured in RPMI 1640 medium containing 10 (v / v)% fetal bovine serum. On the day of the test, Jurkat cells were collected by centrifugation (1000 rpm, 5 minutes) and suspended in PBS (phosphate buffered saline) containing 0.5 (w / v)% bovine serum albumin (Sigma-Aldrich). did. The cells were collected by centrifugation again, and 100 μL of Cell Line Nucleofector Solution V (Amaxa Cell line nucleofector kit V, Lonza) was added to 3 × 10 ⁶ cells and suspended. In 100 μL of this cell suspension, 2 μg of a vector (TrueClone Full-Length cDNA Clones, Origene) in which the sequence of RORγt was inserted downstream of CMV promoter, and ROR response element of human IL-17 were added to pGL4.15 (Promega). 3 μg of the reporter vector inserted upstream of the luciferase gene in (1) was added, and the gene was introduced into the electroporation device (Nucleofector, Lonza) under the condition of X-005.

The cells after gene transfer are cultured in RPMI 1640 medium containing 10 (v / v)% fetal bovine serum for 5 hours, and then collected by centrifugation to obtain assay medium (10 (v / v)% fetal bovine serum). , RPMI 1640 containing 10 mM HEPES and 1 mM sodium pyruvate, no phenol red medium (Life Technologies, Inc.)) and suspended in 1 × 10 ⁵ cells / 50 μL / well in 96-well plate (B & W IsoPlate- 96TC, Perkin Elmer). The test compound was dissolved in dimethyl sulfoxide (DMSO), diluted with the assay medium on the day of the test, and added to the cells. The test compound was added at 20 μL / well, and the final DMSO concentration was 0.1 (v / v)%. After adding the test compound, the cells were cultured overnight in an incubator. Add 10 μL of stimulation solution (phorbol-12-myristate-13-acetate (Sigma Aldrich) at a final concentration of 50 ng / mL and ionomycin (Sigma Aldrich) at a final concentration of 1 μM) to the cells and incubate at 7 It was cultured for 20 minutes.

  Cell viability was measured using the fluorescence method by CellTiter-Fluor cell viability assay (Promega). 20 μL each of CellTiter-Fluor reagent was added to a 96-well plate and incubated in an incubator for 40 minutes. Fluorescence at 495 nm was measured with an excitation wavelength of 340 nm using a microplate reader. The viable cell rate after treatment with the test compound was expressed as% of control with the measured value of cells treated with only 0.1 (v / v)% DMSO and having the stimulation solution added as 100%.

The RORγt activity was measured using the Bright-Glo Luciferase Assay System (Promega) with the luciferase activity as an index. After measuring the cell viability, 100 μL of Bright-Glo reagent was added and incubated at room temperature for 3 minutes. The amount of luminescence was measured using a microplate reader. Wells treated with only 0.1 (v / v)% DMSO and stimulated solution were treated with 100%, 0.1 (v / v)% DMSO only, without stimulation solution added. The luciferase activity after treatment with the test compound was expressed as% of control, with the amount of luminescence being 0%. The IC ₅₀ value of the test compound was calculated from the linear expression of a straight line passing through two points sandwiching 50% of control.

Tables 47 and 48 show the results of RORγt inhibitory effect evaluation. Compounds with IC ₅₀ values less than 300 nM are designated by the letter "A", compounds having an IC ₅₀ value of less than 300 nM or 900 nM is represented by the letter "B".

The pyrazole derivative of the present invention has an excellent RORγt inhibitory activity, and has rheumatoid arthritis, psoriasis, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), multiple sclerosis, systemic lupus erythematosus, ankylosing spine. It is useful as an active ingredient of a medicament for the prevention and / or treatment of various autoimmune diseases such as inflammation and uveitis and allergic diseases (asthma, atopic dermatitis, chronic obstructive pulmonary disease, etc.).

Claims (20)

General formula (I):

[In the formula,
R ¹ is a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group or a C ₃ -C ₆ cycloalkyl group,
R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group or a C ₃ -C ₆ cycloalkyl group,
R ³ and R ⁴ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group optionally substituted with a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ hydroxyalkyl group, COR ^a (wherein R ^a represents OH, C ₁ -C ₆ alkoxy group or NH ₂ ), C ₃ -C ₆ cycloalkyl group or 4-6 membered oxacycloalkyl group, or R ³ and R ⁴ are bonded to each other. May form a 3- to 6-membered cycloalkyl or a 4- to 6-membered oxacycloalkyl together with the carbon atom
R ⁵ is a C ₁ -C ₆ alkyl group which may be substituted with R ^k (wherein R ^k is a C ₃ -C ₆ cycloalkyl group or a 4-6 membered oxacycloalkyl group), A C ₁ -C ₆ haloalkyl group or NHR ^b (where R ^b represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a 4-6 membered oxacycloalkyl group),
Y ¹ , Y ² , Y ³ and Y ⁴ are each independently N or CR ^c1 , CR ^c2 , CR ^c3 or CR ^c4 (wherein R ^c1 , R ^c2 , R ^c3 and R ^c4 are each independent. And represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ haloalkyl group),
R ⁷ is a hydrogen atom; a halogen atom; a cyano group; a C ₁ -C ₆ alkyl group which may be substituted with R ^d (wherein R ^d is a C ₁ -C ₆ alkoxy group or di C ₁ -C). ₆ shows the alkylamino _group); C 2 -C ₆ alkenyl _group; C 1 -C ₆ alkoxy group; is a good _C 2 be ~ substituted with a hydroxyl group; a hydroxyl group in an optionally substituted _C 1 -C ₆ haloalkyl group C _{6 alkynyl;} C 1 -C ₆ haloalkoxy _group; C 1 -C ₆ haloalkyl group or _C 3 -C ₆ cycloalkyl group optionally substituted _C 1 -C ₆ hydroxyalkyl group; oR ^e (wherein in ^{R e} _is shown a C 1 -C ₆ haloalkyl _group, C 1 -C ₆ hydroxyalkyl _group, C 3 -C ₆ cycloalkyl _C 1 -C ₆ alkyl or 4-6 membered oxacycloalkyl group ); In ^NR f ^{R g} (wherein, ^{R f} and ^{R g} each independently represents a hydrogen _atom, C 1 -C ₆ haloalkoxy optionally substituted _C 1 -C ₆ alkyl group with a group, a hydroxyl group An optionally substituted C ₃ -C ₆ cycloalkyl group, C ₁ -C ₆ hydroxyalkyl group or R ^f and R ^g are combined with the adjacent nitrogen atom to form a 4- to 6-membered nitrogen-containing heterocycle. And the nitrogen-containing heterocycle may be substituted with a hydroxyl group, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ hydroxyalkyl group); C substituted with NR ^h R ⁱ ₁ -C ₆ alkyl group (wherein, ^{R h} and ^{R i} are each independently hydrogen _atom, C 1 -C ₆ haloalkoxy group optionally substituted _C 1 -C ₆ alkyl group, _{C 3} -C ₆ cycloalkyl group, _{C 1} C ₆ hydroxyalkyl group or R ^h and R ⁱ is may form a nitrogen-containing heterocyclic ring having 4 to 6 membered together with the adjacent nitrogen atom, also those nitrogen-containing heterocycles, hydroxyl, C ₁ To C ₆ alkyl group or C _{1 to} C ₆ hydroxyalkyl group); or a C _{1 to} C ₆ alkylcarbonyl group,
R ⁸ is a hydrogen atom, a halogen atom, a cyano group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ haloalkyl group, a C ₁ -C ₆ haloalkoxy group or C ₁ -C. ₆ -hydroxyalkyl group,
R ⁹ is a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a C ₁ -C ₆ haloalkyl group,
X ^a is an oxygen atom or NR ^j (wherein R ^j is a hydrogen atom or a C ₁ -C ₆ alkyl group),
X ^b is an oxygen atom or NH,
n is an integer from 0 to 3,
Ring A represents 6-10 membered aryl or 5-10 membered heteroaryl]
Or a pharmaceutically acceptable salt thereof. In the general formula (I), R ⁵ is a C ₁ -C ₆ alkyl group, and X ^b is an oxygen atom, The compound or a pharmaceutically acceptable salt thereof. In the general formula (I), R ¹ is a C ₁ -C ₆ alkyl group, and R ² is a C ₁ -C ₆ alkyl group, or a compound or a pharmaceutically acceptable thereof. Salt. In the general formula (I), ring A is phenyl or pyridyl, The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3. In the general formula (I),
R ¹ is a C ₁ -C ₆ alkyl group, R ² is a C ₁ -C ₆ alkyl group, R ³ and R ⁴ are each independently a hydrogen atom or a hydroxymethyl group, and R ⁵ is C _{1 to} C ₆ alkyl group, R ⁸ is C _{1 to} C ₆ haloalkyl group, X ^a is oxygen atom, and ring A is phenyl or pyridyl. Acceptable salt. In the general formula (I), R ⁵ is a methyl group or an ethyl group, and X ^b is an oxygen atom, The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. In the general formula (I), R ¹ is a tert-butyl group, and R ² is a methyl group or an ethyl group, or a compound or a pharmaceutically acceptable salt thereof. In the general formula (I), ring A is pyridyl, The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. The compound according to claim 8, wherein Ring A is 2-pyridyl or 3-pyridyl, or a pharmaceutically acceptable salt thereof. In ring A which is 2-pyridyl or 3-pyridyl, the substitution positions of R ⁷ and R ⁸ are

The compound according to claim 9 or a pharmaceutically acceptable salt thereof. In the general formula (I), R ⁸ is a trifluoromethyl group, and the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10. In the general formula (I), R ⁷ is hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxypropyl group, cyclopropyl (hydroxy) methyl group, 2,2-difluoro-1-hydroxyethyl group or 2,2. , 2-Trifluoro-1-hydroxyethyl group, The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. The compound represented by the general formula (I) is

The compound or pharmaceutically acceptable salt thereof according to claim 1, which is any one of the following: A medicament comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier. The medicine according to claim 14, which is a RORγt inhibitor. The medicament according to claim 15, which suppresses differentiation and / or activation of Th17 cells. The medicament according to any one of claims 14 to 16, for prevention and / or treatment of a disease involving Th17 cells. The medicament according to claim 14 or 15, which is used for prevention and / or treatment of a disease involving an inflammatory cytokine. The medicine according to claim 18, wherein the inflammatory cytokine is IL-17A and / or IL-17F. Psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, multiple sclerosis, scleroderma, uveitis, asthma, ankylosing spondylitis, systemic lupus erythematosus, atopic dermatitis 20. The medicament according to any one of claims 14 to 19, for treating and / or preventing one or more diseases selected from the group consisting of and chronic obstructive pulmonary disease.