JP6986955B2 - Method for producing pyrazole derivative - Google Patents

Description

The present invention relates to a novel method for producing a pyrazole derivative useful as a pharmaceutical product.

Transient Receptor Potential (TRP) channels are non-selective cation channels that are activated by various stimuli such as temperature and chemicals, such as TRPM, TRPA, TRPV, TRPC, TRPP, and TRPML. , TRPN family. Further, TRPM1, TRPM2, TRPM3, TRPM4a, TRPM4b, TRPM5, TRPM6, TRPM7, and TRPM8 are known in the TRPM family (see, for example, Non-Patent Document 1).
TRPM8 is the eighth channel of the TRPM family cloned in 2002 (see, for example, Non-Patent Document 2), also known as CMR1 (cold and menthol sensitive receptor-1), cold at 8 ° C to 28 ° C. It is activated by chemical substances (menthol and Icilin) that cause irritation and cold sensation (see, for example, Non-Patent Documents 1 and 2). TRPM8 is expressed in primary afferent nerves (Aδ fibers and C fibers) and trigeminal nerves, as well as taste papilla, vascular endothelium, aorta, pulmonary artery, prostate, male reproductive organs (see, for example, Non-Patent Document 3), and human bladder. It is also expressed in nerve fibers that control the epithelium (see, for example, Non-Patent Document 4), prostate cancer (see, for example, Non-Patent Document 5), oral squamous cell carcinoma (see, for example, Non-Patent Document 6), and the like. It has been reported.
In TRPM8 knockout mice, lack of cold perception, lack of hypersensitivity to cold stimuli after neuropathy or inflammation, etc. are observed (see, for example, Non-Patent Document 3).
In nervous system diseases, it has been reported that the expression of TRPM8 is increased in sciatic nerve disorder model rats and is involved in low temperature hyperalgesia (see, for example, Non-Patent Document 7). It has also been shown that the expression of TRPM8 is increased due to peripheral neuropathy caused by oxaliplatin in rats and mice, and that TRPM8 is involved in low temperature hyperalgesia caused by oxaliplatin (for example, Non-Patent Document 8 and 9). In addition, since patients taking oxaliplatin are more responsive to menthol than healthy subjects, TRPM8 is involved in peripheral neuropathic pain caused by oxaliplatin in humans as well as rodents. (See, for example, Non-Patent Document 10).
Regarding urinary system diseases, it has been reported that TRPM8 is involved in pollakiuria symptoms caused by low temperature in rats (see, for example, Non-Patent Document 11). In addition, TRPM8 is expressed in the nerve that double-controls the skin and bladder in rats, and is considered to be involved in the urgency of urination caused by low temperature (see, for example, Non-Patent Document 12). In cats and patients with upper central nervous system disorders such as stroke and spinal cord injury, injecting a small amount of cold water into the bladder induces an unusual micturition reflex, which is enhanced by menthol (eg, menthol). , Non-Patent Documents 13 and 14). In cats, desensitization of C fibers reduces this micturition reflex, suggesting that menthol-sensitive C fibers are involved (see, for example, Non-Patent Document 13).
In addition, it was reported that an increase in the expression level of TRPM8 was confirmed in the nerve fibers under the bladder of patients with idiopathic detrusor hyperactivity / bladder pain syndrome, and that the expression level of TRPM8 was correlated with the frequency of micturition / pain score. (See, for example, Non-Patent Document 15), TRPM8 may play an important role in urinary storage in the bladder afferent tract.
Therefore, inhibition of TRPM8 is expected to treat or prevent diseases or symptoms caused by activation of TRPM8.
On the other hand, as the pyrazole derivative, the formula (A):

（式中、Ｒ^１、Ｒ^２およびＲ^３は、非特許文献１６の定義と同義である。）
で表される化合物が知られている（例えば、非特許文献１６参照）。
非特許文献１６には、フタルイミドとリチウムアセチリドを反応させて、式（A）で表されるピラゾール誘導体を得る製造方法が開示されているのみであり、本発明の製造方法について記載も示唆もない。また、非特許文献１６記載の化合物は、式（I）で表されるピラゾール誘導体とは構造が異なる。
また、特許文献１〜９記載の化合物も、式（I）で表される化合物とは構造が異なる上、本発明の製造方法については記載されていない。

(In the formula, R ¹ , R ² and R ³ are synonymous with the definition of Non-Patent Document 16.)
The compound represented by (for example, see Non-Patent Document 16) is known.
Non-Patent Document 16 only discloses a production method for obtaining a pyrazole derivative represented by the formula (A) by reacting phthalimide with lithium acetylide, and neither describes nor suggests the production method of the present invention. .. Further, the compound described in Non-Patent Document 16 has a structure different from that of the pyrazole derivative represented by the formula (I).
Further, the compounds described in Patent Documents 1 to 9 have different structures from the compounds represented by the formula (I), and the production method of the present invention is not described.

Makoto Tominaga, "Journal of Japanese Pharmacology", 2004, Vol. 124, p.219-227 McKemy DD. Et al., "Nature", 2002, 416, p.52-58 Broad LM. Et al., "Expert Opin Ther Targets", 2009, Volume 13, p.69-81 Andersson KE. Et al., "BJU Int", 2010, Vol. 106, p.1114-1127 Zhang L. et al., "Endocr Relat Cancer", 2006, Volume 13, p.27-38 Okamoto Y. et al., "Int J Oncol", 2012, Vol. 40, p.1431-1440 Su L. et al., "BMC Neurosci", 2011, Volume 12, p.120 Kawashiri T. et al., "Mol Pain", 2012, Volume 8, p.7 Gauchan P. et al., "Neurosci Lett", 2009, 458, p.93-95 Kono T. et al., "Brain Behav", 2012, Volume 2, p.68-73 Lei Z. et al., "Neurourol Urodyn", 2012, doi: 10.1002 / nau.22325 Shibata Y. et al., "Neuroreport", 2011, Vol. 22, p.61-67 Lindstrom S. et al., "Acta Physiol Scand", 1991, Vol. 141, p.1-10 Geirsson G. et al., "J Urol", 1993, Volume 150, p.427-430 Mukerji G. et al., "BMC Urol", 2006, Volume 6, p.6 J. Chem. Soc. Perkin Trans. 1, 2002, p. 207-210

Special Table 2009-515997 International Publication No. 2006/08903 Pamphlet International Publication No. 2004/099164 Pamphlet International Publication No. 2002/000651 Pamphlet Japanese Unexamined Patent Publication No. 2000-256358 International Publication No. 2004/067002 Pamphlet International Publication No. 2004/018436 Pamphlet International Publication No. 2001/0126227 Pamphlet Special Table 2010-536922 Gazette

It is an object of the present invention to provide a novel method for producing a pyrazole derivative or a pharmacologically acceptable salt thereof.

The present inventors have found a pyrazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof having a strong TRPM8 inhibitory action, and have diligently studied the production method thereof to complete the present invention. It came to.

〔式中、
環Ａは、Ｃ_３−６シクロアルキル、Ｃ_６−１０アリールまたはヘテロ環であり；
Ｘは、独立して、ＣＲ^４aまたは窒素原子であり；
Ｒ^１およびＲ^２は、それぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ、アミノ、ヒドロキシＣ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルキル、ハロＣ_１−６アルキル、シアノ、Ｃ_１−６アルキルスルホニルアミノ、イミダゾリル、１，３−ジオキソリルまたはモノ（ジ）Ｃ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^３は、水素原子、ハロゲン原子またはＣ_１−６アルキルであり；
Ｒ^４およびＲ^{４ a}は、それぞれ独立して、水素原子、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルコキシＣ_１−６アルコキシ、ハロＣ_１−６アルキル、ハロＣ_１−６アルコキシ、ヒドロキシＣ_１−６アルキル、ヒドロキシＣ_１−６アルコキシ、シアノ、カルバモイル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルコキシ、Ｃ_７−１０アラルキルオキシ、Ｃ_７−１０アラルキルオキシＣ_１−６アルコキシまたは１,３−ジオキソリルであり；
環Ｂは、Ｃ_６−１０アリールまたはヘテロ環であり；
Ｒ^５は、水素原子、Ｃ_１−６アルキル、モノ（ジ）ヒドロキシＣ_１−６アルキル、Ｃ_１−６アルコキシ（ヒドロキシ）Ｃ_１−６アルキル、カルボキシＣ_１−６アルキルまたはＣ_１−６アルコキシカルボニルＣ_１−６アルキルであり;
Ｒ^６ａは、水素原子、Ｃ（＝Ｏ）Ｒ^９、Ｃ（＝Ｏ）ＮＲ^１０Ｒ^１１、ＣＲ^１２Ｒ^１３Ｒ
^１４または以下の式：

（（＊＊）は結合位置を表す）であり;
Ｒ^７ａは、独立して、水素原子、フッ素原子、ヒドロキシ、ヒドロキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルコキシＣ_１−６アルキルまたはアミノＣ_１−６アルキルであり;
Ｒ^７ｂは、独立して、水素原子、フッ素原子またはＣ_１−６アルキルであるか、Ｒ^５またはＲ^６ａは、環Ｂと一緒になって６員環またはＲ^７ａと一緒になって５員環を形成し；
Ｒ^６ｂは、水素原子またはＣ_１−６アルキルであり；
Ｒ^８は、水素原子、ハロゲン原子、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、ヒドロキシ、アミノ、シアノ、Ｃ_１−６アルコキシカルボニル、Ｃ_１−６アルコキシＣ_１−６アルコキシ、カルバモイル、Ｃ_１−６アルコキシＣ_１−６アルキル、カルボキシ、アジド、ハロＣ_１−６アルキルまたはテトラゾリルであり；
Ｒ^９は、ヒドロキシ、Ｃ_１−６アルキルまたはヒドロキシピロリジニルであり；
Ｒ^１０およびＲ^１１は、それぞれ独立して、水素原子、Ｃ_１−６アルキル、ヒドロキシＣ_１−６アルキル、モノ（ジ）Ｃ_１−６アルキルアミノＣ_１−６アルキル、ピロリジニルまたはピペリジニルであり；
Ｒ^１２、Ｒ^１３および Ｒ^１４は、それぞれ独立して、水素原子、ヒドロキシ、Ｃ_１−６アルキル、ＮＲ^１５Ｒ^１６、Ｒ^１５Ｒ^１６Ｎ-Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、モノ（ジ）ヒドロキシＣ_１−６アルキル、カルバモイル、Ｃ_７−１０アラルキルオキシＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、フッ素原子またはフルオロＣ_１−６アルキルであり；
Ｒ^１５は、水素原子、Ｃ_１−６アルキル、（Ｃ_１−６アルキル）カルボニルまたはＣ_７−１０アラルキルであり；
Ｒ^１６は、水素原子、Ｃ_１−６アルキルまたはＣ_７−１０アラルキルであり；
Ｒ^１７は、水素原子またはＣ_１−６アルキルであり；
ｎは、０、１または２である。〕で表される化合物またはその薬理学的に許容される塩の製造方法であって、 That is, the means for solving the above problems are as follows.
[1] Equation (I):

[In the formula,
Ring A is a C _3-6 cycloalkyl, C _6-10 aryl or heterocycle;
X is independently a CR ^4a or nitrogen atom;
R ¹ and R ² are independently hydrogen atom, halogen atom, hydroxy, amino, hydroxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano, respectively. C _1-6 Alkoxysulfonylamino, imidazolyl, 1,3-dioxolyl or mono (di) C _1-6 alkoxy C _1-6 alkyl;
R ³ is a hydrogen atom, a halogen atom or a C _1-6 alkyl;
R ⁴ and R ^{4 a} are independently hydrogen atom, halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, and halo C _1-6 alkyl, respectively. , halo _{C 1-6} alkoxy, hydroxy _{C 1-6} alkyl, hydroxy _{C 1-6} alkoxy, cyano, _{carbamoyl, C 1-6} alkoxycarbonyl _{C 1-6 alkoxy, C 7-10 aralkyloxy, C 7-10} aralkyl Oxy-C _1-6 alkoxy or 1,3-dioxolyl;
Ring B is a C _6-10 aryl or heterocycle;
R ⁵ is a hydrogen atom, C _1-6 alkyl, mono (di) hydroxy C _1-6 alkyl, C _1-6 alkoxy (hydroxy) C _1-6 alkyl, carboxy C _1-6 alkyl or C _1-6 alkoxy. It is a carbonyl C _1-6 alkyl;
R ^6a is a hydrogen atom, C (= O) R ⁹ , C (= O) NR ¹⁰ R ¹¹ , CR ¹² R ¹³ R.
¹⁴ or the following formula:

((**) represents the bond position);
R ^7a can independently be hydrogen atom, fluorine atom, hydroxy, hydroxy C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl or amino C _{1- 6} alkyl;
R ^7b is independently a hydrogen atom, a fluorine atom or a C _1-6 alkyl, or R ⁵ or R ^6a is a 6-membered ring with ring B or a 5-membered ^{ring with R 7a.} Form a ring;
R ^6b is a hydrogen atom or C _1-6 alkyl;
R ⁸ contains hydrogen atom, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkoxy C _1-6 alkoxy, carbamoyl, C _{1 -6} Alkoxy C _1-6 alkyl, carboxy, azide, halo C _1-6 alkyl or tetrazolyl;
R ⁹ is hydroxy, C _1-6 alkyl or hydroxypyrrolidinyl;
R ¹⁰ and R ¹¹ are independently hydrogen atoms, C _1-6 alkyl, hydroxy C _1-6 alkyl, mono (di) C _1-6 alkyl amino C _1-6 alkyl, pyrrolidinyl or piperidinyl;
R ¹² , R ¹³ and R ¹⁴ are independently hydrogen atom, hydroxy, C _1-6 alkyl, NR ¹⁵ R ¹⁶ , R ¹⁵ R ¹⁶ NC _1-6 alkyl, C _1-6 alkoxy, mono. (Di) Hydroxy C _1-6 alkyl, carbamoyl, C _7-10 aralkyloxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, fluorine atom or fluoro C _1-6 alkyl;
R ¹⁵ is a hydrogen _{atom, C 1-6 alkyl, (C 1-6} alkyl) carbonyl or _{C 7-10} aralkyl;
R ¹⁶ is a hydrogen atom, C _1-6 alkyl or C _7-10 aralkyl;
R ¹⁷ is a hydrogen atom or C _1-6 alkyl;
n is 0, 1 or 2. ], Which is a method for producing a compound represented by [] or a pharmacologically acceptable salt thereof.

〔式中、環Ａは、前記定義の通りであり；
Ｘ^Ｐは、独立して、ＣＲ^４aＰまたは窒素原子であり；
Ｒ^１ＰおよびＲ^２Ｐは、それぞれ独立して、水素原子、ハロゲン原子、保護基で保護されていてもよいヒドロキシ、保護基で保護されていてもよいアミノ、保護基で保護されていてもよいヒドロキシＣ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルキル、ハロＣ_１−６アルキル、シアノ、Ｃ_１−６アルキルスルホニルアミノ、イミダゾリル、１，３-ジオキソリルまたはモノ（ジ）Ｃ_１−６アルコキシＣ_１−６アルキルであり；
Ｒ^３Ｐは、水素原子、ハロゲン原子またはＣ_１−６アルキルであり；
Ｒ^４ＰおよびＲ^４ａＰは、それぞれ独立して、水素原子、ハロゲン原子、保護基で保護されていてもよいヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルコキシＣ_１−６アルコキシ、ハロＣ_１−６アルキル、ハロＣ_１−６アルコキシ、保護基で保護されていてもよいヒドロキシＣ_１−６アルキル、保護基で保護されていてもよいヒドロキシＣ_１−６アルコキシ、シアノ、カルバモイル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルコキシ、Ｃ_７−１０アラルキルオキシ、Ｃ_７−１０アラルキルオキシＣ_１−６アルコキシまたは１,３-ジオキソリルであり；
Ｐは水素原子または保護基である。〕で表される化合物またはその塩と、 The following formula:

[In the formula, ring A is as defined above;
X ^P is independently CR ^4ap or a nitrogen atom;
R ^1P and R ^2P are independently hydrogen atom, halogen atom, hydroxy which may be protected by a protecting group, amino which may be protected by a protecting group, and hydroxy which may be protected by a protecting group. C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano, C _1-6 alkyl sulfonylamino, imidazolyl, 1,3-dioxolyl or mono (di) C _{1- 6} Alkoxy C _1-6 alkyl;
R ^3P is a hydrogen atom, a halogen atom or a C _1-6 alkyl;
R ^4P and R ^4aP are independently protected by hydrogen atom, halogen atom and protective group, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _{1-6, respectively.} Alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, hydroxy C _1-6 alkyl, which may be protected by a protective group, hydroxy C _1-6 alkoxy, which may be protected by a protective group, cyano, Carbamoyl, C _1-6 Alkoxycarbonyl C _1-6 Alkoxy, C _7-10 Alkoxy Oxy, C _7-10 Alkoxy Oxy C _1-6 Alkoxy or 1,3-dioxolyl;
P is a hydrogen atom or a protecting group. ] With the compound represented by] or a salt thereof,

〔式中、環Ｂ、ｎは、前記定義の通りであり；
Ｒ^５Ｐは、水素原子、Ｃ_１−６アルキル、保護基で保護されていてもよいモノ（ジ）ヒドロキシＣ_１−６アルキル、保護基で保護されていてもよいＣ_１−６アルコキシ（ヒドロキシ）Ｃ_１−６アルキル、保護基で保護されていてもよいカルボキシＣ_１−６アルキルまたはＣ_１−６アルコキシカルボニルＣ_１−６アルキルであり；
Ｒ^６ａＰは、水素原子、Ｃ（＝Ｏ）Ｒ^９Ｐ、Ｃ（＝Ｏ）ＮＲ^１０ＰＲ^１１Ｐ、ＣＲ^１２ＰＲ^１３ＰＲ^１４Ｐまたは以下の式：

（（＊＊）は結合位置を表す）であり；
Ｒ^７ａＰは、独立して、水素原子、フッ素原子、保護基で保護されていてもよいヒドロキシ、保護基で保護されていてもよいヒドロキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルコキシＣ_１−６アルキルまたは保護基で保護されていてもよいアミノＣ_１−６アルキルであり；
Ｒ^７ｂＰは、独立して、水素原子、フッ素原子またはＣ_１−６アルキルであるか、Ｒ^５ＰまたはＲ^６ａＰは、環Ｂと一緒になって６員環またはＲ^７ａＰと一緒になって５員環を形成し；
Ｒ^６ｂＰは、水素原子またはＣ_１−６アルキルであり；
Ｒ^８Ｐは、水素原子、ハロゲン原子、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、保護基で保護されていてもよいヒドロキシ、保護基で保護されていてもよいアミノ、シアノ、Ｃ_１−６アルコキシカルボニル、Ｃ_１−６アルコキシＣ_１−６アルコキシ、カルバモイル、Ｃ_１−６アルコキシＣ_１−６アルキル、保護基で保護されていてもよいカルボキシ、アジド、ハロＣ_１−６アルキルまたはテトラゾリルであり；
Ｒ^９Ｐは、保護基で保護されていてもよいヒドロキシ、Ｃ_１−６アルキルまたは保護基で保護されていてもよいヒドロキシピロリジニルであり；
Ｒ^１０ＰおよびＲ^１１Ｐは、それぞれ独立して、水素原子、Ｃ_１−６アルキル、保護基で保護されていてもよいヒドロキシＣ_１−６アルキル、保護基で保護されていてもよいモノ（ジ）Ｃ_１−６アルキルアミノＣ_１−６アルキル、保護基で保護されていてもよいピロリジニルまたは保護基で保護されていてもよいピペリジニルであり；
Ｒ^１２Ｐ、Ｒ^１３ＰおよびＲ^１４Ｐは、それぞれ独立して、水素原子、保護基で保護されていてもよいヒドロキシ、Ｃ_１−６アルキル、保護基で保護されていてもよいＮＲ^１５Ｒ^１６、保護基で保護されていてもよいＲ^１５Ｒ^１６Ｎ-Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、保護基で保護されていてもよいモノ（ジ）ヒドロキシＣ_１−６アルキル、カルバモイル、Ｃ_７−１０アラルキルオキシＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル、フッ素原子またはフルオロＣ_１−６アルキルであり；
Ｒ^１５は、水素原子、Ｃ_１−６アルキル、（Ｃ_１−６アルキル）カルボニルまたはＣ_７−１０アラルキルであり；
Ｒ^１６は、水素原子、Ｃ_１−６アルキルまたはＣ_７−１０アラルキルであり；
Ｒ^１７は、水素原子またはＣ_１−６アルキルである。〕で表される化合物またはその塩を用いることを特徴とする、製造方法。 Equation (IV):

[In the formula, rings B and n are as defined above;
R ^5P is a hydrogen atom, C _1-6 alkyl, mono (di) hydroxy C _1-6 alkyl which may be protected by a protecting group, C _1-6 alkoxy (hydroxy) which may be protected by a protecting group. C _{1-6 alkyl, carboxy C 1-6} alkyl which may be protected with a protecting group or C _1-6 alkoxycarbonyl C _1-6 alkyl;
R ^6aP is a hydrogen atom, C (= O) R ^9P , C (= O) NR ^10P R ^11P , CR ^12P R ^13P R ^14P or the following formula:

((**) represents the bond position);
R ^7aP is independently hydrogen atom, fluorine atom, hydroxy which may be protected by a protecting group, hydroxy C _1-6 alkyl which may be protected by a protecting group, C _1-6 alkyl, C _{1- 6} Alkoxy, C _1-6 Alkoxy C _{1-6 Alkyl or Amino C 1-6} Alkyl which may be protected with a protecting group;
R ^7bP is independently a hydrogen atom, a fluorine atom or C _1-6 alkyl, or R ^5P or R ^6aP is a 6-membered ring with ring B or 5-membered with ^{R 7aP.} Form a ring;
R ^6bP is a hydrogen atom or C _1-6 alkyl;
R ^8P is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy which may be protected by a protective group, amino, cyano, C _{1-6 which may be protected by a protective group.} Alkoxycarbonyl, C _1-6 alkoxy C _1-6 alkoxy, carbamoyl, C _1-6 alkoxy C _1-6 alkyl, carboxy, azide, halo C _1-6 alkyl or tetrazolyl which may be protected with a protective group. ;
R ^9P _{is hydroxy, C 1-6} alkyl, which may be protected with a protecting group, or hydroxypyrrolidinyl, which may be protected by a protecting group;
R ^10P and R ^11P are independently hydrogen atom, C _1-6 alkyl, hydroxy C _1-6 alkyl which may be protected by a protecting group, and mono (di) which may be protected by a protecting group. C _1-6 alkyl amino C _1-6 alkyl, pyrrolidinyl which may be protected with a protecting group or piperidinyl which may be protected by a protecting group;
R ^12P , R ^13P and R ^14P are independently hydrogen atom, hydroxy which may be _{protected by a protecting group, C 1-6} ^{alkyl, NR 15} R ¹⁶ which may be protected by a protecting group, and protection. Group-protected R ¹⁵ R ¹⁶ NC _1-6 alkyl, C _1-6 alkoxy, protecting group-protected mono (di) hydroxy C _1-6 alkyl, carbamoyl, C _{7 -10} Aralkyloxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, fluorine atom or fluoro C _1-6 alkyl;
R ¹⁵ is a hydrogen _{atom, C 1-6 alkyl, (C 1-6} alkyl) carbonyl or _{C 7-10} aralkyl;
R ¹⁶ is a hydrogen atom, C _1-6 alkyl or C _7-10 aralkyl;
R ¹⁷ is a hydrogen atom or a C _1-6 alkyl. ], A production method comprising the use of the compound represented by) or a salt thereof.

[2] The manufacturing method according to [1].
A compound represented by the above formula (IIC) or (IID) or a salt thereof,
A production method comprising the use of the compound represented by the formula (IV) or a salt thereof.
[3] The manufacturing method according to [1].
The compound represented by the above formula (III) or a salt thereof, and
A production method comprising the use of the compound represented by the formula (IV) or a salt thereof.
[4] The production method according to any one of [1] to [3].
Ring A is C _3-6 cycloalkyl, C _6-10 aryl, pyridyl, benzo [1,3] dioxolyl or thienyl;
Ring B is selected _{from the group consisting of C 6-10} aryl or the following: pyridyl, pyrimidyl, piperidinyl, morpholinyl, thiazolyl, pyrazinyl, pyrazolyl, imidazolyl, pyridazinyl, azindridinyl, indolyl, isoquinolyl, triazolyl, tetrazolyl and dihydropyrimidinyl. A manufacturing method that is a heterocycle.
[5] The manufacturing method according to [4], wherein n is 1.
[6] The manufacturing method according to [5].
Ring A is phenyl;
X is CR ^4a ;
X ^{P is,} there in the ^{CR 4aP;}
R ^4a are independently hydrogen atom, halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, halo C _1-6 alkyl, halo C _{1 -6} alkoxy, hydroxy _{C 1-6} alkyl, hydroxy _{C 1-6} alkoxy, cyano, _{carbamoyl, C 1-6} alkoxycarbonyl _{C 1-6 alkoxy, C 7-10 aralkyloxy, C 7-10} aralkyloxy _{C 1- 6} Alkoxy or 1,3-dioxolyl;
R ^4aP may be independently protected by hydrogen atom, halogen atom, protective group, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, halo. C _1-6 alkyl, halo C _1-6 alkoxy, hydroxy C _1-6 alkyl, which may be protected by a protective group, hydroxy C _1-6 alkoxy, which may be protected by a protective group, cyano, carbamoyl, C. _1-6 Alkoxycarbonyl C _1-6 Alkoxy, C _7-10 Alkoxy Oxy, C _7-10 Alkoxy Oxy C _1-6 Alkoxy or 1,3-dioxolyl.

〔式中、（＊＊）は結合位置を表す〕であり；
Ｒ^７ａが、水素原子、フッ素原子、ヒドロキシ、ヒドロキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルコキシＣ_１−６アルキルまたはアミノＣ_１−６アルキルであり；
Ｒ^７ｂが、水素原子、フッ素原子またはＣ_１−６アルキルであるか；
Ｒ^６ａが、環ＢまたはＲ^７ａと一緒になって以下の式：

〔式中、（＊＊）は結合位置を表す〕
を形成し；
Ｒ^６ａＰが、水素原子、Ｃ（＝Ｏ）Ｒ^９Ｐ、Ｃ（＝Ｏ）ＮＲ^１０ＰＲ^１１Ｐ、ＣＲ^１２ＰＲ^１３ＰＲ^１４Ｐまたは以下の式：

〔式中、（＊＊）は結合位置を表す〕であり；
Ｒ^７ａＰが、水素原子、フッ素原子、保護基で保護されていてもよいヒドロキシ、保護基で保護されていてもよいヒドロキシＣ_１−６アルキル、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルコキシＣ_１−６アルキルまたは保護基で保護されていてもよいアミノＣ_１−６アルキルであり；
Ｒ^７ｂＰが、水素原子、フッ素原子またはＣ_１−６アルキルであるか；
Ｒ^６ａＰが、環ＢまたはＲ^７ａＰと一緒になって以下の式：

〔式中、（＊＊）は結合位置を表す〕
を形成する、製造方法。 [7] The manufacturing method according to [6].
R ⁵ is hydrogen atom;
A ^{production method in which R 5P} is a hydrogen atom.
[8] The manufacturing method according to [7].
R ^6a is a hydrogen atom, C (= O) R ⁹ , C (= O) NR ¹⁰ R ¹¹ , CR ¹² R ¹³ R ¹⁴ or the following formula:

[In the formula, (**) represents the bond position];
R ^7a is a hydrogen atom, a fluorine atom, a hydroxy, a hydroxy C _1-6 alkyl, a C _1-6 alkyl, a C _1-6 alkoxy, a C _1-6 alkoxy C _1-6 alkyl or an amino C _1-6 alkyl. ;
Is R ^7b a hydrogen atom, a fluorine atom or a C _1-6 alkyl;
R ^6a , together with ring B or R ^7a , has the following equation:

[In the formula, (**) represents the bond position]
Form;
R ^6aP is a hydrogen atom, C (= O) R ^9P , C (= O) NR ^10P R ^11P , CR ^12P R ^13P R ^14P or the following formula:

[In the formula, (**) represents the bond position];
R ^7aP is a hydrogen atom, a fluorine atom, a hydroxy that may be protected by a protecting group, a hydroxy that may be protected by a protecting group, C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C. _1-6 Alkoxy C _{1-6 Alkyl or Amino C 1-6} Alkyl which may be protected with a protecting group;
^Is R 7bP a hydrogen atom, a fluorine atom or a C _1-6 alkyl;
R ^6aP together with ring B or R ^7aP has the following equation:

[In the formula, (**) represents the bond position]
Forming, manufacturing method.

〔式中、環Ａ、Ｘ^Ｐ、Ｒ^１P、Ｒ^２Ｐ、Ｒ^３Ｐ、Ｒ^４Ｐ、Ｐは、〔１〕記載の通りである。〕
で表される化合物またはその塩。
〔１４〕以下の式：

〔式中、環Ａ、Ｘ^Ｐ、Ｒ^１P、Ｒ^２Ｐ、Ｒ^３Ｐ、Ｒ^４Ｐは、〔１〕記載の通りである。〕
で表される化合物またはその塩。 [9] The manufacturing method according to [8].
A manufacturing method in which X and ^{XP are CH.}
[10] The manufacturing method according to [9].
R ¹ and R ² are not hydrogen atoms at the same time;
A ^{production method in which R 1P} and R ^2P are not hydrogen atoms at the same time.
[11] The manufacturing method according to [10].
R ^6b , R ^7a and R ^7b are hydrogen atoms;
A production method in which ^{R 6bP} , R ^7aP and R ^{7bP are hydrogen atoms.}
[12] The production method according to any one of [1] to [11].
R ^6a is CR ¹² R ¹³ R ¹⁴ ;
R ^6aP is CR ^12P R ^13P R ^14P ;
R ¹² is hydroxy or mono (di) hydroxy C _1-6 alkyl;
The method of preparation, wherein R ^12P is a hydroxy protected by a protecting group or a mono (di) hydroxy C _{1-6 alkyl which may be protected by a protecting group.}
[13] The following formula:

Wherein Ring ^{A, X P, R 1P,} R 2P, R 3P, R 4P, P is as [1]. ]
A compound represented by or a salt thereof.
[14] The following formula:

Wherein Ring ^{A, X P, R 1P,} R 2P, R 3P, R 4P is as [1]. ]
A compound represented by or a salt thereof.

〔式中、環Ａ、Ｘ^Ｐ、Ｒ^１P、Ｒ^２Ｐ、Ｒ^３Ｐ、Ｒ^４Ｐ、Ｐは、〔１〕記載の通りである。〕
で表される化合物またはその塩。
〔１６〕〔１３〕〜〔１５〕の何れかに記載の化合物であって、
環Ａが、Ｃ_３−６シクロアルキル、Ｃ_６−１０アリール、ピリジル、ベンゾ[１，３]ジオキソリルまたはチエニルである、化合物またはその塩。
〔１７〕〔１６〕に記載の化合物であって、
環Ａが、フェニルであり；
Ｘ^Ｐが、ＣＲ^４ａＰであり；
Ｒ^４ａＰが、それぞれ独立して、水素原子、ハロゲン原子、保護基で保護されていていてもよいヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルコキシＣ_１−６アルコキシ、ハロＣ_１−６アルキル、ハロＣ_１−６アルコキシ、保護基で保護されていてもよいヒドロキシＣ_１−６アルキル、保護基で保護されていてもよいヒドロキシＣ_１−６アルコキシ、シアノ、カルバモイル、Ｃ_１−６アルコキシカルボニルＣ_１−６アルコキシ、Ｃ_７−１０アラルキルオキシ、Ｃ_７−１０アラルキルオキシＣ_１−６アルコキシまたは１,３-ジオキソリルである、化合物またはその塩。
〔１８〕〔１７〕に記載の化合物であって、
Ｘ^Ｐが、ＣＨである、化合物またはその塩。
〔１９〕〔１８〕に記載の化合物であって、
Ｒ^１ＰおよびＲ^２Ｐが、同時に水素原子ではない、化合物またはその塩。 [15] The following formula:

Wherein Ring ^{A, X P, R 1P,} R 2P, R 3P, R 4P, P is as [1]. ]
A compound represented by or a salt thereof.
[16] The compound according to any one of [13] to [15].
A compound or a salt thereof, wherein ring A is C _3-6 cycloalkyl, C _6-10 aryl, pyridyl, benzo [1,3] dioxolyl or thienyl.
[17] The compound according to [16].
Ring A is phenyl;
X ^{P is,} there in the ^{CR 4aP;}
R ^4aP may be independently protected by a hydrogen atom, a halogen atom, and a protective group, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, respectively. halo _{C 1-6} alkyl, halo _{C 1-6} alkoxy, hydroxy may be protected with a protecting group _{C 1-6} alkyl, which may be protected by a protecting group hydroxy _{C 1-6} alkoxy, cyano, carbamoyl, C _1-6 Alkoxycarbonyl C _1-6 Alkoxy, C _7-10 Alkoxy Oxy, C _7-10 Alkoxy Oxy C _1-6 Alkoxy or 1,3-dioxolyl, a compound or salt thereof.
[18] The compound according to [17].
X ^P is CH, and the compound or a salt thereof.
[19] The compound according to [18].
A ^{compound or salt thereof in which R 1P} and R ^2P are not hydrogen atoms at the same time.

The present invention is, for example, a pyrazole derivative represented by the formula (I) or a drug thereof having a strong inhibitory effect in an Icilin-induced wet-dog shake inhibitory effect confirmation test according to the method described in International Publication No. 2009/012430. It is useful as providing a manufacturing method for advantageously preparing a physically acceptable salt. The pyrazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof produced according to the production method of the present invention is a therapeutic or prophylactic agent for a disease or symptom caused by hyperexcitability or disorder of afferent nerves. It is useful as.

The terms used herein will be described.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. It is preferably a fluorine atom or a chlorine atom.

The “C _1-6 alkyl” means an alkyl group having 1 to 6 carbon atoms which may be branched. For example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl. , N-Hexyl, Isohexyl and the like.

The “C _1-6 alkoxy” means an alkoxy group having 1 to 6 carbon atoms which may be branched. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like can be mentioned.

By "halo C _1-6 alkyl" is meant the _{C 1-6} alkyl substituted with 1-5 homologous or dissimilar halogen atoms. For example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2,2-tri Fluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 2-fluoropropyl, 1-fluoropropyl, 3,3-difluoropropyl, 2, Examples thereof include 2-difluoropropyl, 1,1-difluoropropyl, 1-fluorobutyl, 1-fluoropentyl, 1-fluorohexyl and the like.

By "fluoro C _1-6 alkyl" is meant the _{C 1-6} alkyl substituted with 1-5 fluorine atoms.

By "halo C _1-6 alkoxy" is meant the _{C 1-6} alkoxy substituted with 1-5 homologous or dissimilar halogen atoms. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-chloroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 2,2,2- Trifluoroethoxy, 1,1,2,2,2-pentafluoroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 2-fluoropropoxy, 1-fluoropropoxy, 3,3-difluoropropoxy, 2 , 2-Difluoropropoxy, 1,1-difluoropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, 6-fluorohexyloxy and the like.

"Hydroxy C _1-6 alkyl" means the _{above C 1-6} alkyl substituted with hydroxy. For example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl and the like can be mentioned.

By "mono (di) hydroxy C _1-6 alkyl" is meant the _{C 1-6} alkyl substituted with one or two hydroxys. For example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 1,3-dihydroxy Examples include propyl and the like.

"Hydroxy C _1-6 alkoxy" means the _{above C 1-6} alkoxy substituted with hydroxy. For example, hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxypropane-2-yloxy, 2-hydroxyethoxy, 2-hydroxy-2-methylpropoxy, 3-hydroxypropoxy and the like can be mentioned.

The _{"C 1-6} alkoxy _{C 1-6} alkyl", the _{C 1-6} alkoxy means the above _{C 1-6} alkyl substituted.

By "mono (di) C _1-6 alkoxy C _1-6 alkyl" is meant the _{C 1-6} alkyl substituted with one or two of the C _{1-6 alkoxys. The C 1-6} alkoxy in the case of di-substitution may be different from each other.

The _{"C 1-6} alkoxy _{C 1-6} alkoxy", said _{C 1-6} alkoxy means the above _{C 1-6} alkoxy substituted.

"C _6-10 aryl" means phenyl or naphthyl.

By "C _7-10 aralkyl" is meant an alkyl having 1 to 4 carbon atoms substituted with phenyl. For example, benzyl, phenethyl and the like can be mentioned.

"C _7-10 aralkyloxy" means an alkoxy having 1 to 4 carbon atoms substituted with phenyl. For example, benzyloxy, phenethyloxy and the like can be mentioned.

"(C _7-10 aralkyloxy) C _1-6 alkyl" means the _{C 1-6} alkyl substituted with the _{C 7-10 aralkyloxy.}

"(C _7-10 aralkyloxy) C _1-6 alkoxy" means the _{C 1-6} alkoxy substituted with the _{C 7-10 aralkyloxy.}

By "carboxy C _1-6 alkyl" is meant the _{above C 1-6 alkyl substituted with carboxy.}

By "amino C _1-6 alkyl" is meant the _{above C 1-6 alkyl substituted with amino.}

The "mono _{(di) C 1-6} alkylamino _{C 1-6} alkyl" refers to the amino _{C 1-6} alkyl mono- or di-substituted by the above _{C 1-6} alkyl. _{The C 1-6} alkyl in the case of di-substitution may be different from each other.

"C _1-6 alkyl sulfonyl amino" means a group represented by _{(C 1-6} alkyl) -SO _{2 NH-.} For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino and the like can be mentioned.

The “(C _1-6 alkyl) carbonyl” means a carbonyl substituted with the _{above C 1-6 alkyl.} For example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexylcarbonyl and the like can be mentioned.

The “C _1-6 alkoxycarbonyl” means a carbonyl substituted with the _{above C 1-6 alkoxy.} For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like can be mentioned.

The “C _1-6 alkoxycarbonyl C _1-6 alkyl” means the _{C 1-6} alkyl substituted with the _{C 1-6 alkoxycarbonyl.}

The _{"C 1-6} alkoxycarbonyl _{C 1-6} alkoxy", the _{C 1-6} alkoxycarbonyl means the above _{C 1-6} alkoxy substituted.

"C _3-6 cycloalkyl" means a monocyclic saturated alicyclic hydrocarbon having 3 to 6 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl can be mentioned.

"C _1-6 alkoxy (hydroxy) C _1-6 alkyl" refers to the _{C 1-6 alkyl substituted with C 1-6} alkoxy and hydroxy. For example, 1-hydroxy-2-methoxyethyl, 1-hydroxy-3-methoxypropyl, 2-hydroxy-3-methoxypropyl, 1-methoxy-2-hydroxyethyl, 1-methoxy-3-hydroxypropyl, 2-methoxy. -3-Hydroxypropyl and the like can be mentioned.

A "heterocycle" refers to a 5- or 6-membered heterocycle containing 1 to 4 heteroatoms selected from sulfur, oxygen and nitrogen atoms, such as frills, thienyl, pyrrolyl, pyrazolyl. Aromatic heterocycles such as imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, 1-oxide pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, frazanyl, pyrrolinyl, imidazolinyl. , Pyrazolinyl, dihydropyranyl, dihydrothiopyranyl, dihydropyridyl, dihydropyrimidinyl and other unsaturated heterocycles, and morphonyl, thiomorphonyl, pyrrolidinyl, imidazolidinyl, pyrazoridinyl, piperidinyl, piperazinyl, tetrahydrofuranyl and other unsaturated heterocycles. can. The above "heterocycle" may be fused with another cyclic group, for example, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, chromenyl, chromanonyl. , Xanthenyl, phenoxatiinyl, indridinyl, isoindolidinyl, indolyl, indazolyl, prynyl, quinolidinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyldinyl, quinoxalinyl, quinazolinyl, carbazolyl, carborinyl, acridinyl, isoindolinyl, 2,3-dihydrobenzofla Nyl, imidazole [1,2-a] pyridyl, imidazole [1,2-a] pyrazinyl, benzo [1,3] dioxolyl, benzothienyl, 5,6,7,8-tetrahydroimidazole [1,2-a] Examples thereof include pyrazinyl and azindridinyl.
The "heterocycle" of ring A preferably includes pyridyl, benzo [1,3] dioxolyl or thienyl.
Preferred examples of the "heterocycle" of ring B include pyridyl, pyrimidyl, piperidinyl, morpholinyl, thiazolyl, pyrazinyl, pyrazolyl, imidazolyl, pyridazinyl, azindridinyl, indolyl, isoquinolyl, triazolyl, tetrazolyl or dihydropyrimidinyl. More preferably, 2-pyridyl, 2-pyrimidyl, 1-pyrazolyl, 1,2,3-triazole-2-yl, 2-thiazolyl or 4-thiazolyl may be mentioned.

"May be protected by a protecting group" means that hydroxy, amino and carboxy may be protected by a group commonly used as a protecting group, as long as it functions as a protecting group. It may be such a group. As a protecting group, for example, Theodra W. et al. Greene & Peter G. M. Wuts ed., "Greene's Protective Groups in Organic Synthesis", fourth edition, Wiley-Interscience, 2006 or Peter G. et al. M. Protecting groups described in Wuts, "Greene's Protective Groups in Organic Synthesis", fifth edition, Wiley-Interscience, 2014 can be mentioned.

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

また、例えば、式（IIa）および（IIb）のような互変異性体が挙げられ、該互変異性体に保護基を導入した式（IIc）および（IId）の異性体も挙げられる。

（式中、ＰＧは保護基を表す。）
例えば、式（IIC）または（IID）で表される化合物には、それぞれの前記互変異性体および異性体（式（IIC）には式（IIa）および式（IIc）が含まれ、式（IID）には式（IIb）および式（IId）が含まれる）を包含する。

The compounds represented by the formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV) include optical isomers, geometric isomers, tautomers and the like. Such stereoisomers are also included.
The optical isomers of the compounds represented by the formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV) have an R configuration at each asymmetric carbon atom. Alternatively, any of the three-dimensional arrangements of the S arrangement may be used. Further, any optical isomer is included in the present invention, and a mixture of these optical isomers is also included. Further, in the mixture of optically active substances, a racemate composed of equal amounts of each optical isomer is also included in the scope of the present invention.
When the compounds represented by the formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV) are racemic solids or crystals, racemic compounds, racemic mixtures and Racemic solid solutions are also included in the scope of the present invention.
If geometric isomers are present in the compounds represented by the formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV), the present invention is the same. Includes any of.
Further, when tautomers are present in the compounds represented by the formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV), the present invention is the present invention. Includes any of the tautomers.
For example, tautomers such as the following formulas (I) and (I') can be mentioned.

Further, for example, tautomers such as the formulas (IIa) and (IIb) are mentioned, and isomers of the formulas (IIc) and (IId) in which a protecting group is introduced into the tautomers are also mentioned.

(In the formula, PG represents a protecting group.)
For example, the compounds represented by formula (IIC) or (IID) include the said tautomers and isomers, respectively (formula (IIC) includes formulas (IIa) and formulas (IIc), respectively. IID) includes equations (IIb) and (IId)).

The compound represented by the formula (I) can be a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Examples of such a salt include an acid addition salt or a salt with a base.
The compounds represented by the formulas (IIC), (IID), (III) and (IV) can be salt thereof, if necessary, according to a conventional method. Examples of such a salt include an acid addition salt or a salt with a base.

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

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

Further, the compound represented by the formula (I) or a pharmacologically acceptable salt thereof also includes a solvate with a pharmaceutically acceptable solvent such as hydrate and ethanol.

TRPM8 is a cation channel that is expressed in the dorsal root ganglion and trigeminal ganglion of the spinal cord. TRPM8 inhibitors reduce the intracellular cation influx through TRPM8 and suppress the increase in intracellular cation concentration. Based on this effect, TRPM8 inhibitors are useful as therapeutic or prophylactic agents for lower urinary tract symptoms (LUTS), especially overactive bladder (OAB), by suppressing excessively excited afferent nerve activity. be.
In addition, the TRPM8 inhibitory effect can be evaluated by the effect of suppressing the wet-dog shake effect induced by the administration of Icilin, which is a TRPM8 agonist. Furthermore, the effect on overactive bladder (OAB) can be evaluated by a test for confirming the prolongation effect on the micturition interval of acetic acid-induced detrusor hyperactive bladder according to the method described in J.Urol., 2001,166,1142. ..

Examples of the compound represented by the formula (I) include the following compounds or pharmacologically acceptable salts thereof.

As another embodiment of the compound represented by the formula (I),
Ring A is phenyl;
X is CR ^4a ;
R ¹ is a hydrogen atom;
R ² is a halogen atom;
R ³ is a hydrogen atom or a halogen atom;
R ⁴ and R ^4a are independently hydrogen or halogen atoms;
Ring B is phenyl, 2-pyridyl, 2-pyrimidyl, 1,2,3-triazole-2-yl or 1-pyrazolyl;
R ⁵ is hydrogen atom;
R ^6a is C (= O) NR ¹⁰ R ¹¹ or CR ¹² R ¹³ R ¹⁴ ;
R ^7a is a hydrogen atom or C _1-6 alkyl;
R ^7b is a hydrogen atom;
R ^6b is a hydrogen atom;
R ⁸ is hydrogen atom or a halogen atom;
R ¹⁰ and R ¹¹ are hydrogen atoms;
R ¹² , R ¹³ and R ¹⁴ are independently hydrogen atoms, hydroxy, C _1-6 alkoxy, hydroxy C _1-6 alkyl or fluorine atoms;
n is 1.

As another embodiment of the compound represented by the formulas (IIC), (IID), (IICC), (IIDC), (III),
Ring A is phenyl;
X ^{P is,} there in the ^{CR 4aP;}
R ^1P is a hydrogen atom;
R ^2P is a halogen atom;
R ^3P is a hydrogen atom or a halogen atom;
R ^4P and R ^4aP are independent hydrogen atoms or halogen atoms, respectively.

As another embodiment of the compound represented by the formula (IV),
Ring B is phenyl, 2-pyridyl, 2-pyrimidyl, 1,2,3-triazole-2-yl or 1-pyrazolyl;
R ^5P is a hydrogen atom;
R ^6aP is C (= O) NR ^10P R ^11P or CR ^12P R ^13P R ^14P ;
R ^7aP is a hydrogen atom or C _1-6 alkyl;
R ^7bP is a hydrogen atom;
R ^6bP is a hydrogen atom;
R ^8P is a hydrogen atom or a halogen atom;
R ^10P and R ^11P are hydrogen atoms;
R ^12P , R ^13P and R ^14P are independently hydrogen atom, hydroxy which may be _{protected by a protecting group, C 1-6 alkoxy, hydroxy C 1-6} alkyl which may be protected by a protecting group, respectively. Or a fluorine atom;
n is 1.

（（＊＊）は結合位置を表す）であり；
Ｒ^７ａが、水素原子、フッ素原子、ヒドロキシ、Ｃ_１−６アルキルまたはＣ_１−６アルコキシであり；
Ｒ^７ｂが、水素原子、フッ素原子またはＣ_１−６アルキルであり；
Ｒ^６ｂが、水素原子またはＣ_１−６アルキルであり；
Ｒ^８が、水素原子、ハロゲン原子、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、シアノまたはハロＣ_１−６アルキルであり；
Ｒ^１０およびＲ^１１が、水素原子であり；
Ｒ^１２、Ｒ^１３およびＲ^１４が、それぞれ独立して、水素原子、ヒドロキシ、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルキル、ＮＲ^１５Ｒ^１６、Ｃ_１−６アルコキシ、モノ（ジ）ヒドロキシＣ_１−６アルキル、カルバモイル、フッ素原子またはフルオロＣ_１−６アルキルであり；
Ｒ^１５およびＲ^１６が、水素原子であり；
ｎが、１である。 As another embodiment of the compound represented by the formula (I),
Ring A is phenyl;
X is CR ^4a ;
R ¹ is a hydrogen atom or a halogen atom;
R ² is hydrogen atom or a halogen atom;
R ³ is a hydrogen atom or a halogen atom;
R ⁴ and R ^4a are independently hydrogen, halogen or halo C _1-6 alkoxy;
Ring B is phenyl, 2-pyridyl, 2-pyrimidyl, 2-thiazolyl, 4-thiazolyl, 1-pyrazolyl, 2-imidazolyl or 1,2,3-triazole-2-yl;
R ⁵ is hydrogen atom;
R ^6a is a hydrogen atom, C (= O) NR ¹⁰ R ¹¹ , CR ¹² R ¹³ R ¹⁴ or the following formula:

((**) represents the bond position);
R ^7a is a hydrogen atom, a fluorine atom, a hydroxy, a C _1-6 alkyl or a C _1-6 alkoxy;
R ^7b is a hydrogen atom, a fluorine atom or a C _1-6 alkyl;
R ^6b is a hydrogen atom or C _1-6 alkyl;
R ⁸ is a hydrogen atom, a halogen atom, a C _1-6 alkyl, a C _1-6 alkoxy, a cyano or a halo C _1-6 alkyl;
R ¹⁰ and R ¹¹ are hydrogen atoms;
R ¹² , R ¹³ and R ¹⁴ are independently hydrogen atom, hydroxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl, NR ¹⁵ R ¹⁶ , C _1-6 alkoxy, mono ( D) Hydroxy C _1-6 alkyl, carbamoyl, fluorine atom or fluoro C _1-6 alkyl;
R ¹⁵ and R ¹⁶ are hydrogen atoms;
n is 1.

As another embodiment of the compound represented by the formulas (IIC), (IID), (IICC), (IIDC), (III),
Ring A is phenyl;
X ^{P is,} there in the ^{CR 4aP;}
R ^1P is a hydrogen atom or a halogen atom;
R ^2P is a hydrogen atom or a halogen atom;
R ^3P is a hydrogen atom or a halogen atom;
R ^4P and R ^4aP are independently hydrogen atoms, halogen atoms or halo C _1-6 alkoxy.

（（＊＊）は結合位置を表す）であり；
Ｒ^７ａＰが、水素原子、フッ素原子、保護基で保護されていてもよいヒドロキシ、Ｃ_１−６アルキルまたはＣ_１−６アルコキシであり；
Ｒ^７ｂＰが、水素原子、フッ素原子またはＣ_１−６アルキルであり；
Ｒ^６ｂＰが、水素原子またはＣ_１−６アルキルであり；
Ｒ^８Ｐが、水素原子、ハロゲン原子、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、シアノまたはハロＣ_１−６アルキルであり；
Ｒ^１０ＰおよびＲ^１１Ｐが、水素原子であり；
Ｒ^１２Ｐ、Ｒ^１３ＰおよびＲ^１４Ｐが、それぞれ独立して、水素原子、保護基で保護されていてもよいヒドロキシ、Ｃ_１−６アルコキシＣ_１−６アルキル、Ｃ_１−６アルキル、保護基で保護されていてもよいＮＲ^１５Ｒ^１６、Ｃ_１−６アルコキシ、保護基で保護されていてもよいモノ（ジ）ヒドロキシＣ_１−６アルキル、カルバモイル、フッ素原子またはフルオロＣ_１−６アルキルであり；
Ｒ^１５およびＲ^１６が、水素原子であり；
ｎが、１である。 As another embodiment of the compound represented by the formula (IV),
Ring B is phenyl, 2-pyridyl, 2-pyrimidyl, 2-thiazolyl, 4-thiazolyl, 1-pyrazolyl, 2-imidazolyl or 1,2,3-triazole-2-yl;
R ^5P is a hydrogen atom;
R ^6aP is a hydrogen atom, C (= O) NR ^10P R ^11P , CR ^12P R ^13P R ^14P or the following formula:

((**) represents the bond position);
R ^7aP _{is a hydroxy, C 1-6} alkyl or C _1-6 alkoxy that may be protected by a hydrogen atom, a fluorine atom, a protecting group;
R ^7bP is a hydrogen atom, a fluorine atom or a C _1-6 alkyl;
R ^6bP is a hydrogen atom or C _1-6 alkyl;
R ^8P is a hydrogen atom, a halogen atom, a C _1-6 alkyl, a C _1-6 alkoxy, a cyano or a halo C _1-6 alkyl;
R ^10P and R ^11P are hydrogen atoms;
R ^12P , R ^13P and R ^14P are independently protected by a hydrogen atom, a hydroxy which may be protected by a protecting group, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl, and a protecting group, respectively. It may be NR ¹⁵ R ¹⁶ , C _1-6 alkoxy, mono (di) hydroxy C _1-6 alkyl, which may be protected with a protecting group, carbamoyl, fluorine atom or fluoro C _1-6 alkyl;
R ¹⁵ and R ¹⁶ are hydrogen atoms;
n is 1.

式中、記号は上記〔１〕と同じ意味である。 Further, as one embodiment, in the compound represented by the formula (I), ^{the 6-membered ring formed by R 5} or R ^6a together with the ring B is a group represented by the following formula.

In the formula, the symbols have the same meaning as the above [1].

式中、記号は上記〔１〕と同じ意味である。 Further, as one embodiment, in the compound represented by the formula (IV), ^{the 6-membered ring formed by R 5P} or R ^6aP together with the ring B is a group represented by the following formula.

In the formula, the symbols have the same meaning as the above [1].

式中、Ｒ^１８は、アミノまたはヒドロキシＣ_１−６アルキルであり、それ以外の記号は、上記〔１〕と同じ意味である。 Further, as one embodiment, in the compound represented by the formula (I), ^{the 5-membered ring formed by R 5} or R ^6a together with R ^7a is a group represented by the following formula.

In the formula, R ¹⁸ is amino or hydroxy C _1-6 alkyl, and the other symbols have the same meanings as in [1] above.

式中、Ｒ^１８Ｐは、保護基で保護されていてもよいアミノまたは保護基で保護されていてもよいヒドロキシＣ_１−６アルキルであり、それ以外の記号は、上記〔１〕と同じ意味である。 Further, as one embodiment, in the compound represented by the formula (IV), ^{the 5-membered ring formed by R 5P} or R ^6aP together with R ^7aP is a group represented by the following formula.

In the formula, R ^18P is an amino protected by a protecting group or a hydroxy C _1-6 alkyl which may be protected by a protecting group, and the other symbols have the same meanings as in [1] above. be.

Method for producing a compound represented by the formula (I) of the present invention The compound represented by the formula (I) or a pharmacologically acceptable salt thereof is a method described in detail below or a method similar thereto, or It can be manufactured according to the method described in other documents or a method similar thereto.

Compound (4) shown in Scheme 1 can be produced according to the method described in 2012 or a method similar thereto in Journal of Organic Chemistry, 77 (8), 3887-3906;

（式中、環Ａ、Ｒ^１Ｐ、Ｒ^２Ｐ、Ｒ^４ＰおよびＸ^Ｐは前記と同義である）

(Wherein ring ^{A, R 1P, R 2P,} R 4P and ^{X P} are as defined above)

As the compound (1) and the compound (2), commercially available products can be used, and the compound (1) and the compound (2) can be produced according to the method described in the literature or a method similar thereto.

Compound (4) can also be produced by the method shown in Scheme 2.

（式中、環Ａ、Ｒ^１Ｐ、Ｒ^２Ｐ、Ｒ^４ＰおよびＸ^Ｐは前記と同義であり；Ｕは塩素原子、臭素原子、ヨウ素原子等の脱離基であり；ＲａはＣ_１−６アルキルである）

(Wherein ring ^{A, R 1P, R 2P,} R 4P and ^{X P} is an defined as above; U is a chlorine atom, a bromine atom, a leaving group such as iodine atom; Ra is _{C 1-6} alkyl Is)

Process 2-1
The compound (7) can be produced by reacting the compound (5) with the compound (6) in a solvent and then reacting with the compound (2) in the presence of a base. Examples of the solvent used include toluene, benzene, acetonitrile, tetrahydrofuran, 1,4-dioxane and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, tert-potassium butoxy, potassium carbonate, cesium carbonate and the like. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 2 hours to 3 days.
As the compound (5) and the compound (2), commercially available products can be used, or they can be produced according to the method described in the literature or a method similar thereto.

Process 2-2
Compound (8) can be produced by reacting compound (7) with carbon monoxide in the presence of RaOH, a base and a palladium catalyst in a solvent. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. Examples of RaOH include n-propanol and n-butanol. Examples of the base include triethylamine, N, N-diisopropylethylamine and the like. Examples of the palladium catalyst include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride, and tetrakis (triphenylphosphine) palladium (0). ) And so on. If necessary, ligands such as 1,3-bis (diphenylphosphine) propane, 1,1'-bis (diphenylphosphino) ferrocene, and bis (adamantane-1-yl) (butyl) phosphine can be used. It can be added. The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 2 hours to 3 days.

Process 2-3
Compound (4) can be produced by hydrolyzing compound (8) in a solvent using a base. Examples of the solvent used include methanol, ethanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, water, and a mixed solvent thereof. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 3 days. In this step, acid hydrolysis and hydrogenation decomposition can be used as needed, and the methods thereof include Theodora W. et al.
Greene & Peter G. M. The methods described in Wuts, "Greene's Protective Groups in Organic Synthesis", fourth edition, Wiley-Interscience, 2006 can be mentioned.

Compound (7) can also be produced by the method shown in Scheme 3.

（式中、環Ａ、Ｒ^１Ｐ、Ｒ^２Ｐ、Ｒ^４Ｐ、Ｘ^ＰおよびＵは前記と同義である）

(Wherein ring ^{A, R 1P, R 2P,} R 4P, X P and U are as defined above)

Process 3
Compound (7) can be produced from compound (9), compound (6), a base and compound (10) by the same method as in step 2-1.
The compound (10) and the compound (9) can be produced by using commercially available products or by following the methods described in the literature or similar methods thereof.

Compound (13) or compound (13a) can be produced by the method shown in Scheme 4.

（式中、環Ａ、Ｒ^１Ｐ、Ｒ^２Ｐ、Ｒ^４Ｐ、Ｘ^Ｐ、ＵおよびＲａは前記と同義であり；Ｒ^３ａＰはフッ素原子または塩素原子であり；Ｐは水素原子または保護基である）

(Wherein ring ^{A, R 1P, R 2P,} R 4P, X P, U and Ra is an defined as ^{above; R 3 ap} is a fluorine atom or a chlorine atom; P is a hydrogen atom or a protecting group)

Process 4-1
When R ^3aP is a fluorine atom, compound (7a) can be reacted with a fluorinating agent in a solvent to produce compound (11). Examples of the solvent used include acetonitrile, acetone, dichloromethane, 1,2-dichloroethane and the like. Examples of the fluorinating agent include N-fluoro-N'-(chloromethyl) triethylenediammonium (bistetrafluoroborate), N-fluorobenzenesulfonimide, 1-fluoro-2,4,6-trimethylpyridiniumtetrafluoro. Benzene and the like can be mentioned. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 1 hour to 3 days.

Process 4-2
When R ^3aP is a chlorine atom, compound (7a) can be reacted with a chlorinating agent in a solvent to produce compound (11). Examples of the solvent used include dichloromethane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran and the like. Examples of the chlorinating agent include N-chlorosuccinimide, thionyl chloride and the like. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 1 hour to 3 days.

Process 4-3 to Process 4-4
The compound (13) can be produced from the compound (11) by the same method as in Steps -2-2 to Steps 2-3.

Compound (15) or (15a) can be produced by the method shown in Scheme 5.

（式中、環Ａ、Ｒ^１Ｐ、Ｒ^２Ｐ、Ｒ^４Ｐ、Ｘ^Ｐ、ＰおよびＲａは前記と同義であり；Ｒ^３ｂＰは臭素原子であり、Ｒ^３ｃＰはＣ_１−６アルキルである）

(Wherein ring ^{A, R 1P, R 2P,} R 4P, X P, the P and Ra be defined as ^{above; R 3 bp} is bromine ^{atom, R 3 cP} is _{C 1-6} alkyl)

Process 5-1
Compound (12) can be produced by reacting compound (8a) with a brominating agent in a solvent. Examples of the solvent used include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran and the like. Examples of the brominating agent include N-bromosuccinimide, tribromoisocyanuric acid, bromine and the like. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 1 hour to 3 days.

Step 5-2
Compound (14) can be produced by reacting compound (12) with alkylboronic acid or an anhydride thereof in a solvent in the presence of a base or a palladium catalyst. Examples of the solvent used include toluene, acetonitrile, N, N-dimethylformamide, tetrahydrofuran and the like. Examples of the base include cesium carbonate, potassium carbonate, triethylamine, N, N-diisopropylethylamine and the like. Examples of alkylboronic acid or its anhydride include trimethylboronic acid, methylboronic acid, ethylboronic acid, butylboronic acid and the like. Examples of the palladium catalyst include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride, and tetrakis (triphenylphosphine) palladium (0). ) And so on. If necessary, ligands such as 1,3-bis (diphenylphosphine) propane, 1,1'-bis (diphenylphosphino) ferrocene, and bis (adamantane-1-yl) (butyl) phosphine can be used. It may be added. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 1 hour to 3 days.

Step 5-3
Compound (15) can be produced from compound (14) in the same manner as in Steps 2-3.

The optically active compound (21) can be produced by the method shown in Scheme 6.

（式中、Ｒ^６ａＰ、Ｒ^６ｂＰ、Ｒ^７ａＰおよびＲ^７ｂＰは前記と同義であり；環Ｂ１はＣ_６−１０アリールまたは、ＮＨを含まないヘテロ環であり；Ｒ^８Ｐ’はヒドロキシ、アミノ、カルバモイルおよびカルボキシを除くＲ^８Ｐであり（Ｒ^８Ｐは前記と同義である）；＊はキラル原子である）

(In the formula, R ^6aP , R ^6bP , R ^7aP and R ^7bP are synonymous with the above; ring B1 is a C _6-10 aryl or NH-free heterocycle; R ^8P'is hydroxy, amino, carbamoyl. And R ^8P excluding carboxy (R ^8P is synonymous with the above); * is a chiral atom)

Step 6-1
Compound (17) can be produced by reacting compound (17) with compound (16) in the presence of Lewis acid in a solvent. Examples of the solvent used include tetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, toluene and the like. Examples of Lewis acid include tetraethyl orthotitanium and tetraisopropyl orthotitanium. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 1 hour to 3 days.
The compound (16) and the compound (17) can be produced by using commercially available products or by following the methods described in the literature or similar methods thereof.

Step 6-2
The compound (20) can be produced by reacting the compound (18) with the compound (19) in a solvent in the presence of a base. Such a method for synthesizing an optically active amine using Ellman's imine is well known to those skilled in the art, and can be synthesized, for example, by using the method described in Chemical Reviews 2010, 110, 3600-3740. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, toluene and the like. Examples of the base include n-butyllithium, lithium diisopropylamide, bis (trifluoromethanesulfonyl) imidelithium and the like. The reaction temperature is −78 ° C. to room temperature, and the reaction time is usually 1 hour to 12 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
In addition to using a commercially available product, compound (18) can be produced according to the method described in the literature or a method similar thereto.

Step 6-3
The compound (21) can be produced by using an acid in the solvent of the compound (20). Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, methanol, ethanol, acetonitrile, water, a mixed solvent thereof and the like. Examples of the acid include hydrogen chloride, trifluoroacetic acid, acetic acid, sulfuric acid and the like. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 10 minutes to 1 day.

Compound (21a) or compound (21b) can be produced by the method shown in Scheme 7.

（式中、環Ｂ、Ｒ^６ａＰ、Ｒ^６ｂＰ、Ｒ^７ａＰ、Ｒ^７ｂＰ、Ｒ^８ＰおよびＵは前記と同義であり；Ｑは保護基である）

(In the formula, rings B, R ^6aP , R ^6bP , R ^7aP , R ^7bP , R ^8P and U are synonymous with the above; Q is a protecting group).

Process 7-1
The compound (23) can be produced by reacting the compound (22) with an organic phosphorus compound and an iodizing agent in a solvent in the presence of a base. Substitution of hydroxy to iodine atoms using such organophosphorus compounds and iodination agents is well known to those of skill in the art and is described, for example, in Angewandte Chemie International Edition in English 1975, 14, 801-811. Alternatively, it can be synthesized by using a method similar thereto. Examples of the solvent used include tetrahydrofuran, acetonitrile, dichloromethane, acetone, N, N-dimethylformamide, N, N-dimethylacetamide and the like. Examples of the base include imidazole and pyridine. Examples of the iodinating agent include iodine and sodium iodide. Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 1 day.
In addition to using a commercially available product, compound (22) can be produced according to the method described in the literature or a method similar thereto.

Step 7-2
Compound (21a) can be produced by reacting compound (23) with zinc in a solvent and then reacting with compound (24) in the presence of a palladium catalyst. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran and the like. Examples of the palladium catalyst include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocene palladium (II) dichloride, and tetrakis (triphenylphosphine) palladium (0). ), Bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) and the like. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 1 day.
In addition to using a commercially available product, compound (24) can be produced according to the method described in the literature or a method similar thereto.

Compound (21c) or compound (21d) can be produced by the method shown in Scheme 8.

（式中、Ｒ^６ａＰ、Ｒ^６ｂＰ、Ｒ^７ａＰ、Ｒ^７ｂＰ、Ｒ^８ＰおよびＱは前記と同義であり；環Ｂ２は、ＮＨを含むヘテロ環であり；環Ｂ３は、含窒素ヘテロ環であり；Ｙは、メタンスルホニルオキシ、ｐ−トルエンスルホニルオキシ、ヨウ素原子等の脱離基である）

(In the formula, R ^6aP , R ^6bP , R ^7aP , R ^7bP , R ^8P and Q are synonymous with the above; ring B2 is a heterocycle containing NH; ring B3 is a nitrogen-containing heterocycle; Y is a leaving group for methanesulfonyloxy, p-toluenesulfonyloxy, iodine atom, etc.)

Step 8-1
Compound (25) can be produced by reacting compound (22) with a sulfonyl halide or a sulfonic acid anhydride in a solvent in the presence of a base. Examples of the solvent used include dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile and the like. Examples of the base include pyridine, triethylamine, N, N-diisopropylethylamine and the like. Examples of the sulfonyl halide include p-toluenesulfonyl chloride and methanesulfonyl chloride. Examples of the sulfonic acid anhydride include trifluoromethanesulfonic anhydride and the like. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 1 day.

Step 8-2
The compound (21c) can be produced by reacting the compound (25) with the compound (26) in a solvent in the presence of a base. Further, compound (21c) can also be produced by reacting compound (25) in a solvent in the presence of a base to produce compound (27), and then reacting with compound (26). Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran and the like. Examples of the base include cesium carbonate, potassium carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, tert-potassium butoxy, sodium hydride and the like. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 3 days.
In addition to using a commercially available product, compound (26) can be produced according to the method described in the literature or a method similar thereto.

Compound (21d) can also be produced by the method shown in Scheme 9.

（式中、環Ｂ２、環Ｂ３、Ｒ^６ａＰ、Ｒ^６ｂＰ、Ｒ^７ａＰ、Ｒ^７ｂＰおよびＲ^８Ｐは前記と同義であり；Ｗは、メタンスルホニルオキシ、ｐ−トルエンスルホニルオキシ等の脱離基である）

(In the formula, ring B2, ring B3, R ^6aP , R ^6bP , R ^7aP , R ^7bP and R ^8P are synonymous with the above; W is a leaving group for methanesulfonyloxy, p-toluenesulfonyloxy and the like. )

Step 9-1
The compound (29) can be produced by reacting the compound (28) with an organic phosphorus compound in a solvent in the presence of an azo reagent. Examples of the solvent used include tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene and the like. Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine. Examples of the azo reagent include azodicarboxylic acid diisopropyl ester, azodicarboxylic acid diethyl ester, and azodicarbonyl dipiperazine. The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 2 days.
In addition to using a commercially available product, compound (28) can be produced according to the method described in the literature or a method similar thereto.

Step 9-2
Compound (30) can be produced by reacting compound (29) with compound (26) in the presence or absence of a base in a solvent. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, toluene, acetonitrile, tetrahydrofuran and the like. Examples of the base include cesium carbonate, potassium carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, tert-butoxypotassium, sodium hydride and the like. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 2 days.

Step 9-3
Compound (31) can be produced from compound (30) by the same method as in step 8-1.

Step 9-4
Compound (32) can be produced by reacting compound (31) with an agglutination reagent in a solvent. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene and the like. Examples of the azide reagent include sodium azide and the like. The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 2 days.

Step 9-5
Compound (21d) can be produced by reacting compound (32) with hydrogen in a solvent in the presence of a catalyst. Examples of the solvent used include methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid and the like. Examples of the catalyst include palladium carbon, platinum carbon and the like. The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 1 day. Further, the compound (21d) can be produced by reacting the organic phosphorus compound with water in the solvent of the compound (32). Examples of the solvent used include tetrahydrofuran, 1,4-dioxane and the like. Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine. The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 1 hour to 3 days.

The compound represented by the formula (I) can be produced by the method shown in Scheme 10.

（式中、環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６ａ、Ｒ^６ｂ、Ｒ^７ａ、Ｒ^７ｂ、Ｒ^８、Ｘ、Ｒ^１Ｐ、Ｒ^２Ｐ、Ｒ^３Ｐ、Ｒ^４Ｐ、Ｒ^５Ｐ、Ｒ^６ａＰ、Ｒ^６ｂＰ、Ｒ^７ａＰ、Ｒ^７ｂＰ、Ｒ^８Ｐ、Ｘ^Ｐおよびｎは前記と同義である）

(In the formula, ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , X, R ^1P , R ^2P , R ^{3P. , R 4P, R 5P, R} 6aP, R 6bP, R 7aP, R 7bP, R 8P, X P and n are as defined above)

Process 10-1
By reacting compound (33) with a condensing agent and compound (34) in a solvent in the presence or absence of a base, the compound represented by the formula (I) can be produced. Examples of the solvent used include N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, methanol, water and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine and the like. As the condensing agent, various reagents used for amidation of carboxylic acid can be used. For example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N'-carbonyldiimidazole, 1H-benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4, 6-Dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride, anhydrous propylphosphonic acid and the like can be mentioned.
If necessary, an activator such as 1-hydroxybenzotriazole or 1-hydroxyazabenzotriazole may be added. The reaction temperature ranges from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 7 days.
As the compound (33) and the compound (34), commercially available products are used, and they can also be produced according to the method described in the literature or a method similar thereto.

Step 10-2
The compound (33) is reacted in a solvent in the presence of a base and a condensing agent to produce the compound (35), and then reacted with the compound (34) to produce the compound represented by the formula (I). You can also. Examples of the solvent used include N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, methanol, water and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine and the like. As the condensing agent, various reagents used for amidation of carboxylic acid can be used. For example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N'-carbonyldiimidazole, 1H-benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4, 6-Dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride, anhydrous propylphosphonic acid and the like can be mentioned. If necessary, an activator such as 1-hydroxybenzotriazole or 1-hydroxyazabenzotriazole may be added. The reaction temperature ranges from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 7 days.

The compound represented by the formula (I) of the present invention can also be produced by the method shown in Scheme 11.

（式中、環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６ａ、Ｒ^６ｂ、Ｒ^７ａ、Ｒ^７ｂ、Ｒ^８、Ｒ^１Ｐ、Ｒ^２Ｐ、Ｒ^３Ｐ、Ｒ^４Ｐ、Ｒ^５Ｐ、Ｒ^６ａＰ、Ｒ^６ｂＰ、Ｒ^７ａＰ、Ｒ^７ｂＰ、Ｒ^８Ｐ、Ｑ、Ｘ、Ｘ^Ｐおよびｎは前記と同義であり、Ｌは、塩素原子、臭素原子、（Ｃ_１−６アルキル）カルボニルオキシ、Ｃ_１−６アルコキシカルボニルオキシ、Ｃ_１−６アルキルスルホニルオキシ、またはハロゲン原子、ニトロおよびＣ_１−６アルキルよりなる群から選択される置換基を有していてもよいＣ_６−１０アリールスルホニルオキシなどの脱離基である。）

(In the formula, ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a , R ^6b , R ^7a , R ^7b , R ⁸ , R ^1P , R ^2P , R ^3P , R. ^{4P, R 5P, R 6aP,} R 6bP, R 7aP, R 7bP, R 8P, Q, X, X P and n are as defined above, L is a chlorine atom, a bromine _{atom, (C 1-6} alkyl _{) C 6-} which may have a substituent selected from the group consisting of carbonyloxy, C _1-6 alkoxycarbonyloxy, C _1-6 alkyl sulfonyloxy, or halogen atom, nitro and C _{1-6 alkyl. 10} arylsulfonyloxy a leaving group such.)

Process 11-1
Compound (Ia) can be produced from compound (33a) by the same method as in step 10-1.
In addition to using a commercially available product, the compound (33a) can also be produced according to the method described in the literature or a method similar thereto.

Step 11-2
The compound (33a) is reacted with a chlorinating agent or a carboxy group activator in a solvent to produce the compound (36), and then reacted with the compound (34) in the presence or absence of a base to produce the compound (36). Ia) can be manufactured. Examples of the solvent used include dichloromethane, 1,2-dichloroethane and the like. Examples of the chlorinating agent include 1-chloro-N, N, 2-trimethylpropenylamine, thionyl chloride, oxalyl chloride and the like. Examples of the carboxy group activator include acetyl chloride, chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like.
Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine and the like. If necessary, an activator such as N, N-dimethylformamide may be added.
As a method for producing the compound (36) from the compound (33a), it is preferable to react it with a halogenating agent in a solvent, and it is more preferable to react it with a chlorinating agent such as thionyl chloride and oxalyl chloride.
The reaction temperature is from room temperature to the reflux temperature of the solvent, and the reaction time varies depending on the raw material used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 3 days.

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

Further, when a protecting group is required depending on the type of functional group, protection and deprotection operations can be appropriately combined and carried out according to a conventional method. Regarding the types of protecting groups, protection and deprotection, for example, Theodra W. et al. Greene & Peter G. M. Wuts ed., "Greene's Protective Groups in Organic Synthesis", fourth edition, Wiley-Interscience, 2006 or Peter G. et al. M. The methods described in Wuts, "Greene's Protective Groups in Organic Synthesis", fifth edition, Wiley-Interscience, 2014 can be mentioned.

The compounds represented by the formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV) are optionally well-known isolations to those skilled in the art. -It can be isolated and purified by solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography, etc., which are purification means.

As the pharmaceutical composition containing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, various dosage forms are used depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, sublinguals and the like. Administered orally or parenterally.

These pharmaceutical compositions are prepared by suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents by known methods depending on the dosage form. , Emulsifiers, dispersants, stabilizers, solubilizers and other pharmaceutical additives can be appropriately mixed, diluted and dissolved. In addition, when the compound represented by the formula (I) or a pharmacologically acceptable salt thereof is used in combination with a drug other than the TRPM8 inhibitor, the respective active ingredients are used simultaneously or separately as described above. It can be produced by formulating in the same manner.

The compound represented by the formula (I), or a pharmacologically acceptable salt thereof, exhibits a strong inhibitory effect based on TRPM8 inhibition in the Icilin-induced wet-dog shake inhibitory effect confirmation test. Therefore, a drug containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient can treat or prevent a disease or symptom caused by activation of TRPM8 by a TRPM8 inhibitory action. It can be used as a medicine.

"Disease or symptom due to activation of TRPM8" means a disease or symptom due to hyperexcitability or disorder of afferent nerves.
"Disease or symptom caused by hyperexcitability or disorder of afferent nerve" includes anxiety, depression, lower urinary tract symptom (LUTS), pain, circulatory disorder, itching, numbness, urticaria and the like.

In one embodiment, the compound of formula (I), or a pharmacologically acceptable salt thereof, is a lower urinary tract symptom (a disease or symptom caused by hyperexcitability or disorder of the afferent nerve). It is particularly useful as a LUTS) or a therapeutic or prophylactic agent for pain.

"Lower urinary tract symptom (LUTS)" refers to symptoms caused by lower urinary tract dysfunction, etc., and "lower urinary tract dysfunction" includes overactive bladder, urinary muscle overactivity, nocturia, and interstitial cyst. Examples thereof include cystitis such as cystitis, prostatic inflammation such as chronic prostatic inflammation, bladder pain syndrome, hypersensitive bladder syndrome, urinary incontinence, benign prostatic hyperplasia, and urethral stricture. Preferred examples include overactive bladder, urinary muscle overactivity, interstitial cystitis, and bladder pain syndrome.

Examples of the "circulatory disorder" include cold rhinitis and Raynaud's disease.

Examples of "pain" include tooth pain, oxaliplatin-induced peripheral neuropathy, migraine headache, postoperative pain, cold allodynia, anticancer drug-induced peripheral neuropathy, and diabetic peripheral neuropathy. Preferred examples include toothache, oxaliplatin-induced peripheral neuropathy, migraine, postoperative pain, and cold allodynia.

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

Drugs that can be used in combination with the compound represented by formula (I) or a pharmaceutically acceptable salt thereof include opioid analgesics, non-steroidal anti-inflammatory agents (NSAIDs), barbiturate sedatives, and sedative effects. benzodiazepines having, H ₁ blockers having sedative effects, sedatives, skeletal muscle relaxants, NMDA receptor antagonists, alpha-adrenergic receptor agonists, tricyclic antidepressants, anticonvulsants, tachykinin antagonists ( NK antagonists), muscarinic receptor antagonists, COX-2 selective inhibitors, coaltal analgesics, neuroleptics, TRPV1 agonists, TRPV1 inhibitors, β-adrenaline receptor blockers, local anesthetics, corticosteroids, 5-HT receptor agonist, 5-HT _2A receptor antagonist, cholinergic analgesic, PDE5 inhibitor, PDE9 inhibitor, α2δ ligand, cannabinoid, metabolic glutamate receptor 1 antagonist (mGluR1 antagonist), Metabolic glutamate receptor 5 antagonist (mGluR5 antagonist), serotonin reuptake inhibitor, noradrenaline reuptake inhibitor, serotonin / noradrenaline reuptake inhibitor, induced nitrogen monoxide synthase inhibitor (iNOS inhibitor), acetyl Cholinesterase inhibitor (AChE inhibitor), EP4 antagonist, leukotrien B4 antagonist, 5-lipoxygenase inhibitor, sodium channel blocker, 5-HT3 antagonist, drug for chemotherapy, EP1 antagonist, β3 adrenaline receptor activation Drugs, TRPA1 inhibitors, TRPV3 inhibitors, TRPV4 inhibitors, T-type calcium channel inhibitors, ATIC inhibitors, P2X inhibitors, Trk inhibitors, FAAH inhibitors, botulinum toxins, 5α reductase inhibitors, anti-NGF antibodies, Examples thereof include NGF regulators, IgE production inhibitors, histamine H2 inhibitors, bladder mucosa protectors, NOS activity regulators, bladder muscle relaxants, GABA reuptake inhibitors, GABA receptor regulators, GABA aminotransferase inhibitors and the like.

Further, the agents used in combination are specifically exemplified as follows, but the content of the present invention is not limited thereto. In addition, specific compounds include the free form thereof and other pharmacologically acceptable salts.

Examples of the "α-adrenergic receptor agonist" include doxazosin, tamsulosin, silodosin, clonidine, guanfacine, dexmedetomidine, tizanidine, moxonidine and the like.

Examples of the "muscarinic antagonist" include oxybutynin, tolterodine, propiverine, darifenacin, solifenacin, temiberin, ipratropium bromide, trospium, propantherin, temiberin, imidafenacin, fesoterodine and the like.

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

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

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

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

In addition, the compound represented by the formula (I) or a pharmacologically acceptable salt thereof can be added to the prevention or treatment of the above-mentioned diseases by administering it in appropriate combination with one or more of the above-mentioned agents. It is possible to obtain a more advantageous effect than the effect. Alternatively, similarly, the amount used may be reduced as compared with the case of administration alone, the side effects of drugs other than the TRPM8 inhibitor used in combination may be reduced, or the side effects of drugs other than the TRPM8 inhibitor used in combination may be avoided. Or it can be reduced.

The pharmaceutical composition containing the compound represented by the formula (I) or a pharmacologically acceptable salt thereof may be systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal). It can be administered by internal, subcutaneous, intramuscular, transdermal, etc.).

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

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

Of the symbols used in each reference example, each embodiment, and each table, Ref. Ex. Is a reference example number, Ex. No. Is an example number, Strc. Means the chemical structural formula, PD means the spectral data, and PC means the purification conditions. * Means a chiral atom. Rel. Means relative configuration. ^{1 1} H-NMR means hydrogen nuclear magnetic resonance spectrum, and CDCl ₃ is chloroform-d, DM.
SO-d ₆ means dimethyl sulfoxide-d ₆ and CD ₃ OD means methanol-d ₄ . MS means mass spectrometry and ESI-MS means electrospray ionization mass spectrometry. RT means the retention time of high speed liquid column chromatography. SiO2 means silica gel column chromatography, and APS means aminopropyl silica gel column chromatography. Further, low polarity or LP means a compound that elutes first when a mixture of stereoisomers is separated and purified by normal phase column chromatography, and high polarity or HP means a compound that elutes later. .. TBS means tert-butyldimethylsilyl, TBDPS means tert-butyldiphenylsilyl, Bn means benzyl, MOM means methoxymethyl, Cbz means benzyloxycarbonyl, Boc means tert-butoxycarbonyl, and Bu means n-butyl.
As described above, the present invention also includes tautomers of the compound represented by the formula (I). Therefore, the compound names in Reference Examples and Examples and the chemical structural formulas in the table are not limited to those compound names and the formulas in the table, and include their tautomers.

In each reference example, the microwave irradiation was performed by Biotage's Initiator.

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

Reference Example 1-1-1
2- [5- (3-Fluorophenyl) -1H-pyrazole-3-yl] benzoic acid Journal of Organic Chemistry, 77 (8), 3887-3906; The compound was obtained. The structural formula, spectral data and purification conditions are shown in Table 3.

Reference example 1-1-2-1-1-16
Using the corresponding raw materials, Reference Examples 1-12-1 to 1-1-16 were synthesized in the same manner as in Reference Example 1-1-1. The structural formula, spectral data and purification conditions are shown in Tables 3 to 4.

Reference example 1-2-1
4-Ethynyl-1-fluoro-3-methoxybenzene 4-bromo-1-fluoro-3-methoxybenzene (0.513 g), trimethylsilylacetylene (0.737 g) in tetrahydrofuran (5 mL) mixed with triethylamine (3.795 g) ), Bistriphenylphosphine palladium (II) dichloride (0.175 g) and copper (I) iodide (0.048 g) were added, and the mixture was stirred at 110 ° C. for 1 hour under microwave irradiation. This mixture was passed through a Celite pad. A saturated aqueous solution of ammonium chloride was added to the filtrate, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran (5 mL), a tetra-n-butylammonium tetrahydrofuran solution (1 mol / L, 5 mL) was added under ice-cooling, and the mixture was stirred for 30 minutes. After adding saturated aqueous ammonium chloride solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (0.375 g). The structural formula, spectral data and purification conditions are shown in Table 5.

Reference example 1-2-2
Reference Example 1-2-2 was synthesized in the same manner as in Reference Example 1-2-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 5.

Reference example 1-3-1
3-Bromo-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzamide and 3-bromo-2- [5- (4-fluorophenyl) -2 -Mixed mixture of -(methoxymethyl) -2H-pyrazole-3-yl] benzamide To a solution of 2,6-dibromobenzaldehyde (1.6 g) in toluene (40 mL), p-toluenesulfonyl hydrazine (1.13 g) was added, and 110 The mixture was stirred at 1.5 hours. After cooling the reaction mixture to room temperature, sodium ethoxide (1.65 g) was added, and the mixture was stirred for 10 minutes. To this mixture was added 1-ethynyl-4-fluorobenzene (1.09 g) and stirred at 110 ° C. for 20 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3- (2,6-dibromophenyl) -5- (4-fluorophenyl). ) -1H-Pyrazole (0.35 g) was obtained. Cesium carbonate (0.86 g) and chloromethyl methyl ether (0.14 g) were added to a solution of the product (0.35 g) in N, N-dimethylformamide (2 mL), and the mixture was stirred at 60 ° C. for 1 day. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3- (2,6-dibromophenyl) -5- (4-fluorophenyl). ) -1- (methoxymethyl) -1H-pyrazole and 3- (2,6-dibromophenyl) -5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole mixture (0.30 g) Got The product (0.30 g) was dissolved in tetrahydrofuran (3 mL). A solution of n-butyllithium n-hexane (2.6 mol / L, 0.51 mL) was added dropwise to this mixture at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. After adding a large excess of dry ice to this mixture, the temperature was raised from −78 ° C. to room temperature, and the mixture was stirred for 1 hour. Hydrochloric acid (1 mol / L) was added to the reaction mixture to make it acidic, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to remove 3-bromo-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoic acid and 3-bromo-2- [5. A mixture of − (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid (0.27 g) was obtained. N, N-dimethylformamide (2 mL) was added to the product (0.27 g). To this mixture are 1-hydroxybenzotriazole monohydrate (0.21 g), ammonium chloride (0.36 g), triethylamine (0.69 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( 0.26 g) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.127 g). The structural formula, spectral data and purification conditions are shown in Table 5.

Reference example 1-4-1
3-Methyl-2- (5-phenyl-1H-pyrazole-3-yl) benzoic acid 2-iodo-3-methylbenzoic acid Ethyl ester (2.93 g), trimethylsilylacetylene (1.19 g), bis (triphenyl) A mixture of phosphinic palladium (II) dichloride (354 mg), copper (I) iodide (38 mg) and triethylamine (20 mL) was stirred at 95 ° C. for 3 hours under an argon atmosphere. The mixture was passed through a Celite pad and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain 3-methyl-2- (trimethylsilylethynyl) benzoic acid ethyl ester (2.47 g). Potassium carbonate (2.62 g) was added to a solution of the product (2.47 g) in methanol (25 mL) at room temperature. The mixture was stirred overnight and poured into water. The crude product was extracted with ethyl acetate, the organic layer was washed with water and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane). The obtained crude product was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain 2-ethynyl-3-methylbenzoate methyl ester (2.20 g). P-Toluenesulfonyl hydrazine (784 mg) was added to a solution of benzaldehyde (447 mg) in toluene (18 mL) at room temperature, and the mixture was stirred at 50 ° C. for 1.5 hours. The mixture was cooled to room temperature, sodium ethoxide (716 mg) was added and the mixture was stirred for 15 minutes. A solution of 2-ethynyl-3-methylbenzoic acid methyl ester (2.2 g) in toluene (12 mL) was added to this mixture, and the mixture was stirred at 90 ° C. overnight. The mixture was cooled to room temperature and hydrochloric acid (1 mol / L, 16 mL) was added. The crude product was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (229 mg). The structural formula, spectral data and purification conditions are shown in Table 5.

Reference Example 1-5-1
2-Bromo-6-Methoxymethoxybenzaldehyde 2-bromo-6-hydroxybenzaldehyde (1.47 g) in N, N-dimethylformamide (15 mL) solution with sodium hydride (60% oil dispersion, 380 mg) at 0 ° C. And stirred for 10 minutes. Chloromethyl methyl ether (707 mg) was added to this mixture, and the mixture was stirred at 0 ° C. to room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (690 mg). The structural formula, spectral data and purification conditions are shown in Table 5.

Reference Example 1-6-1
3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) -1H-pyrazole 2-bromo-6-fluorobenzaldehyde (4.439 g) in a toluene (96 mL) solution to p-toluenesulfonyl hydrazine (4.072 g) was added, and the mixture was stirred at 110 ° C. for 3 hours. The mixture was cooled to room temperature, a solution of sodium ethoxide (4.464 g) and 1-ethynyl-4-fluorobenzene (3.94 g) in toluene (68 mL) was added and stirred at 110 ° C. for 16 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (3.283 g). The structural formula, spectral data and purification conditions are shown in Table 6.

Reference example 1-6-2 to 1-6-42
Using the corresponding raw materials, Reference Examples 1-6-2 to 1-6-42 were synthesized in the same manner as in Reference Example 1-6-1. The structural formula, spectral data and purification conditions are shown in Tables 6 to 10.

Reference Example 1-7-1
3- (2-Bromophenyl) -5- (thiophen-2-yl) -1H-pyrazole Thiophene-2-carbaldehyde (207 mg) was added to a solution of p-toluenesulfonyl hydrazine (343 mg) in toluene (12 mL). The mixture was stirred at 50 ° C. for 1.5 hours and cooled to room temperature. Sodium ethoxide (313 mg) was added to this mixture and stirred for 15 minutes. A solution of 1-bromo-2-ethynylbenzene (1.00 g) in toluene (8 mL) was added to this mixture, and the mixture was stirred at 90 ° C. overnight. The mixture was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (42 mg). The structural formula, spectral data and purification conditions are shown in Table 11.

Reference example 1-7-2 to 1-7-4
Using the corresponding raw materials, Reference Examples 1-7-2 to 1-7-4 were synthesized in the same manner as in Reference Example 1-7-1. The structural formula, spectral data and purification conditions are shown in Table 11.

Reference example 1-8-1
Mixture of 3- (2-bromophenyl) -1-methoxymethyl-5-phenyl-1H-pyrazole and 3- (2-bromophenyl) -2-methoxymethyl-5-phenyl-2H-pyrazole 3- (2- (2-) Sodium hydride (60% oil dispersion, 43 mg) is added to a solution of bromophenyl) -5-phenyl-1H-pyrazol (272 mg) in N, N-dimethylformamide (4 mL) at 0 ° C. and the mixture is stirred for 10 minutes. did. Chloromethyl methyl ether (81 mg) was added to this mixture and stirred overnight at room temperature. The mixture was poured into water and the crude product was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (282 mg). The structural formula, spectral data and purification conditions are shown in Table 12.

Reference example 1-8-2 to 1-8-6
Using the corresponding raw materials, Reference Examples 1-8-2 to 1-8-6 were synthesized in the same manner as in Reference Example 1-8-1. The structural formula, spectral data and purification conditions are shown in Tables 12 to 13.

Reference example 1-9-1
2- [1- (Methoxymethyl) -5-phenyl-1H-pyrazole-3-yl] benzoic acid and 2- [2- (methoxymethyl) -5-phenyl-2H-pyrazole-3-yl] benzoic acid Mixture 3- (2-bromophenyl) -1-methoxymethyl-5-phenyl-1H-pyrazole and 3- (2-bromophenyl) -2-methoxymethyl-5-phenyl-2H-pyrazole (1)
To a mixture of 40 mg) was added n-propanol (2 mL) and N-methylpyrrolidone (1 mL). To this mixture is added 1,1'-bis (diphenylphosphino) ferrocene (23 mg), 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (34 mg) and triethylamine (120 mg). rice field. The mixture was stirred at 100 ° C. overnight under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [1- (methoxymethyl) -5-phenyl-1H-pyrazole-3. A mixture (90 mg) of -yl] benzoic acid propyl ester and 2- [2- (methoxymethyl) -5-phenyl-2H-pyrazole-3-yl] benzoic acid propyl ester was obtained. Aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) was added to the mixture of product (90 mg) and methanol (2 mL), and the mixture was stirred at 60 ° C. for 2.5 hours. After cooling the reaction mixture to room temperature, hydrochloric acid (2 mol / L, 0.55 mL) and water were added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (45 mg). The structural formula, spectral data and purification conditions are shown in Table 14.

Reference example 1-9-2 to 1-9-3
Reference Examples 1-9-2 to 1-9-3 were synthesized by the same method as in Reference Example 1-9-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 15.

Reference Example 1-10-1
2- {5- [4- (imidazol-1-yl) phenyl] -1-methoxymethyl-1H-pyrazole-3-yl} benzoic acid and 2- {5- [4- (imidazol-1-yl) phenyl ] -2-Methyl-2H-pyrazole-3-yl} Mix of benzoic acid 3- (2-bromophenyl) -5- [4- (imidazole-1-yl) phenyl] -1-methoxymethyl-1H- A mixture of pyrazole and 3- (2-bromophenyl) -5- [4- (imidazol-1-yl) phenyl] -2-methoxymethyl-2H-pyrazole (248 mg) with dimethylsulfoxide (3 mL) and n-butyl alcohol. Dissolved in (2 mL) mixture. To this mixture was added 1,3-bis (diphenylphosphino) propane (25 mg) and N, N-diisopropylethylamine (392 mg) and replaced with argon. Palladium acetate (II) (14 mg) was added to this mixture, and the mixture was stirred overnight at 110 ° C. under a carbon monoxide atmosphere. The reaction mixture was passed through a Celite pad and water was added to the filtrate. The crude product was extracted with ethyl acetate, the extract was washed with water and then concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- {5- [4- (imidazol-1-yl) phenyl] -1-methoxymethyl-1H-pyrazole. A mixture of -3-yl} benzoic acid butyl ester and 2- {5- [4- (imidazol-1-yl) phenyl] -2-methoxymethyl-2H-pyrazole-3-yl} benzoic acid butyl ester (198 mg). Got The product (198 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) -methanol (1 mL) -water (1 mL). Lithium hydroxide monohydrate (160 mg) was added to this mixture, and the mixture was stirred at 50 ° C. overnight. Hydrochloric acid (1 mol / L, 3.81 mL) was added to this mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (113 mg). The structural formula, spectral data and purification conditions are shown in Table 15.

Reference Example 1-11-1
3-Fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1H-pyrazole-3-yl] Benzoic acid 3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) ) -Selectfluor® (0.38 g) was added to a solution of -1H-pyrazole (0.30 g) in acetonitrile (3 mL), and the mixture was stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature, added to saturated aqueous sodium hydrogen carbonate solution, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3- (2-bromo-6-fluorophenyl) -4-fluoro-5. (4-Fluorophenyl) -1H-pyrazole (0.22 g) was obtained. A mixture of product (0.22 g), n-propanol (3 mL) and N-methylpyrrolidone (1 mL) with triethylamine (0.19 g), 1,1'-bis (diphenylphosphino) ferrocene (0.035 g). And 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (0.051 g) was added, and the mixture was stirred at 100 ° C. for 5 hours under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl)). -1H-pyrazole-3-yl] benzoic acid propyl ester (0.113 g) was obtained. Aqueous sodium hydroxide solution (2 mol / L, 0.9 mL) was added to a solution of the product (0.113 g) in methanol (1 mL), and the mixture was stirred at 60 ° C. for 1.5 hours. After cooling the reaction mixture to room temperature, hydrochloric acid (2 mol / L, 0.94 mL) was added. The precipitate was collected by filtration to give the title compound (80 mg). The structural formula, spectral data and purification conditions are shown in Table 16.

Reference Examples 1-11-2 to 1-11-4
Using the corresponding raw materials, Reference Examples 1-11-2 to 1-11-4 were synthesized in the same manner as in Reference Example 1-11-1. The structural formula, spectral data and purification conditions are shown in Table 16.

Reference Example 1-12-1
3-Fluoro-2- (5-Phenyl-1H-Pyrazole-3-yl) Benzoic Acid 3- (2-Bromo-6-Fluorophenyl) -5-Phenyl-1H-Pyrazole (150 mg) n-propanol (3 mL) ) Add dimethylsulfoxide (1 mL), triethylamine (72 mg), 1,3-bis (diphenylphosphino) propane (20 mg) and palladium (II) acetate (11 mg) to the suspension, and add 100 ° C. under a carbon monoxide atmosphere. Was stirred overnight. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3-fluoro-2- (5-phenyl-1H-pyrazole-3-3). Ill) Propyl benzoate propyl ester (120 mg) was obtained. Aqueous sodium hydroxide solution (2 mol / L, 750 μL) was added to a solution of the product (120 mg) in methanol (2 mL), and the mixture was stirred at 60 ° C. for 1 hour. Hydrochloric acid (2 mol / L, 800 μL) was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (86 mg). The structural formula, spectral data and purification conditions are shown in Table 17.

Reference example 1-12-2 to 1-12-6
Using the corresponding raw materials, Reference Examples 1-12-2 to 1-12-6 were synthesized in the same manner as in Reference Example 1-12-1. The structural formula, spectral data and purification conditions are shown in Table 17.

Reference Example 1-13-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] Benzoic acid 3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) -1H- N-Methylpyrrolidone (7.5 mL), triethylamine (1.053 g), 1,1'-bis (diphenylphosphino) ferrocene (0.192 g) in an n-propanol (22 mL) suspension of pyrazole (1.163 g). ) And 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (0.284 g) were added, and the mixture was stirred at 100 ° C. for 10 hours under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, hydrochloric acid (1 mol / L) was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole). -3-Il] Benzoic acid propyl ester (1.114 g) was obtained. An aqueous sodium hydroxide solution (2 mol / L, 10 mL) was added to a solution of the product (1.114 g) in methanol (10 mL), and the mixture was stirred at room temperature for 10 hours. Hydrochloric acid (1 mol / L) was added to the reaction mixture under ice-cooling. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (0.844 g). The structural formula, spectral data and purification conditions are shown in Table 18.

Reference example 1-13-2 to 1-13-17
Using the corresponding raw materials, Reference Examples 1-13-2 to 1-13-17 were synthesized in the same manner as in Reference Example 1-13-1. The structural formula, spectral data and purification conditions are shown in Tables 18 to 19.

Reference Example 1-14-1
2- (4-Chloro-1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) benzoic acid and 2- (4-chloro-2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) ) Mix of benzoic acid Mix of 3- (2-bromophenyl) -1-methoxymethyl-5-phenyl-1H-pyrazole and 3- (2-bromophenyl) -2-methoxymethyl-5-phenyl-2H-pyrazole (2.0 g) was dissolved in a mixture of dimethyl sulfoxide (30 mL) and n-butyl alcohol (20 mL). To this mixture was added 1,3-bis (diphenylphosphino) propane (240 mg) and N, N-diisopropylethylamine (3.77 g) and substituted with argon. Palladium acetate (II) (130 mg) was added to this mixture, and the mixture was stirred overnight at 110 ° C. under a carbon monoxide atmosphere. The reaction mixture was passed through a Celite pad, and hydrochloric acid (0.5 mol / L) was added to the filtrate. The crude product was extracted with ethyl acetate, the extract was washed with water and saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) with 2- (1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) benzoic acid butyl ester and 2- (1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl). A mixture (1.52 g) of 2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) benzoic acid butyl ester was obtained. The product (200 mg) was dissolved in dichloromethane (4 mL). N-Chlorosuccinimide (88 mg) was added to this mixture at room temperature, and the mixture was stirred overnight. This mixture was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- (4-chloro-1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) butyl benzoate. A mixture (240 mg) of the ester and 2- (4-chloro-2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) benzoic acid butyl ester was obtained. The product (219 mg) was dissolved in a mixture of tetrahydrofuran (1 mL) -methanol (0.5 mL) -water (0.5 mL). Lithium hydroxide monohydrate (168 mg) was added to this mixture, and the mixture was stirred at 50 ° C. overnight. Hydrochloric acid (2 mol / L, 4 mL) was added to this mixture and the crude product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (188 mg). The structural formula, spectral data and purification conditions are shown in Table 20.

Reference Example 1-14-2
Using the corresponding raw materials, Reference Example 1-14-2 was synthesized in the same manner as in Reference Example 1-14-1. The structural formula, spectral data and purification conditions are shown in Table 20.

Reference Example 1-15-1
2- (4-Bromo-1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) benzoic acid butyl ester and 2- (4-bromo-2-methoxymethyl-5-phenyl-2H-pyrazole-3) -Il) Mix of benzoic acid butyl ester 3- (2-bromophenyl) -1-methoxymethyl-5-phenyl-1H-pyrazole and 3- (2-bromophenyl) -2-methoxymethyl-5-phenyl-2H -A mixture of pyrazoles (2.0 g) was dissolved in a mixture of dimethylsulfoxide (30 mL) and n-butyl alcohol (20 mL). To this mixture was added 1,3-bis (diphenylphosphino) propane (240 mg) and N, N-diisopropylethylamine (3.77 g) and substituted with argon. Palladium acetate (II) (130 mg) was added to this mixture, and the mixture was stirred overnight at 110 ° C. under a carbon monoxide atmosphere. The reaction mixture was passed through a Celite pad, and hydrochloric acid (0.5 mol / L) was added to the filtrate. The crude product was extracted with ethyl acetate, the extract was washed with water and saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) with 2- (1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) benzoic acid butyl ester and 2- (1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl). A mixture (1.52 g) of 2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) benzoic acid butyl ester was obtained. The product (1.22 g) was dissolved in dichloromethane (20 mL). N-Bromosuccinimide (715 mg) was added to this mixture at room temperature, and the mixture was stirred overnight. This mixture was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (1.29 g). The structural formula, spectral data and purification conditions are shown in Table 20.

Reference example 1-15-2
Using the corresponding raw materials, Reference Example 1-15-2 was synthesized in the same manner as in Reference Example 1-15-1. The structural formula, spectral data and purification conditions are shown in Table 20.

Reference Example 1-16-1
2- (1-methoxymethyl-4-methyl-5-phenyl-1H-pyrazole-3-yl) benzoic acid and 2- (2-methoxymethyl-4-methyl-5-phenyl-2H-pyrazole-3-yl) ) Benzoic acid mixture 2- (4-bromo-1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) benzoic acid butyl ester and 2- (4-bromo-2-methoxymethyl-5-phenyl-) A mixture of 2H-pyrazole-3-yl) benzoic acid butyl ester (109 mg), 2,4,6-trimethylboroxin (62 mg) and potassium carbonate (170 mg) were added to N, N-dimethylformamide (3 mL). The reaction system was replaced with argon, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (20 mg) was added to the mixture, and the mixture was stirred at 110 ° C. for 3 hours. The mixture was diluted with ethyl acetate and passed through a Celite pad. The filtrate was washed twice with water and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- (1-methoxymethyl-4-methyl-5-phenyl-1H-pyrazole-3-yl) benzoic acid butyl ester. And 2- (2-Methyl-4-methyl-5-phenyl-2H-pyrazole-3-yl) benzoic acid butyl ester mixture (93 mg) was obtained. The product (93 mg) was dissolved in a mixture of tetrahydrofuran (1 mL) -methanol (0.5 mL) -water (0.5 mL). Lithium hydroxide monohydrate (118 mg) was added to this mixture, and the mixture was stirred at 50 ° C. overnight. Hydrochloric acid (2 mol / L, 2.81 mL) was added to this mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (79 mg). The structural formula, spectral data and purification conditions are shown in Table 21.

Reference Example 1-16-2
Using the corresponding raw materials, Reference Example 1-16-2 was synthesized in the same manner as in Reference Example 1-16-1. The structural formula, spectral data and purification conditions are shown in Table 21.

Reference Example 1-17-1
2- (1-methoxymethyl-5-phenyl-4-vinyl-1H-pyrazole-3-yl) benzoic acid and 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazole-3-yl) ) Benzoic acid mixture 2- (4-bromo-1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) benzoic acid butyl ester and 2- (4-bromo-2-methoxymethyl-5-phenyl-) A mixture of 2H-pyrazole-3-yl) benzoic acid butyl ester (500 mg), tributylvinyltin (536 mg), tetrakis (triphenylphosphine) palladium (0) (130 mg) was added to toluene (6 mL). The mixture was heated to reflux for 6 hours. The mixture was cooled to 0 ° C., an aqueous potassium fluoride solution (0.5 mol / L, 5 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was passed through a Celite pad and the insoluble material was washed with ethyl acetate. The filtrate was washed with water and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- (1-methoxymethyl-5-phenyl-4-vinyl-1H-pyrazole-3-yl) benzoic acid butyl ester. And 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazole-3-yl) benzoic acid butyl ester mixture (0.44 g) was obtained. The product (0.44 g) was dissolved in a mixture of tetrahydrofuran (6 mL) -methanol (3 mL) -water (3 mL). Lithium hydroxide monohydrate (303 mg) was added to this mixture, and the mixture was stirred at 50 ° C. overnight. Hydrochloric acid (2 mol / L, 3.61 mL) was added to this mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (377 mg). The structural formula, spectral data and purification conditions are shown in Table 21.

Reference Example 1-18-1
4-Fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindole-8-on 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3 -Il] N, N-diisopropylethylamine (0.30 g) and T3P® N, N-dimethylformamide solution (1.6 mol / L,) in a dichloromethane (2 mL) suspension of benzoic acid (0.20 g). 0.79 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.19 g). The structural formula, spectral data and purification conditions are shown in Table 22.

Reference Examples 1-18-2 to 1-18-3
Using the corresponding raw materials, Reference Examples 1-18-2 to 1-18-3 were synthesized in the same manner as in Reference Example 1-18-1. The structural formula, spectral data and purification conditions are shown in Table 22.

Reference Example 1-19-1
3-Hydroxy-2- (2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 3- (2-benzyloxy-6-) A mixture of bromophenyl) -1-methoxymethyl-5-phenyl-1H-pyrazole and 3- (2-benzyloxy-6-bromophenyl) -2-methoxymethyl-5-phenyl-2H-pyrazole (1.63 g). Was dissolved in dimethyl sulfoxide (20 mL). In this mixture 1,3-bis (diphenylphosphino) propane (302 mg), N, N-diisopropylethylamine (1.41 g) and 2- (
Pyridine-2-yl) Ethylamine (1.33 g) was added and substituted with argon. Palladium acetate (II) (164 mg) was added to this mixture, and the mixture was stirred overnight at 110 ° C. under a carbon monoxide atmosphere. The reaction mixture was passed through a Celite pad and water was added to the filtrate. The crude product was extracted with ethyl acetate, the extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 3-benzyloxy-2- (1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) -N- [2. -(Pyridine-2-yl) ethyl] benzamide (393 mg) and 3-benzyloxy-2- (2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) -N- [2- (pyridin-2) -Il) Ethyl] benzamide (736 mg) was obtained. 10% Palladium on carbon (50% wet, 140 mg) was added to a solution of the product (736 mg) in tetrahydrofuran (20 mL) and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. 10% Palladium on carbon (50% wet, 140 mg) was added to this mixture, and the mixture was stirred at 70 ° C. for 8 hours. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (525 mg). The structural formula, spectral data and purification conditions are shown in Table 22.

Reference Example 1-20-1
3-Cyano-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoic acid and 3-cyano-2- [5- (4-fluorophenyl)- 2- (Methoxymethyl) -2H-pyrazole-3-yl] Mixture of benzoic acid 3-bromo-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] A mixture (0.11 g) of benzamide and 3-bromo-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzamide was dissolved in ethyl acetate (1 mL). .. To this mixture was added a T3P® ethyl acetate solution (1.7 mol / L, 1 mL), and the mixture was stirred under heating under reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3-bromo-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-. A mixture (0.090 g) of yl] benzonitrile and 3-bromo-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzonitrile was obtained. Products (90 mg), n-propanol (3 mL), N-methylpyrrolidone (1 mL), triethylamine (70 mg), 1,1'-bis (diphenylphosphino) ferrocene (20 mg) and 1,1'-bis (diphenyl) A mixture of phosphino) ferrocene palladium (II) dichloride dichloromethane adduct (29 mg) was stirred at 100 ° C. for 5 hours under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, hydrochloric acid (1 mol / L) and water were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3-cyano-2- [5- (4-fluorophenyl) -1- ( Methoxymethyl) -1H-pyrazole-3-yl] benzoic acid propyl ester and 3-cyano-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid A mixture of propyl esters was obtained. Methanol (1 mL) and aqueous sodium hydroxide solution (2 mol / L, 470 μL) were added to the product, and the mixture was stirred at 60 ° C. for 1.5 hours. Hydrochloric acid (2 mol / L) was added to the reaction mixture to make it acidic, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (45 mg). The structural formula, spectral data and purification conditions are shown in Table 23.

Reference Example 1-21-1
2- [5- (4-Fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] -3-[(methoxymethoxy) methyl] benzoic acid and 2- [5- (4-fluorophenyl) ) -2- (Methoxymethyl) -2H-pyrazole-3-yl] -3-[(Methoxymethoxy) methyl] benzoic acid mixture 3- (2,6-dibromophenyl) -5- (4-fluorophenyl) A mixture (145 mg) of -1- (methoxymethyl) -1H-pyrazole and 3- (2,6-dibromophenyl) -5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole was added in tetrahydrofuran (145 mg). Dissolved in 3 mL). A solution of n-butyllithium n-hexane (2.6 mol / L, 0.25 mL) was added dropwise to this mixture at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. N, N-dimethylformamide (40 μL) was added to this mixture, and the mixture was stirred at −78 ° C. for 30 minutes and then heated to room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Methanol (1 mL) was added to this residue, sodium borohydride (13 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / hexane), and {3-bromo-2- [5- (4-fluorophenyl) -1- (methoxy). Methyl) -1H-pyrazole-3-yl] phenyl} Methanol and {3-bromo-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] phenyl } A mixture of methanol (20 mg) was obtained. The product (20 mg) was dissolved in tetrahydrofuran (2 mL). Sodium hydride (60% oil dispersion, 5 mg) and chloromethyl methyl ether (17 mg) were added to this mixture under ice-cooling. The mixture was stirred at 60 degrees for 3 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3-{2-bromo-6-[(methoxymethoxy) methyl] phenyl}-. 5- (4-Fluorophenyl) -1- (methoxymethyl) -1H-pyrazole and 3- {2-bromo-6-[(methoxymethoxy) methyl] phenyl} -5- (4-fluorophenyl) -2- A mixture of (methoxymethyl) -2H-pyrazol (22 mg) was obtained. N-propanol (3 mL) and N-methylpyrrolidone (1 mL) were added to the product (22 mg). To this mixture is added triethylamine (15 mg), 1,1'-bis (diphenylphosphino) ferrocene (4 mg) and 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (6 mg). The mixture was stirred at 100 ° C. for 5 hours under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [5- (4-fluorophenyl) -1- (methoxymethyl)-. 1H-pyrazole-3-yl] -3-[(methoxymethoxy) methyl] benzoic acid propyl ester and 2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] A mixture of -3-[(methoxymethoxy) methyl] benzoic acid propyl ester was obtained. Methanol (1 mL) and aqueous sodium hydroxide solution (2 mol / L, 200 μL) were added to the product, and the mixture was stirred at 60 ° C. for 1.5 hours. Hydrochloric acid (2 mol / L) was added to the reaction mixture to make it acidic, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (20 mg). The structural formula, spectral data and purification conditions are shown in Table 23.

Reference Example 1-22-1
2-Bromo-4- (1,3-dioxolane-2-yl) benzaldehyde 2-bromo-4-formyl benzoic acid methyl ester (1.867 g) in a toluene (50 mL) solution with ethylene glycol (4.767 g) and p. -Toluene sulfonic acid monohydrate (
0.146 g) was added, and the mixture was heated under reflux at 150 ° C. for 18 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2-bromo-4- (1,3-dioxolan-2-yl) benzoic acid. Methyl ester (1.792 g) was obtained. Tetrahydrofuran of 2-bromo-4- (1,3-dioxolan-2-yl) benzoic acid methyl ester (1.446 g) under ice-cooling in a suspension of lithium aluminum hydride (0.286 g) in tetrahydrofuran (9 mL). A (8 mL) solution was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, diluted with diethyl ether, and stirred for 30 minutes. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure to give [2-bromo-4- (1,3-dioxolane-2-yl) phenyl] methanol (1.196 g). Iodobenzene diacetate (1.634 g) and AZADOL® (0.070 g) were added to a solution of the product (1.196 g) in dichloromethane (30 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. A 10% aqueous sodium sulfite solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (0.938 g). The structural formula, spectral data and purification conditions are shown in Table 23.

Reference example 1-23-1
2- [5- (4-Fluorophenyl) -1- (methoxymethyl) -4-methyl-1H-pyrazole-3-yl] benzoic acid and 2- [5- (4-fluorophenyl) -2- (methoxy) Methyl) -4-methyl-2H-pyrazole-3-yl] benzoic acid mixture 3- (2-bromophenyl) -5- (4-fluorophenyl) -1H-pyrazole (0.6 g) n-propanol (0.6 g) 12 mL) N-methylpyrrolidone (4 mL), triethylamine (0.574 g), 1,1'-bis (diphenylphosphino) ferrocene (0.105 g) and 1,1'-bis (diphenylphosphino) in a suspension. A ferrocene palladium (II) dichloride dichloromethane adduct (0.154 g) was added, and the mixture was stirred at 100 ° C. for 10 hours under a carbon monoxide atmosphere. After cooling to room temperature, hydrochloric acid (1 mol / L) was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl. ] Benzoic acid propyl ester (0.545 g) was obtained. Cesium carbonate (2.735 g) and chloromethyl methyl ether (0.338 g) were added to a solution of the product (0.545 g) in N, N-dimethylformamide (8 mL), and the mixture was stirred at 60 ° C. for 13 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [5- (4-fluorophenyl) -1- (methoxymethyl)-. Mixture of 1H-pyrazole-3-yl] benzoic acid propyl ester and 2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid propyl ester (0.320 g) ) Was obtained. Dichloromethane (8 mL) was added to the product (0.320 g). N-Bromosuccinimide (0.155 g) was added to this mixture, and the mixture was stirred overnight at room temperature. The residue obtained by distilling off the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [4-bromo-5- (4-fluorophenyl) -1-. (Methoxymethyl) -1H-pyrazole-3-yl] benzoic acid propyl ester and 2- [4-bromo-5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoate A mixture of acid propyl esters (0.388 g) was obtained. The product (0.200 g) was dissolved in N, N-dimethylformamide (4 mL). Potassium carbonate (0.309 g), trimethylboroxin (0.112 g) and 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (0.183 g) were added to this mixture at 110 ° C. Was stirred for 3 hours. The reaction mixture was diluted with ethyl acetate and passed through a Celite pad. The filtrate was washed with water and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [5- (4-fluorophenyl) -1- (methoxy). Methyl) -4-methyl-1H-pyrazole-3-yl] benzoic acid propyl ester and 2- [5- (4-fluorophenyl) -2- (methoxymethyl) -4-methyl-2H-pyrazole-3-yl] ] A mixture of benzoic acid propyl ester (0.131 g) was obtained. Methanol (1 mL) and an aqueous sodium hydroxide solution (2 mol / L, 1 mL) were added to this mixture (0.131 g), and the mixture was stirred at 60 ° C. for 2 hours. Hydrochloric acid (2 mol / L, 1 mL) was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (0.103 g). The structural formula, spectral data and purification conditions are shown in Table 24.

Reference Example 1-24-1
2- [5- (4-Fluorophenyl) -1- (methoxymethyl) -4-chloro-1H-pyrazole-3-yl] benzoic acid and 2- [5- (4-fluorophenyl) -2- (methoxy) Methyl) -4-chloro-2H-pyrazole-3-yl] benzoic acid mixture 2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoic acid propyl ester And 2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid propyl ester mixture (0.214 g) was dissolved in dichloromethane (5 mL). Sulfuryl chloride (0.090 g) was added to this mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [4-chloro-5- (4-fluorophenyl) -1- ( Methoxymethyl) -1H-pyrazole-3-yl] benzoic acid propyl ester and 2- [4-chloro-5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid A mixture of propyl esters (0.174 g) was obtained. Methanol (2 mL) and an aqueous sodium hydroxide solution (2 mol / L, 1 mL) were added to the product (0.160 g), and the mixture was stirred at 60 ° C. for 2 hours. Hydrochloric acid (2 mol / L, 1 mL) was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (0.126 g). The structural formula, spectral data and purification conditions are shown in Table 24.

Reference Example 1-25-1
3- (5-Phenyl-1H-Pyrazole-3-yl) Pyridine-2-Carboxylic Acid 2-Bromo-3- (1-Methoxymethyl-5-Phenyl-1H-Pyrazole-3-yl) Pyridine and 2-bromo A mixture of -3- (2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) pyridine (1.61 g) was dissolved in a mixture of dimethylsulfoxide (18 mL) and n-butyl alcohol (6 mL). To this mixture was added 1,3-bis (diphenylphosphino) propane (193 mg) and N, N-diisopropylethylamine (3.02 g) and substituted with argon. Palladium acetate (II) (104 mg) was added to this mixture, and the mixture was stirred overnight at 110 ° C. under a carbon monoxide atmosphere. The reaction mixture was passed through a Celite pad, and hydrochloric acid (0.5 mol / L) was added to the filtrate. The crude product was extracted with ethyl acetate, the extract was washed with water and saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3- (1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) pyridin-2-carboxylic acid butyl ester. And 3- (2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) pyridin-2-carboxylic acid butyl ester mixture (558 mg) was obtained. The product (558 mg) was dissolved in ethanol (5 mL). Ethyl acetate solution of hydrogen chloride (4 mol / L, 10 mL) was added to this mixture. The mixture was stirred at 60 ° C. for 2 hours and poured into saturated aqueous sodium hydrogen carbonate solution. The crude product was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, and then concentrated under reduced pressure to obtain 3- (5-phenyl-1H-pyrazole-3-yl) pyridin-2-carboxylic acid butyl ester (364 mg). Lithium hydroxide monohydrate (274 mg) was added to a mixture of the product (364 mg) in tetrahydrofuran (2 mL) -methanol (1 mL) -water (1 mL) and the mixture was stirred at 60 ° C. overnight. Hydrochloric acid (2 mol / L, 6.53 mL) was added to this mixture. The insoluble material was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (253 mg). The structural formula, spectral data and purification conditions are shown in Table 24.

Reference Example 1-26-1
3-Fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoic acid and 3-fluoro-2- [4-fluoro-5 -(4-Fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid mixture 3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) -1 In a mixture (0.391 g) of-(methoxymethyl) -1H-pyrazole and 3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole. , N-propanol (6 mL) and N-methylpyrrolidone (2 mL) were added. Triethylamine (0.313 g), 1,1'-bis (diphenylphosphino) ferrocene (0.057 g) and 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (0) to this mixture. .085 g) was added, and the mixture was stirred at 100 ° C. for 10 hours under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, hydrochloric acid (1 mol / L) was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3-fluoro-2- [5- (4-fluorophenyl) -1- ( Methoxymethyl) -1H-pyrazole-3-yl] benzoic acid propyl ester and 3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid A mixture of propyl esters (0.264 g) was obtained. Selectfluor® (0.294 g) was added to a mixture of product (0.264 g) and acetonitrile (2.3 mL) and stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate solution, and the crude product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl)). -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoic acid propyl ester and 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl) -2- (methoxymethyl) -2H- A mixture of pyrazole-3-yl] benzoic acid propyl ester (0.140 g) was obtained. The product (0.140 g) was dissolved in methanol (2.4 mL). An aqueous sodium hydroxide solution (2 mol / L, 1 mL) was added to this mixture, and the mixture was stirred at 60 ° C. for 10 hours. Hydrochloric acid (2 mol / L, 1 mL) was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (0.112 g). The structural formula, spectral data and purification conditions are shown in Table 24.

Reference Example 1-27-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] Benzonitrile 3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) -1H- A mixture of pyrazole (3.00 g), copper (I) cyanide (0.96 g), copper (I) iodide (0.34 g) and N-methylpyrrolidone (21 mL) was stirred at 120 ° C. for 1.5 hours. .. After cooling the reaction mixture to 0 ° C., 28% aqueous ammonia (20 mL), water (20 mL) and ethyl acetate / n-hexane (10/1) were added, and the mixture was stirred for 30 minutes. The mixture was partitioned with water and ethyl acetate / n-hexane (10/1). The aqueous layer was extracted 3 times with ethyl acetate / n-hexane (10/1). The combined organic layer was washed with water and saturated brine. 28% aqueous ammonia (40 mL) and water (40 mL) were added to the organic layer, and the mixture was stirred for 30 minutes. Water was added to the mixture and the crude product was extracted with ethyl acetate / n-hexane (10/1). The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.51 g). The structural formula, spectral data and purification conditions are shown in Table 24.

Reference Example 2-1-1
(R) -2-Amino-3- (pyridin-2-yl) propionamide dihydrochloride (R) -2-tert-butoxycarbonylamino-3- (pyridin-2-yl) propionic acid (500 mg) in tetrahydrofuran Carbonyldiimidazole (609 mg) was added to the (8 mL) solution at room temperature and the mixture was stirred for 30 minutes. 28% aqueous ammonia (4 mL) was added to the reaction mixture, the mixture was stirred for 1 hour, and the mixture was poured into water. The crude product was extracted with ethyl acetate, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was suspended in ethyl acetate, and the insoluble material was collected by filtration to obtain (R) -2-tert-butoxycarbonylamino-3- (pyridin-2-yl) propionamide (177 mg). Ethyl acetate solution of hydrogen chloride (4 mol / L, 3 mL) was added to a suspension of product (193 mg) in ethanol (3 mL) at room temperature. The mixture was stirred for 15 minutes and diisopropyl ether was added. The solvent was decanted. The precipitate was washed with diisopropyl ether and dried under reduced pressure to give the title compound (173 mg). The structural formula, spectral data and purification conditions are shown in Table 25.

Reference example 2-1-2
Using the corresponding raw materials, Reference Example 2-1-2 was synthesized in the same manner as in Reference Example 2-1-1. The structural formula, spectral data and purification conditions are shown in Table 25.

Reference example 2-2-1
(2R) -2-Amino-N-Methyl-3- (pyridin-2-yl) propionamide hydrochloride
(2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyridin-2-yl) propionic acid (0.10 g) in N, N-dimethylformamide (1 mL) suspension with 1-hydroxybenzo Add triazole monohydrate (0.086 g), methylamine hydrochloride solution (2 mol / L, 0.9 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.11 g) at room temperature. Was stirred for 2 days. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(1R) -1- (methylcarbamoyl) -2- (pyridine-2-yl) ethyl] carbamic acid. A tert-butyl ester (0.050 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 2 mL) was added to a solution of the product (0.050 g) in methanol (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. The precipitate was collected by filtration to give the title compound (0.036 g). The structural formula, spectral data and purification conditions are shown in Table 25.

Reference example 2-2-2
Reference Example 2-2-2 was synthesized by the same method as in Reference Example 2-2-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 25.

Reference example 2-3-1
N-((2R) -2-Amino-3-phenylpropyl) phthalimide hydrochloride N-[(2R) -1-hydroxy-3-phenylpropan-2-yl] carbamic acid tert-butyl ester (0.10 g) To a solution of phthalimide (0.065 g), triphenylphosphine (0.16 g) and an azodicarboxylate diethyl ester toluene solution (2.2 mol / L, 270 μL) in tetrahydrofuran (0.5 mL), add 1 hour at room temperature. Stirred. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -1- (1,3-dioxo-2,3). -Dihydro-1H-isoindole-2-yl) -3-phenylpropan-2-yl] Carbamate tert-butyl ester (0.115 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (0.115 g) in tetrahydrofuran (1 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (0.085 g). The structural formula, spectral data and purification conditions are shown in Table 25.

Reference example 2-3-2-2-3-3
Using the corresponding raw materials, Reference Example 2-3-2-2-3-3 was synthesized in the same manner as in Reference Example 2-3-1. The structural formula, spectral data and purification conditions are shown in Table 25.

Reference example 2-4-1
N- [6- (2-aminoethyl) pyridin-2-yl] carbamic acid tert-butyl ester hydrochloride 6- {2-[(tert-butoxycarbonyl) amino] ethyl} pyridine-2-carboxylic acid (0. To a solution of 254 g) of tert-butyl alcohol (3 mL) was added triethylamine (0.065 g) and diphenylphosphoryl azide (0.34 g), and the mixture was stirred at 100 ° C. overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N- (6- {2-[(tert-butoxycarbonyl) amino] ethyl}. Pyridine-2-yl) Carbamic acid tert-butyl ester (0.30 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 2 mL) was added to a solution of the product (0.30 g) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration to give the title compound (0.19 g). The structural formula, spectral data and purification conditions are shown in Table 26.

Reference Example 2-5-1
Sodium hydride (60% oil dispersion, 153 mg) in a solution of 3- (tert-butyldimethylsilyl) oxy-2-phenylpropylamine 2-phenylpropane-1,3-diol (556 mg) in tetrahydrofuran (20 mL) is 0. The mixture was added at room temperature and stirred at room temperature for 20 minutes. To this mixture was added tert-butyldimethylchlorosilane (578 mg) at 0 ° C. and stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to 3- (tert-butyldimethylsilyloxy) -2-phenylpropan-1-ol (972 mg). ) Was obtained. Phthalimide (590 mg), triphenylphosphine (1.05 g), and azodicarboxylate diethyl ester toluene solution (2.2 mol / L, 1.8 mL) are added to a solution of the product (972 mg) in tetrahydrofuran (20 mL) at room temperature. The mixture was stirred for 16 hours. The mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to N- {3-[(tert-butyldimethylsilyl) oxy] -2-phenylpropyl. } Phtalimide (1.38 g) was obtained. Hydrazine monohydrate (1.75 g) was added to a solution of the product (1.38 g) in ethanol (17 mL), and the mixture was stirred at 80 ° C. for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (791 mg). The structural formula, spectral data and purification conditions are shown in Table 26.

Reference example 2-5-2
Reference Example 2-5-2 was synthesized in the same manner as in Reference Example 2-5-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 26.

Reference Example 2-6-1
N- [2- (2-Aminoethyl) Pyridine-3-yl] Carbamic Acid tert-Butyl Ester N- [2- (Hydroxymethyl) Pyridine-3-yl] Carbamic Acid tert-Butyl Ester (0.15 g) Thionyl chloride (0.096 g) was added to a solution of dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 hour. Pour the reaction mixture into saturated aqueous sodium hydrogen carbonate solution and pour.
The crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and N- [2- (chloromethyl) pyridine-3-yl] carbamic acid tert- Butyl ester (0.12 g) was obtained. A mixture of product (0.12 g), dichloromethane (2 mL), potassium cyanide (0.039 g), tetrabutylammonium hydrogensulfate (0.017 g) and water (0.5 mL) was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and tert-butyl N- [2- (cyanomethyl) pyridine-3-yl] carbamic acid. Obtained ester. Concentrated hydrochloric acid (0.072 g) and 10% palladium carbon (50% wet, 0.03 g) were added to the product methanol (3 mL) -dichloromethane (3 mL) mixture overnight at room temperature under a hydrogen atmosphere (0.32 MPa). Stirred. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.011 g). The structural formula, spectral data and purification conditions are shown in Table 26.

Reference Example 2-7-1
(2R) -2- (Methylamino) -3- (Pyridine-2-yl) Propane-1-ol
2-Nitrobenzene-1-sulfonyl chloride (0.) In a solution of (2R) -2-amino-3- (pyridin-2-yl) propionate methyl ester (338 mg) and triethylamine (0.57 g) in dichloromethane (8 mL). 50 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Potassium carbonate (0.52 g) and iodomethane (0.80 g) were added to a solution of the residue in N, N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2R) -2- (N-methyl-2-nitrobenzenesulfonylamino) -3. -(Pyridine-2-yl) propionic acid methyl ester (0.32 g) was obtained. A mixture of product (0.24 g), thiophenols (77 mg), potassium carbonate (0.26 g) and acetonitrile (2 mL) was stirred at room temperature overnight. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol), and (2R) -2- (methylamino) -3- (pyridine-2-yl) was purified. ) Propionic acid methyl ester (0.11 g) was obtained. Lithium aluminum hydride (20 mg) was added to a solution of the product (0.10 g) in tetrahydrofuran (2 mL) at 0 ° C. and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the filtrate was concentrated under reduced pressure through a Celite pad. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.046 g). The structural formula, spectral data and purification conditions are shown in Table 26.

Reference example 2-8-1
[(3,4-trans) -4- (pyridin-2-yl) pyrrolidine-3-yl] methanol
Lithium aluminum hydride (36 mg) was added to a solution of (3,4-trans) -1-benzyl-4- (pyridin-2-yl) pyrrolidine-3-carboxylic acid ethyl ester (0.30 g) in tetrahydrofuran (3 mL). It was added under ice-cooling and stirred at 0 ° C. for 1 hour. Diethyl ether and water were added to the reaction mixture and the mixture was passed through a Celite pad. The filtrate was concentrated under reduced pressure to give [(3,4-trans) -1-benzyl-4- (pyridin-2-yl) pyrrolidine-3-yl] metalnol (0.26 g). Ethanol (3 mL) and 10% palladium carbon (50% wet, 0.02 g) were added to the product (0.10 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.05 g). The structural formula, spectral data and purification conditions are shown in Table 26.

Reference example 2-9-1
4- (benzyloxy) -1- (pyridin-2-yl) butane-2-amine 2-methylpyridine (0.93 g) in a solution of tetrahydrofuran (5 mL) at -78 ° C to n-butyllithium n-hexane The solution (2.6 mol / L, 4.0 mL) was added, and the mixture was stirred at the same temperature for 10 minutes and under ice-cooling for 0.5 hours. After cooling the reaction mixture to −30 ° C., a solution of 3- (benzyloxy) propanal (1.0 g) in tetrahydrofuran (2 mL) was added dropwise, and the mixture was stirred at the same temperature for 10 minutes under ice-cooling for 1 hour. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 4- (benzyloxy) -1- (pyridin-2-yl) butane-2. -All (1.16 g) was obtained. Phthalimide (0.258 g), triphenylphosphine (0.459 g) and azodicarboxylate diethyl ester toluene solution (2.2 mol / L, 800 μL) were added to a solution of the product (0.30 g) in tetrahydrofuran (2 mL) at room temperature. Was stirred for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N- [4- (benzyloxy) -1- (pyridin-2-yl). Butan-2-yl] phthalimide (0.45 g) was obtained. Hydrazine monohydrate (0.58 g) was added to a solution of the product (0.45 g) in methanol (3 mL), and the mixture was stirred under heating under reflux for 4 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (0.10 g). The structural formula, spectral data and purification conditions are shown in Table 26.

Reference Example 2-10-1
(3R) -3-amino-4- (pyridin-2-yl) butane-2-ol
(2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyridine-2-yl) propionic acid (0.500 g) in N, N-dimethylformamide (3.5 mL) solution under ice-cooling N, O-dimethylhydroxylamine hydrochloride (0.238 g), 1-hydroxybenzotriazole monohydrate (0.374 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0. 468 g) and triethylamine (0.950 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate) and N-[(1R) -1- (N-methoxy-N-methylcarbamoyl) -2. -(Pyridin-2-yl) ethyl] carbamic acid tert-butyl ester (0.432 g) was obtained. A methyllithium diethyl ether solution (1.13 mol / L, 1.6 mL) was added to a solution of the product (0.432 g) in diethyl ether (14 mL) under ice-cooling, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -3-oxo-1- (pyridine-2). -Il) Butan-2-yl] Carbamic acid tert-butyl ester (0.261 g) was obtained. Sodium borohydride (0.045 g) was added to a solution of the product (0.261 g) in methanol (9 mL) under ice-cooling, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to obtain a diastereomer mixture. The mixture was purified by reverse phase preparative liquid chromatography (Inertsil ODS-3, elution solvent: acetonitrile / water) and N-[(2R) -3-hydroxy-1- (pyridin-2-yl) butane-2. -Il] Carbamic acid tert-butyl ester (0.065 g) was obtained as a highly polar diastereomer. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 0.2 mL) was added to a 1,4-dioxane (3 mL) solution of the product (0.065 g), and the mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.025 g). The structural formula, spectral data and purification conditions are shown in Table 26.

Reference example 2-10-2
Using the corresponding raw materials, Reference Example 2-10-2 was synthesized in the same manner as in Reference Example 2-10-1. The structural formula, spectral data and purification conditions are shown in Table 26.

Reference Example 2-11-1
(3R) -3-amino-4- (pyridin-2-yl) butane-2-ol hydrochloride
(2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyridine-2-yl) propionic acid (1.000 g) in N, N-dimethylformamide (10 mL) solution under ice-cooling. N, O-dimethylhydroxylamine hydrochloride (0.476 g), 1-hydroxybenzotriazole monohydrate (0.748 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.936 g) ) And triethylamine (1.900 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate) and N-[(1R) -1- (N-methoxy-N-methylcarbamoyl) -2. -(Pyridin-2-yl) ethyl] carbamic acid tert-butyl ester (0.563 g) was obtained. A solution of methyl magnesium bromide diethyl ether (3.0 mol / L, 0.8 mL) was added to a solution of the product (0.563 g) in diethyl ether (14 mL) under ice-cooling, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel aminopropyl column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -3-oxo-1- (pyridine-2). -Il) Butan-2-yl] Carbamic acid tert-butyl ester (0.463 g) was obtained. To a solution of the product (0.463 g) in tetrahydrofuran (5 mL) at −78 ° C., a solution of tri (sec-butyl) boron lithium-tetrahydrofuran (1.0 mol / L, 3.5 mL) was added and the temperature was the same for 5 hours. Stirred. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the temperature was raised to room temperature. The crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to obtain a diastereomer mixture. The mixture was purified by reverse phase preparative liquid chromatography (Inertsil ODS-3, elution solvent: acetonitrile / water) and N-[(2R) -3-hydroxy-1- (pyridin-2-yl) butane-2. -Il] Carbamic acid tert-butyl ester (0.051 g) was obtained as a low polar diastereomer. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 0.3 mL) was added to a solution of the product (0.051 g) in 1,4-dioxane (3 mL), and the mixture was stirred at 80 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with n-hexane to give the title compound (0.046 g). The structural formula, spectral data and purification conditions are shown in Table 27.

Reference example 2-11-2
Using the corresponding raw materials, Reference Example 2-11-2 was synthesized in the same manner as in Reference Example 2-11-1. The structural formula, spectral data and purification conditions are shown in Table 27.

Reference Example 2-12-1
(3R) -3-Amino-4- (pyridin-2-yl) butane-1-ole hydrochloride in a solution of 3- (tert-butyldimethylsilyloxy) propanol (0.40 g) in tetrahydrofuran (4 mL). (R) -2-Methylpropan-2-sulfinamide (0.258 g) and tetraethyl orthotitarate (0.63 g) were added, and the mixture was stirred at room temperature for 1 hour. Saturated saline was added to the reaction mixture and passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy). ) Propyriden] -2-Methylpropan-2-sulfinamide (0.33 g) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 0.96 mL) was added to a solution of 2-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. .. A solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propyridene] -2-methylpropan-2-sulfinamide (0.33 g) in tetrahydrofuran (2 mL) is added dropwise to this mixture. Then, the mixture was stirred at −78 ° C. for 0.5 hours. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water) and used as a highly polar product (R) -N-[(2R) -4- (tert-butyldimethylsilyl). Oxy) -1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.174 g), and as a low polar product (R) -N-[(2S) -4- (tert-Butyldimethylsilyloxy) -1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.060 g) was obtained. (R) -N-[(2R) -4- (tert-butyldimethylsilyloxy) -1- (pyridine-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of methanol (1 mL) of 174 g), and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration to give the title compound (0.098 g). The structural formula, spectral data and purification conditions are shown in Table 28.

Reference example 2-12-2 to 2-12-30
Using the corresponding raw materials, Reference Examples 2-12-2 to 2-12-30 were synthesized in the same manner as in Reference Example 2-12-1. The structural formula, spectral data and purification conditions are shown in Tables 28 to 31.

Reference Example 2-13-1
In a solution of 4- (tert-butyldimethylsilyloxy) -2- (pyridin-2-yl) butylamine 2- (pyridin-2-yl) ethyl acetate ester (0.50 g) in N, N-dimethylformamide (8 mL). , Tert-Butoxypotassium (0.50 g) and 2-bromoethyl (tert-butyldimethylsilyl) ether (0.79 g) were added under ice-cooling and stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 4- (tert-butyldimethylsilyloxy) -2- (pyridine-2). -Il) Butanoic acid ethyl ester (0.94 g) was obtained. Tetrahydrofuran (5 mL) of 4- (tert-butyldimethylsilyloxy) -2- (pyridin-2-yl) butanoic acid ethyl ester (0.94 g) in a solution of lithium aluminum hydride (0.22 g) in tetrahydrofuran (5 mL). ) The solution was added dropwise under ice-cooling, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was diluted with diethyl ether, water was added, and the mixture was passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 4- (tert-butyldimethylsilyloxy) -2- (pyridin-2-yl). ) Butane-1-ol (0.37 g) was obtained. To a solution of the product (0.16 g) in tetrahydrofuran (2 mL) was added phthalimide (0.12 g), triphenylphosphine (0.22 g) and a solution of azodicarboxylate diethyl ester toluene (2.2 mol / L, 420 μL). The mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N- {4- (tert-butyldimethylsilyloxy) -2- (pyridine-). 2-Il) butyl} phthalimide (0.22 g) was obtained. Hydrazine monohydrate (0.28 g) was added to a solution of the product (0.22 g) in methanol (3 mL), and the mixture was stirred under heating under reflux for 2 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.10 g). The structural formula, spectral data and purification conditions are shown in Table 32.

Reference Example 2-14-1
(R) -3-Amino-4-phenylbutylamide hydrochloride N-[(2R) -1-carbamoyl-3-phenylpropan-2-yl] carbamic acid tert-butyl ester (0.100 g) 1,4 -A hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was added to the dioxane (2 mL) solution, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the residue was washed with n-hexane to give the title compound (0.076 g). The structural formula, spectral data and purification conditions are shown in Table 32.

Reference Example 2-15-1
(3S) -3-Amino-4- (pyridin-2-yl) butane-1-ol hydrochloride 3- (tert-butyldimethylsilyloxy) propanal (0.30 g) in a solution of (S) in tetrahydrofuran (4 mL). ) -2-Methylpropan-2-sulfinamide (0.19 g) and tetraethyl orthotitamate (0.47 g) were added, and the mixture was stirred at room temperature for 1 hour. Saturated saline was added to the reaction mixture and passed through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (S) -N- [(1E) -3- (tert-butyldimethylsilyloxy) propyridene] -2-methylpropane- 2-Sulfinamide (0.30 g) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 0.96 mL) was added to a solution of 2-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. .. A solution of (S) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propyridene] -2-methylpropan-2-sulfinamide (0.30 g) in tetrahydrofuran (2 mL) is added dropwise to this mixture. Then, the mixture was stirred at −78 ° C. for 0.5 hours. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water) and used as a highly polar product (S) -N-[(2S) -4- (tert-butyldimethylsilyl). Oxy) -1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.08 g) and as a low polar product (S) -N- [(2R)- 4-tert-Butyldimethylsilyloxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.030 g) was obtained. (S) -N-[(2S) -4- (tert-butyldimethylsilyloxy) -1- (pyridine-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of methanol (1 mL) of 08 g), and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration to give the title compound (0.045 g). The structural formula, spectral data and purification conditions are shown in Table 32.

Reference example 2-15-2 to 2-15-3
Using the corresponding raw materials, Reference Examples 2-15-2 to 2-15-3 were synthesized in the same manner as in Reference Example 2-15-1. The structural formula, spectral data and purification conditions are shown in Table 32.

Reference Example 2-161
(3R) -3-amino-4- (6-aminopyridine-2-yl) butane-1-ol 3- (tert-butyldimethylsilyloxy) propanal (0.40 g) in a solution of (0.40 g) in tetrahydrofuran (4 mL) ( R) -2-Methylpropan-2-sulfinamide (0.258 g) and tetraethyl orthotitanate (0.63 g) were added, and the mixture was stirred at room temperature for 1 hour. Saturated saline was added to the reaction mixture and passed through a Celite pad. The residue obtained by distilling off the solvent of the filtrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (R) -N- [(1E) -3- (tert-butyldimethylsilyl). Oxy) Propyridene] -2-methylpropan-2-sulfinamide (0.33 g) was obtained. To a solution of 2-azido-6-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) at -78 ° C, add a solution of n-butyllithium n-hexane (2.6 mol / L, 0.65 mL) at the same temperature. The mixture was stirred for 10 minutes. A solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propyridene] -2-methylpropan-2-sulfinamide (0.20 g) in tetrahydrofuran (2 mL) is added dropwise to this mixture. Then, the mixture was stirred at −78 ° C. for 0.5 hours. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R) -1- (6-azidopyridin-2-yl)-. 4- (tert-Butyldimethylsilyloxy) butane-2-yl] -2-methylpropan-2-sulfinamide (0.11 g) was obtained. A mixture of product (0.11 g), tetrahydrofuran (1 mL), water (0.3 mL) and triphenylphosphine (0.27 g) was stirred at 90 ° C. overnight. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(2R) -1- (6-aminopyridine-2-yl) -4- (tert-). Butane dimethylsilyloxy) butane-2-yl] -2-methylpropan-2-sulfinamide was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product in methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.046 g). The structural formula, spectral data and purification conditions are shown in Table 33.

Reference Example 2-17-1
(4S) -4-Amino-5- (Pyridine-2-yl) Pentan-1-ol
(2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyridine-2-yl) propionic acid (1.000 g) in N, N-dimethylformamide (10 mL) solution under ice-cooling. N, O-dimethylhydroxylamine hydrochloride (0.476 g), 1-hydroxybenzotriazole monohydrate (0.748 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.936 g) ) And triethylamine (1.900 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate) and N-[(1R) -1- (N-methoxy-N-methylcarbamoyl) -2. -(Pyridin-2-yl) ethyl] carbamic acid tert-butyl ester (0.959 g) was obtained. A solution of diisobutylaluminum aluminum n-hexane hydride (0.95 mol / L, 0.7 mL) was added to a solution of the product (0.158 g) in dichloromethane (4 mL) at −78 ° C., and the mixture was stirred at the same temperature for 2 hours. An aqueous solution of potassium sodium tartrate was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. The crude product was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in dichloromethane (1 mL), added to (carboethoxymethylene) triphenylphosphorane (0.214 g) under ice-cooling, and stirred at room temperature for 5 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate), and (2E, 4R) -4-[(tert-butoxycarbonyl) amino] -5. -(Pyridin-2-yl) penta-2-enoic acid ethyl ester (0.101 g) was obtained. 10% Palladium on carbon (50% wet, 100 mg) was added to a solution of the product (0.101 g) in methanol (1.5 mL) under ice-cooling, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S) -4-[(tert-butoxycarbonyl) amino] -5- (pyridin-2-yl) pentanoic acid ethyl ester. (0.088 g) was obtained. Lithium aluminum hydride (0.026 g) was added to a solution of the product (0.088 g) in tetrahydrofuran (1.5 mL) under ice-cooling, and the mixture was stirred at 0 ° C. for 1 hour. Water and diethyl ether were added to the reaction mixture, and the mixture was stirred for 30 minutes. Then, the reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N-[(2S) -5-hydroxy-1- (pyridine-2-yl) pentane-2-yl] carbamate tert-butyl. Ester (0.047 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 0.5 mL) was added to a solution of the product (0.047 g) in 1,4-dioxane (3 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.023 g). The structural formula, spectral data and purification conditions are shown in Table 33.

Reference Example 2-18-1
(2R) -2-Amino-3- (pyridin-2-yl) butane-1-ol hydrochloride 2-ethylpyridine (0.309 g) in a solution in tetrahydrofuran (3 mL) at −78 ° C. n-butyllithium n -A hexane solution (2.6 mol / L, 1 mL) was added, and the mixture was stirred at the same temperature for 30 minutes. Add a solution of (R) -N- [(E) -2- (tert-butyldimethylsilyloxy) ethylidene] -2-methylpropan-2-sulfinamide (0.500 g) in tetrahydrofuran (3 mL) at the same temperature and further. The mixture was stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain a diastereomeric mixture. This mixture was purified by reverse phase preparative liquid chromatography (Inertsil ODS-3, elution solvent: acetonitrile / water) and (R) -N- [(2R) -1- (tert-butyldimethylsilyloxy) -3. -(Pyrid-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.162 g) was obtained as a highly polar diastereomer. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (0.056 g) in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with n-hexane to give the title compound (0.022 g). The structural formula, spectral data and purification conditions are shown in Table 33.

Reference example 2-18-2 to 2-18-3
Reference Examples 2-18-2 to 2-18-3 were synthesized by the same method as in Reference Example 2-18-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 33.

Reference Example 2-19-1
(4S) -4-Amino-3- (pyridin-2-yl) pentane-1-ol hydrochloride 2- (pyridin-2-yl) acetate methyl ester (0.46 g) N, N-dimethylformamide (8 mL) ) To the solution, tert-butoxypotassium (0.41 g) and 2-bromoethyl (tert-butyldimethylsilyl) ether (0.79 g) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 4- (tert-butyldimethylsilyloxy) -2- (pyridine-2). -Il) Butanoic acid methyl ester (0.94 g) was obtained. Aqueous sodium hydroxide solution (2 mol / L, 1.3 mL) was added to a solution of the product (0.40 g) in methanol (5 mL), and the mixture was stirred overnight at room temperature. Hydrochloric acid (2 mol / L, 1.30 mL) was added to the reaction mixture for neutralization. In this mixture, N, O-dimethylhydroxylamine hydrochloride (0.19 g), triethylamine (0.39 g) and 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4- Methylmorpholinium chloride n-hydrate (0.54 g) was added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 4- (tert-butyldimethylsilyloxy) -N-methoxy-N-methyl-2-. (Pyridine-2-yl) Butylamide (0.33 g) was obtained. A solution of methylmagnesium bromide in tetrahydrofuran (1 mol / L, 600 μL) was added to a solution of the product (0.10 g) in tetrahydrofuran (1.5 mL) under ice-cooling, and the mixture was stirred at 0 ° C. for 1 hour. Hydrochloric acid (1 mol / L) and water were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 5- (tert-butyldimethylsilyloxy) -3- (pyridine-2-yl). ) Pentan-2-one (0.05 g) was obtained. (S) -2-Methylpropan-2-sulfinamide (0.023 g) and tetraethyl orthotitanium (0.077 g) were added to a solution of the product (0.05 g) in tetrahydrofuran (2 mL), and the temperature was 70 ° C. overnight. Stirred. After cooling the reaction mixture to 0 ° C., sodium borohydride (5 mg) and water (0.2 mL) were added, and the mixture was stirred at the same temperature for 2 hours. Acetone was added to the reaction mixture to quench the reaction. Saturated saline was added to this mixture and passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to obtain (S) -N-[(2S) -5- (tert-butyl) as a low-polarity product. Dimethylsilyloxy) -3- (pyridin-2-yl) pentane-2-yl] -2-methylpropan-2-sulfinamide (21 mg) and as a highly polar product (S) -N-[(2R)- 5- (tert-Butyldimethylsilyloxy) -3- (pyridin-2-yl) pentane-2-yl] -2-methylpropan-2-sulfinamide (16 mg) was obtained. (S) -N-[(2S) -5- (tert-butyldimethylsilyloxy) -3- (pyridine-2-yl) pentane-2-yl] -2-methylpropan-2-sulfinamide (21 mg) Hydrogen chloride 1,4-dioxane solution (4 mol / L, 0.5 mL) was added to a solution of methanol (0.5 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (13 mg). The structural formula, spectral data and purification conditions are shown in Table 33.

Reference example 2-19-2
Reference Example 2-19-2 was synthesized by the same method as in Reference Example 2-19-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 33.

Reference Example 2-20-1
(4R) -4-Amino-2-methyl-5- (pyridin-2-yl) pentane-2-ol 2 hydrochloride
(S) Imidazole (1.383 g) and tert-butyldimethylchlorosilane (3.062 g) are added to a solution of -3-hydroxybutanoic acid methyl ester (2.000 g) in N, N-dimethylformamide (40 mL) under ice-cooling. And stirred at room temperature for 3 hours. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (3S) -3- (tert-butyldimethylsilyloxy) butanoic acid methyl ester ( 3.934 g) was obtained. A solution of diisobutylaluminum n-hexane hydride (1.02 mol / L, 22 mL) was added to a solution of the product (3.934 g) in diethyl ether (60 mL) at −78 ° C., and the mixture was stirred at the same temperature for 2 hours. An aqueous solution of potassium sodium tartrate was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. The crude product was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (3S) -3- (tert-butyldimethylsilyloxy) butanal (3.076 g). ) Was obtained. Add (R)-(+)-2-methylpropan-2-sulfinamide (1.246 g) and tetraethyl orthotitanium (2.886 g) to a solution of the product (1.600 g) in tetrahydrofuran (20 mL) at room temperature. Stirred overnight. Saturated saline was added to the reaction mixture, diluted with ethyl acetate, and then passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(1E, 3S) -3- (tert-butyl). Didimethylsilyloxy) Butylidene] -2-methylpropan-2-sulfinamide (2.050 g) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 2.2 mL) was added to a solution of 2-methylpyridine (0.572 g) in tetrahydrofuran (3 mL) at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. .. (R) -N-[(1E, 3S) -3- (tert-butyldimethylsilyloxy) butylidene] -2-methylpropan-2-sulfinamide (1.250 g) in tetrahydrofuran (3 mL) at the same temperature. In addition, the mixture was further stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(2R, 4S) -4- (tert-butyl). Dimethylsilyloxy) -1- (pyridine-2-yl) pentane-2-yl] -2-methylpropan-2-sulfinamide (0.639 g) was obtained as a highly polar diastereomer. A solution of tetra-n-butylammonium fluoride (tetrahydrofuran (1 mol / L, 2 mL) was added to a solution of the product (0.400 g) in tetrahydrofuran (6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. After adding saturated aqueous ammonium chloride solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and (R) -N-[(2R, 4S) -4-hydroxy-1- (pyridine). -2-yl) Pentane-2-yl] -2-methylpropan-2-sulfinamide (0.284 g) was obtained. Dess-Martin peryodinane (0.509 g) was added to a solution of the product (0.284 g) in dichloromethane (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium sulfite solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and (R) -2-methyl-N-[(2R) -4-oxo-1-. (Pyridin-2-yl) Pentane-2-yl] Propane-2-sulfinamide (0.201 g) was obtained. A solution of methyl magnesium bromide diethyl ether (3.0 mol / L, 0.91 mL) was added to a solution of the product (0.201 g) in tetrahydrofuran (3 mL) under ice-cooling, and the mixture was stirred at the same temperature for 7 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and (R) -N- [(2R) -4-hydroxy-4-methyl-1- (Pyridin-2-yl) Pentane-2-yl] -2-Methylpropan-2-sulfinamide (0.015 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 0.5 mL) was added to a solution of the product (0.015 g) in 1,4-dioxane (0.5 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with n-hexane to give the title compound (0.015 g). The structural formula, spectral data and purification conditions are shown in Table 33.

Reference Example 2-21-1
(2R) -4-Methoxy-1- (pyridin-2-yl) butane-2-amine hydrochloride 3- (tert-butyldimethylsilyloxy) propanal (0.40 g) in a solution of (R) in tetrahydrofuran (4 mL). ) -2-Methylpropan-2-sulfinamide (0.258 g) and tetraethyl orthotitarate (0.63 g) were added, and the mixture was stirred at room temperature for 1 hour. Saturated saline was added to the reaction mixture and passed through a Celite pad. The residue obtained by distilling off the solvent of the filtrate was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (R) -N- [(1E) -3- (tert-butyldimethylsilyl). Oxy) Propyridene] -2-methylpropan-2-sulfinamide (0.33 g) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 0.96 mL) was added to a solution of 2-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. .. A solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propyridene] -2-methylpropan-2-sulfinamide (0.33 g) in tetrahydrofuran (2 mL) is added dropwise to this mixture. Then, the mixture was stirred at −78 ° C. for 0.5 hours. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and as a highly polar product, (R) -N-[(2R) -4- (tert-butyldimethylsilyl). Oxy) -1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.174 g) was obtained. A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 mol / L, 580 μL) was added to a solution of the product (0.15 g) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol), and (R) -N- [(2R) -4-hydroxy-1- (pyridin-2). -Il) Butan-2-yl] -2-methylpropan-2-sulfinamide (0.093 g) was obtained. Sodium hydride (60% oil dispersion, 16 mg) and iodomethane (0.27 g) were added to a solution of the product (0.093 g) in tetrahydrofuran (1 mL) under ice cooling and stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Methanol (1 mL) and a hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) were added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.036 g). The structural formula, spectral data and purification conditions are shown in Table 34.

Reference example 2-21-2
Using the corresponding raw materials, Reference Example 2-21-2 was synthesized in the same manner as in Reference Example 2-21-1. The structural formula, spectral data and purification conditions are shown in Table 34.

Reference Example 2-22-1
(R) -4- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) butane-2-amine
N, N-diisopropylethylamine (87 mg) and tert-butyldimethylchlorosilane (3R) in a solution of (3R) -3-amino-4- (pyridin-2-yl) butane-1-ol hydrochloride (40 mg) in dichloromethane (1 mL). 30 mg) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (47 mg). The structural formula, spectral data and purification conditions are shown in Table 34.

Reference example 2-22-2 to 2-22-5
Using the corresponding raw materials, Reference Examples 2-22-2 to 2-22-5 were synthesized in the same manner as in Reference Example 2-22-1. The structural formula, spectral data and purification conditions are shown in Table 34.

Reference example 2-23-1
(2R) -2-Amino-3- (pyrimidine-2-yl) propan-1-ol hydrochloride
A suspension of (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionate methyl ester (613 mg) and zinc (268 mg) in N, N-dimethylformamide (10 mL) at room temperature under an argon atmosphere. The mixture was stirred for 2 hours. To this mixture was added 2-bromopyrimidine (296 mg) and bis (triphenylphosphine) palladium (II) dichloride (131 mg), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to this mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyrimidine-2-yl) propion. Acid methyl ester (310 mg) was obtained. Sodium borohydride (104 mg) was added at 0 ° C. to a mixture of product (310 mg) ethanol (3 mL) and water (3 mL), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 3 mL) was added to a solution of the residue in methanol (3 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to give the title compound (84 mg). The structural formula, spectral data and purification conditions are shown in Table 35.

Reference example 2-23-2 to 2-23-16
Using the corresponding raw materials, Reference Examples 2-23-2 to 2-23-16 were synthesized in the same manner as in Reference Example 2-23-1. The structural formula, spectral data and purification conditions are shown in Tables 35 to 36.

Reference Example 2-24-1
(2S, 3R) -3-amino-4- (pyrimidine-2-yl) butane-1,2-diol hydrochloride N-{(1R) -1-[(4S) -2,2-dimethyl-1, 3-Dioxolane-4-yl] -2-hydroxyethyl} Carbamic acid tert-butyl ester (1.25 g), imidazole (521 mg), triphenylphosphine (2.01 g), tetrahydrofuran (10 mL) and iodine (1) .7 g) was added at 0 ° C. and stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N- {(1S) -1-[(4S) -2,2-dimethyl-1). , 3-Dioxolan-4-yl] -2-iodoethyl} carbamic acid tert-butyl ester (1.45 g) was obtained. A mixture of N, N-dimethylformamide (5 mL) of product (1.45 g) and zinc (562 mg) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture was added 2-bromopyrimidine (621 mg) and bis (triphenylphosphine) palladium (II) dichloride (274 mg), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to this mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-{(1R) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-". 4-Il] -2- (pyrimidine-2-yl) ethyl} carbamic acid tert-butyl ester (928 mg) was obtained. A mixture of product (150 mg), 1,4-dioxane (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (119 mg). The structural formula, spectral data and purification conditions are shown in Table 37.

Reference Example 2-25-1
(2R) -2-Amino-3- (1H-pyrazol-1-yl) Propane-1-ol Hydrochloride
(2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionate methyl ester (1.45 g), pyrazole (100 mg), cesium carbonate (957 mg), N, N-dimethylformamide (5 mL) The mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature, water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to (2R) -2-[(tert-butoxycarbonyl) amino] -3- (1H-). Pyrazol-1-yl) propionate methyl ester (103 mg) was obtained. Sodium borohydride (35 mg) was added at 0 ° C. to a mixture of the product (103 mg) in ethanol (1 mL) and water (1 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A mixture of the residue, methanol (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (64 mg). The structural formula, spectral data and purification conditions are shown in Table 37.

Reference Example 2-26-1
(2S, 3R) -3-amino-4- (1H-pyrazol-1-yl) butane-1,2-diol hydrochloride N-{(1R) -1-[(4S) -2,2- Didimethyl-1,3-dioxolan-4-yl] -2-hydroxyethyl} carbamic acid tert-butyl ester (3.32 g), imidazole (1.38 g), triphenylphosphine (5.33 g), tetrahydrofuran (30 mL) Hydrochloride (4.52 g) was added to the mixed solution of the above at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N- {(1S) -1-[(4S) -2,2-dimethyl-1). , 3-Dioxolan-4-yl] -2-iodoethyl} carbamic acid tert-butyl ester (3.25 g) was obtained. A mixture of product (545 mg), pyrazole (100 mg), cesium carbonate (957 mg) and N, N-dimethylformamide (5 mL) was stirred at 80 ° C. for 13 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N- {(1R) -1-[(4S) -2,2-dimethyl-1,3-dioxolane-4-". Il] -2- (1H-pyrazol-1-yl) ethyl} carbamic acid tert-butyl ester (220 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a 1,4-dioxane solution (1 mL) of the product (220 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (52 mg). The structural formula, spectral data and purification conditions are shown in Table 37.

Reference Example -2-27-1
(3R) -3-amino-1,2,3,4-tetrahydro-1,5-naphthylidine-2-one hydrochloride
A mixture of (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionate methyl ester (1.02 g) and zinc (447 mg) in N, N-dimethylformamide (5 mL) in an argon atmosphere. The mixture was stirred at room temperature for 2 hours. To this mixture was added 2-bromo-3-nitropyridine (631 mg) and bis (triphenylphosphine) palladium (II) dichloride (218 mg), and the mixture was stirred at room temperature for 13 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2R) -2-[(tert-butoxycarbonyl) amino] -3- (3-nitropyridine-2-). Il) Propyl acid methyl ester (440 mg) was obtained. To a solution of the product (440 mg) in ethanol (5 mL) was added 10% palladium carbon (50% wet, 20 mg) and stirred at 50 ° C. for 10 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-((3R) -2-oxo-1,2,3,4-tetrahydro-1,5-naphthylidine). -3-yl) Carbamic acid tert-butyl ester was obtained. A mixture of product, methanol (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (40 mg). The structural formula, spectral data and purification conditions are shown in Table 37.

Reference Examples 2-28-1, 2-28-2
(R) -N-[(2S) -1,3-di (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropan-2-sulfinamide (2-28-1: HP)
(R) -N-[(2S) -1,3-di (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropan-2-sulfinamide (2-28-2: LP)
In a 2- (tert-butyldimethylsilyloxy) acetaldehyde (2.000 g) tetrahydrofuran (30 mL) solution, (R)-(+) -2-methylpropan-2-sulfinamide (1.88 g) and tetraethyl orthotitadate (1.808 g) 4.188 g) was added, and the mixture was stirred overnight at room temperature. Saturated brine and ethyl acetate were added to the reaction mixture, and the mixture was passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (R) -N- [(1E) -2- (tert-butyldimethylsilyl). Oxy) ethylidene] -2-methylpropan-2-sulfinamide (2.185 g) was obtained. To a solution of 2- (tert-butyldimethylsilyloxymethyl) pyridine (0.282 g) in tetrahydrofuran (2 mL) at −78 ° C., add a solution of n-butyllithium n-hexane (2.6 mol / L, 0.4 mL). , Stirred at the same temperature for 30 minutes. Add a solution of (R) -N- [(1E) -2- (tert-butyldimethylsilyloxy) ethylidene] -2-methylpropan-2-sulfinamide (0.263 g) in tetrahydrofuran (2 mL) at the same temperature and further. The mixture was stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and the title compound (2-28-1: 0.085 g, 2-28-2: 0.076 g) was obtained. The structural formula, spectral data and purification conditions are shown in Table 37.

Reference example 2-28-3 to 2-28-4
Reference Examples 2-28-3 to 2-28-4 were synthesized in the same manner as in Reference Example 2-28-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 37.

Reference Example 2-29-1
(2R, 3S) -4- (benzyloxy) -3-methoxy-1- (pyridin-2-yl) butane-2-amine 3- (benzyloxy) -2-methoxypropanol (1.90 g) tetrahydrofuran To the (20 mL) solution, (R) -2-methylpropan-2-sulfinamide (1.53 g) and tetraethyl orthotitanium acid (3.53 g) were added, and the mixture was stirred overnight at room temperature. Saturated saline was added to the reaction mixture and passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) as a highly polar product (R) -N-[(1E, 2S) -3-. (Benzyloxy) -2-methoxypropyridene] -2-methylpropan-2-sulfinamide (0.57 g) and as a low polar product (R) -N-[(1E, 2R) -3- (benzyloxy) ) -2-Methoxypropyridene] -2-methylpropan-2-sulfinamide (0.70 g) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 1.0 mL) was added to a solution of 2-methylpyridine (0.27 g) in tetrahydrofuran (2 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. .. In this mixture, (R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxypropyridene] -2-methylpropan-2-sulfinamide (0.57 g) in tetrahydrofuran (4 mL). The solution was added dropwise and the mixture was stirred at the same temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water) and used as a highly polar product (R) -N-[(2R, 3S) -4- (benzyloxy). -3-methoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.20 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 2 mL) was added to a solution of this product (0.20 g) in methanol (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.15 g). The structural formula, spectral data and purification conditions are shown in Table 38.

Reference example 2-30-1
(2R, 3R) -4- (benzyloxy) -3-methoxy-1- (pyridin-2-yl) butane-2-amine 3- (benzyloxy) -2-methoxypropanol (1.90 g) tetrahydrofuran To the (20 mL) solution, (R) -2-methylpropan-2-sulfinamide (1.53 g) and tetraethyl orthotitanium acid (3.53 g) were added, and the mixture was stirred overnight at room temperature. Saturated saline was added to the reaction mixture and passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) as a highly polar product (R) -N-[(1E, 2S) -3-. (Benzyloxy) -2-methoxypropyridene] -2-methylpropan-2-sulfinamide (0.57 g) and as a low polar product (R) -N-[(1E, 2R) -3- (benzyloxy) ) -2-Methoxypropyridene] -2-methylpropan-2-sulfinamide (0.70 g) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 1.0 mL) was added to a solution of 2-methylpyridine (0.19 g) in tetrahydrofuran (2 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. .. In this mixture, (R) -N-[(1E, 2R) -3- (benzyloxy) -2-methoxypropyridene] -2-methylpropan-2-sulfinamide (0.40 g) in tetrahydrofuran (2 mL) The solution was added dropwise and the mixture was stirred at the same temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and (R) -N-[(2R, 3R) -4- (benzyloxy) -3. -Methoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide and (R) -N-[(2S, 3R) -4- (benzyloxy) -3 A mixture (0.47 g) of −methoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide was obtained. Tetrahydrofuran (4 mL) and a hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) were added to the product (0.42 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.15 g) as a low polar product. The structural formula, spectral data and purification conditions are shown in Table 38.

Reference Example 2-31-1
(2R) -2-Amino-2-methyl-3- (pyridin-2-yl) propanamide
(2R) -2-Amino-2-methyl-3- (pyridin-2-yl) propan-1-ol hydrochloride (64 mg) in dichloromethane (1 mL) solution with N, N-diisopropylethylamine (121 mg) and chlorogenic acid. Benzyl ester (64 mg) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -1-hydroxy-2- (pyridine-2-ylmethyl). ) Propane-2-yl] Carbamate benzyl ester (35 mg) was obtained. Dess-Martin peryodinane (80 mg) was added to a solution of the product (35 mg) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate solution (1 mol / L) and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-[(2R) -1-oxo-2- (pyridin-2-ylmethyl) propan-2-yl] carbamic acid benzyl ester (34 mg). Product (34 mg), sodium dihydrogen phosphate dihydrate (21 mg), tert-butyl alcohol (2 mL), acetonitrile (400 μL), water (800 μL), 2-methyl-2-butene (35 mg) and chlorite The mixture of sodium phosphate (45 mg) was stirred at room temperature for 2 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain (2R) -2-[(benzyloxycarbonyl) amino] -2-methyl-3- (pyridin-2-yl) propionic acid (36 mg). Ammonium chloride (61 mg), N, N-diisopropylethylamine (147 mg) and 1,1'-carbonyldiimidazole (30 mg) were added to a suspension of the product (36 mg) in N, N-dimethylformamide (1 mL) at room temperature. Was stirred for 1 day. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-[(1R) -1-carbamoyl-1-methyl-2- (pyridin-2-yl) ethyl] carbamic acid benzyl ester (13 mg). Ethanol (2 mL) and 10% palladium carbon (50% wet, 0.02 g) were added to the product (13 mg), and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad and the filtrate was concentrated under reduced pressure to give the title compound (7 mg). The structural formula, spectral data and purification conditions are shown in Table 38.

Reference example 2-31-2
Using the corresponding raw materials, Reference Example 2-31-2 was synthesized in the same manner as in Reference Example 2-31-1. The structural formula and purification conditions are shown in Table 38.

Reference Example 2-32-1
(3R) -3-amino-4-hydroxybutanenitrile hydrochloride
To a solution of (2R) -2-[(tert-butoxycarbonyl) amino] -3-cyanopropionic acid (500 mg) in tetrahydrofuran (5 mL), triethylamine (710 mg) and chloroformic acid isobutyl ester (637 mg) were added at 0 ° C. , Stirred at the same temperature for 1 hour. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. Sodium borohydride (178 mg) was added to a solution of the residue in methanol (5 mL) at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. Hydrochloric acid (1 mol / L) was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 2 mL) was added to a solution of the residue in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration to give the title compound (100 mg). The structural formula, spectral data and purification conditions are shown in Table 38.

Reference Example 2-33-1
(3R) -3-amino-4- (1,6-dihydropyrimidine-2-yl) butane-1-ol-2 hydrochloride
(2S) -4- (tert-butoxy) -2-[(tert-butoxycarbonyl) amino] -4-oxobutanoic acid (2 g) in a solution of N-methylmorpholine (840 mg), isobutyl chloroformate in tetrahydrofuran (10 mL). Ester (1.04 g) was added at 0 ° C. and stirred at the same temperature for 1 hour. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. Sodium borohydride (525 mg) was added to a solution of the residue in methanol (10 mL) at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. Hydrochloric acid (1 mol / L) was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (3S) -3-[(tert-butoxycarbonyl) amino] -4-hydroxybutanoic acid tert-butyl ester (1. 93 g) was obtained. Iodine (2.49 g) was added at 0 ° C. to a mixture of product (1.93 g), imidazole (763 mg), triphenylphosphine (2.94 g) and tetrahydrofuran (20 mL) and stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (3S) -3-[(tert-butoxycarbonyl) amino] -4-yo-. Dobutanoic acid tert-butyl ester (2.3 g) was obtained. A mixture of product (1 g) and zinc (374 mg) in N, N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture was added 2-bromopyrimidine (413 mg), bis (triphenylphosphine) palladium (II) dichloride (182 mg), and the mixture was stirred at 40 ° C. for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (3R) -3-[(tert-butoxycarbonyl) amino] -4- (pyrimidine-2-yl) butanoate tert. -Butyl ester (460 mg) was obtained. Lithium aluminum hydride (99 mg) was added to a solution of the product (350 mg) in tetrahydrofuran (5 mL) at 0 ° C. and the mixture was stirred at room temperature for 1 hour. Water (100 μL), aqueous sodium hydroxide solution (15%, 100 μL) and water (300 μL) were added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. Methanol (2 mL) and a hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) were added to the residue, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (200 mg). The structural formula, spectral data and purification conditions are shown in Table 38.

Reference Example 2-34-1
(3R) -3-amino-2-methyl-4- (6-methyl-1,6-dihydropyrimidine-2-yl) butane-2-ol2 hydrochloride
A mixture of (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionate methyl ester (800 mg) and zinc (350 mg) in N, N-dimethylformamide (10 mL) at room temperature under an argon atmosphere. The mixture was stirred for 2 hours. To this mixture was added 2-bromopyrimidine (386 mg), bis (triphenylphosphine) palladium (II) dichloride (171 mg), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to (2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyrimidine-2-yl) propion. Acid methyl ester (450 mg) was obtained. A solution of methyllithium diethyl ether (1.1 mol / L, 5.8 mL) was added to a solution of the product (450 mg) in diethyl ether (5 mL) at −78 ° C., and the mixture was stirred for 30 minutes. Saturated ammonium chloride was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Methanol (2 mL) and a hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) were added to the residue, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (40 mg). The structural formula, spectral data and purification conditions are shown in Table 38.

Reference Example 2-35-1
(3R) -3-amino-4- (pyrimidine-2-yl) butane-1-ol hydrochloride
(2S) -2-[(tert-butoxycarbonyl) amino] -4-methoxy-4-oxobutanoic acid (2 g) in a solution of N-methylmorpholine (981 mg) in tetrahydrofuran (10 mL), chloroformic acid isobutyl ester (1) .22 g) was added at 0 ° C. and stirred at the same temperature for 1 hour. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. Sodium borohydride (337 mg) was added to a solution of the residue in methanol (10 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (3S) -3-[(tert-butoxycarbonyl) amino] -4-hydroxybutanoic acid methyl ester (1.18 g). Got Iodine (1.8 g) was added at 0 ° C. to a mixture of product (1.18 g), imidazole (551 mg), triphenylphosphine (2.12 g) and tetrahydrofuran (40 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (3S) -3-[(tert-butoxycarbonyl) amino] -4-yo-. Dobutanoic acid methyl ester (1.5 g) was obtained. A mixture of N, N-dimethylformamide (10 mL) of product (1.5 g) and zinc (629 mg) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture was added 2-bromopyrimidine (695 mg), bis (triphenylphosphine) palladium (II) dichloride (307 mg), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (3R) -3-[(tert-butoxycarbonyl) amino] -4- (pyrimidine-2-yl) butane. Acid methyl ester (746 mg) was obtained. Sodium borohydride (239 mg) was added at 0 ° C. to a mixture of the product (746 mg) in ethanol (3 mL) and water (3 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -4-hydroxy-1- (pyrimidine-2-yl) butane-2-yl]. Carbamic acid tert-butyl ester was obtained. Methanol (3 mL) and a hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) were added to the product, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (50 mg). The structural formula, spectral data and purification conditions are shown in Table 38.

Reference example 2-36-1
N-[(2R, 3R) -3-amino-1-benzyloxy-4- (pyridine-2-yl) butane-2-yl] carbamic acid benzyl ester N- [1-benzyloxy-3-oxopropane- 2-Il] Tetraethyl orthotitanium (0.959 mL) was added to a mixed solution of benzyl carbamate (975 mg) and (R) -tert-butylsulfinamide (490 mg) in tetrahydrofuran (15 mL). The mixture was stirred overnight, saturated brine (1.5 mL) was added, and the mixture was passed through a Celite pad. Water and ethyl acetate were added to the filtrate to separate the liquids, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N- {1-benzyloxy-3-[((R) -tert-butylsulfinyl) imino] propan-2-yl}. Carbamate benzyl ester (863 mg) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 1.05 mL) was added to a solution of 2-methylpyridine (289 mg) in tetrahydrofuran (6 mL) at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. did. A solution of N- {1-benzyloxy-3-[((R) -tert-butylsulfinyl) imino] propan-2-yl} carbamic acid benzyl ester (863 mg) in tetrahydrofuran (6 mL) was added to this mixture. The mixture was stirred at −78 ° C. for 1.25 hours and at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride (5 mL) was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water) and N-{(2R, 3R) -1-benzyloxy-3-[((R) -tert-). Butylsulfinyl) amino] -4- (pyridin-2-yl) butane-2-yl} carbamate benzyl ester (46 mg) and a mixture of the corresponding three diastereomers (74 mg) were obtained. N-{(2R, 3R) -1-benzyloxy-3-[((R) -tert-butylsulfinyl) amino] -4- (pyridine-2-yl) butane-2-yl} carbamic acid benzyl ester ( A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 0.2 mL) was added to a solution of 46 mg) of methanol (1 mL) at room temperature, and the mixture was stirred for 1.3 hours. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (36 mg). The structural formula, spectral data and purification conditions are shown in Table 38.

Reference example 2-37-1
N-[(2R, 3RS) -3-amino-1-benzyloxy-4- (pyridine-2-yl) butane-2-yl] carbamate benzyl ester (R) -3-benzyloxy-2- (benzyl) To a solution of oxycarbonylamino) propionic acid methyl ester (990 mg) in dichloromethane (15 mL) at -78 ° C, an n-hexane solution of diisobutylaluminum hydride (1.02 mol / L, 5.09 mL) was added, and the mixture was added. The mixture was stirred for 5 hours. Methanol (5 mL) and saturated brine (10 mL) were added to the mixture, and the mixture was passed through a Celite pad. The insoluble material was washed with ethyl acetate, and the organic layer of the filtrate was separated. The crude product was extracted from the aqueous layer with ethyl acetate, and the combined organic layer was concentrated under reduced pressure. Tetraethyl orthotitanium (0.906 mL) was added to a mixture of this residue and (R) -tert-butylsulfinamide (525 mg) in tetrahydrofuran (20 mL). The mixture was stirred overnight at room temperature, saturated brine (5 mL) and ethyl acetate (10 mL) were added, and the mixture was passed through a Celite pad. Water and ethyl acetate were added to the filtrate to separate the liquids, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N- {(S) -1-benzyloxy-3-[((R) -tert-butylsulfinyl) imino] propane- 2-Il} carbamate benzyl ester (993 mg) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 1.19 mL) was added to a solution of 2-methylpyridine (333 mg) in tetrahydrofuran (7 mL) at −78 ° C., and the mixture was stirred for 30 minutes. To this mixture was added a solution of {(S) -1-benzyloxy-3-[((R) -tert-butylsulfinyl) imino] propan-2-yl} carbamic acid benzyl ester (993 mg) in tetrahydrofuran (7 mL). .. The mixture was stirred at −78 ° C. for 2 hours and at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride (2 mL) was added to the reaction solution. The crude product was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N-{(S) -1-benzyloxy-3-[((R) -tert-butylsulfinyl) amino] -4-( Pyridine-2-yl) butane-2-yl} carbamate benzyl ester (489 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 0.461 mL) was added to a solution of the product (484 mg) in methanol (15 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (350 mg). The structural formula, spectral data and purification conditions are shown in Table 39.

Reference example 2-372
Using the corresponding raw materials, Reference Example 2-37-1 was synthesized in the same manner as in Reference Example 2-37-1. The structural formula, spectral data and purification conditions are shown in Table 39.

Reference Example 2-381
(2R, 3S) -3,4-dimethoxy-1- (pyridin-2-yl) butane-2-amine hydrochloride
Triethylamine (0.32 g) and di-tert-butyl dicarbonate in a solution of (2S, 3R) -3-amino-4- (pyridin-2-yl) butane-1,2-diol (0.20 g) in tetrahydrofuran (3 mL). -Butyl (0.19 g) was added and stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N-[(2R, 3S) -3,4-dihydroxy-1- (pyridine-2). -Il) Butan-2-yl] Carbamate tert-butyl ester (0.22 g) was obtained. Sodium hydride (60% oil dispersion, 15 mg) and iodomethane (125 mg) were added to the product (50 mg) in tetrahydrofuran (1 mL) under ice cooling and stirred at room temperature for 1 day. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N-[(2R, 3S) -3,4-dimethoxy-1- (pyridine-2). -Il) Butan-2-yl] Carbamate tert-butyl ester (10 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 0.5 mL) was added to a solution of the product (10 mg) in methanol (0.5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (9 mg). The structural formula, spectral data and purification conditions are shown in Table 39.

Reference Example 2-391
(2S, 3R) -3-amino-1-ethoxy-4- (pyridin-2-yl) butane-2-ol
Potassium hydroxide (1.03 g) was added to a solution of (2R) -2-[(benzyloxy) methyl] oxylan (1.00 g) in ethanol (10 mL), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2R) -1- (benzyloxy) -3-ethoxypropane-2-ol. (1.25 g) was obtained. Imidazole (1.01 g) and tert-butyldimethylchlorosilane (0.99 g) were added to a solution of the product (1.25 g) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and [(2R) -1- (benzyloxy) -3-ethoxypropane-2-. Il] (tert-butyldimethylsilyl) ether (2.00 g) was obtained. 10% Palladium on carbon (50% wet, 0.2 g) was added to a solution of the product (2.00 g) in ethanol (20 mL), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), iodobenzene diacetate (2.87 g) and AZADOL® (0.046 g) were added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. An aqueous sodium thiosulfate solution (1 mol / L) and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Tetrahydrofuran (20 mL), (R) -tert-butylsulfinamide (790 mg) and tetraethyl orthotitanium (1.85 mL) were added to the residue. The mixture was stirred at room temperature overnight. Saturated saline and ethyl acetate were added to the reaction mixture, and the mixture was passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(1E, 2S) -2- (tert-butyldimethyl). Cyriloxy) -3-ethoxypropyridene] -2-methylpropan-2-sulfinamide (0.85 g) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 2.2 mL) was added to a solution of 2-methylpyridine (0.35 g) in tetrahydrofuran (2 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. .. In this mixture, (R) -N-[(1E, 2S) -2- (tert-butyldimethylsilyloxy) -3-ethoxypropyridene] -2-methylpropan-2-sulfinamide (0.85 g) A solution of tetrahydrofuran (3 mL) was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water) and used as a highly polar product (R) -N-[(2R, 3S) -3- (tert-butyl). Dimethylsilyloxy) -4-ethoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.36 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 2 mL) was added to a solution of the product (0.36 g) in methanol (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.16 g). The structural formula, spectral data and purification conditions are shown in Table 39.

Reference example 2-39-2 to 2-39-4
Reference Examples 2-39-2 to 2-39-4 were synthesized by the same method as in Reference Example 2-391 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 39.

Reference Example 2-40-1
(2R, 3S) -4- (benzyloxy) -3-ethoxy-1- (pyridin-2-yl) butane-2-amine
(4R) -4-[(benzyloxy) methyl] -2,2-dimethyl-1,3-dioxolane (8.00 g) in methanol and hydrogen chloride 1,4-dioxane solution (4 mol / L, 20 mL) Was added, and the mixture was stirred at room temperature for 3 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (2S) -3- (benzyloxy) propane-1,2-diol (7.30 g). Got N, N-diisopropylethylamine (12.2 g) and chloromethyl methyl ether (3.35 g) were added to a solution of the product (6.90 g) in dichloromethane (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. .. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (2R) -1-benzyloxy-3- (methoxymethoxy) propan-2- All (2.30 g) was obtained. Sodium hydride (60% oil dispersion, 53 mg) and iodoethane (0.42 g) were added to a solution of the product (0.20 g) in tetrahydrofuran (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and [(2R) -1- (benzyloxy) -3- (methoxymethoxy) propane. -2-yl] Ethyl ether (0.21 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 2 mL) was added to a solution of the product (0.21 g) in methanol (2 mL), and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2S) -3- (benzyloxy) -2-ethoxypropane-1-ol. (0.137 g) was obtained. Iodobenzene diacetate (315 mg) and AZADOL® (5 mg) were added to a solution of the product (137 mg) in dichloromethane (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. An aqueous sodium thiosulfate solution (1 mol / L) and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Tetrahydrofuran (3 mL), (R) -tert-butylsulfinamide (103 mg) and tetraethyl orthotitanium (215 μL) were added to the residue obtained by distilling off the solvent under reduced pressure. The mixture was stirred at room temperature overnight. Saturated saline and ethyl acetate were added to the reaction mixture, and the mixture was passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(1E, 2S) -3- (benzyloxy)-. 2-ethoxypropylidene] -2-methylpropan-2-sulfinamide (120 mg) was obtained. A solution of n-butyllithium n-hexane (2.6 mol / L, 0.2 mL) was added to a solution of 2-methylpyridine (54 mg) in tetrahydrofuran (2 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. To this mixture was a solution of (R) -N-[(1E, 2S) -3- (benzyloxy) -2-ethoxypropyridene] -2-methylpropan-2-sulfinamide (120 mg) in tetrahydrofuran (3 mL). The mixture was added dropwise and stirred at the same temperature for 1.5 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water) and used as a highly polar product (R) -N-[(2R, 3S) -4- (benzyloxy). -3-ethoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (35 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (35 mg) in methanol (1 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (12 mg). The structural formula and purification conditions are shown in Table 39.

Reference Example 2-41-1
(1R) -1-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyrimidine-2-yl) ethane-1-amine N-[(1R) -1 -((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] carbamate benzyl ester (1.78 g), imidazole (656 mg), triphenylphosphine (2.53 g) ), Ethyl (2.14 g) was added to a mixed solution of tetrahydrofuran (20 mL) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(1S) -1-((4R) -2,2-dimethyl-). 1,3-Dioxolane-4-yl) -2-iodoethyl] carbamate benzyl ester (1.9 g) was obtained. A mixture of N, N-dimethylformamide (10 mL) of product (1.9 g) and zinc (355 mg) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture was added 2-bromopyrimidine (392 mg) and bis (triphenylphosphine) palladium (II) dichloride (173 mg), and the mixture was stirred at room temperature for 13 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(1R) -1-((4R) -2,2-dimethyl-1,3-dioxolan-). 4-Il) -2- (pyrimidine-2-yl) ethyl] carbamate benzyl ester (614 mg) was obtained. A mixture of product (400 mg), 10% palladium carbon (50% wet, 10 mg) and ethyl acetate (5 mL) was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad and the filtrate was concentrated under reduced pressure to give the title compound (140 mg). The structural formula, spectral data and purification conditions are shown in Table 39.

Reference Example 2-42-1
(2S) -3- (benzyloxy) -1-methoxy-1- (pyridin-2-yl) propan-2-amine hydrochloride 2- (tert-butyldimethylsilyloxymethyl) pyridine (1.032 g) in tetrahydrofuran A butyllithium n-hexane solution (2.6 mol / L, 1.5 mL) was added to the (5 mL) solution at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. To this mixture is added a solution of (R) -N- [(1E) -2- (benzyloxy) ethylidene] -2-methylpropan-2-sulfinamide (0.836 g) in tetrahydrofuran (5 mL) at the same temperature for an additional 30. Stir for minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N- [(2S) -3- (benzyloxy) -1. -(Tert-Butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropan-2-sulfinamide (HP, 0.345 g) and (R) -N- [ (2S) -3- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropan-2-sulfinamide (LP, 0.354 g) was obtained. (R) -N- [(2S) -3- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane- Tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 1 mL) was added to a solution of 2-sulfinamide (0.345 g) in tetrahydrofuran (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. After adding saturated aqueous ammonium chloride solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and (R) -N-[(2S) -3- (benzyloxy) -1-hydroxy. -1- (Pyridine-2-yl) propan-2-yl] -2-methylpropan-2-sulfinamide (0.185 g) was obtained. Sodium hydride (60% oil dispersion, 0.006 g) under ice-cooling is added to a solution of the product (0.093 g) in tetrahydrofuran (1 mL), stirred at room temperature for 30 minutes, and then iodomethane (0.145 g) is added at room temperature. Stirred overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N- [(2S) -3- (benzyloxy) -1. −methoxy-1- (pyridin-2-yl) propan-2-yl] -2-methylpropan-2-sulfinamide (0.042 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (0.024 g) in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with n-hexane to give the title compound (0.015 g). The structural formula, spectral data and purification conditions are shown in Table 40.

Reference example 2-42-2 to 2-42-4
Using the corresponding raw materials, Reference Examples 2-4-2-2 to 2-42-4 were synthesized in the same manner as in Reference Example 2-42-1. The structural formula, spectral data and purification conditions are shown in Table 40.

Reference Example 2-43-1
(2R, 3S) -4- (benzyloxy) -1,3-dimethoxy-1- (pyridin-2-yl) butane-2-amine
(R)-(+)-2-Methylpropan-2-sulfinamide (0.145 g) in a solution of (2R) -3-benzyloxy-2-methoxypropanol (0.213 g) in tetrahydrofuran (8 mL). And tetraethyl orthotitamate (0.401 g) were added, and the mixture was stirred overnight at room temperature. Saturated brine and ethyl acetate were added to the reaction mixture, and the mixture was passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(1E, 2S) -3- (benzyloxy). -2-Methylpropylidene] -2-Methylpropan-2-sulfinamide (0.247 g) was obtained. To a solution of 2- (tert-butyldimethylsilyloxymethyl) pyridine (0.260 g) in tetrahydrofuran (3 mL) at −78 ° C., add a solution of n-butyllithium n-hexane (2.6 mol / L, 0.4 mL). The mixture was stirred for 30 minutes. A solution of (R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxypropyridene] -2-methylpropan-2-sulfinamide (0.247 g) in tetrahydrofuran (3 mL) to this mixture. Was added at the same temperature and stirred for another 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain a mixture of three diastereomers. This mixture was purified by reverse phase preparative liquid chromatography (Inertsil ODS-3, elution solvent: acetonitrile / water) and (R) -N-[(2S, 3S) -4- (benzyloxy) -1-(. tert-Butyldimethylsilyloxy) -3-methoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide single diastereomeric (LP: 0.082 g) ) And (R) -N-[(2S, 3S) -4- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -3-methoxy-1- (pyridin-2-yl) butane-2- Il] -2-methylpropan-2-sulfinamide with a single diastereomer and (R) -N-[(2R, 3S) -4- (benzyloxy) -1- (tert-butyldimethylsilyloxy) A single diastereomeric mixture of -3-methoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (HP: 0.085 g) was obtained. (R) -N-[(2S, 3S) -4- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -3-methoxy-1- (pyridine-2-yl) butane-2-yl] A single diastereomer of -2-methylpropan-2-sulfinamide and (R) -N-[(2R, 3S) -4- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -3 -Methoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide to a mixture of single diastereomers (0.085 g) with tetrahydrofuran (1 mL) was added. .. Tetra-n-butylammonium tetrahydrofuran solution (1 mol / L, 0.25 mL) was added to this mixture under ice-cooling, and the mixture was stirred for 30 minutes. After adding saturated aqueous ammonium chloride solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and (R) -N-[(2R, 3S) -4- (benzyloxy) -1. -Hydroxy-3-methoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.033 g) was obtained as a low-polarity diastereomer. Sodium hydride (60% oil dispersion, 0.003 g) is added to a solution of the product (0.033 g) in tetrahydrofuran (1 mL) under ice cooling, stirred for 30 minutes, and then iodomethane (0.046 g) is added at room temperature. Stirred overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(2R, 3S) -4- (benzyloxy). -1,3-Dimethoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.018 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a 1,4-dioxane (1 mL) solution of the product (0.018 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with n-hexane to give the title compound (0.013 g). The structural formula, spectral data and purification conditions are shown in Table 40.

Reference example 24-43-2
Using the corresponding raw materials, Reference Example 2-43-2 was synthesized in the same manner as in Reference Example 2-43-1. The structural formula, spectral data and purification conditions are shown in Table 40.

Reference Example 2-444-1
(2R, 3R) -2-amino-4-methoxy-3- (pyridin-2-yl) butane-1-ol and (2R, 3S) -2-amino-4-methoxy-3- (pyridin-2-yl) Il) Butane-1-ol mixture 2-bromopyrididine (0.72 g) in tetrahydrofuran (10 mL) at -78 ° C with n-butyllithium n-hexane solution (2.6 mol / L, 1.7 mL). The mixture was stirred for 10 minutes. (4S) Add a solution of -4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) in tetrahydrofuran (5 mL) at the same temperature and stir for another 1.5 hours. did. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (4S) -4-[(R) -hydroxy (pyridine-2-yl). Methyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester and (4S) -4-[(S) -hydroxy (pyridine-2-yl) methyl] -2,2- A mixture of dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (1.16 g) was obtained. Dess-Martin peryodinane (2.39 g) was added to a mixture of product (1.16 g) and dichloromethane (10 mL) and stirred at room temperature for 2 days. An aqueous sodium thiosulfate solution (1 mol / L) and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S) -2,2-dimethyl-4- (pyridine-2-carbonyl). -1,3-Oxazozolidin-3-carboxylic acid tert-butyl ester (1.02 g) was obtained. A potassium bis (trimethylsilyl) amide tetrahydrofuran solution (1.0 mol / L, 1.2 mL) was added to a suspension of (methoxymethyl) triphenylphosphonium chloride (447 mg) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 1 hour. To this mixture is added ice-cooled (4S) -2,2-dimethyl-4- (pyridin-2-carbonyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (200 mg) at room temperature. Stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R) -4- [2-methoxy-1- (pyridin-2-yl) ethenyl] -2,2-dimethyl-. A 1,3-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg) was obtained. 10% Palladium on carbon (50% wet, 10 mg) was added to a solution of the product (100 mg) in ethanol (3 mL), and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to purify (4R) -4-[(1R) -2. -Methoxy-1- (pyridin-2-yl) ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester and (4R) -4-[(1S) -2-methoxy A mixture (80 mg) of -1- (pyridine-2-yl) ethyl] -2,2-dimethyl-1,3-oxazolidin-3-carboxylic acid tert-butyl ester was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a mixture of the product (80 mg) and methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (40 mg). The structural formula, spectral data and purification conditions are shown in Table 40.

Reference Example 24-451
(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (1H-pyrazole-1-yl) butane-2-amine
(1S) -2- (benzyloxy) -1-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) ethane-1-ol (9.7 g), phthalimide (11.31 g) ) And triphenylphosphine (20.17 g) in tetrahydrofuran (70 mL), a solution of azodicarboxylate diethyl ester toluene (2.2 mol / L, 35 mL) was added, and the mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane). Diethyl ether was added to the purified product and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and N-[(1R) -2- (benzyloxy) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) ethyl] phthalimide (10. 6 g) was obtained. Hydrazine monohydrate (19.24 g) was added to a solution of the product (10.6 g) in ethanol (50 mL), and the mixture was stirred at 80 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Di-tert-butyl dicarbonate (6.71 g) and 20% palladium hydroxide carbon (50% wet, 2 g) were added to a solution of the residue in ethanol (20 mL), and the mixture was stirred at 50 ° C. for 2 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolane-4-). Il) -2-hydroxyethyl] carbamic acid tert-butyl ester (4.9 g) was obtained. N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] carbamic acid tert-butyl ester (12.6 g) in dichloromethane (12.6 g) Triethylamine (9.76 g) and methanesulfonyl chloride (7.18 g) were added to the 70 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The extract was concentrated under reduced pressure. Cesium carbonate (47.13 g) and pyrazole (6.57 g) were added to a solution of the residue in N, N-dimethylformamide (100 mL), and the mixture was stirred at 80 ° C. for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolane-4-). Il) -2- (1H-pyrazole-1-yl) ethyl] carbamic acid tert-butyl ester (6.5 g) was obtained. Trifluoroacetic acid (1.6 mL) was added to a mixture of methanol (21 mL) and water (7 mL) of the product (6.5 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N-[(2R, 3S) -3,4-dihydroxy-1- (1H-pyrazole-). 1-Il) Butan-2-yl] Carbamic acid tert-butyl ester (5.0 g) was obtained. Imidazole (1.71 g) and tert-butyldiphenylchlorosilane (6.31 g) were added to a solution of the product (5.0 g) in N, N-dimethylformamide (20 mL) at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. .. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy)-. 3-Hydroxy-1- (1H-pyrazole-1-yl) butane-2-yl] carbamate tert-butyl ester (7.8 g) was obtained. A mixture of product (7.8 g), iodomethane (2.61 g), tetrahydrofuran (30 mL), N, N-dimethylformamide (3 mL) with a small amount of sodium hydride (60% oil dispersion, 642 mg) at 0 ° C. They were added one by one and stirred at the same temperature for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy)-. 3-methoxy-1- (1H-pyrazole-1-yl) butane-2-yl] carbamate tert-butyl ester (6.8 g) was obtained. Trifluoroacetic acid (10 mL) was added to a solution of the product (6.8 g) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydroxide solution (2 mol / L) was added to the residue, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (4.5 g). The structural formula, spectral data and purification conditions are shown in Table 41.

Reference example 2-45-2 to 2-45-8
Using the corresponding raw materials, Reference Examples 2-45-2 to 2-45-8 were synthesized in the same manner as in Reference Example 2-45-1. The structural formula, spectral data and purification conditions are shown in Table 41.

Reference Example 2-46-1
N-[(2S, 3S) -4- (tert-butyldiphenylsilyloxy) -1-iodo-3-methoxybutane-2-yl] carbamic acid tert-butyl ester
(4S) -4-[(1R) -1-azido-2- (benzyloxy) ethyl] -2,2-dimethyl-1,3-dioxolane (2.3 g) in a methanol (5 mL) solution and hydrogen chloride A 1,4-dioxane solution (4 mol / L, 10 mL) was added, and the mixture was stirred at room temperature for 4 hours. A hydrogen chloride 1,4-dioxane solution (4 mol / L, 10 mL) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Imidazole (678 mg) and tert-butyldiphenylchlorosilane (2.51 g) were added to a solution of the residue in N, N-dimethylformamide (25 mL) at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2S, 3R) -3-azido-4- (benzyloxy) -1-(. tert-Butyldiphenylsilyloxy) butane-2-ol (4.58 g) was obtained. To a mixture of product (4.58 g), N, N-dimethylformamide (10 mL) and iodomethane (2.05 g), sodium hydride (60% oil dispersion, 425 mg) was added at 0 ° C. and 1 at the same temperature. Stir for hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and [(2S, 3R) -3-azido-4- (benzyloxy) -2-. Methoxybutyl] (tert-butyldiphenylsilyl) ether (4.3 g) was obtained. A mixture of product (4.3 g), di-tert-butyl dicarbonate (2.3 g), 20% palladium hydroxide carbon (50% wet, 2 g) and ethanol (30 mL) at 60 ° C under a hydrogen atmosphere at 13 degrees. Stir for hours. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -1-hydroxy-3-methoxybutane. -2-yl] Carbamic acid tert-butyl ester (2.88 g) was obtained. Iodine (2.16 g) was added at 0 ° C. to a mixture of product (2.88 g), imidazole (662 mg), triphenylphosphine (2.55 g) and tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (3.08 g). The structural formula, spectral data and purification conditions are shown in Table 42.

Reference Example 2-46-2
Reference Example 2-46-2 was synthesized by the same method as in Reference Example 2-46-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 42.

Reference Example 24-47-1
(2S, 3R) -3-amino-2-methoxy-4- (pyrimidine-2-yl) butane-1-ol N-[(2S, 3S) -4- (tert-butyldiphenylsilyloxy) -1- A mixture of iodo-3-methoxybutane-2-yl] carbamic acid tert-butyl ester (1.09 g) and zinc (268 mg) in N, N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture was added 2-bromopyrimidine (296 mg) and bis (triphenylphosphine) palladium (II) dichloride (131 mg), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1-. (Pyrimidine-2-yl) Butane-2-yl] Carbamic acid tert-butyl ester (455 mg) was obtained. A mixture of product (455 mg) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 5 mL) was stirred at 50 ° C. for 2 days. The reaction mixture was concentrated under reduced pressure. A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 mol / L, 1 mL) was added to a solution of the residue in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (150 mg). The structural formula, spectral data and purification conditions are shown in Table 42.

Reference Example 2-48-1
(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (pyrimidine-2-yl) butane-2-amine N-[(2S, 3S) -4- (tert-butyl) Diphenylsilyloxy) -1-iodo-3-methoxybutane-2-yl] carbamic acid tert-butyl ester (600 mg), zinc (148 mg) N, N-dimethylformamide (5 mL) mixture at room temperature under argon atmosphere 2 Stirred for hours. To this mixture was added 2-bromopyrimidine (163 mg), bis (triphenylphosphine) palladium (II) dichloride (72 mg), and the mixture was stirred at room temperature for 3 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1-. (Pyrimidine-2-yl) Butane-2-yl] Carbamic acid tert-butyl ester (290 mg) was obtained. Trifluoroacetic acid (1 mL) was added to a solution of the product (290 mg) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (150 mg). The structural formula, spectral data and purification conditions are shown in Table 42.

Reference example 2-48-2 to 2-48-5
Reference Examples 2-48-2 to 2-48-5 were synthesized in the same manner as in Reference Example 2-48-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 42.

Reference Example 24-49-1
(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -1- (3-fluoropyridine-2-yl) -3-methoxybutane-2-amine trifluoroacetate N-[(2S, 3S) -4- (tert-butyldiphenylsilyloxy) -1-iodo-3-methoxybutane-2-yl] carbamic acid tert-butyl ester (200 mg), zinc (49 mg) and N, N-dimethylformamide (5 mL) The mixture was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture was added 2-bromo-3-fluoropyridine (60 mg) and bis [di-tert-butyl (4-dimethylaminophenyl) phosphine] dichloropalladium (II) (24 mg), and the mixture was stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -1- (3-fluoro). Pyridine-2-yl) -3-methoxybutane-2-yl] carbamic acid tert-butyl ester (45 mg) was obtained. Trifluoroacetic acid (0.2 mL) was added to a solution of the product (45 mg) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (55 mg). The structural formula, spectral data and purification conditions are shown in Table 43.

Reference example 2-49-2
Using the corresponding raw materials, Reference Example 2-49-2 was synthesized in the same manner as in Reference Example 2-49-1. The structural formula, spectral data and purification conditions are shown in Table 43.

Reference Example 2-50-1
(2S, 3R) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (pyrimidine-2-yl) butane-2-amine
(2R) -2-((4S) -2,2-dimethyl-1,3-dioxolane-4-yl) -2-hydroxyacetate methyl ester (5.0 g) in a dichloromethane (50 mL) solution with N, N -Diisopropylethylamine (6.8 g) and methanesulfonyl chloride (3.91 g) were added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Sodium azide (3.42 g) was added to a solution of the residue in N, N-dimethylformamide (40 mL), and the mixture was stirred at 50 ° C. for 15 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2R) -2-azido-2- ((4R) -2,2-dimethyl-1,3-dioxolane-4). -Il) Acetate methyl ester (1.3 g) was obtained. Sodium borohydride (457 mg) was added to a solution of the product (1.3 g) in methanol (20 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to purify (2S) -2-azido-2- ((4R) -2,2). -Dimethyl-1,3-dioxolane-4-yl) ethane-1-ol (1.1 g) was obtained. Sodium hydride (60% oil dispersion, 380 mg) was added to a solution of the product (1.1 g) in N, N-dimethylformamide (10 mL) at 0 ° C. and stirred at room temperature for 30 minutes. Benzyl bromide (1.21 g) was added to this mixture at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to purify (4R) -4-[(1S) -1-azido-2- (1S) -1-azido-2- ( Benzyloxy) ethyl] -2,2-dimethyl-1,3-dioxolane (1.61 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 5 mL) was added to the product (1.61 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to give (2R, 3S) -3-azido-4- (benzyloxy) butane-1,2-diol (1.45 g). Imidazole (541 mg) and tert-butyldiphenylchlorosilane (1.85 g) were added to a solution of the product (1.45 g) in N, N-dimethylformamide (10 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2R, 3S) -3-azido-4- (benzyloxy) -1-(. tert-Butyldiphenylsilyloxy) butane-2-ol (2.49 g) was obtained. Sodium hydride (60% oil dispersion, 315 mg) is added little by little to a mixture of product (2.49 g), iodomethane (966 mg) and N, N-dimethylformamide (5 mL) at 0 ° C and 1 at the same temperature. Stir for hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and [(2R, 3S) -3-azido-4- (benzyloxy) -2-. Methoxybutyl] (tert-butyldiphenylsilyl) ether (1.99 g) was obtained. A mixture of product (1.99 g), di-tert-butyl dicarbonate (893 mg), 20% palladium hydroxide carbon (50% wet, 500 mg) and methanol (10 mL) is stirred at 50 ° C. for 12 hours under a hydrogen atmosphere. did. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2S, 3R) -4- (tert-butyldiphenylsilyloxy) -1-hydroxy-3-methoxybutane. -2-yl] Carbamic acid tert-butyl ester (1.73 g) was obtained. Iodine (750 mg) was added at 0 ° C. to a mixture of product (1 g), imidazole (230 mg), triphenylphosphine (886 mg) and tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3R) -4- (tert-butyldiphenylsilyloxy)-. 1-Iodo-3-methoxybutane-2-yl] carbamic acid tert-butyl ester (1.1 g) was obtained. A mixture of N, N-dimethylformamide (5 mL) of product (500 mg) and zinc (123 mg) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture was added 2-bromopyrimidine (136 mg), bis (triphenylphosphine) palladium (II) dichloride (60 mg), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2S, 3R) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1-. (Pyrimidine-2-yl) Butane-2-yl] Carbamic acid tert-butyl ester (320 mg) was obtained. Trifluoroacetic acid (0.5 mL) was added to a solution of the product (320 mg) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (90 mg). The structural formula, spectral data and purification conditions are shown in Table 43.

Reference Example 2-50-2
Reference Example 2-50-2 was synthesized by the same method as in Reference Example 2-50-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 43.

Reference Example 2-51-1
(2S) -2-Amino-3,3-difluoro-3- (pyridin-2-yl) propanol-1-ol
(R) -N- [(1E) -2- (tert-butyldimethylsilyloxy) ethylidene] -2-methylpropan-2-sulfinamide (0.330 g) and 2-difluoromethylpyridine (0.153 g) A lithium diisopropylamide tetrahydrofuran solution (1.13 mol / L, 1.3 mL) was added to a tetrahydrofuran (6 mL) solution at −78 ° C., and the mixture was stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(2S) -3- (tert-butyldimethylsilyl). Oxy) -1,1-difluoro-1- (pyridine-2-yl) propan-2-yl] -2-methylpropan-2-sulfinamide (0.064 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (0.064 g) in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.026 g). The structural formula, spectral data and purification conditions are shown in Table 43.

Reference example 2-51-2 to 2-51-3
Using the corresponding raw materials, Reference Examples 2-51-2 to 2-51-1 were synthesized in the same manner as in Reference Example 2-51-1. The structural formula, spectral data and purification conditions are shown in Table 43.

Reference Example 2-52-1
(2S, 3S) -4- (benzyloxy) -1,1-difluoro-3-methoxy-1- (pyridin-2-yl) butane-2-amine
(R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxypropyridene] -2-methylpropan-2-sulfinamide (0.122 g) and 2-difluoromethylpyridine (0. A lithium diisopropylamide tetrahydrofuran solution (1.13 mol / L, 0.36 mL) was added to a solution of 053 g) in tetrahydrofuran (4 mL) at −78 ° C., and the mixture was stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N-[(2S, 3S) -4-benzyloxy-1. , 1-Difluoro-3-methoxy-1- (pyridin-2-yl) butane-2-yl] -2-methylpropan-2-sulfinamide (0.036 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (0.036 g) in 1,4-dioxane (1 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.041 g). The structural formula, spectral data and purification conditions are shown in Table 43.

Reference Example 2-53-1
(2S) -2-Amino-3- (pyridin-2-yl) butane-1,3-diol 2-bromopyridine (0.885 g) in a solution of n-butyllithium at −78 ° C. n-butyllithium n -A hexane solution (2.6 mol / L, 1.9 mL) was added and stirred for 30 minutes. (4S) A solution of -4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.917 g) in tetrahydrofuran (15 mL) was added at the same temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S) -4- [hydroxy (pyridine-2-yl) methyl] -2. , 2-Dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester was obtained as a diastereomeric mixture (0.903 g). The diastereomeric mixture (0.903 g) was dissolved in dichloromethane (30 mL). Dess-Martin peryodinan (1.491 g) was added to this mixture under ice-cooling, and the mixture was stirred overnight at room temperature. A 10% aqueous sodium sulfite solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain (4S) -2,2-dimethyl-4- (pyridin-2-carbonyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.805 g). rice field. A solution of methyl magnesium bromide diethyl ether (3.0 mol / L, 0.3 mL) was added to a solution of the product (0.200 g) in tetrahydrofuran (1 mL) at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S) -4- [1-hydroxy-1- (pyridine-2-yl). ) Ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester diastereomeric mixture (0.205 g) was obtained. A hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a mixture of 1,4-dioxane (3 mL) of this product (0.205 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.060 g). The structural formula, spectral data and purification conditions are shown in Table 44.

Reference Example 2-53-2
Using the corresponding raw materials, Reference Example 2-53-2 was synthesized in the same manner as in Reference Example 2-53-1. The structural formula, spectral data and purification conditions are shown in Table 44.

Reference Example 2-541
(2S) -2-Amino-3-methoxy-3- (pyridin-2-yl) butane-1-ol
(4S) A diastereomeric mixture of -4- [1-hydroxy-1- (pyridin-2-yl) ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester. .201 g) was dissolved in tetrahydrofuran (3 mL). Sodium hydride (60% oil dispersion, 0.037 g) was added to this mixture under ice-cooling. The reaction mixture was stirred for 30 minutes, iodomethane (0.352 g) was added, and the mixture was stirred overnight at room temperature. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to distill off (4S) -4- [1-methoxy-1- (pyridin-2-yl) ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-. A diastereomeric mixture of butyl esters (0.169 g) was obtained. The product (0.164 g) was dissolved in 1,4-dioxane (2 mL). A hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was added to this mixture, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.025 g). The structural formula, spectral data and purification conditions are shown in Table 44.

Reference Example 2-55-1
(2S) -2-Amino-3-fluoro-3- (pyridin-2-yl) propan-1-ol 2-bromopyridine (0.398 g) in a solution of n-butyl at −78 ° C. A lithium n-hexane solution (2.6 mol / L, 0.8 mL) was added, and the mixture was stirred for 30 minutes. (4S) Tetrahydrofuran (8 mL) of -4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.412 g)
) The solution was added at the same temperature and stirred for another 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S) -4- [hydroxy (pyridine-2-yl) methyl] -2. , 2-Dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester was obtained as a diastereomeric mixture (0.317 g). The product (0.317 g) was dissolved in dichloromethane (4 mL). Deoxo-Fluor (registered trademark) (0.455 g) was added to this mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S) -4- [fluoro (pyridine-2-yl) methyl] -2. , 2-Dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.145 g) was obtained as a single diastereomeric. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a 1,4-dioxane (3 mL) solution of the product (0.145 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.054 g). The structural formula, spectral data and purification conditions are shown in Table 44.

Reference Example 2-56-1
(2S, 3R) -3-amino-1-methoxy-4- (pyrimidine-2-yl) butane-2-ol hydrochloride N-[(1R) -2- (benzyloxy) -1-((4S)) -2,2-dimethyl-1,3-dioxolan-4-yl) ethyl] carbamic acid tert-butyl ester (550 mg), methanol (2 mL), water (0.5 mL), trifluoroacetic acid (60 μL) Was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and residual water was removed by toluene azeotrope. Imidazole (149 mg) and tert-butyldiphenylchlorosilane (473 mg) were added to a solution of the residue in N, N-dimethylformamide (2 mL) at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. To a solution of the residue in toluene (5 mL), p-toluenesulfonic acid monohydrate (30 mg) and 2,2-dimethoxypropane (1.9 mL) were added, and the mixture was stirred at 85 ° C. for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solution of tetra-n-butylammonium fluoride tetrahydrofuran (1 mol / L, 3.13 mL) was added to a solution of the residue in tetrahydrofuran (3 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R, 5S) -4-[(benzyloxy) methyl] -5 (hydroxy). Methyl) -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (450 mg) was obtained. Sodium hydride (60% oil dispersion, 77 mg) was added to a solution of the product (450 mg) in N, N-dimethylformamide (5 mL) at 0 ° C. and stirred at room temperature for 20 minutes. Iodomethane (218 mg) was added to this mixture at 0 ° C. and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R, 5S) -4-[(benzyloxy) methyl] -5- (methoxymethyl) -2,2-dimethyl. -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (420 mg) was obtained. A mixture of product (420 mg), 20% palladium hydroxide carbon (50% wet, 50 mg) and methanol (5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R, 5S) -4- (hydroxymethyl) -5 (methoxymethyl) -2,2-dimethyl-1, A 3-oxazolidine-3-carboxylic acid tert-butyl ester (310 mg) was obtained. Iodine (400 mg) was added at 0 ° C. to a mixture of product (310 mg), imidazole (123 mg), triphenylphosphine (473 mg) and tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S, 5S) -4- (iodomethyl) -5- (methoxymethyl) -2. , 2-Dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (370 mg) was obtained. A mixture of N, N-dimethylformamide (5 mL) of product (370 mg) and zinc (138 mg) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture was added 2-bromopyrimidine (153 mg), bis (triphenylphosphine) palladium (II) dichloride (68 mg), and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R, 5S) -5- (methoxymethyl) -2,2-dimethyl-4- (pyrimidine-2-). Ilmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (230 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (230 mg) in methanol (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (180 mg). The structural formula, spectral data and purification conditions are shown in Table 44.

Reference Example 2-57-1
(2R, 3S) -4- (benzyloxy) -3-fluoro-1- (pyrimidine-2-yl) butane-2-amine
(1S) -2- (benzyloxy) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (1.4 g) in dichloromethane (10 mL) (Dichloromethane) sulfatrifluoride (1.34 g) was added to the mixture at −78 ° C., and the mixture was stirred at the same temperature for 1 hour and further at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S) -4-[(1R) -2- (benzyloxy) -1. -Fluoroethyl] -2,2-dimethyl-1,3-dioxolane (0.52 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 3 mL) was added to a solution of the product (0.52 g) in methanol (3 mL), and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (2S, 3R) -4- (benzyloxy) -3-fluorobutane-1. , 2-diol (0.21 g) was obtained. Imidazole (169 mg) and tert-butyldiphenylchlorosilane (300 mg) were added to a solution of the product (210 mg) in N, N-dimethylformamide (2.5 mL) at 0 ° C., and the mixture was stirred for 1 hour. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2S, 3R) -4-benzyloxy-1- (tert-butyldiphenylsilyl). Oxy) -3-fluorobutane-2-ol (0.45 g) was obtained. To a solution of the product (0.45 g) in dichloromethane (1 mL) was added N, N-diisopropylethylamine (0.322 g), 4-dimethylaminopyridine (12 mg) and methanesulfonyl chloride (0.125 g) at 0 ° C. The mixture was stirred at room temperature for 0.5 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. N, N-dimethylformamide (3 mL) and sodium azide (0.19 g) were added to the residue, and the mixture was stirred at 100 ° C. overnight. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and [(2R, 3S) -2-azido-4-benzyloxy-3-fluoro. Butan-1-yl] (tert-butyldiphenylsilyl) ether (0.27 g) was obtained. Di-tert-butyl dicarbonate (0.20 g), 10% palladium carbon (50% wet, 30 mg) was added to a solution of the product (0.27 g) in ethanol (3 mL), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. did. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. Tetrahydrofuran (3 mL) and a tetra-n-butylammonium tetrahydrofuran solution (1 mol / L, 670 μL) were added to this residue, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (benzyloxy) -3-fluoro. -1-Hydroxybutane-2-yl] Carbamic acid tert-butyl ester (113 mg) was obtained. Iodine (122 mg) was added at 0 ° C. to a mixture of product (100 mg), imidazole (33 mg), triphenylphosphine (126 mg) and tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2S, 3S) -4- (benzyloxy) -3-fluoro-. 1-Iodobutan-2-yl] carbamic acid tert-butyl ester (135 mg) was obtained. A mixture of product (135 mg), zinc (46 mg), iodine (one chip) and N, N-dimethylformamide (1.5 mL) was stirred at room temperature for 1 hour under an argon atmosphere. To this mixture was added 2-bromopyrimidine (51 mg), bis (triphenylphosphine) palladium (II) dichloride (22 mg), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. Water was added to the filtrate and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (benzyloxy) -3-fluoro. -1- (Pyrimidine-2-yl) Butan-2-yl] Carbamic acid tert-butyl ester (70 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (70 mg) in methanol (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (50 mg). The structural formula, spectral data and purification conditions are shown in Table 44.

Reference example 2-57-2 to 2-57-4
Reference Examples 2-57-2 to 2-57-4 were synthesized in the same manner as in Reference Example 2-57-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 44.

Reference Example 2-581-1
(2R, 3S) -4- (benzyloxy) -3-fluoro-1- (1H-pyrazole-1-yl) butane-2-amine
(1S) -2- (benzyloxy) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (1.4 g) in dichloromethane (10 mL) (Dichloromethane) sulfatrifluoride (1.34 g) was added to the mixture at −78 ° C., and the mixture was stirred at the same temperature for 1 hour and further at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4S) -4-[(1R) -2- (benzyloxy) -1. -Fluoroethyl] -2,2-dimethyl-1,3-dioxolane (0.52 g) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 3 mL) was added to a solution of the product (0.52 g) in methanol (3 mL), and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (2S, 3R) -4- (benzyloxy) -3-fluorobutane-1. , 2-diol (0.21 g) was obtained. Triphenylphosphine (67 mg) and a solution of azodicarboxylate diethyl ester toluene (2.2 mol / L, 116 μL) were added to a solution of the product (50 mg) in toluene (1 mL), and the mixture was stirred overnight at 80 ° C. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain (2R) -2-[(1R) -2- (benzyloxy) -1-fluoroethyl] oxylan (40 mg). rice field. Cesium carbonate (133 mg) and pyrazole (15 mg) were added to a solution of the product (40 mg) in N, N-dimethylformamide (1 mL), and the mixture was stirred at 100 ° C. for 1 hour. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2S, 3R) -4- (benzyloxy) -3-fluoro-1- (1H-pyrazol-1-yl) butane-2-ol (32 mg) was obtained. N, N-diisopropylethylamine (40 mg), 4-dimethylaminopyridine (2 mg) and methanesulfonyl chloride (18 mg) were added to a solution of the product (32 mg) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 0.5 hours. .. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. N, N-dimethylformamide (2 mL) and sodium azide (24 mg) were added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred at 100 ° C. for 2 days. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 1-[(2R, 3S) -2-azido-4- (benzyloxy). -3-Fluorobutyl] -1H-pyrazole (33 mg) was obtained. 10% Palladium on carbon (50% wet, 10 mg) was added to a solution of the product (33 mg) in ethanol (3 mL), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (21 mg). The structural formula, spectral data and purification conditions are shown in Table 45.

Reference example 2-58-2 to 2-58-6
Reference Examples 2-58-2 to 2-58-6 were synthesized in the same manner as in Reference Example 2-58-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 45.

Reference Example 2-59-1
(2R) -4- (benzyloxy) -3,3-difluoro-1- (1H-pyrazole-1-yl) butane-2-amine
Triphenylphosphine (678 mg) and azodicarboxylate diethyl ester toluene in a toluene (1.5 mL) solution of (2S) -4- (benzyloxy) -3,3-difluorobutane-1,2-diol (0.50 g). The solution (2.2 mol / L, 1.17 mL) was added and stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain (2S) -2- [2- (benzyloxy) -1,1-difluoroethyl] oxylan (350 mg). Cesium carbonate (1.07 g) and pyrazole (123 mg) were added to a solution of the product (350 mg) in N, N-dimethylformamide (1 mL), and the mixture was stirred at 100 ° C. for 1 hour. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (2S) -4- (benzyloxy) -3,3-difluoro-1-. (1H-Pyrazole-1-yl) butane-2-ol (400 mg) was obtained. Pyridine (1 mL) and trifluoromethanesulfonic anhydride (560 mg) were added to a solution of the product (400 mg) in dichloromethane (4 mL) at −20 ° C. and stirred at the same temperature for 2 hours. Hydrochloric acid (0.5 mol / L) was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. N, N-dimethylformamide (3 mL) and sodium azide (278 mg) were added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred at 100 ° C. for 1 day. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 1-[(2R) -2-azido-4- (benzyloxy) -3. , 3-Difluorobutyl] -1H-pyrazole (400 mg) was obtained. 10% Palladium on carbon (50% wet, 80 mg) was added to a solution of the product (400 mg) in ethanol (5 mL), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (154 mg). The structural formula, spectral data and purification conditions are shown in Table 45.

Reference example 2-59-2
(2R) -4- (benzyloxy) -3,3-difluoro-1- (2H-1,2,3-triazole-2-yl) butane-2-amine hydrochloride [(2R) -2-azido- Di-tert-butyl dicarbonate (1.7 g) in an ethanol (20 mL) solution of 4-benzyloxy-3,3-difluorobutane-1-yl] (tert-butyldiphenylsilyl) ether (3.5 g). 10% Palladium carbon (50% wet, 500 mg) was added, and the mixture was stirred at room temperature in a hydrogen atmosphere for 5 hours. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. Tetrahydrofuran (10 mL) and tetra-n-butylammonium tetrahydrofuran solution (1 mol / L, 8.5 mL) were added to this residue, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -4- (benzyloxy) -3,3-difluoro. -1-Hydroxybutane-2-yl] Carbamic acid tert-butyl ester (1.5 g) was obtained. Triethylamine (611 mg) and methanesulfonyl chloride (450 mg) were added to a solution of the product (1.0 g) in dichloromethane (5 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Cesium carbonate (2.95 g) and 1,2,3-triazole (417 mg) were added to a solution of this residue in N, N-dimethylformamide (5 mL), and the mixture was stirred at 60 ° C. for 3 hours. After cooling the reaction mixture to room temperature, saturated aqueous ammonium chloride solution was added to the mixture, and the crude product was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2R) -4- (benzyloxy) -3,3-difluoro-1- (2H-1,2). , 3-Triazole-2-yl) Butan-2-yl] Carbamic acid tert-butyl ester (590 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (590 mg) in methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (480 mg). The structural formula, spectral data and purification conditions are shown in Table 45.

Reference Example 2-60-1
(2R) -4- (benzyloxy) -3,3-difluoro-1- (pyrimidine-2-yl) butane-2-amine [(2R) -2-azido-4-benzyloxy-3,3-difluoro To a solution of butane-1-yl] (tert-butyldiphenylsilyl) ether (170 mg) in ethanol (2 mL) is added di-tert-butyl dicarbonate (112 mg) and 10% palladium carbon (50% wet, 50 mg). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. Tetrahydrofuran (2 mL) and a tetra-n-butylammonium tetrahydrofuran solution (1 mol / L, 500 μL) were added to this residue, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -4- (benzyloxy) -3,3-difluoro. -1-Hydroxybutane-2-yl] Carbamic acid tert-butyl ester (90 mg) was obtained. Iodine (104 mg) was added at 0 ° C. to a mixture of product (90 mg), imidazole (28 mg), triphenylphosphine (107 mg) and tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2S) -4- (benzyloxy) -3,3-difluoro-. 1-Iodobutan-2-yl] carbamic acid tert-butyl ester (56 mg) was obtained. A mixture of product (56 mg), zinc (18 mg), iodine (one chip) and N, N-dimethylformamide (1 mL) was stirred at room temperature for 1 hour under an argon atmosphere. To this mixture was added 2-bromopyrimidine (20 mg), bis (triphenylphosphine) palladium (II) dichloride (9 mg), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was passed through a Celite pad. The crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -4- (benzyloxy) -3,3-difluoro. -1- (Pyrimidine-2-yl) Butan-2-yl] Carbamic acid tert-butyl ester (25 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1.5 mL) was added to a solution of the product (25 mg) in methanol (1.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (20 mg). The structural formula, spectral data and purification conditions are shown in Table 46.

Reference example 2-60-2
Reference Example 2-60-2 was synthesized by the same method as in Reference Example 2-60-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 46.

Reference Example 2-61-1
[((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl] [2- (pyridin-2-yl) ethyl] amine
(4R) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (0.5 g), 1
-To a mixture of hydroxybenzotriazole monohydrate (0.262 g), 2- (pyridin-2-yl) ethane-1-amine (0.46 g), triethylamine (0.693 g) and dichloromethane (34.2 mL) 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.79 g) was added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R) -2,2-dimethyl-N- [2- (pyridin-2-yl) ethyl] -1, 3-Dioxolane-4-carboxamide (0.80 g) was obtained. (4R) -2,2-dimethyl-N- [2- (pyridin-2-yl) ethyl] -1,3-dioxolane-4- in a suspension of lithium aluminum hydride (365 mg) in tetrahydrofuran (30 mL). A solution of carboxamide (0.80 g) in tetrahydrofuran (12.8 mL) was added dropwise at 0 ° C. and the mixture was stirred at room temperature for 20 hours. Water (0.366 mL), aqueous sodium hydroxide solution (15%, 0.366 mL) and water (0.366 mL) were sequentially added to the reaction mixture and quenched. The mixture was stirred at room temperature for 21 hours and passed through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and [((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl] [2-. (Pyridin-2-yl) ethyl] amine (0.275 g) was obtained. Triethylamine (351 mg) and trifluoroacetic anhydride (364 mg) were sequentially added to a solution of the product (273 mg) in dichloromethane (5.78 mL) at 0 ° C. The mixture was stirred at room temperature for 36 hours. Methanol (1 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to this mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methyl] -2, 2,2-Trifluoro-N- [2- (pyridin-2-yl) ethyl] acetamide (211 mg) was obtained. Aqueous sodium hydroxide solution (2 mol / L, 944 μL) was added to a solution of the product (209 mg) in ethanol (6.29 mL) at room temperature and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water. The crude product was extracted with dichloromethane. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (144 mg). The structural formula, spectral data and purification conditions are shown in Table 46.

Reference example 2-61-2
Reference Example 2-61-2 was synthesized in the same manner as in Reference Example 2-61-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 46.

Reference Example 2-62-1
[(2R) -3- (benzyloxy) -2-methoxypropyl] [2- (pyridin-2-yl) ethyl] amine
Add 2- (pyridin-2-yl) ethylamine (0.744 g) to a solution of (2R) -2-[(benzyloxy) methyl] oxylane (0.500 g) in tert-butyl alcohol (10.2 mL) at room temperature. , The mixture was stirred at 100 degrees for 11.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in acetonitrile (10.2 mL). 4-Dimethylaminopyridine (1.488 g) and acetic anhydride (0.836 mL) were added to this solution, and the mixture was stirred at room temperature for 3 hours. Methanol (3 mL) was added to this mixture, and the mixture was further stirred for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and acetic acid ((2R) -1- (benzyloxy) -3- {N- [2- (pyridin-2-yl) ethyl]-. N-Acetylamino} propan-2-yl) ester (0.644 g) was obtained. Aqueous sodium hydroxide solution (2 mol / L, 6.93 mL) was added to a solution of the product (0.642 g) in ethanol (6.93 mL) at room temperature and the mixture was stirred at 70 ° C. for 45.5 hours. The reaction mixture was cooled to room temperature, diluted with water and the crude product was extracted with dichloromethane. The aqueous layer was extracted once with dichloromethane. The combined organic layer was dried over sodium sulfate, concentrated under reduced pressure, and [(2R) -3- (benzyloxy) -2-hydroxypropyl] [2- (pyridin-2-yl) ethyl] amine (0.500 g). ) Was obtained. Sodium hydride (60% oil dispersion, 84 mg) was added in two portions to a solution of the product (499 mg) in tetrahydrofuran (8.71 mL) at 0 ° C. and the mixture was stirred for 1 hour. Iodomethane (163 μL) was added dropwise to this mixture, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. A saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction mixture. The mixture was partitioned between ethyl acetate (80 mL) and water (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (214 mg). The structural formula, spectral data and purification conditions are shown in Table 46.

Reference example 2-62-2
Using the corresponding raw materials, Reference Example 2-62-1 was synthesized in the same manner as in Reference Example 2-62-1. The structural formula, spectral data and purification conditions are shown in Table 46.

Reference Example 2-63-1
((2R) -2-Hydroxy-3-methoxypropyl) [2- (pyridin-2-yl) ethyl] amine
2- (Pyridine-2-yl) ethane-1-amine (0.624 g) in a tert-butyl alcohol (12.2 mL) solution of (2R) -2- (methoxymethyl) oxylane (0.300 g) at room temperature. In addition, the mixture was stirred at 100 degrees for 14 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (17.0 mL) and triethylamine (1.90 mL) was added at 0 ° C. Then, trifluoroacetic anhydride (1.92 mL) was added dropwise to this mixture, and the mixture was stirred at room temperature for 3 hours. Methanol (3 mL) was added to this mixture, and the mixture was further stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2,2,2-trifluoro-N-((2R) -2-hydroxy-3-methoxypropyl) -N- [ 2- (Pyridine-2-yl) ethyl] acetamide (0.562 g) was obtained. Aqueous sodium hydroxide solution (2 mol / L, 2.74 mL) was added to a solution of the product (0.56 g) in ethanol (6.40 mL) at room temperature and the mixture was stirred at 60 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature and diluted with water. The crude product was extracted with dichloromethane. The aqueous layer was extracted 5 times with dichloromethane. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (366 mg). The structural formula, spectral data and purification conditions are shown in Table 46.

Reference example 2-63-2
Reference Example 2-63-2 was synthesized by the same method as in Reference Example 2-63-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 46.

Reference Example 2-64-1
N-((2R) -2-Amino-3-phenylpropyl) -N-methyl-2-nitrobenzene-1-sulfonamide hydrochloride N-((2R) -1-hydroxy-3-phenylpropan-2-yl) ) Carbamic acid tert-butyl ester (503 mg), triphenylphosphine (630 mg), N-methyl-2-nitrobenzene-1-sulfonamide (454 mg) and tetrahydrofuran (5 mL) in a mixture of azodicarboxylate diethyl ester toluene solution (2). .2 mol / L, 1.1 mL) was added, and the mixture was stirred at room temperature for 1 hour. N-Hexane (5 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. This mixture was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain a crude product. The crude product was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -1- (N-methyl-2-nitrobenzenesulfonylamino) -3-phenylpropane. -2-yl] Carbamic acid tert-butyl ester (430 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 5 mL) was added to the product (430 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with diethyl ether and stirred for 30 minutes. The precipitate was collected by filtration to give the title compound (323 mg). The structural formula, spectral data and purification conditions are shown in Table 46.

Reference Example 2-65-1
(R) -N-[(1R) -1-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridin-2-yl) ethyl] -2-methyl Propane-2-sulfinamide 2-methylpyridine (0.120 g) in tetrahydrofuran (2 mL) is added with n-butyllithium n-hexane solution (2.6 mol / L, 0.46 mL) at −78 ° C. for 30 minutes. Stirred. (R) -N- [(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropan-2-sulfinamide (0.200 g) A solution of tetrahydrofuran (2 mL) was added at the same temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.170 g) as a highly polar diastereomer. The structural formula, spectral data and purification conditions are shown in Table 47.

Reference example 2-65-2 to 2-65-3
Using the corresponding raw materials, Reference Examples 2-65-2 to 2-65-1 were synthesized in the same manner as in Reference Example 2-65-1. The structural formula, spectral data and purification conditions are shown in Table 47.

Reference Example 2-66-1
(S) -N-[(1S) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridin-2-yl) ethyl] -2-methyl Propane-2-sulfinamide Add n-butyllithium n-hexane solution (2.6 mol / L, 0.83 mL) to a solution of 2-methylpyridine (0.215 g) in tetrahydrofuran (3.5 mL) at -78 ° C. , Stirred for 30 minutes. (S) -N- [(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropan-2-sulfinamide (0.360 g) A solution of tetrahydrofuran (7 mL) was added at the same temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (0.200 g) as a highly polar diastereomer. The structural formula, spectral data and purification conditions are shown in Table 47.

Reference example 2-66-2
Reference Example 2-66-2 was synthesized by the same method as in Reference Example 2-66-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 47.

Reference example 2-67-1
(R) -N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridin-2-yl) propyl] -2-methyl Propyl-2-sulfinamide 2-ethylpyridine (0.110 g) in tetrahydrofuran (2 mL) is added with n-butyllithium n-hexane solution (2.6 mol / L, 0.36 mL) at -78 ° C for 30 minutes. Stirred. (R) -N- [(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropan-2-sulfinamide (0.200 g) A solution of tetrahydrofuran (2 mL) was added at the same temperature, and the mixture was further stirred for 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to obtain the title compound (0.150 g) as a highly polar diastereomer. The structural formula, spectral data and purification conditions are shown in Table 48.

Reference example 2-67-2
Using the corresponding raw materials, Reference Example 2-67-2 was synthesized in the same manner as in Reference Example 2-67-1. The structural formula, spectral data and purification conditions are shown in Table 48.

Reference Example 2-68-1
(R) -N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-methoxy-2- (pyridin-2-yl) ethyl] -2-Methylpropan-2-sulfinamide 2- (tert-butyldimethylsilyloxymethyl) pyridine (0.669 g) in tetrahydrofuran (4 mL) at −78 ° C. n-butyllithium n-hexane solution (2. 6 mol / L (1.07 mL) was added, and the mixture was stirred for 30 minutes. (R) -N- [(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropan-2-sulfinamide (0.467 g) A solution of tetrahydrofuran (4 mL) was added at the same temperature and stirred for an additional 30 minutes. The reaction mixture was heated to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (R) -N- [(1S) -2- (tert-butyldimethylsilyl). Oxy) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridine-2-yl) ethyl] -2-methylpropan-2-sulfinamide dia A stereomer mixture (0.554 g) was obtained as a low polarity product. The product (0.277 g) was dissolved in tetrahydrofuran (3 mL). Tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 0.6 mL) was added to this mixture under ice-cooling, and the mixture was stirred for 30 minutes. After adding saturated aqueous ammonium chloride solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: methanol / ethyl acetate), and (R) -N- [(1R) -1-((4S) -2,2). -Dimethyl-1,3-dioxolan-4-yl) -2-hydroxy-2- (pyridin-2-yl) ethyl] -2-methylpropan-2-sulfinamide (0.119 g) with highly polar diastereomers Obtained as. Sodium hydride (60% oil dispersion, 0.003 g) under ice-cooling is added to a solution of the product (0.030 g) in N, N-dimethylformamide (0.5 mL), and the mixture is stirred for 30 minutes and then iodine methane (0). .049 g) was added and the mixture was stirred overnight at room temperature. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography ((eluting solvent: methanol / ethyl acetate) to obtain the title compound (0.021 g). It is shown in Table 48.

Reference Example 2-69-1
(2S, 3R) -3-amino-1-methoxy-4- (1H-pyrazol-1-yl) butane-2-ol hydrochloride N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) ) -3-Hydroxy-1- (1H-pyrazol-1-yl) butane-2-yl] Carbamic acid tert-butyl ester (1.90 g), p-toluenesulfonic acid monohydrate (71 mg), 2, A mixture of 2-dimethoxypropane (3.88 g) and toluene (10 mL) was stirred at 80 ° C. for 8 hours. After cooling the reaction mixture to room temperature, this saturated aqueous sodium hydrogen carbonate solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. A solution of tetra-n-butylammonium fluoride (tetrahydrofuran (1 mol / L, 4.47 mL) was added at 0 ° C. to a solution of the residue obtained by distilling off the solvent under reduced pressure in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-. 4- (1H-Pyrazole-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.98 g) was obtained. Iodomethane (110 mg) and sodium hydride (60% oil dispersion, 35 mg) were sequentially added to a solution of the product (160 mg) in N, N-dimethylformamide (1 mL) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to this reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R, 5S) -5- (methoxymethyl) -2,2-dimethyl-4-. (1H-Pyrazole-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (150 mg) in methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (100 mg). The structural formula, spectral data and purification conditions are shown in Table 48.

Reference Example 2-70-1
(2S, 3R) -3-amino-1-fluoro-4- (1H-pyrazole-1-yl) butan-2-ol hydrochloride
Tetrahydrofuran of (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-4- (1H-pyrazole-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (580 mg) To the (5 mL) solution was added 1,8-diazabicyclo [5.4.0] -7-undecene (567 mg) and perfluorobutane sulfonylfluoride (1.13 g) at 0 ° C. and stirred at room temperature for 12 hours. Water and dichloromethane were added to this reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and (4R, 5S) -5- (fluoromethyl) -2,2-dimethyl-4-. (1H-Pyrazole-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (240 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (40 mg) in methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (27 mg). The structural formula, spectral data and purification conditions are shown in Table 48.

Reference Example 2-71-1
(2R, 3S) -4-fluoro-3-methoxy-1- (1H-pyrazole-1-yl) butane-2-amine hydrochloride
Triethylamine (194 mg) at room temperature in a solution of (2S, 3R) -3-amino-1-fluoro-4- (1H-pyrazole-1-yl) butane-2-ol hydrochloride (133 mg) in methanol (1 mL), Di-tert-butyl dicarbonate (140 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4-fluoro-3-hydroxy-1-(. 1H-pyrazole-1-yl) butane-2-yl] carbamic acid tert-butyl ester (170 mg) was obtained. Sodium hydride (60% oil dispersion, 30 mg) was added at 0 ° C. to a mixture of product (170 mg), tetrahydrofuran (1 mL), N, N-dimethylformamide (0.1 mL) and iodomethane (97 mg). The mixture was stirred at warm temperature for 5 hours. A saturated aqueous solution of ammonium chloride was added to this reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4-fluoro-3-methoxy-1- (1H). -Pyrazole-1-yl) Butan-2-yl] Carbamic acid tert-butyl ester (150 mg) was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product (150 mg) in methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (90 mg). The structural formula, spectral data and purification conditions are shown in Table 48.

Example 1-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R) -4-hydroxy-1- (pyridin-2-yl) butane-2-yl ] Benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] 1-hydroxy in N, N-dimethylformamide (1 mL) suspension of benzoic acid (0.35 g) Benzotriazole monohydrate (0.23 g), (3R) -3-amino-4- (pyridin-2-yl) butane-1-ol hydrochloride (0.28 g), N, N-diisopropylethylamine (0) .75 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.29 g) were added and stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.18 g). The structural formula, spectral data and purification conditions are shown in Table 49.

Examples 1-2-1-204, 1-208-1-209, 1-212-1-246, 43-26
Examples 1-2-1-204, 1-208-1-209, 1-212-1-246, 43-26 were synthesized using the corresponding raw materials in the same manner as in Example 1-1. The structural formulas, spectral data and purification conditions are shown in Tables 49 to 84 and 118.

Example 2-1
2- (4-Ethyl-5-phenyl-1H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 2- (1-methoxymethyl-5-phenyl-4-vinyl) Mixture of -1H-pyrazole-3-yl) benzoic acid and 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazole-3-yl) benzoic acid (480 mg), 1-hydroxybenzotriazole 1 The hydrate (220 mg), 2- (pyridin-2-yl) ethylamine (351 mg) and triethylamine (436 mg) were dissolved in N, N-dimethylformamide (5 mL). To this mixture was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (551 mg) at room temperature and stirred overnight. The reaction mixture was poured into water and the crude product was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 2- (1-methoxymethyl-5-phenyl-4-vinyl-1H-pyrazole-3-yl) -N- [2- ( Pyridine-2-yl) ethyl] benzamide and 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide (453 mg) was obtained. 10% Palladium on carbon (50% wet, 10 mg) was added to a mixture of the product (50 mg) in tetrahydrofuran (2 mL). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (1 mL) and a solution of ethyl hydrogen chloride acetate (4 mol / L, 2 mL) was added. The mixture was stirred at 60 ° C. for 5 hours and poured into saturated aqueous sodium hydrogen carbonate solution. The crude product was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, and then concentrated under reduced pressure to give the title compound (42 mg). The structural formula, spectral data and purification conditions are shown in Table 85.

Example 3-1
2- (4-formyl-5-phenyl-1H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 2- (1-methoxymethyl-5-phenyl-4-vinyl) -1H-Pyrazole-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide and 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazole-3-yl) A mixture of -N- [2- (pyridin-2-yl) ethyl] benzamide (100 mg) and an aqueous solution of N-methylmorpholin-N-oxide (4.8 mol / L, 0.071 mL) was added in tetrahydrofuran (2 mL) and water (2 mL). 0.5 mL) was added to the mixture. An osmium tetroxide tert-butyl alcohol solution (0.1 mol / L, 0.012 mL) was added to this mixture, and the mixture was stirred overnight at room temperature. Sodium periodate (146 mg) was added to this mixture and the mixture was stirred overnight at room temperature. The mixture was passed through a Celite pad and the insoluble material was washed with ethyl acetate. The filtrate was washed with saturated brine and concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 2- (4-formyl-1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) -N- [ 2- (Pyridine-2-yl) ethyl] benzamide and 2- (4-formyl-2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) A mixture of ethyl] benzamide (30 mg) was obtained. The product (30 mg) was dissolved in tetrahydrofuran (1 mL). Hydrochloric acid (6 mol / L, 1 mL) was added to this mixture, and the mixture was stirred at 50 ° C. for 3 hours. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (11 mg). The structural formula, spectral data and purification conditions are shown in Table 85.

Example 4-1
2- (5-Phenyl-1H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) ethyl] -3-trifluoromethoxybenzamide 3- (2-bromo-6-trifluoromethoxyphenyl) )-5-Phenyl-1H-pyrazole (100 mg) in a dimethylsulfoxide (4 mL) solution with 1,3-bis (diphenylphosphino) propane (22 mg), N, N-diisopropylethylamine (169 mg) and 2- (pyridine- 2-Il) Ethylamine (191 mg) was added and replaced with argon. Palladium acetate (II) (12 mg) was added to this mixture, and the mixture was stirred at 110 ° C. under a carbon monoxide atmosphere for 5 hours. The reaction mixture was passed through a Celite pad and water was added to the filtrate. The crude product was extracted with ethyl acetate, the extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (43 mg). The structural formula, spectral data and purification conditions are shown in Table 86.

Examples 4-2-4-11, 5-4-5-7
Examples 4-2-4-11 and 5-4-5-7 were synthesized in the same manner as in Example 4-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Tables 86 to 88.

Example 5-1
2- [5- (3-formylphenyl) -1H-pyrazole-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide 2- {5- [3- (1,3-dioxolane) -2-yl) Phenyl] -1H-pyrazole-3-yl} -N- [2- (pyridin-2-yl) ethyl] benzamide (0.202 g) in a solution of hydrochloric acid (1 mol / 1 mol /) in tetrahydrofuran (1.5 mL). L, 3 mL) was added, and the mixture was stirred at 60 ° C overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.134 g). The structural formula, spectral data and purification conditions are shown in Table 88.

Examples 5-2-5-3
Examples 5-2-5-3 were synthesized in the same manner as in Example 5-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 88.

Example 6-1
2- {5- [3- (Hydroxymethyl) phenyl] -1H-pyrazole-3-yl} -N- [2- (pyridin-2-yl) ethyl] benzamide 2- [5- (3-formylphenyl) Sodium borohydride (0.016 g) in a solution of -1H-pyrazole-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide (0.112 g) in methanol (3 mL) under ice-cooling. Was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.114 g). The structural formula, spectral data and purification conditions are shown in Table 89.

Examples 6-2 to 6-3
Examples 6-2 to 6-3 were synthesized by the same method as in Example 6-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 89.

Example 7-1
2- [5- (2-Acetylaminophenyl) -1H-pyrazole-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide 2- [5- (2-aminophenyl) -1H -Pyrazole-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide (40 mg) and triethylamine (21 mg) in a dichloromethane (2 mL) mixture was added anhydrous acetic acid (12 mg) at room temperature. .. The mixture was stirred overnight and diluted with water. The crude product was extracted with ethyl acetate, the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (31 mg). The structural formula, spectral data and purification conditions are shown in Table 89.

Examples 7-2 to 7-3
Examples 7-2 to 7-3 were synthesized by the same method as in Example 7-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 89.

Example 8-1
2- [5- (2-Methanesulfonylaminophenyl) -1H-pyrazole-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide 2- [5- (2-aminophenyl)- 1H-Pyrazole-3-yl] -N- [2- (pyridin-2-yl) ethyl] methanesulfonyl chloride (15 mg) in a mixed solution of dichloromethane (2 mL) of benzamide (44 mg) and triethylamine (23 mg) at room temperature. added. The mixture was stirred at room temperature overnight and diluted with water. The crude product was extracted with ethyl acetate, the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (18 mg). The structural formula, spectral data and purification conditions are shown in Table 89.

Example 9-1
(S) -3-Phenyl-2- [2- (5-phenyl-1H-pyrazole-3-yl) benzoylamino] propionic acid 2- (5-phenyl-1H-pyrazole-3-yl) benzoic acid (0) .50 g) N, N-dimethylformamide (5 mL) suspension with 1-hydroxybenzotriazole monohydrate (0.44 g), (2S) -2-amino-3-phenylpropionic acid benzyl ester p-toluene Sulfonate (0.97 g), N, N-diisopropylethylamine (0.73 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.54 g) were added and stirred overnight at room temperature. .. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (S) -3-phenyl-2- [2- (5-phenyl-). 1H-pyrazole-3-yl) benzoylamino] propionic acid benzyl ester (0.95 g) was obtained. 10% Palladium on carbon (50% wet, 0.1 g) was added to a solution of the product (0.95 g) in tetrahydrofuran (6 mL) at room temperature, and the mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was passed through a Celite pad. The filtrate was concentrated under reduced pressure to give the title compound (0.80 g). The structural formula, spectral data and purification conditions are shown in Table 90.

Example 9-2
Example 9-2 was synthesized by the same method as in Example 9-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 90.

Example 10-1
N-((S) -1-dimethylcarbamoyl-2-phenylethyl) -2- (5-phenyl-1H-pyrazole-3-yl) benzamide (S) -3-phenyl-2- [2- (5- (5-) Phenyl-1H-pyrazole-3-yl) benzoylamino] 1-hydroxybenzotriazole monohydrate (0.034 g), dimethyl in N, N-dimethylformamide (1 mL) suspension of propionic acid (0.06 g) An amine tetrahydrofuran solution (2 mol / L, 0.36 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.042 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to give the title compound (0.015 g). The structural formula, spectral data and purification conditions are shown in Table 90.

Examples 10-2 to 10-3
Examples 10-2 to 10-3 were synthesized by the same method as in Example 10-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 90.

Example 11-1
3-Benzyloxy-2- (5-phenyl-1H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 3- (2-benzyloxy-6-bromophenyl)- A mixture (1.63 g) of 1-methoxymethyl-5-phenyl-1H-pyrazole and 3- (2-benzyloxy-6-bromophenyl) -2-methoxymethyl-5-phenyl-2H-pyrazole was added to dimethylsulfoxide (1.63 g). It was dissolved in 20 mL). To this mixture is added 1,3-bis (diphenylphosphino) propane (302 mg), N, N-diisopropylethylamine (1.41 g) and 2- (pyridin-2-yl) ethylamine (1.33 g) with argon. Replaced. Palladium acetate (II) (164 mg) was added to this mixture, and the mixture was stirred at 110 ° C. under a carbon monoxide atmosphere for 5 hours. The reaction mixture was passed through a Celite pad and water was added to the filtrate. The crude product was extracted with ethyl acetate, the extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 3-benzyloxy-2- (1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl) -N- [2. -(Pyridine-2-yl) ethyl] benzamide and 3-benzyloxy-2- (2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) A mixture of ethyl] benzamide (1.13 g) was obtained. The mixture (50 mg) was dissolved in ethanol (1 mL). A solution of ethyl hydrogen chloride acetate (4 mol / L, 2 mL) was added to this solution, and the mixture was stirred at 60 ° C. for 2 hours. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (44 mg). The structural formula, spectral data and purification conditions are shown in Table 90.

Example 12-1
(2- (5-Phenyl-1H-pyrazole-3-yl) -3-{N- [2- (pyridin-2-yl) ethyl] carbamoyl} phenoxy) Ethyl acetate ester 3-Hydroxy-2- (2-) Ethylmethyl-5-phenyl-2H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide (200 mg) was dissolved in N, N-dimethylformamide (3 mL). Potassium carbonate (193 mg) and ethyl bromoacetate (117 mg) were added to this mixture, and the mixture was stirred overnight at room temperature. The mixture was poured into water and the crude product was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 2- (2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) -3- {N- [2- ( Pyridine-2-yl) ethyl] carbamoyl} phenyloxy) ethyl acetate ester (299 mg) was obtained. The product (204 mg) was dissolved in ethanol (2 mL). A solution of ethyl hydrogen chloride acetate (4 mol / L, 4 mL) was added to this solution, and the mixture was stirred at 60 ° C. for 4 hours. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (134 mg). The structural formula, spectral data and purification conditions are shown in Table 91.

Examples 12-2 to 12-4
Examples 12-2 to 12-4 were synthesized by the same method as in Example 12-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 91.

Example 13-1
3- (2-Hydroxyethoxy) -2- (5-phenyl-1H-pyrazole-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 2- (2-methoxymethyl-5-yl) Phenyl-2H-pyrazole-3-yl) -3- {N- [2- (pyridin-2-yl) ethyl] carbamoyl} phenoxy) Ethyl acetate (95 mg) was dissolved in ethanol (2 mL). Sodium borohydride (21 mg) was added to this mixture at room temperature, and the mixture was stirred for 3 hours. Sodium borohydride (42 mg) was added to this mixture, stirred overnight and diluted with water. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to 3- (2-hydroxyethoxy) -2- (1-methoxymethyl-5-phenyl-1H-pyrazole-3-yl)-. N- [2- (pyridin-2-yl) ethyl] benzamide and 3- (2-hydroxyethoxy) -2- (2-methoxymethyl-5-phenyl-2H-pyrazole-3-yl) -N- [2 A mixture of − (pyridin-2-yl) ethyl] benzamide (58 mg) was obtained. The mixture (58 mg) was dissolved in ethanol (1 mL). A solution of ethyl hydrogen chloride acetate (4 mol / L, 2 mL) was added to this solution, and the mixture was stirred at 60 ° C. for 2 hours. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (38 mg). The structural formula, spectral data and purification conditions are shown in Table 91.

Example 14-1
(2S) -3-Phenyl-2- [2- (5-phenyl-1H-pyrazole-3-yl) benzoylamino] -N- (pyrrolidin-3-yl) propanamide (S) -3-phenyl-2 -[2- (5-Phenyl-1H-pyrazole-3-yl) benzoylamino] propionic acid (0.06 g) in a dichloromethane (1 mL) suspension with 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester ( 0.03 g), N, N-diisopropylethylamine (0.066 g) and T3P® ethyl acetate solution (1.7 mol / L, 0.17 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, the insoluble material was collected by filtration, and 3-{(2S) -3-phenyl-2- [2- (5-phenyl-1H-pyrazole-3-yl) benzoylamino] propylamino} pyrrolidine was added. A -1-carboxylic acid tert-butyl ester was obtained. Tetrahydrofuran (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) were added to the product, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to this residue, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate / n-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, and the insoluble material was collected by filtration to give the title compound (0.037 g). The structural formula, spectral data and purification conditions are shown in Table 91.

Example 14-2
Example 14-2 was synthesized in the same manner as in Example 14-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 91.

Example 15-1
N-[(2S) -1-((3S) -3-hydroxypyrrolidine-1-yl) -1-oxo-3-phenylpropan-2-yl] -2- (5-phenyl-1H-pyrazole-3) -Il) Benzamide
(S) -3-Phenyl-2- [2- (5-phenyl-1H-pyrazole-3-yl) benzoylamino] propionic acid (0.05 g) in a solution of (3S) -pyrrolidine-3 in methanol (2 mL) -Add all (0.016 g) and 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride n-hydrate (0.05 g). , Stirred at room temperature for 2 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.05 g). The structural formula, spectral data and purification conditions are shown in Table 92.

Example 15-2
Example 15-2 was synthesized in the same manner as in Example 15-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 92.

Example 16-1
N-((2R) -1-amino-3-phenylpropan-2-yl) -2- (5-phenyl-1H-pyrazole-3-yl) benzamide 2- (5-phenyl-1H-pyrazole-3-yl) Il) 1-Hydroxybenzotriazole monohydrate (0.092 g), N-((2R) -2-amino-3) in an N, N-dimethylformamide (1 mL) suspension of benzoic acid (0.105 g). -Phenylpropyl) phthalimide (0.126 g), N, N-diisopropylethylamine (0.154 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.114 g) were added and 2 at room temperature. Stirred for hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -1- (1,3-dioxo-). 2,3-Dihydro-1H-isoindole-2-yl) -3-phenylpropan-2-yl] -2- (5-phenyl-1H-pyrazole-3-yl) benzamide (0.10 g) was obtained. .. The product (0.10 g) was dissolved in methanol (1 mL), hydrazine monohydrate (0.10 g) was added, and the mixture was stirred under heating under reflux for 2 hours. Water was added to the residue obtained by concentrating the reaction mixture under reduced pressure, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.03 g). The structural formula, spectral data and purification conditions are shown in Table 92.

Examples 16-2 to 16-11
Examples 16-2 to 16-11 were synthesized by the same method as in Example 16-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Tables 92 to 93.

Example 17-1
2- [5- (3,4-difluorophenyl) -1H-pyrazole-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide 3- (2-bromophenyl) -5-( Triethylamine (0.091 g), palladium (II) acetate (0.007 g), bis (adamantan) in a 1,4-dioxane (3.4 mL) solution of 3,4-difluorophenyl) -1H-pyrazole (0.200 g). -1-yl) (butyl) phosphine (0.011 g) and 2- (2-aminoethyl) pyridine (0.109 g) were added, and the mixture was stirred at 100 ° C. for 23 hours under a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature and then passed through a Celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.070 g). The structural formula, spectral data and purification conditions are shown in Table 94.

Examples 17-2 to 17-11
Examples 17-2 to 17-11 were synthesized by the same method as in Example 17-1 using the corresponding raw materials. The structural formulas, spectral data and purification conditions are shown in Tables 94 to 95.

Example 18-1
2- [5- (3-Aminophenyl) -1H-pyrazole-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide N- {3- [3- (2-bromophenyl) -1H-Pyrazole-5-yl] Phenyl} Carbamate tert-butyl ester (0.352 g) in a 1,4-dioxane (5 mL) solution with triethylamine (0.129 g), palladium (II) acetate (0.010 g) , Bis (adamantan-1-yl) (butyl) phosphine (0.015 g) and 2- (2-aminoethyl) pyridine (0.156 g) were added, and the mixture was stirred at 100 ° C. for 19 hours under a carbon monoxide atmosphere. .. The reaction mixture was cooled to room temperature and then passed through a Celite pad. The filtrate is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol), and N- {3- [3- (2-{[2- (pyridine-2-yl) ethyl) ethyl. ] Carbamoyl} phenyl) -1H-pyrazole-5-yl] phenyl} carbamic acid tert-butyl ester (0.094 g) was obtained. An ethyl acetate solution of hydrogen chloride (4 mol / L, 2 mL) was added to a solution of the product (0.094 g) in ethyl acetate (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.053 g). The structural formula, spectral data and purification conditions are shown in Table 95.

Example 18-2
Example 18-2 was synthesized by the same method as in Example 18-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 95.

Example 19-1
2- [5- (4-Fluoro-2-hydroxyphenyl) -1H-pyrazole-3-yl] -N-[(2R) -1-hydroxy-3- (pyridin-2-yl) propan-2-yl ] Benzamide 2- [5- (4-fluoro-2-methoxyphenyl) -1H-pyrazole-3-yl] -N-[(2R) -1-hydroxy-3- (pyridin-2-yl) propan-2 -Il] A solution of boron tribromide dichloromethane (1 mol / L, 0.46 mL) under ice-cooling was added to a solution of benzamide (0.041 g) in dichloromethane (1 mL), and the mixture was stirred at the same temperature for 2 hours at room temperature overnight. After adding saturated aqueous sodium hydrogen carbonate solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.017 g). The structural formula, spectral data and purification conditions are shown in Table 96.

Examples 19-2 to 19-8
Examples 19-2 to 19-8 were synthesized by the same method as in Example 19-1 using the corresponding raw materials. The structural formulas, spectral data and purification conditions are shown in Tables 96 to 97.

Example 20-1
N- [2- (4-Aminophenyl) ethyl] -2- (5-phenyl-1H-pyrazole-3-yl) benzamide 2- (5-phenyl-1H-pyrazole-3-yl) benzoic acid (0. 05 g) N, N-dimethylformamide (1 mL) suspension, 1-hydroxybenzotriazole monohydrate (0.043 g), 2- (4-nitrophenyl) ethylamine hydrochloride (0.038 g), triethylamine (0.057 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.055 g) were added and stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (1 mL), 10% palladium carbon (50% wet, 20 mg) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.056 g). The structural formula, spectral data and purification conditions are shown in Table 97.

Examples 20-2 to 20-3
Examples 20-2 to 20-3 were synthesized by the same method as in Example 20-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 97.

Example 21-1
N- [2- (2-Carbamoylphenyl) ethyl] -2- (5-phenyl-1H-pyrazole-3-yl) benzamide 2- (5-phenyl-1H-pyrazole-3-yl) benzoic acid (0. 05 g) of N, N-dimethylformamide (1 mL) suspension, 1-hydroxybenzotriazole monohydrate (0.043 g), 2- (2-aminoethyl) benzoic acid methyl ester (0.034 g), Triethylamine (0.06 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.055 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- {2- [2- (5-phenyl-1H-pyrazole-3-3). Il) Benzoylamino] ethyl} benzoic acid methyl ester (0.063 g) was obtained. Aqueous sodium hydroxide solution (2 mol / L, 0.22 mL) was added to a solution of the product (0.063 g) in methanol (2 mL), and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was cooled to room temperature and then neutralized by adding hydrochloric acid (2 mol / L). Water was added to this mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. 1-Hydroxybenzotriazole monohydrate (0.031 g), ammonium chloride (0.036 g), triethylamine (0.095 g) and 1-ethyl- in a suspension of the residue in N, N-dimethylformamide (1 mL). 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.039 g) was added, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.007 g). The structural formula, spectral data and purification conditions are shown in Table 97.

Example 22-1
N- [2- (3-Aminopyridine-2-yl) ethyl] -2- (5-phenyl-1H-pyrazole-3-yl) benzamide 2- (5-phenyl-1H-pyrazole-3-yl) benzoic acid 1-Hydroxybenzotriazole monohydrate (0.010 g), N- [2- (2-aminoethyl) pyridine-3) in an N, N-dimethylformamide (1 mL) suspension of acid (0.011 g). -Il] Add carbamic acid tert-butyl ester (0.01 g), N, N-diisopropylethylamine (0.022 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.012 g). , Stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.007 g). The structural formula, spectral data and purification conditions are shown in Table 97.

Example 22-2
Example 22-2 was synthesized by the same method as in Example 22-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 97.

Example 23-1
3-Fluoro-2- {5- [4-fluoro-3- (hydroxymethyl) phenyl] -1H-pyrazole-3-yl} -N-[(2R) -1-hydroxy-3- (pyridin-2-) Il) Propyl-2-yl] benzamide 2-{5- [3- (1,3-dioxolan-2-yl) -4-fluorophenyl] -1H-pyrazole-3-yl} -3-fluorobenzoic acid ( 0.086 g) of N, N-dimethylformamide (1 mL) solution in (2R) -2-amino-3- (pyridin-2-yl) propan-1-ol (0.053 g), 1-hydroxybenzotriazole. Hydrate (0.53 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.067 g) and N, N-diisopropylethylamine (0.12 g) were added and stirred overnight at room temperature. .. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 2-{5- [3- (1,3-dioxolan-2-yl)). -4-Fluorophenyl] -1H-pyrazole-3-yl} -3-fluoro-N-[(2R) -1-hydroxy-3- (pyridin-2-yl) propan-2-yl] benzamide (0. 07 g) was obtained. Hydrochloric acid (2 mol / L, 3 mL) was added to a solution of the product (0.070 g) in tetrahydrofuran (1 mL) and stirred at 60 ° C. overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and purified by 3-fluoro-2- [5- (4-fluoro-3-formylphenyl) -1H. -Pyrazole-3-yl] -N- [(2R) -1-hydroxy-3- (pyridin-2-yl) propan-2-yl] benzamide (0.062 g) was obtained. Sodium borohydride (0.008 g) was added to a solution of the product (0.062 g) in methanol (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.057 g). The structural formula, spectral data and purification conditions are shown in Table 98.

Examples 23-2 to 23-3
Examples 23-2 to 23-3 were synthesized by the same method as in Example 23-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 98.

Example 24-1
(2S) -2- {3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoylamino} -2-methyl-3-phenylpropanamide 3-fluoro-2- [5- (4-Fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] Benzoic acid and 3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-Pyrazole-3-yl] dichloromethane (2 mL) was added to the mixture of benzoic acid (0.15 g). 1-Chloro-N, N, 2-trimethylpropenylamine (0.116 g) was added to this suspension, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Dichloromethane (2 mL), (S) -2-amino-2-methyl-3-phenylpropaneamide hydrochloride (0.094 g), triethylamine (0.44 g) and 4-dimethylaminopyridine (10 mg) were added to the residue. The mixture was stirred overnight under heating and reflux. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane), and (2S) -2- {3-fluoro-2- [5-( 4-Fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoylamino} -2-methyl-3-phenylpropanamide and (2S) -2- {3-fluoro-2- [5] A mixture of − (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoylamino} -2-methyl-3-phenylpropanamide was obtained. Methanol (1 mL) and a hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) were added to this mixture, and the mixture was stirred at 50 ° C. for 4 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.064 g). The structural formula, spectral data and purification conditions are shown in Table 99.

Examples 24-2 to 24-7
Examples 24-2 to 24-7 were synthesized by the same method as in Example 24-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 99.

Example 25-1
2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N- (3,4-trans-4-phenylpyrrolidine-3-yl) benzamide N- (3,4-trans-1) -Benzyl-4-phenylpyrrolidine-3-yl) -2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzamide (0.12 g) in ethanol (2 mL) solution with 10% palladium carbon (50% wet, 0.05 g) was added at room temperature, and the mixture was stirred at 60 ° C. for 3 hours under a hydrogen atmosphere. After cooling the reaction mixture to room temperature, the catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.082 g). The structural formula, spectral data and purification conditions are shown in Table 100.

Example 26-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N- [4-hydroxy-1- (pyridin-2-yl) butane-2-yl] benzamide 3- 1-Hydroxybenzotriazole in a N, N-dimethylformamide (1 mL) suspension of fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoic acid (0.041 g). Japanese product (0.031 g), 4- (benzyloxy) -1- (pyridin-2-yl) butane-2-amine (0.035 g), N, N-diisopropylethylamine (0.071 g) and 1-ethyl -3- (3-Didimethylaminopropyl) carbodiimide hydrochloride (0.040 g) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N- [4- (benzyloxy) -1- (pyridin-2-yl). Butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzamide (0.05 g) was obtained. Water (0.1 mL) and dimethyl sulfide (0.2 mL) were added to a solution of the product (0.05 g) in trifluoroacetic acid (0.95 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.028 g). The structural formula, spectral data and purification conditions are shown in Table 100.

Example 26-2
Example 26-2 was synthesized in the same manner as in Example 26-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 100.

Example 27-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (1H-pyrazole-1) -Il) Butan-2-yl] benzamide 3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] Benzoic acid (40 mg) in N, N-dimethylformamide (1 mL) (2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (1H-pyrazole-1-yl) butane-2-amine (56 mg), 1-hydroxybenzotriazole monohydrate A substance (22 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (28 mg) and N, N-diisopropylethylamine (68 μL) were added, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (1H-). Pyrazole-1-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide (47 mg) was obtained. A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 mol / L, 150 μL) was added to a solution of the product (47 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (27 mg). The structural formula, spectral data and purification conditions are shown in Table 101.

Examples 27-2 to 27-31
Examples 27-2 to 27-31 were synthesized by the same method as in Example 27-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Tables 101 to 105.

Example 28-1
3-Fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N- [(2R) -4-hydroxy-1- (pyridin-2-yl) butane -2-yl] benzamide 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoic acid and 3-fluoro-2- [4-Fluoro-5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] N, N-dimethylformamide (2.5 mL) in a mixture of benzoic acid (0.112 g) Was added. In this mixture, (3R) -3-amino-4- (pyridin-2-yl) butane-1-ol hydrochloride (0.074 g), 1-hydroxybenzotriazole monohydrate (0.057 g), 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.71 g) and triethylamine (0.125 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography, and 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole. -3-yl] -N- [(2R) -4-hydroxy-1- (pyridin-2-yl) butane-2-yl] benzamide and 3-fluoro-2- [4-fluoro-5- (4-fluoro-5- (4-fluoro-5)] Fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] -N-[(2R) -4-hydroxy-1- (pyridin-2-yl) butane-2-yl] benzamide mixture ( 0.086 g) was obtained. To this mixture (0.086 g), 1,4-dioxane (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) were added, and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.047 g). The structural formula, spectral data and purification conditions are shown in Table 106.

Examples 28-2 to 28-9
Examples 28-2 to 28-9 were synthesized in the same manner as in Example 28-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Tables 106 to 107.

Example 29-1
2- (5-Phenyl-1H-pyrazole-3-yl) -N- [2- (piperidin-2-yl) ethyl] benzamide hydrochloride 2- (5-phenyl-1H-pyrazole-3-yl) benzoic acid 1-Hydroxybenzotriazole monohydrate (0.061 g), 2- (2-aminoethyl) piperidin-1-carboxylic acid tert in a (0.07 g) N, N-dimethylformamide (1 mL) suspension. -Butyl ester (0.073 g), triethylamine (0.08 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.076 g) were added and stirred overnight at room temperature. After adding water to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- {2- [2- (5-phenyl-1H-pyrazole-). 3-Il) Benzoylamino] ethyl} piperidine-1-carboxylic acid tert-butyl ester was obtained. An ethyl acetate solution (4 mol / L, 2 mL) was added to a solution of the product in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 4 hours. Diethyl ether was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (0.11 g). The structural formula, spectral data and purification conditions are shown in Table 108.

Example 29-2
Example 29-2 was synthesized in the same manner as in Example 29-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 108.

Example 30-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N- [3-hydroxy-2- (pyridin-2-yl) propyl] benzamide 3-fluoro-2- [5- (4-Fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] Benzoic acid and 3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -N, N-Dimethylformamide (1 mL) was added to a mixture of -2H-pyrazole-3-yl] benzoic acid (0.07 g). To this mixture are 1-hydroxybenzotriazole monohydrate (0.046 g), 2- {1-amino-3- (tert-butyldimethylsilyloxy) propan-2-yl} pyridine (0.054 g), N. , N-diisopropylethylamine (0.11 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.058 g) were added, and the mixture was stirred overnight at room temperature. After adding water to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N- {3- (tert-butyldimethylsilyloxy) -2- (pyridine-). 2-Il) Propyl} -3-Fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzamide and N- {3- (tert-butyldimethyl) Cyriloxy) -2- (pyridin-2-yl) propyl} -3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzamide mixture Got Methanol (1 mL) and a hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) were added to this mixture, and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.05 g). The structural formula, spectral data and purification conditions are shown in Table 108.

Example 30-2
Example 30-2 was synthesized by the same method as in Example 30-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 108.

Example 31-1
N-[(2R, 3R) -3,4-dihydroxy-1- (pyrimidine-2-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole -3-yl] Benzamide 3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] Benzoic acid (38 mg) in N, N-dimethylformamide (1 mL) solution (1R) -1-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyrimidine-2-yl) ethylamine (31 mg), 1-hydroxybenzotriazole monohydrate (21 mg)
), 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (27 mg) and N, N-diisopropylethylamine (33 μL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N-[(1R) -1-((4R) -2,2-dimethyl-1, 3-Dioxolan-4-yl) -2- (pyrimidine-2-yl) ethyl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzamide was obtained. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the product in methanol (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (28 mg). The structural formula, spectral data and purification conditions are shown in Table 108.

Example 32-1
N-[(2R, 3S) -3-amino-4-benzyloxy-1- (pyridin-2-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl)- 1H-pyrazole-3-yl] benzylamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoic acid (76 mg), N-[(2S) -3-amino- 1-Benzyloxy-4- (pyridin-2-yl) butane-2-yl] carbamate benzyl ester (100 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (62 mg), 1- A mixture of hydroxybenzotriazole monohydrate (49 mg) and triethylamine (75 mg) in N, N-dimethylformamide (2 mL) was stirred at room temperature for 11.5 hours. This mixture was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain a diastereomer mixture (138 mg). This mixture was purified by reverse phase preparative liquid chromatography (CapcelllPakC18 UG80, elution solvent: acetonitrile / water) and N-[(2S, 3R) -1-benzyloxy-3- {3-fluoro-2- [5]. -(4-Fluorophenyl) -1H-pyrazole-3-yl] benzoylamino} -4- (pyridin-2-yl) butane-2-yl] carbamate benzyl ester (78 mg) and N-[(2S, 3S) ) -1-benzyloxy-3-{3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoylamino} -4- (pyridin-2-yl) butane-2 -Il] Carbamate benzyl ester (25 mg) was obtained. N-[(2S, 3R) -1-benzyloxy-3- {3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoylamino} -4- (pyridine-) A mixture of 2-yl) butane-2-yl] carbamate benzyl ester (72 mg) and 10% palladium carbon (50% wet, 40 mg) in ethanol (3 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad. The filtrate was concentrated under reduced pressure to give the title compound (57 mg). The structural formula, spectral data and purification conditions are shown in Table 108.

Example 32-2
Example 32-2 was synthesized in the same manner as in Example 32-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 108.

Example 33-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R) -3-hydroxy-3-methyl-1- (pyridin-2-yl) butane -2-yl] benzamide 3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoic acid (0.060 g) in an N, N-dimethylformamide (3 mL) solution (3 mL) 2R) -2-Amino-3- (pyridin-2-yl) propionic acid methyl ester (0.036 g), 1-hydroxybenzotriazole monohydrate (0.037 g), 1-ethyl-3- (3-) Didimethylaminopropyl) carbodiimide hydrochloride (0.046 g) and triethylamine (0.081 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol), and (2R) -2- {3-fluoro-2- [5- (4-fluorophenyl) ) -1H-Pyrazole-3-yl] benzoylamino} -3- (pyridin-2-yl) propionate methyl ester (0.059 g) was obtained. A solution of methyl magnesium bromide diethyl ether (3 mol / L, 1.13 mL) was added to a solution of the product (0.059 g) in tetrahydrofuran (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After adding saturated aqueous ammonium chloride solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.037 g). The structural formula, spectral data and purification conditions are shown in Table 109.

Examples 33-2 to 33-5
Examples 33-2 to 33-5 were synthesized by the same method as in Example 33-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 109.

Examples 34-1HP, 34-1LP
2- [5- (4-chlorophenyl) -1H-pyrazole-3-yl] -3-fluoro-N-[(2R) -3-hydroxy-3-methyl-1- (pyridin-2-yl) butane- 2-Il] Benzamide (Example 34-1HP)
2- [5- (4-chlorophenyl) -1H-pyrazole-3-yl] -3-fluoro-N-[(2R) -3-oxo-1- (pyridin-2-yl) butane-2-yl] Benzamide (Example 34-1LP)
3-Fluoro-2- [5- (4-chlorophenyl) -1H-pyrazole-3-yl] benzoic acid (0.063 g) in an N, N-dimethylformamide (3 mL) solution in (2R) -2-amino- 3- (Pyridine-2-yl) propionic acid methyl ester (0.047 g), 1-hydroxybenzotriazole monohydrate (0.037 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.046 g) and triethylamine (0.081 g) were added and stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and (2R) -2- {3-fluoro-2- [5- (4-chlorophenyl)). -1H-pyrazole-3-yl] benzoylamino} -3- (pyridin-2-yl) propionate methyl ester (0.068 g) was obtained. A methyllithium diethyl ether solution (1.1 mol / L, 0.32 mL) was added to a solution of the product (0.034 g) in tetrahydrofuran (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. After adding saturated aqueous ammonium chloride solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (HP: 0.015 g, LP: 0.004 g). The structural formula, spectral data and purification conditions are shown in Table 110.

Example 35-1
2- [5- (4-Chlorophenyl) -1H-pyrazole-3-yl] -3-fluoro-N-[(2R) -4-hydroxy-3- (hydroxymethyl) -3-methyl-1- (pyridin) -2-yl) Butan-2-yl] benzamide 3-Fluoro-2- [5- (4-chlorophenyl) -1H-pyrazole-3-yl] N, N-dimethylformamide (0.022 g) of benzoic acid (0.022 g) 1 mL) solution in (1R) -1- (5-methyl-2-phenyl-1,3-dioxane-5-yl) -2- (pyridin-2-yl) ethylamine hydrochloride (0.033 g), 1- Hydroxybenzotriazole monohydrate (0.013 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.016 g) and triethylamine (0.028 g) were added and stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 2- [5- (4-chlorophenyl) -1H-pyrazole-3-yl] -3. -Fluoro-N-[(1R) -1- (5-methyl-2-phenyl-1,3-dioxane-5-yl) -2- (pyridin-2-yl) ethyl] benzamide (0.021 g) Obtained. Water (0.2 mL) was added to a solution of the product (0.021 g) in acetic acid (0.8 mL), and the mixture was stirred at 70 ° C. for 12 hours. After adding saturated aqueous sodium hydrogen carbonate solution to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.004 g). The structural formula, spectral data and purification conditions are shown in Table 110.

Examples 35-2 to 35-5
Examples 35-2 to 35-5 were synthesized in the same manner as in Example 35-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 110.

Example 36-1
3-Chloro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R) -4-hydroxy-1- (pyridin-2-yl) butane-2-yl ] Benzamide 4-chloro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindole-8-one (0.05 g) in tetrahydrofuran (1 mL) suspension, (2R)- 4- (tert-Butyldimethylsilyloxy) -1- (pyridin-2-yl) butane-2-amine (0.047 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -4- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl). Butane-2-yl] -3-chloro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzamide was obtained. Tetra-n-butylammonium fluoride hydrochloride solution (1 mol / L, 180 μL) was added to the product, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.043 g). The structural formula, spectral data and purification conditions are shown in Table 111.

Example 36-2
Example 36-2 was synthesized by the same method as in Example 36-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 111.

Example 37-1
(2R) -2- {3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoylamino} -3- (pyridin-2-yl) propanamide 3-fluoro- 2- [5- (4-Fluorophenyl) -1H-pyrazole-3-yl] benzoic acid (0.047 g) in a dichloromethane (1 mL) suspension with (2R) -2-amino-3- (pyridin-2) -Il) Propanamide dihydrochloride (0.038 g), N, N-diisopropylethylamine (0.112 g) and T3P® N, N-dimethylformamide solution (1.6 mol / L, 0.2 mL). In addition, the mixture was stirred at room temperature for 5 days. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate / n-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, and the insoluble material was collected by filtration to give the title compound (0.022 g). The structural formula, spectral data and purification conditions are shown in Table 111.

Examples 37-2 to 37-3
Examples 37-2 to 37-3 were synthesized by the same method as in Example 37-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 111.

Example 38-1
3- (2- {3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoylamino} ethyl) Benzoic acid 3-Fluoro-2- [5- (4-fluoro) Phenyl) -1H-pyrazole-3-yl] 2- (3-bromophenyl) ethylamine (0.038 g), 1-hydroxy in a solution of benzoic acid (0.057 g) in N, N-dimethylformamide (1.5 mL). Benzotriazole monohydrate (0.035 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.044 g) and triethylamine (0.058 g) were added and stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N- [2- (3-bromophenyl) ethyl] -3-fluoro-2- [ 5- (4-Fluorophenyl) -1H-pyrazole-3-yl] benzamide (0.052 g) was obtained. N-Methylpyrrolidone (0.5 mL), triethylamine (0.033 g), 1,1'-bis (diphenylphosphino) ferrocene (1.5 mL) suspension of product (0.052 g) n-propanol (1.5 mL). 0.006 g) and 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (0.009 g) were added, and the mixture was stirred at 100 ° C. for 13 hours under a carbon monoxide atmosphere. After cooling the reaction mixture to room temperature, hydrochloric acid (1 mol / L) was added. The crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3- (2- {3-fluoro-2- [5- (4-fluoro). Phenyl) -1H-pyrazole-3-yl] benzoylamino} ethyl) benzoic acid propyl ester (0.026 g) was obtained. Aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) was added to a solution of the product (0.026 g) in methanol (0.5 mL), and the mixture was stirred at 60 ° C. for 2 hours. After cooling the reaction mixture to room temperature, hydrochloric acid (2 mol / L, 0.5 mL) was added. The precipitate was collected by filtration to give the title compound (0.021 g). The structural formula, spectral data and purification conditions are shown in Table 112.

Examples 38-2 to 38-3
Examples 38-2 to 38-3 were synthesized by the same method as in Example 38-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 112.

Example 39-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-((2R, 3S) -3,4-dihydroxy-1-phenylbutane-2-yl) benzamide (2S, 3R) -3-amino in a solution of 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindole-8-one (0.030 g) in tetrahydrofuran (1 mL). -2-Hydroxy-4-phenyl-1-butanol hydrochloride (0.020 g) and triethylamine (0.016 g) were added, and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.023 g). The structural formula, spectral data and purification conditions are shown in Table 113.

Example 39-2
Example 39-2 was synthesized in the same manner as in Example 39-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 113.

Example 40-1
(2R) -2- {3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoylamino} -2-methyl-3- (pyridin-2-yl) propanamide (2R) -2-Amino-2 in a solution of 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindole-8-one (11 mg) in tetrahydrofuran (0.5 mL). -Methyl-3- (pyridin-2-yl) propanamide (7 mg), N, N-diisopropylethylamine (10 mg) and 4-dimethylaminopyridine (1 mg) were added, and the mixture was stirred at 60 ° C. for 7 days. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (5 mg). The structural formula, spectral data and purification conditions are shown in Table 113.

Example 40-2
Example 40-2 was synthesized by the same method as in Example 40-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 113.

Example 41-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-((3R) -2H, 3H, 4H-pyrano [3,2-b] pyridin-3-3 Il) Benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R) -1- (3-fluoropyridin-2-yl) -3- Hydroxypropan-2-yl] N, N'-dimethylpropylene urea (0.031 g) and sodium hydride (60% oil) in an N, N-dimethylformamide (2 mL) solution of benzamide (0.074 g) under ice cooling. Dispersion (0.039 g) was added, and the mixture was stirred at 40 ° C. for 18 hours. After adding water to the reaction mixture, the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.045 g). The structural formula, spectral data and purification conditions are shown in Table 113.

Example 41-2
Example 41-2 was synthesized by the same method as in Example 41-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 113.

Example 42-1
2- [5- (4-Chlorophenyl) -1H-pyrazole-3-yl] -3-fluoro-N-[(2R) -1- (methylamino) -3-phenylpropan-2-yl] benzamide 2- [5- (4-Chlorophenyl) -1H-pyrazole-3-yl] -3-fluorobenzoic acid (0.05 g) in N, N-dimethylformamide (1 mL) suspension with N-((2R) -2 -Amino-3-phenylpropyl) -N-methyl-2-nitrobenzene-1-sulfonamide hydrochloride (0.061 g), 1-hydroxybenzotriazole monohydrate (0.029 g), 1-ethyl-3- (3-Dimethylaminopropyl) Carbodiimide Hydrochloride (0.03)
6 g) and triethylamine (0.064 g) were added, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [5- (4-chlorophenyl) -1H-pyrazole-3-yl]. -3-Fluoro-N-[(2R) -1- (N-methyl-2-nitrobenzenesulfonylamino) -3-phenylpropan-2-yl] benzamide (0.1 g) was obtained. Thiophenol (0.021 g) and cesium carbonate (0.154 g) were added to a solution of the product (0.1 g) in acetonitrile (2 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.05 g). The structural formula, spectral data and purification conditions are shown in Table 114.

Example 42-2
Example 42-2 was synthesized by the same method as in Example 42-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 114.

Example 43-1
2- [5- (4-Chlorophenyl) -1H-pyrazole-3-yl] -3-fluoro-N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (pyridin-2-yl) Butan-2-yl] benzamide 2- [5- (4-chlorophenyl) -1H-pyrazole-3-yl] -3-fluorobenzoic acid (0.03 g) N, N-dimethylformamide (1 mL) suspension (2R, 3S) -4- (benzyloxy) -3-methoxy-1- (pyridin-2-yl) butane-2-amine (0.027 g), 1-hydroxybenzotriazole monohydrate (0. 016 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.02 g) and triethylamine (0.038 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and N-[(2R, 3S) -4- (benzyloxy) -3-methoxy-1. -(Pyridine-2-yl) butane-2-yl] -2- [5- (4-chlorophenyl) -1H-pyrazole-3-yl] -3-fluorobenzamide (0.035 g) was obtained. Water (0.1 mL) and dimethyl sulfide (0.2 mL) were added to a solution of the product (0.035 g) in trifluoroacetic acid (0.95 mL), and the mixture was stirred at 60 ° C. for 1 day. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium hydrogen carbonate solution, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.02 g). The structural formula, spectral data and purification conditions are shown in Table 115.

Examples 43-2 to 43-9, 43-11 to 43-25, 43-27 to 43-46
Examples 43-2 to 43-9, 43-11 to 43-25, and 43-27 to 43-46 were synthesized using the corresponding raw materials in the same manner as in Example 43-1. The structural formula, spectral data and purification conditions are shown in Tables 115 to 121.

Example 44-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R) -1-hydroxy-3- [3- (2H-1,2,3) 4-Tetrazole-5-yl) Pyridine-2-yl] Propan-2-yl] Benzamide N-[(2R) -1- (3-cyanopyridin-2-yl) -3-hydroxypropan-2-yl] -3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzamide (55 mg) in N-methylpyrrolidone (2 mL) solution with sodium azide (39 mg), ammonium chloride (32 mg) ), Lithium chloride (7 mg) was added, and the mixture was stirred at 120 ° C. for 28 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (5 mg). The structural formula, spectral data and purification conditions are shown in Table 122.

Example 44-2
Example 44-2 was synthesized in the same manner as in Example 44-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 122.

Example 45-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R, 3S) -4-hydroxy-3-methylamino-1- (pyridin-2-) Il) Butan-2-yl] Benzylamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoic acid (77 mg), N-[(2S) -3-amino- 1-Benzyloxy-4- (pyridin-2-yl) butane-2-yl] -N-methylcarbamic acid benzyl ester (103 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (62 mg) , 1-Hydroxybenzotriazole monohydrate (49 mg), triethylamine (75 mg) N, N-dimethylformamide (2 mL) mixture was stirred at room temperature for 12 hours. Dichloromethane was added to the reaction mixture and washed twice with water. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) to obtain a diastereomeric mixture. This mixture was purified by reverse phase preparative liquid chromatography (CapcelllPakC18 UG80, elution solvent: acetonitrile / water) and N-[(2S, 3R) -1-benzyloxy-3- {3-fluoro-2- [5]. -(4-Fluorophenyl) -1H-pyrazole-3-yl] benzoylamino} -4- (pyridin-2-yl) butane-2-yl] -N-methylcarbamic acid benzyl ester (83 mg) and N-[((4-fluorophenyl) -1H-pyrazole-3-yl] -N-methylcarbamic acid benzyl ester (83 mg) 2S, 3S) -1-benzyloxy-3-{3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoylamino} -4- (pyridin-2-yl) Butan-2-yl] -N-methylcarbamic acid benzyl ester (25 mg) was obtained. N-[(2S, 3R) -1-benzyloxy-3- {3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoylamino} -4- (pyridine-) A mixture of 2-yl) butane-2-yl] -N-methylcarbamic acid benzyl ester (83 mg) and 10% palladium carbon (50% wet, 50 mg) in ethanol (2 mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad. The filtrate is concentrated under reduced pressure to concentrate N-[(2R, 3S) -4-benzyloxy-3-methylamino-1- (pyridin-2-yl) butane-2-yl] -3-fluoro-2- [5. -(4-Fluorophenyl) -1H-pyrazole-3-yl] benzamide (61 mg) was obtained. A mixture of product (61 mg), water (0.2 mL) and dimethyl sulfide (0.4 mL) in trifluoroacetic acid (1.9 mL) was stirred at 60 ° C. for 34 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to adjust the pH to 7. Ethyl acetate was added to this mixture, the organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (37 mg). The structural formula, spectral data and purification conditions are shown in Table 122.

Examples 45-2 to 45-3, 43-10
Examples 45-2 to 45-3 and 43-10 were synthesized by the same method as in Example 45-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 122 and Table 116.

Example 46-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R) -3-hydroxy-3-methyl-1- (4-methylpyrimidine-2-yl) Il) Butan-2-yl] benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N- [(2R) -3-hydroxy-3-methyl-1 -(6-Methyl-1,6-dihydropyrimidine-2-yl) butane-2-yl] 2,3-dichloro-5,6-dicyano-p-benzoquinone (20 mg) in a toluene (1 mL) solution. 19 mg) was added, and the mixture was stirred at 80 ° C. for 30 minutes. The reaction mixture was cooled to room temperature and purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (4 mg). The structural formula, spectral data and purification conditions are shown in Table 122.

Example 47-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] -N-[(1R) -1-((4S) -2-oxo-1,3-oxazolidine-4) -Il) -2- (Pyridine-2-yl) ethyl] benzamide N-[(2R, 3S) -3-amino-4-hydroxy-1- (pyridin-2-yl) butane-2-yl] -3 -Carbonyldiimidazole (9 mg) was added to a solution of fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzamide (13 mg) in tetrahydrofuran (2 mL) for 1.5 hours at room temperature. Stirred. This mixture was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (13 mg). The structural formula, spectral data and purification conditions are shown in Table 123.

Examples 47-2 to 47-3
Examples 47.2 to 47-3 were synthesized by the same method as in Example 47-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 123.

Example 48-1
N-[(2R, 3S) -3-dimethylamino-4-hydroxy-1- (pyridin-2-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl)- 1H-Pyrazole-3-yl] benzamide N-[(2R, 3S) -3-amino-4-hydroxy-1- (pyridin-2-yl) butane-2-yl] -3-fluoro-2- [5] -(4-Fluorophenyl) -1H-pyrazole-3-yl] benzamide (29 mg), 35% aqueous formaldehyde solution (0.106 mL) in tetrahydrofuran (0.5 mL) mixed solution with sodium triacetoxyborohydride (46 mg). It was added at room temperature and the mixture was stirred for 15 minutes. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (23 mg). The structural formula, spectral data and purification conditions are shown in Table 123.

Example 48-2
Example 48-2 was synthesized in the same manner as in Example 48-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 123.

Example 49-1
N-[(2S, 3S) -1,1-difluoro-4-hydroxy-3-methoxy-1- (pyridin-2-yl) butane-2-yl] -3-fluoro-2- [5- (4) -Fluorophenyl) -1H-pyrazole-3-yl] benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoic acid and 3-yl Dichloromethane (1 mL) was added to a mixture (0.052 g) of fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid. 1-Chloro-N, N, 2-trimethylpropenylamine (0.034 g) was added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to concentrate 3-fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoyl chloride and 3-fluoro-2- [5. A mixture of − (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoyl chloride was obtained. (2S, 3S) -4- (benzyloxy) -1,1-difluoro-3-methoxy-1- (pyridin-2-yl) butane-2-amine (0.041 g), triethylamine (0.038 g), 3-Fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] in a mixture of 4-dimethylaminopyridine (0.003 g) and dichloromethane (1 mL) Add a mixed solution of benzoyl chloride and 3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoyl chloride in dichloromethane (1 mL), and add the mixture at room temperature for 1 hour. Stirred. After adding water to the reaction mixture, the crude product was extracted with dichloromethane. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2S, 3S) -4- (benzyloxy) -1,1 -Difluoro-3-methoxy-1- (pyridin-2-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole- 3-yl] benzamide and N-[(2S, 3S) -4- (benzyloxy) -1,1-difluoro-3-methoxy-1- (pyridin-2-yl) butane-2-yl] -3- A mixture (0.064 g) of fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzamide was obtained. Water (0.1 mL) and dimethyl sulfide (0.2 mL) were added to a solution of the product (0.064 g) in trifluoroacetic acid (0.95 mL) and stirred at 60 ° C. overnight. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.015 g). The structural formula, spectral data and purification conditions are shown in Table 123.

Example 50-1
N-[(2R) -3,3-difluoro-4-hydroxy-1- (1H-pyrazole-1-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-Pyrazole-3-yl] benzamide 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindole-8-one (35 mg) in tetrahydrofuran (0.5 mL) Add (2R) -4- (benzyloxy) -3,3-difluoro-1- (1H-pyrazole-1-yl) butane-2-amine (35 mg) and N, N-diisopropylethylamine (16 mg) to the turbid solution. In addition, the mixture was stirred at 85 ° C. for 20 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Trifluoroacetic acid (0.95 mL), water (0.1 mL) and dimethyl sulfide (0.2 mL) were added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred at 85 ° C. for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (30 mg). The structural formula, spectral data and purification conditions are shown in Table 124.

Examples 50-2 to 50-11
Examples 50-2 to 50-11 were synthesized by the same method as in Example 50-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Tables 124 to 125.

Examples 50-12
N-[(2R) -3,3-difluoro-4-hydroxy-1- (2H-1,2,3-triazole-2-yl) butane-2-yl] -3-fluoro-2- [5- (4-Fluorophenyl) -1H-pyrazole-3-yl] benzamide 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindole-8-one (48 mg) cyclopentyl (2R) -4- (benzyloxy) -3,3-difluoro-1- (2H-1,2,3-triazole-2-yl) butane-2-amine hydrochloride in a methyl ether (1 mL) suspension (54 mg) and N, N-diisopropylethylamine (66 mg) were added, and the mixture was stirred at 80 ° C. for 2 days. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and N-[(2R) -4- (benzyloxy) -3,3-difluoro. -1- (2H-1,2,3-triazole-2-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide (48 mg) was obtained. Trifluoroacetic acid (1 mL), water (0.1 mL) and dimethyl sulfide (0.2 mL) were added to the product (48 mg) and stirred at 60 ° C. for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (13 mg). The structural formula, spectral data and purification conditions are shown in Table 125.

Example 51-1
2- {5- [4- (1,3-dioxolane-2-yl) phenyl] -1H-pyrazole-3-yl} -N- [2- (pyridine-2-yl) ethyl] benzamide 2- (4) − Add n-butyllithium n-hexane solution (1.6 mol / L, 0.75 mL) to a solution of −1,3-dioxolane (0.209 g) in tetrahydrofuran (5 mL) at −78 ° C. to 0. The temperature was raised to the degree. A solution of N- [2- (pyridin-2-yl) ethyl] phthalimide (0.252 g) in tetrahydrofuran (5 mL) was added to this mixture, and the mixture was stirred for 10 minutes. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethanol (5 mL) and hydrazine (0.192 g) were added to this residue, and the mixture was stirred at 60 ° C. for 3 hours. After cooling the reaction mixture, the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, water was added to the residue, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.038 g). The structural formula, spectral data and purification conditions are shown in Table 126.

Example 52-1
N- {3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoyl} -N- [2- (pyridin-2-yl) ethyl] glycine
(N- {3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoyl} -N- [2- (pyridin-2-yl) ethyl] glycine methyl ester (58 mg) ), Lithium hydroxide monohydrate (15 mg) was added to a mixture of tetrahydrofuran (1 mL), methanol (1 mL) and water (0.3 mL), and the mixture was stirred at 40 ° C. for 3 hours. After cooling the reaction mixture to room temperature. , Hydrochloride (1 mol / L) was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography. Purification with (eluting solvent: ethyl acetate / methanol) gave the title compound (39 mg). The structural formula, spectral data and purification conditions are shown in Table 126.

Example 52-2
Example 52-2 was synthesized by the same method as in Example 52-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 126.

Example 53-1
2- [5- (4-Fluorophenyl) -1H-pyrazole-3-yl] -N-[(2R) -1-hydroxy-3- (pyridin-2-yl) propan-2-yl] benzene-1 , 3-Dicarboxamide 3-bromo-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzamide and 3-bromo-2- [5- (4- (4- (4-) Fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzamide mixture (5 mg) in n-propanol (2 mL) suspension with N-methylpyrrolidone (0.5 mL), triethylamine (5 mg) , 1,1'-Bis (diphenylphosphino) ferrocene (2 mg) and 1,1'-bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane addition (2 mg) under a carbon monoxide atmosphere, 100 The mixture was stirred at degree for 5 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 3-carbamoyl-2- [5- (4-fluorophenyl) -1- (. Methoxymethyl) -1H-pyrazole-3-yl] benzoic acid propyl ester and 3-carbamoyl-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid A mixture of propyl esters (5 mg) was obtained. Methanol (1 mL) and an aqueous sodium hydroxide solution (2 mol / L, 100 μL) were added to this mixture (5 mg), and the mixture was stirred at 60 ° C. for 1.5 hours. Hydrochloric acid (2 mol / L) was added to the reaction mixture to make it acidic, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 3-carbamoyl-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-3-yl] benzoic acid and 3-carbamoyl-2- [5] were distilled off. A mixture of − (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] benzoic acid (4.5 mg) was obtained. N, N-dimethylformamide (1 mL), (2R) -2-amino-3- (pyridin-2-yl) propan-1-ol (3 mg), 1-hydroxybenzotriazole in this mixture (4.5 mg). Hydrate (3 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4 mg) and triethylamine (7 mg) were added and stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) and 2- [5- (4-fluorophenyl) -1- (methoxymethyl)-. 1H-pyrazole-3-yl] -N-[(2R) -1-hydroxy-3- (pyridin-2-yl) propan-2-yl] benzene-1,3-dicarboxamide and 2- [5-( 4-Fluorophenyl) -2- (methoxymethyl) -2H-pyrazole-3-yl] -N- [(2R) -1-hydroxy-3- (pyridin-2-yl) propan-2-yl] benzene- A mixture of 1,3-dicarboxamide was obtained. Tetrahydrofuran (1 mL) and ethyl acetate solution of hydrogen chloride (4 mol / L, 1 mL) were added to this mixture, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.5 mg). The structural formula and purification conditions are shown in Table 126.

Example 54-1
N-[(2S) -1,3-dihydroxy-1- (pyridin-2-yl) propan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3 -Il] Benzamide
(R) -N-[(2S) -1,3-di (tert-butyldimethylsilyloxy) -1- (pyridine-2-yl) propan-2-yl] -2-methylpropan-2-sulfinamide A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of (0.085 g) 1,4-dioxane (1 mL), and the mixture was stirred at 60 ° C. for 24 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. In a solution of the residue in N, N-dimethylformamide (1 mL), 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoic acid (0.030 g), 1-hydroxybenzo Triazole monohydrate (0.019 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.023 g) and triethylamine (0.040 g) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (0.013 g). The structural formula, spectral data and purification conditions are shown in Table 127.

Examples 54-2-54-2, 1-205-1-207, 1-210-1211
Examples 54-2 to 54-20, 1-205 to 1-207, 1-210 to 1-211 were synthesized by the same method as in Example 54-1 using the corresponding raw materials. The structural formulas, spectral data and purification conditions are shown in Tables 78 to 79 and 127 to 130.

Example 55-1
N-[(2R) -1- (6-aminopyridin-2-yl) -3-hydroxypropan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole- 3-Il] benzamide N- [(2R) -1- (6-azidopyridin-2-yl) -3-hydroxypropan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) A mixture of -1H-pyrazole-3-yl] benzamide (36 mg), tetrahydrofuran (2 mL), water (0.2 mL) and triphenylphosphine (77 mg) was stirred at 80 ° C. for 2 days. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (8 mg). The structural formula, spectral data and purification conditions are shown in Table 130.

Example 56-1
N-[(2R) -3,3-difluoro-4-hydroxy-1- (2H-1,2,3-triazole-2-yl) butane-2-yl] -3-fluoro-2- [4- Fluoro-5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzamide 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1H-pyrazole-3-yl] benzoic acid (40 mg), (2R) -4- (benzyloxy) -3,3-difluoro-1- (2H-1,2,3-triazole-2-yl) butane-2-amine hydrochloride (44 mg), N , N-Diisopropylethylamine (163 mg), T3P® ethyl acetate solution (1.7 mol / L, 0.15 mL), N-methylpyrrolidone (1 mL) was stirred at 80 ° C. for 2 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane). Water (0.1 mL) and dimethyl sulfide (0.2 mL) were added to a solution of the product in trifluoroacetic acid (1 mL), and the mixture was stirred at 60 ° C. for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (28 mg). The structural formula, spectral data and purification conditions are shown in Table 131.

Example 57-1
2- (5-Phenyl-1H-pyrazole-3-yl) -N- (pyridin-2-ylmethyl) benzamide 2- (5-phenyl-1H-pyrazole-3-yl) benzoic acid (50 mg) N, N -Dimethylformamide (1 mL) solution in 2-amino-2- (pyridin-2-yl) acetate ethyl ester hydrochloride (49 mg), 1-hydroxybenzotriazole monohydrate (44 mg), 1-ethyl-3- (1 mL) 3-Dimethylaminopropyl) carbodiimide hydrochloride (54 mg) and N, N-diisopropylethylamine (73 mg) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane) and 2- [2- (5-phenyl-1H-pyrazole-3-yl). ) Benzoylamino] -2- (pyridin-2-yl) ethyl acetate ester (29 mg) was obtained. An aqueous sodium hydroxide solution (2 mol / L, 0.05 mL) was added to a mixture of ethanol (1 mL) -tetrahydrofuran (1 mL) of the product (29 mg), and the mixture was stirred at room temperature for 2 hours. Hydrochloric acid (2 mol / L, 0.06 mL) and water were added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.021 g). The structural formula, spectral data and purification conditions are shown in Table 131.

Example 57-2
Example 57-2 was synthesized in the same manner as in Example 57-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 131.

Reference Example 2-72-1
Using the corresponding raw materials, Reference Example 2-72-1 was synthesized in the same manner as in Reference Example 2-69-1. The structural formula, spectral data and purification conditions are shown in Table 132.

Reference Example 2-73-1
(2S, 3R) -4-benzyloxy-3-fluoro-1- (2H-1,2,3-triazole-2-yl) butane-2-amine hydrochloride
(1R) -2- (benzyloxy) -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (660 mg) in a solution of 1 in tetrahydrofuran (10 mL). , 8-Diazabicyclo [5.4.0] -7-undecene (798 mg) and perfluoro-1-butanesulfonylfluoride (1.58 g) were added at 0 ° C. and stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 1 mL) was added to a solution of the residue (228 mg) in methanol (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) to obtain (2R, 3S) -4- (benzyloxy) -3-fluorobutane-1,2-diol (156 mg). rice field. P-Toluenesulfonyl chloride (153 mg) was added to a solution of the product (156 mg) in pyridine (2 mL) at 0 ° C. and stirred at room temperature for 2 hours. P-Toluenesulfonyl chloride (200 mg) was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (2R, 3S) -1- (benzyloxy) -3-fluoro-4-[(4-methylbenzenesulfonyl) oxy. ] Butane-2-ol (305 mg) was obtained. A mixture of product (305 mg), methanol (1 mL), tetrahydrofuran (1 mL) and 28% aqueous ammonia (2 mL) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. Di-tert-butyl dicarbonate (271 mg) and triethylamine (252 mg) were added to a solution of the residue in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2R, 3S) -4- (benzyloxy) -3-fluoro-2-hydroxybutane-1-yl. ] Carbamic acid tert-butyl ester (101 mg) was obtained. Triethylamine (65 mg) and methanesulfonyl chloride (48 mg) were added to a solution of the product (101 mg) in dichloromethane (3 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Cesium carbonate (315 mg) and 1,2,3-triazole (33 mg) were added to a solution of the residue in N, N-dimethylformamide (1 mL) at room temperature, and the mixture was stirred at 70 ° C. for 3 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2S, 3R) -4- (benzyloxy) -3-fluoro-1- (2H-1,2). , 3-Triazole-2-yl) Butan-2-yl] Carbamic acid tert-butyl ester (37 mg) was obtained. A mixture of product (37 mg), methanol (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 0.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (30 mg). The structural formula, spectral data and purification conditions are shown in Table 132.

Reference Example 2-74-1
(2R, 3S) -3-fluoro-4-methoxy-1- (2H-1,2,3-triazole-2-yl) butane-2-amine hydrochloride and (2R, 3R) -3-fluoro-4 A mixture of −methoxy-1- (2H-1,2,3-triazole-2-yl) butane-2-amine hydrochloride
(1S) -2- (benzyloxy) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (5.0 g) in tetrahydrofuran (30 mL) To 1,8-diazabicyclo [5.4.0] -7-undecene (6.03 g) and perfluoro-1-butanesulfonylfluoride (12.0 g) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solution of hydrogen chloride 1,4-dioxane (4 mol / L, 5 mL) was added to a solution of the residue in methanol (15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (2S, 3R) -4- (benzyloxy) -3-fluorobutane-1,2-diol (1.4 g). Got Triphenylphosphine (2.57 g) and azodicarboxylate diethyl ester toluene solution (2.2 mol / L, 4.5 mL) were added to a toluene (10 mL) solution of the product (1.4 g) at room temperature, and 15 at 80 ° C. Stirred for hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) to give (2S) -2-[(1R) -2- (benzyloxy) -1-fluoroethyl] oxylan (550 mg). Obtained. A mixture of product (670 mg), methanol (4 mL) and 28% aqueous ammonia (20 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. Di-tert-butyl dicarbonate (745 mg) was added to a solution of the residue in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2S, 3R) -4- (benzyloxy) -3-fluoro-2-hydroxybutane-1-yl. ] Carbamic acid tert-butyl ester (940 mg) was obtained. Triethylamine (607 mg) and methanesulfonyl chloride (447 mg) were added to a solution of the product (940 mg) in dichloromethane (5 mL) at 0 ° C. and stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Cesium carbonate (2.9 g) and 1,2,3-triazole (311 mg) were added to a solution of the residue in N, N-dimethylformamide (5 mL) at room temperature, and the mixture was stirred at 70 ° C. for 12 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2R, 3S) -4- (benzyloxy) -3-fluoro-1- (2H-1,2). , 3-Triazole-2-yl) Butan-2-yl] Carbamic acid tert-butyl ester (400 mg) was obtained. 20% Palladium hydroxide carbon (50% wet, 100 mg) was added to a solution of the product (400 mg) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After passing the reaction mixture through Celite pad, the filtrate was concentrated under reduced pressure. Sodium hydride (60% oil dispersion, 43 mg) was added to the mixture of residue, tetrahydrofuran (3 mL), N, N-dimethylformamide (0.3 mL) and iodomethane (190 mg) at 0 ° C. and stirred at room temperature for 1 hour. did. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate). A mixture of product (220 mg), methanol (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (170 mg). The structural formula, spectral data and purification conditions are shown in Table 132.

Reference Example 2-75-1
N-[(2R, 3R) -3-amino-2-hydroxy-4- (1H-pyrazole-1-yl) butane-1-yl] phthalimide
(1S) -2-amino-1-[(4R) -2,2-dimethyl-1,3-dioxolane-4-
To a solution of ethane-1-ol (1.0 g) in dichloromethane (10 mL) was added triethylamine (1.26 g) and benzyl chloroformate (1.06 g) at 0 ° C., and the mixture was stirred at room temperature for 13 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Triethylamine (1.26 g) and methanesulfonyl chloride (853 mg) were added to a solution of the residue in dichloromethane (10 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Cesium carbonate (6.06 g) and pyrazole (634 mg) were added to a solution of the residue in N, N-dimethylformamide (10 mL), and the mixture was stirred at 70 ° C. for 16 hours. Cesium carbonate (3.0 g) and pyrazole (300 mg) were added to the reaction mixture, and the mixture was stirred at 80 ° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N- {(1R) -1-[(4S) -2,2. -Dimethyl-1,3-dioxolan-4-yl] -2- (1H-pyrazol-1-yl) ethyl} carbamate benzyl ester (890 mg) was obtained. A mixture of product (890 mg), methanol (1 mL), water (0.3 mL) and trifluoroacetic acid (294 mg) was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was azeotroped twice with toluene. Imidazole (440 mg) was added to a solution of the residue in N, N-dimethylformamide (3 mL), tert-butyldiphenylchlorosilane (1.06 g) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxy-1- (1H). -Pyrazole-1-yl) Butan-2-yl] Carbamate benzyl ester (650 mg) was obtained. To a solution of the product (650 mg) in toluene (5 mL) was added p-toluenesulfonic acid monohydrate (23 mg) and 2,2-dimethoxypropane (1.25 g), and the mixture was stirred at 85 ° C. for 14 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solution of tetra-n-butylammonium fluoride tetrahydrofuran (1 mol / L, 1.43 mL) was added to a solution of the residue in tetrahydrofuran (5 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-4- (1H-pyrazole-1-). Ilmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (330 mg) was obtained. Phthalimide (281 mg), triphenylphosphine (501 mg) and azodicarboxylate diethyl ester toluene solution (2.2 mol / L, 0.87 mL) were added to a solution of the product (330 mg) in tetrahydrofuran (5 mL) for 20 hours at room temperature. Stirred. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5R) -5-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2). -Il) Methyl] -2,2-Dimethyl-4- (1H-pyrazole-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (500 mg) was obtained. A mixture of product (290 mg), methanol (2 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. Methanol (2 mL) and 10% palladium carbon (50% wet, 20 mg) were added to the residue, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad. The filtrate was concentrated under reduced pressure to give the title compound (180 mg). The structural formula, spectral data and purification conditions are shown in Table 132.

Reference Example 2-76-1
N-[(2R, 3R) -3-amino-2-hydroxy-4- (2H-1,2,3-triazole-2-yl) butane-1-yl] acetamide
(1S) -2-Amino-1-[(4R) -2,2-dimethyl-1,3-dioxolane-4-yl] ethane-1-ol (3.3 g) in a dichloromethane (30 mL) solution, N. , N-diisopropylethylamine (6.3 g) and benzyl chloroformate (5.06 g) were added at 0 ° C., and the mixture was stirred at room temperature for 13 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-{(2S) -2-[(4R) -2,2-dimethyl-1,3-dioxolane-4-. Il] -2-hydroxyethyl} carbamate benzyl ester (4.1 g) was obtained. Triethylamine (1.37 g) and methanesulfonyl chloride (930 mg) were added to a solution of the product (2.0 g) in dichloromethane (10 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Cesium carbonate (6.62 g) and 1,2,3-triazole (702 mg) were added to a solution of the residue in N, N-dimethylformamide (10 mL), and the mixture was stirred at 70 ° C. for 6 hours. After cooling the reaction mixture to room temperature, water was added and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) to N- {(1R) -1-[(4S) -2, 2-Dimethyl-1,3-dioxolan-4-yl] -2- (2H-1,2,3-triazol-2-yl) ethyl} carbamate benzyl ester (800 mg) was obtained. A mixture of product (800 mg), methanol (5 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was azeotroped twice with toluene. Imidazole (393 mg) and tert-butyldiphenylchlorosilane (952 mg) were added to a solution of the residue in N, N-dimethylformamide (3 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxy-1- (2H). -1,2,3-triazole-2-yl) butane-2-yl] carbamate benzyl ester (1.0 g) was obtained. To a solution of the product (1.0 g) in toluene (5 mL) was added p-toluenesulfonic acid monohydrate (35 mg) and 2,2-dimethoxypropane (1.91 g), and the mixture was stirred at 85 ° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solution of tetra-n-butylammonium fluoride tetrahydrofuran (1 mol / L, 2.2 mL) was added to a solution of the residue in tetrahydrofuran (5 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-4- (2H-1,2, 3-Triazole-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (470 mg) was obtained. Phthalimide (399 mg), triphenylphosphine (711 mg) and azodicarboxylate diethyl ester toluene solution (2.2 mol / L, 1.23 mL) were added to a solution of the product (470 mg) in tetrahydrofuran (3 mL) for 5 hours at room temperature. Stirred. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5R) -5-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2). -Il) Methyl] -2,2-dimethyl-4- (2H-1,2,3-triazole-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (620 mg) was obtained. A mixture of product (620 mg), ethanol (3 mL) and hydrazine monohydrate (680 mg) was stirred at 80 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5R) -5- (aminomethyl) -2,2-dimethyl-4- (2H-1, 2,3-Triazole-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (430 mg) was obtained. A mixture of product (430 mg), methanol (2 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and N-[(2R, 3R) -4-amino-3-hydroxy-1- (2H-1,2,3-triazole-2-yl) butane-2-yl] benzyl carbamate. Ester hydrochloride (420 mg) was obtained. A mixture of product (200 mg), tetrahydrofuran (3 mL), triethylamine (178 mg) and acetic anhydride (120 mg) was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. 10% Palladium on carbon (50% wet, 50 mg) was added to a solution of the residue in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad. The filtrate was concentrated under reduced pressure to give the title compound (110 mg). The structural formula, spectral data and purification conditions are shown in Table 132.

Reference example 2-76-2
Reference Example 2-76-2 was synthesized in the same manner as in Reference Example 2-76-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 132.

Reference Example 2-77-1
(5R) -5-[(1R) -1-amino-2- (2H-1,2,3-triazole-2-yl) ethyl] -1,3-oxazolidine-2-one N-[(2R, 3R) -4-Amino-3-hydroxy-1- (2H-1,2,3-triazole-2-yl) butane-2-yl] carbamate benzyl ester hydrochloride (320 mg), triethylamine (284 mg), carbonyl A mixture of diimidazole (303 mg) and tetrahydrofuran (3 mL) was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. 10% Palladium on carbon (50% wet, 50 mg) was added to a solution of the residue in methanol (2 mL), and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was passed through a Celite pad. The filtrate was concentrated under reduced pressure to give the title compound (160 mg). The structural formula, spectral data and purification conditions are shown in Table 133.

Reference example 2-77-2
Reference Example 2-77-2 was synthesized in the same manner as in Reference Example 2-77-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 133.

Reference Example 2-78-1
(2S, 3R) -3-amino-1-methoxy-4- (2H-1,2,3-triazole-2-yl) butane-2-ol hydrochloride N-[(2S) -2-((4R) ) -2,2-Dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] Triethylamine (660 mg) and methanesulfonyl chloride (660 mg) in a solution of carbamic acid tert-butyl ester (850 mg) in dichloromethane (5 mL). 485 mg) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Cesium carbonate (3.18 g) and 1,2,3-triazole (337 mg) were added to a solution of the residue in N, N-dimethylformamide (5 mL), and the mixture was stirred at 70 ° C. for 4 hours. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-). Il) -2- (2H-1,2,3-triazole-2-yl) ethyl} carbamate tert-butyl ester (500 mg) was obtained. A mixture of product (500 mg), methanol (3 mL), water (1 mL) and trifluoroacetic acid (182 mg) was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was azeotroped twice with toluene. Imidazole (272 mg) was added to a solution of the residue in N, N-dimethylformamide (3 mL), tert-butyldiphenylchlorosilane (660 mg) was added at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxy-1- (2H). -1,2,3-triazole-2-yl) butane-2-yl] carbamic acid tert-butyl ester (610 mg) was obtained. To a solution of the product (610 mg) in toluene (5 mL) was added p-toluenesulfonic acid monohydrate (23 mg) and 2,2-dimethoxypropane (1.25 g) at room temperature and stirred at 80 ° C. for 3 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. A solution of tetra-n-butylammonium fluoride tetrahydrofuran (1 mol / L, 1.4 mL) was added to a solution of the residue in tetrahydrofuran (5 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-4- (2H-1,2, 3-Triazole-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (240 mg) was obtained. Iodomethane (164 mg) was added to a solution of the product (240 mg) in N, N-dimethylformamide (1 mL), sodium hydride (60% oil dispersion, 55 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5S) -5- (methoxymethyl) -2,2-dimethyl-4- (2H-1,2). , 3-Triazole-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (220 mg) was obtained. A mixture of product (220 mg), methanol (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (100 mg). The structural formula, spectral data and purification conditions are shown in Table 133.

Reference Example 2-79-1
N-[(2R, 3R) -3-amino-2-hydroxy-4- (pyridin-2-yl) butane-1-yl] phthalimide N-[(2R, 3S) -3,4-dihydroxy-1- (Pyridine-2-yl) Butane-2-yl] Imidazole (44 mg) and tert-butyldiphenylchlorosilane (163 mg) in an N, N-dimethylformamide (2 mL) solution of carbamic acid tert-butyl ester (140 mg) at 0 ° C. And stirred overnight at room temperature. Water was added to the reaction mixture and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxy-1- (pyridine). -2-yl) Butan-2-yl] Carbamic acid tert-butyl ester (277 mg) was obtained. To a solution of the product (130 mg) in toluene (2 mL) was added p-toluenesulfonic acid monohydrate (5 mg) and 2,2-dimethoxypropane (260 mg), and the mixture was stirred at 85 ° C. overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5S) -5-[(tert-butyldiphenylsilyloxy) methyl] -2,2-dimethyl-4-. A (pyridine-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester was obtained. A solution of tetra-n-butylammonium fluoride tetrahydrofuran (1 mol / L, 0.42 mL) was added to a solution of the product in tetrahydrofuran (1 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Tetrahydrofuran (1 mL), phthalimide (53 mg), triphenylphosphine (95 mg) and a solution of azodicarboxylate diethyl ester toluene (2.2 mol / L, 164 μL) were added to the residue, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and (4R, 5R) -5-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2). -Il) methyl] -2,2-dimethyl-4- (pyridine-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (40 mg) was obtained. A mixture of product (40 mg), methanol (0.5 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 0.5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: methanol / ethyl acetate) to give the title compound (22 mg). The structural formula, spectral data and purification conditions are shown in Table 133.

Examples 58-1 to 58-2
Examples 58-1 to 58-2 were synthesized by the same method as in Example 1-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 134.

Example 59-1
Example 59-1 was synthesized in the same manner as in Example 16-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 134.

Example 60-1
Example 60-1 was synthesized by the same method as in Example 39-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 134.

Example 61-1
Example 61-1 was synthesized by the same method as in Example 43-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 134.

Example 62-1
Example 62-1 was synthesized in the same manner as in Example 47-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 135.

Example 63-1
Example 63-1 was synthesized in the same manner as in Example 50-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 135.

Example 64-1
N-((2R, 3R) -3- {3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoylamino} -2-hydroxy-4- (2H-1) , 2,3-Triazole-2-yl) butane-1-yl) acetamide 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindole-8-one (50 mg) , N-[(2R, 3R) -3-amino-2-hydroxy-4- (2H-1,2,3-triazole-2-yl) butane-1-yl] acetamide (40 mg), N, N- A mixture of diisopropylethylamine (115 mg), T3P® ethyl acetate solution (1.7 mol / L, 0.2 mL) and N-methylpyrrolidone (1 mL) was stirred at 80 ° C. for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol). The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (14 mg). The structural formula, spectral data and purification conditions are shown in Table 135.

Examples 64-2 to 64-4
Examples 64-2 to 64-4 were synthesized in the same manner as in Example 64-1 using the corresponding raw materials. The structural formula, spectral data and purification conditions are shown in Table 135.

Example 65-1
N-[(2R, 3R) -4-amino-3-hydroxy-1- (1H-pyrazole-1-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-Pyrazole-3-yl] benzamide 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindole-8-one (100 mg), N-[(2R, 3R) ) -3-Amino-2-hydroxy-4- (1H-pyrazole-1-yl) butane-1-yl] Phenylimide (111 mg), N, N-diisopropylethylamine (230 mg), T3P® ethyl acetate solution A mixture of (1.7 mol / L, 0.2 mL) and N-methylpyrrolidone (1 mL) was stirred at 80 ° C. for 2 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate) and N-[(2R, 3R) -4- (1,3-dioxo-2,). 3-Dihydro-1H-isoindole-2-yl) -3-hydroxy-1- (1H-pyrazol-1-yl) butane-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) ) -1H-pyrazole-3-yl] benzamide (60 mg) was obtained. Hydrazine monohydrate (177 mg) was added to a solution of the product (60 mg) in ethanol (2 mL), and the mixture was stirred at 60 ° C. for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluting solvent: ethyl acetate / methanol) to give the title compound (23 mg). The structural formula, spectral data and purification conditions are shown in Table 135.

Test Example 1
Icilin-induced wet-dog shake inhibitory effect confirmation test

The test compound is dissolved in dimethylacetamide (Wako Pure Chemical Industries, Ltd.), and a 0.5% methylcellulose solution (Wako Pure Chemical Industries, Ltd.) is added so that the content of dimethylacetamide becomes 5% to prepare a solution or suspension, and then female. SD rats were orally administered at 0.3 to 10 mg / kg / 5 mL. After 1 hour, Icilin (1 mg / kg) dissolved in polyethylene glycol 400 (Wako Pure Chemical Industries, Ltd.) was intraperitoneally administered to induce a wet-dog shake. From 5 minutes after administration of Icilin, the wet-dog shake for 5 minutes was counted. As a comparative test, a medium (dimethylacetamide (Wako Pure Chemical Industries, Ltd.): 0.5% methylcellulose solution (Wako Pure Chemical Industries, Ltd.) = 5:95 mixed solution) was administered in the same manner, and the number of wet-dog shakes at this time was also the same. Counted to. The wet-dog shake suppression rate of the test compound was calculated from the following formula: [1- (count of wet-dog shake of test compound administration / count of wet-dog shake of vehicle administration)] × 100. The results are shown in Tables 136-138.

Test Example 2
Acetic acid-induced detrusor hyperactivity A test to confirm the prolonging effect on the urinary interval of the bladder

Urethane (sigma) was dissolved in pure water to a concentration of 25% w / v, and was subcutaneously administered to female SD rats to a concentration of 1.25 g / kg for anesthesia. A catheter was inserted into the bladder and femoral veins of this rat and the bladder catheter was connected to a syringe pump and pressure transducer. At the same time as monitoring the intravesical pressure using a pressure transducer, a 0.25% acetic acid / physiological saline solution was continuously infused into the bladder at 3.6 mL / hour to induce detrusor overactivity. A solution prepared by dissolving the test compound in a mixed solution of dimethylacetamide and physiological saline (20:80) was administered from an intravenous catheter. The Elongation of micturition interval (%) of the test compound was calculated from the following formula: [Average value of 3 urination intervals immediately after administration / Average value of 3 urination intervals immediately before administration] × 100. The doses and results are shown in Table 139.

As shown in Tables 136 to 138, the compounds of the present invention showed a strong TRPM8 inhibitory effect. Furthermore, as shown in Table 139, it was found that the compound of the present invention has an effect of prolonging the micturition interval and is effective in suppressing detrusor muscle overactivity.

The production method of the present invention is useful as a production method of a pyrazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof. The pyrazole derivative represented by the formula (I) or a pharmacologically acceptable salt thereof is a therapeutic or prophylactic agent for a disease or symptom caused by activation of TRPM8, particularly lower urinary tract symptom (LUTS), particularly. It is useful as a therapeutic or prophylactic agent for overactive bladder (OAB).

Claims (5)

Equation (I):

[In the formula,
Ring A is a C _3-6 cycloalkyl, C _6-10 aryl or heterocycle;
X is independently a CR ^4a or nitrogen atom;
R ¹ and R ² are independently hydrogen atom, halogen atom, hydroxy, amino, hydroxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano, respectively. C _1-6 Alkoxysulfonylamino, imidazolyl, 1,3-dioxolyl or mono (di) C _1-6 alkoxy C _1-6 alkyl;
R ³ is a hydrogen atom, a halogen atom or a C _1-6 alkyl;
R ⁴ and R ^4a are independently hydrogen atom, halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, halo C _1-6 alkyl, respectively. halo _{C 1-6} alkoxy, hydroxy _{C 1-6} alkyl, hydroxy _{C 1-6} alkoxy, cyano, _{carbamoyl, C 1-6} alkoxycarbonyl _{C 1-6 alkoxy, C 7-10 aralkyloxy, C 7-10} aralkyloxy C _1-6 alkoxy or 1,3-dioxolyl;
Ring B is a C _6-10 aryl or heterocycle;
R ⁵ is a hydrogen atom, C _1-6 alkyl, mono (di) hydroxy C _1-6 alkyl, C _1-6 alkoxy (hydroxy) C _1-6 alkyl, carboxy C _1-6 alkyl or C _1-6 alkoxy. It is a carbonyl C _1-6 alkyl;
R ^6a is a hydrogen atom, C (= O) R ⁹ , C (= O) NR ¹⁰ R ¹¹ , CR ¹² R ¹³ R ¹⁴ or the following formula:

((**) represents the bond position);
R ^7a can independently be hydrogen atom, fluorine atom, hydroxy, hydroxy C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl or amino C _{1- 6} alkyl;
R ^7b is independently a hydrogen atom, a fluorine atom or a C _1-6 alkyl, or R ⁵ or R ^6a is a 6-membered ring with ring B or a 5-membered ^{ring with R 7a.} Form a ring;
R ^6b is a hydrogen atom or C _1-6 alkyl;
R ⁸ contains hydrogen atom, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkoxy C _1-6 alkoxy, carbamoyl, C _{1 -6} Alkoxy C _1-6 alkyl, carboxy, azide, halo C _1-6 alkyl or tetrazolyl;
R ⁹ is hydroxy, C _1-6 alkyl or hydroxypyrrolidinyl;
R ¹⁰ and R ¹¹ are independently hydrogen atoms, C _1-6 alkyl, hydroxy C _1-6 alkyl, mono (di) C _1-6 alkyl amino C _1-6 alkyl, pyrrolidinyl or piperidinyl;
R ¹² , R ¹³ and R ¹⁴ are independently hydrogen atom, hydroxy, C _1-6 alkyl, NR ¹⁵ R ¹⁶ , R ¹⁵ R ¹⁶ NC _1-6 alkyl, C _1-6 alkoxy, mono. (Di) Hydroxy C _1-6 alkyl, carbamoyl, C _7-10 aralkyloxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, fluorine atom or fluoro C _1-6 alkyl;
R ¹⁵ is a hydrogen _{atom, C 1-6 alkyl, (C 1-6} alkyl) carbonyl or _{C 7-10} aralkyl;
R ¹⁶ is a hydrogen atom, C _1-6 alkyl or C _7-10 aralkyl;
R ¹⁷ is a hydrogen atom or C _1-6 alkyl;
n is 0, 1 or 2. ], Which is a method for producing a compound represented by [] or a pharmacologically acceptable salt thereof.
The following formula:

[In the formula, ring A is as defined above;
X ^P is independently CR ^4ap or a nitrogen atom;
R ^1P and R ^2P are independently hydrogen atom, halogen atom, hydroxy which may be protected by a protecting group, amino which may be protected by a protecting group, and hydroxy which may be protected by a protecting group. C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano, C _1-6 alkyl sulfonylamino, imidazolyl, 1,3-dioxolyl or mono (di) C _{1- 6} Alkoxy C _1-6 alkyl;
R ^3P is a hydrogen atom, a halogen atom or a C _1-6 alkyl;
R ^4P and R ^4aP are independently protected by hydrogen atom, halogen atom and protective group, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _{1-6, respectively.} Alkoxy, halo C _1-6 alkyl, halo C _1-6 alkoxy, hydroxy C _1-6 alkyl, which may be protected by a protective group, hydroxy C _1-6 alkoxy, which may be protected by a protective group, cyano, Carbamoyl, C _1-6 Alkoxycarbonyl C _1-6 Alkoxy, C _7-10 Alkoxy Oxy, C _7-10 Alkoxy Oxy C _1-6 Alkoxy or 1,3-dioxolyl;
P is a hydrogen atom or a protecting group. ] With the compound represented by] or a salt thereof,
Equation (IV):

[In the equation, rings B and n are as defined above;
R ^5P is a hydrogen atom, C _1-6 alkyl, mono (di) hydroxy C _1-6 alkyl which may be protected by a protecting group, C _1-6 alkoxy (hydroxy) which may be protected by a protecting group. C _{1-6 alkyl, carboxy C 1-6} alkyl which may be protected with a protecting group or C _1-6 alkoxycarbonyl C _1-6 alkyl;
R ^6aP is a hydrogen atom, C (= O) R ^9P , C (= O) NR ^10P R ^11P , CR ^12P R ^13P R ^14P or the following formula:

((**) represents the bond position);
R ^7aP is independently hydrogen atom, fluorine atom, hydroxy which may be protected by a protecting group, hydroxy C _1-6 alkyl which may be protected by a protecting group, C _1-6 alkyl, C _{1- 6} Alkoxy, C _1-6 Alkoxy C _{1-6 Alkyl or Amino C 1-6} Alkyl which may be protected with a protecting group;
R ^7bP is independently a hydrogen atom, a fluorine atom or C _1-6 alkyl, or R ^5P or R ^6aP is a 6-membered ring with ring B or 5-membered with ^{R 7aP.} Form a ring;
R ^6bP is a hydrogen atom or C _1-6 alkyl;
R ^8P is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, hydroxy which may be protected by a protective group, amino, cyano, C _{1-6 which may be protected by a protective group.} Alkoxycarbonyl, C _1-6 alkoxy C _1-6 alkoxy, carbamoyl, C _1-6 alkoxy C _1-6 alkyl, carboxy, azide, halo C _1-6 alkyl or tetrazolyl which may be protected with a protective group. ;
R ^9P _{is hydroxy, C 1-6} alkyl, which may be protected with a protecting group, or hydroxypyrrolidinyl, which may be protected by a protecting group;
R ^10P and R ^11P are independently hydrogen atom, C _1-6 alkyl, hydroxy C _1-6 alkyl which may be protected by a protecting group, and mono (di) which may be protected by a protecting group. C _1-6 alkyl amino C _1-6 alkyl, pyrrolidinyl which may be protected with a protecting group or piperidinyl which may be protected by a protecting group;
R ^12P , R ^13P and R ^14P are independently hydrogen atom, hydroxy which may be _{protected by a protecting group, C 1-6} ^{alkyl, NR 15} R ¹⁶ which may be protected by a protecting group, and protection. Group-protected R ¹⁵ R ¹⁶ NC _1-6 alkyl, C _1-6 alkoxy, protecting group-protected mono (di) hydroxy C _1-6 alkyl, carbamoyl, C _{7 -10} Aralkyloxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, fluorine atom or fluoro C _1-6 alkyl;
R ¹⁵ is a hydrogen _{atom, C 1-6 alkyl, (C 1-6} alkyl) carbonyl or _{C 7-10} aralkyl;
R ¹⁶ is a hydrogen atom, C _1-6 alkyl or C _7-10 aralkyl;
R ¹⁷ is a hydrogen atom or a C _1-6 alkyl. ], A production method comprising the use of the compound represented by) or a salt thereof. The manufacturing method according to claim 1.
A compound represented by the formula (IIC) or (IID) or a salt thereof,
A production method comprising the use of the compound represented by the formula (IV) or a salt thereof. The manufacturing method according to claim 1.
The compound represented by the above formula (III) or a salt thereof, and
A production method comprising the use of the compound represented by the formula (IV) or a salt thereof. The manufacturing method according to any one of claims 1 to 3.
Ring A is C _3-6 cycloalkyl, C _6-10 aryl, pyridyl, benzo [1,3] dioxolyl or thienyl;
Ring B is selected _{from the group consisting of C 6-10} aryl or the following: pyridyl, pyrimidyl, piperidinyl, morpholinyl, thiazolyl, pyrazinyl, pyrazolyl, imidazolyl, pyridazinyl, azindridinyl, indolyl, isoquinolyl, triazolyl, tetrazolyl and dihydropyrimidinyl. A manufacturing method that is a heterocycle. The manufacturing method according to claim 4.
A manufacturing method in which n is 1.