JP2018108988A - Method for producing pyrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a pyrazole derivative.SOLUTION: There is provided the method for producing a pyrazole derivative by using a compound represented by formula (IIC), (IID) or (III) and a compound represented by formula (IV).SELECTED DRAWING: None

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

(In the formula, R ¹ , R ² and R ³ have the same definitions as in Non-Patent Document 16.)
The compound represented by these is known (for example, refer nonpatent literature 16).
Non-Patent Document 16 only discloses a production method for obtaining a pyrazole derivative represented by the formula (A) by reacting phthalimide and lithium acetylide, and there is no description or suggestion of the production method of the present invention. . The compound described in Non-Patent Document 16 has a structure different from that of the pyrazole derivative represented by the formula (I).
In addition, the compounds described in Patent Documents 1 to 9 have a structure different from that of the compound represented by formula (I), and the production method of the present invention is not described.

Makoto Tominaga, “The Journal of Japanese Pharmacology”, 2004, 124, 219-227 McKemy DD. Et al., “Nature”, 2002, 416, 52-58 Broad LM. Et al., "Expert Opin Ther Targets", 2009, 13, p.69-81 Andersson KE. Et al., "BJU Int", 2010, 106, p.1114-1127 Zhang L. et al., “Endocr Relat Cancer”, 2006, 13, p.27-38 Okamoto Y. et al., “Int J Oncol”, 2012, 40, 1431-1440 Su L. et al., “BMC Neurosci”, 2011, 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, pages 68-73 Lei Z. et al., “Neurourol Urodyn”, 2012, doi: 10.1002 / nau.22325 Shibata Y. et al., “Neuroreport”, 2011, Vol. 22, pp. 61-67 Lindstrom S. et al., "Acta Physiol Scand", 1991, 141, p.1-10 Geirsson G. et al., “J Urol”, 1993, 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 gazette International Publication No. 2006/088903 Pamphlet International Publication No. 2004/099164 Pamphlet International Publication No. 2002/000651 Pamphlet JP 2000-256358 A International Publication No. 2004/067002 Pamphlet International Publication No. 2004/018463 Pamphlet International Publication No. 2001/012627 Pamphlet JP 2010-536922 gazette

  An object of the present invention is 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) having a potent TRPM8 inhibitory action or a pharmacologically acceptable salt thereof, and as a result of intensive studies on its production method, the present invention is completed. It came to.

That is, the means for solving the above problems are as follows.
[1] Formula (I):
[Where,
Ring A is C _3-6 cycloalkyl, C _6-10 aryl or heterocycle;
X is independently CR ^4a or a nitrogen atom;
R ¹ and R ² are each independently a hydrogen atom, a halogen atom, hydroxy, amino, hydroxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano, C _1-6 alkylsulfonylamino, imidazolyl, 1,3-dioxolyl or mono (di) C _1-6 alkoxyC _1-6 alkyl;
R ³ is a hydrogen atom, a halogen atom or C _1-6 alkyl;
R ⁴ and R ^{4 a} are each independently a hydrogen atom, a 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 aralkyl OxyC _1-6 alkoxy or 1,3-dioxolyl;
Ring B is C _6-10 aryl or heterocycle;
R ⁵ is a hydrogen atom, C _1-6 alkyl, mono (di) hydroxyC _1-6 alkyl, C _1-6 alkoxy (hydroxy) C _1-6 alkyl, carboxy C _1-6 alkyl or C _1-6 alkoxy 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 is independently a hydrogen atom, a 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 C _1-6 alkyl, or R ⁵ or R ^6a together with ring B is a 6-membered ring or together with R ^7a is a 5-membered Forming a ring;
R ^6b is a hydrogen atom or C _1-6 alkyl;
R ⁸ is a hydrogen atom, a 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, haloC _1-6 alkyl or tetrazolyl;
R ⁹ is hydroxy, C _1-6 alkyl or hydroxypyrrolidinyl;
R ¹⁰ and R ¹¹ are each independently a hydrogen atom, C _1-6 alkyl, hydroxy C _1-6 alkyl, mono (di) C _1-6 alkylamino C _1-6 alkyl, pyrrolidinyl or piperidinyl;
R ¹² , R ¹³ and R ¹⁴ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, NR ¹⁵ R ¹⁶ , R ¹⁵ R ¹⁶ N—C _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, a 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. Or a pharmacologically acceptable salt thereof, comprising:

The following formula:
[Wherein ring A is as defined above;
X ^P is independently CR ^4ap or a nitrogen atom;
R ^1P and R ^2P each independently represent a hydrogen atom, a halogen atom, hydroxy that may be protected with a protecting group, amino that may be protected with a protecting group, or hydroxy that may be protected with a protecting group. C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano, C _1-6 alkylsulfonylamino, 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 C _1-6 alkyl;
R ^4P and R ^4aP each independently represent a hydrogen atom, a halogen atom, an optionally protected 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 optionally protected with a protecting group, hydroxy C _1-6 alkoxy optionally protected with a protecting group, 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;
P is a hydrogen atom or a protecting group. Or a salt thereof, and

Formula (IV):
[Wherein ring B and n are as defined above;
R ^5P is a hydrogen atom, C _1-6 alkyl, mono (di) hydroxy C _1-6 alkyl optionally protected with a protecting group, or C _1-6 alkoxy (hydroxy) optionally protected with a protecting group. C _1-6 alkyl, optionally protected carboxy C _1-6 alkyl 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 binding position);
R ^7aP is independently a hydrogen atom, a fluorine atom, a hydroxy ^optionally protected with a protecting group, a hydroxy C _1-6 alkyl ^optionally protected with a protecting group, a C _1-6 alkyl, C _{1- 6 alkoxy, C 1-6} alkoxy _{C 1-6} alkyl or protected optionally protected amino _{C 1-6} alkyl group;
R ^7bP is independently a hydrogen atom, a fluorine atom or C _1-6 alkyl, or R ^5P or R ^6aP is a ^5- membered ring together with ring B or a 6-membered ring or R ^7aP Forming 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 optionally protected with a protecting group, amino optionally protected with a protecting group, cyano, C _1-6 Alkoxycarbonyl, C _1-6 alkoxy C _1-6 alkoxy, carbamoyl, C _1-6 alkoxy C _1-6 alkyl, optionally protected carboxy, azide, halo C _1-6 alkyl or tetrazolyl ;
R ^9P is hydroxy optionally protected with a protecting group, C _1-6 alkyl or hydroxypyrrolidinyl optionally protected with a protecting group;
R ^10P and R ^11P each independently represent a hydrogen atom, C _1-6 alkyl, a hydroxy C _1-6 alkyl _optionally protected with a protecting group, or a mono (di) optionally protected with a protecting group. C _1-6 alkylamino C _1-6 alkyl, pyrrolidinyl optionally protected with a protecting group or piperidinyl optionally protected with a protecting group;
R ^12P , R ^13P and R ^14P are each independently a hydrogen atom, hydroxy _optionally protected with a protecting group, C _1-6 alkyl, _optionally protected with NR ¹⁵ R ¹⁶ , protected R ¹⁵ R ¹⁶ N—C _1-6 alkyl, C _1-6 alkoxy, optionally protected with a group, mono (di) hydroxy C _1-6 alkyl, carbamoyl, C ₇ optionally protected with a protecting group _-10 aralkyloxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, a 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. ] The manufacturing method characterized by using the compound or its salt represented by this.

[2] The production method according to [1],
A compound represented by the formula (IIC) or (IID) or a salt thereof;
A production method using the compound represented by the formula (IV) or a salt thereof.
[3] The production method according to [1],
A compound represented by the formula (III) or a salt thereof;
A production method using 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 pyridyl, pyrimidyl, piperidinyl, morpholinyl, thiazolyl, pyrazinyl, pyrazolyl, imidazolyl, pyridazinyl, azaindolidinyl, indolyl, isoquinolyl, triazolyl, tetrazolyl and dihydropyrimidinyl The manufacturing method which is a heterocyclic ring.
[5] The production method according to [4], wherein n is 1.
[6] The production method according to [5],
Ring A is phenyl;
X is CR ^4a ;
X ^{P is,} there in the ^{CR 4aP;}
Each R ^4a independently represents a hydrogen atom, a halogen atom, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, haloC _1-6 alkyl, haloC _{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 each independently represents a hydrogen atom, a halogen atom, an optionally protected 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 optionally protected with a protecting group, hydroxy C _1-6 alkoxy optionally protected with a protecting group, 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.

[7] The production method according to [6],
R ⁵ is a hydrogen atom;
The production method, wherein R ^5P is a hydrogen atom.
[8] The production 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:
[Wherein (**) represents a bonding position];
R ^7a is a hydrogen atom, a 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 ;
Whether R ^7b is a hydrogen atom, a fluorine atom or C _1-6 alkyl;
R ^6a together with ring B or R ^7a has the formula:
[Wherein (**) represents a bonding position]
Forming;
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:
[Wherein (**) represents a bonding position];
R ^7aP is a hydrogen atom, a fluorine atom, hydroxy optionally protected with a protecting group, hydroxy optionally protected with a protecting group C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 be protected alkoxy _{C 1-6} alkyl or a protecting group be an amino _{C 1-6} alkyl;
^Whether R ^7bP is a hydrogen atom, a fluorine atom or C _1-6 alkyl;
R ^6aP together with ring B or R ^7aP has the formula:
[Wherein (**) represents a bonding position]
Forming method.

[9] The production method according to [8],
A production process wherein X and ^XP are CH.
[10] The production method according to [9],
R ¹ and R ² are not simultaneously hydrogen atoms;
A production method wherein R ^1P and R ^2P are not simultaneously hydrogen atoms.
[11] The production method according to [10],
R ^6b , R ^7a and R ^7b are hydrogen atoms;
The production method, wherein 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) hydroxyC _1-6 alkyl;
The production method, wherein R ^12P is hydroxy optionally protected with a protecting group or mono (di) hydroxyC _1-6 alkyl optionally protected with a protecting group.
[13] The following formula:
Wherein Ring ^{A, X P, R 1P,} R 2P, R 3P, R 4P, P is as [1]. ]
Or a salt thereof.
[14] The following formula:
[Wherein, ring A, X ^P , R ^1P , R ^2P , R ^3P , R ^4P are as described in [1]. ]
Or a salt thereof.

[15] The following formula:
Wherein Ring ^{A, X P, R 1P,} R 2P, R 3P, R 4P, P is as [1]. ]
Or a salt thereof.
[16] The compound according to any one of [13] to [15],
The 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 each independently represents a hydrogen atom, a halogen atom, an optionally protected 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 optionally protected with a protecting group, hydroxy C _1-6 alkoxy optionally protected with a protecting group, cyano, carbamoyl, A compound or a salt thereof, which is C _1-6 alkoxycarbonyl C _1-6 alkoxy, C _7-10 aralkyloxy, C _7-10 aralkyloxy C _1-6 alkoxy or 1,3-dioxolyl.
[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 a salt thereof, wherein R ^1P and R ^2P are not simultaneously a hydrogen atom.

  The present invention provides, for example, a pyrazole derivative represented by formula (I) or a drug thereof having a strong inhibitory action in an Icilin-induced wet-dog shake inhibitory action 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) produced according to the production method of the present invention or a pharmacologically acceptable salt thereof is a therapeutic or prophylactic agent for a disease or symptom caused by hyperexcitation or disorder of afferent nerve. Useful as.

  Terms used in this specification will be described.

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

“C _1-6 alkyl” means an 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.

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

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

“Fluoro C _1-6 alkyl” means the above C _1-6 alkyl substituted with 1 to 5 fluorine atoms.

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

“Hydroxy C _1-6 alkyl” means the above C _1-6 alkyl substituted with hydroxy. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl and the like.

“Mono (di) hydroxyC _1-6 alkyl” means the above C _1-6 alkyl substituted with 1 or 2 hydroxys. For example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 1,3-dihydroxy And propyl.

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

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

The term “mono (di) C _1-6 alkoxy C _1-6 alkyl” means the above C _1-6 alkyl substituted with 1 or 2 C _1-6 alkoxy. 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” means the above C _1-6 alkoxy substituted by the above C _1-6 alkoxy.

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

“C _7-10 aralkyl” means 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 above C _1-6 alkyl substituted by the above C _7-10 aralkyloxy.

“(C _7-10 aralkyloxy) C _1-6 alkoxy” means the above C _1-6 alkoxy substituted by the above C _7-10 aralkyloxy.

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

“Amino C _1-6 alkyl” means 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. In the case of di-substitution, C _1-6 alkyl may be different from each other.

“C _1-6 alkylsulfonylamino” means a group represented by (C _1-6 alkyl) -SO ₂ NH—. Examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino and the like.

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

“C _1-6 alkoxycarbonyl” means a carbonyl substituted with the above C _1-6 alkoxy. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

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

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

“C _3-6 cycloalkyl” means a monocyclic saturated alicyclic hydrocarbon having 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“C _1-6 alkoxy (hydroxy) C _1-6 alkyl” refers to the above 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.

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

  The phrase “may be protected with a protecting group” means that hydroxy, amino, or carboxy may be protected with a group that is usually used as a protecting group. Such a group may be used. Examples of protecting groups include Theodora W. et al. Greene & Peter G. M.M. Edited by Wuts, "Green's Protective Groups in Organic Synthesis", fourth edition, Wiley-Interscience, 2006 or Peter G. M.M. Protective groups described in Wuts, “Green's Protective Groups in Organic Synthesis”, fifth edition, Wiley-Interscience, 2014 can be mentioned.

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

Compounds represented by formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV) include optical isomers, geometric isomers, tautomers and the like. Such stereoisomers are also included.
In the optical isomers of the compounds represented by formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV), the configuration at each asymmetric carbon atom is R configuration. Or any three-dimensional arrangement of S arrangement may be sufficient. In addition, any optical isomer is included in the present invention, and a mixture of these optical isomers is also included. Furthermore, a racemate consisting of an equal amount of each optical isomer in a mixture of optically active substances is also included in the scope of the present invention.
When the compounds represented by 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 within the scope of the present invention.
In the compounds represented by the formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV), when a geometric isomer exists, the present invention relates to the geometric isomer. Any of these are included.
In the compounds represented by the formulas (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV), when tautomers exist, the present invention Any tautomer is included.
For example, tautomers such as the following formulas (I) and (I ′) can be mentioned.
Moreover, for example, tautomers such as formulas (IIa) and (IIb) are included, and isomers of formulas (IIc) and (IId) in which a protecting group is introduced into the tautomers are also included.
(In the formula, PG represents a protecting group.)
For example, the compound represented by the formula (IIC) or (IID) includes the respective tautomers and isomers (the formula (IIC) includes the formula (IIa) and the formula (IIc), (IID) includes formula (IIb) and formula (IId)).

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

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

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

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

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

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

As another aspect of the compound represented by 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 each independently a hydrogen atom or a halogen atom;
Ring B is phenyl, 2-pyridyl, 2-pyrimidyl, 1,2,3-triazol-2-yl or 1-pyrazolyl;
R ⁵ is a 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 a hydrogen atom or a halogen atom;
R ¹⁰ and R ¹¹ are hydrogen atoms;
R ¹² , R ¹³ and R ¹⁴ are each independently a hydrogen atom, hydroxy, C _1-6 alkoxy, hydroxy C _1-6 alkyl or fluorine atom;
n is 1.

As another aspect of the compound represented by the formula (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 each independently a hydrogen atom or a halogen atom.

As another aspect of the compound represented by the formula (IV),
Ring B is phenyl, 2-pyridyl, 2-pyrimidyl, 1,2,3-triazol-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 each independently a hydrogen atom, hydroxy that may be protected with a protecting group, C _1-6 alkoxy, or hydroxy C _1-6 alkyl that may be protected with a protecting group Or a fluorine atom;
n is 1.

As another aspect of the compound represented by Formula (I),
Ring A is phenyl;
X is CR ^4a ;
R ¹ is a hydrogen atom or a halogen atom;
R ² is a hydrogen atom or a halogen atom;
R ³ is a hydrogen atom or a halogen atom;
R ⁴ and R ^4a are each independently a hydrogen atom, a halogen atom or haloC _1-6 alkoxy;
Ring B is phenyl, 2-pyridyl, 2-pyrimidyl, 2-thiazolyl, 4-thiazolyl, 1-pyrazolyl, 2-imidazolyl or 1,2,3-triazol-2-yl;
R ⁵ is a 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 binding position);
R ^7a is a hydrogen atom, a fluorine atom, hydroxy, C _1-6 alkyl or C _1-6 alkoxy;
R ^7b is a hydrogen atom, a fluorine atom or C _1-6 alkyl;
R ^6b is a hydrogen atom or C _1-6 alkyl;
R ⁸ is a hydrogen atom, a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, cyano or haloC _1-6 alkyl;
R ¹⁰ and R ¹¹ are hydrogen atoms;
R ¹² , R ¹³ and R ¹⁴ are each independently a hydrogen atom, hydroxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl, NR ¹⁵ R ¹⁶ , C _1-6 alkoxy, mono ( Di) 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 aspect of the compound represented by the formula (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 each independently a hydrogen atom, a halogen atom or a haloC _1-6 alkoxy.

As another aspect 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-triazol-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 binding position);
R ^7aP is a hydrogen atom, a fluorine atom, an optionally protected hydroxy, C _1-6 alkyl or C _1-6 alkoxy;
R ^7bP is a hydrogen atom, a fluorine atom or C _1-6 alkyl;
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, cyano or haloC _1-6 alkyl;
R ^10P and R ^11P are hydrogen atoms;
R ^12P , R ^13P and R ^14P are each independently protected with a hydrogen atom, hydroxy optionally protected with a protecting group, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkyl, or a protecting group. NR ¹⁵ R ¹⁶ , C _1-6 alkoxy, which may be substituted, mono (di) hydroxy C _1-6 alkyl, carbamoyl, fluorine atom or fluoro C _1-6 alkyl, which may be protected with a protecting group;
R ¹⁵ and R ¹⁶ are hydrogen atoms;
n is 1.

In another 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 in the above [1].

In 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 in the above [1].

In another 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 other symbols have the same meanings as in the above [1].

In another 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 amino optionally protected with a protecting group or hydroxy C _1-6 alkyl optionally protected with a protecting group, and other symbols have the same meaning as in the above [1]. is there.

Method for Producing Compound Represented by Formula (I) of the Present Invention The compound represented by formula (I) or a pharmacologically acceptable salt thereof is a method described in detail below or a method analogous thereto, or In addition, it can be produced according to a method described in the literature or a method analogous thereto.

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

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

  Compound (1) and compound (2) can be produced according to methods described in the literature or a method analogous thereto, in addition to using commercially available products.

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

(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)

Step 2-1
Compound (7) can be produced by reacting compound (5) with compound (6) in a solvent and then reacting with 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-butoxy potassium, potassium carbonate, cesium carbonate and the like. The reaction temperature is 0 ° C. to solvent reflux temperature, and the reaction time is usually 2 hours to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (5) and compound (2) can be produced according to methods described in the literature or a method analogous thereto, in addition to using commercially available products.

Step 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, and dimethyl sulfoxide. Examples of RaOH include n-propanol and n-butanol. Examples of the base include triethylamine and N, N-diisopropylethylamine. Examples of the palladium catalyst include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0 ) And the like. If necessary, a ligand such as 1,3-bis (diphenylphosphino) propane, 1,1′-bis (diphenylphosphino) ferrocene, bis (adamantan-1-yl) (butyl) phosphine may be added. It can be performed by adding. The reaction temperature is from room temperature to the solvent reflux temperature, and the reaction time is usually from 2 hours to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 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, a mixed solvent thereof and the like. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like. In addition, this process can also use acid hydrolysis and hydrogenolysis as needed, and those methods include Theodora W., et al.
Greene & Peter G. M.M. Examples include a method described in Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.

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

(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), base and compound (10) in the same manner as in Step 2-1.
Compound (10) and compound (9) can be produced according to methods described in the literature or a method analogous thereto, in addition to using commercially available products.

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

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

Step 4-1
When R ^3aP is a fluorine atom, compound ( ^11a ) can be produced by reacting compound (7a) with a fluorinating agent in a solvent. Examples of the solvent used include acetonitrile, acetone, dichloromethane, 1,2-dichloroethane and the like. As the fluorinating agent, N-fluoro-N ′-(chloromethyl) triethylenediammonium (bistetrafluoroborate), N-fluorobenzenesulfonimide, 1-fluoro-2,4,6-trimethylpyridinium tetrafluoro Examples include borate. The reaction temperature is 0 ° C. to the solvent reflux temperature, and the reaction time is usually 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 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 and thionyl chloride. The reaction temperature is 0 ° C. to the solvent reflux temperature, and the reaction time is usually 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

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

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

(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)

Step 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 0 ° C. to the solvent reflux temperature, and the reaction time is usually 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 5-2
Compound (14) can be produced by reacting compound (12) with an alkyl boronic acid or its anhydride in the presence of a base and a palladium catalyst in a solvent. 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 the alkylboronic acid or its anhydride include trimethylboroxine, 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) ferrocenepalladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0 ) And the like. If necessary, a ligand such as 1,3-bis (diphenylphosphino) propane, 1,1′-bis (diphenylphosphino) ferrocene, bis (adamantan-1-yl) (butyl) phosphine may be added. You may carry out by adding. The reaction temperature is 0 ° C. to the solvent reflux temperature, and the reaction time is usually 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

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

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

( ^Wherein R ^6aP , R ^6bP , R ^7aP and R ^7bP are as defined above; ring B 1 is C _6-10 aryl or a heterocycle containing no NH; R ^{8P ′} is hydroxy, amino, carbamoyl; And R ^8P excluding carboxy (R ^8P is as defined above); * is a chiral atom)

Step 6-1
Compound (19) can be produced by reacting compound (17) with compound (16) in the presence of a Lewis acid in a solvent. Examples of the solvent used include tetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, toluene and the like. Examples of Lewis acids include tetraethyl orthotitanate and tetraisopropyl orthotitanate. The reaction temperature is 0 ° C. to the solvent reflux temperature, and the reaction time is usually 1 hour to 3 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (16) and compound (17) can be produced according to methods described in the literature or a method analogous thereto, in addition to using commercially available products.

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

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

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

(In the formula, ring B, R ^6aP , R ^6bP , R ^7aP , R ^7bP , R ^8P and U are as defined above; Q is a protecting group)

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

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) ferrocenepalladium (II) dichloride, 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 solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
Compound (24) can be produced according to a method described in the literature or a method analogous thereto, in addition to using a commercially available product.

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

^Wherein R ^6aP , R ^6bP , R ^7aP , R ^7bP , R ^8P and Q are as defined above; ring B2 is a heterocycle containing NH; ring B3 is a nitrogen-containing heterocycle; Y is a leaving group such as methanesulfonyloxy, p-toluenesulfonyloxy, iodine atom)

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

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

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

(Wherein ring B2, ring ^{B3, R 6aP, R 6bP,} R 7aP, R 7bP and ^{R 8P} is in the same meaning; W is, methanesulfonyloxy, a leaving group such as a p- toluenesulfonyloxy )

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

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

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 azide reagent in a solvent. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene and the like. Examples of the azide reagent include sodium azide. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

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 and platinum carbon. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, solvent, reaction temperature and the like. In addition, compound (21d) can be produced by reacting compound (32) in a solvent with an organic phosphorus compound and water. Examples of the solvent used include tetrahydrofuran and 1,4-dioxane. Examples of the organic phosphorus compound include triphenylphosphine and tri (n-butyl) phosphine. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 1 hour to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

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

(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)

Step 10-1
The compound represented by formula (I) can be produced by reacting compound (33) with a condensing agent and compound (34) in a solvent in the presence or absence of a base. Examples of the solvent used include N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, methanol, water and the like. Examples of the base include triethylamine, N, N-diisopropylethylamine, pyridine and the like. 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-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4 6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, propylphosphonic anhydride and the like.
If necessary, an activator such as 1-hydroxybenzotriazole or 1-hydroxyazabenzotriazole may be added. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 7 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.
Compound (33) and compound (34) may each be a commercially available product, or can be produced according to methods described in the literature or methods analogous thereto.

Step 10-2
Compound (33) is reacted in the presence of a base and a condensing agent in a solvent to produce compound (35), and then reacted with compound (34) to produce a compound represented by 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-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 4- (4 6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride, propylphosphonic anhydride and the like. If necessary, an activator such as 1-hydroxybenzotriazole or 1-hydroxyazabenzotriazole may be added. The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 7 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

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

(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 ) _{carbonyloxy, C 1-6 alkoxycarbonyloxy, C 1-6} alkylsulfonyloxy or halogen atom, which may have a substituent selected from the group consisting of nitro and _{C 1-6} alkyl _{C, 6-} Leaving group such as ₁₀ arylsulfonyloxy.)

Step 11-1
Compound (Ia) can be produced from compound (33a) by the same method as in Step 10-1.
Compound (33a) may be a commercially available product, or can be produced according to a method described in the literature or a method analogous thereto.

Step 11-2
Compound (33a) is reacted with a chlorinating agent or a carboxy group activator in a solvent to produce compound (36), and then reacted with compound (34) in the presence or absence of a base to give compound ( Ia) can be produced. Examples of the solvent used include dichloromethane and 1,2-dichloroethane. 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 compound (36) from compound (33a), it is preferably reacted with a halogenating agent in a solvent, and more preferably reacted with a chlorinating agent such as thionyl chloride or oxalyl chloride.
The reaction temperature is from room temperature to solvent reflux temperature, and the reaction time is usually from 30 minutes to 3 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

  The scheme shown above is an illustration of a method for producing a compound represented by formula (I) or a production intermediate thereof. These can be variously modified into schemes that can be easily understood by those skilled in the art.

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

  Compounds of formula (I), (IIC), (IID), (IICC), (IIDC), (III) and (IV) may be isolated, as required, by those skilled in the art. -It can be isolated and purified by means of purification such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography and the like.

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

  These pharmaceutical compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents. When a compound represented by formula (I) or a pharmacologically acceptable salt thereof and a drug other than a TRPM8 inhibitor are used in combination, the respective active ingredients may be used simultaneously or separately. It can manufacture by formulating similarly.

  The compound represented by the formula (I) or a pharmacologically acceptable salt thereof exhibits a strong suppressive action based on TRPM8 inhibition in an Icilin-induced wet-dog shake inhibitory action confirmation test. Therefore, a medicament containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient treats or prevents a disease or symptom caused by TRPM8 activation due to TRPM8 inhibitory action. Can be used as a medicine.

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

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

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

  Examples of “circulatory disturbance” include cold rhinitis and Raynaud's disease.

  “Pain” includes toothache, oxaliplatin-induced peripheral neuropathy, migraine, postoperative pain, cold allodynia, anticancer drug-induced peripheral neuropathy, 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 be used in appropriate combination with at least one drug other than the TRPM8 inhibitor.

Examples of the drug that can be used in combination with the compound represented by the formula (I) or a pharmacologically acceptable salt thereof include opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), barbiturates, sedatives 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 antagonist), muscarinic receptor antagonist, COX-2 selective inhibitor, coal tar analgesic, neuroleptic, TRPV1 agonist, TRPV1 inhibitor, β-adrenergic receptor blocker, local anesthetic, corticosteroid, 5-HT receptor agonist, 5-HT _2A receptor antagonist, cholinergic analgesic, PDE5 inhibitor, PDE9 inhibitor, α2δ Riga And cannabinoids, metabotropic glutamate receptor 1 antagonist (mGluR1 antagonist), metabotropic glutamate receptor 5 antagonist (mGluR5 antagonist), serotonin reuptake inhibitor, noradrenaline reuptake inhibitor, serotonin / noradrenaline reuptake inhibitor Drug, inducible nitric oxide synthase inhibitor (iNOS inhibitor), acetylcholinesterase inhibitor (AChE inhibitor), EP4 antagonist, leukotriene B4 antagonist, 5-lipoxygenase inhibitor, sodium channel blocker, 5-HT3 antagonist Drugs, drugs for chemotherapy, EP1 antagonists, β3 adrenergic receptor agonists, TRPA1 inhibitors, TRPV3 inhibitors, TRPV4 inhibitors, T-type calcium channel inhibitors, ASIC inhibitors, P2X inhibitors, Trk inhibitors , FAAH obstruction Medicine, botulinum toxin, 5α reductase inhibitor, anti-NGF antibody, NGF regulator, IgE production inhibitor, histamine H2 inhibitor, bladder mucosa protective agent, NOS activity regulator, bladder muscle relaxant, GABA reuptake inhibitor, GABA receptor modulator, GABA aminotransferase inhibitor and the like.

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

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

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

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

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

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

When a compound represented by formula (I) or a pharmacologically acceptable salt thereof and one or more of the above drugs are administered in combination, the following 1) to 5):
1) Simultaneous administration with combination drug,
2) As separate formulations, co-administration by the same route of administration,
3) As separate formulations, co-administration by different routes of administration,
Any method of administration, including 4) administration at different times by the same route of administration as separate formulations, and 5) administration at different times by different routes of administration as separate formulations is included. In addition, when administered at different times as separate preparations such as 4) or 5), the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with the above-mentioned There is no particular limitation on the order of administration with drugs.

  In addition, the compound represented by the formula (I) or a pharmacologically acceptable salt thereof can be added in combination with one or more kinds of the above drugs as appropriate to prevent or treat the above diseases. An advantageous effect more than the effect can be obtained. Or, similarly, reduce the amount used compared to when administered alone, reduce the side effects of drugs other than the combined TRPM8 inhibitor, or avoid the side effects of drugs other than the combined TRPM8 inhibitor Or it can be reduced.

  The pharmaceutical composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal) (Internal, subcutaneous, intramuscular, transdermal, etc.).

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

  EXAMPLES Hereinafter, although an Example, a reference example, and a test example demonstrate this invention further in detail, the scope of the present invention is not limited to these.

Of the symbols used in each reference example, each example, and each table, Ref. Ex. Are reference example numbers, Ex. No. Is an example number, Str. Means chemical structural formula, PD means spectral data, and PC means purification conditions. * Means a chiral atom. Rel. Means relative configuration. ¹ H-NMR means hydrogen nuclear magnetic resonance spectrum, CDCl ₃ means chloroform-d, DM
_{SO-d 6} dimethylsulfoxide _-d 6, _CD 3 OD means methanol -d _4. MS means mass spectrometry and ESI-MS means electrospray ionization mass spectrometry. RT means retention time of high performance liquid column chromatography. SiO2 means silica gel column chromatography, and APS means aminopropyl silica gel column chromatography. Low polarity or LP means a compound that elutes first when a mixture of stereoisomers is separated and purified using normal phase column chromatography. High polarity or HP means a compound that elutes later. . 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.
In addition, as above-mentioned, this invention also includes the tautomer of the compound represented by a formula (I). Therefore, the compound names in the Reference Examples and Examples and the chemical structural formulas in the tables are not limited to those compound names and formulas in the tables, and also include tautomers thereof.

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

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

Reference Example 1-1-1
2- [5- (3-Fluorophenyl) -1H-pyrazol-3-yl] benzoic acid Journal of Organic Chemistry, 77 (8), 3887-3906; according to the method described in 2012 or a method analogous thereto, A compound was obtained. The structural formula, spectral data and purification conditions are shown in Table 3.

Reference Example 1-1-2 to 1-1-16
Reference Examples 1-1-2 to 1-1-16 were synthesized in the same manner as Reference Example 1-1-1 using the corresponding starting materials. 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 To a mixed solution of 4-bromo-1-fluoro-3-methoxybenzene (0.513 g) and trimethylsilylacetylene (0.737 g) in tetrahydrofuran (5 mL) was added 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 ammonium chloride solution 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 evaporating the solvent under reduced pressure was dissolved in tetrahydrofuran (5 mL), and tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 5 mL) was added under ice cooling, followed by stirring 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain 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 Reference Example 1-2-1 using the corresponding starting 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-pyrazol-3-yl] benzamide and 3-bromo-2- [5- (4-fluorophenyl) -2 -(Methoxymethyl) -2H-pyrazol-3-yl] benzamide mixture To a solution of 2,6-dibromobenzaldehyde (1.6 g) in toluene (40 mL) was added p-toluenesulfonylhydrazine (1.13 g). Stir for 1.5 hours. After the reaction mixture was cooled to room temperature, sodium ethoxide (1.65 g) was added and stirred for 10 minutes. To this mixture, 1-ethynyl-4-fluorobenzene (1.09 g) was added and stirred at 110 degrees 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 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 the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3- (2,6-dibromophenyl) -5- (4-fluorophenyl). ) -1- (methoxymethyl) -1H-pyrazole and 3- (2,6-dibromophenyl) -5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazole (0.30 g) Got. The product (0.30 g) was dissolved in tetrahydrofuran (3 mL). An n-butyllithium n-hexane solution (2.6 mol / L, 0.51 mL) was added dropwise to the mixture at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. A large excess of dry ice was added to the mixture, and then the temperature was raised from −78 ° C. to room temperature and 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-pyrazol-3-yl] benzoic acid and 3-bromo-2- [5. A mixture (0.27 g) of-(4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid was obtained. To the product (0.27 g) was added N, N-dimethylformamide (2 mL). To this mixture was added 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 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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-pyrazol-3-yl) benzoic acid 2-iodo-3-methylbenzoic acid ethyl ester (2.93 g), trimethylsilylacetylene (1.19 g), bis (triphenyl) A mixture of phosphine) 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 (elution solvent: ethyl acetate / n-hexane) to obtain 3-methyl-2- (trimethylsilylethynyl) benzoic acid ethyl ester (2.47 g). To a solution of the product (2.47 g) in methanol (25 mL) was added potassium carbonate (2.62 g) at room temperature. The mixture was stirred overnight and poured into water. The crude product was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane). The resulting crude product was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain 2-ethynyl-3-methylbenzoic acid methyl ester (2.20 g). P-Toluenesulfonylhydrazine (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 degrees for 1.5 hours. The mixture was cooled to room temperature, sodium ethoxide (716 mg) was added and stirred for 15 minutes. To this mixture was added a solution of 2-ethynyl-3-methylbenzoic acid methyl ester (2.2 g) in toluene (12 mL), and the mixture was stirred at 90 ° 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 (eluent: 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 To a solution of 2-bromo-6-hydroxybenzaldehyde (1.47 g) in N, N-dimethylformamide (15 mL), sodium hydride (60% oil dispersion, 380 mg) was added 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 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 p-Toluenesulfonylhydrazine was added to a solution of 2-bromo-6-fluorobenzaldehyde (4.439 g) in toluene (96 mL). (4.072 g) was added and stirred at 110 degrees for 3 hours. This 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 the mixture was 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain 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
Reference Examples 1-6-2 to 1-6-42 were synthesized in the same manner as Reference Example 1-6-1 using the corresponding starting materials. The structural formulas, 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 To a solution of thiophene-2-carbaldehyde (207 mg) in toluene (12 mL) was added p-toluenesulfonylhydrazine (343 mg). The mixture was stirred at 50 degrees for 1.5 hours and cooled to room temperature. Sodium ethoxide (313 mg) was added to the mixture and stirred for 15 minutes. To this mixture was added 1-bromo-2-ethynylbenzene (1.00 g) in toluene (8 mL), and the mixture was stirred at 90 ° 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 (eluent: 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 Examples 1-7-2 to 1-7-4
Reference Examples 1-7-2 to 1-7-4 were synthesized in the same manner as Reference Example 1-7-1 using the corresponding starting materials. 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- To a solution of bromophenyl) -5-phenyl-1H-pyrazole (272 mg) in N, N-dimethylformamide (4 mL) was added sodium hydride (60% oil dispersion, 43 mg) at 0 degrees and the mixture was stirred for 10 minutes. did. Chloromethyl methyl ether (81 mg) was added to the mixture and stirred at room temperature overnight. 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 (eluent: 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 Examples 1-8-2 to 1-8-6
Reference Examples 1-8-2 to 1-8-6 were synthesized in the same manner as in Reference Example 1-8-1 using the corresponding starting materials. The structural formulas, spectral data, and purification conditions are shown in Tables 12 to 13.

Reference Example 1-9-1
Of 2- [1- (methoxymethyl) -5-phenyl-1H-pyrazol-3-yl] benzoic acid and 2- [2- (methoxymethyl) -5-phenyl-2H-pyrazol-3-yl] benzoic acid Mixtures 3- (2-bromophenyl) -1-methoxymethyl-5-phenyl-1H-pyrazole and 3- (2-bromophenyl) -2-methoxymethyl-5-phenyl-2H-pyrazole (1
40 mg) n-propanol (2 mL) and N-methylpyrrolidone (1 mL) were added. To this mixture was added 1,1′-bis (diphenylphosphino) ferrocene (23 mg), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (34 mg) and triethylamine (120 mg). It was. The mixture was stirred overnight at 100 degrees under a carbon monoxide atmosphere. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 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-pyrazol-3-yl] benzoic acid propyl ester was obtained. To a mixture of the product (90 mg) and methanol (2 mL), an aqueous sodium hydroxide solution (2 mol / L, 0.5 mL) was added, and the mixture was stirred at 60 degrees for 2.5 hours. After the reaction mixture was cooled 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 distilled off under reduced pressure to obtain the title compound (45 mg). The structural formula, spectral data and purification conditions are shown in Table 14.

Reference Examples 1-9-2 to 1-9-3
Reference Examples 1-9-2 to 1-9-3 were synthesized in the same manner as Reference Example 1-9-1 using the corresponding starting 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-pyrazol-3-yl} benzoic acid and 2- {5- [4- (imidazol-1-yl) phenyl ] -2-Methoxymethyl-2H-pyrazol-3-yl} benzoic acid mixture 3- (2-Bromophenyl) -5- [4- (imidazol-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) was added to dimethylsulfoxide (3 mL) and n-butyl alcohol. Dissolved in (2 mL) mixture. To this mixture, 1,3-bis (diphenylphosphino) propane (25 mg) and N, N-diisopropylethylamine (392 mg) were added and replaced with argon. To this mixture was added palladium (II) acetate (14 mg), and the mixture was stirred overnight at 110 ° C. in 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, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- {5- [4- (imidazol-1-yl) phenyl] -1-methoxymethyl-1H-pyrazole. -3-yl} benzoic acid butyl ester and 2- {5- [4- (imidazol-1-yl) phenyl] -2-methoxymethyl-2H-pyrazol-3-yl} benzoic acid butyl ester mixture (198 mg) Got. The product (198 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) -methanol (1 mL) -water (1 mL). To this mixture was added lithium hydroxide monohydrate (160 mg), 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 obtain 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-pyrazol-3-yl] benzoic acid 3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) ) -1H-pyrazole (0.30 g) in acetonitrile (3 mL) was added Selectfluor (registered trademark) (0.38 g) and stirred overnight at 80 degrees. 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3- (2-bromo-6-fluorophenyl) -4-fluoro-5- (4-Fluorophenyl) -1H-pyrazole (0.22 g) was obtained. To a mixture of product (0.22 g), n-propanol (3 mL) and N-methylpyrrolidone (1 mL) was added triethylamine (0.19 g), 1,1′-bis (diphenylphosphino) ferrocene (0.035 g). Then, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (0.051 g) was added, and the mixture was stirred at 100 ° C. for 5 hours in a carbon monoxide atmosphere. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl). -1H-pyrazol-3-yl] benzoic acid propyl ester (0.113 g) was obtained. A sodium hydroxide aqueous 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 degrees for 1.5 hours. After the reaction mixture was cooled 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 Example 1-11-2 to 1-11-4
Reference Examples 1-11-2 to 1-11-4 were synthesized in the same manner as Reference Example 1-11-1 using the corresponding starting materials. The structural formula, spectrum data, and purification conditions are shown in Table 16.

Reference Example 1-12-1
3-Fluoro-2- (5-phenyl-1H-pyrazol-3-yl) benzoic acid 3- (2-Bromo-6-fluorophenyl) -5-phenyl-1H-pyrazole (150 mg) in n-propanol (3 mL) ) To the suspension were added dimethyl sulfoxide (1 mL), triethylamine (72 mg), 1,3-bis (diphenylphosphino) propane (20 mg) and palladium (II) acetate (11 mg), and 100 ° C. in a carbon monoxide atmosphere. At rt overnight. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- (5-phenyl-1H-pyrazole-3- Yl) benzoic acid propyl ester (120 mg) was obtained. An 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. To the reaction mixture, hydrochloric acid (2 mol / L, 800 μL) was added, 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 obtain the title compound (86 mg). The structural formula, spectral data and purification conditions are shown in Table 17.

Reference Examples 1-12-2 to 1-12-6
Reference Examples 1-12-2 to 1-12-6 were synthesized in the same manner as Reference Example 1-12-1 using the corresponding starting materials. 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-pyrazol-3-yl] benzoic acid 3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) -1H- To a suspension of pyrazole (1.163 g) in n-propanol (22 mL) was added N-methylpyrrolidone (7.5 mL), triethylamine (1.053 g), 1,1′-bis (diphenylphosphino) ferrocene (0.192 g). ) And 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (0.284 g) were added, and the mixture was stirred at 100 ° C. for 10 hours in a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature, hydrochloric acid (1 mol / L) was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole. -3-yl] 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. To the reaction mixture, hydrochloric acid (1 mol / L) was added 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 1-1-3-2 to 1-13-17
Reference Examples 1-1-2 to 1-13-17 were synthesized in the same manner as Reference Example 1-13-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 18 to Table 19.

Reference Example 1-14-1
2- (4-Chloro-1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) benzoic acid and 2- (4-chloro-2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) ) Mixture of benzoic acid Mixture 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, 1,3-bis (diphenylphosphino) propane (240 mg) and N, N-diisopropylethylamine (3.77 g) were added and replaced with argon. To this mixture was added palladium (II) acetate (130 mg), and the mixture was stirred overnight at 110 ° C. in 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, and 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 (elution solvent: ethyl acetate / n-hexane) to give 2- (1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) benzoic acid butyl ester and 2- ( A mixture (1.52 g) of 2-methoxymethyl-5-phenyl-2H-pyrazol-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 stirred overnight. The mixture was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give butyl 2- (4-chloro-1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) benzoate. A mixture (240 mg) of ester and 2- (4-chloro-2-methoxymethyl-5-phenyl-2H-pyrazol-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). To this mixture was added lithium hydroxide monohydrate (168 mg), 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 obtain the title compound (188 mg). The structural formula, spectral data, and purification conditions are shown in Table 20.

Reference Example 1-14-2
Reference Example 1-14-2 was synthesized in the same manner as in Reference Example 1-14-1 using the corresponding starting materials. 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-pyrazol-3-yl) benzoic acid butyl ester and 2- (4-bromo-2-methoxymethyl-5-phenyl-2H-pyrazole-3) -Yl) A mixture of butyl benzoate 3- (2-bromophenyl) -1-methoxymethyl-5-phenyl-1H-pyrazole and 3- (2-bromophenyl) -2-methoxymethyl-5-phenyl-2H -A mixture of pyrazole (2.0 g) was dissolved in a mixture of dimethyl sulfoxide (30 mL) and n-butyl alcohol (20 mL). To this mixture, 1,3-bis (diphenylphosphino) propane (240 mg) and N, N-diisopropylethylamine (3.77 g) were added and replaced with argon. To this mixture was added palladium (II) acetate (130 mg), and the mixture was stirred overnight at 110 ° C. in 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, and 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 (elution solvent: ethyl acetate / n-hexane) to give 2- (1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) benzoic acid butyl ester and 2- ( A mixture (1.52 g) of 2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) benzoic acid butyl ester was obtained. The product (1.22 g) was dissolved in dichloromethane (20 mL). To this mixture was added N-bromosuccinimide (715 mg) at room temperature and stirred overnight. The mixture was purified by silica gel column chromatography (eluent: 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
Reference Example 1-15-2 was synthesized in the same manner as Reference Example 1-15-1 using the corresponding starting materials. 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-pyrazol-3-yl) benzoic acid and 2- (2-methoxymethyl-4-methyl-5-phenyl-2H-pyrazol-3-yl) ) Mixture of benzoic acid 2- (4-Bromo-1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) benzoic acid butyl ester and 2- (4-bromo-2-methoxymethyl-5-phenyl-) A mixture of 2H-pyrazol-3-yl) benzoic acid butyl ester (109 mg), 2,4,6-trimethylboroxine (62 mg), potassium carbonate (170 mg) was added to N, N-dimethylformamide (3 mL). The reaction system was replaced with argon, and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (20 mg) was added to the mixture, followed by stirring 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 was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- (1-methoxymethyl-4-methyl-5-phenyl-1H-pyrazol-3-yl) benzoic acid butyl ester. And a mixture (93 mg) of 2- (2-methoxymethyl-4-methyl-5-phenyl-2H-pyrazol-3-yl) benzoic acid butyl ester. 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 obtain the title compound (79 mg). The structural formula, spectral data and purification conditions are shown in Table 21.

Reference Example 1-16-2
Reference Example 1-16-2 was synthesized in the same manner as Reference Example 1-16-1 using the corresponding starting materials. 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-pyrazol-3-yl) benzoic acid and 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazol-3-yl) ) Mixture of benzoic acid 2- (4-Bromo-1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) benzoic acid butyl ester and 2- (4-bromo-2-methoxymethyl-5-phenyl-) A mixture of 2H-pyrazol-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 was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- (1-methoxymethyl-5-phenyl-4-vinyl-1H-pyrazol-3-yl) benzoic acid butyl ester. And 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazol-3-yl) benzoic acid butyl ester (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). To this mixture was added lithium hydroxide monohydrate (303 mg), and the mixture was stirred at 50 ° C. overnight. Hydrochloric acid (2 mol / L, 3.61 mL) was added to the 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 obtain 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-one 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole-3 -Il] benzoic acid (0.20 g) in dichloromethane (2 mL) in N, N-diisopropylethylamine (0.30 g) and T3P® N, N-dimethylformamide solution (1.6 mol / L, 0.79 mL) was added, and the mixture was stirred at room temperature for 0.5 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 solvent was distilled off under reduced pressure to obtain the title compound (0.19 g). The structural formula, spectral data and purification conditions are shown in Table 22.

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

Reference Example 1-19-1
3-hydroxy-2- (2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 3- (2-benzyloxy-6- 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). To this mixture was added 1,3-bis (diphenylphosphino) propane (302 mg), N, N-diisopropylethylamine (1.41 g) and 2- (
Pyridin-2-yl) ethylamine (1.33 g) was added and replaced with argon. To this mixture was added palladium (II) acetate (164 mg), and the mixture was stirred overnight at 110 ° C. in 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, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give 3-benzyloxy-2- (1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) -N- [2 -(Pyridin-2-yl) ethyl] benzamide (393 mg) and 3-benzyloxy-2- (2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) -N- [2- (pyridine-2 -Yl) ethyl] benzamide (736 mg) was obtained. To a solution of the product (736 mg) in tetrahydrofuran (20 mL) was added 10% palladium on carbon (50% wet, 140 mg), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. To this mixture was added 10% palladium carbon (50% wet, 140 mg), and the mixture was stirred at 70 degrees 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 (eluent: 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-pyrazol-3-yl] benzoic acid and 3-cyano-2- [5- (4-fluorophenyl)- 2- (Methoxymethyl) -2H-pyrazol-3-yl] benzoic acid mixture 3-bromo-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] A mixture of benzamide and 3-bromo-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzamide (0.11 g) was dissolved in ethyl acetate (1 mL). . To this mixture was added T3P (registered trademark) ethyl acetate solution (1.7 mol / L, 1 mL), and the mixture was stirred with 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 (elution solvent: ethyl acetate / n-hexane) to give 3-bromo-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole-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. Product (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 carbon monoxide atmosphere. After the reaction mixture was cooled 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-cyano-2- [5- (4-fluorophenyl) -1- ( Methoxymethyl) -1H-pyrazol-3-yl] benzoic acid propyl ester and 3-cyano-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid A mixture of propyl esters was obtained. Methanol (1 mL) and aqueous sodium hydroxide (2 mol / L, 470 μL) were added to the product, and the mixture was stirred at 60 degrees 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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-pyrazol-3-yl] -3-[(methoxymethoxy) methyl] benzoic acid and 2- [5- (4-fluorophenyl) ) -2- (Methoxymethyl) -2H-pyrazol-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 to tetrahydrofuran (145 mg). 3 mL). An n-butyllithium n-hexane solution (2.6 mol / L, 0.25 mL) was added dropwise to the mixture at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. N, N-dimethylformamide (40 μL) was added to the mixture, and the mixture was stirred at −78 ° C. for 30 minutes, and then warmed 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 hr. 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane), and {3-bromo-2- [5- (4-fluorophenyl) -1- (methoxy Methyl) -1H-pyrazol-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). To this mixture was added sodium hydride (60% oil dispersion, 5 mg) and chloromethyl methyl ether (17 mg) under ice cooling. The mixture was stirred at 60 degrees for 3 hours. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 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 (22 mg) of (methoxymethyl) -2H-pyrazole was obtained. To the product (22 mg) was added n-propanol (3 mL) and N-methylpyrrolidone (1 mL). To this mixture was added triethylamine (15 mg), 1,1′-bis (diphenylphosphino) ferrocene (4 mg) and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (6 mg), The mixture was stirred at 100 ° C. for 5 hours in a carbon monoxide atmosphere. After the reaction mixture was cooled 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- [5- (4-fluorophenyl) -1- (methoxymethyl)- 1H-pyrazol-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 distilled off under reduced pressure to obtain 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-dioxolan-2-yl) benzaldehyde To a solution of 2-bromo-4-formylbenzoic acid methyl ester (1.867 g) in toluene (50 mL) was added ethylene glycol (4.767 g) and p. -Toluenesulfonic acid monohydrate (
0.146 g) was added, and the mixture was heated to reflux at 150 degrees for 18 hours. After the reaction mixture was cooled to room temperature, a 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 (elution solvent: ethyl acetate / n-hexane) to give 2-bromo-4- (1,3-dioxolan-2-yl) benzoic acid. The methyl ester (1.792 g) was obtained. Tetrahydrofuran of 2-bromo-4- (1,3-dioxolan-2-yl) benzoic acid methyl ester (1.446 g) in a tetrahydrofuran (9 mL) suspension of lithium aluminum hydride (0.286 g) under ice-cooling (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 obtain [2-bromo-4- (1,3-dioxolan-2-yl) phenyl] methanol (1.196 g). To a solution of the product (1.196 g) in dichloromethane (30 mL) was added iodobenzene diacetate (1.634 g) and AZADOL (registered trademark) (0.070 g) under ice cooling, and the mixture was stirred at room temperature overnight. 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain 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-pyrazol-3-yl] benzoic acid and 2- [5- (4-fluorophenyl) -2- (methoxy) (Methyl) -4-methyl-2H-pyrazol-3-yl] benzoic acid mixture 3- (2-bromophenyl) -5- (4-fluorophenyl) -1H-pyrazole (0.6 g) of n-propanol ( 12 mL) suspension with N-methylpyrrolidone (4 mL), triethylamine (0.574 g), 1,1′-bis (diphenylphosphino) ferrocene (0.105 g) and 1,1′-bis (diphenylphosphino) Ferrocene palladium (II) dichloride dichloromethane adduct (0.154 g) was added, and the mixture was stirred at 100 ° C. for 10 hours in 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 (elution solvent: ethyl acetate / n-hexane) to give 2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl. Obtained benzoic acid propyl ester (0.545 g). 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- [5- (4-fluorophenyl) -1- (methoxymethyl)- 1H-pyrazol-3-yl] benzoic acid propyl ester and 2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid propyl ester (0.320 g ) Dichloromethane (8 mL) was added to the product (0.320 g). N-bromosuccinimide (0.155 g) was added to the mixture and stirred overnight at room temperature. The residue obtained by evaporating the reaction mixture under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- [4-bromo-5- (4-fluorophenyl) -1- (Methoxymethyl) -1H-pyrazol-3-yl] benzoic acid propyl ester and 2- [4-bromo-5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid A mixture of acid propyl esters (0.388 g) was obtained. The product (0.200 g) was dissolved in N, N-dimethylformamide (4 mL). To this mixture was added potassium carbonate (0.309 g), trimethylboroxine (0.112 g) and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (0.183 g) at 110 ° C. For 3 hours. The reaction mixture was diluted with ethyl acetate and passed through a celite pad. The filtrate was washed with water and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- [5- (4-fluorophenyl) -1- (methoxy Methyl) -4-methyl-1H-pyrazol-3-yl] benzoic acid propyl ester and 2- [5- (4-fluorophenyl) -2- (methoxymethyl) -4-methyl-2H-pyrazol-3-yl A mixture of propyl benzoate (0.131 g) was obtained. Methanol (1 mL) and aqueous sodium hydroxide (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-pyrazol-3-yl] benzoic acid and 2- [5- (4-fluorophenyl) -2- (methoxy) Methyl) -4-chloro-2H-pyrazol-3-yl] benzoic acid mixture 2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzoic acid propyl ester And 2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid propyl ester (0.214 g) were dissolved in dichloromethane (5 mL). To this mixture was added sulfuryl chloride (0.090 g), 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- [4-chloro-5- (4-fluorophenyl) -1- ( Methoxymethyl) -1H-pyrazol-3-yl] benzoic acid propyl ester and 2- [4-chloro-5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid A mixture of propyl esters (0.174 g) was obtained. Methanol (2 mL) and aqueous sodium hydroxide (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-pyrazol-3-yl) pyridine-2-carboxylic acid 2-bromo-3- (1-methoxymethyl-5-phenyl-1H-pyrazol-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 dimethyl sulfoxide (18 mL) and n-butyl alcohol (6 mL). To this mixture, 1,3-bis (diphenylphosphino) propane (193 mg) and N, N-diisopropylethylamine (3.02 g) were added and replaced with argon. To this mixture was added palladium (II) acetate (104 mg), and the mixture was stirred overnight at 110 ° C. in 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, and 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 (elution solvent: ethyl acetate / n-hexane) to give 3- (1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) pyridine-2-carboxylic acid butyl ester And 3- (2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) pyridine-2-carboxylic acid butyl ester (558 mg) was obtained. The product (558 mg) was dissolved in ethanol (5 mL). To this mixture was added hydrogen chloride ethyl acetate solution (4 mol / L, 10 mL). The mixture was stirred at 60 degrees for 2 hours and poured into saturated aqueous sodium bicarbonate solution. 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 to give 3- (5-phenyl-1H-pyrazol-3-yl) pyridine-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 degrees overnight. To this mixture was added hydrochloric acid (2 mol / L, 6.53 mL). 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-pyrazol-3-yl] benzoic acid and 3-fluoro-2- [4-fluoro-5 -(4-Fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid mixture 3- (2-bromo-6-fluorophenyl) -5- (4-fluorophenyl) -1 To 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. To this mixture was added triethylamine (0.313 g), 1,1′-bis (diphenylphosphino) ferrocene (0.057 g) and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (0 0.085 g) was added, and the mixture was stirred at 100 ° C. for 10 hours in a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature, hydrochloric acid (1 mol / L) was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- [5- (4-fluorophenyl) -1- ( Methoxymethyl) -1H-pyrazol-3-yl] benzoic acid propyl ester and 3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-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 degrees overnight. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogen carbonate solution, and the crude product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzoic acid propyl ester and 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl) -2- (methoxymethyl) -2H- A mixture (0.140 g) of pyrazol-3-yl] benzoic acid propyl ester was obtained. The product (0.140 g) was dissolved in methanol (2.4 mL). To this mixture was added an aqueous sodium hydroxide solution (2 mol / L, 1 mL), 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-pyrazol-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 degrees for 1.5 hours. . After the reaction mixture was cooled to 0 degree, 28% aqueous ammonia (20 mL), water (20 mL) and ethyl acetate / n-hexane (10/1) were added and stirred for 30 minutes. The mixture was partitioned with water and ethyl acetate / n-hexane (10/1). The aqueous layer was extracted with ethyl acetate / n-hexane (10/1) three times. 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 distilled off under reduced pressure to obtain 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 To the (8 mL) solution was added carbonyldiimidazole (609 mg) at room temperature and the mixture was stirred for 30 minutes. 28% aqueous ammonia (4 mL) was added to the reaction mixture, stirred for 1 hour, and 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 (elution solvent: ethyl acetate / methanol). This crude product was suspended in ethyl acetate, and insoluble matter was collected by filtration to obtain (R) -2-tert-butoxycarbonylamino-3- (pyridin-2-yl) propionamide (177 mg). A hydrogen chloride ethyl acetate solution (4 mol / L, 3 mL) was added to a suspension of the 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 removed by decantation. 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
Reference Example 2-1-2 was synthesized in the same manner as Reference Example 2-1-1 using the corresponding starting materials. 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
To a suspension of (2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyridin-2-yl) propionic acid (0.10 g) in N, N-dimethylformamide (1 mL) was added 1-hydroxybenzo. Add triazole monohydrate (0.086 g), methylamine tetrahydrofuran solution (2 mol / L, 0.9 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.11 g) at room temperature. For 2 days. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane), and N-[(1R) -1- (methylcarbamoyl) -2- (pyridin-2-yl) ethyl] carbamic acid Tert-butyl ester (0.050 g) was obtained. To a solution of the product (0.050 g) in methanol (2 mL) was added a hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) at room temperature, and the mixture was stirred at room temperature overnight. 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 in the same manner as Reference Example 2-2-1 using the corresponding starting 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 tetrahydrofuran (0.5 mL) solution of phthalimide (0.065 g), triphenylphosphine (0.16 g) and azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 270 μL) were added, and the mixture was stirred at room temperature for 1 hour. Stir. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -1- (1,3-dioxo-2,3 -Dihydro-1H-isoindol-2-yl) -3-phenylpropan-2-yl] carbamic acid tert-butyl ester (0.115 g) was obtained. Hydrogen chloride 1,4-dioxane solution (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 at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.085 g). The structural formula, spectral data and purification conditions are shown in Table 25.

Reference Example 2-3-2 to 2-3-3
Reference Examples 2-3-2 to 2-3-3 were synthesized in the same manner as Reference Example 2-3-1 using the corresponding starting materials. 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. Triethylamine (0.065 g) and diphenylphosphoryl azide (0.34 g) were added to a solution of 254 g) in tert-butyl alcohol (3 mL), 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 (elution solvent: ethyl acetate / n-hexane), and N- (6- {2-[(tert-butoxycarbonyl) amino] ethyl} Pyridin-2-yl) carbamic acid tert-butyl ester (0.30 g) was obtained. Hydrogen chloride 1,4-dioxane solution (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
3- (tert-Butyldimethylsilyl) oxy-2-phenylpropylamine To a solution of 2-phenylpropane-1,3-diol (556 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% oil dispersion, 153 mg) to 0. And stirred for 20 minutes at room temperature. To this mixture, tert-butyldimethylchlorosilane (578 mg) was added at 0 degree and stirred at room temperature for 16 hours. 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 (elution solvent: ethyl acetate / n-hexane) to give 3- (tert-butyldimethylsilyloxy) -2-phenylpropan-1-ol (972 mg). ) To a solution of the product (972 mg) in tetrahydrofuran (20 mL) is added phthalimide (590 mg), triphenylphosphine (1.05 g), azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 1.8 mL), and at room temperature. Stir for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N- {3-[(tert-butyldimethylsilyl) oxy] -2-phenylpropyl. } Phthalimide (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. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: 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 Reference Example 2-5-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 26.

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

Reference Example 2-7-1
(2R) -2- (Methylamino) -3- (pyridin-2-yl) propan-1-ol
To a solution of (2R) -2-amino-3- (pyridin-2-yl) propionic acid methyl ester (338 mg) and triethylamine (0.57 g) in dichloromethane (8 mL) was added 2-nitrobenzene-1-sulfonyl chloride (0. 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. To a solution of the residue in N, N-dimethylformamide (5 mL) were added potassium carbonate (0.52 g) and iodomethane (0.80 g), 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2R) -2- (N-methyl-2-nitrobenzenesulfonylamino) -3. -(Pyridin-2-yl) propionic acid methyl ester (0.32 g) was obtained. A mixture of product (0.24 g), thiophenol (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 evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / methanol) to give (2R) -2- (methylamino) -3- (pyridin-2-yl). ) Propionic acid methyl ester (0.11 g) was obtained. To a solution of the product (0.10 g) in tetrahydrofuran (2 mL), lithium aluminum hydride (20 mg) was added at 0 degree, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, passed through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (0.046 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) pyrrolidin-3-yl] methanol
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) was added lithium aluminum hydride (36 mg). It added under ice-cooling and stirred at 0 degree for 1 hour. Diethyl ether and water were added to the reaction mixture and passed through a celite pad. The filtrate was concentrated under reduced pressure to obtain [(3,4-trans) -1-benzyl-4- (pyridin-2-yl) pyrrolidin-3-yl] methanol (0.26 g). 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 (eluent: 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) butan-2-amine To a solution of 2-methylpyridine (0.93 g) in tetrahydrofuran (5 mL) at -78 ° C, 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 hour. After the reaction mixture was cooled to −30 degrees, 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 and 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 4- (benzyloxy) -1- (pyridin-2-yl) butane-2. -All (1.16 g) was obtained. To a solution of the product (0.30 g) in tetrahydrofuran (2 mL) was added phthalimide (0.258 g), triphenylphosphine (0.459 g) and azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 800 μL) at room temperature. For 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (elution 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 with heating under reflux for 4 hours. After the reaction mixture was cooled 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 solvent was evaporated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain 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) butan-2-ol
(2R) -2-[(tert-Butoxycarbonyl) amino] -3- (pyridin-2-yl) propionic acid (0.500 g) in N, N-dimethylformamide (3.5 mL) 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 stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution 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. Methyl lithium 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. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to give N-[(2R) -3-oxo-1- (pyridine-2). -Il) butan-2-yl] carbamic acid tert-butyl ester (0.261 g) was obtained. To a solution of the product (0.261 g) in methanol (9 mL) was added sodium borohydride (0.045 g) under ice cooling, and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate) to obtain a diastereomeric 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 solution of the product (0.065 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. The residue was purified by aminopropyl silica gel column chromatography (eluent: 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
Reference Example 2-10-2 was synthesized in the same manner as Reference Example 2-10-1 using the corresponding starting materials. 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) butan-2-ol hydrochloride
To a solution of (2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyridin-2-yl) propionic acid (1.000 g) in N, N-dimethylformamide (10 mL) 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 stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution 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. To a solution of the product (0.563 g) in diethyl ether (14 mL) was added methylmagnesium bromide diethyl ether solution (3.0 mol / L, 0.8 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel aminopropyl column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-[(2R) -3-oxo-1- (pyridine-2). -Il) butan-2-yl] carbamic acid tert-butyl ester (0.463 g) was obtained. A solution of the product (0.463 g) in tetrahydrofuran (5 mL) at −78 ° C. was added tri (sec-butyl) boron lithium lithium tetrahydrofuran solution (1.0 mol / L, 3.5 mL) at the same temperature for 5 hours. Stir. A saturated aqueous ammonium chloride solution 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate) to obtain a diastereomeric 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. Hydrogen chloride 1,4-dioxane solution (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 obtain the title compound (0.046 g). The structural formula, spectral data, and purification conditions are shown in Table 27.

Reference Example 2-11-2
Reference Example 2-11-2 was synthesized in the same manner as Reference Example 2-11-1 using the corresponding starting materials. 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) butan-1-ol hydrochloride To a solution of 3- (tert-butyldimethylsilyloxy) propanal (0.40 g) in tetrahydrofuran (4 mL) (R) -2-Methylpropane-2-sulfinamide (0.258 g) and tetraethyl orthotitanate (0.63 g) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated brine and passed through a celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy). ) Propylidene] -2-methylpropane-2-sulfinamide (0.33 g) was obtained. To a solution of 2-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.96 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. . To this mixture was added dropwise a solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propylidene] -2-methylpropane-2-sulfinamide (0.33 g) in tetrahydrofuran (2 mL). And stirred at -78 degrees for 0.5 hours. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse-phase preparative column chromatography (CapcellPak C18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R) -4- (tert-butyldimethylsilyl) as a highly polar product. Oxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.174 g) and (R) -N-[(2S) as the low polarity product -4- (tert-Butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.060 g) was obtained. (R) -N-[(2R) -4- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0. 174 g) in methanol (1 mL) was added hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) and 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 Examples 2-12-2 to 2-12-30
Reference Examples 2-12-2 to 2-12-30 were synthesized in the same manner as in Reference Example 2-12-1, using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 28 to Table 31.

Reference Example 2-13-1
4- (tert-Butyldimethylsilyloxy) -2- (pyridin-2-yl) butylamine To a solution of 2- (pyridin-2-yl) acetic acid ethyl 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 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 4- (tert-butyldimethylsilyloxy) -2- (pyridine-2 -Yl) butanoic acid ethyl ester (0.94 g) was obtained. To a solution of lithium aluminum hydride (0.22 g) in tetrahydrofuran (5 mL) was added 4- (tert-butyldimethylsilyloxy) -2- (pyridin-2-yl) butanoic acid ethyl ester (0.94 g) in tetrahydrofuran (5 mL). ) The solution was added dropwise under ice cooling and 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 column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to give 4- (tert-butyldimethylsilyloxy) -2- (pyridin-2-yl). ) Butan-1-ol (0.37 g) was obtained. To a solution of the product (0.16 g) in tetrahydrofuran (2 mL), phthalimide (0.12 g), triphenylphosphine (0.22 g) and azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 420 μL) were added, Stir at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N- {4- (tert-butyldimethylsilyloxy) -2- (pyridine- 2-yl) 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 with heating under reflux for 2 hours. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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-phenylbutyramide 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) butan-1-ol hydrochloride To a solution of 3- (tert-butyldimethylsilyloxy) propanal (0.30 g) in tetrahydrofuran (4 mL) (S ) -2-methylpropane-2-sulfinamide (0.19 g) and tetraethyl orthotitanate (0.47 g) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated brine and passed through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (S) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propylidene] -2-methylpropane- 2-Sulfinamide (0.30 g) was obtained. To a solution of 2-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.96 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. . To this mixture was added dropwise a solution of (S) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propylidene] -2-methylpropane-2-sulfinamide (0.30 g) in tetrahydrofuran (2 mL). And stirred at -78 degrees for 0.5 hours. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and (S) -N-[(2S) -4- (tert-butyldimethylsilyl) as a highly polar product. Oxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.08 g) and (S) -N-[(2R)-as the low polarity product 4-tert-butyldimethylsilyloxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.030 g) was obtained. (S) -N-[(2S) -4- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0. (08 g) in methanol (1 mL) was added hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) and 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
Reference Examples 2-15-2 to 2-15-3 were synthesized in the same manner as in Reference Example 2-15-1, using the corresponding starting materials. The structural formula, spectrum data, and purification conditions are shown in Table 32.

Reference Example 2-16-1
To a solution of (3R) -3-amino-4- (6-aminopyridin-2-yl) butan-1-ol 3- (tert-butyldimethylsilyloxy) propanal (0.40 g) in tetrahydrofuran (4 mL) ( R) -2-methylpropane-2-sulfinamide (0.258 g) and tetraethyl orthotitanate (0.63 g) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated brine and passed through a celite pad. The residue obtained by evaporating the solvent of the filtrate was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E) -3- (tert-butyldimethylsilyl). Oxy) propylidene] -2-methylpropane-2-sulfinamide (0.33 g) was obtained. To a solution of 2-azido-6-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) was added an n-butyllithium n-hexane solution (2.6 mol / L, 0.65 mL) at −78 ° C., and at the same temperature. Stir for 10 minutes. To this mixture was dropwise added a solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propylidene] -2-methylpropane-2-sulfinamide (0.20 g) in tetrahydrofuran (2 mL). And stirred at -78 degrees for 0.5 hours. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPak C18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R) -1- (6-azidopyridin-2-yl)- 4- (tert-Butyldimethylsilyloxy) butan-2-yl] -2-methylpropane-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 degrees 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 (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(2R) -1- (6-aminopyridin-2-yl) -4- (tert- Butyldimethylsilyloxy) butan-2-yl] -2-methylpropane-2-sulfinamide was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a methanol (1 mL) solution of the product, 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 (eluent: 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- (pyridin-2-yl) pentan-1-ol
To a solution of (2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyridin-2-yl) propionic acid (1.000 g) in N, N-dimethylformamide (10 mL) 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 stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution 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. To a solution of the product (0.158 g) in dichloromethane (4 mL) was added diisobutylaluminum hydride n-hexane solution (0.95 mol / L, 0.7 mL) at −78 ° C., and the mixture was stirred at the same temperature for 2 hours. A potassium sodium tartrate aqueous solution was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 30 minutes. The crude product was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate), and (2E, 4R) -4-[(tert-butoxycarbonyl) amino] -5. -(Pyridin-2-yl) pent-2-enoic acid ethyl ester (0.101 g) was obtained. To a solution of the product (0.101 g) in methanol (1.5 mL) was added 10% palladium on carbon (50% wet, 100 mg) under ice cooling, and the mixture was stirred at room temperature overnight 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 (elution solvent: ethyl acetate / n-hexane), and (4S) -4-[(tert-butoxycarbonyl) amino] -5- (pyridin-2-yl) pentanoic acid ethyl ester. (0.088 g) was obtained. To a solution of the product (0.088 g) in tetrahydrofuran (1.5 mL) was added lithium aluminum hydride (0.026 g) 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. 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 (elution solvent: ethyl acetate / methanol), and tert-butyl N-[(2S) -5-hydroxy-1- (pyridin-2-yl) pentan-2-yl] carbamate. The ester (0.047g) was obtained. Hydrogen chloride 1,4-dioxane solution (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 at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluent: 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) butan-1-ol hydrochloride To a solution of 2-ethylpyridine (0.309 g) 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. A solution of (R) -N-[(E) -2- (tert-butyldimethylsilyloxy) ethylidene] -2-methylpropane-2-sulfinamide (0.500 g) in tetrahydrofuran (3 mL) was added at the same temperature. Stir for 30 minutes. The reaction mixture was warmed 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain a diastereomer 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 -(Pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.162 g) was obtained as a highly polar diastereomer. Hydrogen chloride 1,4-dioxane solution (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 in the same manner as in Reference Example 2-18-1, using the corresponding starting 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) pentan-1-ol hydrochloride 2- (Pyridin-2-yl) acetic acid methyl ester (0.46 g) in N, N-dimethylformamide (8 mL) ) To the solution were added tert-butoxypotassium (0.41 g) and 2-bromoethyl (tert-butyldimethylsilyl) ether (0.79 g) 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 4- (tert-butyldimethylsilyloxy) -2- (pyridine-2 -Yl) butanoic acid methyl ester (0.94 g) was obtained. To a solution of the product (0.40 g) in methanol (5 mL) was added aqueous sodium hydroxide solution (2 mol / L, 1.3 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. To this mixture, N, O-dimethylhydroxylamine hydrochloride (0.19 g), triethylamine (0.39 g) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4- Methylmorpholinium chloride n-hydrate (0.54 g) was added and 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and 4- (tert-butyldimethylsilyloxy) -N-methoxy-N-methyl-2- (Pyridin-2-yl) butyramide (0.33 g) was obtained. To a solution of the product (0.10 g) in tetrahydrofuran (1.5 mL) was added methylmagnesium bromide tetrahydrofuran solution (1 mol / L, 600 μL) 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 5- (tert-butyldimethylsilyloxy) -3- (pyridin-2-yl). ) Pentan-2-one (0.05 g) was obtained. To a solution of the product (0.05 g) in tetrahydrofuran (2 mL) was added (S) -2-methylpropane-2-sulfinamide (0.023 g) and tetraethyl orthotitanate (0.077 g), and overnight at 70 ° C. Stir. The reaction mixture was cooled 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 hr. Acetone was added to the reaction mixture to quench the reaction. To this mixture was added saturated brine and passed through a celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give (S) -N-[(2S) -5- (tert-butyl) as a low polarity product. Dimethylsilyloxy) -3- (pyridin-2-yl) pentan-2-yl] -2-methylpropane-2-sulfinamide (21 mg) and (S) -N-[(2R)-as the highly polar product 5- (tert-Butyldimethylsilyloxy) -3- (pyridin-2-yl) pentan-2-yl] -2-methylpropane-2-sulfinamide (16 mg) was obtained. (S) -N-[(2S) -5- (tert-Butyldimethylsilyloxy) -3- (pyridin-2-yl) pentan-2-yl] -2-methylpropane-2-sulfinamide (21 mg) Hydrogen chloride 1,4-dioxane solution (4 mol / L, 0.5 mL) was added to a methanol (0.5 mL) solution, and the mixture was stirred at room temperature overnight. 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 in the same manner as Reference Example 2-19-1 using the corresponding starting 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) pentan-2-ol dihydrochloride
To a solution of (S) -3-hydroxybutanoic acid methyl ester (2.000 g) in N, N-dimethylformamide (40 mL) was added imidazole (1.383 g) and tert-butyldimethylchlorosilane (3.062 g) 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (3S) -3- (tert-butyldimethylsilyloxy) butanoic acid methyl ester ( 3.934 g) was obtained. To a solution of the product (3.934 g) in diethyl ether (60 mL) was added diisobutylaluminum hydride n-hexane solution (1.02 mol / L, 22 mL) at −78 ° C., and the mixture was stirred at the same temperature for 2 hours. A potassium sodium tartrate aqueous solution was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 30 minutes. The crude product was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (3S) -3- (tert-butyldimethylsilyloxy) butanal (3.076 g). ) To a solution of the product (1.600 g) in tetrahydrofuran (20 mL) was added (R)-(+)-2-methylpropane-2-sulfinamide (1.246 g) and tetraethyl orthotitanate (2.886 g) at room temperature. Stir overnight. To the reaction mixture was added saturated brine, diluted with ethyl acetate, and passed through a celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E, 3S) -3- (tert-butyl). Dimethylsilyloxy) butylidene] -2-methylpropane-2-sulfinamide (2.050 g) was obtained. To a solution of 2-methylpyridine (0.572 g) in tetrahydrofuran (3 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 2.2 mL) at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. . A solution of (R) -N-[(1E, 3S) -3- (tert-butyldimethylsilyloxy) butylidene] -2-methylpropane-2-sulfinamide (1.250 g) in tetrahydrofuran (3 mL) at the same temperature. The mixture was further stirred for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(2R, 4S) -4- (tert-butyl). Dimethylsilyloxy) -1- (pyridin-2-yl) pentan-2-yl] -2-methylpropane-2-sulfinamide (0.639 g) was obtained as a highly polar diastereomer. To a solution of the product (0.400 g) in tetrahydrofuran (6 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 2 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate), and (R) -N-[(2R, 4S) -4-hydroxy-1- (pyridine). -2-yl) pentan-2-yl] -2-methylpropane-2-sulfinamide (0.284 g) was obtained. Dess-Martin periodinane (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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate), and (R) -2-methyl-N-[(2R) -4-oxo-1- (Pyridin-2-yl) pentan-2-yl] propane-2-sulfinamide (0.201 g) was obtained. To a solution of the product (0.201 g) in tetrahydrofuran (3 mL) was added a methylmagnesium bromide diethyl ether solution (3.0 mol / L, 0.91 mL) under ice cooling, and the mixture was stirred at the same temperature for 7 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate), and (R) -N-[(2R) -4-hydroxy-4-methyl-1- (Pyridin-2-yl) pentan-2-yl] -2-methylpropane-2-sulfinamide (0.015 g) was obtained. Hydrogen chloride 1,4-dioxane solution (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 obtain 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) butan-2-amine hydrochloride To a solution of 3- (tert-butyldimethylsilyloxy) propanal (0.40 g) in tetrahydrofuran (4 mL) (R ) -2-Methylpropane-2-sulfinamide (0.258 g) and tetraethyl orthotitanate (0.63 g) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated brine and passed through a celite pad. The residue obtained by evaporating the solvent of the filtrate was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E) -3- (tert-butyldimethylsilyl). Oxy) propylidene] -2-methylpropane-2-sulfinamide (0.33 g) was obtained. To a solution of 2-methylpyridine (0.14 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.96 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. . To this mixture was added dropwise a solution of (R) -N-[(1E) -3- (tert-butyldimethylsilyloxy) propylidene] -2-methylpropane-2-sulfinamide (0.33 g) in tetrahydrofuran (2 mL). And stirred at -78 degrees for 0.5 hours. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse-phase preparative column chromatography (CapcellPak C18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R) -4- (tert-butyldimethylsilyl) as a highly polar product. Oxy) -1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.174 g) was obtained. To a solution of the product (0.15 g) in tetrahydrofuran (1 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 580 μL), 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 (elution solvent: ethyl acetate / methanol), and (R) -N-[(2R) -4-hydroxy-1- (pyridine-2). -Il) butan-2-yl] -2-methylpropane-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), 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. Methanol (1 mL) and 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
Reference Example 2-21-2 was synthesized in the same manner as Reference Example 2-21-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 34.

Reference Example 22-1
(R) -4- (tert-Butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-2-amine
To a solution of (3R) -3-amino-4- (pyridin-2-yl) butan-1-ol hydrochloride (40 mg) in dichloromethane (1 mL) was added N, N-diisopropylethylamine (87 mg) and tert-butyldimethylchlorosilane ( 30 mg) was added and 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 evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to obtain 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
Reference Examples 2-22-2 to 2-22-5 were synthesized in the same manner as in Reference Example 2-22-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 34.

Reference Example 2-23-1
(2R) -2-Amino-3- (pyrimidin-2-yl) propan-1-ol hydrochloride
A suspension of (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionic acid methyl ester (613 mg), zinc (268 mg) in N, N-dimethylformamide (10 mL) at room temperature under an argon atmosphere. Stir for 2 hours. To this mixture, 2-bromopyrimidine (296 mg) and bis (triphenylphosphine) palladium (II) dichloride (131 mg) were added and stirred at room temperature for 4 hours. To this mixture was added saturated aqueous sodium bicarbonate and 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 removed under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyrimidin-2-yl) propion. Acid methyl ester (310 mg) was obtained. To a mixture of the product (310 mg) in ethanol (3 mL) and water (3 mL) was added sodium borohydride (104 mg) at 0 degrees and stirred at room temperature for 12 hours. 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 removed under reduced pressure. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a methanol (3 mL) solution of the residue, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 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
Reference Examples 2-23-2 to 2-23-16 were synthesized in the same manner as in Reference Example 2-23-1 using the corresponding starting materials. 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- (pyrimidin-2-yl) butane-1,2-diol hydrochloride N-{(1R) -1-[(4S) -2,2-dimethyl-1, 3-Dioxolan-4-yl] -2-hydroxyethyl} carbamic acid tert-butyl ester (1.25 g), imidazole (521 mg), triphenylphosphine (2.01 g), tetrahydrofuran (10 mL) in a mixture of iodine (1 0.7 g) was added at 0 degree and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution 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 the product (1.45 g) and zinc (562 mg) in N, N-dimethylformamide (5 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (621 mg) and bis (triphenylphosphine) palladium (II) dichloride (274 mg) were added and stirred at room temperature for 4 hours. To this mixture was added saturated aqueous sodium bicarbonate and 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 removed under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-{(1R) -1-[(4S) -2,2-dimethyl-1,3-dioxolane- 4-yl] -2- (pyrimidin-2-yl) ethyl} carbamic acid tert-butyl ester (928 mg) was obtained. A mixture of the product (150 mg), 1,4-dioxane (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (119 mg). 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) propan-1-ol hydrochloride
(2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionic acid methyl ester (1.45 g), pyrazole (100 mg), cesium carbonate (957 mg), N, N-dimethylformamide (5 mL) The mixture was stirred at 80 degrees 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 (elution solvent: ethyl acetate / n-hexane), and (2R) -2-[(tert-butoxycarbonyl) amino] -3- (1H- Pyrazol-1-yl) propionic acid methyl ester (103 mg) was obtained. To a mixture of the product (103 mg) in ethanol (1 mL) and water (1 mL) was added sodium borohydride (35 mg) at 0 degrees and stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was removed 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- Dimethyl-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) To the mixed solution was added iodine (4.52 g) at 0 degree and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution 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 the product (545 mg), pyrazole (100 mg), cesium carbonate (957 mg), N, N-dimethylformamide (5 mL) was stirred at 80 degrees for 13 hours. After the reaction mixture was cooled 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-{(1R) -1-[(4S) -2,2-dimethyl-1,3-dioxolane-4- Yl] -2- (1H-pyrazol-1-yl) ethyl} carbamic acid tert-butyl ester (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-naphthyridin-2-one hydrochloride
A mixture of (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionic acid methyl ester (1.02 g), zinc (447 mg) in N, N-dimethylformamide (5 mL) was added to an argon atmosphere. The mixture was stirred at room temperature for 2 hours. To this mixture, 2-bromo-3-nitropyridine (631 mg) and bis (triphenylphosphine) palladium (II) dichloride (218 mg) were added and stirred at room temperature for 13 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate / n-hexane) to give (2R) -2-[(tert-butoxycarbonyl) amino] -3- (3-nitropyridine-2- Yl) propionic 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 the mixture was stirred at 50 ° C. for 10 hours in 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 (elution solvent: ethyl acetate / n-hexane), and N-((3R) -2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine was obtained. -3-yl) carbamic acid tert-butyl ester was obtained. A mixture of the product, methanol (1 mL), 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, 2-28-1
(R) -N-[(2S) -1,3-di (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (2-28-1: HP)
(R) -N-[(2S) -1,3-di (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (2-28-2: LP)
To a solution of 2- (tert-butyldimethylsilyloxy) acetaldehyde (2.000 g) in tetrahydrofuran (30 mL) was added (R)-(+)-2-methylpropane-2-sulfinamide (1.808 g) and tetraethyl orthotitanate ( 4.188 g) was added and stirred at room temperature overnight. To the reaction mixture were added saturated brine and ethyl acetate, 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 (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E) -2- (tert-butyldimethylsilyl). Oxy) ethylidene] -2-methylpropane-2-sulfinamide (2.185 g) was obtained. To a solution of 2- (tert-butyldimethylsilyloxymethyl) pyridine (0.282 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.4 mL) at -78 degrees. The mixture was stirred at the same temperature for 30 minutes. A solution of (R) -N-[(1E) -2- (tert-butyldimethylsilyloxy) ethylidene] -2-methylpropane-2-sulfinamide (0.263 g) in tetrahydrofuran (2 mL) was added at the same temperature. Stir for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 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 Reference Example 2-28-1 using the corresponding starting 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) butan-2-amine 3- (benzyloxy) -2-methoxypropanal (1.90 g) in tetrahydrofuran To the (20 mL) solution, (R) -2-methylpropane-2-sulfinamide (1.53 g) and tetraethyl orthotitanate (3.53 g) were added and stirred at room temperature overnight. To the reaction mixture was added saturated brine and passed through a celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (R) -N-[(1E, 2S) -3- as a highly polar product. (Benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.57 g) and (R) -N-[(1E, 2R) -3- (benzyloxy) as the low polarity product ) -2-Methoxypropylidene] -2-methylpropane-2-sulfinamide (0.70 g) was obtained. To a solution of 2-methylpyridine (0.27 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 1.0 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. . To this mixture was added (R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.57 g) in tetrahydrofuran (4 mL). The solution was added dropwise 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R, 3S) -4- (benzyloxy) as a highly polar product. -3-Methoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.20 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was added to a solution of 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 column chromatography on aminopropyl silica gel (eluent: 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) butan-2-amine 3- (benzyloxy) -2-methoxypropanal (1.90 g) in tetrahydrofuran To the (20 mL) solution, (R) -2-methylpropane-2-sulfinamide (1.53 g) and tetraethyl orthotitanate (3.53 g) were added and stirred at room temperature overnight. To the reaction mixture was added saturated brine and passed through a celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (R) -N-[(1E, 2S) -3- as a highly polar product. (Benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.57 g) and (R) -N-[(1E, 2R) -3- (benzyloxy) as the low polarity product ) -2-Methoxypropylidene] -2-methylpropane-2-sulfinamide (0.70 g) was obtained. To a solution of 2-methylpyridine (0.19 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 1.0 mL) at −78 ° C., and the mixture was stirred at the same temperature for 10 minutes. . To this mixture was added (R) -N-[(1E, 2R) -3- (benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.40 g) in tetrahydrofuran (2 mL). The solution was added dropwise 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 (elution solvent: ethyl acetate / methanol) to give (R) -N-[(2R, 3R) -4- (benzyloxy) -3. -Methoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide and (R) -N-[(2S, 3R) -4- (benzyloxy) -3 A mixture (0.47 g) of -methoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide was obtained. To the product (0.42 g) were added tetrahydrofuran (4 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 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 silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (0.15 g) as a low polarity 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
To a solution of (2R) -2-amino-2-methyl-3- (pyridin-2-yl) propan-1-ol hydrochloride (64 mg) in dichloromethane (1 mL) was added N, N-diisopropylethylamine (121 mg) and chloroformic acid. Benzyl ester (64 mg) was added and 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 silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-[(2R) -1-hydroxy-2- (pyridin-2-ylmethyl). ) Propan-2-yl] carbamic acid benzyl ester (35 mg) was obtained. Dess-Martin periodinane (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. A sodium thiosulfate aqueous solution (1 mol / L) and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with 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 chlorous acid A mixture of sodium acid (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). To a suspension of the product (36 mg) in N, N-dimethylformamide (1 mL) was added ammonium chloride (61 mg), N, N-diisopropylethylamine (147 mg) and 1,1′-carbonyldiimidazole (30 mg) at room temperature. 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
Reference Example 2-31-2 was synthesized in the same manner as in Reference Example 2-31-1 using the corresponding starting materials. 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) was added triethylamine (710 mg) and chloroformic acid isobutyl ester (637 mg) at 0 degrees. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. To a solution of the residue in methanol (5 mL), sodium borohydride (178 mg) was added at 0 degree, 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 removed under reduced pressure. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was added to a 1,4-dioxane (3 mL) solution of the residue, 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-dihydropyrimidin-2-yl) butan-1-ol dihydrochloride
To a solution of (2S) -4- (tert-butoxy) -2-[(tert-butoxycarbonyl) amino] -4-oxobutanoic acid (2 g) in tetrahydrofuran (10 mL) was added N-methylmorpholine (840 mg), isobutyl chloroformate. Ester (1.04 g) was added at 0 degree 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. To a solution of the residue in methanol (10 mL), sodium borohydride (525 mg) was added at 0 degree and 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (3S) -3-[(tert-butoxycarbonyl) amino] -4-hydroxybutanoic acid tert-butyl ester (1. 93 g) was obtained. To a mixed solution of the product (1.93 g), imidazole (763 mg), triphenylphosphine (2.94 g) and tetrahydrofuran (20 mL) was added iodine (2.49 g) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and (3S) -3-[(tert-butoxycarbonyl) amino] -4-io- Dobutanoic acid tert-butyl ester (2.3 g) was obtained. A mixture of product (1 g), zinc (374 mg) in N, N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (413 mg) and bis (triphenylphosphine) palladium (II) dichloride (182 mg) were added and stirred at 40 degrees for 5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (3R) -3-[(tert-butoxycarbonyl) amino] -4- (pyrimidin-2-yl) butanoic acid tert. -Butyl ester (460 mg) was obtained. To a solution of the product (350 mg) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (99 mg) at 0 degrees, 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 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-dihydropyrimidin-2-yl) butan-2-ol dihydrochloride
A mixture of (2S) -2-[(tert-butoxycarbonyl) amino] -3-iodopropionic acid methyl ester (800 mg), zinc (350 mg) in N, N-dimethylformamide (10 mL) at room temperature under an argon atmosphere. Stir for 2 hours. To this mixture, 2-bromopyrimidine (386 mg) and bis (triphenylphosphine) palladium (II) dichloride (171 mg) were added, and the mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2R) -2-[(tert-butoxycarbonyl) amino] -3- (pyrimidin-2-yl) propion. Acid methyl ester (450 mg) was obtained. To a solution of the product (450 mg) in diethyl ether (5 mL), methyl lithium diethyl ether solution (1.1 mol / L, 5.8 mL) was added at −78 degrees and 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 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- (pyrimidin-2-yl) butan-1-ol hydrochloride
To a solution of (2S) -2-[(tert-butoxycarbonyl) amino] -4-methoxy-4-oxobutanoic acid (2 g) in tetrahydrofuran (10 mL) was added N-methylmorpholine (981 mg), chloroformic acid isobutyl ester (1 .22 g) was added at 0 degree 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. To a solution of the residue in methanol (10 mL), sodium borohydride (337 mg) was added at 0 degree and stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and (3S) -3-[(tert-butoxycarbonyl) amino] -4-hydroxybutanoic acid methyl ester (1.18 g). Got. To a mixed solution of the product (1.18 g), imidazole (551 mg), triphenylphosphine (2.12 g) and tetrahydrofuran (40 mL) was added iodine (1.8 g) at 0 degree, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and (3S) -3-[(tert-butoxycarbonyl) amino] -4-io- Dobutanoic acid methyl ester (1.5 g) was obtained. A mixture of the product (1.5 g), zinc (629 mg) in N, N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (695 mg) and bis (triphenylphosphine) palladium (II) dichloride (307 mg) were added, and the mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (3R) -3-[(tert-butoxycarbonyl) amino] -4- (pyrimidin-2-yl) butane. Acid methyl ester (746 mg) was obtained. To a mixture of the product (746 mg) in ethanol (3 mL) and water (3 mL), sodium borohydride (239 mg) was added at 0 degree and stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -4-hydroxy-1- (pyrimidin-2-yl) butan-2-yl] Carbamic acid tert-butyl ester was obtained. Methanol (3 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) were added to the product, 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- (pyridin-2-yl) butan-2-yl] carbamic acid benzyl ester N- [1-benzyloxy-3-oxopropane- To a mixed solution of 2-yl] carbamic acid benzyl ester (975 mg) and (R) -tert-butylsulfinamide (490 mg) in tetrahydrofuran (15 mL) was added tetraethyl orthotitanate (0.959 mL). The mixture was stirred overnight, saturated brine (1.5 mL) was added and passed through a celite pad. Water and ethyl acetate were added to the filtrate for liquid separation, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N- {1-benzyloxy-3-[((R) -tert-butylsulfinyl) imino] propan-2-yl} Carbamic acid benzyl ester (863 mg) was obtained. To a solution of 2-methylpyridine (289 mg) in tetrahydrofuran (6 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 1.05 mL) at −78 degrees, and the mixture was stirred at the same temperature for 30 minutes. did. To this mixture was added a solution of N- {1-benzyloxy-3-[((R) -tert-butylsulfinyl) imino] propan-2-yl} carbamic acid benzyl ester (863 mg) in tetrahydrofuran (6 mL). The mixture was stirred at -78 degrees for 1.25 hours and at room temperature for 1 hour. A saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, 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 (elution 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) butan-2-yl} carbamic acid benzyl ester (46 mg) and the corresponding mixture of three diastereomers (74 mg) were obtained. N-{(2R, 3R) -1-benzyloxy-3-[((R) -tert-butylsulfinyl) amino] -4- (pyridin-2-yl) butan-2-yl} carbamic acid benzyl ester ( 46 mg) in methanol (1 mL) at room temperature was added hydrogen chloride 1,4-dioxane solution (4 mol / L, 0.2 mL) and the mixture was stirred for 1.3 hours. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluent: 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- (pyridin-2-yl) butan-2-yl] carbamic acid 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. was added n-hexane solution of diisobutylaluminum hydride (1.02 mol / L, 5.09 mL), and this mixture was added to 1. Stir for 5 hours. Methanol (5 mL) and saturated brine (10 mL) were added to this mixture and 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 layers were concentrated under reduced pressure. Tetraethyl orthotitanate (0.906 mL) was added to a tetrahydrofuran (20 mL) mixture of this residue and (R) -tert-butylsulfinamide (525 mg). The mixture was stirred at room temperature overnight, 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 for liquid separation, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-{(S) -1-benzyloxy-3-[((R) -tert-butylsulfinyl) imino] propane- 2-yl} carbamic acid benzyl ester (993 mg) was obtained. To a solution of 2-methylpyridine (333 mg) in tetrahydrofuran (7 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 1.19 mL) at -78 degrees, 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 degrees for 2 hours and at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (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 (elution solvent: ethyl acetate / methanol), and N-{(S) -1-benzyloxy-3-[((R) -tert-butylsulfinyl) amino] -4- ( Pyridin-2-yl) butan-2-yl} carbamic acid benzyl ester (489 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (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 (eluent: 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 2-37-2
Reference Example 2-37-2 was synthesized in the same manner as Reference Example 2-37-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 39.

Reference Example 2-38-1
(2R, 3S) -3,4-Dimethoxy-1- (pyridin-2-yl) butan-2-amine hydrochloride
To a solution of (2S, 3R) -3-amino-4- (pyridin-2-yl) butane-1,2-diol (0.20 g) in tetrahydrofuran (3 mL) was added triethylamine (0.32 g) and ditert-dicarbonate. -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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N-[(2R, 3S) -3,4-dihydroxy-1- (pyridine-2). -Il) butan-2-yl] carbamic acid tert-butyl ester (0.22 g) was obtained. Sodium hydride (60% oil dispersion, 15 mg) and iodomethane (125 mg) were added to tetrahydrofuran (1 mL) of the product (50 mg) under ice cooling, 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N-[(2R, 3S) -3,4-dimethoxy-1- (pyridine-2). -Il) butan-2-yl] carbamic acid tert-butyl ester (10 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (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 2-39-1
(2S, 3R) -3-Amino-1-ethoxy-4- (pyridin-2-yl) butan-2-ol
To a solution of (2R) -2-[(benzyloxy) methyl] oxirane (1.00 g) in ethanol (10 mL) was added potassium hydroxide (1.03 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2R) -1- (benzyloxy) -3-ethoxypropan-2-ol. (1.25 g) was obtained. To a solution of the product (1.25 g) in dichloromethane (20 mL) were added imidazole (1.01 g) and tert-butyldimethylchlorosilane (0.99 g), 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and [(2R) -1- (benzyloxy) -3-ethoxypropane-2- Yl] (tert-butyldimethylsilyl) ether (2.00 g) was obtained. To a solution of the product (2.00 g) in ethanol (20 mL) was added 10% palladium carbon (50% wet, 0.2 g), and the mixture was stirred at room temperature for 2 hours in 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 (registered trademark) (0.046 g) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A sodium thiosulfate aqueous solution (1 mol / L) and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with 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 orthotitanate (1.85 mL) were added to the residue. The mixture was stirred at room temperature overnight. To the reaction mixture were added saturated brine and ethyl acetate, 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 (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E, 2S) -2- (tert-butyldimethyl). Silyloxy) -3-ethoxypropylidene] -2-methylpropane-2-sulfinamide (0.85 g) was obtained. To a solution of 2-methylpyridine (0.35 g) in tetrahydrofuran (2 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 2.2 mL) at −78 degrees, and the mixture was stirred at the same temperature for 10 minutes. . To this mixture was added (R) -N-[(1E, 2S) -2- (tert-butyldimethylsilyloxy) -3-ethoxypropylidene] -2-methylpropane-2-sulfinamide (0.85 g). A tetrahydrofuran (3 mL) solution was added dropwise, 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse-phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R, 3S) -3- (tert-butyl) as a highly polar product. Dimethylsilyloxy) -4-ethoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.36 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 2 mL) was added to a solution of the product (0.36 g) in methanol (2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as Reference Example 2-39-1 using the corresponding starting 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) butan-2-amine
To a methanol solution of (4R) -4-[(benzyloxy) methyl] -2,2-dimethyl-1,3-dioxolane (8.00 g), a hydrogen chloride 1,4-dioxane solution (4 mol / L, 20 mL). And stirred at room temperature for 3 hours. The residue obtained by concentrating the reaction mixture was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2S) -3- (benzyloxy) propane-1,2-diol (7.30 g). Got. To a solution of the product (6.90 g) in dichloromethane (30 mL), N, N-diisopropylethylamine (12.2 g) and chloromethyl methyl ether (3.35 g) were added 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2R) -1-benzyloxy-3- (methoxymethoxy) propane-2- All (2.30 g) was obtained. Sodium hydride (60% oil dispersion, 53 mg) and iodoethane (0.42 g) were added to a tetrahydrofuran (5 mL) solution of the product (0.20 g) 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give [(2R) -1- (benzyloxy) -3- (methoxymethoxy) propane. -2-yl] ethyl ether (0.21 g) was obtained. Hydrogen chloride 1,4-dioxane solution (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 (elution solvent: ethyl acetate / n-hexane), and (2S) -3- (benzyloxy) -2-ethoxypropan-1-ol. (0.137 g) was obtained. To a solution of the product (137 mg) in dichloromethane (2 mL), iodobenzene diacetate (315 mg) and AZADOL (registered trademark) (5 mg) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A sodium thiosulfate aqueous solution (1 mol / L) and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Tetrahydrofuran (3 mL), (R) -tert-butylsulfinamide (103 mg) and tetraethyl orthotitanate (215 μL) were added to the residue obtained by evaporating the solvent under reduced pressure. The mixture was stirred at room temperature overnight. To the reaction mixture were added saturated brine and ethyl acetate, 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 (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E, 2S) -3- (benzyloxy)- 2-Ethoxypropylidene] -2-methylpropane-2-sulfinamide (120 mg) was obtained. To a solution of 2-methylpyridine (54 mg) in tetrahydrofuran (2 mL) was added an n-butyllithium n-hexane solution (2.6 mol / L, 0.2 mL) at -78 degrees, and the mixture was stirred at the same temperature for 10 minutes. To this mixture was added a solution of (R) -N-[(1E, 2S) -3- (benzyloxy) -2-ethoxypropylidene] -2-methylpropane-2-sulfinamide (120 mg) in tetrahydrofuran (3 mL). The solution 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by reverse phase preparative column chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and (R) -N-[(2R, 3S) -4- (benzyloxy) as a highly polar product. -3-Ethoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (35 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a solution of the product (35 mg) in methanol (1 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain the title compound (12 mg). The structural formula and purification conditions are shown in Table 39.

Reference Example 24-1
(1R) -1-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyrimidin-2-yl) ethan-1-amine N-[(1R) -1 -((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] carbamic acid benzyl ester (1.78 g), imidazole (656 mg), triphenylphosphine (2.53 g ) And tetrahydrofuran (20 mL) were added iodine (2.14 g) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and N-[(1S) -1-((4R) -2,2-dimethyl- 1,3-Dioxolan-4-yl) -2-iodoethyl] carbamic acid benzyl ester (1.9 g) was obtained. A mixture of the product (1.9 g), zinc (355 mg) in N, N-dimethylformamide (10 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (392 mg) and bis (triphenylphosphine) palladium (II) dichloride (173 mg) were added, and the mixture was stirred at room temperature for 13 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane) to give N-[(1R) -1-((4R) -2,2-dimethyl-1,3-dioxolane- 4-yl) -2- (pyrimidin-2-yl) ethyl] carbamic acid benzyl ester (614 mg) was obtained. A mixture of product (400 mg), 10% palladium on carbon (50% wet, 10 mg), ethyl acetate (5 mL) was stirred at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was passed through a celite pad, 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 was added a solution of (R) -N-[(1E) -2- (benzyloxy) ethylidene] -2-methylpropane-2-sulfinamide (0.836 g) in tetrahydrofuran (5 mL) at the same temperature, and an additional 30 Stir for minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(2S) -3- (benzyloxy) -1 -(Tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (HP, 0.345 g) and (R) -N- [ (2S) -3- (Benzyloxy) -1- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (LP, 0.354 g) was obtained. (R) -N-[(2S) -3- (Benzyloxy) -1- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) propan-2-yl] -2-methylpropane- To a tetrahydrofuran (4 mL) solution of 2-sulfinamide (0.345 g), a tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 1 mL) was added 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate), and (R) -N-[(2S) -3- (benzyloxy) -1-hydroxy. -1- (Pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (0.185 g) was obtained. To a solution of the product (0.093 g) in tetrahydrofuran (1 mL) was added sodium hydride (60% oil dispersion, 0.006 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes, and then iodomethane (0.145 g) was added. And 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (R) -N-[(2S) -3- (benzyloxy) -1 -Methoxy-1- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (0.042 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a solution of the product (0.024 g) in 1,4-dioxane (1 mL), 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 obtain 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
Reference examples 2-42-2 to 2-42-4 were synthesized in the same manner as in Reference Example 24-2-1, using the corresponding starting materials. 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) butan-2-amine
(R)-(+)-2-methylpropane-2-sulfinamide (0.145 g) was added to a solution of (2R) -3-benzyloxy-2-methoxypropanal (0.213 g) in tetrahydrofuran (8 mL). And tetraethyl orthotitanate (0.401 g) were added and stirred at room temperature overnight. To the reaction mixture were added saturated brine and ethyl acetate, and passed through a celite pad. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1E, 2S) -3- (benzyloxy) -2-Methoxypropylidene] -2-methylpropane-2-sulfinamide (0.247 g) was obtained. To a solution of 2- (tert-butyldimethylsilyloxymethyl) pyridine (0.260 g) in tetrahydrofuran (3 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.4 mL) at -78 degrees. Stir for 30 minutes. To this mixture was added (R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.247 g) in tetrahydrofuran (3 mL). Was added at the same temperature and stirred for another 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution 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- ( single diastereomer (LP: 0.082 g) of tert-butyldimethylsilyloxy) -3-methoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide ) And (R) -N-[(2S, 3S) -4- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -3-methoxy-1- (pyridin-2-yl) butane-2- A single diastereomer of (yl) -2-methylpropane-2-sulfinamide and (R) -N-[(2R, 3S) -4- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -3-Metoki 1- (pyridin-2-yl) butan-2-yl] single mixture of diastereomers of 2-methylpropane-2-sulfinamide (HP: 0.085 g) was obtained. (R) -N-[(2S, 3S) -4- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -3-methoxy-1- (pyridin-2-yl) butan-2-yl] A single diastereomer of 2-methylpropane-2-sulfinamide and (R) -N-[(2R, 3S) -4- (benzyloxy) -1- (tert-butyldimethylsilyloxy) -3 To a mixture of single diastereomers of -methoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.085 g) was added tetrahydrofuran (1 mL). . To this mixture, tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 0.25 mL) was added under ice-cooling and 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate), and (R) -N-[(2R, 3S) -4- (benzyloxy) -1 -Hydroxy-3-methoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.033 g) was obtained as a low polarity diastereomer. To a solution of the product (0.033 g) in tetrahydrofuran (1 mL), sodium hydride (60% oil dispersion, 0.003 g) was added under ice cooling and stirred for 30 minutes, and then iodomethane (0.046 g) was added at room temperature. Stir 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(2R, 3S) -4- (benzyloxy) -1,3-Dimethoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.018 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a solution of the product (0.018 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 obtain the title compound (0.013 g). The structural formula, spectral data and purification conditions are shown in Table 40.

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

Reference Example 2-44-1
(2R, 3R) -2-amino-4-methoxy-3- (pyridin-2-yl) butan-1-ol and (2R, 3S) -2-amino-4-methoxy-3- (pyridin-2- Yl) Butan-1-ol mixture To a solution of 2-bromopyridine (0.72 g) in tetrahydrofuran (10 mL) at −78 ° C. is added an n-butyllithium n-hexane solution (2.6 mol / L, 1.7 mL). Added and stirred for 10 minutes. A solution of (4S) -4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) in tetrahydrofuran (5 mL) was added at the same temperature, and the mixture was further stirred for 1.5 hours. did. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4S) -4-[(R) -hydroxy (pyridin-2-yl) Methyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester and (4S) -4-[(S) -hydroxy (pyridin-2-yl) methyl] -2,2- A mixture (1.16 g) of dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester was obtained. To a mixture of product (1.16 g) and dichloromethane (10 mL) was added Dess-Martin periodinane (2.39 g) and stirred at room temperature for 2 days. A sodium thiosulfate aqueous solution (1 mol / L) and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the crude product was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4S) -2,2-dimethyl-4- (pyridine-2-carbonyl). -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (1.02 g) was obtained. To a suspension of (methoxymethyl) triphenylphosphonium chloride (447 mg) in tetrahydrofuran (3 mL) was added potassium bis (trimethylsilyl) amide tetrahydrofuran solution (1.0 mol / L, 1.2 mL), and the mixture was stirred at room temperature for 1 hour. To this mixture was added (4S) -2,2-dimethyl-4- (pyridine-2-carbonyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (200 mg) under ice cooling, and at room temperature. Stir for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4R) -4- [2-methoxy-1- (pyridin-2-yl) ethenyl] -2,2-dimethyl- 1,3-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg) was obtained. To a solution of the product (100 mg) in ethanol (3 mL) was added 10% palladium carbon (50% wet, 10 mg), 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 resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (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- (pyridin-2-yl) ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester was obtained. Hydrogen chloride 1,4-dioxane solution (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 resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain the title compound (40 mg). The structural formula, spectral data and purification conditions are shown in Table 40.

Reference Example 2-45-1
(2R, 3S) -4- (tert-Butyldiphenylsilyloxy) -3-methoxy-1- (1H-pyrazol-1-yl) butan-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 a tetrahydrofuran (70 mL) mixed solution was added azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 35 mL), 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 (elution 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. 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. To a solution of the residue in ethanol (20 mL) were added ditert-butyl dicarbonate (6.71 g) and 20% palladium hydroxide on carbon (50% wet, 2 g), 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 (elution solvent: ethyl acetate / n-hexane), and N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolane-4- Yl) -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 ( 70 mL), triethylamine (9.76 g) and methanesulfonyl chloride (7.18 g) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The extract was concentrated under reduced pressure. To a solution of the residue in N, N-dimethylformamide (100 mL), cesium carbonate (47.13 g) and pyrazole (6.57 g) were added, and the mixture was stirred at 80 ° C. for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolane-4- Yl) -2- (1H-pyrazol-1-yl) ethyl] carbamic acid tert-butyl ester (6.5 g) was obtained. Trifluoroacetic acid (1.6 mL) was added to a mixture of the product (6.5 g) in methanol (21 mL) and water (7 mL), 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 (elution solvent: ethyl acetate / methanol), and N-[(2R, 3S) -3,4-dihydroxy-1- (1H-pyrazole- 1-yl) butan-2-yl] carbamic acid tert-butyl ester (5.0 g) was obtained. To a solution of the product (5.0 g) in N, N-dimethylformamide (20 mL), imidazole (1.71 g) and tert-butyldiphenylchlorosilane (6.31 g) were added at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. . 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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy)- 3-Hydroxy-1- (1H-pyrazol-1-yl) butan-2-yl] carbamic acid tert-butyl ester (7.8 g) was obtained. To a mixture of the product (7.8 g), iodomethane (2.61 g), tetrahydrofuran (30 mL), N, N-dimethylformamide (3 mL), a small amount of sodium hydride (60% oil dispersion, 642 mg) at 0 ° C. The mixture was added in portions and stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy)- 3-Methoxy-1- (1H-pyrazol-1-yl) butan-2-yl] carbamic acid tert-butyl ester (6.8 g) was obtained. 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 distilled off under reduced pressure, and the residue was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to obtain 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
Reference Examples 2-45-2 to 2-45-8 were synthesized in the same manner as Reference Example 2-45-1 using the corresponding starting materials. 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-methoxybutan-2-yl] carbamic acid tert-butyl ester
To a solution of (4S) -4-[(1R) -1-azido-2- (benzyloxy) ethyl] -2,2-dimethyl-1,3-dioxolane (2.3 g) in methanol (5 mL) was added hydrogen chloride. 1,4-Dioxane solution (4 mol / L, 10 mL) was added, and the mixture was stirred at room temperature for 4 hours. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 10 mL) was added to the reaction mixture, and the mixture was stirred at 60 degrees for 2 hours. The reaction mixture was concentrated under reduced pressure. To a solution of the residue in N, N-dimethylformamide (25 mL), imidazole (678 mg) and tert-butyldiphenylchlorosilane (2.51 g) were added at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and (2S, 3R) -3-azido-4- (benzyloxy) -1- ( tert-Butyldiphenylsilyloxy) butan-2-ol (4.58 g) was obtained. To a mixture of the product (4.58 g), N, N-dimethylformamide (10 mL), iodomethane (2.05 g), sodium hydride (60% oil dispersion, 425 mg) was added at 0 ° C. Stir for hours. Saturated aqueous ammonium chloride 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 (elution 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 the product (4.3 g), di-tert-butyl dicarbonate (2.3 g), 20% palladium hydroxide on carbon (50% wet, 2 g), ethanol (30 mL) was mixed at 13 ° C. under a hydrogen atmosphere at 60 ° C. 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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -1-hydroxy-3-methoxybutane. -2-yl] carbamic acid tert-butyl ester (2.88 g) was obtained. To a mixed solution of the product (2.88 g), imidazole (662 mg), triphenylphosphine (2.55 g), and tetrahydrofuran (10 mL) was added iodine (2.16 g) at 0 degree, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane) to obtain 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 in the same manner as Reference Example 2-46-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 42.

Reference Example 2-47-1
(2S, 3R) -3-Amino-2-methoxy-4- (pyrimidin-2-yl) butan-1-ol N-[(2S, 3S) -4- (tert-butyldiphenylsilyloxy) -1- A mixture of iodo-3-methoxybutan-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, 2-bromopyrimidine (296 mg) and bis (triphenylphosphine) palladium (II) dichloride (131 mg) were added and stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane) to give N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (Pyrimidin-2-yl) butan-2-yl] carbamic acid tert-butyl ester (455 mg) was obtained. A mixture of the product (455 mg) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 5 mL) was stirred at 50 degrees for 2 days. The reaction mixture was concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (1 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 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 column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / methanol) to obtain 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- (pyrimidin-2-yl) butan-2-amine N-[(2S, 3S) -4- (tert-butyl Diphenylsilyloxy) -1-iodo-3-methoxybutan-2-yl] carbamic acid tert-butyl ester (600 mg), zinc (148 mg) in N, N-dimethylformamide (5 mL) was added at room temperature under an argon atmosphere at room temperature. Stir for hours. To this mixture, 2-bromopyrimidine (163 mg) and bis (triphenylphosphine) palladium (II) dichloride (72 mg) were added and stirred at room temperature for 3 days. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane) to give N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (Pyrimidin-2-yl) butan-2-yl] carbamic acid tert-butyl ester (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 (eluent: 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 starting materials. The structural formula, spectral data, and purification conditions are shown in Table 42.

Reference Example 2-49-1
(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -1- (3-fluoropyridin-2-yl) -3-methoxybutan-2-amine trifluoroacetate N-[(2S, 3S) Of 4- (tert-butyldiphenylsilyloxy) -1-iodo-3-methoxybutan-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 were 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. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -1- (3-fluoro Pyridin-2-yl) -3-methoxybutan-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
Reference Example 2-49-2 was synthesized in the same manner as in Reference Example 2-49-1 using the corresponding starting materials. 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- (pyrimidin-2-yl) butan-2-amine
To a solution of (2R) -2-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyacetic acid methyl ester (5.0 g) in dichloromethane (50 mL) was added N, N -Diisopropylethylamine (6.8g) and methanesulfonyl chloride (3.91g) were added at 0 degree | times, and it stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The 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 (elution solvent: ethyl acetate / n-hexane) to give (2R) -2-azido-2-((4R) -2,2-dimethyl-1,3-dioxolane-4. -Yl) Acetic acid methyl ester (1.3 g) was obtained. To a solution of the product (1.3 g) in methanol (20 mL), sodium borohydride (457 mg) was added at 0 degree and stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2S) -2-azido-2-((4R) -2,2 -Dimethyl-1,3-dioxolan-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 degree, and the mixture was 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. Saturated aqueous ammonium chloride 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 residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (4R) -4-[(1S) -1-azido-2- ( [Benzyloxy) ethyl] -2,2-dimethyl-1,3-dioxolane (1.61 g) was obtained. Hydrogen chloride 1,4-dioxane solution (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 obtain (2R, 3S) -3-azido-4- (benzyloxy) butane-1,2-diol (1.45 g). To a solution of the product (1.45 g) in N, N-dimethylformamide (10 mL), imidazole (541 mg) and tert-butyldiphenylchlorosilane (1.85 g) were added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with 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 (elution solvent: ethyl acetate / n-hexane), and (2R, 3S) -3-azido-4- (benzyloxy) -1- ( tert-Butyldiphenylsilyloxy) butan-2-ol (2.49 g) was obtained. To a mixed solution of the product (2.49 g), iodomethane (966 mg) and N, N-dimethylformamide (5 mL), sodium hydride (60% oil dispersion, 315 mg) was added little by little at 0 ° C., and 1 at the same temperature. Stir for hours. Saturated aqueous ammonium chloride 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 (elution 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 the product (1.99 g), di-tert-butyl dicarbonate (893 mg), 20% palladium hydroxide on carbon (50% wet, 500 mg) and methanol (10 mL) was stirred at 50 ° C. for 12 hours under 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 (elution 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 to a mixture of the product (1 g), imidazole (230 mg), triphenylphosphine (886 mg), and tetrahydrofuran (5 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3R) -4- (tert-butyldiphenylsilyloxy)- 1-iodo-3-methoxybutan-2-yl] carbamic acid tert-butyl ester (1.1 g) was obtained. A mixture of the product (500 mg) and zinc (123 mg) in N, N-dimethylformamide (5 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (136 mg) and bis (triphenylphosphine) palladium (II) dichloride (60 mg) were added, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate. The 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 (elution solvent: ethyl acetate / n-hexane) to give N-[(2S, 3R) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (Pyrimidin-2-yl) butan-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 (eluent: 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 in the same manner as Reference Example 2-50-1 using the corresponding starting 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) propan-1-ol
(R) -N-[(1E) -2- (tert-butyldimethylsilyloxy) ethylidene] -2-methylpropane-2-sulfinamide (0.330 g) and 2-difluoromethylpyridine (0.153 g) Lithium diisopropylamide tetrahydrofuran solution (1.13 mol / L, 1.3 mL) was added to the tetrahydrofuran (6 mL) solution at −78 ° C. and stirred for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(2S) -3- (tert-butyldimethylsilyl). Oxy) -1,1-difluoro-1- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide (0.064 g) was obtained. Hydrogen chloride 1,4-dioxane solution (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 (eluent: 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
Reference Examples 2-51-2 to 2-51-3 were synthesized in the same manner as in Reference Example 2-51-1 using the corresponding starting materials. 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) butan-2-amine
(R) -N-[(1E, 2S) -3- (benzyloxy) -2-methoxypropylidene] -2-methylpropane-2-sulfinamide (0.122 g) and 2-difluoromethylpyridine (0. 053 g) in tetrahydrofuran (4 mL) was added lithium diisopropylamide tetrahydrofuran solution (1.13 mol / L, 0.36 mL) at −78 ° C. and stirred for 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (R) -N-[(2S, 3S) -4-benzyloxy-1 , 1-Difluoro-3-methoxy-1- (pyridin-2-yl) butan-2-yl] -2-methylpropane-2-sulfinamide (0.036 g) was obtained. Hydrogen chloride 1,4-dioxane solution (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 (elution solvent: methanol / ethyl acetate) to obtain 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 To a solution of 2-bromopyridine (0.885 g) in tetrahydrofuran (15 mL) at -78 degrees n-butyllithium -A hexane solution (2.6 mol / L, 1.9 mL) was added and stirred for 30 minutes. A solution of (4S) -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 warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (4S) -4- [hydroxy (pyridin-2-yl) methyl] -2. , 2-Dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.903 g) was obtained. This diastereomeric mixture (0.903 g) was dissolved in dichloromethane (30 mL). Dess-Martin periodinane (1.491 g) was added to the 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- (pyridine-2-carbonyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.805 g). It was. To a solution of the product (0.200 g) in tetrahydrofuran (1 mL) was added a methylmagnesium bromide diethyl ether solution (3.0 mol / L, 0.3 mL) at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (4S) -4- [1-hydroxy-1- (pyridin-2-yl). ) Ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.205 g). Hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a 1,4-dioxane (3 mL) mixture 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 (elution solvent: methanol / ethyl acetate) to obtain the title compound (0.060 g). The structural formula, spectral data and purification conditions are shown in Table 44.

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

Reference Example 2-54-1
(2S) -2-Amino-3-methoxy-3- (pyridin-2-yl) butan-1-ol
Diastereomeric mixture of (4S) -4- [1-hydroxy-1- (pyridin-2-yl) ethyl] -2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0 .201 g) was dissolved in tetrahydrofuran (3 mL). Sodium hydride (60% oil dispersion, 0.037 g) was added to the mixture under ice cooling. The reaction mixture was stirred for 30 min, iodomethane (0.352 g) was added, and the mixture was stirred at room temperature overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give (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). 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 column chromatography on aminopropyl silica gel (eluent: 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 tetrahydrofuran (8 mL) at −78 ° C. and n-butyl Lithium n-hexane solution (2.6 mol / L, 0.8 mL) was added and stirred for 30 minutes. Tetrahydrofuran (8 mL) of (4S) -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 warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (4S) -4- [hydroxy (pyridin-2-yl) methyl] -2. , 2-Dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.317 g) was obtained. The product (0.317 g) was dissolved in dichloromethane (4 mL). To this mixture, Deoxo-Fluor (registered trademark) (0.455 g) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4S) -4- [fluoro (pyridin-2-yl) methyl] -2 , 2-Dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.145 g) was obtained as a single diastereomer. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a solution of the product (0.145 g) in 1,4-dioxane (3 mL), 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 (elution solvent: methanol / ethyl acetate) to obtain 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- (pyrimidin-2-yl) butan-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 azeotropy. To a solution of the residue in N, N-dimethylformamide (2 mL), imidazole (149 mg) and tert-butyldiphenylchlorosilane (473 mg) were added at 0 degree, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. To a toluene (5 mL) solution of the residue, p-toluenesulfonic acid monohydrate (30 mg) and 2,2-dimethoxypropane (1.9 mL) were added, and the mixture was stirred at 85 degrees for 6 hours. 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. To a tetrahydrofuran (3 mL) solution of the residue, a tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 3.13 mL) was added at 0 degree, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with 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 (elution 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 the mixture was stirred at room temperature for 20 minutes. To this mixture was added iodomethane (218 mg) at 0 degrees and stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution 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 the product (420 mg), 20% palladium hydroxide on 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 (elution solvent: ethyl acetate / n-hexane), and (4R, 5S) -4- (hydroxymethyl) -5- (methoxymethyl) -2,2-dimethyl-1, 3-Oxazolidine-3-carboxylic acid tert-butyl ester (310 mg) was obtained. To a mixture of the product (310 mg), imidazole (123 mg), triphenylphosphine (473 mg), and tetrahydrofuran (5 mL) was added iodine (400 mg) at 0 degrees, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution 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 the product (370 mg) and zinc (138 mg) in N, N-dimethylformamide (5 mL) was stirred at room temperature for 2 hours under an argon atmosphere. To this mixture, 2-bromopyrimidine (153 mg) and bis (triphenylphosphine) palladium (II) dichloride (68 mg) were added, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate. The 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 (eluent: ethyl acetate / n-hexane) to give (4R, 5S) -5- (methoxymethyl) -2,2-dimethyl-4- (pyrimidine-2- (Ilmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (230 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (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- (pyrimidin-2-yl) butan-2-amine
(1S) -2- (benzyloxy) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (1.4 g) in dichloromethane (10 mL) (Diethylamino) sulfur trifluoride (1.34 g) was added 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (4S) -4-[(1R) -2- (benzyloxy) -1 -Fluoroethyl] -2,2-dimethyl-1,3-dioxolane (0.52 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a solution of the product (0.52 g) in methanol (3 mL), 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 (elution solvent: ethyl acetate / n-hexane), and (2S, 3R) -4- (benzyloxy) -3-fluorobutane-1 , 2-diol (0.21 g) was obtained. To a solution of the product (210 mg) in N, N-dimethylformamide (2.5 mL), imidazole (169 mg) and tert-butyldiphenylchlorosilane (300 mg) were added at 0 degrees and 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (2S, 3R) -4-benzyloxy-1- (tert-butyldiphenylsilyl). Oxy) -3-fluorobutan-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 degrees, Stir at room temperature for 0.5 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 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 degrees overnight. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution 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. To a solution of the product (0.27 g) in ethanol (3 mL) was added di-tert-butyl dicarbonate (0.20 g), 10% palladium carbon (50% wet, 30 mg), and the mixture was stirred overnight at room temperature in 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 tetra-n-butylammonium fluoride solution (1 mol / L, 670 μL) were added to the 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-[(2R, 3S) -4- (benzyloxy) -3-fluoro. -1-Hydroxybutan-2-yl] carbamic acid tert-butyl ester (113 mg) was obtained. Iodine (122 mg) was added to a mixture of the product (100 mg), imidazole (33 mg), triphenylphosphine (126 mg), and tetrahydrofuran (2 mL) at 0 degrees, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution 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, 2-bromopyrimidine (51 mg) and bis (triphenylphosphine) palladium (II) dichloride (22 mg) were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. Water was added to the filtrate and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give N-[(2R, 3S) -4- (benzyloxy) -3-fluoro. -1- (Pyrimidin-2-yl) butan-2-yl] carbamic acid tert-butyl ester (70 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (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 resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 starting materials. The structural formula, spectral data, and purification conditions are shown in Table 44.

Reference Example 2-58-1
(2R, 3S) -4- (Benzyloxy) -3-fluoro-1- (1H-pyrazol-1-yl) butan-2-amine
(1S) -2- (benzyloxy) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (1.4 g) in dichloromethane (10 mL) (Diethylamino) sulfur trifluoride (1.34 g) was added 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (4S) -4-[(1R) -2- (benzyloxy) -1 -Fluoroethyl] -2,2-dimethyl-1,3-dioxolane (0.52 g) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 3 mL) was added to a solution of the product (0.52 g) in methanol (3 mL), 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 (elution solvent: ethyl acetate / n-hexane), and (2S, 3R) -4- (benzyloxy) -3-fluorobutane-1 , 2-diol (0.21 g) was obtained. Triphenylphosphine (67 mg) and azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 116 μL) were added to a solution of the product (50 mg) in toluene (1 mL), and the mixture was 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 (elution solvent: ethyl acetate / n-hexane) to obtain (2R) -2-[(1R) -2- (benzyloxy) -1-fluoroethyl] oxirane (40 mg). It was. 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 the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (2S, 3R) -4- (benzyloxy) -3-fluoro-1- (1H-pyrazol-1-yl) butan-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 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 solvent was evaporated under reduced pressure, N, N-dimethylformamide (2 mL) and sodium azide (24 mg) were added to the resulting residue, and the mixture was stirred at 100 ° C. for 2 days. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 1-[(2R, 3S) -2-azido-4- (benzyloxy). -3-Fluorobutyl] -1H-pyrazole (33 mg) was obtained. To a solution of the product (33 mg) in ethanol (3 mL) was added 10% palladium carbon (50% wet, 10 mg), 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 (eluent: 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 starting 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-pyrazol-1-yl) butan-2-amine
To a solution of (2S) -4- (benzyloxy) -3,3-difluorobutane-1,2-diol (0.50 g) in toluene (1.5 mL) was added triphenylphosphine (678 mg) and azodicarboxylic acid diethyl ester toluene. The solution (2.2 mol / L, 1.17 mL) was added and stirred overnight at 80 degrees. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain (2S) -2- [2- (benzyloxy) -1,1-difluoroethyl] oxirane (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 the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (2S) -4- (benzyloxy) -3,3-difluoro-1- (1H-pyrazol-1-yl) butan-2-ol (400 mg) was obtained. To a solution of the product (400 mg) in dichloromethane (4 mL), pyridine (1 mL) and trifluoromethanesulfonic anhydride (560 mg) were added at −20 degrees 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. The solvent was evaporated under reduced pressure, N, N-dimethylformamide (3 mL) and sodium azide (278 mg) were added to the resulting residue, and the mixture was stirred at 100 ° C. for 1 day. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 1-[(2R) -2-azido-4- (benzyloxy) -3. , 3-Difluorobutyl] -1H-pyrazole (400 mg) was obtained. To a solution of the product (400 mg) in ethanol (5 mL) was added 10% palladium carbon (50% wet, 80 mg), and the mixture was stirred at room temperature for 1 hour in 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 (eluent: 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-triazol-2-yl) butan-2-amine hydrochloride [(2R) -2-azido- To a solution of 4-benzyloxy-3,3-difluorobutan-1-yl] (tert-butyldiphenylsilyl) ether (3.5 g) in ethanol (20 mL), di-tert-butyl dicarbonate (1.7 g), 10% palladium carbon (50% wet, 500 mg) was added, and the mixture 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. Tetrahydrofuran (10 mL) and a tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 8.5 mL) were added to the residue, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -4- (benzyloxy) -3,3-difluoro was obtained. -1-Hydroxybutan-2-yl] carbamic acid tert-butyl ester (1.5 g) was obtained. Triethylamine (611 mg) and methanesulfonyl chloride (450 mg) were added to a solution of the product (1.0 g) in dichloromethane (5 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was removed 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. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added to the mixture, and the crude product was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate), and N-[(2R) -4- (benzyloxy) -3,3-difluoro-1- (2H-1,2, , 3-Triazol-2-yl) butan-2-yl] carbamic acid tert-butyl ester (590 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a solution of the product (590 mg) in methanol (1 mL), 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- (pyrimidin-2-yl) butan-2-amine [(2R) -2-azido-4-benzyloxy-3,3-difluoro To a solution of butan-1-yl] (tert-butyldiphenylsilyl) ether (170 mg) in ethanol (2 mL) was added di-tert-butyl dicarbonate (112 mg), 10% palladium on carbon (50% wet, 50 mg), Stir overnight at room temperature under hydrogen atmosphere. The reaction mixture was passed through a celite pad and the filtrate was concentrated under reduced pressure. Tetrahydrofuran (2 mL) and tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 500 μL) were added to the 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -4- (benzyloxy) -3,3-difluoro was obtained. -1-Hydroxybutan-2-yl] carbamic acid tert-butyl ester (90 mg) was obtained. Iodine (104 mg) was added to a mixture of the product (90 mg), imidazole (28 mg), triphenylphosphine (107 mg) and tetrahydrofuran (2 mL) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution 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, 2-bromopyrimidine (20 mg) and bis (triphenylphosphine) palladium (II) dichloride (9 mg) were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and passed through a celite pad. The crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -4- (benzyloxy) -3,3-difluoro was obtained. -1- (Pyrimidin-2-yl) butan-2-yl] carbamic acid tert-butyl ester (25 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (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 resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as Reference Example 2-60-1 using the corresponding starting 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) ethan-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 with water and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (4R) -2,2-dimethyl-N- [2- (pyridin-2-yl) ethyl] -1, 3-Dioxolane-4-carboxamide (0.80 g) was obtained. To a suspension of lithium aluminum hydride (365 mg) in tetrahydrofuran (30 mL) was added (4R) -2,2-dimethyl-N- [2- (pyridin-2-yl) ethyl] -1,3-dioxolane-4- A solution of carboxamide (0.80 g) in tetrahydrofuran (12.8 mL) was added dropwise at 0 degree and stirred at room temperature for 20 hours. To the reaction mixture, water (0.366 mL), aqueous sodium hydroxide solution (15%, 0.366 mL) and water (0.366 mL) were sequentially added to quench. 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 (elution 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. To a solution of the product (273 mg) in dichloromethane (5.78 mL), triethylamine (351 mg) and trifluoroacetic anhydride (364 mg) were sequentially added at 0 degrees. The mixture was stirred at room temperature for 36 hours. Methanol (1 mL) was added to the reaction mixture and stirred for 1 hour. To this mixture was added saturated aqueous sodium hydrogen carbonate solution, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution 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. To a solution of the product (209 mg) in ethanol (6.29 mL) was added aqueous sodium hydroxide (2 mol / L, 944 μL) at room temperature, and the mixture was stirred at 60 degrees 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 Reference Example 2-61-1 using the corresponding starting 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
2- (Pyridin-2-yl) ethylamine (0.744 g) was added to a solution of (2R) -2-[(benzyloxy) methyl] oxirane (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 hr. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. 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 (elution 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. To a solution of the product (0.642 g) in ethanol (6.93 mL) was added aqueous sodium hydroxide (2 mol / L, 6.93 mL) at room temperature, and the mixture was stirred at 70 degrees 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 layers were dried over sodium sulfate, concentrated under reduced pressure, and [(2R) -3- (benzyloxy) -2-hydroxypropyl] [2- (pyridin-2-yl) ethyl] amine (0.500 g). ) To a solution of the product (499 mg) in tetrahydrofuran (8.71 mL) was added sodium hydride (60% oil dispersion, 84 mg) in two portions at 0 ° C., and the mixture was stirred for 1 hour. To this mixture was added dropwise iodomethane (163 μL), and the mixture was warmed to room temperature and stirred for 2 hours. To the reaction mixture was added saturated aqueous ammonium chloride (30 mL). The mixture was partitioned with 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 (eluent: 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
Reference Example 2-62-2 was synthesized in the same manner as Reference Example 2-62-1 using the corresponding starting materials. 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- (Pyridin-2-yl) ethan-1-amine (0.624 g) was added to a solution of (2R) -2- (methoxymethyl) oxirane (0.300 g) in tert-butyl alcohol (12.2 mL) 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 degrees. Next, trifluoroacetic anhydride (1.92 mL) was added dropwise to the mixture, and the mixture was stirred at room temperature for 3 hours. Methanol (3 mL) was added to this mixture and stirred for another 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. 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 (elution solvent: ethyl acetate / n-hexane), and 2,2,2-trifluoro-N-((2R) -2-hydroxy-3-methoxypropyl) -N- [ 2- (Pyridin-2-yl) ethyl] acetamide (0.562 g) was obtained. To a solution of the product (0.56 g) in ethanol (6.40 mL) was added aqueous sodium hydroxide (2 mol / L, 2.74 mL) at room temperature, and the mixture was stirred at 60 degrees 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 layers were 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 in the same manner as Reference Example 2-63-1 using the corresponding starting 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 ) Carboxylic 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 azodicarboxylic acid diethyl ester in 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 stirred for 30 minutes. This mixture was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to obtain a crude product. The crude product was purified by column chromatography on aminopropyl silica gel (elution 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. Hydrogen chloride 1,4-dioxane solution (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) at −78 ° C. was added n-butyllithium n-hexane solution (2.6 mol / L, 0.46 mL) for 30 minutes. Stir. (R) -N-[(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropane-2-sulfinamide (0.200 g) Tetrahydrofuran (2 mL) solution was added at the same temperature and stirred for another 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate) to obtain 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
Reference Examples 2-65-2 to 2-65-3 were synthesized in the same manner as in Reference Example 2-65-1 using the corresponding starting materials. The structural formula, spectrum 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 2-methylpyridine (0.215 g) in tetrahydrofuran (3.5 mL) was added n-butyllithium n-hexane solution (2.6 mol / L, 0.83 mL) at -78 degrees. And stirred for 30 minutes. (S) -N-[(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropane-2-sulfinamide (0.360 g) Tetrahydrofuran (7 mL) solution was added at the same temperature and stirred for another 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methanol / ethyl acetate) to obtain 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 in the same manner as Reference Example 2-66-1 using the corresponding starting materials. The structural formula, spectrum 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 Propane-2-sulfinamide 2-ethylpyridine (0.110 g) in tetrahydrofuran (2 mL) at −78 ° C. is added n-butyllithium n-hexane solution (2.6 mol / L, 0.36 mL) for 30 minutes. Stir. (R) -N-[(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropane-2-sulfinamide (0.200 g) Tetrahydrofuran (2 mL) solution was added at the same temperature and stirred for another 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution 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
Reference Example 2-67-2 was synthesized in the same manner as Reference Example 2-67-1 using the corresponding starting materials. 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-Methylpropane-2-sulfinamide 2- (tert-butyldimethylsilyloxymethyl) pyridine (0.669 g) in tetrahydrofuran (4 mL) at −78 ° C. with n-butyllithium n-hexane solution (2. 6 mol / L, 1.07 mL) was added and stirred for 30 minutes. Of (R) -N-[(1E)-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) methylidene] -2-methylpropane-2-sulfinamide (0.467 g) Tetrahydrofuran (4 mL) solution was added at the same temperature and stirred for another 30 minutes. The reaction mixture was warmed to room temperature, saturated aqueous ammonium chloride solution was added, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (R) -N-[(1S) -2- (tert-butyldimethylsilyl). Oxy) -1-((4S) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyridin-2-yl) ethyl] -2-methylpropane-2-sulfinamide A stereomeric mixture (0.554 g) was obtained as a low polarity product. The product (0.277 g) was dissolved in tetrahydrofuran (3 mL). To this mixture was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 0.6 mL) 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution 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-methylpropane-2-sulfinamide (0.119 g) as a highly polar diastereomer Got as. Sodium hydride (60% oil dispersion, 0.003 g) was added to a solution of the product (0.030 g) in N, N-dimethylformamide (0.5 mL) under ice-cooling, and the mixture was stirred for 30 minutes. 0.049 g) was added and stirred at room temperature overnight. Ice was added to the reaction mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography ((elution solvent: methanol / ethyl acetate) to give the title compound (0.021 g). The structural formula, spectral data and purification conditions were It is shown in Table 48.

Reference Example 2-69-1
(2S, 3R) -3-Amino-1-methoxy-4- (1H-pyrazol-1-yl) butan-2-ol hydrochloride N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) ) -3-Hydroxy-1- (1H-pyrazol-1-yl) butan-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 degrees for 8 hours. After the reaction mixture was cooled 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. To a tetrahydrofuran (10 mL) solution of the residue obtained by distilling off the solvent under reduced pressure, a tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 4.47 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl- 4- (1H-pyrazol-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (0.98 g) was obtained. To a solution of the product (160 mg) in N, N-dimethylformamide (1 mL) were sequentially added iodomethane (110 mg) and sodium hydride (60% oil dispersion, 35 mg) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4R, 5S) -5- (methoxymethyl) -2,2-dimethyl-4- (1H-pyrazol-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (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-pyrazol-1-yl) butan-2-ol hydrochloride
Tetrahydrofuran of (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-4- (1H-pyrazol-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (580 mg) To the (5 mL) solution, 1,8-diazabicyclo [5.4.0] -7-undecene (567 mg) and perfluorobutanesulfonyl fluoride (1.13 g) were added at 0 ° C., and the mixture was stirred at room temperature for 12 hours. Water and dichloromethane 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 sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and (4R, 5S) -5- (fluoromethyl) -2,2-dimethyl-4- (1H-pyrazol-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (240 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (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-pyrazol-1-yl) butan-2-amine hydrochloride
To a solution of (2S, 3R) -3-amino-1-fluoro-4- (1H-pyrazol-1-yl) butan-2-ol hydrochloride (133 mg) in methanol (1 mL), triethylamine (194 mg) at room temperature, 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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4-fluoro-3-hydroxy-1- ( 1H-pyrazol-1-yl) butan-2-yl] carbamic acid tert-butyl ester (170 mg) was obtained. To a mixture of the product (170 mg), tetrahydrofuran (1 mL), N, N-dimethylformamide (0.1 mL) and iodomethane (97 mg), sodium hydride (60% oil dispersion, 30 mg) was added at 0 ° C. Stir at temperature for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4-fluoro-3-methoxy-1- (1H -Pyrazol-1-yl) butan-2-yl] carbamic acid tert-butyl ester (150 mg) was obtained. Hydrogen chloride 1,4-dioxane solution (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-pyrazol-3-yl] -N-[(2R) -4-hydroxy-1- (pyridin-2-yl) butan-2-yl ] Benzamide 1-hydroxy in a suspension of 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (0.35 g) in N, N-dimethylformamide (1 mL) Benzotriazole monohydrate (0.23 g), (3R) -3-amino-4- (pyridin-2-yl) butan-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 at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain the title compound (0.18 g). The structural formula, spectral data and purification conditions are shown in Table 49.

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

Example 2-1
2- (4-Ethyl-5-phenyl-1H-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 2- (1-methoxymethyl-5-phenyl-4-vinyl -1H-pyrazol-3-yl) benzoic acid and 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazol-3-yl) benzoic acid (480 mg), 1-hydroxybenzotriazole 1 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, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (551 mg) was added 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 (elution solvent: ethyl acetate / methanol) to give 2- (1-methoxymethyl-5-phenyl-4-vinyl-1H-pyrazol-3-yl) -N- [2- ( Pyridin-2-yl) ethyl] benzamide and 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide Of 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 hydrogen chloride ethyl acetate solution (4 mol / L, 2 mL) was added. The mixture was stirred at 60 degrees for 5 hours and poured into a saturated aqueous sodium bicarbonate solution. 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 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-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 2- (1-methoxymethyl-5-phenyl-4-vinyl -1H-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide and 2- (2-methoxymethyl-5-phenyl-4-vinyl-2H-pyrazol-3-yl) A mixture of -N- [2- (pyridin-2-yl) ethyl] benzamide (100 mg) and an aqueous N-methylmorpholine-N-oxide solution (4.8 mol / L, 0.071 mL) were added to tetrahydrofuran (2 mL) and water ( 0.5 mL) of the mixture. To this mixture was added osmium tetroxide tert-butyl alcohol solution (0.1 mol / L, 0.012 mL), and the mixture was stirred at room temperature overnight. To this mixture was added sodium periodate (146 mg), and the mixture was stirred at room temperature overnight. 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 (elution solvent: ethyl acetate / methanol) to give 2- (4-formyl-1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) -N- [ 2- (Pyridin-2-yl) ethyl] benzamide and 2- (4-formyl-2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) -N- [2- (pyridin-2-yl) Ethyl] benzamide mixture (30 mg) was obtained. The product (30 mg) was dissolved in tetrahydrofuran (1 mL). Hydrochloric acid (6 mol / L, 1 mL) was added to the mixture and stirred at 50 degrees for 3 hours. The mixture was poured into saturated aqueous sodium bicarbonate and the crude product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and water, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 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-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] -3-trifluoromethoxybenzamide 3- (2-Bromo-6-trifluoromethoxyphenyl) ) -5-Phenyl-1H-pyrazole (100 mg) in dimethyl sulfoxide (4 mL) was added 1,3-bis (diphenylphosphino) propane (22 mg), N, N-diisopropylethylamine (169 mg) and 2- (pyridine- 2-yl) ethylamine (191 mg) was added and replaced with argon. To this mixture was added palladium (II) acetate (12 mg), and the mixture was stirred at 110 ° C. for 5 hours in 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, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 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 to 4-11, 5-4 to 5-7
Examples 4-2 to 4-11 and 5-4 to 5-7 were synthesized in the same manner as in Example 4-1, using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 86 to Table 88.

Example 5-1
2- [5- (3-Formylphenyl) -1H-pyrazol-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide 2- {5- [3- (1,3-dioxolane) 2-yl) phenyl] -1H-pyrazol-3-yl} -N- [2- (pyridin-2-yl) ethyl] benzamide (0.202 g) in tetrahydrofuran (1.5 mL) was added hydrochloric acid (1 mol / L, 3 mL) was added and stirred overnight at 60 degrees. 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain the title compound (0.134 g). The structural formula, spectral data, and purification conditions are shown in Table 88.

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

Example 6-1
2- {5- [3- (hydroxymethyl) phenyl] -1H-pyrazol-3-yl} -N- [2- (pyridin-2-yl) ethyl] benzamide 2- [5- (3-formylphenyl) -1H-pyrazol-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide (0.112 g) in methanol (3 mL) in sodium borohydride (0.016 g) under ice-cooling And stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate.
The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner 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-pyrazol-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide 2- [5- (2-aminophenyl) -1H Acetic anhydride (12 mg) was added to a mixture of -pyrazol-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide (40 mg) and triethylamine (21 mg) in dichloromethane (2 mL) at room temperature. . The mixture was stirred overnight and diluted with 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 (eluent: ethyl acetate / methanol) and aminopropyl silica gel column chromatography (eluent: 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 in the same manner 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-pyrazol-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide 2- [5- (2-aminophenyl)- 1H-pyrazol-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide (44 mg) and triethylamine (23 mg) in dichloromethane (2 mL) were mixed with methanesulfonyl chloride (15 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, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by aminopropyl silica gel column chromatography (eluent: 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-pyrazol-3-yl) benzoylamino] propionic acid 2- (5-phenyl-1H-pyrazol-3-yl) benzoic acid (0 .50 g) in a suspension of N, N-dimethylformamide (5 mL), 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 at room temperature overnight. . Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give (S) -3-phenyl-2- [2- (5-phenyl- 1H-pyrazol-3-yl) benzoylamino] propionic acid benzyl ester (0.95 g) was obtained. To a solution of the product (0.95 g) in tetrahydrofuran (6 mL) was added 10% palladium carbon (50% wet, 0.1 g) 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 obtain 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 in the same manner as Example 9-1 using the corresponding starting 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-pyrazol-3-yl) benzamide (S) -3-phenyl-2- [2- (5- Phenyl-1H-pyrazol-3-yl) benzoylamino] propionic acid (0.06 g) in N, N-dimethylformamide (1 mL) suspension in 1-hydroxybenzotriazole monohydrate (0.034 g), dimethyl 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 at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to obtain 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 in the same manner 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-pyrazol-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 converted to dimethyl sulfoxide ( 20 mL). To this mixture was added 1,3-bis (diphenylphosphino) propane (302 mg), N, N-diisopropylethylamine (1.41 g) and 2- (pyridin-2-yl) ethylamine (1.33 g), and argon was added. Replaced. To this mixture was added palladium (II) acetate (164 mg), and the mixture was stirred at 110 ° C. for 5 hours 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, and the extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give 3-benzyloxy-2- (1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl) -N- [2 -(Pyridin-2-yl) ethyl] benzamide and 3-benzyloxy-2- (2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) -N- [2- (pyridin-2-yl) A mixture of ethyl] benzamide (1.13 g) was obtained. This mixture (50 mg) was dissolved in ethanol (1 mL). To this solution was added an ethyl hydrogen chloride solution (4 mol / L, 2 mL), and the mixture was stirred at 60 degrees for 2 hours. The mixture was poured into saturated aqueous sodium bicarbonate and the crude product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 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-pyrazol-3-yl) -3- {N- [2- (pyridin-2-yl) ethyl] carbamoyl} phenoxy) acetic acid ethyl ester 3-hydroxy-2- (2- Methoxymethyl-5-phenyl-2H-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide (200 mg) was dissolved in N, N-dimethylformamide (3 mL). To this mixture were added potassium carbonate (193 mg) and ethyl bromoacetate (117 mg), and the mixture was stirred at room temperature overnight. 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 (elution solvent: ethyl acetate / methanol) to give 2- (2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) -3- {N- [2- ( Pyridin-2-yl) ethyl] carbamoyl} phenoxy) acetic acid ethyl ester (299 mg) was obtained. This product (204 mg) was dissolved in ethanol (2 mL). To this solution was added an ethyl hydrogen chloride solution (4 mol / L, 4 mL), and the mixture was stirred at 60 degrees for 4 hours. The mixture was poured into saturated aqueous sodium bicarbonate and the crude product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 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 in the same manner 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-pyrazol-3-yl) -N- [2- (pyridin-2-yl) ethyl] benzamide 2- (2-methoxymethyl-5- Phenyl-2H-pyrazol-3-yl) -3- {N- [2- (pyridin-2-yl) ethyl] carbamoyl} phenoxy) acetic acid ethyl ester (95 mg) was dissolved in ethanol (2 mL). To this mixture was added sodium borohydride (21 mg) at room temperature and stirred for 3 hours. To this mixture was added sodium borohydride (42 mg), stirred overnight and diluted with water. The mixture was poured into saturated aqueous sodium bicarbonate 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 (elution solvent: ethyl acetate / methanol) to give 3- (2-hydroxyethoxy) -2- (1-methoxymethyl-5-phenyl-1H-pyrazol-3-yl)- N- [2- (pyridin-2-yl) ethyl] benzamide and 3- (2-hydroxyethoxy) -2- (2-methoxymethyl-5-phenyl-2H-pyrazol-3-yl) -N- [2 A mixture (58 mg) of-(pyridin-2-yl) ethyl] benzamide was obtained. This mixture (58 mg) was dissolved in ethanol (1 mL). To this solution was added an ethyl hydrogen chloride solution (4 mol / L, 2 mL), and the mixture was stirred at 60 degrees for 2 hours. The mixture was poured into saturated aqueous sodium bicarbonate and the crude product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and water, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 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-pyrazol-3-yl) benzoylamino] -N- (pyrrolidin-3-yl) propanamide (S) -3-phenyl-2 A suspension of [2- (5-phenyl-1H-pyrazol-3-yl) benzoylamino] propionic acid (0.06 g) in dichloromethane (1 mL) was added to 3-aminopyrrolidine-1-carboxylic acid tert-butyl ester ( 0.03 g), N, N-diisopropylethylamine (0.066 g) and T3P (registered trademark) 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-pyrazol-3-yl) benzoylamino] propylamino} pyrrolidine 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. To this residue was added saturated aqueous sodium hydrogen carbonate solution, 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 evaporated under reduced pressure, ethyl acetate / n-hexane was added to the resulting residue, 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 Example 14-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 91.

Example 15-1
N-[(2S) -1-((3S) -3-hydroxypyrrolidin-1-yl) -1-oxo-3-phenylpropan-2-yl] -2- (5-phenyl-1H-pyrazole-3 -Il) benzamide
(S) -3-Phenyl-2- [2- (5-phenyl-1H-pyrazol-3-yl) benzoylamino] propionic acid (0.05 g) in methanol (2 mL) in (3S) -pyrrolidine-3 -Ol (0.016 g) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n-hydrate (0.05 g) were added And stirred at room temperature for 2 days. 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 Example 15-1 using the corresponding starting 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-pyrazol-3-yl) benzamide 2- (5-phenyl-1H-pyrazole-3- Yl) To a suspension of benzoic acid (0.105 g) in N, N-dimethylformamide (1 mL), 1-hydroxybenzotriazole monohydrate (0.092 g), N-((2R) -2-amino-3 -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. Stir 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 evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -1- (1,3-dioxo- 2,3-dihydro-1H-isoindol-2-yl) -3-phenylpropan-2-yl] -2- (5-phenyl-1H-pyrazol-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 with heating under reflux for 2 hr. 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 (eluent: 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 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 92 to Table 93.

Example 17-1
2- [5- (3,4-Difluorophenyl) -1H-pyrazol-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide 3- (2-bromophenyl) -5- ( To a solution of 3,4-difluorophenyl) -1H-pyrazole (0.200 g) in 1,4-dioxane (3.4 mL), triethylamine (0.091 g), palladium (II) acetate (0.007 g), bis (adamantane) -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 in 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 (eluent: 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 in the same manner as in Example 17-1, using the corresponding raw materials. The structural formula, spectral data, and purification conditions are shown in Table 94 to Table 95.

Example 18-1
2- [5- (3-Aminophenyl) -1H-pyrazol-3-yl] -N- [2- (pyridin-2-yl) ethyl] benzamide N- {3- [3- (2-bromophenyl) 1H-pyrazol-5-yl] phenyl} carbamic acid tert-butyl ester (0.352 g) in 1,4-dioxane (5 mL) was added to triethylamine (0.129 g) and 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 in 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 (elution solvent: ethyl acetate / methanol), and N- {3- [3- (2-{[2- (pyridin-2-yl) ethyl]. ] Carbamoyl} phenyl) -1H-pyrazol-5-yl] phenyl} carbamic acid tert-butyl ester (0.094 g) was obtained. To a solution of the product (0.094 g) in ethyl acetate (2 mL) was added an ethyl hydrogen chloride solution (4 mol / L, 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 (eluent: 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 in the same manner as in Example 18-1, using the corresponding starting material. The structural formula, spectral data, and purification conditions are shown in Table 95.

Example 19-1
2- [5- (4-Fluoro-2-hydroxyphenyl) -1H-pyrazol-3-yl] -N-[(2R) -1-hydroxy-3- (pyridin-2-yl) propan-2-yl ] Benzamide 2- [5- (4-Fluoro-2-methoxyphenyl) -1H-pyrazol-3-yl] -N-[(2R) -1-hydroxy-3- (pyridin-2-yl) propane-2 To a solution of -yl] benzamide (0.041 g) in dichloromethane (1 mL) was added boron tribromide dichloromethane solution (1 mol / L, 0.46 mL) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours and at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 19-1, using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 96 to Table 97.

Example 20-1
N- [2- (4-Aminophenyl) ethyl] -2- (5-phenyl-1H-pyrazol-3-yl) benzamide 2- (5-phenyl-1H-pyrazol-3-yl) benzoic acid (0. 05 g) in N, N-dimethylformamide (1 mL), 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 at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. 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 hr 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 (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner 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-pyrazol-3-yl) benzamide 2- (5-phenyl-1H-pyrazol-3-yl) benzoic acid (0. 05 g) in 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 at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- {2- [2- (5-phenyl-1H-pyrazole-3- Yl) benzoylamino] ethyl} benzoic acid methyl ester (0.063 g) was obtained. An 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 the mixture and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. To a suspension of the residue in N, N-dimethylformamide (1 mL), 1-hydroxybenzotriazole monohydrate (0.031 g), ammonium chloride (0.036 g), triethylamine (0.095 g) and 1-ethyl- 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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-Aminopyridin-2-yl) ethyl] -2- (5-phenyl-1H-pyrazol-3-yl) benzamide 2- (5-phenyl-1H-pyrazol-3-yl) benzoic acid To a suspension of acid (0.011 g) in N, N-dimethylformamide (1 mL) was added 1-hydroxybenzotriazole monohydrate (0.010 g), N- [2- (2-aminoethyl) pyridine-3. -Yl] 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) were added. 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 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. 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 solvent was evaporated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 22-1, using the corresponding starting material. 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-pyrazol-3-yl} -N-[(2R) -1-hydroxy-3- (pyridine-2- Yl) propan-2-yl] benzamide 2- {5- [3- (1,3-dioxolan-2-yl) -4-fluorophenyl] -1H-pyrazol-3-yl} -3-fluorobenzoic acid ( 0.086 g) in N, N-dimethylformamide (1 mL) was added (2R) -2-amino-3- (pyridin-2-yl) propan-1-ol (0.053 g), 1-hydroxybenzotriazole mono 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give 2- {5- [3- (1,3-dioxolan-2-yl). -4-fluorophenyl] -1H-pyrazol-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 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give 3-fluoro-2- [5- (4-fluoro-3-formylphenyl) -1H. -Pyrazol-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. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 23-1, using the corresponding starting 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-pyrazol-3-yl] benzoylamino} -2-methyl-3-phenylpropanamide 3-fluoro-2- [5- (4-Fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzoic acid and 3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) To a mixture of -2H-pyrazol-3-yl] benzoic acid (0.15 g) was added dichloromethane (2 mL). 1-Chloro-N, N, 2-trimethylpropenylamine (0.116 g) was added to this suspension and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dichloromethane (2 mL), (S) -2-amino-2-methyl-3-phenylpropanamide hydrochloride (0.094 g), triethylamine (0.44 g) and 4-dimethylaminopyridine (10 mg), The mixture was stirred overnight with heating under reflux. After the reaction mixture was cooled 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 evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to obtain (2S) -2- {3-fluoro-2- [5- ( 4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzoylamino} -2-methyl-3-phenylpropanamide and (2S) -2- {3-fluoro-2- [5 A mixture of-(4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoylamino} -2-methyl-3-phenylpropanamide was obtained. Methanol (1 mL) and 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. The reaction mixture was cooled 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 solvent was evaporated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 24-1, using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 99.

Example 25-1
2- [5- (4-Fluorophenyl) -1H-pyrazol-3-yl] -N- (3,4-trans-4-phenylpyrrolidin-3-yl) benzamide N- (3,4-trans-1 -Benzyl-4-phenylpyrrolidin-3-yl) -2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide (0.12 g) in ethanol (2 mL) in 10% palladium on 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 the reaction mixture was cooled to room temperature, the catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: ethyl acetate / methanol) to give the title compound (0.082 g). The structural formula, spectral data, and purification conditions are shown in Table 100.

Example 26-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N- [4-hydroxy-1- (pyridin-2-yl) butan-2-yl] benzamide 3- 1-Hydroxybenzotriazole monohydrate in a suspension of fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (0.041 g) in N, N-dimethylformamide (1 mL) Japanese product (0.031 g), 4- (benzyloxy) -1- (pyridin-2-yl) butan-2-amine (0.035 g), N, N-diisopropylethylamine (0.071 g) and 1-ethyl -3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.040 g) was added and 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N- [4- (benzyloxy) -1- (pyridin-2-yl) Butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-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 (eluent: 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 Example 26-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 100.

Example 27-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (1H-pyrazole-1 -Il) butan-2-yl] benzamide solution of 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (40 mg) in N, N-dimethylformamide (1 mL) (2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (1H-pyrazol-1-yl) butan-2-amine (56 mg), 1-hydroxybenzotriazole monohydrate Product (22 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (28 mg) and N, N-diisopropylethylamine (68 μL) were added, and 14 hours at room temperature. It stirred. 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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-methoxy-1- (1H- Pyrazol-1-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide (47 mg) was obtained. To a solution of the product (47 mg) in tetrahydrofuran (1 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 150 μL), and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 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 in the same manner as in Example 27-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 101 to Table 105.

Example 28-1
3-Fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1H-pyrazol-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-pyrazol-3-yl] benzoic acid and 3-fluoro-2- [4-Fluoro-5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid mixture (0.112 g) to N, N-dimethylformamide (2.5 mL) Was added. To this mixture was added (3R) -3-amino-4- (pyridin-2-yl) butan-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 at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to give 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazole. -3-yl] -N-[(2R) -4-hydroxy-1- (pyridin-2-yl) butan-2-yl] benzamide and 3-fluoro-2- [4-fluoro-5- (4- Fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] -N-[(2R) -4-hydroxy-1- (pyridin-2-yl) butan-2-yl] benzamide ( 0.086 g) was obtained. To this mixture (0.086 g) were added 1,4-dioxane (1 mL) and hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL), and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 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 starting materials. The structural formula, spectral data, and purification conditions are shown in Table 106 to Table 107.

Example 29-1
2- (5-Phenyl-1H-pyrazol-3-yl) -N- [2- (piperidin-2-yl) ethyl] benzamide hydrochloride 2- (5-Phenyl-1H-pyrazol-3-yl) benzoic acid To a suspension of (0.07 g) N, N-dimethylformamide (1 mL), 1-hydroxybenzotriazole monohydrate (0.061 g), 2- (2-aminoethyl) piperidine-1-carboxylic acid tert -Butyl ester (0.073 g), triethylamine (0.08 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.076 g) were added, and the mixture was stirred at room temperature overnight. 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 evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to give 2- {2- [2- (5-phenyl-1H-pyrazole- 3-yl) benzoylamino] ethyl} piperidine-1-carboxylic acid tert-butyl ester was obtained. To a solution of the product in tetrahydrofuran (2 mL) was added hydrogen chloride ethyl acetate solution (4 mol / L, 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 starting materials. The structural formula, spectral data, and purification conditions are shown in Table 108.

Example 30-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N- [3-hydroxy-2- (pyridin-2-yl) propyl] benzamide 3-Fluoro-2- [5- (4-Fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-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-pyrazol-3-yl] benzoic acid (0.07 g). To this mixture was added 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 at room temperature overnight. 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N- {3- (tert-butyldimethylsilyloxy) -2- (pyridine- 2-yl) propyl} -3-fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzamide and N- {3- (tert-butyldimethyl) A mixture of silyloxy) -2- (pyridin-2-yl) propyl} -3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzamide Got. Methanol (1 mL) and 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 (eluent: 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 in the same manner as Example 30-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 108.

Example 31-1
N-[(2R, 3R) -3,4-dihydroxy-1- (pyrimidin-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazole -3-yl] benzamide To a solution of 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (38 mg) in N, N-dimethylformamide (1 mL) (1R) -1-((4R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2- (pyrimidin-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 was concentrated under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N-[(1R) -1-((4R) -2,2-dimethyl-1, 3-Dioxolan-4-yl) -2- (pyrimidin-2-yl) ethyl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide was obtained. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a methanol (1 mL) solution of the product, 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 (eluent: 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) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) − 1H-pyrazol-3-yl] benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (76 mg), N-[(2S) -3-amino- 1-benzyloxy-4- (pyridin-2-yl) butan-2-yl] carbamic acid 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 (elution solvent: ethyl acetate / n-hexane) to obtain a diastereomer mixture (138 mg). The mixture was purified by reverse phase preparative liquid chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and N-[(2S, 3R) -1-benzyloxy-3- {3-fluoro-2- [5 -(4-Fluorophenyl) -1H-pyrazol-3-yl] benzoylamino} -4- (pyridin-2-yl) butan-2-yl] carbamic acid 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] carbamic acid benzyl ester (25 mg) was obtained. N-[(2S, 3R) -1-benzyloxy-3- {3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoylamino} -4- (pyridine- A mixture of 2-yl) butan-2-yl] carbamic acid benzyl ester (72 mg) and 10% palladium on carbon (50% wet, 40 mg) in ethanol (3 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. 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 starting materials. The structural formula, spectral data, and purification conditions are shown in Table 108.

Example 33-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-[(2R) -3-hydroxy-3-methyl-1- (pyridin-2-yl) butane -2-yl] benzamide To a solution of 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (0.060 g) in N, N-dimethylformamide (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- Dimethylaminopropyl) carbodiimide hydrochloride (0.046 g) and triethylamine (0.081 g) were added and stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and (2R) -2- {3-fluoro-2- [5- (4-fluorophenyl). ) -1H-pyrazol-3-yl] benzoylamino} -3- (pyridin-2-yl) propionic acid methyl ester (0.059 g). To a solution of the product (0.059 g) in tetrahydrofuran (1 mL) was added methylmagnesium bromide diethyl ether solution (3 mol / L, 1.13 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 33-1, using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 109.

Example 34-1HP, 34-1LP
2- [5- (4-Chlorophenyl) -1H-pyrazol-3-yl] -3-fluoro-N-[(2R) -3-hydroxy-3-methyl-1- (pyridin-2-yl) butane- 2-yl] benzamide (Example 34-1HP)
2- [5- (4-Chlorophenyl) -1H-pyrazol-3-yl] -3-fluoro-N-[(2R) -3-oxo-1- (pyridin-2-yl) butan-2-yl] Benzamide (Example 34-1LP)
To a solution of 3-fluoro-2- [5- (4-chlorophenyl) -1H-pyrazol-3-yl] benzoic acid (0.063 g) in N, N-dimethylformamide (3 mL), (2R) -2-amino- 3- (Pyridin-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 at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give (2R) -2- {3-fluoro-2- [5- (4-chlorophenyl) -1H-pyrazol-3-yl] benzoylamino} -3- (pyridin-2-yl) propionic acid methyl ester (0.068 g) was obtained. To a solution of the product (0.034 g) in tetrahydrofuran (1 mL) was added methyllithium diethyl ether solution (1.1 mol / L, 0.32 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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-pyrazol-3-yl] -3-fluoro-N-[(2R) -4-hydroxy-3- (hydroxymethyl) -3-methyl-1- (pyridine 2-yl) butan-2-yl] benzamide 3-fluoro-2- [5- (4-chlorophenyl) -1H-pyrazol-3-yl] benzoic acid (0.022 g) in N, N-dimethylformamide ( 1 mL) solution to (1R) -1- (5-methyl-2-phenyl-1,3-dioxan-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 the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to give 2- [5- (4-chlorophenyl) -1H-pyrazol-3-yl] -3. -Fluoro-N-[(1R) -1- (5-methyl-2-phenyl-1,3-dioxan-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 degrees for 12 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 starting materials. The structural formula, spectral data, and purification conditions are shown in Table 110.

Example 36-1
3-chloro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-[(2R) -4-hydroxy-1- (pyridin-2-yl) butan-2-yl ] To a suspension of benzamide 4-chloro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindol-8-one (0.05 g) in tetrahydrofuran (1 mL), (2R)- 4- (tert-Butyldimethylsilyloxy) -1- (pyridin-2-yl) butan-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 (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -4- (tert-butyldimethylsilyloxy) -1- (pyridin-2-yl) Butan-2-yl] -3-chloro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide was obtained. To the product was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 180 μL), 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as Example 36-1 using the corresponding starting 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-pyrazol-3-yl] benzoylamino} -3- (pyridin-2-yl) propanamide 3-fluoro- To a suspension of 2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (0.047 g) in dichloromethane (1 mL) was added (2R) -2-amino-3- (pyridine-2). -Yl) propanamide dihydrochloride (0.038 g), N, N-diisopropylethylamine (0.112 g) and T3P® N, N-dimethylformamide solution (1.6 mol / L, 0.2 mL). The mixture was further 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. The solvent was evaporated under reduced pressure, ethyl acetate / n-hexane was added to the resulting residue, 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 in the same manner 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-pyrazol-3-yl] benzoylamino} ethyl) benzoic acid 3-fluoro-2- [5- (4-fluoro (Phenyl) -1H-pyrazol-3-yl] benzoic acid (0.057 g) in N, N-dimethylformamide (1.5 mL) and 2- (3-bromophenyl) ethylamine (0.038 g), 1-hydroxy Benzotriazole monohydrate (0.035 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.044 g) and triethylamine (0.058 g) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N- [2- (3-bromophenyl) ethyl] -3-fluoro-2- [ 5- (4-Fluorophenyl) -1H-pyrazol-3-yl] benzamide (0.052 g) was obtained. To a suspension of the product (0.052 g) in n-propanol (1.5 mL), N-methylpyrrolidone (0.5 mL), triethylamine (0.033 g), 1,1′-bis (diphenylphosphino) ferrocene ( 0.006 g) and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (0.009 g) were added, and the mixture was stirred at 100 ° C. for 13 hours in a carbon monoxide atmosphere. After the reaction mixture was cooled 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3- (2- {3-fluoro-2- [5- (4-fluoro). Phenyl) -1H-pyrazol-3-yl] benzoylamino} ethyl) benzoic acid propyl ester (0.026 g) was obtained. An 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 the reaction mixture was cooled 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 in the same manner as in Example 38-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 112.

Example 39-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-((2R, 3S) -3,4-dihydroxy-1-phenylbutan-2-yl) benzamide To a solution of 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindol-8-one (0.030 g) in tetrahydrofuran (1 mL) (2S, 3R) -3-amino 2-Hydroxy-4-phenyl-1-butanol hydrochloride (0.020 g) and triethylamine (0.016 g) were added and 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 (eluent: 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 starting material. 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-pyrazol-3-yl] benzoylamino} -2-methyl-3- (pyridin-2-yl) propanamide To a solution of 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindol-8-one (11 mg) in tetrahydrofuran (0.5 mL) was added (2R) -2-amino-2. -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 the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as Example 40-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 113.

Example 41-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-((3R) -2H, 3H, 4H-pyrano [3,2-b] pyridine-3- Yl) benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-[(2R) -1- (3-fluoropyridin-2-yl) -3- Hydroxypropan-2-yl] benzamide (0.074 g) in N, N-dimethylformamide (2 mL) under ice cooling with N, N′-dimethylpropyleneurea (0.031 g) and sodium hydride (60% oil) Dispersion, 0.039 g) was added and stirred at 40 degrees 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 41-1 using the corresponding starting materials. The structural formula, spectral data, and purification conditions are shown in Table 113.

Example 42-1
2- [5- (4-Chlorophenyl) -1H-pyrazol-3-yl] -3-fluoro-N-[(2R) -1- (methylamino) -3-phenylpropan-2-yl] benzamide 2- To a suspension of [5- (4-chlorophenyl) -1H-pyrazol-3-yl] -3-fluorobenzoic acid (0.05 g) in N, N-dimethylformamide (1 mL) was added 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 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 2- [5- (4-chlorophenyl) -1H-pyrazol-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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 42-1 using the corresponding starting materials. The structural formula, spectrum data, and purification conditions are shown in Table 114.

Example 43-1
2- [5- (4-Chlorophenyl) -1H-pyrazol-3-yl] -3-fluoro-N-[(2R, 3S) -4-hydroxy-3-methoxy-1- (pyridin-2-yl) Butan-2-yl] benzamide suspension of 2- [5- (4-chlorophenyl) -1H-pyrazol-3-yl] -3-fluorobenzoic acid (0.03 g) in N, N-dimethylformamide (1 mL) (2R, 3S) -4- (benzyloxy) -3-methoxy-1- (pyridin-2-yl) butan-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 stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol), and N-[(2R, 3S) -4- (benzyloxy) -3-methoxy-1 -(Pyridin-2-yl) butan-2-yl] -2- [5- (4-chlorophenyl) -1H-pyrazol-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 degrees for 1 day. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogen carbonate solution, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 43-1, using the corresponding starting materials. 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-pyrazol-3-yl] -N-[(2R) -1-hydroxy-3- [3- (2H-1,2,3, 4-tetrazol-5-yl) pyridin-2-yl] propan-2-yl] benzamide N-[(2R) -1- (3-cyanopyridin-2-yl) -3-hydroxypropan-2-yl] To a solution of -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide (55 mg) in N-methylpyrrolidone (2 mL), 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 the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain the title compound (5 mg). Table 122 shows the structural formula, spectral data, and purification conditions.

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

Example 45-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-[(2R, 3S) -4-hydroxy-3-methylamino-1- (pyridine-2- Yl) butan-2-yl] benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (77 mg), N-[(2S) -3-amino- 1-Benzyloxy-4- (pyridin-2-yl) butan-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) in N, N-dimethylformamide (2 mL) 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 (elution solvent: ethyl acetate / n-hexane) to obtain a diastereomeric mixture. The mixture was purified by reverse phase preparative liquid chromatography (CapcellPakC18 UG80, elution solvent: acetonitrile / water), and N-[(2S, 3R) -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 (83 mg) and N-[( 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-pyrazol-3-yl] benzoylamino} -4- (pyridine- A mixture of 2-yl) butan-2-yl] -N-methylcarbamic acid benzyl ester (83 mg) and 10% palladium on carbon (50% wet, 50 mg) in ethanol (2 mL) was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was passed through a celite pad. The filtrate was concentrated under reduced pressure to give N-[(2R, 3S) -4-benzyloxy-3-methylamino-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5. -(4-Fluorophenyl) -1H-pyrazol-3-yl] benzamide (61 mg) was obtained. A mixture of the product (61 mg), water (0.2 mL), dimethyl sulfide (0.4 mL) in trifluoroacetic acid (1.9 mL) was stirred at 60 degrees 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 the mixture, and 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 (eluent: ethyl acetate / methanol) to give the title compound (37 mg). Table 122 shows the structural formula, spectral data, and purification conditions.

Examples 45-2 to 45-3, 43-10
Examples 45-2 to 45-3 and 43-10 were synthesized in the same manner as in Example 45-1 using the corresponding starting 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-pyrazol-3-yl] -N-[(2R) -3-hydroxy-3-methyl-1- (4-methylpyrimidine-2- Yl) butan-2-yl] benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-[(2R) -3-hydroxy-3-methyl-1 -(6-Methyl-1,6-dihydropyrimidin-2-yl) butan-2-yl] benzamide (20 mg) in toluene (1 mL) was added to 2,3-dichloro-5,6-dicyano-p-benzoquinone ( 19 mg) was added and stirred at 80 ° C. for 30 minutes. The reaction mixture was cooled to room temperature and purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain the title compound (4 mg). Table 122 shows the structural formula, spectral data, and purification conditions.

Example 47-1
3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] -N-[(1R) -1-((4S) -2-oxo-1,3-oxazolidine-4 -Yl) -2- (pyridin-2-yl) ethyl] benzamide N-[(2R, 3S) -3-amino-4-hydroxy-1- (pyridin-2-yl) butan-2-yl] -3 To a solution of -fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide (13 mg) in tetrahydrofuran (2 mL) was added carbonyldiimidazole (9 mg), and the mixture was stirred at room temperature for 1.5 hours. Stir. This mixture was purified by silica gel column chromatography (eluent: 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 in the same manner as in Example 47-1 using the corresponding starting materials. The structural formula, spectrum data, and purification conditions are shown in Table 123.

Example 48-1
N-[(2R, 3S) -3-dimethylamino-4-hydroxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) − 1H-pyrazol-3-yl] benzamide N-[(2R, 3S) -3-amino-4-hydroxy-1- (pyridin-2-yl) butan-2-yl] -3-fluoro-2- [5 To a mixed solution of-(4-fluorophenyl) -1H-pyrazol-3-yl] benzamide (29 mg) and 35% aqueous formaldehyde solution (0.106 mL) in tetrahydrofuran (0.5 mL) was added sodium triacetoxyborohydride (46 mg). At room temperature, the mixture was stirred for 15 minutes. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluent: 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 starting materials. The structural formula, spectrum 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) butan-2-yl] -3-fluoro-2- [5- (4 -Fluorophenyl) -1H-pyrazol-3-yl] benzamide 3-fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzoic acid and 3- Dichloromethane (1 mL) was added to a mixture of fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid (0.052 g). 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 give 3-fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzoyl chloride and 3-fluoro-2- [5. A mixture of-(4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoyl chloride was obtained. (2S, 3S) -4- (benzyloxy) -1,1-difluoro-3-methoxy-1- (pyridin-2-yl) butan-2-amine (0.041 g), triethylamine (0.038 g), 3-Fluoro-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] was added to a mixed solution of 4-dimethylaminopyridine (0.003 g) and dichloromethane (1 mL). A mixture of benzoyl chloride and 3-fluoro-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoyl chloride in dichloromethane (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. Stir. After adding water to the reaction mixture, the crude product was extracted with dichloromethane. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2S, 3S) -4- (benzyloxy) -1,1 -Difluoro-3-methoxy-1- (pyridin-2-yl) butan-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) butan-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 the mixture was stirred at 60 ° C. overnight. The reaction mixture was purified by aminopropyl silica gel column chromatography (eluent: 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-pyrazol-1-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindol-8-one (35 mg) in tetrahydrofuran (0.5 mL) To the suspension, (2R) -4- (benzyloxy) -3,3-difluoro-1- (1H-pyrazol-1-yl) butan-2-amine (35 mg) and N, N-diisopropylethylamine (16 mg) were added. In addition, the mixture was stirred at 85 degrees for 20 hours. After the reaction mixture was cooled 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 solvent was distilled off under reduced pressure, trifluoroacetic acid (0.95 mL), water (0.1 mL) and dimethyl sulfide (0.2 mL) were added to the residue, and the mixture was stirred at 85 degrees 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 (eluent: 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 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 124 to Table 125.

Example 50-12
N-[(2R) -3,3-difluoro-4-hydroxy-1- (2H-1,2,3-triazol-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-Fluorophenyl) -1H-pyrazol-3-yl] benzamide 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindol-8-one (48 mg) cyclopentyl (2R) -4- (benzyloxy) -3,3-difluoro-1- (2H-1,2,3-triazol-2-yl) butan-2-amine hydrochloride in 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. The reaction mixture was cooled 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane), and N-[(2R) -4- (benzyloxy) -3,3-difluoro was obtained. -1- (2H-1,2,3-triazol-2-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide (48 mg) was obtained. To the product (48 mg) was added trifluoroacetic acid (1 mL), water (0.1 mL) and dimethyl sulfide (0.2 mL), and the mixture was stirred at 60 degrees 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 (eluent: 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-Dioxolan-2-yl) phenyl] -1H-pyrazol-3-yl} -N- [2- (pyridin-2-yl) ethyl] benzamide 2- (4 -Ethynylphenyl) -1,3-dioxolane (0.209 g) in tetrahydrofuran (5 mL) was added n-butyllithium n-hexane solution (1.6 mol / L, 0.75 mL) at -78 ° C. The temperature was raised to a degree. To this mixture was added a tetrahydrofuran solution (5 mL) of N- [2- (pyridin-2-yl) ethyl] phthalimide (0.252 g), 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 the residue, and the mixture was stirred at 60 ° C. for 3 hours. After cooling the reaction mixture, the insoluble material was removed by filtration. 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 solvent was distilled off under reduced pressure, and the resulting residue was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain 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-pyrazol-3-yl] benzoyl} -N- [2- (pyridin-2-yl) ethyl] glycine
(N- {3-Fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-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 for 3 hours at 40 ° C. 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 saturated brine, dried over sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure and silica gel column chromatography. The product was purified by (elution solvent: ethyl acetate / methanol) to obtain 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 in the same manner as in Example 52-1, using the corresponding starting material. The structural formula, spectral data, and purification conditions are shown in Table 126.

Example 53-1.
2- [5- (4-Fluorophenyl) -1H-pyrazol-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- Fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzamide mixture (5 mg) in n-propanol (2 mL) suspension in N-methylpyrrolidone (0.5 mL), triethylamine (5 mg) 1,1′-bis (diphenylphosphino) ferrocene (2 mg) and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (2 mg) Under carbon atmosphere and stirred for 5 hours at 100 degrees. After the reaction mixture was cooled to room temperature, water was added and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane) to give 3-carbamoyl-2- [5- (4-fluorophenyl) -1- ( Methoxymethyl) -1H-pyrazol-3-yl] benzoic acid propyl ester and 3-carbamoyl-2- [5- (4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid A mixture of propyl esters (5 mg) was obtained. Methanol (1 mL) and 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 removed under reduced pressure to give 3-carbamoyl-2- [5- (4-fluorophenyl) -1- (methoxymethyl) -1H-pyrazol-3-yl] benzoic acid and 3-carbamoyl-2- [5. A mixture (4.5 mg) of-(4-fluorophenyl) -2- (methoxymethyl) -2H-pyrazol-3-yl] benzoic acid was obtained. To this mixture (4.5 mg) was added N, N-dimethylformamide (1 mL), (2R) -2-amino-3- (pyridin-2-yl) propan-1-ol (3 mg), 1-hydroxybenzotriazole Hydrate (3 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4 mg) and triethylamine (7 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / methanol) to give 2- [5- (4-fluorophenyl) -1- (methoxymethyl)- 1H-pyrazol-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-pyrazol-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 hydrogen chloride ethyl acetate solution (4 mol / L, 1 mL) were added to the 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 (eluent: 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- (pyridin-2-yl) propan-2-yl] -2-methylpropane-2-sulfinamide Hydrogen chloride 1,4-dioxane solution (4 mol / L, 1 mL) was added to a solution of (0.085 g) in 1,4-dioxane (1 mL), and the mixture was stirred at 60 degrees for 24 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To a solution of the residue in N, N-dimethylformamide (1 mL) was added 3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-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 at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol) to obtain the title compound (0.013 g). The structural formula, spectral data, and purification conditions are shown in Table 127.

Examples 54-2 to 54-20, 1-205 to 1-207, 1-210 to 1-211
Examples 54-2 to 54-20, 1-205 to 1-207, and 210 to 1-211 were synthesized in the same manner as in Example 54-1, using the corresponding starting materials. The structural formulas, spectral data, and purification conditions are shown in Tables 78 to 79 and Tables 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-yl] benzamide N-[(2R) -1- (6-azidopyridin-2-yl) -3-hydroxypropan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) A mixture of -1H-pyrazol-3-yl] benzamide (36 mg), tetrahydrofuran (2 mL), water (0.2 mL) and triphenylphosphine (77 mg) was stirred at 80 degrees 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 (eluent: 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-triazol-2-yl) butan-2-yl] -3-fluoro-2- [4- Fluoro-5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide 3-fluoro-2- [4-fluoro-5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzoic acid (40 mg), (2R) -4- (benzyloxy) -3,3-difluoro-1- (2H-1,2,3-triazol-2-yl) butan-2-amine hydrochloride (44 mg), N , N-diisopropylethylamine (163 mg), T3P® ethyl acetate solution (1.7 mol / L, 0.15 mL) and N-methylpyrrolidone (1 mL) were stirred at 80 ° C. for 2 days. 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution 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 degrees 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 (eluent: 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-pyrazol-3-yl) -N- (pyridin-2-ylmethyl) benzamide 2- (5-Phenyl-1H-pyrazol-3-yl) benzoic acid (50 mg) N, N -To a solution of dimethylformamide (1 mL) was added 2-amino-2- (pyridin-2-yl) acetic acid ethyl ester hydrochloride (49 mg), 1-hydroxybenzotriazole monohydrate (44 mg), 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide hydrochloride (54 mg) and N, N-diisopropylethylamine (73 mg) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography on aminopropyl silica gel (elution solvent: ethyl acetate / n-hexane) to give 2- [2- (5-phenyl-1H-pyrazol-3-yl]. ) Benzoylamino] -2- (pyridin-2-yl) acetic acid ethyl ester (29 mg) was obtained. A sodium hydroxide aqueous solution (2 mol / L, 0.05 mL) was added to a mixture of the product (29 mg) in ethanol (1 mL) -tetrahydrofuran (1 mL), 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 distilled off under reduced pressure to obtain 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 starting materials. The structural formula, spectral data, and purification conditions are shown in Table 131.

Reference Example 2-72-1
Reference Example 2-72-1 was synthesized in the same manner as in Reference Example 2-69-1 using the corresponding starting materials. The structural formula, spectrum 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-triazol-2-yl) butan-2-amine hydrochloride
In a solution of (1R) -2- (benzyloxy) -1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (660 mg) in tetrahydrofuran (10 mL), 1 , 8-diazabicyclo [5.4.0] -7-undecene (798 mg) and perfluoro-1-butanesulfonyl fluoride (1.58 g) were added at 0 degree 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 dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure. Hydrogen chloride 1,4-dioxane solution (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 (eluent: n-hexane / ethyl acetate) to give (2R, 3S) -4- (benzyloxy) -3-fluorobutane-1,2-diol (156 mg). It was. To a solution of the product (156 mg) in pyridine (2 mL), p-toluenesulfonyl chloride (153 mg) was added at 0 degree, and the mixture was 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate) to give (2R, 3S) -1- (benzyloxy) -3-fluoro-4-[(4-methylbenzenesulfonyl) oxy. ] Butan-2-ol (305 mg) was obtained. A mixture of the 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. To a solution of the residue in tetrahydrofuran (5 mL) were added di-tert-butyl dicarbonate (271 mg) and triethylamine (252 mg), 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate), and N-[(2R, 3S) -4- (benzyloxy) -3-fluoro-2-hydroxybutan-1-yl Carbamic acid tert-butyl ester (101 mg) was obtained. To a solution of the product (101 mg) in dichloromethane (3 mL) were added triethylamine (65 mg) and methanesulfonyl chloride (48 mg) at 0 degrees, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure. To a solution of the residue in N, N-dimethylformamide (1 mL), cesium carbonate (315 mg) and 1,2,3-triazole (33 mg) were added 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate), and N-[(2S, 3R) -4- (benzyloxy) -3-fluoro-1- (2H-1,2, , 3-Triazol-2-yl) butan-2-yl] carbamic acid tert-butyl ester (37 mg) was obtained. A mixture of the 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 obtain 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-triazol-2-yl) butan-2-amine hydrochloride and (2R, 3R) -3-fluoro-4 -Methoxy-1- (2H-1,2,3-triazol-2-yl) butan-2-amine hydrochloride mixture
(1S) -2- (benzyloxy) -1-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] ethane-1-ol (5.0 g) in tetrahydrofuran (30 mL) 1,8-diazabicyclo [5.4.0] -7-undecene (6.03 g) and perfluoro-1-butanesulfonyl fluoride (12.0 g) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride 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 removed under reduced pressure. Hydrogen chloride 1,4-dioxane solution (4 mol / L, 5 mL) was added to a methanol (15 mL) solution of the residue, 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 (elution solvent: n-hexane / ethyl acetate) to give (2S, 3R) -4- (benzyloxy) -3-fluorobutane-1,2-diol (1.4 g). Got. Triphenylphosphine (2.57 g) and azodicarboxylic acid 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, Stir 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 (eluent: n-hexane / ethyl acetate) to give (2S) -2-[(1R) -2- (benzyloxy) -1-fluoroethyl] oxirane (550 mg). Obtained. A mixture of the 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 (elution solvent: n-hexane / ethyl acetate), and N-[(2S, 3R) -4- (benzyloxy) -3-fluoro-2-hydroxybutan-1-yl Carbamate 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 the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure. To a solution of the residue in N, N-dimethylformamide (5 mL), cesium carbonate (2.9 g) and 1,2,3-triazole (311 mg) were added at room temperature, and the mixture was stirred at 70 degrees 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate), and N-[(2R, 3S) -4- (benzyloxy) -3-fluoro-1- (2H-1,2, , 3-Triazol-2-yl) butan-2-yl] carbamic acid tert-butyl ester (400 mg) was obtained. To a solution of the product (400 mg) in tetrahydrofuran (3 mL) was added 20% palladium hydroxide on carbon (50% wet, 100 mg), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was passed through a celite pad, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, tetrahydrofuran (3 mL), N, N-dimethylformamide (0.3 mL) and iodomethane (190 mg) was added sodium hydride (60% oil dispersion, 43 mg) at 0 degrees and stirred at room temperature for 1 hour. did. Saturated aqueous ammonium chloride 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 removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate). A mixture of the 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-pyrazol-1-yl) butan-1-yl] phthalimide
(1S) -2-Amino-1-[(4R) -2,2-dimethyl-1,3-dioxolane-4-
To a solution of [Il] ethane-1-ol (1.0 g) in dichloromethane (10 mL) were 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. 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. 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 the reaction mixture was cooled 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, and the resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate) to give N-{(1R) -1-[(4S) -2,2 -Dimethyl-1,3-dioxolan-4-yl] -2- (1H-pyrazol-1-yl) ethyl} carbamic acid 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. To a solution of the residue in N, N-dimethylformamide (3 mL) was added imidazole (440 mg), tert-butyldiphenylchlorosilane (1.06 g) was added at 0 degree, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxy-1- (1H -Pyrazol-1-yl) butan-2-yl] carbamic acid benzyl ester (650 mg) was obtained. To a solution of the product (650 mg) in toluene (5 mL), p-toluenesulfonic acid monohydrate (23 mg) and 2,2-dimethoxypropane (1.25 g) were added, and the mixture was stirred at 85 degrees for 14 hours. To the reaction mixture was added 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 sodium sulfate. The solvent was distilled off under reduced pressure. To a tetrahydrofuran (5 mL) solution of the residue, a tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 1.43 mL) was added at 0 degree, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-4- (1H-pyrazole-1- (Ilmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (330 mg) was obtained. To a solution of the product (330 mg) in tetrahydrofuran (5 mL) was added phthalimide (281 mg), triphenylphosphine (501 mg) and azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 0.87 mL), and 20 hours at room temperature. Stir. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give (4R, 5R) -5-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2 -Yl) methyl] -2,2-dimethyl-4- (1H-pyrazol-1-ylmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (500 mg) was obtained. A mixture of the 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-triazol-2-yl) butan-1-yl] acetamide
To a solution of (1S) -2-amino-1-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethan-1-ol (3.3 g) in dichloromethane (30 mL) was added N. , N-diisopropylethylamine (6.3 g) and benzyl chloroformate (5.06 g) were added at 0 degree and the mixture was stirred at room temperature for 13 hours. 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 (elution solvent: n-hexane / ethyl acetate), and N-{(2S) -2-[(4R) -2,2-dimethyl-1,3-dioxolane-4- Yl] -2-hydroxyethyl} carbamic acid 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 degrees and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. To a solution of the residue in N, N-dimethylformamide (10 mL) were added cesium carbonate (6.62 g) and 1,2,3-triazole (702 mg), and the mixture was stirred at 70 degrees for 6 hours. After the reaction mixture was cooled 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate) to give N-{(1R) -1-[(4S) -2, 2-Dimethyl-1,3-dioxolan-4-yl] -2- (2H-1,2,3-triazol-2-yl) ethyl} carbamic acid benzyl ester (800 mg) was obtained. A mixture of the 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. To a solution of the residue in N, N-dimethylformamide (3 mL), imidazole (393 mg) and tert-butyldiphenylchlorosilane (952 mg) were added at 0 degree, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxy-1- (2H -1,2,3-Triazol-2-yl) butan-2-yl] carbamic acid benzyl ester (1.0 g) was obtained. To a toluene (5 mL) solution of the product (1.0 g), p-toluenesulfonic acid monohydrate (35 mg) and 2,2-dimethoxypropane (1.91 g) were added, and the mixture was stirred at 85 degrees for 3 hours. To the reaction mixture was added 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 sodium sulfate. The solvent was distilled off under reduced pressure. To a solution of the residue in tetrahydrofuran (5 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 2.2 mL) at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-4- (2H-1,2, 3-Triazol-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (470 mg) was obtained. To a solution of the product (470 mg) in tetrahydrofuran (3 mL) was added phthalimide (399 mg), triphenylphosphine (711 mg) and azodicarboxylic acid diethyl ester toluene solution (2.2 mol / L, 1.23 mL), and 5 hours at room temperature. Stir. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give (4R, 5R) -5-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2 -Yl) methyl] -2,2-dimethyl-4- (2H-1,2,3-triazol-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 degrees for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give (4R, 5R) -5- (aminomethyl) -2,2-dimethyl-4- (2H-1, 2,3-Triazol-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid benzyl ester (430 mg) was obtained. A mixture of the 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 benzyl N-[(2R, 3R) -4-amino-3-hydroxy-1- (2H-1,2,3-triazol-2-yl) butan-2-yl] 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 removed under reduced pressure. To a solution of the residue in methanol (2 mL) was added 10% palladium carbon (50% wet, 50 mg), 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 Reference Example 2-76-1 using the corresponding starting materials. The structural formula, spectrum data, and purification conditions are shown in Table 132.

Reference Example 2-77-1
(5R) -5-[(1R) -1-amino-2- (2H-1,2,3-triazol-2-yl) ethyl] -1,3-oxazolidin-2-one N-[(2R, 3R) -4-amino-3-hydroxy-1- (2H-1,2,3-triazol-2-yl) butan-2-yl] carbamic acid 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. To a solution of the residue in methanol (2 mL) was added 10% palladium carbon (50% wet, 50 mg), 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 obtain 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 Reference Example 2-77-1 using the corresponding starting 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-triazol-2-yl) butan-2-ol hydrochloride N-[(2S) -2-((4R ) -2,2-dimethyl-1,3-dioxolan-4-yl) -2-hydroxyethyl] carbamic acid tert-butyl ester (850 mg) in dichloromethane (5 mL) was added triethylamine (660 mg) and methanesulfonyl chloride ( 485 mg) was added at 0 degree, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the crude product was extracted with dichloromethane. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure. To a solution of the residue in N, N-dimethylformamide (5 mL) were added cesium carbonate (3.18 g) and 1,2,3-triazole (337 mg), and the mixture was stirred at 70 degrees 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 (elution solvent: n-hexane / ethyl acetate), and N-[(1R) -1-((4S) -2,2-dimethyl-1,3-dioxolane-4- Yl) -2- (2H-1,2,3-triazol-2-yl) ethyl} carbamic acid 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. To a solution of the residue in N, N-dimethylformamide (3 mL) was added imidazole (272 mg), tert-butyldiphenylchlorosilane (660 mg) was added at 0 degree, and the mixture was stirred at the same temperature for 3 hours. 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 (elution solvent: n-hexane / ethyl acetate), and N-[(2R, 3S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxy-1- (2H -1,2,3-Triazol-2-yl) butan-2-yl] carbamic acid tert-butyl ester (610 mg) was obtained. To a solution of the product (610 mg) in toluene (5 mL), p-toluenesulfonic acid monohydrate (23 mg) and 2,2-dimethoxypropane (1.25 g) were added at room temperature, and the mixture was stirred at 80 ° C. for 3 days. To the reaction mixture was added 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 sodium sulfate. The solvent was distilled off under reduced pressure. To a tetrahydrofuran (5 mL) solution of the residue, a tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 1.4 mL) was added at 0 degree, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, 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 (eluent: n-hexane / ethyl acetate) to give (4R, 5S) -5- (hydroxymethyl) -2,2-dimethyl-4- (2H-1,2, 3-Triazol-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (240 mg) was obtained. To a solution of the product (240 mg) in N, N-dimethylformamide (1 mL), iodomethane (164 mg) was added, sodium hydride (60% oil dispersion, 55 mg) was added at 0 degrees, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the crude product was extracted with ethyl acetate. The 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 (elution solvent: n-hexane / ethyl acetate) to give (4R, 5S) -5- (methoxymethyl) -2,2-dimethyl-4- (2H-1,2). , 3-Triazol-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester (220 mg) was obtained. A mixture of the 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) butan-1-yl] phthalimide N-[(2R, 3S) -3,4-dihydroxy-1- To a solution of (pyridin-2-yl) butan-2-yl] carbamic acid tert-butyl ester (140 mg) in N, N-dimethylformamide (2 mL) was added imidazole (44 mg) and tert-butyldiphenylchlorosilane (163 mg) at 0 ° C. And stirred at room temperature overnight. 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 (eluent: 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) were added p-toluenesulfonic acid monohydrate (5 mg) and 2,2-dimethoxypropane (260 mg), and the mixture was stirred at 85 degrees overnight. To the reaction mixture was added 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 solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate) to give (4R, 5S) -5-[(tert-butyldiphenylsilyloxy) methyl] -2,2-dimethyl-4- (Pyridin-2-ylmethyl) -1,3-oxazolidine-3-carboxylic acid tert-butyl ester was obtained. To a solution of the product in tetrahydrofuran (1 mL) was added tetra-n-butylammonium fluoride tetrahydrofuran solution (1 mol / L, 0.42 mL) at 0 degrees, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, 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 azodicarboxylic acid diethyl ester toluene solution (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 (eluent: n-hexane / ethyl acetate) to give (4R, 5R) -5-[(1,3-dioxo-2,3-dihydro-1H-isoindole-2 -Il) methyl] -2,2-dimethyl-4- (pyridin-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 (eluent: 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 in the same manner as in Example 1-1 using the corresponding starting 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 starting materials. The structural formula, spectral data, and purification conditions are shown in Table 134.

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

Example 61-1
Example 61-1 was synthesized in the same manner as in Example 43-1 using the corresponding starting 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 starting 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 starting 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-Triazol-2-yl) butan-1-yl) acetamide 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindol-8-one (50 mg) N-[(2R, 3R) -3-amino-2-hydroxy-4- (2H-1,2,3-triazol-2-yl) butan-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 degrees for 17 hours. 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 evaporating the solvent under reduced pressure was purified by aminopropyl silica gel column chromatography (elution solvent: ethyl acetate / methanol). The crude product was purified by silica gel column chromatography (eluent: 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 starting 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-pyrazol-1-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) -1H-pyrazol-3-yl] benzamide 4-fluoro-2- (4-fluorophenyl) -8H-pyrazolo [5,1-a] isoindol-8-one (100 mg), N-[(2R, 3R ) -3-Amino-2-hydroxy-4- (1H-pyrazol-1-yl) butan-1-yl] phthalimide (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 degrees for 2 days. 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 evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate) to give N-[(2R, 3R) -4- (1,3-dioxo-2, 3-Dihydro-1H-isoindol-2-yl) -3-hydroxy-1- (1H-pyrazol-1-yl) butan-2-yl] -3-fluoro-2- [5- (4-fluorophenyl) ) -1H-pyrazol-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 degrees 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 (eluent: 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 action confirmation test

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

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

Urethane (Sigma) was dissolved in pure water to 25% w / v and anesthetized by subcutaneous administration to female SD rats at 1.25 g / kg. A catheter was inserted into the rat's bladder and femoral vein, and the bladder catheter was connected to a syringe pump and a pressure transducer. Intravesical pressure was monitored using a pressure transducer, and at the same time, 0.25% acetic acid / saline solution was continuously infused into the bladder at 3.6 mL / hour to induce detrusor overactivity. 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 urination interval extension rate (Elongation of micturition interval (%)) of the test compound was calculated from the following formula: [average value of three urination intervals immediately after administration / average value of three urination intervals immediately before administration] × 100. The dosage and results are shown in Table 139.

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

The production method of the present invention is useful as a method for producing 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 preventive agent for a disease or symptom caused by activation of TRPM8, among them lower urinary tract symptoms (LUTS), in particular, It is useful as a therapeutic or prophylactic agent for overactive bladder (OAB).

Claims (5)

Formula (I):
[Where,
Ring A is C _3-6 cycloalkyl, C _6-10 aryl or heterocycle;
X is independently CR ^4a or a nitrogen atom;
R ¹ and R ² are each independently a hydrogen atom, a halogen atom, hydroxy, amino, hydroxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano, C _1-6 alkylsulfonylamino, imidazolyl, 1,3-dioxolyl or mono (di) C _1-6 alkoxyC _1-6 alkyl;
R ³ is a hydrogen atom, a halogen atom or C _1-6 alkyl;
R ⁴ and R ^4a are each independently a hydrogen atom, a 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;
Ring B is C _6-10 aryl or heterocycle;
R ⁵ is a hydrogen atom, C _1-6 alkyl, mono (di) hydroxyC _1-6 alkyl, C _1-6 alkoxy (hydroxy) C _1-6 alkyl, carboxy C _1-6 alkyl or C _1-6 alkoxy 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 binding position);
R ^7a is independently a hydrogen atom, a 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 C _1-6 alkyl, or R ⁵ or R ^6a together with ring B is a 6-membered ring or together with R ^7a is a 5-membered Forming a ring;
R ^6b is a hydrogen atom or C _1-6 alkyl;
R ⁸ is a hydrogen atom, a 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, haloC _1-6 alkyl or tetrazolyl;
R ⁹ is hydroxy, C _1-6 alkyl or hydroxypyrrolidinyl;
R ¹⁰ and R ¹¹ are each independently a hydrogen atom, C _1-6 alkyl, hydroxy C _1-6 alkyl, mono (di) C _1-6 alkylamino C _1-6 alkyl, pyrrolidinyl or piperidinyl;
R ¹² , R ¹³ and R ¹⁴ are each independently a hydrogen atom, hydroxy, C _1-6 alkyl, NR ¹⁵ R ¹⁶ , R ¹⁵ R ¹⁶ N—C _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, a 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. Or a pharmacologically acceptable salt thereof, comprising:
The following formula:
[Wherein ring A is as defined above;
X ^P is independently CR ^4ap or a nitrogen atom;
R ^1P and R ^2P each independently represent a hydrogen atom, a halogen atom, hydroxy that may be protected with a protecting group, amino that may be protected with a protecting group, or hydroxy that may be protected with a protecting group. C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, halo C _1-6 alkyl, cyano, C _1-6 alkylsulfonylamino, 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 C _1-6 alkyl;
R ^4P and R ^4aP each independently represent a hydrogen atom, a halogen atom, an optionally protected 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 optionally protected with a protecting group, hydroxy C _1-6 alkoxy optionally protected with a protecting group, 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;
P is a hydrogen atom or a protecting group. Or a salt thereof, and
Formula (IV):
[Wherein ring B and n are as defined above;
R ^5P is a hydrogen atom, C _1-6 alkyl, mono (di) hydroxy C _1-6 alkyl optionally protected with a protecting group, or C _1-6 alkoxy (hydroxy) optionally protected with a protecting group. C _1-6 alkyl, optionally protected carboxy C _1-6 alkyl 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 binding position);
R ^7aP is independently a hydrogen atom, a fluorine atom, a hydroxy ^optionally protected with a protecting group, a hydroxy C _1-6 alkyl ^optionally protected with a protecting group, a C _1-6 alkyl, C _{1- 6 alkoxy, C 1-6} alkoxy _{C 1-6} alkyl or protected optionally protected amino _{C 1-6} alkyl group;
R ^7bP is independently a hydrogen atom, a fluorine atom or C _1-6 alkyl, or R ^5P or R ^6aP is a ^5- membered ring together with ring B or a 6-membered ring or R ^7aP Forming 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 optionally protected with a protecting group, amino optionally protected with a protecting group, cyano, C _1-6 Alkoxycarbonyl, C _1-6 alkoxy C _1-6 alkoxy, carbamoyl, C _1-6 alkoxy C _1-6 alkyl, optionally protected carboxy, azide, halo C _1-6 alkyl or tetrazolyl ;
R ^9P is hydroxy optionally protected with a protecting group, C _1-6 alkyl or hydroxypyrrolidinyl optionally protected with a protecting group;
R ^10P and R ^11P each independently represent a hydrogen atom, C _1-6 alkyl, a hydroxy C _1-6 alkyl _optionally protected with a protecting group, or a mono (di) optionally protected with a protecting group. C _1-6 alkylamino C _1-6 alkyl, pyrrolidinyl optionally protected with a protecting group or piperidinyl optionally protected with a protecting group;
R ^12P , R ^13P and R ^14P are each independently a hydrogen atom, hydroxy _optionally protected with a protecting group, C _1-6 alkyl, _optionally protected with NR ¹⁵ R ¹⁶ , protected R ¹⁵ R ¹⁶ N—C _1-6 alkyl, C _1-6 alkoxy, optionally protected with a group, mono (di) hydroxy C _1-6 alkyl, carbamoyl, C ₇ optionally protected with a protecting group _-10 aralkyloxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, a 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. ] The manufacturing method characterized by using the compound or its salt represented by this. The manufacturing method according to claim 1,
A compound represented by the formula (IIC) or (IID) or a salt thereof;
A production method using the compound represented by the formula (IV) or a salt thereof. The manufacturing method according to claim 1,
A compound represented by the formula (III) or a salt thereof;
A production method using the compound represented by the formula (IV) or a salt thereof. It is a manufacturing method given in any 1 paragraph of Claims 1-3,
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 pyridyl, pyrimidyl, piperidinyl, morpholinyl, thiazolyl, pyrazinyl, pyrazolyl, imidazolyl, pyridazinyl, azaindolidinyl, indolyl, isoquinolyl, triazolyl, tetrazolyl and dihydropyrimidinyl The manufacturing method which is a heterocyclic ring. The manufacturing method according to claim 4,
A manufacturing method in which n is 1.