JP5930010B2 - Medicament containing heteroaromatic methyl cyclic amine derivative - Google Patents

Description

  The present invention relates to a compound having orexin (OX) receptor antagonistic activity and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising them as active ingredients, particularly sleep disorders, depression, anxiety Disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, The present invention relates to a therapeutic or preventive drug for diseases such as hypertension.

  Orexin is a neuropeptide spliced from preproorexin that is specifically expressed in the lateral hypothalamic area. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep / wake patterns and the regulation of food intake. .

Both OX-A and OX-B act on the OX receptor. The OX receptor has been cloned so far in two subtypes of OX1 and OX2 receptors, both of which are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. . The OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
The tissue distribution varies depending on the subtype of the OX receptor. The OX1 receptor has a high density in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor in the nodule papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). Orexin neurons project to the brain stem and the monoamine nervous system in the hypothalamus and have an excitatory effect on those nerves. Furthermore, the expression of OX2 receptors is also seen in the acetylcholine neurons of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).

In recent years, attention has been focused on the relationship between OX1 and OX2 receptors and sleep / wake regulation, and the usefulness of compounds having OX receptor antagonistic activity has been studied. When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous exercise is increased (see Non-Patent Document 6 and Non-Patent Document 7), the normal behavior is increased (see Non-Patent Document 7), and the awakening time is extended (Non-Patent Document). 6). The action of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8). Furthermore, administration of substances that antagonize OX1 and OX2 receptors to the same extent that can be administered orally has been reported to reduce exercise, shorten sleep onset latency, increase non-REM sleep and REM sleep (non-) (See Patent Document 9 and Non-Patent Document 10).
As an OX receptor antagonistic compound, Patent Document 1 discloses a heteroaromatic ring derivative, but there is no disclosure of a compound having a heteroaromatic methyl cyclic amine skeleton described in the present application. In addition, as OX receptor antagonistic compounds, for example, compounds having various structures described in Non-Patent Document 11 are known as a review, but disclosure of compounds having a heteroaromatic methyl cyclic amine skeleton described in the present application is disclosed. There is no.

WO2003 / 002559 Publication

Zhu Y et al., J. Pharmacol. Sci., 92, 259-266, 2003. Zeitzer JM et al., Trends Pharmacol. Sci., 27, 368-374, 2006. Marcus JN et al., J. Comp. Neurol, 435, 6-25, 2001. Trivedi JP et al., FEBS Lett, 438, 71-75, 1998. Yamanaka A et al., Biochem. Biophys. Res. Commun., 290, 1237-1245, 2002. Hagan JJ et al., Proc. Natl. Acad. Sci. USA, 96, 10911-10916, 1999. Nakamura T et al., Brain Res., 873, 181-187, 2000. Smith MI et al., Neurosci. Lett., 341, 256-258, 2003. Brisbare-Roch C et al., Nat. Med., 13, 150-155, 2007. Cox CD et al., J. Med. Chem., 53, 5320-5332, 2010. John G et al., ChemMedChem., 5, 1197-1214, 2010.

  An object of the present invention is to provide a sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson, characterized by containing a novel compound having an OX receptor antagonistic action as an active ingredient It is to provide a therapeutic or prophylactic agent for diseases such as diseases, Huntington's chorea, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, and hypertension. More specifically, it is intended to provide a medicament characterized by containing a novel compound exhibiting excellent pharmacokinetics and safety as well as excellent OX receptor antagonism as an active ingredient.

As a result of intensive studies on a novel skeletal compound having an antagonistic action on the orexin receptor, the present inventors have demonstrated excellent OX receptor antagonism for certain heteroaromatic methyl cyclic amine derivatives represented by the following formulas: As a result, the present invention was completed.
Hereinafter, the present invention will be described in detail. The embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
(1) Formula (IA)

（式中、
Ｘ¹及びＸ²は、同一に又は異なって窒素原子、又は式ＣＨを示し、
Ｙは、下記式群（ａ）のいずれかの構造を示し、

(Where
X ¹ and X ² are the same or different and represent a nitrogen atom or the formula CH;
Y represents any structure of the following formula group (a),

ｎは１又は２を示し、
Ｒ¹は、水素原子、ハロゲン原子、又はＣ_1-6アルキル基を示し、
Ｒ²は、トリアゾリル基、ピリジル基、又はピリミジニル基を示し、
Ｒ³は、水素原子、ハロゲン原子、又はＣ_1-6アルキル基（該Ｃ_1-6アルキル基は、１〜３個のハロゲン原子で置換されてもよい）を示し、
Ｒ⁴は、水素原子、又はＣ_1-6アルキル基を示す）
で表される化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬。
（２）上記式（ＩA）において、
Ｒ²が、トリアゾリル基、又はピリミジニル基であり、
Ｒ³が、ハロゲン原子である（１）に記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬。
（３）上記式（ＩA）において、
ｎが２である（１）又は（２）いずれかに記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬。
（４）式（Ｉ）

n represents 1 or 2,
R ¹ represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group,
R ² represents a triazolyl group, a pyridyl group, or a pyrimidinyl group;
R ³ represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group)
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease characterized by containing a compound represented by the formula: , Huntington's disease, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension and other therapeutic or preventive drugs.
(2) In the above formula (IA),
R ² is a triazolyl group or a pyrimidinyl group;
Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia characterized by containing as an active ingredient the compound according to (1), wherein R ³ is a halogen atom, or a pharmaceutically acceptable salt thereof , Drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, gastrointestinal diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension and the like.
(3) In the above formula (IA),
a sleep disorder, depression, anxiety disorder, panic disorder characterized by containing as an active ingredient the compound according to any one of (1) or (2), wherein n is 2, or a pharmaceutically acceptable salt thereof, Treatment of diseases such as schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension or Preventive drugs.
(4) Formula (I)

（式中、
Ｘ¹及びＸ²は、同一に又は異なって窒素原子、又は式ＣＨを示し、
Ｙ¹及びＹ²は、いずれか一方が窒素原子、他方がＣＨを示し、
ｎは１又は２を示し、
Ｒ¹は、水素原子、ハロゲン原子、又はＣ_1-6アルキル基を示し、
Ｒ²は、トリアゾリル基、ピリジル基、又はピリミジニル基を示し、
Ｒ³は、水素原子、ハロゲン原子、又はＣ_1-6アルキル基（該Ｃ_1-6アルキル基は、１〜３個のハロゲン原子で置換されてもよい）を示し、
Ｒ⁴は、水素原子、又はＣ_1-6アルキル基を示す）
で表される化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬。
（５）上記式（Ｉ）において、
Ｒ²が、トリアゾリル基、又はピリミジニル基であり、
Ｒ³が、ハロゲン原子である（４）に記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬。
（６）上記式（Ｉ）において、
ｎが２である（４）又は（５）いずれかに記載の化合物、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬。
（７）上記（１）に記載される下記化合物群及びその医薬上許容される塩から選ばれるいずれか１種又は２種以上の混合物を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬。
（−）−（２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサゾリジン−３−イル）［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−（２−｛［４−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサゾリジン−３−イル）［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−（２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル）［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−（２−｛［４−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル）［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［（２Ｓ，５Ｓ）−２−｛［４−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−５−メチル−１，３−オキサゾリジン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［（２Ｓ，５Ｒ）−２−｛［４−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−５−メチル−１，３−オキサゾリジン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
［（２Ｓ，４Ｒ）−２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−４−メチル−１，３−オキサゾリジン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［（２Ｓ，４Ｓ）−２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−４−メチル−１，３−オキサゾリジン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（±）−２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサゾリジン−３−イル］［５−メチル−２−（ピリミジン−２−イル）フェニル］メタノン、
（±）−（２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサゾリジン−３−イル）［５−フルオロ−２−（ピリミジン−２−イル）フェニル］メタノン、
（±）−（２−｛［３−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサゾリジン−３−イル）［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（±）−（２−｛［４−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサゾリジン−３−イル）［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（±）−（２−｛［４−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサゾリジン−３−イル）［５−メチル−２−（ピリミジン−２−イル）フェニル］メタノン、
（−）−（２−｛［３−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサゾリジン−３−イル）［６−メチル−３−（２Ｈ−１，２，３−トリアゾール−２−イル）ピリジン−２−イル］メタノン、
（−）−（２−｛［３−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン-３-イル）［６−メチル−３−（２Ｈ−１，２，３−トリアゾール−２−イル）ピリジン−２−イル］メタノン、
（−）−（２−｛［３−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン-３-イル）［６−メチル−３−（ピリミジン−２−イル）ピリジン−２−イル］メタノン、
（−）−（２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル）［５−フルオロ−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−（２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル）［５−メチル−２−（ピリミジン−２−イル）フェニル］メタノン、
（−）−（２−｛［４−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル）［６−メチル−３−（２Ｈ−１，２，３−トリアゾール−２−イル）ピリジン−２−イル］メタノン、
（−）−（２−｛［４−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル）［６−メチル−３−（ピリミジン−２−イル）ピリジン−２−イル］メタノン、
（−）−［２−｛［３−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル］［５−フルオロ−２−（ピリミジン−２−イル）フェニル］メタノン、
（−）−［２−｛［４−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［２−｛［５−（５−フルオロピリジン−２−イル）−１，２，４−オキサジアゾール−３−イル］メチル｝−１，３−オキサジナン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［２−｛［５−（４−フルオロフェニル）−１，２，４−オキサジアゾール−３−イル］メチル｝−１，３−オキサジナン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［２−｛［５−（４−フルオロフェニル）−１，２，４−オキサジアゾール−３−イル］メチル｝−１，３−オキサジナン−３−イル］［６−メチル−３−（２Ｈ−１，２，３−トリアゾール−２−イル）ピリジン−２−イル］メタノン、
［（２Ｓ，４Ｓ）−２−｛［４−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル}−４−メチル−１，３−オキサジナン−３−イル｝［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［（２Ｓ＊，５Ｓ＊）−２−｛［４−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−５−メチル−１，３−オキサジナン−３−イル］［５−メチル−２−（２Ｈ−１，２，３-トリアゾール−２−イル）フェニル］メタノン、
（−）−［２−｛［３−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル］［５−メチル−２−（ピリミジン−２−イル)フェニル］メタノン、
（±）−［２−｛［１−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−４−イル］メチル｝−１，３−オキサジナン-３-イル］[５-メチル-２-(ピリミジン-２-イル)フェニル］メタノン、
（−）−［２−｛［４−（４−フルオロフェニル）−１Ｈ−ピラゾール−１−イル］メチル｝−１，３−オキサジナン−３−イル］［５−メチル−２−（ピリミジン−２−イル）フェニル］メタノン、
（−）−［２−｛［１−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−４−イル］メチル｝−１，３−オキサジナン−３−イル］［５−フルオロ−２−（ピリミジン−２−イル）フェニル］メタノン、
（−）−［２−｛［１−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−３−イル］メチル｝−１，３−オキサゾリジン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［２−｛［１−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−４−イル］メチル｝−１，３−オキサゾリジン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
（−）−［２−｛［１−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−４−イル］メチル｝−１，３−オキサジナン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン、
及び（−）−［（２Ｓ＊，５Ｒ＊）−２−｛［４−（５−フルオロピリジン−２−イル）−１Ｈ−ピラゾール−１−イル］メチル｝−５−メチル−１，３−オキサジナン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン。

(Where
X ¹ and X ² are the same or different and represent a nitrogen atom or the formula CH;
One of Y ¹ and Y ² represents a nitrogen atom and the other represents CH;
n represents 1 or 2,
R ¹ represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group,
R ² represents a triazolyl group, a pyridyl group, or a pyrimidinyl group;
R ³ represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 halogen atoms);
R ⁴ represents a hydrogen atom or a C _1-6 alkyl group)
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease characterized by containing a compound represented by the formula: , Huntington's disease, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension and other therapeutic or preventive drugs.
(5) In the above formula (I),
R ² is a triazolyl group or a pyrimidinyl group;
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia characterized by containing, as an active ingredient, the compound according to (4), wherein R ³ is a halogen atom, or a pharmaceutically acceptable salt thereof , Drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, gastrointestinal diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension and the like.
(6) In the above formula (I),
Sleep disorder, depression, anxiety disorder, panic disorder characterized by containing as an active ingredient the compound according to any one of (4) and (5), wherein n is 2, or a pharmaceutically acceptable salt thereof, Treatment of diseases such as schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension or Preventive drugs.
(7) Sleep disorder, depression characterized by containing, as an active ingredient, any one or a mixture of two or more selected from the following compound group described in (1) above and a pharmaceutically acceptable salt thereof: Disease, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases Therapeutic or preventive drugs for diseases such as hypertension.
(-)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(−)-(2-{[4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-(2-{[4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(−)-[(2S, 5S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3-oxazolidine-3 -Yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(−)-[(2S, 5R) -2-{[4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3-oxazolidine-3 -Yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
[(2S, 4R) -2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxazolidin-3-yl] [ 5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[(2S, 4S) -2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxazolidine-3 -Yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(±) -2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl] [5-methyl-2- ( Pyrimidin-2-yl) phenyl] methanone,
(±)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [5-fluoro-2- (Pyrimidin-2-yl) phenyl] methanone,
(±)-(2-{[3- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [5-methyl-2- (2H-1 , 2,3-triazol-2-yl) phenyl] methanone,
(±)-(2-{[4- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [5-methyl-2- (2H-1 , 2,3-triazol-2-yl) phenyl] methanone,
(±)-(2-{[4- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [5-methyl-2- (pyrimidine-2 -Yl) phenyl] methanone,
(-)-(2-{[3- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [6-methyl-3- (2H-1 , 2,3-triazol-2-yl) pyridin-2-yl] methanone,
(-)-(2-{[3- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- (2H-1 , 2,3-triazol-2-yl) pyridin-2-yl] methanone,
(-)-(2-{[3- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- (pyrimidine-2 -Yl) pyridin-2-yl] methanone,
(-)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl-2- (Pyrimidin-2-yl) phenyl] methanone,
(-)-(2-{[4- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- (2H-1 , 2,3-triazol-2-yl) pyridin-2-yl] methanone,
(-)-(2-{[4- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- (pyrimidine-2 -Yl) pyridin-2-yl] methanone,
(-)-[2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-fluoro-2- (Pyrimidin-2-yl) phenyl] methanone,
(-)-[2-{[4- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1 , 2,3-triazol-2-yl) phenyl] methanone,
(−)-[2-{[5- (5-Fluoropyridin-2-yl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl] [ 5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(−)-[2-{[5- (4-Fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl- 2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(−)-[2-{[5- (4-Fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl] [6-methyl- 3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,
[(2S, 4S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxazinan-3-yl} [ 5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(−)-[(2S *, 5S *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3-oxazinane -3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(−)-[2-{[3- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- (pyrimidine-2 -Yl) phenyl] methanone,
(±)-[2-{[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- (Pyrimidin-2-yl) phenyl] methanone,
(−)-[2-{[4- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- (pyrimidine-2 -Yl) phenyl] methanone,
(-)-[2-{[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-fluoro-2- (Pyrimidin-2-yl) phenyl] methanone,
(-)-[2-{[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] methyl} -1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[2-{[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[2-{[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
And (−)-[(2S *, 5R *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3- Oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone.

  It was revealed that the heteroaromatic methyl cyclic amine derivative of the present invention exhibits affinity for the OX receptor and antagonizes the stimulation of the receptor by a physiological ligand.

The terms used in the present specification have the following meanings.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -Butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group and the like can be mentioned.
The “sleep disorder” in the present specification is a disorder at the time of falling asleep, a sleep continuation phase, or awakening, and examples thereof include insomnia. Examples of insomnia classification include sleep onset disorder, mid-wake awakening, early morning awakening, and deep sleep disorder.

  As used herein, “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid. Salts with inorganic acids such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycol Salts with organic acids such as acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphthalene-2-sulfonic acid are included. Conversion from the educt to the salt can be performed by conventional methods.

Preferred embodiments of the compound of the present invention are listed below.
R ¹ is preferably a halogen atom or a C _1-6 alkyl group, more preferably a fluorine atom or a methyl group, and even more preferably a methyl group.
R ² is preferably a compound which is a triazolyl group or a pyrimidinyl group, more preferably a 1,2,3-triazol-2-yl group or a pyrimidin-2-yl group.
R ³ is preferably a halogen atom compound, more preferably a fluorine atom or a chlorine atom compound, and further preferably a fluorine atom compound.
R ⁴ is preferably a compound that is a hydrogen atom or a methyl group.
A compound in which n is 2 is preferable.
In addition, when this invention compound forms a hydrate or a solvate, they are also contained in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.

The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.
The compounds according to the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms and halogen atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
The compound according to the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
The compound of the present invention can be orally or parenterally administered to an adult patient in an amount of 0.001 to 500 mg once a day or divided into several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

A typical production method of the compound (I) of the present invention is shown in the following schemes A and B. The following method is an illustration of the production method of the compound of the present invention, and is not limited thereto. In the following examples of production methods, the compound may form a salt that does not hinder the reaction.
Scheme A

(Wherein X ¹ , X ² , Y ¹ , Y ² , R ¹ , R ² , R ³ and R ⁴ are the same as above. A ¹ is a halogen atom, a methanesulfonyloxy group, p-toluenesulfonyl. An oxy group or a trifluoromethanesulfonyloxy group, n is 1 or 2)

Step A-1: Compound (3) can be obtained by a condensation reaction of ethyl glyoxylate (1) and amine compound (2). The reaction in Step A-1 can be carried out in the presence or absence of a base, molecular sieve, anhydrous copper sulfate or other dehydrating agent under the conditions of reacting with an amine compound or its hydrochloride in a solvent. Examples of the base used in this reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide and sodium bicarbonate, and acetates such as sodium acetate and potassium acetate. Solvents used in this reaction include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, and aromatics such as toluene. Group hydrocarbon solvents, ethyl acetate, or a mixed solvent thereof. This reaction can be performed at 0 degreeC-100 degreeC.

Step A-2: Compound (5) can be obtained by a condensation reaction between compound (3) and carboxylic acid (4). The reaction in Step A-2 can be carried out by a general method for amidation of carboxylic acid. For example, a method of reacting (3) after introducing a carboxylic acid to a carboxylic acid halide such as carboxylic acid chloride or carboxylic acid bromide, and a method of reacting (3) with a carboxylic acid in the presence of a dehydrating condensing agent. All of these reactions can be carried out in a solvent in the presence or absence of a base. Examples of the halogenating agent used in this reaction include thionyl chloride, oxalyl chloride, phosphorus oxychloride and phosphorus oxybromide. Examples of the dehydrating condensing agent used in this reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride (EDC / HCl) and [O- (7-azabenzotriazol-1-yl). -N, N, N ', N'-tetramethyluronium hexafluorophosphate] (HATU), propanephosphonic acid anhydride, dicyclohexylcarbodiimide (DDC), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI) Activating agents such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used as necessary. Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, and toluene. An aromatic hydrocarbon solvent, ethyl acetate, or a mixed solvent thereof can be used. Examples of the base used in this reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate and sodium bicarbonate. This reaction can be performed usually at 0 ° C to 150 ° C, preferably 0 ° C to 80 ° C.

Step A-3: Compound (6) can be obtained by the reduction reaction of the ester of Compound (5). The reaction in Step A-3 is carried out in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene, or a mixed solvent thereof, lithium aluminum hydride. The reaction can be carried out under the condition of reacting with a reducing agent such as diisobutylaluminum hydride, sodium borohydride, lithium borohydride and the like. This reaction can be carried out at -80 ° C to 150 ° C, preferably 0 ° C to 25 ° C.

Step A-4: Compound (7) can be obtained by converting the hydroxy group of compound (6) into a general leaving group. Examples of the reaction in Step A-4 include chlorination, bromination, iodination, methanesulfonyloxylation, p-toluenesulfonyloxylation and the like. As an example of the chlorination reaction, for example, a method in which a leaving group is formed using methanesulfonyl chloride or the like and then substituted with a chlorine atom can be mentioned. Further examples include a method using carbon tetrachloride and triphenylphosphine, a method using thionyl chloride and phosphorus oxychloride. At this time, a chloride such as sodium chloride or potassium chloride may be added. Examples of the bromination reaction include a method using carbon tetrabromide and triphenylphosphine. Examples of the iodination reaction include a method using iodine, triphenylphosphine, and imidazole. Methanesulfonyloxylation and p-toluenesulfonyloxylation can be performed using, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, and the like. In these reactions, an appropriate base may be added. Examples of the base to be added include organic bases such as triethylamine and diisopropylethylamine, or inorganic bases such as potassium carbonate. Examples of the reaction solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, acetonitrile, and mixtures thereof. In the solvent, the reaction can be carried out under a temperature condition from about −80 ° C. to the boiling point of the solvent.

Step A-5: Compound (9) can be obtained by reacting compound (7) with compound (8). The reaction in Step A-5 is carried out by using an alcohol solvent such as methanol and ethanol, an ether solvent such as tetrahydrofuran and 1,4-dioxane, an aprotic polar solvent such as N, N-dimethylformamide and acetonitrile, dichloromethane, chloroform and the like. In an organic base such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, potassium tert-butoxide, etc. In the presence of an organic base such as an alkali metal or alkaline earth metal lower alkoxide, the reaction proceeds under a temperature condition from about -80 ° C to the boiling point of the solvent.
Scheme B

(Wherein X ¹ , X ² , Y ¹ , Y ² , R ¹ , R ² , R ³ , and R ⁴ are the same as above, R ⁵ and R ⁶ are alkoxy groups, A ² is a halogen atom, A methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group is shown.)

Step B-1: Compound (12) can be obtained by reacting compound (10) with compound (11). The reaction in Step B-1 can be carried out according to the same reaction conditions as in Step A-5.
Step B-2: Compound (13) can be obtained from compound (12). The reaction in Step B-2 is carried out by using a hydrous alcohol solvent such as hydrous methanol or hydrous ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, a halogen solvent such as dichloromethane or chloroform, a ketone solvent such as acetone, water or It can carry out on the conditions made to react with acids, such as hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, in those mixed solvents. This reaction can be carried out at 0 ° C to 80 ° C.

Step B-3: The compound (15) can be obtained by a condensation reaction of the compound (13) and the compound (14). The reaction in Step B-3 can be carried out according to the same reaction conditions as in Step A-1.
Step B-4: The compound (16) can be obtained by a condensation reaction of the compound (4) and the compound (15). The reaction in Step B-4 can be carried out according to the same reaction conditions as in Step A-2.
Scheme C

(In the formula, X ¹ , X ² , R ¹ , R ² , R ³ and R ⁴ are the same as above. R ⁵ and R ⁶ represent an alkoxy group.)

Step C-1: Compound (19) can be obtained by an amide oximation reaction of compound (17). The reaction in Step C-1 can be obtained under the conditions in which the nitrile body (17) is reacted with hydroxylamine (18) or a hydrochloride thereof in an alcohol solvent such as methanol or ethanol. This reaction can be performed at 0 degreeC-100 degreeC.

Step C-2: Compound (21) can be obtained by oxadiazole cyclization reaction of Compound (19) and Compound (20). The reaction in Step C-2 includes ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, halogen solvents such as dichloromethane and chloroform, and aromatic carbonization such as toluene. Carboxylic acid (20) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride (EDC / HCl), dicyclohexylcarbodiimide (DDC) in a hydrogen-based solvent, ethyl acetate, acetonitrile, or a mixed solvent thereof The reaction can be carried out under conditions for reaction with a dehydration condensing agent such as carbonyldiimidazole (CDI). This reaction can be performed usually at 0 ° C to 150 ° C, preferably 0 ° C to 90 ° C.

Step C-3: The compound (22) can be obtained by acid hydrolysis of the compound (21). The reaction in Step C-3 can be carried out according to the same reaction conditions as in Step B-2.

Step C-4: The compound (23) can be obtained by a condensation reaction of the compound (14) and the compound (22). The reaction in Step C-4 can be carried out according to the same reaction conditions as in Step A-1.

Step C-5: The compound (24) can be obtained by a condensation reaction of the compound (4) and the compound (23). The reaction in Step C-5 can be carried out according to the same reaction conditions as in Step A-2.
Scheme D

(In the formula, X ¹ , X ² , R ¹ , R ³ , and R ⁴ are the same as above. R ⁸ represents a triazolyl group, pyridyl group, or halogen atom, and A ³ represents a halogen atom.)

Step D-1: Compound (27) can be obtained by nucleophilic reaction or coupling reaction of compound (25) and compound (26). The reaction in Step D-1 can be carried out according to the same nucleophilic reaction conditions as in Step A-5. The coupling reaction can be performed by a general method in which an aromatic ring is substituted for a nitrogen atom of an azole compound using a catalyst and a ligand in the presence of a base. For example, the method described in Synlett, 2003, 15, 2428-2439. Examples of the catalyst used in this reaction include copper catalysts such as copper (0), copper (I) iodide, copper (I) chloride, and copper (I) oxide. Examples of the ligand used in this reaction include N, N′-dimethylethylenediamine, N, N′-dimethylcyclohexane-1,2-diamine, 2-aminopyridine, 1,10-phenanthroline, 2-hydroxybenzaldehyde oxime, and the like. Is mentioned. Examples of the base used in this reaction include potassium carbonate, potassium phosphate, potassium hydroxide, tert-butoxypotassium, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, sodium methoxide, tetrabutylammonium hydroxide and the like. . Solvents used in this reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, dichloromethane , Halogen solvents such as chloroform, aromatic hydrocarbon solvents such as toluene, water, or a mixed solvent thereof. This reaction can be carried out usually at 0 ° C to 150 ° C, preferably 25 ° C to 100 ° C.

Step D-2: The compound (28) can be obtained by an oxidation reaction of the hydroxyl group of the compound (27). The reaction in Step D-2 is carried out by using a halogen-based solvent such as dichloromethane or chloroform, an aprotic polar solvent such as dimethyl sulfoxide or acetonitrile, a desvalent reagent, a hypervalent iodine compound such as 2-iodoxybenzoic acid, or pyridinium chlorochromate. In addition, the reaction can be performed under the conditions of reacting with an oxidant such as chromate such as pyridinium dichromate, tetrapropylammonium perruthenate, and manganese dioxide. This reaction can be carried out at 0 ° C to 150 ° C, preferably 25 ° C to 80 ° C.

Step D-3: The compound (29) can be obtained by a condensation reaction of the compound (14) and the compound (28). The reaction in Step D-3 can be carried out according to the same reaction conditions as in Step A-1.

Step D-4: The compound (31) can be obtained by a condensation reaction of the compound (29) and the compound (30). The reaction in Step D-4 can be carried out according to the same reaction conditions as in Step A-2.

Step D-5: The compound (33) can be obtained by a coupling reaction of the compound (31) and the compound (32). The reaction in Step D-5 is carried out under the conditions of Stille coupling reaction using an organotin compound in an aprotic polar solvent such as N, N-dimethylformamide, an aromatic hydrocarbon solvent such as toluene or a mixed solvent thereof. It can be obtained by the following reaction. A comprehensive overview of the Stille coupling reaction can be found, for example, in Angew. Chem. Int. Ed., 43, 4704, (2004).
Scheme E

(In the formula, X ¹ , X ² , R ¹ , R ² , R ³ , R ⁴ and A ³ are the same as described above. R ⁷ is a common protecting group for carboxylic acid such as J.F.W. McOmie al, Protective groups in Organic Chemistry., and T. W. Greene and P.G.M.Wuts al, Protective groups in Organic Synthesis., etc. represents a group described in, for example, C _1-6 alkyl group, A benzyl group, etc.)

Step E-1: Compound (34) can be obtained by nucleophilic reaction or coupling reaction of compound (26) and compound (33). The reaction in Step E-1 can be carried out according to the same reaction conditions as in Step D-1.

Step E-2: The compound (35) can be obtained by the reduction reaction of the ester of the compound (34). The reaction in Step E-2 is performed in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene, or a mixed solvent thereof, lithium aluminum hydride, The reaction can be carried out under conditions for reaction with a reducing agent such as diisobutylaluminum hydride, sodium borohydride, lithium borohydride and the like. This reaction can be carried out at -80 ° C to 150 ° C, preferably 0 ° C to 25 ° C.

Step E-3: The compound (36) can be obtained by an oxidation reaction of the hydroxyl group of the compound (35). The reaction in Step E-3 can be carried out according to the same reaction conditions as in Step D-2.

Step E-4: Compound (38) can be obtained by Wittig reaction of compound (36) and compound (37). In the reaction in Step E-4, methoxymethyltriphenylphosphonium chloride is mixed with sodium hydride, hydrogen in an ether solvent such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene, or a mixed solvent thereof. After treatment with a base such as potassium bromide, tert-butoxypotassium, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, etc., the reaction can be performed under the conditions of reacting with an aldehyde. This reaction can be carried out at 0 ° C to 120 ° C. The produced enol ether can be carried out under the condition of hydrolysis using an inorganic acid such as hydrochloric acid, trifluoroacetic acid or p-toluenesulfonic acid, an organic acid, or a Lewis acid such as mercury acetate. This reaction can be carried out at 0 ° C to 80 ° C.

Step E-5: Compound (39) can be obtained by the condensation reaction of Compound (14) and Compound (38). The reaction in Step E-5 can be carried out according to the same reaction conditions as in Step A-1.

Step E-6: The compound (40) can be obtained by a condensation reaction of the compound (4) and the compound (39). The reaction in Step E-6 can be carried out according to the same reaction conditions as in Step A-2.
Scheme F

(In the formula, X ¹ , X ² , Y ¹ , Y ² , R ¹ , R ² , R ³ and R ⁴ are the same as above.)

Step F-1: Compound (9) can be obtained by Mitsunobu reaction of compound (6) and compound (8). The reaction in Step F-1 is carried out in ether solvents such as tetrahydrofuran and 1,4-dioxane, halogen solvents such as dichloromethane and chloroform or mixed solvents thereof, triphenylphosphine / diethyl azodicarboxylate (DEAD), cyanomethylene. It can be carried out under conditions for reaction with tributylphosphorane (CMBP) or the like. This reaction can be carried out at 0 ° C to 150 ° C, preferably 0 ° C to 80 ° C.
Scheme G

(In the formula, X ¹ , X ² , Y ¹ , Y ² , R ¹ , R ³ , and R ⁴ are the same as above. A ⁴ represents a halogen atom.)

Step G-1: The compound (42) can be obtained by a condensation reaction of the compound (15) and the compound (41). The reaction in Step G-1 can be carried out according to the same reaction conditions as in Step A-2.
Step G-2: The compound (43) can be obtained by a coupling reaction of the compound (32) and the compound (42). The reaction in Step G-2 can be carried out according to the same reaction conditions as in Step D-5.
Scheme H

(Wherein X ¹ , R ¹ , R ² and R ⁴ are the same as above)

Step H-1: The compound (45) can be obtained by optically isolating the compound (44). Step H-1 can be directly separated by HPLC using a polysaccharide derivative chiral column, a protein-bound chiral column, or the like. Furthermore, a method using an enzymatic method or a chemical synthesis method, a method of reacting an optical resolving agent to separate diastereomers, and then converting them to alcohols can be mentioned. In the method using an enzymatic method, an optically active substance can be prepared by dissolving a compound in a solvent and acylating an alcohol by adding lipase in the presence of an acid alkenyl ester. As the lipase, those derived from microorganisms and animals can be used. For example, porcine pancreatic lipases, Candida, Pseudomonas, Aspergillus and the like can be used. Examples of the acid alkenyl ester include vinyl acetate, vinyl propionate, and vinyl hexanoate. Reaction solvents include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as acetonitrile, halogen solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, water, or a mixture thereof. A solvent is mentioned. This reaction can be performed at 20 ° C to 50 ° C, preferably 25 ° C to 35 ° C.

In the synthesis method using a chemical method, an optically active substance can be prepared by asymmetric esterification using an asymmetric catalyst and an ester agent. Examples of the asymmetric catalyst include an optically active bisoxazoline-copper complex. Examples of the optically active bisoxazoline catalyst include (R, R) -2,2′-isopropylidenebis (4-phenyl-2-oxazoline) and (S, S) -2,6-bis (4-isopropyl-2-). (Oxazolin-2-yl) pyridine and the like, and examples of the copper catalyst include copper halides such as copper (II) trifluoromethanesulfonate, copper (II) chloride and copper (II) bromide. Examples of the ester agent include benzoyl chloride and acetyl chloride. Reaction solvents include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as acetonitrile, halogen solvents such as dichloromethane and chloroform, and aromatic carbonization such as toluene. Examples thereof include a hydrogen solvent or a mixed solvent thereof. This reaction can be performed at -30 ° C to 60 ° C, preferably -10 ° C to 30 ° C.

In the diastereomer separation method, (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene, (−)-O-acetyl-D-mandelic acid, etc. After reacting with an optical resolution agent containing chiral carboxylic acid and separating diastereomers by fractional crystallization or column chromatography, acids such as hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, potassium carbonate, potassium phosphate, hydroxylation An optically active substance can be prepared by eliminating an optical resolution agent under basic conditions such as potassium. This reaction can be carried out at 0 ° C to 80 ° C, preferably 0 ° C to 30 ° C.

Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these examples, and may be changed without departing from the scope of the present invention.

In the following Reference Examples and Examples, “KP-Sil” when purified using column chromatography is Biotage SNAPPartridge KP-Sil, “HP-Sil” is Biotage SNAPPartridge HP-Sil, “KPNH” Biotage SNAPCartridge KP-NH was used. Biotage's ISOLUTE Phase Separator was used for “ISOLUTE Phase Separator” in the post-processing operations of the following Reference Examples and Examples.

In the following Reference Examples and Examples, Silica gel 60F254 (manufactured by Merck) was used for purification by thin layer chromatography (PTLC).

In the following Reference Examples and Examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson TritionLC
Column: Waters SunFire prep C18 OBD 5.0 μm 30 × 50 mm or YMC YMC-Actus Triant 5.0 μm 50 × 30 mm
Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% trifluoroacetic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 11 minutes (A solution / B Liquid = 20/80), 12 to 13.5 minutes (liquid A / liquid B = 5/95)
Flow rate: 40 mL / min
Detection method: UV 254 nm

In the following Reference Examples and Examples, high performance liquid chromatography mass spectrum (LCMS) was measured under the following two conditions.
Condition 1
Measuring machine: Agilent Agilent 2900 and Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Solvent: A liquid; 0.1% formic acid-containing water, B liquid; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A liquid / B liquid = 80/20), 1.2 to 1.4 minutes (A liquid / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: UV 254 nm
Ionization method: Electron Impact Ionization (ESI: Electron Spray Ionization)
Condition 2
Measuring machine: SHIMADZU LCMS-2010EV
Column: SHIMADZU Shim-pack XR-ODS 2.2 μm 2.0 mm I.D. D. x30mm
Solvent: A solution; 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 1 minute (A solution / B solution = 60 / 40) 2 minutes (A liquid / B liquid = 0/100), 2.5 minutes (A liquid / B liquid = 0/100)
Flow rate: 0.6 mL / min, detection method: UV 254 nm
Ionization methods: Electron Impact Ionization (ESI) and Atmospheric Pressure Chemical Ionization (APCI)

In the following Reference Examples and Examples, mass spectra (MS) were measured under the following conditions.
MS measuring instrument: SHIMADZU LCMS-2010EV or micromass Platform LC

In the following examples, racemic analysis was performed under any of the following 13 conditions.
Condition 1
Measuring machine: Agilent 1100 Agilent
Column: CHIRALPAK AD-3 (Daicel, 4.6 mm * 250 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 30/70
Condition 2
Measuring machine: Waters Waters 2695 and 2998
Column: CHIRALPAK IB (Daicel, 4.6 mm * 250 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 90/10
Condition 3
Measuring machine: Waters Waters 2695 and 2998
Column: CHIRALPAK IB (Daicel, 4.6 mm * 250 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / 2-propanol = 30/70
Condition 4
Measuring machine: Agilent 1100 Agilent
Column: CHIRALPAK AD-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 20/80
Condition 5
Measuring machine: Agilent 1100 Agilent
Column: CHIRALPAK IB-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 50/50
Condition 6
Measuring machine: Waters Waters 996 and 2795
Column: CHIRALPAK AD-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / 2-propanol = 0/100
Condition 7
Measuring machine: Agilent 1100 Agilent
Column: CHIRALPAK IB-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 70/30
Condition 8
Measuring machine: Waters Waters 996 and 2795
Column: CHIRALPAK IB-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / 2-propanol = 30/70
Condition 9
Measuring machine: Agilent 1100 Agilent
Column: CHIRALPAK AD-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 30/70
Condition 10
Measuring machine: Agilent 1100 Agilent
Column: CHIRALPAK IB-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 90/10
Condition 11
Measuring machine: Agilent 1100 Agilent
Column: CHIRALPAK IB-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 80/20
Condition 12
Measuring machine: Waters Waters 996 and 2795
Column: CHIRALPAK ID-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / 2-propanol = 50/50
Condition 13
Measuring machine: Waters Waters 996 and 2795
Column: CHIRALPAK IA-3 (Daicel, 4.6 mm * 150 mm)
Flow rate: 1.0 mL / min
Mobile phase: hexane / 2-propanol = 20/80

In the following examples, the optical rotation analysis was measured under the following conditions.
Measuring machine: JASCO P-2300

In the following reference examples and examples, the microwave reaction apparatus was implemented using Initiator (Biotage AB).

In the following Reference Examples and Examples, compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).

In the Reference Examples and Examples, the following terms and reagents are expressed as follows.
Na ₂ SO ₄ (anhydrous sodium sulfate), MgSO ₄ (anhydrous magnesium sulfate), Cs ₂ CO ₃ (cesium carbonate), NaHCO ₃ (sodium bicarbonate), TFA (trifluoroacetic acid), THF (tetrahydrofuran), DMF (N , N-dimethylformamide), NMP (N-methyl-2-pyrrolidone) EtOAc (ethyl acetate), CHCl ₃ (chloroform), HATU [O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate], DIPEA (N, N-diisopropylethylamine), TEA (triethylamine), MsCl (methanesulfonyl chloride), NaBH ₄ (sodium borohydride), LiBH ₄ (hydrogen) Lithium borohydride).

Reference Example 1 (±) -ethyl 3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate

To a solution of ethyl glyoxylate (polymer type, 47% toluene solution) (13.4 mL, 63.5 mol) in CHCl ₃ (260 mL), activated molecular sieve 4A (200 g), 2-aminoethanol (4.0 mL, 66. 1 mmol) was added and stirred at room temperature for 24 hours. After molecular sieve 4A was separated by filtration through Celite (registered trademark), the solvent was distilled off under reduced pressure to obtain a pale yellow oil. To a solution of 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (2.7 g, 13.2 mmol) in CHCl ₃ (130 mL) was added thionyl chloride (1.4 mL, 19. 8 mmol) was added dropwise and the mixture was stirred at 75 ° C. for 5 hours. After cooling to room temperature, the solvent and excess thionyl chloride were distilled off under reduced pressure. To a solution of the obtained residue in CHCl ₃ (100 mL), with cooling with ice water, add TEA (3.7 mL, 26.4 mmol) and a CHCl ₃ (30 mL) solution of the pale yellow oil obtained in the above reaction, and warm to room temperature. Warmed and stirred for 3 hours. Water was added to the reaction mixture and extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 150 g, hexane / EtOAc = 88/12 to 0/100) to give the title compound (3.6 g) (pale yellow oil).
MS (ESI / APCI Dual pos.) M / z: 331 [M + H] ⁺

Reference Example 2 (±)-[2- (hydroxymethyl) -1,3-oxazolidine-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

(±) -Ethyl 3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate obtained in Reference Example 1 To a solution of 4.0 g, 12.1 mmol) in MeOH (60 mL), NaBH ₄ (4.6 g, 121 mmol) was added little by little while cooling with ice water, and the mixture was stirred for 1 hour. After raising the temperature to room temperature, the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, hexane / EtOAc = 88/12 to 0/100) to give the title compound (3.6 g) (colorless oil).
MS (ESI / APCI Dual pos.) M / z: 289 [M + H] ⁺

Reference Example 3 (±) -Ethyl 3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane-2-carboxylate

Ethyl glyoxylate (polymer type, 47% toluene solution) (4.3 mL, 20.4 mol), 3-aminopropan-1-ol (1.6 mL, 20.4 mmol), 5-methyl-2- (2H-1 , 2,3-Triazol-2-yl) benzoic acid (1.0 g, 4.9 mmol) was used to give the title compound (1.3 g) in the same manner as in Reference Example 1 (colorless solid).
MS (ESI pos.) M / z: 367 [M + Na] ⁺

Reference Example 4 (±)-[2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

(±) -Ethyl 3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane-2-carboxylate obtained in Reference Example 3 ( A THF solution (0.97 mL, 2.9 mmol) of LiBH ₄ was added to a THF (5 mL) solution of 0.50 g, 1.5 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc = 88/12 to 0/100) to give the title compound (0.34 g) (colorless oil).
MS (ESI pos.) M / z: 303 [M + H] ⁺

Reference Example 5 Ethyl (2RS, 5S) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxy Rat

Ethyl glyoxylate (polymer type, 47% toluene solution) (0.5 mL, 2.4 mmol), (2S) -1-aminopropan-2-ol (0.18 mL, 2.4 mmol), 5-methyl-2- Using (2H-1,2,3-triazol-2-yl) benzoic acid (0.20 g, 0.98 mmol), the title compound (0.11 g) was obtained in the same manner as in Reference Example 1 (colorless oil) object).
MS (ESI / APCI Dual pos.) M / z: 345 [M + H] ⁺

Reference Example 6 Ethyl (2RS, 5R) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxy Rat

Ethyl glyoxylate (polymer type, 47% toluene solution) (0.50 mL, 2.4 mmol), (2R) -1-aminopropan-2-ol (0.18 mL, 2.4 mmol), 5-methyl-2- Using (2H-1,2,3-triazol-2-yl) benzoic acid (0.20 g, 0.98 mmol), the title compound (0.14 g) was obtained in the same manner as in Reference Example 1 (colorless oil) object).
MS (ESI / APCI Dual pos.) M / z: 345 [M + H] ⁺

Reference Example 7 [(2S, 4R) -2- (hydroxymethyl) -4-methyl-1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2) -Yl) phenyl] methanone

Ethyl glyoxylate (polymer type, 47% toluene solution) (2.0 mL, 9.5 mmol), (2R) -2-aminopropan-1-ol (0.73 mL, 9.5 mmol), 5-methyl-2- Using (2H-1,2,3-triazol-2-yl) benzoic acid (1.0 g, 4.9 mmol) in the same manner as in Reference Example 1, ethyl (2RS, 4R) -4-methyl-3- A diastereomeric mixture of [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate was obtained. The resulting diastereomeric mixture was purified by thin layer chromatography (1 mm, hexane / EtOAc = 66/34) to give ethyl (2S, 4R) -4-methyl-3- [5-methyl-2- ( 2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate was obtained (colorless oil). The title compound (0.041 g) was obtained in the same manner as in Reference Example 4 using the obtained colorless oil as a starting material (colorless oil).
MS (ESI pos.) M / z: 303 [M + H] ⁺

Reference Example 8 [(2S, 4S) -2- (hydroxymethyl) -4-methyl-1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2) -Yl) phenyl] methanone

Ethyl glyoxylate (polymer type, 47% toluene solution) (2.0 mL, 9.5 mmol), (2S) -2-aminopropan-1-ol (0.73 mL, 9.5 mmol), 5-methyl-2- Using (2H-1,2,3-triazol-2-yl) benzoic acid (1.0 g, 4.9 mmol) in the same manner as in Reference Example 1, ethyl (2RS, 4S) -4-methyl-3- A diastereomeric mixture of [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate was obtained. The obtained diastereomeric mixture was purified by thin layer chromatography (1 mm, hexane / EtOAc = 66/34) to give ethyl (2S, 4S) -4-methyl-3- [5-methyl-2- ( 2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate was obtained (colorless oil). The title compound (0.19 g) was obtained in the same manner as in Reference Example 4 using the obtained colorless oil as a starting material (colorless solid).
MS (ESI pos.) M / z: 303 [M + H] ⁺

Reference Example 9 5-Fluoro-2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] pyridine

1- (Tetrahydro-2H-pyran-2-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (100.5 g, 0 .36 mol), 2-bromo-5-fluoropyridine (56.5 g, 0.33 mol) and Pd (PPh ₃ ) ₄ (38.0 g, 32.6 mmol) in an ethanol (300 mL) -toluene (300 mL) mixed solution. 2M Na ₂ CO ₃ aqueous solution (0.49 L, 0.99 mol) was added, and the mixture was heated to reflux for 2 hours. After allowing to cool at room temperature, water and EtOAc were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over MgSO ₄ , NH silica gel (400 g) was added to the place where the desiccant was filtered, and the mixture was stirred for 15 hours. This was filtered through acidic silica gel (eluted with n-hexane: AcOEt = 1: 1 → AcOEt), and the solvent was distilled off under reduced pressure to obtain the title compound (100 g) (pale yellow oil).
MS (ESI pos.) M / z: 248 [M + H] ⁺

Reference Example 10 5-Fluoro-2- (1H-pyrazol-3-yl) pyridine

5-Fluoro-2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] pyridine (81.2 g, 0.33 mol) obtained in Reference Example 9 in methanol (250 mL) ) 4M HCl-EtOAc solution (0.25 L, 0.96 mol) was added to the solution and stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, EtOAc (500 mL) was added to the residue, and the mixture was heated to reflux for 1 hour. The mixture was allowed to cool to room temperature and then ice-cooled. The precipitate was collected by filtration and dried to give the hydrochloride of the title compound (colorless solid). Water (700 mL) and EtOAc (350 mL) were added to the obtained hydrochloride, and the mixture was stirred for 30 minutes and then separated. The resulting organic layer was extracted 3 times with 1.2 M hydrochloric acid (100 mL). The aqueous layers were combined, adjusted to pH = 12 using 8M NaOH aqueous solution, and then extracted using CHCl ₃ . The extracted organic layer was passed through an ISOLUTE Phase Separator, and the solvent was distilled off under reduced pressure. Diisopropyl ether (300 mL) was added to the obtained residue, and the mixture was heated to reflux for 2 hours. The mixture was allowed to cool at room temperature and then ice-cooled, and the precipitate was collected by filtration and dried to give the title compound (44.9 g) (pale pink solid).
MS (ESI pos.) M / z: 164 [M + H] ⁺

Reference Example 11 5-Fluoro-2- (1H-pyrazol-4-yl) pyridine

tert-Butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (15.4 g, 52.5 mmol) and 2- To a solution of bromo-5-fluoropyridine (8.4 g, 47.7 mmol) in 1,4-dioxane (100 mL) was added Pd (PPh ₃ ) ₄ (5.5 g, 4.77 mmol), 2M Na ₂ CO ₃ aqueous solution (71 0.6 mL, 0.14 mol) was added, and the mixture was stirred at 100 ° C. for 3 hours, and then stirred at room temperature for 72 hours. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over MgSO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. A small amount of EtOAc was added to the resulting residue, which was collected by filtration and dried to obtain the title compound (4.9 g) (colorless solid).
MS (ESI pos.) M / z: 164 [M + H] ⁺

Reference Example 12 2- [1- (2,2-diethoxyethyl) -1H-pyrazol-3-yl] -5-fluoropyridine

To a solution of 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (11.7 g, 58.6 mmol) obtained in Reference Example 10 in DMF (195 mL), Cs ₂ CO ₃ (57.3 g, 0. 18 mol), 2-bromo-1,1-diethoxyethane (11.5 mL, 76.2 mmol) was stirred at 80 ° C. for 18 hours. After allowing to cool to room temperature, water was added and extracted with EtOAc. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over MgSO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc = 88/12 to 35/65) to obtain the title compound (8.2 g) (colorless oil).
MS (ESI pos.) M / z: 280 [M + H] ⁺

Reference Examples 13 to 15 were obtained by the same method as Reference Example 12. The structural formula, compound name, and MS data of the obtained compound are shown in Table 1.

Reference Example 16 Ethyl (2S, 4S) -4-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl) -1,3-oxazinane-2-carboxy Rat

A solution of (3R) -3-aminobutanoic acid (1.0 g, 9.7 mmol) in THF (10 mL) was added with 0.9 mol / L borane-THF solution (32.3 mL, 29.1 mmol) for 1 hour under ice bath cooling. The mixture was added dropwise and stirred at room temperature for 20 minutes. The temperature was raised to 80 ° C., and the mixture was further heated and stirred for 6 hours. Methanol was added while cooling in an ice bath, and the mixture was stirred for 30 minutes and then concentrated under reduced pressure. The obtained (3R) -3-aminobutan-1-ol and ethyl glyoxylate (polymer type, 47% toluene solution) (2.0 mL, 9.7 mmol), 5-methyl-2- (2H-1,2, Using 3-triazol-2-yl) benzoic acid (0.50 g, 2.5 mmol), a mixture of diastereomers was obtained in the same manner as in Reference Example 1 (colorless oil). The obtained diastereomer mixture was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 90/10 to 0/100) to obtain the title compound (0.37 g) as a low polarity compound ( Colorless oil).
MS (ESI pos.) M / z: 359 [M + H] ⁺

Reference Example 17 [(2S, 4S) -2- (hydroxymethyl) -4-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2) -Yl) phenyl] methanone

Ethyl (2S, 4S) -4-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl) -1,3-oxazinane obtained in Reference Example 16 The title compound (0.068 g) was obtained in the same manner as in Reference Example 2 using 2-carboxylate (0.37 g, 1.0 mmol) (colorless solid).
MS (ESI pos.) M / z: 317 [M + H] ⁺

Reference Example 18 Ethyl (2RS, 5RS) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane-2-carboxy Rat

3-Amino-2-methylpropan-1-ol (0.10 g, 1.1 mmol), ethyl glyoxylate (polymer type, 47% toluene solution) (2.0 mL, 9.7 mmol), 5-methyl-2- Using (2H-1,2,3-triazol-2-yl) benzoic acid (0.5 g, 2.5 mmol), the title compound (0.13 g) was obtained in the same manner as in Reference Example 1 (colorless oil) object).
MS (ESI pos.) M / z: 359 [M + H] ⁺

Reference Example 19 N-hydroxy-3,3-dimethoxypropanimidamide

To a solution of hydroxylamine monohydrochloride (3.2 g, 45.6 mmol) in MeOH (70 mL) was added NaHCO ₃ (3.8 g, 45.6 mmol), stirred at room temperature for 30 minutes, and then 3,3-dimethoxypropanenitrile. A solution of (5.0 g, 43.4 mmol) in MeOH (30 mL) was added dropwise. Stir at 80 ° C. for 15 hours. The salt formed upon cooling to room temperature was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, CHCl ₃ / MeOH = 99/1 to 90/10) to obtain the title compound (4.5 g) (pale yellow oil).
MS (ESI pos.) M / z: 171 [M + Na] ⁺

Reference Example 20 2- [3- (2,2-dimethoxyethyl) -1,2,4-oxadiazol-5-yl] -5-fluoropyridine

A solution of N-hydroxy-3,3-dimethoxypropanimidamide (1.0 g, 6.8 mmol) obtained in Reference Example 19 in DMF (3 mL) was stirred at 40 ° C. for 1 hour. To a solution of carboxylic acid (1.0 g, 7.1 mmol) and carbonyldiimidazole (1.3 g, 8.1 mmol) in DMF (4 mL) was added and stirred for 30 minutes. The reaction solution was heated to 90 ° C. and stirred for 15 hours. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc = 75 / 25-0 / 100) to obtain the title compound (1.2 g) (colorless solid).
MS (ESI pos.) M / z: 254 [M + H] ⁺

Reference Example 21 3- (2,2-dimethoxyethyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole

Using N-hydroxy-3,3-dimethoxypropanimidamide (1.0 g, 6.8 mmol) obtained in Reference Example 19 and 4-fluorobenzoic acid (0.99 g, 7.1 mmol) as raw materials, The title compound (1.4 g) was obtained by a similar method (colorless oil).
MS (ESI pos.) M / z: 253 [M + H] +

Reference Example 22 2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol

To a solution of 2- (1H-pyrazol-4-yl) ethanol (1.0 g, 8.9 mmol) and 2,5-difluoropyridine (0.89 mL, 9.8 mmol) in acetonitrile (45 mL) was added Cs ₂ CO ₃ (9 0.7 g, 17.8 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc = 90 / 10-30 / 70) to obtain the title compound (0.63 g) (colorless solid).
MS (ESI pos.) M / z: 208 [M + H] +

Reference Example 23 (±)-(2-{[3- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) (2-iodo-5-methyl Phenyl) methanone

To a solution of 1- (2,2-diethoxyethyl) -3- (4-fluorophenyl) -1H-pyrazole (0.16 g, 0.57 mmol) obtained in Reference Example 14 in CHCl ₃ (3 mL) was added TFA (3 mL). 0.42 mL, 5.7 mmol) was added, and the mixture was stirred at 35 ° C. for 6 hours. Additional TFA (0.14 mL, 0.19 mmol) was added and stirred at 35 ° C. for 6 hours. After allowing to cool to room temperature, an aqueous NaHCO ₃ solution was added to the reaction mixture, and the mixture was extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , and then the desiccant was filtered off. The solvent was distilled off under reduced pressure to obtain a colorless oil. Activated molecular sieve 4A (0.60 g) and 3-aminopropan-1-ol (0.044 mL, 0.57 mmol) were added to a solution of the obtained colorless oil in CHCl ₃ (3 mL), and the mixture was stirred at room temperature for 24 hours. Stir for hours. After the molecular sieve 4A was separated by filtration through Celite (registered trademark), the solvent was distilled off under reduced pressure to obtain a pale yellow oil. A pale yellow oil obtained by the above reaction with TEA (0.20 mL, 1.4 mmol) under cooling with ice water in a solution of 2-iodo-5-methylbenzoyl chloride (0.19 g, 0.69 mmol) in CHCl ₃ (5 mL). CHCl ₃ (2 mL) solution was added, and the mixture was warmed to room temperature and stirred for 15 hours. Water was added to the reaction mixture and extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc = 80/20 to 0/100) to give the title compound (0.19 g) (pale yellow oil).
MS (ESI pos.) M / z: 506 [M + H] +

Reference Example 24 (±)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) (2-iodo-5-methyl Phenyl) methanone

The same procedure as in Reference Example 23 using 1- (2,2-diethoxyethyl) -4- (4-fluorophenyl) -1H-pyrazole (1.0 g, 3.6 mmol) obtained in Reference Example 15 as a raw material Gave the title compound (1.2 g) (colorless oil).
MS (ESI pos.) M / z: 506 [M + H] +

Reference Example 25 (±)-(2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl) (2-iodo -5-methylphenyl) methanone

To a solution of 2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol (0.21 g, 1.0 mmol) obtained in Reference Example 22 in dimethyl sulfoxide (5 mL), 2 -Iodoxybenzoic acid (0.50 g, 1.1 mmol) was added and stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a colorless oil. The title compound (0.16 g) was obtained in the same manner as in Reference Example 23 using the obtained colorless oil as a starting material (pale yellow oil).
MS (ESI pos.) M / z: 507 [M + H] +

Reference Example 26 (±)-(5-Fluoro-2-iodophenyl) (2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3- Oxazinan-3-yl) methanone

2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol (0.21 g, 1.0 mmol) obtained in Reference Example 22 and 5-fluoro-2-iodobenzoate The title compound (0.15 g) was obtained in the same manner as in Reference Example 25 using acid (0.16 g, 0.60 mmol) (pale yellow oil).
MS (ESI pos.) M / z: 511 [M + H] ⁺

Reference Example 27 Ethyl-1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carboxylate

Copper (I) iodide in a solution of ethyl-1H-pyrazole-3-carboxylate (25.0 g, 178.4 mmol) and 2-bromo-5-fluoropyridine (47.1 g, 267.6 mmol) in DMF (300 mL) (8.5 g, 44.6 mmol), rac-trans-N, N′-dimethylcyclohexane-1,2-diamine (28.1 mL, 178.4 mmol) and Cs ₂ CO ₃ (116.2 g, 356.8 mmol) And stirred at 90 ° C. for 7 hours. After allowing to cool to room temperature, water and EtOAc were added to the reaction mixture, and the mixture was filtered through Celite (registered trademark). The organic layer was taken out from the filtrate, washed with a saturated aqueous solution of sodium chloride, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc = 70/30 to 0/100). The obtained solid was stirred and washed in hexane / EtOAc = 4/1, and then collected by filtration to obtain the title compound (29.0 g) (colorless solid).
MS (ESI pos.) M / z: 236 [M + H] +

Reference Example 28 [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] methanol

Diisobutylaluminum hydride was added to a solution of ethyl-1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carboxylate (10.0 g, 42.5 mmol) obtained in Reference Example 27 in THF (50 mL). (1.01 mol / L toluene solution, 105.2 mL, 106.3 mmol) was added while cooling at −78 ° C. After dropwise addition, the temperature was raised to 0 ° C. and stirred for 2 hours. An aqueous solution of potassium sodium tartrate (Rochelle salt) was added to the reaction mixture under ice-cooling, and the mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over MgSO ₄ , the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (8.0 g) (colorless solid).
MS (ESI pos.) M / z: 194 [M + H] +

Reference Example 29 1- (5-Fluoropyridin-2-yl) -1H-pyrazole-3-carbaldehyde

To a suspension of [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] methanol (8.0 g, 34.0 mmol) obtained in Reference Example 28 in CHCl ₃ (100 mL), 85 was added. % Manganese dioxide (29.6 g, 0.34 mol) was added, and the mixture was stirred at 60 ° C. for 3 hr. The reaction mixture was filtered through Celite (registered trademark), the solid was washed with CHCl ₃ , and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (5.3 g) (light brown solid).
MS (ESI pos.) M / z: 192 [M + H] +

Reference Example 30 [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetaldehyde

N-Butyllithium (2.6 mol / L hexane solution, 6.3 mL, 16.5 mmol) was added to a THF (50 mL) solution of methoxymethyltriphenylphosphonium chloride (5.4 g, 15.7 mmol) at −78 ° C. with cooling. And stirred for 30 minutes. The temperature was raised to 0 ° C., and 1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carbaldehyde (1.5 g, 7.9 mmol) obtained in Reference Example 29 and hexamethylphosphoric triamide were obtained. (0.5 mL) in THF (50 mL) was added and stirred for 3 hours, then warmed to room temperature and stirred for 15 hours. EtOAc and saturated aqueous sodium chloride solution were added to the reaction mixture with cooling in an ice bath and the mixture was stirred, and the organic layer was separated. After drying over MgSO ₄ , the desiccant was filtered off and the solvent was removed under reduced pressure to give a brown oil. An aqueous hydrochloric acid solution (1.2 mol / L, 10 mL) was added to the obtained brown oil, and the mixture was heated to reflux and stirred for 2 hours. After allowing to cool at room temperature, water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over MgSO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc = 80/20 to 20/80) to give the title compound (1.0 g) (light yellow oil).
MS (ESI pos.) M / z: 206 [M + H] +

Reference Example 31 [2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

(±)-[2- (Hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) obtained in Reference Example 4 ) Phenyl] methanone (1.7 g, 5.7 mmol) in toluene (29 mL) and pyridinium paratoluenesulfonate (0.14 g, 0.57 mmol) and (S) -5-allyl-2-oxabicyclo [3. 3.0] oct-8-ene (1.0 g, 6.9 mmol) was added and stirred at an oil bath temperature of 70 ° C. The mixture was allowed to cool to room temperature, saturated aqueous NaHCO ₃ solution was added, and the mixture was extracted with EtOAc. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 160 g, hexane / EtOAc = 75/25 to 40/60) to obtain a low-polarity compound (0.89 g) out of two diastereomeric mixtures. Obtained (colorless solid). Tosylic acid monohydrate (0.075 g, 0.4 mmol) was added to a solution of the obtained colorless solid diastereomer in MeOH (40 mL), and the mixture was stirred at room temperature for 15 hours. A saturated aqueous NaHCO ₃ solution was added to the reaction mixture, and the mixture was extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue is purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 75 / 25-0 / 100), (KP-NH 10 g, hexane / EtOAc = 75 / 25-0 / 100). Gave the title compound (0.58 g, 94% ee) (colorless oil). The optical purity was analyzed based on the racemic analysis conditions described above (condition 10, Rt ¹ = 10.2 min, Rt ² = 11.6 min), and a compound having a short relative retention time (Rt ¹ = 10.2 min) Obtained in excess.
MS (ESI pos.) M / z: 303 [M + H] +

The title compound can also be synthesized by another method shown below.
(±)-[2- (Hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) obtained in Reference Example 4 ) Phenyl] methanone (1.0 mg, 0.0033 mmol), vinyl acetate (0.05 mL), t-butyl methyl ether (1 mL) solution in porcine pancreatic lipase (9.5 mg, trade name Lipase from porcine pancreas Type II, (Manufactured by SIGMA) was added and stirred at 35 ° C. in a screw vial at 250 rpm for 24 hours. The reaction solution was filtered through Excrodisc 13CR (manufactured by Nippon Pole). The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to HPLC analysis under the aforementioned racemic analysis condition 10. As a result, acetic acid {3- [5-methyl-2- (2H-1,2,3-triazol-2-yl ) Benzoyl] -1,3-oxazinan-2-yl} methyl (54.5%, 81.2% ee, Rt ¹ = 7.3 min, Rt ² = 8.9 min) Excess, colorless oil) and title compound (45.5%,> 99.9% ee, Rt ¹ = 10.2 min, Rt ² = 11.6 min, compound with short retention time, excess, colorless oil )
MS (ESI pos.) M / z: 303 [M + H] +

The title compound can also be synthesized by another method shown below.
Copper (II) trifluoromethanesulfonate (0.013 g, 0.040 mmol) and (R, R) -2,2′-isopropylidenebis (4-phenyl-2-oxazoline) (0.012 g, 0.040 mmol) (±)-[2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1, 2,3-triazol-2-yl) phenyl] methanone (0.36 g, 1.2 mmol), potassium carbonate (0.16 g, 1.2 mmol), benzoyl chloride (0.069 g, 0.59 mmol) was added at room temperature. Stir for 3 hours. Water was added to the reaction mixture and extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 75 / 25-0 / 100) to give benzoic acid {3- [5-methyl-2- (2H-1, 2,3-triazol-2-yl) benzoyl] -1,3-oxazinan-2-yl} methyl (0.16 g, 55% ee) was obtained (colorless oil). The optical purity was analyzed based on the racemic analysis conditions described above (condition 10, Rt ¹ = 6.9 min, Rt ² = 7.9 min), and a compound having a short relative retention time (Rt ¹ = 6.9 min) was obtained. Obtained in excess. Potassium carbonate (0.010 g, 0.074 mmol) was added to a MeOH solution (0.5 mL) of the obtained colorless oil (0.020 g, 0.049 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 75 / 25-0 / 100) to give the title compound (0.011 g, 55% ee) (colorless oil ). The optical purity was analyzed based on the racemic analysis conditions described above (condition 10, Rt ¹ = 10.2 min, Rt ² = 11.6 min), and a compound having a short relative retention time (Rt ¹ = 10.2 min) Obtained in excess.
MS (ESI pos.) M / z: 303 [M + H] +

Reference Example 32 [2- (Chloromethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

[2- (Hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone obtained in Reference Example 31 (1.8 g, 5.8 mmol, 86.3% ee) and TEA (1.2 mL, 8.7 mmol) in CHCl ₃ (30 mL) were added with MsCl (0.54 mL, 7.0 mmol) under ice water cooling. added. The mixture was warmed to room temperature and stirred for 3 hours. Water was added to the reaction mixture and extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 88/12 to 0/100). EtOAc (10 mL) was added to the obtained residue, and the mixture was stirred for 30 minutes while cooling with an ice bath. The solid was collected by filtration to give the title compound (0.81 g, 84.2% ee) (colorless solid). The optical purity was analyzed based on the racemic analysis conditions described above (condition 12, Rt ¹ = 7.7 min, Rt ² = 11.9 min), and a compound having a long relative retention time (Rt ² = 11.9 min) was obtained. An excess compound was obtained.
MS (ESI pos.) M / z: 321 [M + H] +

Reference Example 33 Ethyl (2RS, 5SR) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane-2-carboxy Rat

Ethyl (2RS, 5RS) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane obtained in Reference Example 18 To a solution of 2-carboxylate (2.1 g, 6.0 mmol) in ethanol (60 mL) was added potassium carbonate (7.4 g, 53.8 mmol), and the mixture was stirred at 75 ° C. for 7 hours. After allowing to cool to room temperature, water was added to the reaction mixture, the solvent was concentrated under reduced pressure, and the mixture was extracted with EtOAc. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 120 g, hexane / EtOAc = 90 / 10-30 / 70) to give the title compound (0.72 g) (colorless oil).
MS (ESI pos.) M / z: 359 [M + H] +

Reference Example 34 [(2RS, 5SR) -2- (hydroxymethyl) -5-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2) -Yl) phenyl] methanone

Ethyl (2RS, 5SR) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl) -1,3-oxazinane obtained in Reference Example 33 The title compound (0.59 g) was obtained in the same manner as in Reference Example 2 using 2-carboxylate (0.72 g, 2.0 mmol) as a starting material (colorless oil).
MS (ESI pos.) M / z: 317 [M + H] +

Reference Example 35 (2RS, 5SR)-[2- (chloromethyl) -5-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2) -Yl) phenyl] methanone

[(2RS, 5SR) -2- (hydroxymethyl) -5-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3) obtained in Reference Example 34 The title compound (0.52 g) was obtained in the same manner as in Reference Example 32 using -triazol-2-yl) phenyl] methanone (0.59 g, 1.9 mmol) as a starting material (colorless oil).
MS (ESI pos.) M / z: 335 [M + H] +

Example 1 (-)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

参考例２で得られた［２−（ヒドロキシメチル）−１，３−オキサゾリジン−３−イル］［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）フェニル］メタノン（１．７ｇ、５．９ｍｍｏｌ）及びＴＥＡ（１．２ｍＬ、８．８ｍｍｏｌ）のＣＨＣｌ₃（３０ｍＬ）溶液に、氷水冷却下、ＭｓＣｌ（０．５５ｍＬ、７．１ｍｍｏｌ）を加え、１時間撹拌した。氷水冷却下、水を加え、ＣＨＣｌ₃で抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、Ｎａ₂ＳＯ₄で乾燥し、乾燥剤を濾別後、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（ＨＰ−Ｓｉｌ ５０ｇ、ｈｅｘａｎｅ／ＥｔＯＡｃ＝８８／１２〜０／１００）にて精製することにより｛３−［５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）ベンゾイル］−１，３−オキサゾリジン−２−イル｝メチル メタンスルホナートを得た（淡黄色油状物）。得られた淡黄色油状物のＤＭＦ（３０ｍＬ）溶液に５−フルオロ−２−（１Ｈ−ピラゾール−３−イル）ピリジン（１．３ｇ、８．１ｍｍｏｌ）、Ｃｓ₂ＣＯ₃（４．８ｇ、１４．７ｍｍｏｌ）を加え、油浴温度９０℃で２４時間撹拌した。室温まで放冷し、水を加えた後、ＥｔＯＡｃで抽出し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー（ＨＰ−Ｓｉｌ １５０ｇ、ｈｅｘａｎｅ／ＥｔＯＡｃ＝８８／１２〜０／１００）で精製し表題化合物のラセミ混合物（１．２ｇ）を得た（淡黄色油状物）。得られたラセミ混合物を前述のラセミ体分析条件（条件１、Ｒｔ¹＝３．６ ｍｉｎ、Ｒｔ²＝７．０ ｍｉｎ）に基づきセミ分取カラムを用いて分割し、相対保持時間が短い（Ｒｔ¹＝３．６ ｍｉｎ）表題化合物（０．３９ｇ）を得た（無色固体）。
ＬＣＭＳ ｒｅｔｅｎｔｉｏｎ ｔｉｍｅ ０．９０ ｍｉｎ．
ＭＳ （ＥＳＩ ｐｏｓ．）ｍ／ｚ ： ４３４ ［Ｍ＋Ｈ］⁺
［α］_D ²⁵ ＝ −７１．０ （ｃ ＝ ０．０９９４， ＣＨＣｌ₃）

[2- (Hydroxymethyl) -1,3-oxazolidine-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone obtained in Reference Example 2 MsCl (0.55 mL, 7.1 mmol) was added to a CHCl ₃ (30 mL) solution of (1.7 g, 5.9 mmol) and TEA (1.2 mL, 8.8 mmol) under ice water cooling, and the mixture was stirred for 1 hour. . Water was added under ice water cooling, and the mixture was extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc = 88/12 to 0/100) to give {3- [5-methyl-2- (2H-1,2,3). -Triazol-2-yl) benzoyl] -1,3-oxazolidine-2-yl} methyl methanesulfonate was obtained (pale yellow oil). To a solution of the obtained pale yellow oil in DMF (30 mL), 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (1.3 g, 8.1 mmol), Cs ₂ CO ₃ (4.8 g, 14 0.7 mmol) was added, and the mixture was stirred at an oil bath temperature of 90 ° C. for 24 hours. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with EtOAc. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 150 g, hexane / EtOAc = 88/12 to 0/100) to obtain a racemic mixture (1.2 g) of the title compound (pale yellow oil). The obtained racemic mixture was divided using a semi-preparative column based on the aforementioned racemic analysis conditions (condition 1, Rt ¹ = 3.6 min, Rt ² = 7.0 min), and the relative retention time was short ( Rt ¹ = 3.6 min) The title compound (0.39 g) was obtained (colorless solid).
LCMS retention time 0.90 min.
MS (ESI pos.) M / z: 434 [M + H] ⁺
[Α] _D ²⁵ = −71.0 (c = 0.0994, CHCl ₃ )

Examples 2 to 4 were obtained by the same method as in Example 1. Table 2 shows the structural formula, compound name, LCMS data, and specific rotation of the obtained compound.

Example 5 (−)-[(2S, 5S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3- Oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

Ethyl (2RS, 5S) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine obtained in Reference Example 5 2-Carboxylate (0.11 g, 0.33 mmol) as a starting material, [2- (hydroxymethyl) -5-methyl-1,3-oxazolidin-3-yl] [ A diastereomeric mixture of 5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone was obtained (colorless oil). The resulting diastereomeric mixture was purified by thin layer chromatography (1 mm, hexane / EtOAc = 50/50) to obtain [(2S, 5S) -2- (hydroxymethyl) -5-methyl-1,3. -Oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone was obtained (colorless oil). The obtained [(2S, 5S) -2- (hydroxymethyl) -5-methyl-1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2) -Il) phenyl] methanone (30.2 mg, 0.10 mmol) and TEA (0.021 mL, 0.15 mmol) in CHCl ₃ (0.8 mL) under ice water cooling and MsCl (0.011 mL, 0. 1 mL). 15 mmol) was added and stirred for 1 hour. Water was added under ice water cooling, and the mixture was extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. To a solution of the obtained residue in NMP (0.5 mL), 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.033 g, 0.20 mmol), Cs ₂ CO ₃ (0.065 g, .0. 20 mmol) was added. The reaction was performed at 120 ° C. for 1 hour under microwave irradiation. After allowing to cool, water was added and the mixture was extracted with CHCl ₃ , passed through an ISOLUTE Phase Separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC to give the title compound (0.020 g) (colorless oil).
LCMS retention time 0.92 min.
MS (ESI pos.) M / z: 448 [M + H] ⁺
[Α] _D ²⁵ = −80.4 (c = 0.0828, CHCl ₃ )

Examples 6 to 10 were obtained in the same manner as in Example 5. Table 3 shows the structural formula, compound name, LCMS data, and specific rotation of the obtained compound.

Example 11 (±)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidine-3-yl) [2- ( 2H-1,2,3-triazol-2-yl) phenyl] methanone

Of CHCl ₃ obtained in Reference Example 12 2- [1- (2,2-diethoxyethyl)-1H-pyrazol-3-yl] -5-fluoro pyridine (4.0g, 14.3mmol) (72mL) TFA (6.4 mL, 85.9 mmol) was added to the solution and stirred at 35 ° C. for 6 hours. Additional TFA (6.4 mL, 85.9 mmol) was added and stirred at 35 ° C. for 3 hours. After allowing to cool to room temperature, an aqueous NaHCO ₃ solution was added to the reaction mixture, and the mixture was extracted with CHCl ₃ . The organic layer was washed with a saturated aqueous sodium chloride solution and dried over MgSO ₄ , and then the desiccant was filtered off. The solvent was distilled off under reduced pressure to obtain [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] acetaldehyde (colorless oil). To a solution of [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] acetaldehyde in CHCl ₃ (36 mL) was added activated molecular sieve 4A (29 g), 2-aminoethanol (1.1 mL, 14.3 mmol) was added and stirred at room temperature for 48 hours. After molecular sieve 4A was filtered off through Celite (registered trademark), the solvent was distilled off under reduced pressure to obtain a colorless oil. A solution of the resulting colorless oil (0.10 g, 0.40 mmol) and 2- (2H-1,2,3-triazol-2-yl) benzoic acid (76 mg, 0.40 mmol) in DMF (0.4 mL) Were added DIPEA (0.21 mL, 1.2 mmol) and HATU (0.16 g, 0.48 mmol) and stirred at room temperature for 48 hours. The reaction mixture was purified by HPLC to give the title compound (40.8 mg) (colorless solid).
LCMS retention time 0.83 min.
MS (ESI pos.) M / z: 420 [M + H] ⁺

Examples 12 to 38 were obtained by the same method as in Example 11. Examples 26 to 32 and Examples 34 to 38 were optically divided by the same method as in Example 1. The structural formula, compound name, LCMS data, and specific rotation of the obtained compound are shown in Tables 4-1 to 4-4.

Example 39 [(2S, 4S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxazinane-3- Yl} [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

[(2S, 4S) -2- (hydroxymethyl) -4-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3) obtained in Reference Example 17 -Triazol-2-yl) phenyl] methanone (0.070 g, 0.22 mmol) in a toluene (1 mL) solution of 5-fluoro-2- (1H-pyrazol-4-yl) pyridine obtained in Reference Example 11 (0.040 g, 0.24 mmol) and cyanomethylenetributylphosphorane (0.087 mL, 0.33 mmol) were added, and the mixture was heated and stirred at 100 ° C. for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (KP-NH 12 g, hexane / EtOAc = 80/20 to 0/100) (HP-Sil 10 g, hexane / EtOAc = 80/20 to 0 / 100) to give the title compound (0.11 g) (colorless oil).
LCMS retention time 0.96 min.
MS (ESI pos.) M / z: 462 [M + H] ⁺

Example 40 (-)-[(2S *, 5S *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1, 3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

Ethyl (2RS, 5RS) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl) -1,3-oxazinane obtained in Reference Example 18 2- (carboxylate) (0.13 g, 0.36 mmol) was used as a starting material in the same manner as in Reference Example 2 [(2RS, 5RS) -2- (hydroxymethyl) -5-methyl-1,3-oxazinane. -3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (0.098 g) was obtained (colorless oil). The obtained colorless oil (0.098 g, 0.31 mmol) and 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.056 g, 0.34 mmol) obtained in Reference Example 11 were used as raw materials. In the same manner as in Example 39, a racemic mixture (0.11 g) of the title compound was obtained. The obtained racemic mixture was divided using a semi-preparative column based on the aforementioned racemic analysis conditions (condition 7, Rt ¹ = 4.3 min, Rt ² = 4.8 min), and the relative retention time was short ( Rt ¹ = 4.3 min) The title compound (0.044 g) was obtained (colorless oil).
LCMS retention time 0.94 min.
MS (ESI pos.) M / z: 462 [M + H] ⁺
[Α] _D ²³ = −44.1 (c = 0.0704, CHCl ₃ )

Example 41 (-)-[2-{[3- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- ( Pyrimidin-2-yl) phenyl] methanone

(±)-(2-{[3- (4-Fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) (2-iodo) obtained in Reference Example 23 In a solution of (5-methylphenyl) methanone (0.19 g, 0.38 mmol) and 2- (tributylstannanyl) pyrimidine (0.15 mL, 0.46 mmol) in toluene (4 mL), Pd (PPh ₃ ) ₄ (0. 044 g, 0.04 mmol), copper iodide (0.0070 g, 0.040 mmol), and cesium fluoride (0.12 g, 0.76 mmol) were added, and the mixture was heated and stirred at 130 ° C. for 0.5 hours under microwave irradiation. To the reaction mixture was added aqueous potassium fluoride solution, and the mixture was extracted with CHCl ₃ . The organic layer was washed with an aqueous potassium fluoride solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over Na ₂ SO ₄ and the desiccant was filtered off and concentrated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 80 / 20-0 / 100) (KP-NH 12 g, hexane / EtOAc = 80 / 20-0 / 100) A racemic mixture (0.099 g) of the compound was obtained (colorless oil). The obtained racemic mixture was divided using a semi-preparative column based on the aforementioned racemic analysis conditions (condition 4, Rt ¹ = 3.9 min, Rt ² = 13.7 min), and the relative retention time was short ( Rt ¹ = 3.9 min) The title compound (0.036 g) was obtained (colorless oil).
LCMS retention time 1.0 min.
MS (ESI pos.) M / z: 458 [M + H] ⁺
[Α] _D ²³ = −34.1 (c = 0.0914, CHCl ₃ )

Examples 42 to 44 were obtained in the same manner as in Example 41. Table 5 shows the structural formulas, compound names, LCMS data, and specific rotation of Examples 42 to 44.

Example 45 (-)-[2-{[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] methyl} -1,3-oxazolidin-3-yl] [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetaldehyde (0.80 g, 3.9 mmol) obtained in Reference Example 30 was used in the same manner as in Example 11. A racemic mixture (0.063 g) was obtained (light yellow solid). The obtained racemic mixture (0.050 g, 0.12 mmol) was subjected to the aforementioned racemic analysis conditions (condition 9,
The title compound (0.017 g) was separated using a semi-preparative column based on Rt ¹ = 4.6 min, Rt ² = 13.8 min, and the relative retention time was short (Rt ¹ = 4.6 min). Obtained (colorless solid).
LCMS retention time 1.0 min.
MS (ESI pos.) M / z: 434 [M + H] ⁺
[Α] _D ²³ = −104.0 (c = 0.0566, CHCl ₃ )

Example 46 (-)-[2-{[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazolidin-3-yl] [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

Using 2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol (0.30 g, 1.5 mmol) obtained in Reference Example 22 as a starting material, the same as Reference Example 25 The method gave a racemic mixture (0.039 g) of the title compound (colorless oil). The obtained racemic mixture was divided using a semi-preparative column based on the aforementioned racemic analysis conditions (condition 2, Rt ¹ = 16.3 min, Rt ² = 19.2 min), and the relative retention time was short ( Rt ¹ = 16.3 min) The title compound (0.0076 g) was obtained (colorless solid).
LCMS retention time 0.97 min.
MS (ESI pos.) M / z: 434 [M + H] ⁺
[Α] _D ²³ = −80.9 (c = 0.0478, CHCl ₃ )

Example 47 (-)-[2-{[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

Using 2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol (0.30 g, 1.5 mmol) obtained in Reference Example 22 as a starting material, the same as Reference Example 25 The method gave a racemic mixture (0.19 g) of the title compound (colorless solid). The obtained racemic mixture (0.20 g, 0.45 mmol) was analyzed using a semi-preparative column based on the aforementioned racemic analysis conditions (condition 11, Rt ¹ = 9.9 min, Rt ² = 11.5 min). Splitting to give the title compound (0.0095 g) with a short relative retention time (Rt ¹ = 9.9 min) (colorless solid).
LCMS retention time 0.97 min.
MS (ESI pos.) M / z: 448 [M + H] ⁺
[Α] _D ²³ = -21.4 (c = 0.109, CHCl ₃ )

Example 48 (-)-(2-{[3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

To a solution of 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (0.36 g, 2.2 mmol) obtained in Reference Example 10 in DMF (9 mL) was added sodium hydride (55%, 0.12 g, 2.7 mmol) was added and stirred at room temperature for 30 minutes. [2- (Chloromethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone obtained in Reference Example 32 A solution of (0.79 g, 2.5 mmol, 84.2% ee) in DMF (3 mL) was added dropwise. Stir at 90 ° C. for 1 hour. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 40 g, hexane / EtOAc = 70/30 to 0/100). EtOH (10 mL) was added, and the mixture was stirred for 1 hour under cooling in an ice bath and collected by filtration to obtain the title compound (0.60 g,> 99.9% ee, having the same stereochemistry as in Example 3) ( Colorless solid). The optical purity was analyzed based on the racemic analysis conditions described above (condition 9, Rt ¹ = 4.3 min, Rt ² = 6.7 min), and a compound having a short relative retention time (Rt ¹ = 4.3 min) was obtained. Obtained in excess.
LCMS retention time 0.90 min.
MS (ESI pos.) M / z: 448 [M + H] ⁺

Example 49 (-)-[(2S *, 5R *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1, 3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

(2RS, 5SR)-[2- (Chloromethyl) -5-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3) obtained in Reference Example 35 -Triazol-2-yl) phenyl] methanone (0.52 g, 1.5 mmol), 5-fluoro-2- (1H-pyrazol-4-yl) pyridine obtained in Reference Example 11 (0.23 g, 1. 4 mmol) and the title compound (0.44 g) was obtained in the same manner as in Example 48. The obtained racemic mixture (0.070 g) was divided using a semi-preparative column based on the aforementioned racemic analysis conditions (condition 13, Rt ¹ = 6.6 min, Rt ² = 12.4 min), and the relative The retention time was short (Rt ¹ = 6.6 min) to give the title compound (0.030 g) (colorless oil).
LCMS retention time 0.95 min.
MS (ESI pos.) M / z: 462 [M + H] ⁺
[Α] _D ²⁵ = −14.1 (c = 0.0870, CHCl ₃ )

Test example (measurement of orexin antagonistic activity)
The antagonistic activity of test compounds against human orexin type 1 receptor (hOX1R) and orexin type 2 receptor (hOX2R) has been described in the literature (Toshikata Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). The method was modified. Chinese hamster ovary (CHO) cells forcibly expressing hOX1R and hOX2R were seeded in each well of a 96-well Black clear bottom plate (Nunc) at 20,000 cells, 0.1 mM MEM non-essential amino acids, 0. The cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2. After removing the medium, assay buffer containing 25 μM Fluo-3AM ester (Dojin) (25 mM HEPES (Dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM probenecid, 100 μL of 200 μg / ml Amaranth (above Sigma-Aldrich), pH 7.4) was added and incubated for 60 minutes at 37 ° C., 5% CO 2. After removing the assay buffer containing Fluo-3AM ester, the test compound was dissolved in dimethyl sulfoxide to 10 mM, diluted with assay buffer, 150 μL was added, and the mixture was incubated for 30 minutes.
Peptide (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu) substituted with 2 amino acids of human orexin-A which is a ligand -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2; Each was diluted with an assay buffer so as to be 3 nM, and 50 μL of this ligand solution was added to initiate the reaction. For the reaction, the fluorescence value of each well was measured for 3 minutes every second using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics), and the antagonistic activity was determined using the maximum fluorescence value as an index of intracellular Ca 2+ concentration. The antagonistic activity of the test compound was calculated by setting the fluorescence value of the well to which only the dilution buffer was added to 100% and the fluorescence value of the well to which the buffer solution containing no ligand and compound was added to 0%. The 50% inhibitory concentration (IC ₅₀ value) was determined from the fluorescence value upon addition.
The IC ₅₀ values of the compounds of the present invention are shown in Table 6.

  The compound of the present invention was shown to have OX receptor antagonistic action. Accordingly, a medicament comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is a disease regulated by OX receptor antagonism, such as sleep disorder, depression, anxiety disorder, panic Disorders, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, high blood pressure, etc. It can be used as a therapeutic or prophylactic agent.

Claims (7)

Formula (I)

(Where
X ¹ and X ² are the same or different and represent a nitrogen atom or the formula CH;
One of Y ¹ and Y ² represents a nitrogen atom and the other represents CH;
n represents 2,
R ¹ represents a halogen atom or a C _1-6 alkyl group,
R ² represents a triazolyl group or a pyrimidinyl group;
R ³ represents a halogen atom,
R ⁴ represents a hydrogen atom)
Or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising crystalline cellulose, starch, lactose, mannitol, hydroxypropylcellulose, polyvinylpyrrolidone, magnesium stearate, talc and carboxymethylcellulose calcium Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, including one or more pharmacologically acceptable carriers selected from , Tablets, capsules, granules, powders, powders or lozenges for the treatment or prevention of eating disorders, pain, migraine, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension diseases some oral made by agents. A compound according to claim 1 which comprises, as an active ingredient, or oral made agent according to claim 1 dosage is 0.001~500mg per a pharmaceutically acceptable salt thereof. The active ingredient is (−)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5- methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof. The active ingredient is (-)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof. The active ingredient is (-)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- (pyrimidin-2-yl) pyridin-2-yl] methanone, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof. The active ingredient is (−)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5- fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof. The active ingredient is (−)-[2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl] methanone, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof.