JP2014015452A - Medicine containing pyrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel medicine exhibiting OX receptor antagonism for treatment or prevention of diseases such as novel sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer disease, Parkinson disease, Huntington chorea, feeding disorder, headache, migraine, pain, gastrointestinal disease, epilepsy, inflammation, immune-related disease, endocrine related disease and hypertension.SOLUTION: A treatment or prevention drug is characterized by containing a pyrazole derivative represented by the formula (IA) or a pharmaceutically acceptable salt thereof as an active ingredient. In the formula, X represents a nitrogen atom or the formula CH; one of Y1 and Y2 represents a nitrogen atom and the other represents the formula CH; R1 represents a hydrogen atom, a halogen atom, a C1-6 alkyl group or an alkoxy group; R2 represents a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a 4 to 6-membered cyclic ether group; R3 represents a triazolyl group, a pyridyl group or the like; and R4 and R5, identically or differently, represent a hydrogen atom, a halogen atom or the like.

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 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 pyrazole derivative, but there is no disclosure of a compound having a pyrazole-ethylamide skeleton described in the present application. On the other hand, Patent Document 2 discloses a compound having a pyrazole-ethylamide skeleton. However, Patent Document 2 does not disclose an OX receptor antagonistic action or a compound described in the present application.

WO2003 / 002559 Publication WO2008 / 062878

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.

  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, 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 found that a certain pyrazole derivative represented by the following formula has an excellent OX receptor antagonistic action. The headline and the present invention were 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)

(Where
X represents a nitrogen atom or the formula CH;
One of Y ¹ and Y ² represents a nitrogen atom and the other represents the formula CH;
R ¹ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,
R ² represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from Substituent Group 1), C _3-6 cyclo An alkyl group or a 4-6 membered cyclic ether group;
Substituent group 1 is a group consisting of a halogen atom, a C _3-6 cycloalkyl group, and a C _1-6 alkoxy group,
R ³ represents a triazolyl group, a pyridyl group, or a pyrimidyl group,
The triazolyl group, pyridyl group and pyrimidyl group may be substituted with 1 to 3 halogen atoms,
R ⁴ and R ⁵ are the same or different and each 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). Show)
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson, characterized by containing a pyrazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Therapeutic or preventive drug for diseases such as illness, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension.
(2) Sleep disorder, depression, anxiety disorder, panic disorder, integration characterized by containing as an active ingredient the pyrazole derivative of (1), wherein R ⁵ is a hydrogen atom, or a pharmaceutically acceptable salt thereof Treatment of diseases such as ataxia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension Or prophylactic drugs.
(3) Formula (I)

(Where
X represents a nitrogen atom or the formula CH;
One of Y ¹ and Y ² represents a nitrogen atom and the other represents the formula CH;
R ¹ represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group,
R ² represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from Substituent Group 1), C _3-6 cyclo An alkyl group or a 4-6 membered cyclic ether group;
Substituent group 1 is a group consisting of a halogen atom, a C _3-6 cycloalkyl group, and a C _1-6 alkoxy group,
R ³ represents a triazolyl group, a pyridyl group, or a pyrimidyl group,
The triazolyl group, pyridyl group and pyrimidyl group may be substituted with 1 to 3 halogen atoms,
R ⁴ represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group)
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson, characterized by containing a pyrazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Therapeutic or preventive drug for diseases such as illness, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension.

(4) R ² is a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from the above substituent group 1), C _3-6 A pyrazole derivative according to any one of (1) to (3), which is a cycloalkyl group or a 4- to 6-membered cyclic ether group, or a pharmaceutically acceptable salt thereof as an active ingredient Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, A therapeutic or prophylactic agent for diseases such as immune-related diseases, endocrine-related diseases and hypertension.

(5) R ² is a feature in that it contains a methyl group, or ethyl group (1) to (4) pyrazole derivative described in any one, or a pharmaceutically acceptable salt thereof as an active ingredient Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, A therapeutic or prophylactic agent for diseases such as immune-related diseases, endocrine-related diseases and hypertension.
(6) X is a nitrogen atom,
A sleep disorder characterized by containing, as an active ingredient, the pyrazole derivative according to any one of (1) to (5), wherein R ³ is a triazolyl group or a pyrimidyl group, or a pharmaceutically acceptable salt thereof; 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, A therapeutic or prophylactic agent for diseases such as endocrine-related diseases and hypertension.
(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 dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine A therapeutic or prophylactic agent for diseases such as related diseases and hypertension.
N- {2- [4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl Benzamide,
N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide;
N- {2- [4- (4-Fluorophenyl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazol-2-yl) benzamide ,
N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- (cyclopropylmethyl) -N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) benzamide,
N- (cyclopropylmethyl) -N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-5-methyl-N- {2- [3- (pyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole-2- Il) benzamide,
N- {2- [4- (5-chloropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-5-methyl-N- {2- [4- (pyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole-2- Il) benzamide,
N-ethyl-N- {2- [4- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-cyclopropyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3- Triazol-2-yl) benzamide,
N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (propan-2-yl) -2- (2H-1 , 2,3-triazol-2-yl) benzamide,
N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N- {2- [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl Benzamide,
N- {2- [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N- (cyclopropylmethyl) -N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide;
N- {2- [3- (4-Fluorophenyl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazol-2-yl) benzamide ,
N- {2- [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (propan-2-yl) -2- (2H-1 , 2,3-triazol-2-yl) benzamide,
N- (2,2-difluoroethyl) -N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzamide,
5-Fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-methyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-fluoro-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-fluoro-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (2-fluoroethyl) -2- (2H-1, 2,3-triazol-2-yl) benzamide,
N- (cyclopropylmethyl) -N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- (cyclopropylmethyl) -5-methyl-N- [2- (3-phenyl-1H-pyrazol-1-yl) ethyl] -2- (2H-1,2,3-triazol-2-yl) Benzamide,
N-cyclopropyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3- Triazol-2-yl) benzamide,
N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (oxetan-3-yl) -2- (2H-1 , 2,3-triazol-2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
5-chloro-N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyridin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyridin-3-yl) benzamide;
N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
5-methyl-N- {2- [3- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-5-methyl-N- {2- [3- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
5-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
5-chloro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide,
N-ethyl-5-chloro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-4-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-2-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -6- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-2-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -6- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -4-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-3-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-4-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methoxy-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [5- (trifluoromethyl) pyridin-2-yl] -1H -Pyrazol-1-yl} ethyl) benzamide;
N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl] -1H -Pyrazol-1-yl} ethyl) benzamide;
N- {2- [3- (3,4-difluorophenyl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-5-fluoro-2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
5-chloro-N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-5-fluoro-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-5-fluoro-2- (pyrimidin-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-1-yl} ethyl Benzamide,
N-ethyl- (pyrimidin-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-1-yl} ethyl) benzamide;
N- {2- [3- (3,4-difluorophenyl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [4- (trifluoromethyl) pyridin-2-yl] -1H -Pyrazol-1-yl} ethyl) benzamide;
N-ethyl-5-fluoro-2- (pyrimidin-2-yl) -N- (2- {3- [4- (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-1-yl} ethyl Benzamide.

  The pyrazole derivative of the present invention exhibits affinity for the OX receptor and antagonizes the stimulation of the receptor by a physiological ligand, and sleep disorder, depression, anxiety disorder, panic disorder by the novel pyrazole derivative. , 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, hypertension It has become possible to provide a therapeutic or preventive drug.

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- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group and the like.
The “C _3-6 cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group.
The “4-6 membered cyclic ether group” is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl group.
“C _1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec -Butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethylpropoxy, n-hexyloxy 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.
A compound in which X is a nitrogen atom is preferable.

  The compound whose halogen atom is a fluorine atom, a chlorine atom, or a bromine atom is preferable, and the compound whose fluorine atom or a chlorine atom is more preferable.

R ² is a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from Substituent Group 1), a C _3-6 cycloalkyl group, Or the compound which is a 4-6 membered cyclic ether group is preferable, and the compound which is a methyl group or an ethyl group is more preferable.

A compound in which R ³ is a triazolyl group or a pyrimidyl group is preferable.

A compound in which R ⁵ is a hydrogen atom or a halogen atom is preferable, and a compound in which R ⁵ is a hydrogen atom is more 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 fluorine 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 to I. 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, R ¹ , R ² , R ³ and R ⁴ are the same as above. A ¹ , A ² and A ³ are each a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoro group. L represents a methanesulfonyloxy group, L represents a hydroxy group or a halogen atom, Pr ¹ represents a Protective Groups in Organic Chemistry by J. F. W. McOmie, and T. W. Greene and P. G. M. The conventional amino protecting group described in Wuts, Protective Groups in Organic Synthesis.

Step A-1: The compound represented by formula (3) is obtained by reacting the boronic acid derivative represented by formula (1) and the compound represented by (2) under the conditions of the Suzuki-Miyaura coupling reaction. Can be obtained. A comprehensive overview of the Suzuki-Miyaura coupling reaction can be found in Angew. Chem. Int. Ed. 2001, 40, 4544.

Step A-2: The compound represented by formula (5) can be obtained by reacting the compound represented by formula (3) with the compound represented by formula (4). The reaction in Step A-2 is carried out in a solvent such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethanol, water, chloroform, or a mixed solvent thereof, sodium hydride, sodium hydroxide, sodium carbonate, In the presence of an inorganic base such as potassium carbonate or cesium carbonate, an alkali metal such as sodium ethoxide or potassium tert-butoxide, or a lower alkoxide of an alkaline earth metal or an organic base such as triethylamine or diisopropylethylamine, the boiling point of the solvent from about -80 ° C Proceeds under near temperature conditions.

Step A-3: When Pr ^{1 of the} compound represented by the formula (5) is a group deprotected with an acid such as a tert-butoxycarbonyl group, the compound represented by the formula (6) is represented by the formula (5 ) Can be obtained by reacting with an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like. When Pr ^{1 of the} compound represented by the formula (5) is a group that is deprotected by hydrogenolysis such as a benzyloxycarbonyl group, it should be deprotected by a hydrogenolysis reaction using a metal catalyst such as palladium. Can do. A comprehensive overview of the reaction in Step A-3 can be found in F. W. McOmie, Protective Groups in Organic Chemistry. W. Greene and P.A. G. M. Wuts, Protective Groups in Organic Synthesis.

Step A-4: The compound represented by formula (8) can be obtained by reacting the compound represented by formula (6) with the compound represented by formula (7). Examples of the amidation reaction in Step A-4 include a method using a dehydration condensing agent when L of the compound represented by the formula (7) is a hydroxy group. Examples of the dehydrating condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, propylphosphonic anhydride (cyclic trimer), dicyclohexylcarbodiimide, diphenylphosphonyl azide, carbonyldiimidazole, and the like. An activator such as 1-hydroxybenzotriazole or hydroxysuccinimide can be used as necessary. Examples of the reaction solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, toluene, ethyl acetate, and a mixed solvent thereof. In this case, the reaction can be carried out using a base, and examples of the base include organic amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. The reaction can be carried out from −80 ° C. to around the boiling point of the reaction solvent. Furthermore, when L of the compound represented by the formula (7) is a halogen atom, the reaction in Step A-4 is carried out by using a solvent such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethanol, water, chloroform or the like. In or in a mixed solvent thereof, inorganic bases such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, etc., metal lower alkoxides such as sodium ethoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, etc. In the presence of an organic base, the reaction proceeds under a temperature condition from about −80 ° C. to the boiling point of the solvent.

Step A-5: The compound represented by formula (10) can be obtained by reacting the compound represented by formula (8) with the compound represented by formula (9). The reaction in Step A-5 is carried out in a solvent such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethanol, water, chloroform, or a mixed solvent thereof, sodium hydride, sodium hydroxide, sodium carbonate, In the presence of an inorganic base such as potassium carbonate or cesium carbonate, a metal lower alkoxide such as sodium ethoxide or potassium tert-butoxide, or an organic base such as triethylamine or diisopropylethylamine, under a temperature condition from about −80 ° C. to the boiling point of the solvent. proceed.
Scheme B

(In the formula, X, Y ¹ , Y ² , R ¹ , R ² , R ³ , R ⁴ and L are the same as above. A ⁴ and A ⁵ are a halogen atom, a methanesulfonyloxy group, and p-toluene. Represents a sulfonyloxy group or a trifluoromethanesulfonyloxy group, and Pr ² represents Protective Groups in Organic Chemistry, by J. F. W. McOmie, and Protective Groups, by T. W. Greene and PGM Wuts. The conventional protecting group for hydroxy group described in in Organic Synthesis.

Step B-1: The compound represented by Formula (12) is reacted with the compound represented by Formula (7) from the amine derivative represented by Formula (11) according to the same reaction conditions as in Step A-4. Can be obtained.

Step B-2: The compound represented by formula (14) is reacted with the compound represented by formula (12) from the compound represented by formula (13) according to the same reaction conditions as in step A-5. Can be obtained.

Process B-3: The compound represented by Formula (15) is obtained by removing the protecting group of the hydroxy group of the compound represented by Formula (14). A comprehensive overview of the reaction in Step B-3 can be found in F. W. McOmie, Protective Groups in Organic Chemistry. W. Greene and P.A. G. M. Wuts, Protective Groups in Organic Synthesis. When Pr ^{2 of the} compound represented by the formula (14) is a silicon-containing protecting group such as a tert-butyldimethylsilyl group, the compound represented by the formula (15) is represented by the formula (14). The compound can be obtained by reacting with an acid such as hydrochloric acid or trifluoroacetic acid, or a fluoride such as tetrabutylammonium fluoride or hydrogen fluoride.

Step B-4: The compound represented by the formula (16) can be obtained by converting the hydroxy group of the compound represented by the formula (15) into a general leaving group. Examples of the reaction in Step B-4 include chlorination, bromination, iodination, methanesulfonylation, p-toluenesulfonylation and the like. As an example of the chlorination reaction, for example, a method of forming a leaving group using methanesulfonyl chloride or the like and then substituting 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. Methanesulfonylation and p-toluenesulfonylation 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 N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, water, carbon tetrachloride, chloroform, dichloroethane, 1,2-dichloroethane and the like, or a mixture thereof. The reaction can be carried out under a temperature condition from around 0 ° C. to the boiling point of the solvent.

Step B-5: The compound represented by formula (10) is reacted with the compound represented by formula (16) from the pyrazole derivative represented by formula (3) according to the same reaction conditions as in step A-2. Can be obtained.
Scheme C

(In the formula, X, Y ¹ , Y ² , R ¹ , R ² , R ³ , R ⁴ , L and Pr ² are the same as above.)
Step C-1: A compound represented by formula (18) is reacted with an amine derivative represented by formula (11) from an aldehyde derivative represented by formula (17) under the conditions of a reductive amination reaction. Can be obtained. Examples of the conditions for the reductive amination reaction in Step C-1 include a method in which an amine derivative and an aldehyde derivative are added with a reducing agent in the presence or absence of an acid and a base. Further, as a reduction method, for example, a catalytic reduction method by hydrogenation using a catalyst such as palladium-carbon, platinum, Raney nickel, rhodium-alumina, or the like can be used. Examples of the acid include acetic acid and hydrochloric acid. Examples of the base include triethylamine. Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like. The reaction solvent is methanol, ethanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, chloroform, dichloromethane, N, N-dimethylformamide, acetonitrile, water, or a mixed solvent thereof. It can be performed under temperature conditions near the boiling point.

Step C-2: The compound represented by Formula (14) is reacted with the amine derivative represented by Formula (18) from the compound represented by Formula (7) according to the same reaction conditions as in Step A-4. Can be obtained.
Step C-3: The compound represented by formula (10) is carried out from the compound represented by formula (14) according to the same reaction conditions as in step B-3, step B-4 and step B-5. Can be obtained.
Scheme D

(In the formula, X, R ¹ , R ² , R ³ , R ⁴ , A ¹ , A ² , A ³ , L and Pr ¹ are the same as above.)
Step D-1: The compound represented by the formula (20) is prepared from the boronic acid derivative represented by the formula (19) and the compound represented by (2) in the same manner as in the step A-1, Suzuki-Miyaura Cup. It can be obtained by reacting under ring reaction conditions.
Step D-2: The compound represented by the formula (21) can be obtained by reacting the compound represented by the formula (20) with an acid such as hydrochloric acid or trifluoroacetic acid. As the reaction solvent, for example, in a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, ethyl acetate, chloroform, or a mixed solvent thereof, the reaction is performed at a temperature of about −80 ° C. to the boiling point of the solvent. Can be done.

Step D-3: The compound represented by Formula (22) is reacted with the compound represented by Formula (21) from the compound represented by Formula (4) according to the same reaction conditions as in Step A-2. Can be obtained.
Step D-4: The compound represented by Formula (23) can be obtained by reacting the compound represented by Formula (22) according to the same reaction conditions as in Step A-3.
Step D-5: The compound represented by formula (24) is reacted according to the same reaction conditions as in step A-4 from the amine derivative represented by formula (23) and the compound represented by formula (7). Can be obtained.
Step D-6: The compound represented by Formula (25) is reacted from the compound represented by Formula (24) and the compound represented by Formula (9) according to the same reaction conditions as in Step A-5. Can be obtained.
Scheme E

(In the formula, X, R ¹ , R ² , R ³ , R ⁴ and L are the same as above. R ^a and R ^b are the same or different and represent a hydrogen atom or an alkyl group.)
Step E-1: The compound represented by the formula (27) is obtained by reductive amination similar to the step C-1 from the amine derivative represented by the formula (23) and the compound represented by the formula (26). It can be obtained by reacting under reaction conditions.
Step E-2: The compound represented by Formula (25) is reacted according to the same reaction conditions as in Step A-4 from the amine derivative represented by Formula (27) and the compound represented by Formula (7). Can be obtained.
Scheme F

(In the formula, X, R ¹ , R ² , R ³ , R ⁴ , A ² and L are the same as above. R ^c and R ^d represent an alkoxy group.)
Step F-1: The compound represented by Formula (29) is reacted under the same reaction conditions as in Step A-2 from the pyrazole derivative represented by Formula (21) and the compound represented by Formula (28). Can be obtained.
Step F-2: The compound represented by the formula (30) can be obtained by reacting the compound represented by the formula (29) with an acid such as hydrochloric acid, trifluoroacetic acid or p-toluenesulfonic acid. . As the reaction solvent, for example, in a solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water, ethyl acetate, chloroform, acetone, or a mixed solvent thereof, the reaction is performed at a temperature from about −80 ° C. to about the boiling point of the solvent. It can be performed under conditions.

Step F-3: The compound represented by the formula (27) is prepared by reductive amination similar to the step C-1 from the compound represented by the formula (30) and the amine derivative represented by the formula (11). It can be obtained by reacting under reaction conditions.
Step F-4: The compound represented by formula (25) is reacted according to the same reaction conditions as in step A-4 from the amine derivative represented by formula (27) and the compound represented by formula (7). Can be obtained.
Scheme G

(In the formula, X, R ¹ , R ² , R ³ , R ⁴ , A ³ , Pr ¹ and L are the same as above.)
Step G-1: The compound represented by formula (31) is reacted from the compound represented by formula (22) and the compound represented by formula (9) according to the same reaction conditions as in step A-5. Can be obtained.
Step G-2: The compound represented by formula (32) can be obtained by reacting the compound represented by formula (31) according to the same reaction conditions as in step A-3.
Step G-3: The compound represented by Formula (25) is reacted according to the same reaction conditions as in Step A-4 from the amine derivative represented by Formula (32) and the compound represented by Formula (7). Can be obtained.
Scheme H

(In the formula, X, Y ¹ , Y ² , R ¹ , R ² , R ³ , R ⁴ and L are the same as above. A ⁶ represents a halogen atom.)
Step H-1: The compound represented by formula (35) is reacted according to the same reaction conditions as in step A-4 from the amine derivative represented by formula (33) and the compound represented by formula (34). Can be obtained.
Step H-2: The compound represented by Formula (36) is reacted with the compound represented by Formula (35) and a boronic acid derivative under the conditions of the Suzuki-Miyaura coupling reaction in the same manner as in Step A-1. Can be obtained. Moreover, it can also obtain by making it react on the conditions of Stille coupling reaction using an organotin compound. A comprehensive overview of the Stille coupling reaction can be found, for example, in Angew. Chem. Int. Ed., 43, 4704, (2004).
Scheme I

(In the formula, X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as above.)
Step I-1: The compound represented by formula (39) can be obtained by reacting the compound represented by formula (37) with the compound represented by formula (38). The reaction in Step I-1 is carried out in a solvent such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, chloroform, or a mixed solvent thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, carbonic acid. In the presence of an inorganic base such as cesium or sodium hydride, an alkali metal such as sodium ethoxide or potassium tert-butoxide, or a lower alkoxide of an alkaline earth metal, or an organic base such as triethylamine or diisopropylethylamine, from about −80 ° C. to the boiling point of the solvent Proceeds under near temperature conditions.
Step I-2: The compound represented by Formula (41) is reacted according to the same reaction conditions as in Step A-4 from the amine derivative represented by Formula (39) and the compound represented by Formula (40). Can be obtained.

  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, the microwave reactor used was Biotage Initiator.

  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, “KP-Sil”. For NH, Biotage SNAP cartridge KP-NH was used.

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 preparative HPLC system
Column: Shiseido Capcelpak C18 MGII 5 μm 20 × 150 mm
Solvent: A solution; 0.1% trifluoroacetic acid-containing water, B solution; 0.1% trifluoroacetic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 22 minutes (A solution / B Liquid = 20/80), 25 minutes (A liquid / B liquid = 10/90)
Flow rate: 20 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 conditions.
Condition 1
Measuring machine: Micromass Platform LC and Agilent Agilent 1100
Column: Waters SunFire C18 2.5 μm 4.6 × 50 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), 0.5 minutes (A solution / B liquid = 90/10), 5.5 minutes (A liquid / B liquid = 20/80), 6.0 minutes (A liquid / B liquid = 1/99), 6.3 minutes (A liquid / B Liquid = 1/99)
Flow rate: 1 mL / min, detection method: 254 nm
Ionization method: Electron impact ionization (Electron Spray Ionization: ESI)
Condition 2
Measuring machine: Agilent Agilent 2900 and Agilent Agilent 6150
Column: Waters Acquity CSH C18 1.7um, 2.1x50mm
Solvent: solution A; 0.1% formic acid-containing water, solution B; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (solution A / solution B = 80/20), 1.2-1.4 minutes (solution A) / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: 254 nm
Ionization method: Electron impact ionization (Electron Spray Ionization: ESI)

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 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), Na ₂ CO ₃ (sodium carbonate), Cs ₂ CO ₃ (cesium carbonate), NaHCO ₃ (sodium bicarbonate), NaOH (sodium hydroxide), MeOH (methanol), EtOH ( Ethanol), Et ₂ O (diethyl ether), THF (tetrahydrofuran), DMF (N, N-dimethylformamide), MeCN (acetonitrile), EtOAc (ethyl acetate), CHCl ₃ (chloroform), HOBt · H ₂ O (1 -Hydroxybenzotriazole monohydrate), EDC.HCl [1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.monohydrochloride], HATU [O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophospha _{DOO], Pd (PPh 3) 4} [ tetrakistriphenylphosphine palladium (0)], brine (saturated brine), Boc (tert-butoxycarbonyl), THP (tetrahydropyranyl), DIPEA (N, N- diisopropylethylamine ), TEA (triethylamine), MeI (methyl iodide), EtI (ethyl iodide), TBS (tert-butyldimethylsilyl), TBAF (tetrabutylammonium fluoride), MsCl (methanesulfonyl chloride), NaBH ₄ (hydrogen) Sodium borohydride)}, NaH (sodium hydride), HCl (hydrogen chloride).

Reference Example 1 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 (1.0 g, 3 .6 mmol) and 2-bromo-5-fluoropyridine (0.82 g, 4.7 mmol) in EtOH (10 mL) and toluene (10 mL) mixed solution with Pd (PPh ₃ ) ₄ (0.42 g, 0.36 mmol), 2 mol / L Na ₂ CO ₃ aqueous solution (4 mL) was added, and the mixture was heated to reflux and stirred for 2 hours. After cooling at room temperature, water was added to the reaction mixture, and the mixture was extracted with EtOAc. The extracted organic layer was washed with brine, dried using 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 (KP-NH 28 g, hexane / EtOAc = 80/20 to 20/80) to give the title compound (0.84 g) (colorless oil).
MS (ESI pos.) M / z: 248 [M + H] +

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

A 4 mol / L HCl-EtOAc solution (5 mL) was added to a solution of the compound obtained in Reference Example 1 (0.84 g, 3.4 mmol) in MeOH (10 mL), and the mixture was stirred at room temperature for 16 hours and at 60 ° C. for 3 hours. After cooling at room temperature, the solvent of the reaction mixture was distilled off under reduced pressure. The resulting residue was stirred in Et ₂ O for 1 hour, and then the precipitated solid was collected by filtration and dried by heating under reduced pressure to obtain the title compound (0.62 g) (colorless powder).
MS (ESI pos.) M / z: 164 [M + H] +, 186 [M + Na] +

Reference Example 3 tert-butyl {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} carbamate

To a solution of the compound obtained in Reference Example 2 (1.3 g, 6.5 mmol) in DMF (50 mL) was added tert-butyl N- (2-bromoethyl) carbamate (1.9 g, 8.5 mmol), Cs ₂ CO _3. (6.4 g, 19.5 mmol) was added and stirred at 80 ° C. for 3 hours. After cooling at room temperature, water was added to the reaction mixture, and the mixture was extracted with EtOAc. The extracted organic layer was washed with brine, dried using 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 (KP-NH 110 g, hexane / EtOAc = 100/0 to 80/20) to give the title compound (1.3 g) (colorless oil).
MS (ESI pos.) M / z: 307 [M + H] +, 329 [M + Na] +

Reference Example 4 2- [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethanamine dihydrochloride

A 4 mol / L HCl-EtOAc solution (5 mL) was added to a solution of the compound obtained in Reference Example 3 (1.3 g, 4.2 mmol) in CHCl ₃ (20 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was stirred in Et ₂ O for 1 hour. The precipitated solid was collected by filtration, and dried by heating under reduced pressure to give the title compound (0.86 g) (colorless) Powder).
MS (ESI pos.) M / z: 207 [M + H] +

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

4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate tert-butyl (1.8 g, 6.3 mmol) and 2- A solution of bromo-5-fluoropyridine (1.0 g, 5.7 mmol) in 1,4-dioxane (11 mL) was added with a ₂ mol / L Na ₂ CO ₃ aqueous solution (8.5 mL, 17.1 mmol) and Pd (PPh ₃ ) _4. (0.20 g, 0.17 mmol) was added, and the mixture was stirred at an oil bath temperature of 90 ° C. for 4 hours. Then, it stirred at room temperature for 2 days. Brine was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. EtOAc was added to the resulting residue, and the precipitated solid was collected by filtration to give the title compound (0.66 g) (colorless solid).
MS (ESI pos.) M / z: 164 [M + H] +

Reference Example 6 {2- [4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} carbamate tert-butyl

Compound (0.20 g, 1.2 mmol) obtained in Reference Example 5, tert-butyl (2-bromoethyl) carbamate (0.30 g, 1.4 mmol), Cs ₂ CO ₃ (0.80 g, 2.5 mmol) ) And MeCN (2.5 mL) were stirred at an oil bath temperature of 80 ° C. for 1 hour, tert-butyl (2-bromoethyl) carbamate (0.030 g, 0.13 mmol) was added, and the mixture was stirred at the same temperature for 2 hours. did. After cooling to room temperature, water was added and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (0.34 g) (colorless solid).
MS (ESI pos.) M / z: 307 [M + H] +, 329 [M + Na] +

Reference Example 7 2- [4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethanamine dihydrochloride

To a solution of the compound obtained in Reference Example 6 (0.34 g, 1.1 mmol) in EtOAc (1 mL) was added 4 mol / L HCl-EtOAc solution (5.5 mL) at room temperature. EtOAc (4 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. Then, a 4 mol / L HCl-EtOAc solution (2.5 mL) was added, and the mixture was stirred at the same temperature for 2 hours. The precipitated solid was collected by filtration and washed with EtOAc to give the title compound (0.29 g) (colorless solid).
MS (ESI pos.) M / z: 207 [M + H] +

Reference Example 8 N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

Of 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (3.0 g, 14.8 mmol) and ethylamine (2 mol / L THF solution, 8.9 mL, 17.8 mmol) HOBt · H ₂ O (4.05 g, 26.6 mmol) and EDC · HCl (5.1 g, 26.6 mmol) were added to a DMF (54 mL) solution at room temperature and stirred overnight. To the reaction mixture was added aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with water and brine, 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 (KP-Sil 100 g, hexane / EtOAc = 85/15 to 0/100). The obtained solid was washed with stirring with a mixed solvent of hexane / EtOAc (9/1) and then collected by filtration to obtain the title compound (2.5 g) (colorless solid).
MS (ESI pos.) M / z: 231 [M + H] +, 253 [M + Na] +

Reference Example 9 N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

To a solution of the compound obtained in Reference Example 8 (2.0 g, 8.7 mmol) in DMF (87 mL) was added 60% NaH (0.47 g, 10.9 mmol) at room temperature, and the mixture was stirred for 30 minutes. A solution of (2-bromoethoxy) -tert-butyldimethysilane (2.60 g, 10.9 mmol) in DMF (1 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 1 hour and at an oil bath temperature of 50 ° C. for 4 hours. . Then, it stirred at room temperature for 2 days. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with water and brine, 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 (KP-Sil 100 g, hexane / EtOAc = 85/15 to 0/100) to obtain the title compound (3.6 g) (brown oil).
MS (ESI pos.) M / z: 389 [M + H] +
Reference Example 10 N-ethyl-N- (2-hydroxyethyl) -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

To a THF (10 mL) solution of the compound (0.76 g, 2.0 mmol) obtained in Reference Example 9 was added 1 mol / L TBAF (THF solution, 2.3 mL, 2.3 mmol) under ice-water cooling, and the mixture was allowed to reach room temperature. The temperature was raised and stirred for 1 hour. The mixture was cooled again with ice water, NaHCO ₃ aqueous solution was added, and THF was distilled off under reduced pressure. EtOAc was added to the residue for extraction, and the organic layer was washed with brine and dried over Na ₂ SO ₄ . After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (KP-Sil 25 g, hexane / EtOAc = 70/30 to 0/100) to obtain the title compound (0.53 g) (colorless solid).
MS (ESI pos.) M / z: 275 [M + H] +, 297 [M + Na] +

Reference Example 11 N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) cyclopropanamine

To a solution of cyclopropylamine (0.090 g, 1.6 mmol) in MeOH (3.2 mL) was added {[tert-butyl (dimethyl) silyl] oxy} acetaldehyde (0.30 mL, 1.6 mmol) at room temperature. Stir for hours. NaBH ₄ (0.071 g, 1.9 mmol) was added at the same temperature, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, MeOH was distilled off under reduced pressure, then brine was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (0.32 g) (oil). It was used in the next reaction without further purification.
MS (ESI pos.) M / z: 216 [M + H] +

Reference Example 12 N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -N-cyclopropyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

The compound (0.32 g, 1.5 mmol) obtained in Reference Example 11 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.31 g, 1.5 mmol) DIPEA (0.78 mL, 4.5 mmol) and HATU (0.68 g, 1.8 mmol) were added to a DMF (4.5 mL) solution at room temperature and stirred for 15 hours. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with water and brine, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (KP-NH 28 g, hexane / EtOAc = 80/20 to 0/100) and further (KP-Sil 25 g, hexane / EtOAc = 95/5 to 0/100) The title compound (0.33 g) was obtained (colorless amorphous).
MS (ESI pos.) M / z: 401 [M + H] +, 423 [M + Na] +

Reference Example 13 N-cyclopropyl-N- (2-hydroxyethyl) -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

Using the compound (0.33 g, 0.82 mmol) obtained in Reference Example 12 as a starting material, the title compound (0.21 g) was obtained (colorless amorphous) by the same method as Reference Example 10.
MS (ESI pos.) M / z: 287 [M + H] +, 309 [M + Na] +

Reference Example 14 tert-butyl ethyl {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} carbamate

60% NaH (0.056 g, 1.4 mmol) was added to a DMF (5 mL) solution of the compound obtained in Reference Example 3 (0.35 g, 1.1 mmol), and the mixture was stirred at room temperature for 30 minutes. EtI (0.11 mL, 1.4 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with EtOAc. The extracted organic layer was washed with brine, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (0.40 g) (pale yellow oil).
MS (ESI pos.) M / z: 335 [M + H] +

Reference Example 15-1 N-ethyl-2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethanamine dihydrochloride

A 4 mol / L HCl-EtOAc solution (2 mL) was added to a CHCl ₃ (5 mL) solution of the compound (0.37 g, 1.1 mmol) obtained in Reference Example 14, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was stirred in Et ₂ O for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.23 g) (colorless) Powder).
MS (ESI pos.) M / z: 234 [M + H] +
Reference Example 15-2 N-ethyl-2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethanamine dihydrochloride In addition, the title compound is obtained as follows. You can also.

To the mixture obtained in Reference Example 2 (2.00 g, 10.0 mmol), NaOH (1.00 g, 25 mmol), MeCN (22 mL) at 67 to 71 ° C., 3-ethyl-1,2,3-oxa A solution of thiazolidine-2,2-dioxide (2.27 g, 15.0 mmol) in MeCN (3.2 mL) was added dropwise and stirred at the same temperature for 1 hour. Ice-cooled and 25% H ₂ SO ₄ (12 mL) was added at 18 ° C. The reaction mixture was heated and stirred at 68 ° C. for 4 hours. The mixture was ice-cooled, 10 mol / L aqueous NaOH solution (8.5 mL) was added, and the layers were separated. The organic layer was evaporated under reduced pressure. The residue was stirred in EtOAc (16 mL) and 4 mol / L HCl-EtOAc solution (5.3 mL) was added under ice cooling. After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration. The obtained solid was heated and dried under reduced pressure to obtain the title compound (2.49 g) (pale yellow crystals).
Reference Example 16 N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} propan-2-amine

The compound (0.32 g, 1.1 mmol) obtained in Reference Example 4 was dissolved in water, 2 mol / L NaOH aqueous solution was added, and the mixture was extracted with CHCl ₃ . The extracted organic layer was washed with brine, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. Acetone (0.25 mL, 3.4 mmol) was added to a solution of the obtained residue in EtOH (5 mL), and the mixture was stirred at 60 ° C. for 30 min. After allowing to cool at room temperature, NaBH ₄ (0.13 g, 3.4 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hr. 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 brine, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure to give the title compound (0.11 g) (pale yellow oil).
MS (ESI pos.) M / z: 249 [M + H] +

Reference Example 17 N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} cyclopropanamine

Bromoacetaldehyde diethyl acetal (1.5 mL, 9.8 mmol), Cs ₂ CO ₃ (7.3 g, 22.5 mmol) in a DMF (50 mL) solution of the compound obtained in Reference Example 2 (1.5 g, 7.5 mmol). ) And stirred at 80 ° C. for 4 hours. After cooling at room temperature, water was added to the reaction mixture, and the mixture was extracted with EtOAc. The extracted organic layer was washed with brine, dried using 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 (KP-Sil 100 g, hexane / EtOAc = 100/0 to 80/20) to give 2- [1- (2,2-diethoxyethyl) -1H-pyrazole- 3-yl] -5-fluoropyridine (1.3 g) was obtained as a colorless oil. The obtained 2- [1- (2,2-diethoxyethyl) -1H-pyrazol-3-yl] -5-fluoropyridine (1.3 g, 4.7 mmol) in CHCl ₃ (20 mL) was cooled with ice. Underneath, trifluoroacetic acid (2.0 mL, 27.9 mmol) was added dropwise. After completion of dropping, the temperature was raised to room temperature and stirred for 20 hours. Saturated aqueous NaHCO ₃ solution was added to the reaction mixture and extracted with CHCl ₃ . The organic layer was washed with brine, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure to give [3- (5-fluoropyridin-2-yl) -1H-pyrazole-1 -Ill] acetaldehyde (0.6 g) was obtained (pale yellow oil). Cyclopropylamine (0.092 mg) was added to a solution of [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] acetaldehyde (0.3 g, 1.5 mmol) in CHCl ₃ (10 mL). 1.6 mmol) and stirred at room temperature for 30 minutes. Thereto was added sodium triacetoxyborohydride (0.95 g, 4.5 mmol), and the mixture was stirred at room temperature for 24 hours. A saturated aqueous NaHCO ₃ solution was added to the reaction solution, and the mixture was extracted with CHCl ₃ . The organic layer was washed with brine, 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 (KP-NH 28 g, hexane / EtOAc = 80/20 to 20/80) to give the title compound (0.20 g) (colorless oil).
MS (ESI pos.) M / z: 247 [M + H] +

Reference Example 18 tert-butyl ethyl {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} carbamate

Using the compound (1.2 g, 3.9 mmol) obtained in Reference Example 6, the title compound (1.4 g) was obtained in the same manner as in Reference Example 14 (colorless amorphous).
MS (ESI pos.) M / z: 335 [M + H] +

Reference Example 19 N-ethyl-2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethanamine

To a solution of the compound obtained in Reference Example 18 (1.4 g, 4.1 mmol) in EtOAc (5 mL) was added 4 mol / L HCl-EtOAc solution (20.3 mL) at room temperature. EtOAc (5 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was basified with 2 mol / L aqueous NaOH and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. Et ₂ O was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title compound (0.81 g) (colorless solid).
MS (ESI pos.) M / z: 235 [M + H] +

Reference Example 20 N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2-iodo-5-methylbenzamide

Using the compound (1.0 g, 3.6 mmol) obtained in Reference Example 4 and 2-iodo-5-methylbenzoic acid (0.97 g, 3.8 mmol) as raw materials, the title was prepared in the same manner as in Reference Example 8. Compound (1.5 g) was obtained (colorless solid).
MS (ESI pos.) M / z: 451 [M + H] +

Reference Example 21 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2-iodo-5-methylbenzamide

Using the compound (0.70 g, 1.8 mmol) obtained in Reference Example 20 as a starting material, the title compound (0.67 g) was obtained in the same manner as in Reference Example 14 (colorless amorphous).
MS (ESI pos.) M / z: 479 [M + H] +

Reference Example 22 tert-butyl {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} carbamate

4- (4-Fluorophenyl) -1H-pyrazole (0.12 g, 0.72 mmol) was used as a starting material, and the title compound (0.22 g, 0.71 mmol) was obtained in the same manner as in Reference Example 6 (colorless) solid).
MS (ESI pos.) M / z: 306 [M + H] +, 328 [M + Na] +

Reference Example 23 2- [4- (4-Fluorophenyl) -1H-pyrazol-1-yl] ethanamine hydrochloride

The title compound (0.17 g, 0.71 mmol) was obtained in the same manner as in Reference Example 7 using the compound (0.22 g, 0.71 mmol) obtained in Reference Example 22 as a raw material (colorless solid).
MS (ESI pos.) M / z: 206 [M + H] +

Reference Example 24 N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5-methyl-N- (propan-2-yl) -2- (2H-1,2,3-triazole- 2-yl) benzamide

N- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) propan-2-amine (0.33 g, 1.5 mmol) was used as a starting material and the title compound (0 .35 g, 0.87 mmol) was obtained (colorless solid).
MS (ESI pos.) M / z: 403 [M + H] +

Reference Example 25 N- (2-hydroxyethyl) -5-methyl-N- (propan-2-yl) -2- (2H-1,2,3-triazol-2-yl) benzamide

The title compound (0.15 g, 0.52 mmol) was obtained in the same manner as in Reference Example 13 using Reference Example 24 (0.35 g, 0.87 mmol) as a starting material (colorless solid).
MS (ESI pos.) M / z: 289 [M + H] +

Reference Example 26 N- (cyclopropylmethyl) -2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethanamine

2- [3- (4-Fluorophenyl) -1H-pyrazol-1-yl] ethanamine hydrochloride (0.43 g, 2.1 mmol) and cyclopropanecarbaldehyde (0.17 mL, 2.3 mmol) as raw materials The title compound (0.41 g) was obtained in the same manner as in Reference Example 16 (colorless oil).
MS (ESI pos.) M / z: 260 [M + H] +

Reference Example 27 N- (cyclopropylmethyl) -2- (3-phenyl-1H-pyrazol-1-yl) ethanamine

The same procedure as in Reference Example 16 using 2- (3-phenyl-1H-pyrazol-1-yl) ethanamine (0.37 g, 2.0 mmol) and cyclopropanecarbaldehyde (0.16 mL, 2.2 mmol) as raw materials Gave the title compound (0.31 g) (colorless oil).
MS (ESI pos.) M / z: 242 [M + H] +

Reference Example 28 N- (oxetane-3-yl) -2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethanamine

Oxetane-3 was added to a solution of [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] acetaldehyde (0.30 g, 1.5 mmol) obtained in Reference Example 17 in CHCl ₃ (10 mL). -Amine hydrochloride (0.092 mg, 1.6 mmol) was added and stirred at room temperature for 30 minutes. Thereto was added sodium triacetoxyborohydride (0.95 g, 4.5 mmol), and the mixture was stirred at room temperature for 24 hours. A saturated aqueous NaHCO ₃ solution was added to the reaction solution, and the mixture was extracted with CHCl ₃ . The extracted organic layer was washed with brine, dried using 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 (KP-NH 28 g, hexane / EtOAc = 80/20 to 20/80) to obtain the title compound (0.20 g) (colorless oil).
MS (ESI pos.) M / z: 263 [M + H] +
Reference Example 29 2-{[3- (6-Methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -1H-isoindole-1,3 (2H) -dione

Reference Example 6 using 2-methyl-6- (1H-pyrazol-3-yl) pyridine (0.46 g, 2.35 mmol) and N- (2-bromoethyl) phthalimide (0.72 g, 2.82 mmol) as raw materials To give the title compound (0.13 g) (colorless oil).
MS (ESI pos.) M / z: 333 [M + H] +

Reference Example 30 2- [3- (6-Methylpyridin-2-yl) -1H-pyrazol-1-yl] ethanamine

Hydrazine monohydrate (0.038 ml, 0.78 mmol) was added to a solution of the compound obtained in Reference Example 29 (0.13 g, 0.39 mmol) in ethanol (5 ml), heated to reflux and stirred for 5 hours. After allowing to cool at room temperature, the precipitated solid was filtered off, and the filtrate was evaporated under reduced pressure to give the title compound (0.080 g) (colorless oil).
MS (ESI pos.) M / z: 203 [M + H] +

Reference Example 31 5-trifluoromethyl-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 (0.68 g, 2 .43 mmol) and 2-bromo-5-trifluoromethylpyridine (0.50 g, 2.21 mmol) as starting materials, the title compound (0.66 g) was obtained in the same manner as in Reference Example 1.
MS (ESI pos.) M / z: 320 [M + Na] +

Reference Example 32 5-trifluoromethyl-2- (1H-pyrazol-5-yl) pyridine hydrochloride

The title compound (0.38 g) was obtained in the same manner as in Reference Example 2 using the compound obtained in Reference Example 31 (0.66 g, 2.22 mmol) as a starting material.
MS (ESI pos.) M / z: 214 [M + H] +

Reference Example 33 N-ethyl-2- [3- (5-trifluoromethylpyridin-2-yl) -1H-pyrazol-1-yl] ethanamine

The title compound (0.030 g) was obtained by the same method as in Reference Example 15-2 using the compound (0.15 g, 0.60 mmol) obtained in Reference Example 32 as a starting material.
MS (ESI pos.) M / z: 285 [M + H] +

Reference Example 34 6-trifluoromethyl-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 (0.63 g, 2 .29 mmol) and 2-bromo-6-trifluoromethylpyridine (0.47 g, 2.08 mmol) as raw materials, and the title compound (0.62 g) was obtained in the same manner as in Reference Example 1.
MS (ESI pos.) M / z: 320 [M + Na] +

Reference Example 35 6-trifluoromethyl-2- (1H-pyrazol-5-yl) pyridine hydrochloride

The title compound (0.50 g) was obtained in the same manner as in Reference Example 2 using the compound obtained in Reference Example 34 (0.62 g, 2.29 mmol) as a starting material.
MS (ESI pos.) M / z: 214 [M + H] +

Reference Example 36 N-ethyl-2- [3- (6-trifluoromethylpyridin-2-yl) -1H-pyrazol-1-yl] ethanamine hydrochloride

The title compound (0.12 g) was obtained in the same manner as in Reference Example 15-2 using the compound obtained in Reference Example 35 (0.50 g, 0.21 mmol) as a starting material.
MS (ESI pos.) M / z: 285 [M + H] +

Reference Example 37 N-ethyl-2- [3- (3,4-difluorophenyl) -1H-pyrazol-1-yl] ethanamine hydrochloride

The title compound (0.11 g) was obtained in the same manner as in Reference Example 15-2 using 5- (3,4-difluorophenyl) -1H-pyrazole (0.50 g, 2.78 mmol) as a starting material.
MS (ESI pos.) M / z: 252 [M + H] +

Reference Example 38 N-ethyl-2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethanamine hydrochloride

The title compound (0.13 g) was obtained in the same manner as in Reference Example 15-2 using 5- (4-fluorophenyl) -1H-pyrazole (0.50 g, 3.08 mmol) as a starting material.
MS (ESI pos.) M / z: 234 [M + H] +

Reference Example 39 4-trifluoromethyl-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 (1.35 g, 4 .87 mmol) and 2-bromo-4-trifluoromethylpyridine (1.0 g, 4.42 mmol) as starting materials, the title compound (1.31 g) was obtained in the same manner as in Reference Example 1.
MS (ESI pos.) M / z: 320 [M + Na] +

Reference Example 40 4-trifluoromethyl-2- (1H-pyrazol-5-yl) pyridine hydrochloride

The title compound (0.80 g) was obtained in the same manner as in Reference Example 2 using the compound obtained in Reference Example 39 (1.31 g, 4.42 mmol) as a starting material.
MS (ESI pos.) M / z: 214 [M + H] +

Reference Example 41 N-ethyl-2- [3- (4-trifluoromethylpyridin-2-yl) -1H-pyrazol-1-yl] ethanamine dihydrochloride

The title compound (0.73 g) was obtained in the same manner as in Reference Example 15-2 using the compound obtained in Reference Example 40 (0.60 g, 2.40 mmol) as a starting material.
MS (ESI pos.) M / z: 285 [M + H] +

Example 1 N- {2- [4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole- 2-yl) benzamide

To a DMF (2.2 mL) solution of the compound obtained in Reference Example 7 (0.20 g, 0.72 mmol), DIPEA (0.62 mL, 3.6 mmol) was added at room temperature. To the reaction solution was added 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.15 g, 0.72 mmol), HATU (0.33 g, 0.86 mmol), Stir at the same temperature for 15 hours. Water and brine were added to the reaction solution, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. A mixed solvent of EtOAc and Et ₂ O was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title compound (0.17 g) (colorless solid).
LCMS retention time 3.84 min. (Condition 1)
MS (ESI pos.) M / z: 392 [M + H] +

Example 2 N- {2- [4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3- Triazol-2-yl) benzamide

To a solution of the compound obtained in Example 1 (0.090 g, 0.23 mmol) in DMF (0.7 mL), 60% NaH (12 mg, 0.28 mmol) was added at room temperature and stirred for 5 minutes. MeI (0.016 mL, 0.25 mmol) was added at the same temperature and stirred overnight at room temperature. Water was added to the reaction solution and extracted with EtOAc. The organic layer was 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 (KP-NH 11 g, hexane / EtOAc = 80/20 to 0/100), and the resulting solid was stirred and washed with Et ₂ O, filtered, and filtered with the title compound ( 0.045 g) was obtained (colorless solid).
LCMS retention time 4.24 min. (Condition 1)
MS (ESI pos.) M / z: 406 [M + H] +

Example 3-1 N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole-2- Il) benzamide

The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 23 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials. (Colorless solid).
MS (ESI pos.) M / z: 391 [M + H] +, 413 [M + Na] +

Example 3-2 N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole- 2-yl) benzamide

The title compound was obtained in the same manner as in Example 2 using the compound obtained in Example 3-1 as a raw material (colorless solid).
LCMS retention time 5.19 min. (Condition 1)
MS (ESI pos.) M / z: 405 [M + H] +

Example 4 N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

MsCl (0.10 mL, 1.3 mmol) was added to a solution of the compound (0.30 g, 1.1 mmol) obtained in Reference Example 10 and TEA (0.30 mL, 2.2 mmol) in CHCl ₃ (6 mL) under ice water cooling. The mixture was heated to room temperature and stirred for 45 minutes. Under cooling with ice water, an aqueous NaHCO ₃ solution was added, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. Cs ₂ CO ₃ (0.18 g, 0.56 mmol) was added to a suspension of the obtained residue and the compound (0.046 g, 0.28 mmol) obtained in Reference Example 5 in MeCN (0.56 mL), The mixture was stirred at an oil bath temperature of 80 ° C. for 1 hour. The mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with EtOAc. The organic layer was evaporated under reduced pressure. The obtained residue was purified by column chromatography (HP-NH 11 g, hexane / EtOAc = 85/15 to 0/100). The obtained solid was stirred and washed in Et ₂ O and collected by filtration to give the title compound (0.065 g) (colorless solid).
LCMS retention time 4.59 min. (Condition 1)
MS (ESI pos.) M / z: 420 [M + H] +

  Using the same method as in Example 4, the compounds of Examples 5 to 14 were obtained.

Example 5 N- (cyclopropylmethyl) -N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzamide

N- (cyclopropylmethyl) -N- (2-hydroxyethyl) -5-methyl-2- (2H-1,2) obtained using the compound obtained in Reference Example 5 and the same method as in Reference Example 10. , 3-Triazol-2-yl) benzamide as a starting material, the title compound was obtained (colorless solid).
LCMS retention time 5.24 min. (Condition 1)
MS (ESI pos.) M / z: 446 [M + H] +

Example 6 N- (cyclopropylmethyl) -N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

4- (4-Fluorophenyl) -1H-pyrazole and N- (cyclopropylmethyl) -N- (2-hydroxyethyl) -5-methyl-2- (2H-1,2,3-triazol-2-yl ) The title compound was obtained from benzamide as a starting material (colorless solid).
LCMS retention time 5.83 min. (Condition 1)
MS (ESI pos.) M / z: 445 [M + H] +

Example 7 N-ethyl-N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole- 2-yl) benzamide

Using the compound obtained in Reference Example 10 and 4- (4-fluorophenyl) -1H-pyrazole as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 5.47 min. (Condition 1)
MS (ESI pos.) M / z: 419 [M + H] +

Example 8 N-ethyl-N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole- 2-yl) benzamide

Using the compound obtained in Reference Example 10 and 3- (4-fluorophenyl) -1H-pyrazole as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 5.65 min. (Condition 1)
MS (ESI pos.) M / z: 419 [M + H] +

Example 9 N-ethyl-5-methyl-N- {2- [3- (pyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide

The title compound was obtained using the compound obtained in Reference Example 10 and 2- (1H-pyrazol-3-yl) pyridine as raw materials (colorless solid).
LCMS retention time 3.37 min. (Condition 1)
MS (ESI pos.) M / z: 402 [M + H] +

Example 10 N- {2- [4- (5-chloropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-5-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

Using the compound obtained in Reference Example 10 and 5-chloro-2- (1H-pyrazol-4-yl) pyridine as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 5.03 min. (Condition 1)
MS (ESI pos.) M / z: 436 [M + H] +

Example 11 N-ethyl-5-methyl-N- {2- [4- (pyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide

Using the compound obtained in Reference Example 10 and 2- (1H-pyrazol-4-yl) pyridine as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 3.30 min. (Condition 1)
MS (ESI pos.) M / z: 402 [M + H] +

Example 12 N-ethyl-N- {2- [4- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

Using the compound obtained in Reference Example 10 and 2-methyl-6- (1H-pyrazol-4-yl) pyridine as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 3.35 min. (Condition 1)
MS (ESI pos.) M / z: 416 [M + H] +

Example 13 N-cyclopropyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) benzamide

Using the compounds obtained in Reference Example 13 and Reference Example 5 as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 4.71 min. (Condition 1)
MS (ESI pos.) M / z: 432 [M + H] +

Example 14 N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (propan-2-yl) -2- ( 2H-1,2,3-triazol-2-yl) benzamide

Using the compounds obtained in Reference Example 25 and Reference Example 5 as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 4.98 min. (Condition 1)
MS (ESI pos.) M / z: 434 [M + H] +

Example 15 N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) Benzamide

To a CHCl ₃ (3 mL) solution of the compound obtained in Reference Example 2 (0.15 g, 0.64 mmol), DIPEA (0.28 mL, 1.6 mmol) was added at room temperature. To the reaction solution, under cooling with ice water, 5-methyl-2- (pyrimidin-2-yl) benzoic acid (0.18 g, 0.83 mmol) and propylphosphonic anhydride (cyclic trimer) (50% EtOAc solution (about 1 0.7 mol / L), 1.1 mL, and 1.9 mmol) were added, and the mixture was stirred at room temperature for 1 hour and further at an oil bath temperature of 50 ° C. for 3 hours. After cooling to room temperature, water was added and extracted with CHCl ₃ . The organic layer was washed with brine, and the organic layer was dried over Na ₂ SO ₄ . The obtained residue was subjected to column chromatography (KP-NH 28 g, hexane / EtOAc = 70/30 to 0/100) and further purified by HPLC to obtain the title compound (0.069 g) (colorless amorphous).
LCMS retention time 4.37 min. (Condition 1)
MS (ESI pos.) M / z: 431 [M + H] +

Example 16 N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole- 2-yl) benzamide

The title compound was obtained in the same manner as in Example 1, using the compound obtained in Reference Example 4 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials. (Colorless solid).
LCMS retention time 4.07 min. (Condition 1)
MS (ESI pos.) M / z: 392 [M + H] +

Example 17 N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3- Triazol-2-yl) benzamide

The title compound was obtained in the same manner as in Example 2 using the compound obtained in Example 16 and MeI as raw materials (colorless solid).
LCMS retention time 4.50 min. (Condition 1)
MS (ESI pos.) M / z: 406 [M + H] +

  Using the same method as in Example 17, the compounds of Examples 18 to 19, 20-2, 21 to 22, 23-2 and 24 were obtained.

Example 18 N- (cyclopropylmethyl) -N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzamide

The title compound was obtained using the compound obtained in Example 16 and cyclopropylmethyl bromide as raw materials (colorless solid).
LCMS retention time 5.23 min. (Condition 1)
MS (ESI pos.) M / z: 446 [M + H] +, 468 [M + Na] +

Example 19 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

The title compound was obtained using the compound obtained in Example 16 and EtI as raw materials (colorless solid).
LCMS retention time 4.78 min. (Condition 1)
MS (ESI pos.) M / z: 420 [M + H] +

Example 20-1 N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole-2- Il) benzamide

2- [3- (4-Fluorophenyl) -1H-pyrazol-1-yl] ethanamine dihydrochloride and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials In the same manner as in Example 1, the title compound was obtained (colorless oil).
MS (ESI pos.) M / z: 391 [M + H] +

Example 20-2 N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole- 2-yl) benzamide

The title compound was obtained using the compound obtained in Example 20-1 and MeI as raw materials (colorless solid).
LCMS retention time 5.37 min. (Condition 1)
MS (ESI pos.) M / z: 405 [M + H] +

Example 21 N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (2-fluoroethyl) -2- (2H -1,2,3-triazol-2-yl) benzamide

Using the compound obtained in Example 16 and 1-fluoro-2-iodoethane as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 4.71 min. (Condition 1)
MS (ESI pos.) M / z: 438 [M + H] +

Example 22 N- (2,2-difluoroethyl) -N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

The title compound was obtained using the compound obtained in Example 16 and 2,2-difluoroethyl trifluoromethanesulfonate as raw materials (colorless solid).
LCMS retention time 5.08 min. (Condition 1)
MS (ESI pos.) M / z: 456 [M + H] +

Example 23-1 5-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3- Triazol-2-yl) benzamide

The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 4 and 5-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials. (Brown powder).
MS (ESI pos.) M / z: 396 [M + H] +

Example 23-2 N-methyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-fluoro-2- (2H-1, 2,3-Triazol-2-yl) benzamide

Using the compound obtained in Example 23-1 and MeI as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 4.37 min. (Condition 1)
MS (ESI pos.) M / z: 410 [M + H] +

Example 24 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-fluoro-2- (2H-1,2, 3-Triazol-2-yl) benzamide

Using the compound obtained in Example 23-1 and EtI as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 4.64 min. (Condition 1)
MS (ESI pos.) M / z: 424 [M + H] +

Example 25 N- {2- [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide

Example 15 using the compound (0.20 g, 0.72 mmol) obtained in Reference Example 7 and 5-methyl-2- (pyrimidin-2-yl) benzoic acid (0.20 g, 0.93 mmol) as raw materials. To give the title compound (0.093 g) (colorless solid).
MS (ESI pos.) M / z: 403 [M + H] +

Example 26 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) Benzamide

Using the compound (0.093 g, 0.23 mmol) and EtI (0.020 mL, 0.25 mmol) obtained in Example 25 as raw materials, the title compound (0.055 g) was obtained in the same manner as in Example 2. (Colorless solid).
LCMS retention time 4.63 min. (Condition 1)
MS (ESI pos.) M / z: 431 [M + H] +

  In the same manner as in Example 1, the compounds of Examples 27 to 33 were obtained.

Example 27 N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (propan-2-yl) -2- ( 2H-1,2,3-triazol-2-yl) benzamide

Using the compound obtained in Reference Example 16 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials, the title compound was obtained (colorless amorphous).
LCMS retention time 5.24 min. (Condition 1)
MS (ESI pos.) M / z: 434 [M + H] +

Example 28 N- (cyclopropylmethyl) -N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

Using the compound obtained in Reference Example 26 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 6.04 min. (Condition 1)
MS (ESI pos.) M / z: 445 [M + H] +

Example 29 N- (cyclopropylmethyl) -5-methyl-N- [2- (3-phenyl-1H-pyrazol-1-yl) ethyl] -2- (2H-1,2,3-triazole-2 -Yl) benzamide

Using the compound obtained in Reference Example 27 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials, the title compound was obtained (colorless amorphous).
LCMS retention time 5.95 min. (Condition 1)
MS (ESI pos.) M / z: 427 [M + H] +

Example 30 N-cyclopropyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2 , 3-Triazol-2-yl) benzamide

The title compound was obtained using the compound obtained in Reference Example 17 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials (colorless powder).
LCMS retention time 4.95 min. (Condition 1)
MS (ESI pos.) M / z: 432 [M + H] +

Example 31 N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (oxetan-3-yl) -2- ( 2H-1,2,3-triazol-2-yl) benzamide

Using the compound obtained in Reference Example 28 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials, the title compound was obtained (colorless powder).
LCMS retention time 4.43 min. (Condition 1)
MS (ESI pos.) M / z: 448 [M + H] +

Example 32 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole- 2-yl) benzamide

The title compound was obtained using the compound obtained in Reference Example 15-1 and 2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials (colorless solid).
LCMS retention time 4.56 min. (Condition 1)
MS (ESI pos.) M / z: 406 [M + H] +

Example 33 5-Chloro-N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2, 3-Triazol-2-yl) benzamide

Using the compound obtained in Reference Example 15-1 and 5-chloro-2- (2H-1,2,3-triazol-2-yl) benzoic acid as raw materials, the title compound was obtained (colorless solid).
LCMS retention time 5.03 min. (Condition 1)
MS (ESI pos.) M / z: 440 [M + H] +

Example 34 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide

The title compound was obtained in the same manner as in Example 15 using the compound obtained in Reference Example 15-1 and 2- (pyrimidin-2-yl) benzoic acid as raw materials (colorless solid).
LCMS retention time 4.32 min. (Condition 1)
MS (ESI pos.) M / z: 417 [M + H] +

Example 35 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyridin-2-yl) Benzamide

To a solution of the compound (0.17 g, 0.36 mmol) obtained in Reference Example 21 and 2- (tributylstannanyl) pyridine (0.17 g, 0.46 mmol) in toluene (9 mL) was added Pd (PPh ₃ ) ₄ (0 0.028 g, 0.020 mmol), copper iodide (0.011 g, 0.030 mmol) and cesium fluoride (0.11 g, 0.71 mmol) were added, and the mixture was stirred at an oil bath temperature of 110 ° C. for 15 hours. Brine was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was further purified by column chromatography (KP-NH 28 g, hexane / EtOAc = 70/30 to 0/100) and HPLC. Et ₂ O was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title compound (0.048 g) (colorless solid).
LCMS retention time 3.44 min. (Condition 1)
MS (ESI pos.) M / z: 430 [M + H] +

Example 36 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyridin-3-yl) Benzamide

To a solution of the compound obtained in Reference Example 21 (0.17 g, 0.34 mmol) and pyridin-3-ylboronic acid (0.13 g, 1.1 mmol) in 1,4-dioxane (0.7 mL) was added 2 mol / L Na. ₂ CO ₃ aqueous solution (1.0 mL, 2.1 mmol) and Pd (PPh ₃ ) ₄ (0.026 g, 0.020 mmol) were added, and the mixture was stirred at an oil bath temperature of 110 ° C. for 15 hours. After cooling to room temperature, brine was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was further purified by column chromatography (KP-NH 28 g, hexane / EtOAc = 70/30 to 0/100) and HPLC. Et ₂ O was added to the obtained residue, and the precipitated solid was collected by filtration to obtain the title compound (0.10 g) (colorless solid).
LCMS retention time 3.24 min. (Condition 1)
MS (ESI pos.) M / z: 430 [M + H] +

Example 37 N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide

The title compound was obtained in the same manner as in Example 15 using the compound obtained in Reference Example 19 and 2- (pyrimidin-2-yl) benzoic acid as raw materials (colorless amorphous).
LCMS retention time 4.14 min. (Condition 1)
MS (ESI pos.) M / z: 417 [M + H] +

Example 38 5-Methyl-N- {2- [3- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole- 2-yl) benzamide

Compound obtained in Reference Example 30 (0.079 g, 0.39 mmol) and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.13 g, 0.47 mmol) Was used as a starting material to give the title compound (0.090 g) by the same method as in Example 1.
MS (ESI pos.) M / z: 388 [M + H] +

Example 39 N-ethyl-5-methyl-N- {2- [3- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2, 3-Triazol-2-yl) benzamide

Using the compound (0.079 g, 0.23 mmol) obtained in Example 38 and ethyl iodide (0.022 ml, 0.28 mmol) as raw materials, the title compound (0.090 g) was prepared in the same manner as in Example 2. Got.
LCMS retention time 3.49 min. (Condition 2)
MS (ESI pos.) M / z: 416 [M + H] +

Example 40 5-Fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide

Using the compound (0.20 g, 0.72 mmol) obtained in Reference Example 4 and 5-fluoro-2- (pyrimidin-2-yl) benzoic acid (0.20 g, 0.93 mmol) as raw materials, Example 15 In the same manner, the title compound (0.040 g) was obtained.
MS (ESI pos.) M / z: 407 [M + H] +

Example 41 N-ethyl-5-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) Benzamide

Using the compound obtained in Example 40 (0.040 g, 0.10 mmol) and ethyl iodide (0.008 ml, 0.10 mmol) as raw materials, the title compound (0.034 g) was prepared in the same manner as in Example 2. Got.
LCMS retention time 0.89 min. (Condition 2)
MS (ESI pos.) M / z: 435 [M + H] +

Example 42 5-Chloro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide

Using the compound obtained in Reference Example 4 (0.20 g, 0.72 mmol) and 5-chloro-2- (pyrimidin-2-yl) benzoic acid (0.22 g, 0.93 mmol) as raw materials, Example 15 In the same manner, the title compound (0.037 g) was obtained.
MS (ESI pos.) M / z: 423 [M + H] +

Example 43 N-ethyl-5-chloro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) Benzamide

Using the compound (0.037 g, 0.09 mmol) obtained in Example 42 and ethyl iodide (0.007 ml, 0.09 mmol) as raw materials, the title compound (0.025 g) was prepared in the same manner as in Example 2. Got.
LCMS retention time 0.96 min. (Condition 2)
MS (ESI pos.) M / z: 451 [M + H] +

Example 44 N-ethyl-4-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2, 3-Triazol-2-yl) benzamide

The compound (0.020 g, 0.09 mmol) obtained in Reference Example 15-2 and 4-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.021 g,. 10 mmol) was used as a starting material, and the title compound (0.040 g) was obtained in the same manner as in Example 1.
LCMS retention time 0.91 min. (Condition 2)
MS (ESI pos.) M / z: 424 [M + H] +

Example 45 N-ethyl-2-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -6- (2H-1,2, 3-Triazol-2-yl) benzamide

The compound (0.059 g, 0.19 mmol) obtained in Reference Example 15-2 and 2-fluoro-6- (2H-1,2,3-triazol-2-yl) benzoic acid (0.040 g,. 19 mmol) was used as a starting material, and the title compound (0.021 g) was obtained in the same manner as in Example 1.
LCMS retention time 0.84, 0.92 min. (Condition 2)
MS (ESI pos.) M / z: 424 [M + H] +

Example 46 N-ethyl-2-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -6- (pyrimidin-2-yl) Benzamide

Conducted using the compound (0.040 g, 0.14 mmol) obtained in Reference Example 15-2 and 2-fluoro-6- (pyrimidin-2-yl) benzoic acid (0.034 g, 0.16 mmol) as raw materials In the same manner as in Example 15, the title compound (0.008 g) was obtained.
LCMS retention time 0.82, 0.91 min. (Condition 2)
MS (ESI pos.) M / z: 435 [M + H] +

Example 47 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -4-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

The compound (0.050 g, 0.16 mmol) obtained in Reference Example 15-2 and 4-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.040 g, 0. 20 mmol) as a starting material, and the title compound (0.036 g) was obtained in the same manner as in Reference Example 8.
LCMS retention time 0.94 min. (Condition 2)
MS (ESI pos.) M / z: 420 [M + H] +

Example 48 N-ethyl-3-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2, 3-Triazol-2-yl) benzamide

The compound obtained in Reference Example 15-2 (0.030 g, 0.10 mmol) and 3-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.024 g,. 12 mmol) was used as a starting material, and the title compound (0.029 g) was obtained in the same manner as in Reference Example 8.
LCMS retention time 0.84 min. (Condition 2)
MS (ESI pos.) M / z: 424 [M + H] +

Example 49 N-ethyl-4-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) Benzamide

Conducted using the compound (0.050 g, 0.16 mmol) obtained in Reference Example 15-2 and 4-fluoro-2- (pyrimidin-2-yl) benzoic acid (0.046 g, 0.21 mmol) as raw materials In the same manner as in Example 15, the title compound (0.028 g) was obtained.
LCMS retention time 0.89 min. (Condition 2)
MS (ESI pos.) M / z: 435 [M + H] +

Example 50 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methoxy-2- (2H-1,2, 3-Triazol-2-yl) benzamide

The compound obtained in Reference Example 15-2 (0.060 g, 0.20 mmol) and 5-methoxy-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.070 g, .0. 30 mmol) was used as a starting material, and the title compound (0.013 g) was obtained in the same manner as in Example 1.
LCMS retention time 0.76 min. (Condition 2)
MS (ESI pos.) M / z: 436 [M + H] +

Example 51 N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-1-yl} ethyl) benzamide

Compound obtained in Reference Example 33 (0.030 g, 0.11 mmol) and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.026 g, 0.13 mmol) As a starting material, the title compound (0.026 g) was obtained in the same manner as in Reference Example 8.
LCMS retention time 1.07 min. (Condition 2)
MS (ESI pos.) M / z: 470 [M + H] +

Example 52 N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-1-yl} ethyl) benzamide

The compound obtained in Reference Example 36 (0.050 g, 0.16 mmol) and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.050 g, 0.23 mmol) As a starting material, the title compound (0.010 g) was obtained in the same manner as in Example 1.
LCMS retention time 1.09 min. (Condition 2)
MS (ESI pos.) M / z: 492 [M + Na] +

Example 53 N- {2- [3- (3,4-difluorophenyl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-5-fluoro-2- (pyrimidin-2-yl) benzamide

Using the compound (0.050 g, 0.17 mmol) obtained in Reference Example 37 and 5-fluoro-2- (pyrimidin-2-yl) benzoic acid (0.045 g, 0.21 mmol) as raw materials, Example 15 In the same manner, the title compound (0.009 g) was obtained.
LCMS retention time 1.06 min. (Condition 2)
MS (ESI pos.) M / z: 452 [M + H] +

Example 54 N-ethyl-5-fluoro-N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide

Using the compound (0.050 g, 0.19 mmol) obtained in Reference Example 38 and 5-fluoro-2- (pyrimidin-2-yl) benzoic acid (0.055 g, 0.24 mmol) as raw materials, Example 15 The title compound (0.050 g) was obtained by the same procedure.
LCMS retention time 1.03 min. (Condition 2)
MS (ESI pos.) M / z: 434 [M + H] +

Example 55 5-chloro-N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2, 3-Triazol-2-yl) benzamide

The compound (0.10 g, 0.43 mmol) obtained in Reference Example 19 and 5-chloro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.14 g, 0.64 mmol) As a starting material, the title compound (0.093 g) was obtained in the same manner as in Example 1.
LCMS retention time 0.95 min. (Condition 2)
MS (ESI pos.) M / z: 440 [M + H] +

Example 56 N-ethyl-5-fluoro-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2, 3-Triazol-2-yl) benzamide

Compound (0.10 g, 0.43 mmol) obtained in Reference Example 19 and 5-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.11 g, 0.51 mmol) Was used as a starting material to give the title compound (0.099 g) by the same method as in Example 1.
LCMS retention time 0.86 min. (Condition 2)
MS (ESI pos.) M / z: 424 [M + H] +

Example 57 N-ethyl-5-fluoro-2- (pyrimidin-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazole-1- Il} ethyl) benzamide

Using the compound (0.035 g, 0.11 mmol) obtained in Reference Example 36 and 4-fluoro-2- (pyrimidin-2-yl) benzoic acid (0.036 g, 0.17 mmol) as raw materials, Example 15 In the same manner, the title compound (0.008 g) was obtained.
LCMS retention time 1.06 min. (Condition 2)
MS (ESI pos.) M / z: 485 [M + H] +

Example 58 N-ethyl- (pyrimidin-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-1-yl} ethyl) benzamide

Using the compound obtained in Reference Example 36 (0.035 g, 0.11 mmol) and 2- (pyrimidin-2-yl) benzoic acid (0.035 g, 0.17 mmol) as raw materials, the same procedure as in Example 15 was used. To give the title compound (0.039 g).
LCMS retention time 1.03 min. (Condition 2)
MS (ESI pos.) M / z: 467 [M + H] +

Example 59 N- {2- [3- (3,4-difluorophenyl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-2- (pyrimidin-2-yl) benzamide

Using the compound (0.050 g, 0.17 mmol) obtained in Reference Example 37 and 2- (pyrimidin-2-yl) benzoic acid (0.050 g, 0.24 mmol) as raw materials, the same procedure as in Example 15 was used. To give the title compound (0.060 g).
LCMS retention time 1.04 min. (Condition 2)
MS (ESI pos.) M / z: 434 [M + H] +

Example 60 N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [4- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-1-yl} ethyl) benzamide

The compound (0.10 g, 0.28 mmol) obtained in Reference Example 41 and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.068 g, 0.34 mmol) As a starting material, the title compound (0.082 g) was obtained in the same manner as in Example 1.
LCMS retention time 1.06 min. (Condition 2)
MS (ESI pos.) M / z: 470 [M + H] +

Example 61 N-ethyl-5-fluoro-2- (pyrimidin-2-yl) -N- (2- {3- [4- (trifluoromethyl) pyridin-2-yl] -1H-pyrazole-1- Il} ethyl) benzamide

Using the compound (0.10 g, 0.28 mmol) obtained in Reference Example 41 and 4-fluoro-2- (pyrimidin-2-yl) benzoic acid (0.073 g, 0.34 mmol) as raw materials, Example 15 In the same manner, the title compound (0.13 g) was obtained.
LCMS retention time 1.02 min. (Condition 2)
MS (ESI pos.) M / z: 485 [M + H] +

Test example (measurement of orexin receptor antagonist 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 (Toshikatsu Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). The method was modified. Chinese hamster ovary (CHO) cells in which hOX1R and hOX2R are forcibly expressed were seeded at 20,000 in each well of a 96-well Black clear bottom plate (Nunc), and 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-4AM 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 under conditions of 37 ° C. and 5% CO ₂ . After removing the assay buffer containing Fluo-4AM ester, the test compound was dissolved in dimethyl sulfoxide to a concentration of 10 mM, diluted with assay buffer, 150 μL was added, and the mixture was incubated for 30 minutes.

Peptide substituted with 2 amino acids of human orexin-A ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is a final concentration of 300 pM for hOX1R and hOX2R 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 1.
In Examples 3-1, 20-1, 23-1, and 25, the orexin receptor antagonistic activity test was not performed.

  The compound of the present invention was shown to have OX receptor antagonistic action. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof is a disease modulated by OX receptor antagonism, such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease , Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc. .

Claims (7)

Formula (IA)

(Where
X represents a nitrogen atom or the formula CH;
One of Y ¹ and Y ² represents a nitrogen atom and the other represents the formula CH;
R ¹ represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,
R ² represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from Substituent Group 1), C _3-6 cyclo An alkyl group or a 4-6 membered cyclic ether group;
Substituent group 1 is a group consisting of a halogen atom, a C _3-6 cycloalkyl group, and a C _1-6 alkoxy group,
R ³ represents a triazolyl group, a pyridyl group, or a pyrimidyl group,
The triazolyl group, pyridyl group and pyrimidyl group may be substituted with 1 to 3 halogen atoms,
R ⁴ and R ⁵ are the same or different and each 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). Show)
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson, characterized by containing a pyrazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Remedy or preventive for illness, Huntington's disease, eating disorder, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension. The sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia characterized by containing as an active ingredient the pyrazole derivative according to claim 1, wherein R ⁵ is a hydrogen atom, or a pharmaceutically acceptable salt thereof, Drugs for treatment, prevention of Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension. Formula (I)

(Where
X represents a nitrogen atom or the formula CH;
One of Y ¹ and Y ² represents a nitrogen atom and the other represents the formula CH;
R ¹ represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group,
R ² represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from Substituent Group 1), C _3-6 cyclo An alkyl group or a 4-6 membered cyclic ether group;
Substituent group 1 is a group consisting of a halogen atom, a C _3-6 cycloalkyl group, and a C _1-6 alkoxy group,
R ³ represents a triazolyl group, a pyridyl group, or a pyrimidyl group,
The triazolyl group, pyridyl group and pyrimidyl group may be substituted with 1 to 3 halogen atoms,
R ⁴ represents a hydrogen atom, a halogen atom, or a C _1-6 alkyl group)
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson, characterized by containing a pyrazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient Remedy or preventive for illness, Huntington's disease, eating disorder, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension. R ² represents a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from the above substituent group 1), a C _3-6 cycloalkyl group. Or a 4- to 6-membered cyclic ether group, comprising the pyrazole derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient, depression Disease, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine Treatment or prevention of related diseases and diseases of hypertension. R ² is a methyl group or an ethyl group. Sleep disorder, depression comprising the pyrazole derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. Disease, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine Treatment or prevention of related diseases and diseases of hypertension. X is a nitrogen atom,
R ³ is triazolyl group, or a pyrazole derivative according to any one of claims 1 to 5 is a pyrimidyl group, or a sleep disorder characterized by containing a pharmaceutically acceptable salt thereof as an active ingredient, 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 Therapeutic or preventive drug for diseases and hypertension. A sleep disorder, depression, anxiety disorder characterized by containing as an active ingredient any one or a mixture of two or more selected from the following compound group described in claim 1 and pharmaceutically acceptable salts thereof , 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, hypertension Therapeutic or prophylactic agent for diseases.
N- {2- [4- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl Benzamide,
N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide;
N- {2- [4- (4-Fluorophenyl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazol-2-yl) benzamide ,
N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- (cyclopropylmethyl) -N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) benzamide,
N- (cyclopropylmethyl) -N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [4- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-5-methyl-N- {2- [3- (pyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole-2- Il) benzamide,
N- {2- [4- (5-chloropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-5-methyl-N- {2- [4- (pyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole-2- Il) benzamide,
N-ethyl-N- {2- [4- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-cyclopropyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3- Triazol-2-yl) benzamide,
N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (propan-2-yl) -2- (2H-1 , 2,3-triazol-2-yl) benzamide,
N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N- {2- [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl Benzamide,
N- {2- [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N- (cyclopropylmethyl) -N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide;
N- {2- [3- (4-Fluorophenyl) -1H-pyrazol-1-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazol-2-yl) benzamide ,
N- {2- [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (propan-2-yl) -2- (2H-1 , 2,3-triazol-2-yl) benzamide,
N- (2,2-difluoroethyl) -N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzamide,
5-Fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-methyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-fluoro-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-fluoro-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (2-fluoroethyl) -2- (2H-1, 2,3-triazol-2-yl) benzamide,
N- (cyclopropylmethyl) -N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- (cyclopropylmethyl) -5-methyl-N- [2- (3-phenyl-1H-pyrazol-1-yl) ethyl] -2- (2H-1,2,3-triazol-2-yl) Benzamide,
N-cyclopropyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (2H-1,2,3- Triazol-2-yl) benzamide,
N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-N- (oxetan-3-yl) -2- (2H-1 , 2,3-triazol-2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
5-chloro-N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyridin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methyl-2- (pyridin-3-yl) benzamide;
N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
5-methyl-N- {2- [3- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-5-methyl-N- {2- [3- (6-methylpyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
5-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
5-chloro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide,
N-ethyl-5-chloro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-4-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-2-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -6- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-2-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -6- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -4-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-3-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-4-fluoro-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -5-methoxy-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [5- (trifluoromethyl) pyridin-2-yl] -1H -Pyrazol-1-yl} ethyl) benzamide;
N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl] -1H -Pyrazol-1-yl} ethyl) benzamide;
N- {2- [3- (3,4-difluorophenyl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-5-fluoro-2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [3- (4-fluorophenyl) -1H-pyrazol-1-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
5-chloro-N-ethyl-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-5-fluoro-N- {2- [4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-5-fluoro-2- (pyrimidin-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-1-yl} ethyl Benzamide,
N-ethyl- (pyrimidin-2-yl) -N- (2- {3- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-1-yl} ethyl) benzamide;
N- {2- [3- (3,4-difluorophenyl) -1H-pyrazol-1-yl] ethyl} -N-ethyl-2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-methyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {3- [4- (trifluoromethyl) pyridin-2-yl] -1H -Pyrazol-1-yl} ethyl) benzamide;
N-ethyl-5-fluoro-2- (pyrimidin-2-yl) -N- (2- {3- [4- (trifluoromethyl) pyridin-2-yl] -1H-pyrazol-1-yl} ethyl Benzamide.