JP2014111586A - Pharmaceutical containing heteroaromatic ring derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new therapeutic or preventive agent of diseases such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer disease, Parkinson disease, Huntington chorea, eating disorder, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immunity related disease, endocrine related disease and hypertension.SOLUTION: A therapeutic or preventive agent of diseases such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer disease, Parkinson disease, Huntington chorea, eating disorder, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immunity related disease, endocrine related disease and hypertension is characterized by containing a heteroaromatic ring derivative represented by the general formula (IA) having an ohlexin (OX) receptor antagonism or a pharmaceutically acceptable salt thereof as an active ingredient.

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, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc. The present invention relates to a drug for the treatment or prevention of diseases.

  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 previously cloned into 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 paid to the relationship between OX1 and OX2 receptors and sleep / wake regulation, and the usefulness of compounds having OX receptor antagonistic activity has been studied. When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous exercise is increased (see Non-Patent Document 6 and Non-Patent Document 7), the normal behavior is increased (see Non-Patent Document 7), and the awakening time is extended (Non-Patent Document). 6). The action of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8). Furthermore, administration of a substance that antagonizes OX1 and OX2 receptors to the same extent that can be administered orally has been reported to reduce exercise, shorten sleep onset latency, and increase non-REM sleep and REM sleep (non-) (See Patent Document 9 and Non-Patent Document 10).
As OX receptor antagonistic compounds, for example, compounds having various structures described in Non-Patent Document 11 as a review are known.

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

  An object of the present invention is to provide a sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson, characterized by containing a novel compound having an OX receptor antagonistic action as an active ingredient It is to provide a therapeutic or prophylactic agent for diseases such as diseases, Huntington's chorea, eating disorders, pain, migraine, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, or 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 an excellent OX receptor antagonistic action on certain heteroaromatic ring derivatives represented by the following formulas: As a result, the present invention has been completed.
That is, the present invention
(1) Formula (IA)

(Where
X represents a nitrogen atom or the formula CH;
Y represents any one of the following formula group (II),

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 (wherein the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from Substituent Group 1), C _{3 -6} cycloalkyl 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 pyrimidinyl group;
The triazolyl group, pyridyl group and pyrimidinyl 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). )
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease characterized by containing a heteroaromatic ring derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient , Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, therapeutic or preventive drugs for diseases such as hypertension,
(2) R ⁴ is a halogen atom,
A sleep disorder, depression, anxiety disorder, wherein R ⁵ contains the heteroaromatic ring derivative according to (1), which is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof as an active ingredient, Panic disorders, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc. Treatment or prevention of
(3) Formula (I)

(Where
X represents a nitrogen atom or the formula CH;
Y represents any one of the following formula group (II),

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 pyrimidinyl group;
The triazolyl group, pyridyl group and pyrimidinyl 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 characterized by containing a heteroaromatic ring derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient , Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, therapeutic or preventive drugs for diseases such as hypertension,

(4) X is a nitrogen atom,
R ² is a C _1-6 alkyl group,
R ³ is a triazolyl group or a pyrimidinyl group;
A sleep disorder characterized by containing as an active ingredient the heteroaromatic ring derivative according to any one of (1) to (3), wherein R ⁴ is a halogen atom, or a pharmaceutically acceptable salt thereof; Depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immune related diseases, endocrine related Treatment or prevention of diseases, diseases such as hypertension,
(5) The heteroaromatic ring derivative according to any one of (1) to (4) or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ² is a methyl group or an ethyl group. Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation , Immune-related diseases, endocrine-related diseases, therapeutic or preventive drugs for diseases such as hypertension,
(6) Sleep disorder, depression characterized by containing as active ingredient any one or a mixture of two or more selected from the following compound group described in (1) above and a pharmaceutically acceptable salt thereof Disease, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immune related diseases, endocrine related diseases Therapeutic or preventive drugs for diseases such as hypertension.
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-fluoro-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethyl} -5-methyl-2- (2H-1,2,3 -Triazol-2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] ethyl} -5-methyl-2- (2H-1 , 2,3-triazol-2-yl) benzamide,
5-chloro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -N-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-4-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-2-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-2-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -6- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl) benzamide;
N-ethyl-N- {2- [1- (6-methylpyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {1- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazole-3 -Yl} ethyl) benzamide,
N- {2- [1- (3,4-difluorophenyl) -1H-pyrazol-3-yl] ethyl} -N-ethyl-2- (2H-1,2,3-triazol-2-yl) benzamide ,
N-ethyl-5-fluoro-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [1- (6-methylpyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N- {2- [1- (3,4-difluorophenyl) -1H-pyrazol-3-yl] ethyl} -N-ethyl-5-fluoro-2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N- {2- [5- (4-Fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3 -Triazol-3-yl) benzamide,
N-ethyl-N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) benzamide,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (2H-1,2,3 -Triazol-2-yl) benzamide,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide ,
N-ethyl-5-fluoro-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide ,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (2H-1,2,3-triazole-2 -Yl) benzamide, and
N-ethyl-N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
It is.

  The heteroaromatic ring derivative of the present invention exhibits affinity for the OX receptor and antagonizes the stimulation of the receptor by a physiological ligand. The novel heteroaromatic ring derivative allows sleep disorder, depression, anxiety. Disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc. It has become possible to provide therapeutic or preventive drugs for these diseases.

The terms used in this specification have the following meanings.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -Butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group and the like can be mentioned.
The “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, or Salt with inorganic acid such as nitric acid, or 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, Salts with organic acids such as glycolic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or 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.
Y is preferably a compound of any one of the following formula group (IIa).

R ¹ is preferably a hydrogen atom, a halogen atom other than iodine, or a C _1-6 alkyl group, and more preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group.
R ² is preferably a compound having a C _1-6 alkyl group, more preferably a compound having a methyl group or an ethyl group.
R ³ is preferably a compound that is a triazolyl group or a pyrimidinyl group, and more preferably a 1,2,3-triazol-2-yl group or a pyrimidin-2-yl group.
R ⁴ is preferably a halogen atom compound, more preferably a compound other than iodine, more preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom.
R ⁵ is preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom or a fluorine atom.
Examples of preferred compounds in the compounds of the present invention include
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-fluoro-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethyl} -5-methyl-2- (2H-1,2,3 -Triazol-2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] ethyl} -5-methyl-2- (2H-1 , 2,3-triazol-2-yl) benzamide,
5-chloro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -N-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-4-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-2-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-2-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -6- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl) benzamide;
N-ethyl-N- {2- [1- (6-methylpyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {1- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazole-3 -Yl} ethyl) benzamide,
N- {2- [1- (3,4-difluorophenyl) -1H-pyrazol-3-yl] ethyl} -N-ethyl-2- (2H-1,2,3-triazol-2-yl) benzamide ,
N-ethyl-5-fluoro-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [1- (6-methylpyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N- {2- [1- (3,4-difluorophenyl) -1H-pyrazol-3-yl] ethyl} -N-ethyl-5-fluoro-2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N- {2- [5- (4-Fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3 -Triazol-3-yl) benzamide,
N-ethyl-N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) benzamide,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (2H-1,2,3 -Triazol-2-yl) benzamide,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide ,
N-ethyl-5-fluoro-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide ,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (2H-1,2,3-triazole-2 -Yl) benzamide, and
N-ethyl-N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
Or a pharmaceutically acceptable salt thereof.
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.

Representative schemes for producing the compounds (I) and (IA) of the present invention are shown in the following schemes A to L. 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

(In the formula, A ¹ and A ² represent a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group, and other symbols are as defined above.)

Step A-1: Compound (3) can be obtained by a condensation reaction of compound (1) and compound (2). The reaction in Step A-1 can be carried out by a general method for amidation of carboxylic acid. Examples thereof include a method of reacting a carboxylic acid with an amine after introducing the carboxylic acid to a carboxylic acid halide such as carboxylic acid chloride or carboxylic acid bromide, and a method of reacting the carboxylic acid with an amine in the presence of a dehydrating condensing agent. All of these reactions can be carried out in a solvent in the presence or absence of a base. Examples of the halogenating agent used in this reaction include thionyl chloride, oxalyl chloride, phosphorus oxychloride and phosphorus oxybromide. Examples of the dehydrating condensing agent used in this reaction include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, propanephosphonic acid anhydride, dicyclohexylcarbodiimide, diphenylphosphonyl azide, carbonyldiimidazole and the like. Activating agents such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used as necessary. Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, and toluene. An aromatic hydrocarbon solvent, ethyl acetate, or a mixed solvent thereof can be used. Examples of the base used in this reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate and sodium bicarbonate. This reaction can be carried out usually at 0 ° C to 150 ° C, preferably 25 ° C to 80 ° C.

Step A-2: Compound (5) can be obtained by a coupling reaction of compound (3) and compound (4). The reaction in Step A-2 can be performed by a general method in which an aromatic ring is substituted with a nitrogen atom of an azole compound using a catalyst and a ligand in the presence of a base. For example, the method described in Synlett, 2003, 15, 2428-2439. Examples of the catalyst used in this reaction include copper catalysts such as copper (0), copper (I) iodide, copper (I) chloride, and copper (I) oxide. Examples of the ligand used in this reaction include N, N′-dimethylethylenediamine, N, N′-dimethylcyclohexane-1,2-diamine, 2-aminopyridine, 1,10-phenanthroline, 2-hydroxybenzaldehyde oxime, and the like. Is mentioned. Examples of the base used in this reaction include potassium carbonate, potassium phosphate, potassium hydroxide, tert-butoxypotassium, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium acetate, sodium methoxide, tetrabutylammonium hydroxide and the like. . Solvents used in this reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, dichloromethane , Halogen solvents such as chloroform, aromatic hydrocarbon solvents such as toluene, water, or a mixed solvent thereof. This reaction can be carried out usually at 0 ° C to 150 ° C, preferably 25 ° C to 100 ° C.

Step A-3: The compound (Ia) of the present invention can be obtained by an alkylation reaction of the compound (5). The reaction in Step A-3 can be carried out by a general method for alkylating amides. Examples of the base used in this reaction include inorganic bases such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal lower alkoxides such as sodium ethoxide and tert-butoxy potassium, and organic such as triethylamine and diisopropylethylamine. A base. Solvents used in this reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, dichloromethane , Halogen solvents such as chloroform, aromatic hydrocarbon solvents such as toluene, water, or a mixed solvent thereof. This reaction can be performed usually at 0 ° C to 150 ° C, preferably 20 ° C to 100 ° C.
Scheme B

(Wherein R ⁵ is a common protecting group for carboxylic acids, such as J.F.W.McOmie, Protective Groups in Organic Chemistry., And T.W.Greene and P.G.M.Wuts, Protective. (Indicates a group described in Groups in Organic Synthesis. Etc., for example, a C _1-6 alkyl group, a benzyl group, etc. Other symbols are as defined above.)
The compound (Ib) of the present invention can be produced by the method shown in Scheme B.

Step B-1: Compound (8) can be obtained by a coupling reaction of Compound (7) and Compound (4). The reaction in Step B-1 can be performed according to the same reaction conditions as in Step A-2.

Step B-2: Compound (9) can be obtained by hydrolysis reaction or hydrogenolysis reaction of compound (8). The reaction in Step B-2 is described in J. Am. F. W. McOmie, Protective Groups in Organic Chemistry. W. Greene and P.A. G. M. The reaction can be performed under the reaction conditions described in Wuts, Protective Groups in Organic Synthesis. For example, hydrolysis using a mineral acid such as hydrochloric acid or sulfuric acid, or an inorganic base such as sodium hydroxide or potassium hydroxide, or hydrocracking in the presence of a hydrogen source using a metal catalyst such as palladium or platinum Etc. Examples of the solvent used in this reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, water, or a mixed solvent thereof. This reaction can be performed at 0 degreeC-100 degreeC.

Step B-3: The compound (10) can be obtained by an Arundt-Icetell type carbon increase reaction of the compound (9). The reaction in Step B-3 was first converted to a carboxylic acid chloride by treating the carboxylic acid with thionyl chloride, oxalyl chloride or the like in a halogen-based solvent such as dichloromethane or chloroform or an aromatic hydrocarbon solvent such as toluene. Then, it is converted into α-diazomethyl ketone by treatment with diazomethane or trimethylsilyldiazomethane in an ether solvent such as acetonitrile or tetrahydrofuran or 1,4-dioxane, and finally an ether system such as tetrahydrofuran or 1,4-dioxane. The reaction can be carried out under the condition of reacting with silver oxide, silver acetate or the like in a mixed solvent of a solvent and water.

Step B-4: The compound (12) can be obtained by a condensation reaction of the compound (10) and the compound (11). The reaction in Step B-4 can be carried out according to the same reaction conditions as in Step A-1.

Step B-5: Compound (13) can be obtained by the reduction reaction of the amide of compound (12). The reaction in Step B-5 is carried out by using an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene, or a mixed solvent thereof, lithium aluminum hydride. , Diborane, borane dimethyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. This reaction can be carried out at 0 ° C to 150 ° C.

Step B-6: The compound (Ib) of the present invention can be obtained by a condensation reaction of the compound (13) and the compound (2). The reaction in Step B-6 can be carried out according to the same reaction conditions as in Step A-1.
Scheme C

(Wherein R ⁶ and R ⁷ represent a C _1-6 alkoxy group, R ⁸ represents a C _1-6 alkyl group or a benzyl group, and other symbols are as defined above.)
The compound (Ib) of the present invention can also be produced by the method shown in Scheme C as an alternative method.

Step C-1: The compound (8) can be obtained by a coupling reaction of the compound (7) and the compound (4). The reaction in Step C-1 can be performed according to the same reaction conditions as in Step A-2.

Step C-2: Compound (14) can be obtained by the reduction reaction of the ester of Compound (8). The reaction in Step C-2 is performed in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene, or a mixed solvent thereof, lithium aluminum hydride, The reaction can be carried out under conditions for reaction with a reducing agent such as diisobutylaluminum hydride, sodium borohydride, lithium borohydride and the like. This reaction can be carried out at -80 ° C to 150 ° C, preferably 0 ° C to 25 ° C.

Step C-3: The compound (15) can be obtained by an oxidation reaction of the hydroxyl group of the compound (14). The reaction in Step C-3 is carried out by using a halogen-based solvent such as dichloromethane or chloroform, dimethyl sulfoxide or acetonitrile, a desvalent reagent, a hypervalent iodine compound such as 2-iodoxybenzoic acid, pyridinium chlorochromate, pyridinium dichromate, or the like. The reaction can be carried out under the condition of reacting with an oxidizing agent such as chromate, tetrapropylammonium perruthenate, manganese dioxide. This reaction can be carried out at 0 ° C to 150 ° C, preferably 25 ° C to 80 ° C.

Step C-4: Compound (17) can be obtained by Horner-Wadsworth-Emmons reaction of compound (15). In the reaction in Step C-4, the phosphonic acid ester (16) is converted into an ether solvent such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene or a mixed solvent thereof, sodium hydride, potassium hydride. , Tert-butoxypotassium, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide and the like, followed by reaction with an aldehyde. This reaction can be carried out at 0 ° C to 120 ° C.

Step C-5: Compound (18) can be obtained by the reduction reaction of the double bond of compound (17). The reaction in Step C-5 is hydrogenated in the presence of a metal catalyst such as palladium or platinum in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, ethyl acetate or a mixed solvent thereof. Can be implemented under the following conditions. This reaction can be carried out at 25 ° C to 80 ° C.
Step C-6: Compound (19) can be obtained by hydrolysis of compound (18). The reaction in Step C-6 can be performed according to the same reaction conditions as in Step B-2.

Step C-7: Compound (20) can be obtained from compound (19) by a reaction via Curtius rearrangement. In the reaction in Step C-7, carboxylic acid is first treated with diphenylphosphoric acid azide in an aromatic hydrocarbon solvent such as toluene, and further converted to isocyanate by heating, and then methanol, ethanol, tert-butyl alcohol, benzyl It can be carried out under the condition of reacting with alcohol or the like.
Step C-8: Compound (21) can be obtained by alkylation reaction of compound (20). The reaction in Step C-8 can be carried out according to the same reaction conditions as in Step A-3.

Step C-9: Compound (13) can be obtained by deprotection of compound (21). The reaction in Step C-9 is carried out in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, a halogen solvent such as dichloromethane or chloroform, water or a mixed solvent thereof, hydrochloric acid, trifluoro The treatment can be carried out under conditions of treatment with acetic acid or the like. This reaction can be carried out at 0 ° C to 80 ° C. Alternatively, in an alcoholic solvent such as methanol or ethanol, an etheric solvent such as tetrahydrofuran or 1,4-dioxane, ethyl acetate, water or a mixed solvent thereof, hydrogen is used in the presence of a hydrogen source using a metal catalyst such as palladium or platinum. It can be carried out under the conditions for chemical decomposition. This reaction can be performed at 0 degreeC-100 degreeC.
Step C-10: The compound (Ib) of the present invention can be obtained by a condensation reaction of the compound (13) and the compound (2). The reaction in Step C-10 can be carried out according to the same reaction conditions as in Step A-1.
Scheme D

(In the formula, A ³ represents a halogen atom, and the other symbols have the same meanings as described above.)
Step D-1: The compound (23) can be obtained by a condensation reaction of the compound (22) and the compound (2). The reaction in Step D-1 can be carried out according to the same reaction conditions as in Step A-1.

Step D-2: The compound (24) can be obtained by a deacetalization reaction of the compound (23). The reaction in Step D-2 is performed using an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, a halogen solvent such as dichloromethane or chloroform, acetone, water or a mixed solvent thereof, hydrochloric acid, The reaction can be carried out under the condition of reacting with an acid such as trifluoroacetic acid or p-toluenesulfonic acid. This reaction can be performed at 0 degreeC-80 degreeC.

Step D-3: The compound (26) can be obtained by a condensation reaction of the compound (24) and hydroxylamine (25). The reaction in Step D-3 can be carried out under the condition of reacting with hydroxylamine or its hydrochloride in a solvent in the presence or absence of a base. Examples of the base used in this reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide and sodium bicarbonate, and acetates such as sodium acetate and potassium acetate. Examples of the solvent used in this reaction include alcohol solvents such as methanol and ethanol, water, and mixed solvents thereof. This reaction can be performed at 0 degreeC-100 degreeC.

Step D-4: The compound (29) can be obtained by a isoxazole cyclization reaction after the halogenation reaction of the compound (26). In the reaction in Step D-4, first, an oxime compound is converted into an alcoholic solvent such as methanol or ethanol, an etheric solvent such as tetrahydrofuran or 1,4-dioxane, an aprotic polar solvent such as N, N-dimethylformamide, dichloromethane, After halogenating by treatment with a halogenated imide compound (27) such as N-bromosuccinimide or N-chlorosuccinimide in a halogenated solvent such as chloroform, an aromatic hydrocarbon solvent such as toluene, water or acetonitrile, The reaction can be carried out in an ether solvent such as tetrahydrofuran or 1,4-dioxane in the presence of a base such as triethylamine or sodium hydroxide under the conditions for reacting with the alkynyl compound (28).

Step D-5: The compound (Ic) of the present invention can be obtained by an alkylation reaction of the compound (29). The reaction in Step D-5 can be carried out according to the same reaction conditions as in Step A-3.
Scheme E

(In the formula, the symbols are as defined above.)
Step E-1: Compound (31) can be obtained by a condensation reaction of compound (30) and hydroxylamine (25). The reaction in Step E-1 can be carried out according to the same reaction conditions as in Step D-3.
Step E-2: The compound (33) can be obtained by a isoxazole cyclization reaction after the halogenation reaction of the compound (31). The reaction in Step E-2 can be carried out according to the same reaction conditions as in Step D-4.

Step E-3: The compound (34) can be obtained by deprotection of the compound (33). The reaction in Step E-3 is hydrazine monohydration in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, a halogen solvent such as dichloromethane or chloroform, water or a mixed solvent thereof. It can carry out on the conditions made to react with a thing. This reaction can be carried out at 25 ° C to 100 ° C.
Step E-4: The compound (35) can be obtained by a condensation reaction of the compound (34) and the compound (2). The reaction in Step E-4 can be carried out according to the same reaction conditions as in Step A-1.
Step E-5: The compound (Id) of the present invention can be obtained by an alkylation reaction of the compound (35). The reaction in Step E-5 can be carried out according to the same reaction conditions as in Step A-3.
Scheme F

(In the formula, the symbols are as defined above.)
Step F-1: The compound (37) can be obtained by a condensation reaction of the compound (36) and the compound (2). The reaction in Step F-1 can be carried out according to the same reaction conditions as in Step A-1.

Step F-2: Compound (39) can be obtained by oxadiazole cyclization reaction after amide oximation reaction of compound (37). In the reaction in Step F-2, the nitrile body (37) is first converted into an amide oxime by treatment with an alcohol solvent such as methanol or ethanol, hydroxylamine (25) or a hydrochloride thereof, and then tetrahydrofuran or 1,4- Ether solvents such as dioxane, aprotic polar solvents such as N, N-dimethylformamide, halogen solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, ethyl acetate, acetonitrile, or a mixed solvent thereof Among them, the reaction can be carried out under the condition of reacting with a dehydrating condensing agent such as carboxylic acid (38) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, dicyclohexylcarbodiimide, carbonyldiimidazole and the like.
Step F-3: The compound (Ie) of the present invention can be obtained by an alkylation reaction of the compound (39). The reaction in Step F-3 can be carried out according to the same reaction conditions as in Step A-3.
Scheme G

(In the formula, the symbols are as defined above.)
Step G-1: The compound (41) can be obtained by a condensation reaction of the compound (40) and the compound (2). The reaction in Step G-1 can be carried out according to the same reaction conditions as in Step A-1.
Step G-2: The compound (42) can be obtained by a coupling reaction of the compound (41) and the compound (4). The reaction in Step G-2 can be carried out according to the same reaction conditions as in Step A-2.
Step G-3: The compound (If) of the present invention can be obtained by an alkylation reaction of the compound (42). The reaction in Step G-3 can be performed according to the same reaction conditions as in Step A-3.
Scheme H

(In the formula, the symbols are as defined above.)
Step H-1: The compound (43) can be obtained by deprotection of the compound (20). The reaction in Step H-1 can be carried out according to the same reaction conditions as in Step C-9.
Step H-2: The compound (45) can be obtained by a condensation reaction of the compound (43) and the compound (44). The reaction in Step H-2 can be carried out according to the same reaction conditions as in Step A-1.
Step H-3: The compound (Ig) of the present invention can be obtained by an alkylation reaction of the compound (45). The reaction in Step H-3 can be carried out according to the same reaction conditions as in Step A-3.
Scheme I

(In the formula, the symbols are as defined above.)
Step I-1: Compound (47) can be obtained by Horner-Wadsworth-Emmons reaction of compound (46). The reaction in Step I-1 can be carried out according to the same reaction conditions as in Step C-4.
Step I-2: The compound (48) can be obtained by the reduction reaction of the double bond of the compound (47). The reaction in Step I-2 can be carried out according to the same reaction conditions as in Step C-5.
Step I-3: Compound (49) can be obtained by hydrolysis of compound (48). The reaction in Step I-3 can be carried out according to the same reaction conditions as in Step B-2.
Step I-4: Compound (50) can be obtained from compound (49) by a reaction via Curtius rearrangement. The reaction in Step I-4 can be carried out according to the same reaction conditions as in Step C-7.

Step I-5: Compound (51) can be obtained by deprotection of compound (50). The reaction in Step I-5 can be carried out according to the same reaction conditions as in Step C-9.
Step I-6: Compound (52) can be obtained by the condensation reaction of compound (51) and compound (44). The reaction in Step I-6 can be carried out according to the same reaction conditions as in Step A-1.
Step I-7: Compound (53) can be obtained by alkylation reaction of compound (52). The reaction in Step I-7 can be carried out according to the same reaction conditions as in Step A-3.
Step I-8: Compound (54) can be obtained by deprotection of compound (53). The reaction in Step I-8 is carried out in an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, a halogen solvent such as dichloromethane or chloroform, water or a mixed solvent thereof, hydrochloric acid, trifluoro The treatment can be carried out under conditions of treatment with acetic acid or the like. Moreover, this reaction can be performed at 0 degreeC-100 degreeC.
Step I-9: The compound (IH) of the present invention can be obtained by a coupling reaction of the compound (54) and the compound (55). The reaction in Step I-9 can be carried out according to the same reaction conditions as in Step A-2.
Scheme J

(In the formula, the symbols are as defined above.)
Step J-1: The compound (56) can be obtained by a condensation reaction of the compound (36) and the compound (44). The reaction in Step J-1 can be carried out according to the same reaction conditions as in Step A-1.
Step J-2: Compound (58) can be obtained by oxadiazole cyclization reaction after amide oximation reaction of compound (56). The reaction in Step J-2 can be carried out according to the same reaction conditions as in Step F-2.
Step J-3: The compound (II) of the present invention can be obtained by an alkylation reaction of the compound (58). The reaction in Step J-3 can be carried out according to the same reaction conditions as in Step A-3.
Scheme K

(In the formula, the symbols are as defined above.)
The compound (II) of the present invention can also be produced by the method shown in Scheme K as an alternative method.
Step K-1: The compound (60) can be obtained by an alkylation reaction of the compound (59). The reaction in Step K-1 can be carried out according to the same reaction conditions as in Step A-3.
Step K-2: The compound (61) can be obtained by an oxadiazole cyclization reaction after an amide oximation reaction of the compound (60). The reaction in Step K-2 can be carried out according to the same reaction conditions as in Step F-2.
Step K-3: Compound (62) can be obtained by deprotection reaction of compound (61). The reaction in Step K-3 can be carried out according to the same reaction conditions as in deprotection under the acidic conditions in Step C-9.
Step K-4: The compound (II) of the present invention can be obtained by the condensation reaction of the compound (62) and the compound (44). The reaction in Step K-4 can be carried out according to the same reaction conditions as in Step A-1.
Scheme L

(In the formula, the symbols are as defined above.)
Compound (61) can also be produced by the method shown in Scheme L as an alternative method.
Step L-1: Compound (61) can be obtained by oxadiazole cyclization reaction after amide oximation reaction of compound (60). In the reaction in Step L-1, first, the nitrile body (60) is converted to an amide oxime by treatment with an alcohol solvent such as methanol or ethanol, hydroxylamine (25) or a hydrochloride thereof, and then N, N-dimethylformamide. In a non-protic polar solvent such as p-toluenesulfonic acid monohydrate and zinc chloride in the presence of benzonitrile (63). This reaction can be performed at 80 to 120 ° C.

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

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

In the following Reference Examples and Examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following two 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.
Condition 1
Machine: Gilson preparative HPLC system
Column: Shiseido Capcell Pak C18 MGII 5μm 20x150mm
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

Condition 2
Machine: Gilson TritionLC
Column: Waters SunFire prep C18 OBD 5.0 μm 30 × 50 mm or YMC YMC-Actus Triant C18 5.0 μm 30 × 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), 11 minutes (A solution / B Liquid = 20/80), 12 to 13.5 minutes (liquid A / liquid B = 5/95)
Flow rate: 40 mL / min, detection method: UV 254 nm

In the following Reference Examples and Examples, high performance liquid chromatography mass spectrum (LCMS) was measured under one of the following three conditions.
Condition 1
Measuring machine: Micromass Platform LC and Agilent Agilent 1100
Column: Waters SunFire C18 2.5 μm 4.6 mmI. D. x50mm
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: UV 254 nm
Ionization method: Electron Spray Ionization (ESI: Electron Spray Ionization)

Condition 2
Measuring machine: SHIMADZU LCMS-2010EV
Column: SHIMADZU Shim-pack XR-ODS 2.2 μm 2.0 mm I.D. D. x30mm
Solvent: A solution; 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 1 minute (A solution / B solution = 60 / 40) 2 minutes (A liquid / B liquid = 0/100), 2.5 minutes (A liquid / B liquid = 0/100)
Flow rate: 0.6 mL / min, detection method: UV 254 nm
Ionization method: Electron Spray Ionization (ESI) and Atmospheric Pressure Chemical Ionization (APCI)

Condition 3
Measuring machine: Agilent Agilent 2900 and Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Solvent: A liquid; 0.1% formic acid-containing water, B liquid; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A liquid / B liquid = 80/20), 1.2 to 1.4 minutes (A liquid / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: UV 254 nm
Ionization method: Electron Spray Ionization (ESI: Electron Spray Ionization)

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), NaHCO ₃ (sodium bicarbonate), NaOH (sodium hydroxide), NH ₄ Cl (ammonium chloride), 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 hexafluorophosphate], brine (saturated saline) , Boc (tert-butoxycarbonyl), Et ₃ N (triethylamine), DIPEA (N, N- diisopropylethylamine), MeI (methyl iodide), EtI (ethyl iodide), NaH (sodium hydride), HCl (chloride Hydrogen), DIBAL-H (diisobutylaluminum hydride), MnO ₂ (manganese dioxide).

Reference Example 1 5-Methyl-N- [2- (1H-pyrazol-4-yl) ethyl] -2- (2H-1,2,3-triazol-2-yl) benzamide

Et ₃ N (0.45 mL, 3.3 mmol) was added to a DMF solution (5 mL) of 2- (1H-pyrazol-4-yl) ethanamine dihydrochloride (0.30 g, 1.6 mmol) at room temperature and stirred. To the reaction solution, 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.36 g, 1.8 mmol), HOBt · H ₂ O (0.37 g, 2.4 mmol) was added. ) And EDC.HCl (0.47 g, 2.4 mmol) were added, and the mixture was stirred at room temperature for 3 hours. 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-NH 28 g, CHCl ₃ / MeOH = 100/0 to 97/3) to obtain the title compound (0.43 g) (colorless amorphous).
MS (ESI pos.) M / z: 297 [M + H] +

Reference Example 2 N- [2- (1H-pyrazol-4-yl) ethyl] -2- (2H-1,2,3-triazol-2-yl) benzamide

2- (1H-pyrazol-4-yl) ethanamine dihydrochloride (0.30 g, 1.6 mmol) and 2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.34 g, 1 .8 mmol) as a starting material and the title compound (0.34 g) was obtained in the same manner as in Reference Example 1 (colorless amorphous).
MS (ESI pos.) M / z: 283 [M + H] +

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

5-Methyl-N- [2- (1H-pyrazol-4-yl) ethyl] -2- (2H-1,2,3-triazol-2-yl) benzamide (0.43 g) obtained in Reference Example 1 , 1.5 mmol) and 2-bromo-5-fluoropyridine (0.31 g, 1.7 mmol) in DMF solution (1.5 mL), copper (I) iodide (0.13 g, 0.4 mmol), rac- trans-N, N′-dimethylcyclohexane-1,2-diamine (0.25 g, 1.5 mmol) and cesium carbonate (0.99 g, 3.1 mmol) were added, and the mixture was stirred at 80 ° C. for 15 hours. After cooling to room temperature, brine was added to the reaction mixture, and the mixture was 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 (HP-Sil 50 g, hexane / EtOAc = 70/30 to 0/100 to CHCl ₃ / MeOH = 80/20). The obtained solid was stirred and washed in EtOAc and collected by filtration to give the title compound (0.14 g) (brown solid).
MS (ESI pos.) M / z: 392 [M + H] +

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

N- [2- (1H-pyrazol-4-yl) ethyl] -2- (2H-1,2,3-triazol-2-yl) benzamide (0.34 g, 1.2 mmol) obtained in Reference Example 2 ) And 2-bromo-5-fluoropyridine (0.30 g, 1.7 mmol) as starting materials, the title compound (0.053 g) was obtained in the same manner as in Reference Example 3 (colorless solid).
MS (ESI pos.) M / z: 378 [M + H] +

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

By using ethyl-1H-pyrazole-3-carboxylate (18.3 g, 130.4 mmol) and 2-bromo-5-fluoropyridine (16.1 mL, 156.4 mmol) as raw materials, the same procedure as in Reference Example 3 was performed. To give the title compound (21.1 g) (colorless solid).
MS (ESI pos.) M / z: 236 [M + H] +

Reference Example 6 1- (5-Fluoropyridin-2-yl) -1H-pyrazole-3-carboxylic acid

Ethyl-1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carboxylate (10.4 g, 44.0 mmol) obtained in Reference Example 5 in EtOH (52 mL), H ₂ O (52 mL) ) NaOH (3.52 g, 88.0 mmol) was added to the mixed solution and stirred at 90 ° C. for 2 hours. After allowing to cool at room temperature, the solvent was distilled off under reduced pressure. A 1 mol / L HCl aqueous solution was added to the obtained residue under ice cooling, and the precipitated solid was collected by filtration, washed and dried to obtain the title compound (5.96 g) (colorless solid).
MS (ESI pos.) M / z: 206 [MH]-

Reference Example 7 [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetic acid

To a solution of 1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carboxylic acid (2.79 g, 13.4 mmol) obtained in Reference Example 6 in CHCl ₃ (56 mL), oxalyl chloride (2. 3 mL, 26.8 mmol) and DMF (5 drops) were added, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in THF (28 mL) and CH ₃ CN (28 mL), and trimethylsilyldiazomethane (2 mol / L diethyl ether solution, 13.4 mL, 26.8 mmol) was added under ice cooling, After warming to room temperature, the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was dissolved in 1,4-dioxane (42 mL) and water (42 mL), silver acetate (0.67 g, 4.03 mmol) was added, and the mixture was stirred at 130 ° C. for 11 hr. After cooling at room temperature, Celite (registered trademark) was filtered, and the filtrate was concentrated under reduced pressure. EtOAc and aqueous NaHCO ₃ solution were added to the resulting residue, and only the aqueous layer was taken out. A 1 mol / L aqueous HCl solution was added to the obtained aqueous layer, extraction was performed with CHCl ₃ , the solvent was distilled off under reduced pressure, and the title compound (0.84 g) was obtained by drying (yellow solid).
MS (ESI pos.) M / z: 220 [MH]-

Reference Example 8 N-ethyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetamide

[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetic acid (0.39 g, 1.78 mmol) obtained in Reference Example 7 and ethylamine (2 mol / L THF solution, 1. 8 mL, 3.6 mmol) was used as a starting material, and the title compound (0.26 g) was obtained in the same manner as in Reference Example 1 (yellow solid).
MS (ESI pos.) M / z: 249 [M + H] +

Reference Example 9 N-methyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetamide

[1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetic acid (0.42 g, 1.90 mmol) obtained in Reference Example 7 and methylamine (2 mol / L THF solution, 1 .9 mL, 3.80 mmol) as a starting material, and the title compound (0.27 g) was obtained in the same manner as in Reference Example 1 (yellow solid).
MS (ESI pos.) M / z: 235 [M + H] +

Reference Example 10 N-ethyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine

N-ethyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetamide (1.13 g, 4.59 mmol) obtained in Reference Example 8 in THF (11. 4 mL) solution was added borane tetrahydrofuran complex (1.06 mol / L THF solution, 8.7 mL, 9.17 mmol) and stirred at 70 ° C. for 2 hours. Then, 2 mol / L HCl aqueous solution was added, and it stirred at 70 degreeC for 1 hour. After allowing to cool at room temperature, chloroform and an aqueous HCl solution were added, and only the aqueous layer was taken out. Aqueous sodium hydroxide was added to the aqueous layer, extracted with chloroform, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC (condition 1) to obtain the title compound (0.27 g) (colorless oil).
MS (ESI pos.) M / z: 235 [M + H] +

Reference Example 11 N-methyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine

Using N-methyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetamide (1.04 g, 4.43 mmol) obtained in Reference Example 9 as a raw material, The title compound (0.13 g) was obtained in the same manner as in Reference Example 10 (colorless oil).
MS (ESI pos.) M / z: 221 [M + H] +

Reference Example 12 [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] methanol

To a THF solution (150 mL) of ethyl-1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carboxylate (14.9 g, 64.3 mmol) obtained in Reference Example 5 was added DIBAL-H ( 1.02 mol / L hexane solution, 137 mL, 139 mmol) was added under ice cooling, and the mixture was stirred for 1.5 hours under ice cooling. To the reaction mixture was added 2 mol / L aqueous HCl (45 mL) under ice cooling, and the mixture was stirred at the same temperature for 25 minutes. THF and hexane were distilled off under reduced pressure, MeOH (75 mL), CHCl ₃ (150 mL) and 2 mol / L aqueous HCl (250 mL) were added under ice cooling, and the mixture was stirred at the same temperature for 20 minutes and at room temperature for 50 minutes. To the mixture were added 2 mol / L NaOH aqueous solution (300 mL) and potassium sodium tartrate (Rochelle salt) (39.3 g, 139 mmol) under ice cooling, and the mixture was stirred at room temperature for 20 minutes. The organic and aqueous layers were separated and the aqueous layer was extracted with CHCl ₃ (150 mL) / MeOH (75 mL). Rochelle salt (39.3 g, 139 mmol) was added to the aqueous layer, stirred at room temperature for 2 hours, and extracted three times with CHCl ₃ (150 mL) / MeOH (75 mL). The organic layers were combined, passed through an ISOLUTE Phase Separator and concentrated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 340 g, CHCl ₃ / MeOH = 100/0 to 95/5) to obtain the title compound (11.6 g) (colorless solid).
MS (ESI / APCI pos.) M / z: 194 [M + H] +

Reference Example 13 1- (5-Fluoropyridin-2-yl) -1H-pyrazole-3-carbaldehyde

The [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] methanol (0.76 g, 3.93 mmol) obtained in Reference Example 12 was added to a CHCl ₃ suspension (15 mL). % MnO ₂ (6.04 g, 59.0 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours and at an oil bath temperature of 50 ° C. for 45 minutes. 85% MnO ₂ (10.1 g, 98.4 mmol) and CHCl ₃ (7.6 mL) were added to the reaction mixture and stirred at room temperature for 45 minutes. 85% MnO ₂ (4.02 g, 39.3 mmol) and CHCl ₃ (15 mL) were added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite (registered trademark), the solid was washed with CHCl ₃ , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / CHCl ₃ = 100/0 to 20/80, HP-Sil 10 g, hexane / EtOAc = 100/0 to 80/20), and the title compound (0.133 g) was obtained (colorless solid).
MS (ESI pos.) M / z: 192 [M + H] +

Reference Example 14 (E) -Ethyl-3- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] acrylate

Ethyl-2- (diethoxyphosphoryl) acetate (0.163 mL, 0.816 mmol) was added to a THF suspension (1.3 mL) of 60% NaH (0.033 g, 0.82 mmol) under ice-cooling. For 5 minutes. To a THF suspension (1.3 mL) of 1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carbaldehyde (0.130 g, 0.680 mmol) obtained in Reference Example 13 was added the above. The mixture and THF (0.65 mL) were added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture were added saturated aqueous NH ₄ Cl (0.65 mL), water (2.6 mL) and CHCl ₃ (3.3 mL), and the organic and aqueous layers were separated. The aqueous layer was extracted twice with CHCl ₃ , and the organic layers were combined, passed through an ISOLUTE Phase Separator and concentrated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, CHCl ₃ / MeOH = 100/0) to obtain the title compound (0.177 g) (colorless solid).
MS (ESI pos.) M / z: 262 [M + H] +

Reference Example 15 3- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] propanoic acid

(E) -Ethyl-3- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] acrylate (0.177 g, 0.678 mmol) and 5% obtained in Reference Example 14 A suspension of Pd / C (0.144 g, 0.0678 mmol) in EtOH (3.5 mL) was stirred under a hydrogen atmosphere at room temperature for 17 hours. The reaction mixture was filtered through Celite (registered trademark), and the solid was washed successively with EtOH, CHCl ₃ and CHCl ₃ / MeOH = 1/1, and the filtrate was concentrated under reduced pressure. Water (0.650 mL) and 2 mol / L aqueous NaOH solution (0.650 mL, 1.30 mmol) were added to an EtOH suspension (3.4 mL) of the obtained residue, and the mixture was stirred at 70 ° C. for 2.5 hours. The reaction mixture was allowed to cool to room temperature, EtOH was distilled off under reduced pressure, and water (3.4 mL) and Et ₂ O (3.4 mL) were added. Separate the organic and aqueous layers and add water (0.98 mL), 2 mol / L aqueous HCl (0.98 mL, 1.95 mmol), CHCl ₃ (3.4 mL) and MeOH (1.7 mL) to the aqueous layer. It was. The organic and aqueous layers were separated and the aqueous layer was extracted twice with CHCl ₃ (3.4 mL). The organic layers were combined, dried over Na ₂ SO ₄ , the desiccant was filtered off, washed with CHCl ₃ / MeOH = 2/1, and concentrated under reduced pressure to give the title compound (0.141 g) ( Colorless solid).
MS (ESI / APCI pos.) M / z: 258 [M + Na] +

Reference Example 16 tert-butyl {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate

A suspension of 3- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] propanoic acid (0.141 g, 0.599 mmol) obtained in Reference Example 15 in tert-butyl alcohol To (2.8 mL), diphenylphosphoryl azide (0.155 mL, 0.719 mmol) and Et ₃ N (0.1 mL, 0.719 mmol) were added and heated to reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and CHCl ₃ (8.5 mL), saturated aqueous NaHCO ₃ (1.4 mL), water (4.2 mL) and MeOH (4.2 mL) were added. The organic and aqueous layers were separated and the aqueous layer was extracted with CHCl ₃ (2.8 mL) / MeOH (1.4 mL) and then CHCl ₃ (2.8 mL). The organic layers were combined, passed through an ISOLUTE Phase Separator and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (HP-Sil 10 g, CHCl ₃ / MeOH = 100/0 to 97/3, KP-NH 11 g, hexane / EtOAc = 100/0 to 90/10, HP-Sil 10 g, hexane. / EtOAc = 100/0 to 80/20) to give the title compound (0.088 g) (colorless solid).
MS (ESI / APCI pos.) M / z: 329 [M + Na] +

Reference Example 17 tert-butyl ethyl {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate

THF solution of tert-butyl {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate (0.088 g, 0.29 mmol) obtained in Reference Example 16 (1.8 mL) was added 60% NaH (0.014 g, 0.34 mmol) and EtI (0.028 mL, 0.34 mmol) and stirred at room temperature for 3 hours. To the reaction mixture 60% NaH (0.014 g, 0.34 mmol) and EtI (0.028 mL, 0.34 mmol) were added and stirred at room temperature for 3 days. To the reaction mixture were added saturated aqueous NH ₄ Cl (0.88 mL), water (0.88 mL) and CHCl ₃ (1.8 mL), and the organic and aqueous layers were separated. The aqueous layer was extracted twice with CHCl ₃ (1.8 mL), and the organic layers were combined, passed through an ISOLUTE Phase Separator, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 100/0 to 85/15) to obtain the title compound (0.069 g) (colorless oil).
MS (ESI / APCI pos.) M / z: 335 [M + H] +

Reference Example 18 N-ethyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine hydrochloride

Tert-Butyl ethyl {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate (0.069 g, 0.21 mmol) EtOAc obtained in Reference Example 17 A 4 mol / L HCl-EtOAc solution (1.0 mL, 4.0 mmol) was added to the solution (0.69 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.056 g) (colorless solid).
MS (ESI / APCI pos.) M / z: 235 [M + H] +

Reference Example 19 N- (3,3-diethoxypropyl) -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

3,3-diethoxypropan-1-amine (0.96 mL, 5.9 mmol) and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (1.0 g, 4 .9 mmol) in DMF (18 mL) were added HOBt.H ₂ O (1.1 g, 7.4 mmol) and EDC.HCl (1.4 g, 7.4 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added an aqueous NaHCO ₃ solution, and the mixture was 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 25 g, hexane / EtOAc = 85/15 to 0/100) to obtain the title compound (1.6 g) (colorless solid).
MS (ESI pos.) M / z: 333 [M + H] +

Reference Example 20 N-[(3E) -3- (hydroxyimino) propyl] -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

N- (3,3-diethoxypropyl) -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide (0.88 g, 2.7 mmol) obtained in Reference Example 19 To a THF solution (6 mL) was added 2 mol / L HCl aqueous solution, and the mixture was stirred at room temperature for 1 hour. NaHCO ₃ aqueous solution was added to the reaction solution to adjust the pH to neutral, 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. Sodium acetate (0.31 g, 3.7 mmol) and hydroxylamine hydrochloride (0.26 g, 3.7 mmol) were added to 95% aqueous EtOH solution (7.5 mL) of the obtained residue, and the mixture was stirred for 2 hours in an ice bath. did. To the reaction solution was added an aqueous NaHCO ₃ solution, 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. The obtained solid was stirred and washed in EtOAc and collected by filtration to give the title compound (0.45 g) (colorless solid).
MS (ESI pos.) M / z: 274 [M + H] +

Reference Example 21 N- {2- [5- (5-fluoropyridin-2-yl) -1,2-oxazol-3-yl] ethyl} -5-methyl-2- (2H-1,2,3- Triazol-2-yl) benzamide

N-[(3E) -3- (hydroxyimino) propyl] -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide (0.45 g, obtained in Reference Example 20 1.6 mmol) in DMF (5 mL) was added N-chlorosuccinimide (0.24 g, 1.8 mmol) in an ice bath, and the mixture was warmed to room temperature and stirred for 15 hours. Water was added to the reaction solution, 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. To a THF solution (3.3 mL) of the obtained residue, a THF solution (1 mL) of 2-ethynyl-5-fluoropyridine (0.30 g, 2.5 mmol) was added dropwise in an ice bath. Et ₃ N (0.30 mL, 2.2 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 15 hours. Water was added to the reaction solution 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. The obtained residue was purified by column chromatography (HP-Sil 50 g, CHCl ₃ / MeOH = 99/1 to 95/5). The obtained solid was stirred and washed in EtOAc and collected by filtration to give the title compound (0.27 g) (colorless solid).
MS (ESI pos.) M / z: 393 [M + H] +

Reference Example 22 (E) -1- (5-fluoropyridin-2-yl) -N-hydroxymethanimine

Sodium acetate (0.1 g, 1.2 mmol) and hydroxylamine hydrochloride in 95% aqueous EtOH (2.5 mL) of 5-fluoropyridine-2-carbaldehyde (0.10 g, 0.82 mmol) under ice-cooling (0.085 g, 1.2 mmol) was added and stirred for 2 hours. To the reaction solution was added an aqueous NaHCO ₃ solution, 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. The obtained residue was purified by column chromatography (KP-NH 11 g, hexane / EtOAc = 75 / 25-0 / 100) to give the title compound (0.054 g) (yellow solid).
MS (ESI pos.) M / z: 141 [M + H] +

Reference Example 23 2- {2- [3- (5-Fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethyl} -1H-isoindole-1,3 (2H) -dione

(E) -1- (5-fluoropyridin-2-yl) -N-hydroxymethanimine (0.29 g, 2.0 mmol) and 2- (but-3-yne-1-) obtained in Reference Example 22 Yl) -1H-isoindole-1,3 (2H) -dione (0.31 g, 1.6 mmol) was used as a starting material in the same manner as in Reference Example 21 to give the title compound (0.15 g) ( Colorless solid).
MS (ESI pos.) M / z: 338 [M + H] +

Reference Example 24 2- [3- (5-Fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethanamine

2- {2- [3- (5-Fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethyl} -1H-isoindole-1,3 (2H) obtained in Reference Example 23 -Hydrazine monohydrate (0.043 mL, 0.88 mmol) was added dropwise to an EtOH solution (1.2 mL) of dione (0.15 g, 0.44 mmol), and the mixture was stirred at 90 ° C for 2 hours. After allowing to cool at room temperature, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.094 g) (colorless amorphous).
MS (ESI pos.) M / z: 208 [M + H] +

Reference Example 25 N- {2- [3- (5-fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethyl} -5-methyl-2- (2H-1,2,3- Triazol-2-yl) benzamide

2- [3- (5-Fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethanamine obtained in Reference Example 24 (0.46 g, 0.22 mmol) and 5-methyl-2- The title compound (0.040 g) was obtained in the same manner as in Reference Example 19 using (2H-1,2,3-triazol-2-yl) benzoic acid (0.61 g, 3.0 mmol) as a raw material. (Colorless solid).
MS (ESI pos.) M / z: 393 [M + H] +

Reference Example 26 N- (2-cyanoethyl) -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

Starting from 3-aminopropanenitrile (0.20 mL, 2.7 mmol) and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.61 g, 3.0 mmol) In the same manner as in Reference Example 19, the title compound (0.61 g) was obtained (colorless solid).
MS (ESI pos.) M / z: 256 [M + H] +

Reference Example 27 N- {2- [5- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (2H-1, 2,3-Triazol-2-yl) benzamide

EtOH solution of N- (2-cyanoethyl) -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide (0.20 g, 0.78 mmol) obtained in Reference Example 26 ( 0.8 mL) was added 50% aqueous hydroxylamine solution (0.057 mL, 0.86 mmol), and the mixture was stirred at 90 ° C. for 1 hour. The mixture was allowed to cool to room temperature, 50% aqueous hydroxylamine solution (0.057 mL, 0.86 mmol) was added, and the mixture was again stirred at 90 ° C. for 1 hr. After allowing to cool at room temperature, the reaction solution was concentrated under reduced pressure. A DMF solution (0.3 mL) of the obtained residue was stirred at 40 ° C. for 1 hour with 5-fluoropyridine-2-carboxylic acid (0.12 g, 0.82 mmol) and carbonyldiimidazole (0.15 g, 0.005%). 94 mmol) in DMF (0.5 mL). The reaction solution was heated to 90 ° C. and stirred for 15 hours. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with water and 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 = 75 / 25-0 / 100) to obtain the title compound (0.040 g) (colorless amorphous).
MS (ESI pos.) M / z: 394 [M + H] +

Reference Example 28 N- [2- (1H-imidazol-4-yl) ethyl] -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide

2- (1H-imidazol-4-yl) ethanamine dihydrochloride (0.30 g, 1.6 mmol) and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0 DIPEA (1.4 mL, 8.2 mmol) and HATU (0.74 g, 2.0 mmol) were added to a DMF (5 mL) solution of .33 g, 1.6 mmol) and stirred at room temperature for 15 hours. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with water and brine, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (KP-NH 28 g, CHCl ₃ / MeOH = 100/0 to 80/20) to obtain the title compound (0.18 g) (colorless amorphous).
MS (ESI pos.) M / z: 297 [M + H] +

Reference Example 29 N- {2- [1- (5-fluoropyridin-2-yl) -1H-imidazol-4-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole- 2-yl) benzamide

N- [2- (1H-imidazol-4-yl) ethyl] -5-methyl-2- (2H-1,2,3-triazol-2-yl) benzamide (0.18 g) obtained in Reference Example 28 , 0.60 mmol) and 2-bromo-5-fluoropyridine (0.13 g, 0.72 mmol) as a starting material, the title compound (0.13 g) was obtained in the same manner as in Reference Example 3 (brown Crystalline).
MS (ESI pos.) M / z: 392 [M + H] +

Reference Example 30 tert-butyl methyl {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate

The tert-butyl {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate (0.3 g, 0.98 mmol) obtained in Reference Example 16 was used as a raw material. The title compound (0.31 g) was obtained in the same manner as in Reference Example 17 using MeI (0.073 mL, 1.18 mmol) (colorless oil).
MS (ESI pos.) M / z: 321 [M + H] +

Reference Example 31 2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] -N-methylethanamine hydrochloride

Starting from tert-butyl methyl {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate (0.31 g, 0.98 mmol) obtained in Reference Example 30 Thus, the title compound (0.2 g) was obtained in the same manner as in Reference Example 18 (colorless solid).
MS (ESI pos.) M / z: 221 [M + H] +

Reference Example 32 2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine dihydrochloride

The tert-butyl {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate (0.46 g, 1.49 mmol) obtained in Reference Example 16 was used as a raw material. Thus, the title compound (0.34 g) was obtained in the same manner as in Reference Example 18 (yellowish brown solid).
MS (ESI pos.) M / z: 207 [M + H] +

Reference Example 33 4-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole- 2-yl) benzamide

2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine dihydrochloride free form (0.035 g, 0.17 mmol) and 4 obtained in Reference Example 32 -Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.039 g, 0.19 mmol) in DMF (1.5 mL) was added to HOBt.H ₂ O (39 mg, 0. 25 mmol) and EDC.HCl (0.049 g, 0.25 mmol) were added 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 (HP-Sil 10 g, hexane / EtOAc = 88/12 to 0/100) to obtain the title compound (0.048 g) (colorless oil).
MS (ESI pos.) M / z: 396 [M + H] +

Reference Examples 34 to 37 were obtained in the same manner as Reference Example 33. Table 1 shows the structural formula, compound name, and MS data of the obtained compound.

Reference Example 38 (2E) -3- [1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] prop-2-enoic acid ethyl ester

Using 2- (tetrahydro-pyran-2-yl) -2H-pyrazole-3-carbaldehyde (3.96 g, 22.0 mmol) as a starting material, the title compound (5.15 g) was prepared in the same manner as in Reference Example 14. Obtained (colorless oil).
MS (ESI pos.) M / z: 251 [M + H] +

Reference Example 39 3- [1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] propanoic acid

Ethyl (2E) -3- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] prop-2-enoate obtained in Reference Example 38 (3.37 g, 13. 4 mmol) was used as a starting material, and the title compound (2.85 g) was obtained in the same manner as in Reference Example 15 (colorless oil).
MS (ESI pos.) M / z: 247 [M + Na] +

Reference Example 40 benzyl {2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate

3- [1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] propanoic acid (2.45 g, 10.9 mmol) and benzyl alcohol (1.36 mL) obtained in Reference Example 39 , 13.1 mmol) as a starting material, and the title compound (0.60 g) was obtained in the same manner as in Reference Example 16 (pale yellow oil).
MS (ESI pos.) M / z: 352 [M + Na] +

Reference Example 41 2- [1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] ethanamine

Benzyl {2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] ethyl} carbamate (0.60 g, 1.81 mmol) EtOH (12 mL) obtained in Reference Example 40 ) 10% Pd / C (55% water) (0.035 g, 0.18 mmol) was added to the solution, and the mixture was purged with hydrogen and stirred at room temperature for 1 hour. Insoluble material was removed by Celite (registered trademark) filtration, and the solvent was evaporated under reduced pressure to give the title compound (0.41 g) (colorless oil).
MS (ESI pos.) M / z: 196 [M + H] +

Reference Example 42 N- {2- [1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide

2- [1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] ethanamine (0.35 g, 1.81 mmol) obtained in Reference Example 41 and 2- (2H-1, 2,3-triazol-2-yl) benzoic acid (0.34 g, 1.81 mmol) was used as a starting material to give the title compound (0.47 g, 1.29 mmol) in the same manner as in Reference Example 1 (yellow) Oil).
MS (ESI pos.) M / z: 367 [M + H] +

Reference examples 43 and 44 were obtained in the same manner as in reference example 42. Table 2 shows the structural formula, compound name, and MS data of the obtained compound.

Reference Example 45 N-ethyl-N- {2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide

N- {2- [1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole) obtained in Reference Example 42 2-yl) benzamide (0.47 g, 1.29 mmol) and ethyl iodide (0.13 mL, 1.55 mmol) were used as raw materials in the same manner as in Reference Example 17 to give the title compound (0.37 g). (Yellow oil).
MS (ESI pos.) M / z: 395 [M + H] +

Reference Examples 46 and 47 were obtained in the same manner as Reference Example 45. Table 3 shows the structural formula, compound name, and MS data of the obtained compound.

Reference Example 48 N-ethyl-N- [2- (1H-pyrazol-3-yl) ethyl] -2- (2H-1,2,3-triazol-2-yl) benzamide

N-ethyl-N- {2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2) obtained in Reference Example 45 , 3-Triazol-2-yl) benzamide (0.37 g, 0.93 mmol) in EtOH (10 mL) was added 4 mol / L HCl-1,4-dioxane solution (0.11 mL, 0.47 mmol) at room temperature. And stirred overnight. A 4 mol / L HCl-1,4-dioxane solution (0.23 mL, 0.93 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. Further, 4 mol / L HCl-1,4-dioxane solution (0.23 mL, 0.93 mmol) was added, and the mixture was stirred in an oil bath (50 ° C.) for 3 hours. Saturated aqueous NaHCO ₃ solution was added to the reaction mixture and extracted with CHCl ₃ . After evaporating the solvent under reduced pressure, the obtained residue was purified by column chromatography (SNAP KP-NH 28 g, hexane / EtOAc = 75 / 25-0 / 100) to obtain the title compound (0.24 g) ( Yellow oil).
MS (ESI pos.) M / z: 311 [M + H] +

Reference Examples 49 and 50 were obtained in the same manner as Reference Example 48. Table 4 shows the structural formula, compound name, and MS data of the obtained compound.

Reference Example 51 N- (2-cyanoethyl) -2- (2H-1,2,3-triazol-2-yl) benzamide

３−アミノプロパンニトリル（０．２２ｍＬ、２．９５ｍｍｏｌ）及び２−（２Ｈ−１，２，３−トリアゾール−２−イル）安息香酸（０．６０ｇ、２．９５ｍｍｏｌ）を原料にして、参考例１９と同様の手法により、表題化合物（０．５６ｇ）を得た（無色固体）。
MS (ESI pos.) m/z : 242 [M+H]+

Reference examples using 3-aminopropanenitrile (0.22 mL, 2.95 mmol) and 2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.60 g, 2.95 mmol) as raw materials The title compound (0.56 g) was obtained in the same manner as in 19 (colorless solid).
MS (ESI pos.) M / z: 242 [M + H] +

Reference Example 52 N- {2- [5- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (2H-1,2,3- Triazol-2-yl) benzamide

参考例５１で得られたＮ−（２−シアノエチル）−２−（２Ｈ−１，２，３−トリアゾール−２−イル）ベンズアミド（０．５６ｇ、２．２１ｍｍｏｌ）を原料にして、参考例２７と同様の手法により、表題化合物（０．２２ｇ）を得た。（淡黄色油状物）
MS (ESI pos.) m/z : 380 [M+H]+

Using N- (2-cyanoethyl) -2- (2H-1,2,3-triazol-2-yl) benzamide (0.56 g, 2.21 mmol) obtained in Reference Example 51 as a raw material, Reference Example 27 The title compound (0.22 g) was obtained by a method similar to that described above. (Light yellow oil)
MS (ESI pos.) M / z: 380 [M + H] +

  Reference Examples 53 to 56 were obtained in the same manner as Reference Example 52. Table 5 shows the structural formula, compound name, and MS data of the obtained compound.

Reference Example 57 tert-butyl (2-cyanoethyl) ethylcarbamate

ｔｅｒｔ−ブチル（２−シアノエチル）カルバマート（７．２９ｇ、４２．８ｍｍｏｌ）とヨウ化エチル（５．１ｍＬ、６４．２ｍｍｏｌ）を原料にして参考例１７と同様の手法により、表題化合物（４．７０ｇ）を得た。（淡黄色油状物）
MS (ESI pos.) m/z : 199 [M+H]+

The title compound (4.70 g) was prepared in the same manner as in Reference Example 17 using tert-butyl (2-cyanoethyl) carbamate (7.29 g, 42.8 mmol) and ethyl iodide (5.1 mL, 64.2 mmol) as raw materials. ) (Light yellow oil)
MS (ESI pos.) M / z: 199 [M + H] +

Reference Example 58 tert-butyl ethyl {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} carbamate

A 50% aqueous hydroxylamine solution (2.0 mL) was added to an ethanol solution (20 mL) of tert-butyl (2-cyanoethyl) ethylcarbamate (4.70 g, 23.7 mmol) obtained in Reference Example 57 at 90 ° C. Stir for 5 hours. After cooling at room temperature, the solvent of the reaction solution was distilled off under reduced pressure. Saturated aqueous sodium chloride solution was added to the obtained residue, and the mixture was extracted with chloroform, passed through a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether, collected by filtration and dried under reduced pressure to obtain tert-butyl [3-amino-3- (hydroxyimino) propyl] ethylcarbamate (4.60 g, 19.9 mmol). Obtained. The title compound (1.45 g) was prepared in the same manner as in Reference Example 27 using the obtained tert-butyl [3-amino-3- (hydroxyimino) propyl] ethylcarbamate (1.50 g, 6.49 mmol) as a starting material. ) (Colorless oil)
MS (ESI pos.) M / z: 336 [M + H] +

Reference Example 59 tert-butyl {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} ethylcarbamate

To a solution of tert-butyl [3-amino-3- (hydroxyimino) propyl] ethylcarbamate (1.50 g, 6.49 mmol) obtained in Reference Example 58 in DMF (30 mL), 3,4-benzonitrile (0 .90 g, 6.49 mmol), zinc chloride (0.44 g, 3.24 mmol) and p-toluenesulfonic acid monohydrate (0.62 g, 3.24 mmol) were added, and the mixture was stirred at 90 ° C. for 2 hours. After allowing to cool at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 80/20 to 20/80) to obtain the title compound (0.22 g). (Light yellow oil)
MS (ESI pos.) M / z: 376 [M + Na] +

  Reference Example 60 was obtained in the same manner as Reference Example 59. Table 6 shows the structural formula, compound name, and MS data of the obtained compound.

Reference Example 61 2- [5- (3,4-Difluorophenyl) -1,2,4-oxadiazol-3-yl) -N-ethylethanamine

Tert-Butyl {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} ethylcarbamate (0.22 g, 0) obtained in Reference Example 59 Trifluoroacetic acid (1 mL) was added to a chloroform solution (5 mL) of .62 mmol) and stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extracted organic layer was washed with a saturated aqueous sodium chloride solution, then passed through a phase separator, and the solvent was distilled off under reduced pressure to obtain the title compound (0.10 g, 0.40 mmol). (Light yellow oil)
MS (ESI pos.) M / z: 254 [M + H] +

  Reference Examples 62 and 63 were obtained in the same manner as Reference Example 61. Table 7 shows the structural formula, compound name, and MS data of the obtained compound.

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

N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -5-methyl-2- (2H-1,2, obtained in Reference Example 3 To a DMF solution (1.2 mL) of 3-triazol-2-yl) benzamide (0.14 g, 0.37 mmol) was added 60% NaH (0.019 g, 0.44 mmol), and the mixture was stirred at room temperature for 1 hour. EtI (0.032 mL, 0.40 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, 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 (HP-Sil 25 g, hexane / EtOAc = 80/20 to 0/100). The obtained solid was stirred and washed in Et ₂ O and then collected by filtration to obtain the title compound (0.11 g) (colorless solid).
LCMS retention time 5.70 min. (Condition 1)
MS (ESI pos.) M / z: 420 [M + H] +

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

N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -5-methyl-2- (2H-1,2, obtained in Reference Example 3 3-Triazol-2-yl) benzamide (0.06 g, 0.15 mmol) and MeI (0.010 mL, 0.17 mmol) were used as starting materials in the same manner as in Example 1 to obtain the title compound (0.044 g). (Colorless solid) was obtained.
LCMS retention time 5.39 min. (Condition 1)
MS (ESI pos.) M / z: 406 [M + H] +

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

N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -2- (2H-1,2,3-triazole-) obtained in Reference Example 4 2-yl) benzamide (0.05 g, 0.13 mmol) and EtI (0.012 mL, 0.15 mmol) were used as raw materials in the same manner as in Example 1 to obtain the title compound (0.043 g) ( Colorless solid).
LCMS retention time 5.41 min. (Condition 1)
MS (ESI pos.) M / z: 406 [M + H] +

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

N-ethyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine (0.022 g, 0.09 mmol) obtained in Reference Example 10 in DMF (0 .8 mL) to 2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.02 g, 0.1 mmol), HOBt.H ₂ O (0.022 g, 0.14 mmol) and EDC. HCl (0.027 g, 0.14 mmol) was added and stirred at room temperature for 2 hours. Aqueous NaHCO ₃ solution was added to the reaction mixture, extraction was performed with EtOAc, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 80/20 to 0/100, KP-NH 11 g, hexane / EtOAc = 88/12 to 0/100), Et ₂ O The title compound (0.013 g) was obtained by washing with stirring in the middle (colorless solid).
LCMS retention time 5.54 min. (Condition 1)
MS (ESI pos.) M / z: 406 [M + H] +

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

N-methyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine (0.062 g, 0.28 mmol) obtained in Reference Example 11 and 5-methyl- Using 2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.11 g, 0.56 mmol) as a starting material, the title compound (0.014 g) was prepared in the same manner as in Example 4. Obtained (yellow oil).
LCMS retention time 5.50 min. (Condition 1)
MS (ESI pos.) M / z: 406 [M + H] +

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

N-ethyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine obtained in Reference Example 10 (0.063 g, 0.27 mmol) and 5-methyl- The title compound (0.061 g) was obtained in the same manner as in Example 4 using 2- (pyrimidin-2-yl) benzoic acid (0.371 g, 1.96 mmol) as a starting material (pale orange solid).
LCMS retention time 1.83 min. (Condition 2)
MS (ESI / APCI pos.) M / z: 431 [M + H] +

Example 7 N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-fluoro-2- (2H-1,2, 3-Triazol-2-yl) benzamide

CHCl _{3 of} N-ethyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine hydrochloride (0.028 g, 0.10 mmol) obtained in Reference Example 18 To the solution (1.0 mL) was added Et ₃ N (0.017 mL, 0.12 mmol), 5-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.032 g,. 15 mmol), HOBt · H ₂ O (0.019 g, 0.12 mmol) and EDC · HCl (0.024 g, 0.12 mmol) were added, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added Et ₃ N (0.017 mL, 0.12 mmol), 5-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.032 g, 0.15 mmol), HOBt. H ₂ O (0.019 g, 0.12 mmol) and EDC · HCl (0.024 g, 0.12 mmol) were added, and the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 3 hours. Aqueous NaHCO ₃ solution (1.0 mL), water (1.0 mL) and CHCl ₃ were added to the reaction mixture, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with CHCl ₃ , and the organic layers were combined, passed through an ISOLUTE Phase Separator, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (KP-NH 11 g, hexane / EtOAc = 100/0 to 75/25) to obtain the title compound (0.033 g) (colorless solid).
LCMS retention time 1.83 min. (Condition 2)
MS (ESI / APCI pos.) M / z: 424 [M + H] +

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

N-ethyl-2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethanamine hydrochloride (0.028 g, 0.10 mmol) obtained in Reference Example 18 and 5- The title compound (0.030 g) was prepared in the same manner as in Example 7 using methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.031 g, 0.15 mmol) as a starting material. ) Was obtained (colorless solid).
LCMS retention time 1.88 min. (Condition 2)
MS (ESI / APCI pos.) M / z: 420 [M + H] +

Example 9 N- {2- [5- (5-fluoropyridin-2-yl) -1,2-oxazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

N- {2- [5- (5-fluoropyridin-2-yl) -1,2-oxazol-3-yl] ethyl} -5-methyl-2- (2H-1, obtained in Reference Example 21 2,3-triazol-2-yl) benzamide (0.080 g, 0.20 mmol) and MeI (0.014 mL, 0.22 mmol) were used as starting materials in the same manner as in Example 1, and the title compound (0. 039 g) (colorless solid).
LCMS retention time 5.11 min. (Condition 1)
MS (ESI pos.) M / z: 407 [M + H] +

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

N- {2- [5- (5-fluoropyridin-2-yl) -1,2-oxazol-3-yl] ethyl} -5-methyl-2- (2H-1, obtained in Reference Example 21 2,3-triazol-2-yl) benzamide (0.080 g, 0.20 mmol) and EtI (0.018 mL, 0.22 mmol) were used as starting materials in the same manner as in Example 1, and the title compound (0. 060 g) was obtained (colorless solid).
LCMS retention time 5.42 min. (Condition 1)
MS (ESI pos.) M / z: 421 [M + H] +

Example 11 N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethyl} -5-methyl-2- (2H-1, 2,3-Triazol-2-yl) benzamide

N- {2- [3- (5-fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethyl} -5-methyl-2- (2H-1, obtained in Reference Example 25 2,3-triazol-2-yl) benzamide (0.040 g, 0.10 mmol) and EtI (0.009 mL, 0.11 mmol) were used as starting materials in the same manner as in Example 1 to prepare the title compound (0. 032 g) was obtained (colorless solid).
LCMS retention time 5.56 min. (Condition 1)
MS (ESI pos.) M / z: 421 [M + H] +

Example 12 N-ethyl-N- {2- [5- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- ( 2H-1,2,3-triazol-2-yl) benzamide

N- {2- [5- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (obtained in Reference Example 27 2H-1,2,3-triazol-2-yl) benzamide (0.040 g, 0.10 mmol) and EtI (0.009 mL, 0.11 mmol) were used as starting materials in the same manner as in Example 1, Compound (0.027 g) was obtained (colorless solid).
LCMS retention time 5.19 min. (Condition 1)
MS (ESI pos.) M / z: 422 [M + H] +

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

N- {2- [1- (5-Fluoropyridin-2-yl) -1H-imidazol-4-yl] ethyl} -5-methyl-2- (2H-1,2, obtained in Reference Example 29 3-Triazol-2-yl) benzamide (0.13 g, 0.32 mmol) and EtI (0.028 mL, 0.35 mmol) were used as starting materials in the same manner as in Example 1 to obtain the title compound (0.12 g). (Colorless amorphous) was obtained.
LCMS retention time 3.56 min. (Condition 1)
MS (ESI pos.) M / z: 420 [M + H] +

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

2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] -N-methylethanamine hydrochloride (0.080 g, 0.31 mmol) and 2 obtained in Reference Example 31 The title compound (0.075 g) was obtained in the same manner as in Example 7 using-(2H-1,2,3-triazol-2-yl) benzoic acid (0.065 g, 0.34 mmol) as a starting material. (Colorless amorphous).
LCMS retention time 1.74 min. (Condition 2)
MS (ESI pos.) M / z: 392 [M + H] +

Example 15 5-Fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -N-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzamide

2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] -N-methylethanamine hydrochloride (0.050 g, 0.19 mmol) and 5 obtained in Reference Example 31 Using the same procedure as in Example 7, starting from -fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.044 g, 0.21 mmol), the title compound (0. 055 g) was obtained (colorless amorphous).
LCMS retention time 1.79 min. (Condition 2)
MS (ESI pos.) M / z: 410 [M + H] +

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

2- [1- (5-Fluoropyridin-2-yl) -1H-pyrazol-3-yl] -N-methylethanamine hydrochloride obtained in Reference Example 31 (0.050 g, 0.19 mmol) 5- The title compound (0.070 g) was prepared in the same manner as in Example 7 using chloro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.048 g, 0.21 mmol) as a starting material. (Colorless amorphous).
LCMS retention time 1.82 min. (Condition 2)
MS (ESI pos.) M / z: 426 [M + H] +

Example 17 N-ethyl-4-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2, 3-Triazol-2-yl) benzamide

4-Fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2, obtained in Reference Example 33 To a solution of 3-triazol-2-yl) benzamide (0.048 g, 0.12 mmol) in DMF (0.4 mL) was added 60% NaH (0.006 g, 0.15 mmol), and the mixture was stirred at room temperature for 30 minutes. EtI (0.011 mL, 0.13 mmol) was added thereto and stirred at room temperature for 1 hour. Water was added to the reaction mixture and 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. The obtained residue was purified by column chromatography (KP-NH 28 g, hexane / EtOAc = 88/12 to 0/100). The obtained solid was washed with stirring with Et ₂ O and then collected by filtration to obtain the title compound (0.040 g) (colorless solid).
LCMS retention time 1.04 min. (Condition 3)
MS (ESI pos.) M / z: 424 [M + H] +

Examples 18 to 21 were obtained in the same manner as in Example 17. Table 8 shows the structural formula, compound name, and LCMS data of the obtained compound.

Example 22 N-ethyl-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl) Benzamide

N-ethyl-N- [2- (1H-pyrazol-3-yl) ethyl] -2- (2H-1,2,3-triazol-2-yl) benzamide (0.050 g) obtained in Reference Example 48 0.16 mmol) in DMF (0.4 mL), 1-bromo-4-fluorobenzene (0.042 g, 0.24 mmol), trans-N, N′-dimethylcyclohexane-1,2-diamine (0. 026 mL, 0.16 mmol), copper iodide (0.008 g, 0.04 mmol), cesium carbonate (0.11 g, 0.32 mmol) were added, and the mixture was stirred at 90 ° C. for 4 hours. Add 1-bromo-4-fluorobenzene (0.042 g, 0.24 mmol), trans-N, N′-dimethylcyclohexane-1,2-diamine (0.026 mL, 0.16 mmol) and add 4 at 90 ° C. Stir for hours. The reaction mixture was purified by HPLC (condition 2), and further purified by PLC (NH silica 0.75 mm, hexane / EtOAc = 1/1). The resulting oily substance was lyophilized to give the title compound (0.028 g) (colorless amorphous).
LCMS retention time 1.01 min. (Condition 3)
MS (ESI pos.) M / z: 405 [M + H] +

  Examples 23 to 30 were obtained in the same manner as in Example 22. Table 9 shows the structural formula, compound name, and LCMS data of the obtained compound.

実施例３１ Ｎ−｛２−［５−（４−フルオロフェニル）１，２，４−オキサジアゾール−３−イル］エチル｝−Ｎ−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）ベンズアミド

Example 31 N- {2- [5- (4-fluorophenyl) 1,2,4-oxadiazol-3-yl] ethyl} -N-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide

N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (2H-1,2,3- obtained in Reference Example 53 The title compound (0.08 g) was prepared in the same manner as in Example 1 using triazol-2-yl) benzamide (0.09 g, 0.24 mmol) and methyl iodide (0.18 mL, 0.29 mmol) as raw materials. Got. (Colorless and amorphous)
LCMS retention time 0.95 min. (Condition 3)
MS (ESI pos.) M / z: 393 [M + H] +

Examples 32 to 37 were obtained in the same manner as in Example 31. Table 10 shows the structural formula, compound name, and LCMS data of the obtained compound.

Example 38 N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (2H-1, 2,3-Triazol-2-yl) benzamide

参考例６２で得られた２−［５−（４−フルオロフェニル) −１，２，４−オキサジアゾール−３−イル）−Ｎ−エチルエタンアミン（０．０５ｇ、０．２１ｍｍｏｌ）と５−メチル−２−（２Ｈ−１，２，３−トリアゾール−２−イル）安息香酸（０．０４３ｇ、０．２１ｍｍｏｌ）を原料にして、実施例７と同様の手法により、表題化合物（０．０２２ｇ）を得た。（無色固体）
LCMS retention time 1.07 min.（条件３）
MS (ESI pos.) m/z : 421 [M+H]+

2- [5- (4-Fluorophenyl) -1,2,4-oxadiazol-3-yl) -N-ethylethanamine (0.05 g, 0.21 mmol) obtained in Reference Example 62 and 5 Using the same procedure as in Example 7, starting from -methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (0.043 g, 0.21 mmol), the title compound (0. 022 g) was obtained. (Colorless solid)
LCMS retention time 1.07 min. (Condition 3)
MS (ESI pos.) M / z: 421 [M + H] +

Examples 39 to 46 were obtained in the same manner as in Example 38. Table 11 shows the structural formula, compound name, and LCMS data of the obtained compound.

Test example (measurement of orexin antagonistic activity)
The antagonistic activity of test compounds against human orexin type 1 receptor (hOX1R) and orexin type 2 receptor (hOX2R) was 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 and 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 at 37 ° C., 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 12.

  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 It can be used as a therapeutic or prophylactic agent for Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension and the like.

Claims (6)

Formula (IA)

(Where
X represents a nitrogen atom or the formula CH;
Y represents any one of the following formula group (II),

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 (wherein the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from Substituent Group 1), C _{3 -6} cycloalkyl 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 pyrimidinyl group;
The triazolyl group, pyridyl group and pyrimidinyl 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). )
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease characterized by containing a heteroaromatic ring derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient , Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, therapeutic or preventive drugs for hypertension. R ⁴ is a halogen atom,
R ⁵ is a hydrogen atom or a heteroaromatic ring derivative according to claim 1 is a halogen atom, or sleep disorders characterized by containing a pharmaceutically acceptable salt thereof as an active ingredient, depression, anxiety disorders, Panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension Therapeutic or prophylactic agent. Formula (I)

(Where
X represents a nitrogen atom or the formula CH;
Y represents any one of the following formula group (II),

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 (wherein the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from Substituent Group 1), C _{3 -6} cycloalkyl 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 pyrimidinyl group;
The triazolyl group, pyridyl group and pyrimidinyl 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 characterized by containing a heteroaromatic ring derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient , Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, therapeutic or preventive drugs for hypertension. X is a nitrogen atom,
R ² is a C _1-6 alkyl group,
R ³ is a triazolyl group or a pyrimidinyl group;
R ⁴ is a halogen atom. Sleep disorder or depression characterized by containing the heteroaromatic ring derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. , Anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, Treatment or prevention drug for hypertension. R ² is, sleep characterized by containing as an active ingredient a heteroaromatic ring derivatives, or their pharmaceutically acceptable salts according to claim 1 which is methyl group, or an ethyl group Disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, Therapeutic or prophylactic agent for endocrine related diseases and hypertensive diseases. 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, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension diseases Treatment or prevention drug.
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole-2 -Yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-fluoro-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -5-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1,2-oxazol-5-yl] ethyl} -5-methyl-2- (2H-1,2,3 -Triazol-2-yl) benzamide,
N-ethyl-N- {2- [3- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-5-yl] ethyl} -5-methyl-2- (2H-1 , 2,3-triazol-2-yl) benzamide,
5-chloro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -N-methyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-4-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-2-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide,
N-ethyl-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-2-fluoro-N- {2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -6- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl) benzamide;
N-ethyl-N- {2- [1- (6-methylpyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (2H-1,2,3-triazol-2-yl Benzamide,
N-ethyl-2- (2H-1,2,3-triazol-2-yl) -N- (2- {1- [6- (trifluoromethyl) pyridin-2-yl] -1H-pyrazole-3 -Yl} ethyl) benzamide,
N- {2- [1- (3,4-difluorophenyl) -1H-pyrazol-3-yl] ethyl} -N-ethyl-2- (2H-1,2,3-triazol-2-yl) benzamide ,
N-ethyl-5-fluoro-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N-ethyl-5-fluoro-N- {2- [1- (6-methylpyridin-2-yl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N- {2- [1- (3,4-difluorophenyl) -1H-pyrazol-3-yl] ethyl} -N-ethyl-5-fluoro-2- (pyrimidin-2-yl) benzamide;
N-ethyl-N- {2- [1- (4-fluorophenyl) -1H-pyrazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide;
N- {2- [5- (4-Fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3-triazole -2-yl) benzamide,
N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -N, 5-dimethyl-2- (2H-1,2,3 -Triazol-3-yl) benzamide,
N-ethyl-N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) benzamide,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (2H-1,2,3 -Triazol-2-yl) benzamide,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -5-methyl-2- (pyrimidin-2-yl) benzamide ,
N-ethyl-5-fluoro-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (pyrimidin-2-yl) benzamide ,
N-ethyl-N- {2- [5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (2H-1,2,3-triazole-2 -Yl) benzamide, and
N-ethyl-N- {2- [5- (3,4-difluorophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -2- (2H-1,2,3-triazole -2-yl) benzamide.