WO2016084866A1 - Novel diazabicyclo derivative - Google Patents

Abstract

Provided are: compounds having orexin receptor antagonistic effects; a pharmaceutical composition characterized by comprising the compounds as an active ingredient; and medical applications thereof, particularly prophylactic and/or therapeutic agents for diseases relating to orexin receptors, sleep disorders, mental disorders, neurodegenerative diseases, memory disorders and eating disorders, particularly sleep disorders such as insomnia. Specifically, provided are compounds represented by formula (I), or pharmaceutically acceptable salts thereof, or solvates thereof.

Description

New diazabicyclo derivatives

The present invention relates to a compound having an orexin receptor antagonism, particularly a compound having a diazabicyclo structure represented by the following formula (I), or a pharmaceutically acceptable salt thereof, or a compound thereof: The present invention relates to a solvate and a pharmaceutical composition containing them as an active ingredient. The present invention also relates to diseases involving orexin receptors, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity) Sexual disorders, autism, autism spectrum disorder, drug dependence, etc.), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) and eating disorders (eg, bulimia), especially insomnia The present invention relates to a preventive and / or therapeutic agent for sleep disorders.

Orexin (hereinafter sometimes abbreviated as “OX”) is a neuropeptide specifically expressed in neurons existing in the lateral hypothalamic area, OX-A consisting of 33 amino acids and 28 OX-B consisting of the following amino acids has been identified. The orexin receptor, which is a specific receptor for these peptides, has been reported in two subtypes, the OX1 receptor and the OX2 receptor. Each receptor is a seven-transmembrane G protein-coupled receptor expressed in the central nervous system, but the tissue distribution differs depending on the subtype and has various effects on various nerves. Has been suggested to have complex physiological activities.
At the beginning of the identification of orexin, attention was focused on the regulation and regulation function of feeding behavior, but in recent years, the relationship between orexin and regulation of sleep / wakefulness has attracted attention. By administering orexin into the rat ventricle, wakefulness-promoting effects such as increased spontaneous momentum and prolonged wakefulness are observed (Non-patent Documents 1 and 2). In addition, inhibition of arousal is observed in orexin KO mice and OX2 receptor KO mice (Non-patent Document 3). From these findings, orexin receptor antagonists are considered to be excellent insomnia treatments as sleep-inducing agents that induce sleep by suppressing wakefulness.
Almorexant and suvorexant are known as orexin receptor antagonists. These antagonists are substances (dual antagonists) that antagonize the OX1 receptor and the OX2 receptor to the same extent, and improvement of insomnia symptoms has been reported (Non-patent Documents 4 and 5). Suvorexant has been approved for manufacture and sale as a therapeutic agent for insomnia (Belsomura (registered trademark)). On the other hand, side effects such as daytime sleepiness (carry-over effect) and sleep behavior disorder are concerned.
From studies using KO mice, it has been reported that the arousal action and non-REM sleep inhibitory action by orexin are mainly mediated by OX2 receptors (Non-patent Document 6). Therefore, an OX2 receptor selective antagonist induces physiological sleep and may be a therapeutic agent for insomnia with a low risk of side effects. As OX2 receptor selective antagonists, MIN-202 and MK-1064 (Non-patent Document 7) have been developed as therapeutic agents for insomnia.

As compounds having an orexin receptor antagonistic activity, WO2008 / 008517 pamphlet (Patent Document 1) includes a compound having a diazabicyclo structure such as a diazabicyclo [4.2.1] nonane derivative, WO2011 / 050198 pamphlet (Patent Document 2). ) For diazabicyclo [3.3.0] octane derivative, WO2012 / 085852 pamphlet (patent document 3), for diazabicyclo [4.2.0] octane derivative, and WO2013 / 0500938 pamphlet (patent document 4). Discloses diazabicyclo [3.3.1] nonane derivatives, respectively. However, the derivatives disclosed therein are different in basic skeleton from compounds having a diazabicyclo [3.2.1] octane or diazabicyclo [3.1.1] heptane structure, and diazabicyclo [3.2.1] octane. Alternatively, there is no disclosure or suggestion about a compound having a diazabicyclo [3.1.1] heptane structure.

In addition, a piperidine derivative is disclosed as a compound having an orexin receptor antagonistic activity in WO 2014/066196 pamphlet (Patent Document 5), but diazabicyclo [3.2.1] octane or diazabicyclo [3.1. 1] The basic skeleton is different from a compound having a heptane structure.

In the FR2531709 pamphlet (Patent Document 6), a diazabicyclo [3.2.1] octane derivative is disclosed as a compound having an anxiolytic action, but the disclosure of the specific compound of the present invention as shown below is disclosed. Absent.
In WO2011 / 090935 (Patent Document 7), as a compound having an mTOR inhibitory action, and in WO2002 / 102778 (Patent Document 8), as a compound having a PDEIV inhibitory action, diazabicyclo [3.2.1]. Although a group of compounds containing an octane derivative is disclosed, there is no disclosure of specific compounds of the present invention as shown below.

Now, in drug development, it is required to satisfy severe criteria not only in the intended pharmacological activity but also in various aspects such as absorption, distribution, metabolism, and excretion. For example, drug interaction, desensitization or tolerance, digestive tract absorption after oral administration, transfer rate into the small intestine, absorption rate and first-pass effect, organ barrier, protein binding, induction and inhibition of drug metabolizing enzymes, excretion route and Various examination subjects are required in the body clearance, application method (application site, method, purpose) and the like, and it is difficult to find one that satisfies these. However, challenges in medicine will always arise.

WO2008 / 008517 pamphlet WO2011 / 050198 Pamphlet WO2012 / 085852 pamphlet WO2013 / 0500938 pamphlet WO2014 / 066196 pamphlet French Patent Application Publication No. 2531709 Pamphlet WO2011 / 090935 Pamphlet WO2002 / 102778 pamphlet

At present, various insomnia drugs are available for pharmacotherapy of sleep disorders such as insomnia, but the treatment satisfaction is low and the development of new insomnia drugs with better side effect profile There is still a need.

Although there are multiple reports of compounds having orexin receptor antagonistic activity, there are always comprehensive issues in the development of the aforementioned drugs. More specifically, for example, poor solubility, low metabolic stability, difficulty in systemic exposure by oral administration, poor pharmacokinetics such as absorption and persistence, or arrhythmia It exhibits hERG (human ether-a-go related gene) channel inhibitory activity, induces or inhibits drug metabolizing enzymes (eg, cytochrome P450), and exhibits a high protein binding rate. There are problems of usefulness and safety. There is a need to solve these problems as much as possible and find highly effective compounds.

In order to solve the above-mentioned problems, the present inventors have conducted extensive research to obtain an orexin receptor antagonist that is highly safe and / or excellent in effectiveness. It was found that a compound having a diazabicyclo structure or a pharmaceutically acceptable salt thereof or a solvate thereof has an orexin receptor antagonistic action. The compound of the present invention has an orexin receptor antagonistic action, and has an action of improving psychiatric and neurological disorders including sleep disorders such as insomnia.

The present invention contains a compound having a diazabicyclo structure represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, and an active ingredient thereof. A pharmaceutical composition characterized by comprising:
The compound of the present invention is a compound having an orexin receptor antagonistic action, and has an action of improving psychiatric and neurological disorders including sleep disorders such as insomnia.
The pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally, and sleep such as orexin receptor antagonists, diseases involving orexin receptor, psychiatric and neurological disorders, especially insomnia It is expected as a preventive and / or therapeutic agent for disorders.
In addition, the compound group of the present invention has at least one or more characteristics such as good solubility, high metabolic stability, excellent oral absorbability, and little hERG channel inhibitory action. Since it also has, it is highly useful.

The present invention relates to a compound having a diazabicyclo structure represented by the following formula (I) shown in the following embodiment, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and A pharmaceutical composition characterized by containing them as an active ingredient, as well as their pharmaceutical use, orexin receptor antagonist.

[Aspect of the Invention]
The present invention includes the following embodiments [1] to [14].
[1] The first aspect of the present invention is
Formula (I)

(Where
n represents 1 or 2;
Ring A represents a C _{6 ~ 14} aryl group or a 5-14 membered heteroaryl group, in the ring A, the C _{6 ~ 14} aryl group or a 5-14 membered heteroaryl group, respectively, 1-5 R Optionally substituted by ¹ ;
Ring B represents a phenyl group or a monocyclic heteroaryl group, and the phenyl group or monocyclic heteroaryl group in Ring B may each be substituted with 1 to 4 R ² ;
L is a halogen atom, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxyl group, a halogenated C _{1 ~ 6} alkoxy group, a phenoxy group, a monocyclic non-aromatic heterocyclic group, a phenyl group or a monocyclic heteroaryl Represents an aryl group, and the phenoxy group, monocyclic non-aromatic heterocyclic group, phenyl group or monocyclic heteroaryl group in L may each be substituted with 1 to 5 R ³ , Alternatively, L may be bonded to R ² to form a condensed ring group together with a part of the ring B, and the condensed ring group is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom. Yes;
L on ring B is a substituent adjacent to the bond position of ring A-bicycloring-CO—;
R ¹ is, each independently, a halogen atom, C _{1 ~ 6} alkyl group, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy group, C _{2 ~ 6} alkynyloxy group, C _{2 ~ 7} alkanoyl group, C _{1 ~ 6} alkoxycarbonyl group, C _{1 ~ 6} alkylthio group, -NR ^a R ^b group, optionally cyano group and oxo group represents a group selected, the C _{1 ~ 6} alkyl group in R ^1, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy group, C _{2 ~ 6} alkynyloxy group, C _{2 ~ 7} alkanoyl group, C _{1 ~ 6} alkoxycarbonyl group, or a C _{1 ~ 6} alkylthio group, respectively, substituted with 1 to 5 substituents RI Well;
R ² are each independently a halogen atom, C _{1 ~ 6} alkyl group, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy groups, C _{2 ~ 6} alkynyloxy group, a chosen group optionally cyano group and a monocyclic heteroaryl group, said C _{1 ~ 6} alkyl group in R ^2, C _{2 ~ 6} alkenyl groups, C _2-6 alkynyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _2-6 alkenyloxy group, C _2-6 alkynyloxy group or a monocyclic heteroaryl group, respectively, 1-5 Optionally substituted by one substituent RI;
R ³ are each independently a halogen atom, C _{1 ~ 6} alkyl group, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy group, C _{2 ~} represents ₆ alkynyloxy group and chosen group optionally cyano group, the C _{1 ~ 6} alkyl group in R ^3, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{1 ~ 6} alkoxy group, C _{2 1-6} alkenyloxy group or a C _{2 - 6} alkynyloxy groups may each be substituted with 1 to 5 substituents RI;
R ^a and R ^b represent each independently, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group, a chosen group optionally from C _{2 ~ 6} alkenyl group and C _{2 ~ 6} alkynyl radical, R ^a and R ^b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group, and the monocyclic non-aromatic heterocyclic group in R ^a and R ^b At least one of the carbon atoms may be replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted with a C _1-6 alkyl group;
Each of the substituents RI independently represents a halogen atom or a hydroxyl group)
Or a pharmaceutically acceptable salt or solvate thereof.

Below, each group in the said formula (I) of the said aspect [1] is demonstrated concretely.
In the description of the compounds of the present invention, for example, “C _1-6 ” means that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, carbon atoms of a linear, branched or cyclic group Represents a number. The chain group means “straight or branched chain having 1 to 6 carbon atoms”. Further, the cyclic group means “a cyclic group having 1 to 6 carbon atoms in the ring”. The group containing a chain group and a cyclic group means “a group having 1 to 6 total carbon atoms”.

In the present specification, unless otherwise specified, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In the present specification, unless otherwise specified, “halogenated” means having 1 to 5 “halogen atoms” as a substituent. “Halogenation” is also referred to as “halogeno”.
In the present specification, unless otherwise specified, examples of the “C _1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl and the like. . Examples of the “C _1-4 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and “C _1-2 alkyl group” includes Methyl and ethyl are mentioned.

In the present specification, unless otherwise specified, the “halogenated C _1-6 alkyl group” means a group in which the “C _1-6 alkyl group” is optionally substituted with 1 to 5 halogen atoms. Meaning, for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
In the present specification, unless otherwise specified, “may be substituted with 1 to 5 substituents RI” means that the corresponding substituent (for example, an alkyl group) is 1 to 5 substituents RI. It means that it may be optionally substituted, and in addition to the corresponding unsubstituted substituent (eg, unsubstituted alkyl group), the corresponding group (eg, , An alkyl group).
Specifically, for example, “a C _1-6 alkyl group substituted with 1 to 5 substituents RI” means that the “C _1-6 alkyl group” is 1 to 5 substituents RI, That is, a group optionally substituted with 1 to 5 halogen atoms or hydroxyl groups. For example, in addition to the groups mentioned as the above “halogenated C _1-6 alkyl group”, the “C _1-6 alkyl group substituted with a hydroxyl group” is hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxy- Examples include 2-methyl-ethyl and the like, and 2,2,2-trifluoro-1-hydroxyethyl which is a “C _1-6 alkyl group substituted with a halogen atom and a hydroxyl group”.

In the specification, the "1 to 5 substituents RI group which may be substituted with", in addition to the C _{1 ~ 6} alkyl groups, C _{2 ~ 6} alkenyl groups, C _{2 ~ 6} alkynyl groups, C _3-8 cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy group, C _{2 ~ 6} alkynyloxy group, C _{2 ~ 7} alkanoyl group, C _{1 ~ 6} alkoxycarbonyl group, C _{1 ~ 6} alkylthio Or a monocyclic heteroaryl group, in addition to each corresponding unsubstituted substituent, in addition to the aforementioned “C _1-6 alkyl group substituted by 1 to 5 substituents RI” ”Means a corresponding substituent optionally substituted with 1 to 5 substituents RI.
Herein, unless otherwise specified, as the "C _{2 ~ 6} alkenyl group", for example, vinyl, allyl, isopropenyl, 1-propen-1-yl, butenyl, pentenyl, isopentenyl, and hexenyl and the like Can be mentioned.
Herein, unless otherwise specified, as the "C _{2 ~ 6} alkynyl group", for example, ethynyl, 1-propynyl (= 1-propyn-1-yl), 2-propynyl (= 2-propyn -1 -Yl), butynyl, pentynyl (= 4-pentyn-1-yl), hexynyl (= 5-hexyn-1-yl) and the like.

Herein, unless otherwise specified, as the "C _{3 ~ 8} cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclic alkyl groups such as cycloheptyl and cyclooctyl.
In the present specification, unless otherwise specified, the “aryl group” means “monocyclic aryl group”, “condensed aryl group (including bicyclic or tricyclic)” or “partially A hydrogenated fused-ring aryl group ".
In the present specification, unless otherwise specified, the “partially hydrogenated condensed aryl group” means any hydrogen from a partially hydrogenated condensed ring in the “condensed aryl group”. It means a monovalent group formed by removing an atom, and either a hydrogen atom in an aromatic ring part of a condensed ring or a hydrogen atom in a hydrogenated part may be removed.
Herein, unless otherwise specified, as the "C _{6 ~ 14} aryl group", for example, phenyl, 1-naphthyl, 2-naphthyl, 2-, 3-, 4-biphenyl anthryl, phenanthryl, acenaphthyl, Indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl and the like can be mentioned.

In the present specification, unless otherwise specified, the “heterocyclic group” means a 3 to 14-membered monocyclic or condensed ring containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. A monovalent group formed by removing any hydrogen atom from a cyclic ring.
In the present specification, unless otherwise specified, examples of the “heterocyclic group” include “heteroaryl group” and “non-aromatic heterocyclic group”.
In the present specification, unless otherwise specified, the “heteroaryl group” refers to a 5- to 14-membered heteroaryl ring group containing 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. means.
In the present specification, unless otherwise specified, examples of the “heteroaryl group” include “monocyclic heteroaryl group”, “condensed heteroaryl group”, and “partially hydrogenated fused ring”. Formula heteroaryl group ".
In the present specification, unless otherwise specified, the “monocyclic heteroaryl group” preferably has 5 to 7 ring members. For example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl , Isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl , Pyrazinyl and the like.

In the present specification, unless otherwise specified, the “condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “monocyclic heteroaryl group”. Means a monovalent group formed by removing an arbitrary hydrogen atom from a condensed ring formed by condensation, and the arbitrary hydrogen atom may be removed from any condensed ring.
In the present specification, unless otherwise specified, the “condensed heteroaryl group” is preferably one having 8 to 12 ring members, for example, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, iso Benzothienyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl, chromenyl, isochromenyl, quinolyl , Isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl , Phenazinyl, phenoxathiinyl, thianthrenyl, thianthenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, furo [2,3-c] pyridyl, furo [3,2-c] pyridyl, imidazo [1,5- a] pyrazinyl, 1H-pyrazolo [3,4-c] pyridyl, 1H-pyrazolo [4,3-c] pyridyl, 1H-pyrazolo [4,3-b] pyridyl and the like.

In this specification, unless otherwise specified, the “partially hydrogenated condensed heteroaryl group” means “heterocyclic group” and “aryl group”, or “heterocyclic group” and “heterocyclic group”. In a condensed ring formed by condensing an “aryl group”, it means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring. The arbitrary hydrogen atom is a hydrogen atom in any of the "heterocyclic group", "aryl group" and "heteroaryl group" in the condensed ring, or a hydrogen atom in the hydrogenated ring part. For example, if the quinoline is partially hydrogenated tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl, 1,2,3,4-tetrahydroquinolyl and the like can be mentioned. Depending on the position of any hydrogen atom, these groups can be, for example, 5,6,7,8-tetrahydroquinolyl-2-yl, -3-yl, -4-yl, -5-yl. , -6-yl, -7-yl, -8-yl and the like, and 1,2,3,4-tetrahydroquinolyl, for example, -1-yl, -2-yl, -3- Il, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl and the like are exemplified.
In the present specification, unless otherwise specified, the “partially hydrogenated condensed heteroaryl group” preferably has 8 to 12 ring members, such as indolinyl, 4, 5, 6, 7 -Tetrahydro-1H-indonyl, 2,3-dihydrobenzofuranyl, 4,5,6,7-tetrahydro-benzofuranyl, 2,3-dihydrobenzo [d] oxazolyl, 2,3-dihydrobenzo [d] thiazolyl, 4,5,6,7-tetrahydro-1H-indazolyl, chromanyl, 2H-chromenyl, 4H-chromenyl, isochromanyl, 1H-isochromenyl, 1,3-benzodioxolyl, 2,3-dihydrofuro [3,2-c ] Pyridyl etc. are mentioned.

In the present specification, unless otherwise specified, the “monocyclic non-aromatic heterocyclic group” means a 3 to 8-membered member containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. A monovalent group formed by removing any hydrogen atom from a monocyclic saturated or unsaturated heterocyclic ring.
Unless otherwise specified, in this specification, examples of the “monocyclic non-aromatic heterocyclic group” include aziridinyl, azetidinyl, oxiranyl, thiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, thiolanyl, and pyrazolinyl. , Pyrazolidinyl, imidazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl (oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolidinyl, isoxazolinyl, 1,3-oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, 1,3 -Thiazolidinyl, isothiazolidinyl, oxadiazolinyl, 1,3,4-oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, azepanyl, diaze Cycloalkenyl, oxepanyl, and the like.
In the present specification, unless otherwise specified, the “C _1-6 alkoxyl group” means a group in which the “C _1-6 alkyl group” is substituted with an oxygen atom.
In the present specification, unless otherwise specified, examples of the “C _1-6 alkoxyl group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyl. Examples include oxy. Examples of the “C _1-4 alkoxyl group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, and “C _1-2 alkoxyl group” , Methoxy and ethoxy.

In the present specification, unless otherwise specified, the “halogenated C _1-6 alkoxyl group” means a halogen having 1 to 5 “C _1-6 alkyl groups” in the “C _1-6 alkoxyl group”. Means a group optionally substituted with atoms, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy Etc.
Herein, unless otherwise indicated, the term "C _{2 ~ 6} alkenyloxy group" means a group wherein the above "C _{2 ~ 6} alkenyl group" is substituted with an oxygen atom.
Herein, unless otherwise specified, as the "C _{2 ~ 6} alkenyloxy group", for example, vinyloxy, allyloxy, isopropenyloxy, butenyloxy, and pentenyloxy, and hexenyloxy and the like.
Herein, unless otherwise indicated, the term "C _{2 ~ 6} alkynyloxy group" means a group wherein the above "C _{2 ~ 6} alkynyl group" is substituted with an oxygen atom.
Herein, unless otherwise specified, as the "C _{2 ~ 6} alkynyloxy group", for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, and the like.

Herein, unless otherwise indicated, the term "C _{2 ~ 7} alkanoyl group", the carbonyl group in the "C _{1 ~ 6} alkyl group" bonded, means "C _{1 ~ 6} alkyl group" .
Herein, unless otherwise specified, as the "C _{2 ~ 7} alkanoyl group", for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, Examples include cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, 2-methylcyclopropylcarbonyl and the like.
Unless otherwise specified, in this specification, “C _1-6 alkylthio group” means a group in which the hydrogen atom of “thiol group (—SH)” is substituted with the above “C _1-6 alkyl group”. To do.
Unless otherwise specified, in this specification, examples of the “C _1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. Etc.
In the present specification, unless otherwise specified, the “—NR ^a R ^b group” means a group in which two hydrogen atoms on the nitrogen atom of the “amino group” are substituted with R ^a and R ^b . That is, "- NR ^a R ^b group" refers to two hydrogen atoms on the nitrogen atom of the "amino group" is, independently, "C _{1 ~ 6} alkyl group", "halogenated C _{1 ~ 6} alkyl group "means" C _{2 ~ 6} alkenyl group "and" C _{2 ~ 6} alkynyl group "which is substituted in the group selected arbitrarily from the base, for example, such as" di C _{1 ~ 6} alkyl group "can be mentioned It is done.

In the present specification, unless otherwise specified, examples of the “di-C _1-6 alkylamino group” include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, ethylmethylamino, propylmethylamino and the like. Is mentioned.
Examples of “monocyclic non-aromatic heterocyclic group” in “R ^a and R ^b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded” include: Means a monovalent cyclic group formed by removing a hydrogen atom bonded to a nitrogen atom in the “monocyclic non-aromatic heterocyclic group”, specifically, for example, aziridinyl, azetidinyl, pyrrolidinyl , Piperidinyl, azepanyl, azocanyl and the like.
In R ^a and R ^b , “in the monocyclic non-aromatic heterocyclic group, at least one of the carbon atoms in the ring is replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom” Specific examples of the heterocyclic group as `` optionally '' may include, for example, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, 2-oxo Examples include pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, oxadiazolinyl, oxadiazolidinyl and the like.
In R ^a and R ^b , “in the monocyclic non-aromatic heterocyclic group, at least one of the carbon atoms in the ring is a nitrogen atom (the nitrogen atom is substituted with a C _1-6 alkyl group). Specific examples of the heterocyclic group as “which may be substituted” may include 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-propylpiperazine-1 -Yl and the like.

In the present specification, unless otherwise specified, the “C _1-6 alkoxylcarbonyl group” means a group in which a hydrogen atom of “carboxy group (—COOH)” is substituted with the above “C _1-6 alkyl group”, that is, “Ester group” means.
In the present specification, unless otherwise specified, examples of the “C _1-6 alkoxylcarbonyl group” include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like.

L may be bonded to R ² to form a condensed ring group together with a part of ring B. That is, as shown in the following partial structural formula, L, R ² and ring B (part) can be bonded together to form a condensed ring D.

The formed condensed ring D forms a condensed cyclic group together with a part of the adjacent ring B.
Here, the condensed ring D is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom, and forms a condensed heterocyclic group together with a part of the adjacent ring B.
In L, the “fused ring” in “L may bind to R ² and form a condensed ring group together with a part of ring B”, that is, the condensed ring D is the “heterocyclic group” It means a monocyclic cyclic group, and specific examples include a cyclic group containing an oxygen atom, and a cyclic group containing an oxygen atom is preferred. The condensed heterocyclic group composed of the ring B adjacent to the condensed ring D means a condensed cyclic group in the “heterocyclic group”, specifically, the “condensed heteroaryl group” In addition, among the “partially hydrogenated condensed heteroaryl group”, a condensed cyclic group containing an oxygen atom, and the like are preferable, and a condensed cyclic group containing an oxygen atom is preferable. More specifically, for example, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like can be mentioned.
On ring B, L is a substituent adjacent to the bonding position of ring A-bicycloring-CO—. That is, in formula (I), the carbon atom or heteroatom on ring B to which ring A-bicycloring-CO— is bonded and the carbon atom or heteroatom on ring B to which L is bonded are adjacent to each other. .

[1-1] In the compound of the formula (I) of the embodiment [1], n is preferably 2.
[1-2] In the compound of the formula (I) of the embodiment [1], the ring A is preferably a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group is It may be substituted with 1 to 5 R ¹ .
The above R ¹ is preferably a halogen atom, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 7} alkanoyl group, C _{1 ~ 6} alkylthio group, -NR ^a R ^b group (wherein R ^a and R ^b represent a C _1-6 alkyl group, and R ^a and R ^b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded). The monocyclic non-aromatic heterocyclic group in R ^a and R ^b may be such that at least one carbon atom in the ring is substituted with an oxygen atom, a sulfur atom and a C _1-6 alkyl group. it may be replaced by atoms selected arbitrarily from a nitrogen atom which), a cyano group or an oxo group, more preferably a halogen atom, C _{1 ~ 4} alkyl group, C _{3 ~ 6} cycloalkyl group, C _{1 ~ 4} alkoxyl group, C _{2 ~ 5} alkanoyl group, C _{1 ~ 4} alkylthio A group, —NR ^a R ^b group (wherein R ^a and R ^b represent a C _1-4 alkyl group, and R ^a and R ^b together with the nitrogen atom to which they are attached are monocyclic non-aromatic heterocycles) A cyano group or an oxo group, more preferably a halogen atom, a C _1-2 alkyl group, a C _3-4 cycloalkyl group, a C _1-2 alkoxyl group, a C _2-3 alkanoyl. A group, C _1-2 alkylthio group, —NR ^a R ^b group (wherein R ^a and R ^b represent C _1-2 alkyl groups, and R ^a and R ^b are 5 together with the nitrogen atom to which they are bonded). A cyano group or an oxo group, which may form a 6-membered non-aromatic heterocyclic group), the alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R ¹ above. Are each substituted with 1 to 5 substituents RI May be.

[1-2-a] In the compound of the formula (I) of the embodiment [1], the ring A is more preferably the following partial structural formula (a1), (a2), (a3) or (a4):

(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9 to 10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A1 is composed of 1 to 2 halogen atoms. May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8- to 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A2 is composed of 1 to 2 halogen atoms. May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8- to 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, and the ring A3 is composed of 1 to 2 halogen atoms. May be replaced,
X ₁ represents a nitrogen atom, C—H or C—R ^1a ,
X ₂ represents a nitrogen atom, C—H or C—R ^1d , provided that when X ₁ is a nitrogen atom, X ₂ is C—H or C—R ^1d ,
R ^1a represents C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, a C _{2 ~ 7} alkanoyl group or a cyano group,
R ^1b and R ^1c each independently represents a hydrogen atom or a C _1-6 alkyl group,
R ^1d represents a halogen atom, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{1 ~ 6} alkylthio group, a -NR ^a R ^b group or an oxo group, provided that, When R ^1d is an oxo group, X ₁ is a nitrogen atom which may be substituted with a C _1-6 alkyl group,
R ^1e and R ^1f each independently represents a hydrogen atom or a C _1-6 alkyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R ^1a , R ^1b , R ^1c , R ^1d , R ^1e and R ^1f is each substituted with 1 to 5 substituents RI. May be included).

The ring A is preferably the partial structural formula (a1).
The ring A1 preferably contains one oxygen atom in the ring A1. The ring A1 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group together with the adjacent pyridine ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A1 with an adjacent pyridine ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing a pyridine ring, specifically, isoquinolin-1-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, furo [ 2,3-c] pyridin-7-yl, furo [3,2-c] pyridin-4-yl, 2,3-dihydrofuro [2,3-c] pyridin-7-yl, 2,3-dihydrofuro [ 3,2-c] pyridin-4-yl and the like, preferably, furo [2,3-c] pyridin-7-yl, furo [3,2-c] pyridin-4-yl, 2,3 -Dihydrofuro [2,3-c] pyridine-7- It is suitably a le or 2,3-dihydrofuro [3,2-c] pyridin-4-yl.
Said ring A2 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group with the adjacent pyrazole ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A2 with an adjacent pyrazole ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing a pyrazole ring, specifically, 1H-indazol-3-yl, 4,5,6,7-tetrahydro-1H-indazole-3 -Yl, 1H-pyrazolo [3,4-c] pyridin-3-yl, 1H-pyrazolo [4,3-c] pyridin-3-yl, 1H-pyrazolo [3,4-b] pyridin-3-yl 1H-pyrazolo [4,3-b] pyridin-3-yl, 6,7-dihydro-1H-pyrazolo [4,3-c] pyridin-3-yl, 6,7-dihydro-1H-pyrazolo [4 , 3-b] pyridin-3-yl Preferably, 1H-indazol-3-yl, 4,5,6,7-tetrahydro-1H-indazol-3-yl, 1H-pyrazolo [3,4-c] pyridin-3-yl, 1H-pyrazolo [4,3-c] pyridin-3-yl, 1H-pyrazolo [4,3-b] pyridin-3-yl is suitable.

The ring A3 preferably forms a 9-membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group with an adjacent imidazole ring. A condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group formed by ring A3 with an adjacent imidazole ring is the above-mentioned “condensed heteroaryl group” or “partially hydrogenated”. Examples of the “condensed heteroaryl group” include cyclic groups containing an imidazole ring, specifically, imidazo [1,5-a] pyridin-1-yl, imidazo [1,5-a] pyrimidine -8-yl, imidazo [1,5-a] pyrazin-1-yl, 5,6-dihydro-imidazo [1,5-a] pyrazin-1-yl, and the like, preferably imidazo [1, 5-a] pyrazin-1-yl is suitable.
X ₁ is preferably C—H or C—R ^1a , more preferably C—R ^1a .

Said R ^1a is preferably C _{1 ~ 4} alkyl group, C _{3 ~ 6} cycloalkyl group, C _{1 ~ 4} alkoxyl group, C _{2 ~ 5} alkanoyl group or a cyano group, more preferably C _{1 ~ 2} alkyl groups A C _3-4 cycloalkyl group, a C _1-2 alkoxyl group, a C _2-3 alkanoyl group or a cyano group, more preferably a C _1-2 alkyl group or a cyano group. Each of the alkyl group, cycloalkyl group, alkoxyl group or alkanoyl group in ^1a may be substituted with 1 to 5 substituents RI.
R ^1b and R ^1c are preferably a hydrogen atom or a C _1-4 alkyl group, and more preferably a hydrogen atom or a C _1-2 alkyl group. More preferably, R ^1b is a hydrogen atom, and R ^1c is a hydrogen atom or a C _1-2 alkyl group.
The R ^1d is preferably a halogen atom, C _{1 ~ 4} alkyl group, C _{3 ~ 6} cycloalkyl group, C _{1 ~ 4} alkoxyl group, C _{1 ~ 4} alkylthio group, with -NR ^a R ^b group (wherein the R ^a and R ^b represent a C _1-4 alkyl group, and R ^a and R ^b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bound) or an oxo group More preferably, a halogen atom, a C _1-2 alkyl group, a C _3-4 cycloalkyl group, a C _1-2 alkoxyl group, a C _1-2 alkylthio group, a —NR ^a R ^b group (wherein the R ^a and R ^b represents a C _1-2 alkyl group, and R ^a and R ^b together with the nitrogen atom to which they are attached may form a 5-6 membered non-aromatic heterocyclic group) or an oxo group, preferably suitably be a C _{1 ~ 2} alkoxy group, wherein in the above R ^1d Alkyl group, a cycloalkyl group, an alkoxyl group or alkylthio group, each of which may be substituted with 1 to 5 substituents RI.
However, when R ^1d is an oxo group, X ₁ is a nitrogen atom which may be substituted with a C _1-6 alkyl group, preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group. is there.
R ^1e and R ^1f are preferably a hydrogen atom or a C _1-4 alkyl group, more preferably a hydrogen atom or a C _1-2 alkyl group, and still more preferably a C _1-2 alkyl group. Is appropriate.
When X ₂ is a nitrogen atom, preferably X ₁ is C—R ^1a and R ^1c is other than a hydrogen atom.
When X ₂ is C—H or C—R ^1d , X ₁ is preferably C—R ^1a , and R ^1b and R ^1c are preferably hydrogen atoms.

[1-2-b] In the compound of the formula (I) of the embodiment [1], the ring A is more preferably the partial structural formula (a1), wherein X ₁ is C—R ^1a X ₂ is a nitrogen atom, C—H or C—R ^1d . Here, the R ^1d represents a halogen atom, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{1 ~ 6} alkylthio group or -NR ^a R ^b group. The definitions and preferred ranges of R ^1a , R ^1b and R ^1c when ring A is the partial structural formula (a1) are as described above in the above embodiment [1-2-a].
The R ^1d is preferably a halogen atom, C _{1 ~ 4} alkyl group, C _{3 ~ 6} cycloalkyl group, C _{1 ~ 4} alkoxyl group, C _{1 ~ 4} alkylthio or -NR ^a R ^b group (wherein the R ^a and R ^b represent a C _1-4 alkyl group, and R ^a and R ^b may form a monocyclic non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and more preferably Is a halogen atom, a C _1-2 alkyl group, a C _3-4 cycloalkyl group, a C _1-2 alkoxyl group, a C _1-2 alkylthio group, or a —NR ^a R ^b group (where R ^a and R ^b are A C _1-2 alkyl group, and R ^a and R ^b may form a 5- to 6-membered non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and more preferably C _1-2 Suitably it is an alkoxyl group. The alkyl group, cycloalkyl group, alkoxyl group, and alkylthio group in R ^1d above may each be substituted with 1 to 5 substituents RI.
If the X ₂ is a nitrogen atom, preferably it said R ^1c is other than a hydrogen atom, that is, C _{1 ~ 6} alkyl group, more preferably a C _{1 ~ 4} alkyl groups, more preferably C _{1 ~ 2} alkyl Suitably the group.
When X ₂ is C—H or C—R ^1d , R ^1b and R ^1c are preferably hydrogen atoms.

[1-2-c] In the compound of the formula (I) of the embodiment [1], the ring A is particularly preferably the partial structural formula (a1), wherein X ₁ is C—R ^1a X ₂ is a nitrogen atom, C—H or C—R ^1d , R ^1a represents a C _1-6 alkyl group or a cyano group, R ^1b represents a hydrogen atom, and R ^1c represents a hydrogen atom Or a C _1-6 alkyl group, R ^1d represents a C _1-6 alkoxyl group, and the alkyl group or alkoxyl group in R ^1a , R ^1b , R ^1c and R ^1d is 1-5 It may be substituted with a halogen atom.
R ^1a is preferably a C _1-4 alkyl group or a cyano group, and more preferably a C _1-2 alkyl group or a cyano group.
R ^1c is preferably a hydrogen atom or a C _1-4 alkyl group, and more preferably a hydrogen atom or a C _1-2 alkyl group.
R ^1d is preferably a C _1-4 alkoxyl group, more preferably a C _1-2 alkoxyl group.
If the X ₂ is a nitrogen atom, the R ^1a, R ^1c is preferably each independently C _{1 ~ 6} alkyl group, a C _{1 ~ 4} alkyl groups each independently more preferably, more preferably Suitably each is independently a C _1-2 alkyl group.
When X ₂ is C—H or C—R ^1d , preferably R ^1a is a halogenated C _1-6 alkyl group or a cyano group, more preferably R ^1a is a halogenated C _1-4 alkyl. R ^1a is preferably a halogenated C _1-2 alkyl group or a cyano group.
When X ₂ is C—H or C—R ^1d , R ^1c is suitably a hydrogen atom.

[1-3] In the compound of the formula (I) of the embodiment [1], the ring B preferably represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group in the ring B Alternatively, each heteroaryl group may be substituted with 1 to 4 R ² .
R ² is preferably a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a C _1-6 alkoxyl group, a halogenated C _1-6 alkoxyl group, a cyano group or a monocyclic heteroaryl. A group (the heteroaryl group may be substituted with one halogen atom), more preferably a halogen atom, a C _1-4 alkyl group, a halogenated C _1-4 alkyl group, a C _1-4 alkoxyl. A halogenated C _1-4 alkoxyl group, a cyano group or a 5- to 6-membered heteroaryl group (the heteroaryl group may be substituted with one halogen atom), more preferably a halogen atom, C _1-2 alkyl group, halogenated C _1-2 alkyl group, C _1-2 alkoxyl group, a halogenated C _1-2 alkoxy group, a cyano group or a 5-6 membered heteroaryl group (said heteroar- Lumpur groups are optionally substituted with one halogen atom), especially preferably a halogen atom, C _{1 ~ 2} alkyl group, a halogenated C _{1 ~ 2} alkyl group, C _{1 ~ 2} alkoxy group or cyano It is appropriate that there is a group.

[1-3-a] In the compound of the formula (I) of the embodiment [1], the ring B more preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group in the ring B or Each heteroaryl group may be substituted with one R ² .
The definition and preferred range of R ² are as described above in the above embodiment [1-3].
[1-3-b] In the compound of the formula (I) of the embodiment [1], the ring B is more preferably the following partial structural formula (b1) or (b2):

(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R ^2b ,
R ^2a represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom And
R ^2b represents a halogen atom,
R ^2c represents a hydrogen atom, a C _1-6 alkyl group or a cyano group,
The alkyl group and alkoxyl group in R ^2a and R ^2c may each be substituted with 1 to 5 substituents RI,
1 to 6 represent positions in the ring).
The monocyclic heteroaryl group in R ^2a is preferably located in the para position with respect to the bonding position of L, that is, in the formula (b1), the position of Y in the ring is the first position and the bonding of L If the position is 2nd, it is appropriate to be 5th.
R ^2a is preferably a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a halogenated C _1-4 alkyl group, a C _1-4 alkoxyl group, a halogenated C _1-4 alkoxyl group, or a 5- to 6-membered hetero group. An aryl group, more preferably a hydrogen atom, a halogen atom, a C _1-2 alkyl group, a C _1-2 alkoxyl group or a 5- to 6-membered heteroaryl group, and still more preferably a hydrogen atom or a halogen atom. Is appropriate.
R ^2c is preferably a hydrogen atom, a C _1-4 alkyl group, a halogenated C _1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C _1-2 alkyl group, a halogenated C _1-2 Suitably an alkyl group or a cyano group.

[1-3-c] In the compound of the formula (I) of the embodiment [1], the ring B is particularly preferably the partial structural formula (b1) or (b2), where Y is nitrogen. Represents an atom, C—H or C—R ^2b , R ^2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom and R ^2b is a halogen atom R ^2c represents a hydrogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or a cyano group.
R ^2c is preferably a hydrogen atom, a C _1-4 alkyl group, a halogenated C _1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C _1-2 alkyl group, a halogenated C _1-2 Suitably an alkyl group or a cyano group.

[1-4] In the compound of formula (I) of the embodiment [1], L is preferably, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxyl group, a halogenated C _{1 ~ 6} alkoxy group, Represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in L may each be substituted with 1 to 5 R ³ , or L and R ^{When 2} is a substituent adjacent to each other on ring B, L may be bonded to R ² to form a condensed ring group together with part of ring B. That is, as shown in the following partial structural formula, when L and R ² are adjacent to each other on the ring B (ortho position), L, R ² and ring B (part) are bonded together and condensed. Ring D ′ may be formed.

The formed condensed ring D ′ forms a condensed cyclic group together with a part of the adjacent ring B.
Here, the condensed ring D ′ is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom, and a condensed heterocyclic group together with a part of the adjacent ring B Form. The definition and preferred range of the condensed heterocyclic group consisting of the condensed ring D ′ and the ring B are as described above in the embodiment [1].
R ³ is preferably a halogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, a C _1-6 alkoxyl group, a halogenated C _1-6 alkoxyl group or a cyano group, more preferably A halogen atom, a C _1-4 alkyl group, a halogenated C _1-4 alkyl group, a C _1-4 alkoxyl group, a halogenated C _1-4 alkoxyl group or a cyano group, more preferably a halogen atom, C _1-2 An alkyl group, a halogenated C _1-2 alkyl group, a C _1-2 alkoxyl group, a halogenated C _1-2 alkoxyl group or a cyano group, particularly preferably a halogen atom, a C _1-2 alkyl group or a cyano group It is appropriate to be.

[1-4-a] In the compound of the formula (I) of the embodiment [1], L preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or heteroaryl in L Each group may be substituted with one R ³ .
The definition and preferred range of R ³ are as described above in the above embodiment [1-4].

[1-4-b] In the compound of the formula (I) of the embodiment [1], L preferably represents a phenyl group or a 5- to 6-membered heteroaryl group, and the phenyl group or heteroaryl in L Each group may be substituted with one R ³ , where R ³ represents a C _1-6 alkyl group, a C _1-6 alkoxyl group or a cyano group, wherein R ³ The alkyl group or alkoxyl group may each be substituted with 1 to 5 substituents RI.
R ³ is preferably a C _1-4 alkyl group, a C _1-4 alkoxyl group or a cyano group, more preferably a C _1-2 alkyl group, a C _1-2 alkoxyl group or a cyano group, still more preferably. Is suitably a C _1-2 alkyl group or a cyano group.

[1-4-c] In the compound of the formula (I) of the embodiment [1], L is particularly preferably the following partial structural formula (c1), (c2) or (c3):

(In the formula (c1), (c2) or (c3),
Z ₁ , Z ₂ , and Z ₃ each independently represent a nitrogen atom or C—H, provided that when Z ₂ is C—H, Z ₁ is C—H;
Z ₄ represents an oxygen atom or a sulfur atom,
R ^3a , R ^3b and R ^3c each independently represents a hydrogen atom, a C _1-6 alkyl group or a cyano group.
Z ₄ is preferably a sulfur atom.
R ^3a , R ^3b and R ^3c are each independently preferably a hydrogen atom, a C _1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C _1-2 alkyl group or a cyano group, More preferably, it is a hydrogen atom.

[1-5] In the compound of the formula (I) of the embodiment [1], R ^a and R ^b are preferably each independently a C _1-6 alkyl group, and R ^a and R ^b are A monocyclic non-aromatic heterocyclic group may be formed together with a nitrogen atom to which they are bonded, and the monocyclic non-aromatic heterocyclic group in R ^a and R ^b is at least one of carbon atoms in the ring. May be replaced with an atom arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom which may be substituted with a C _1-6 alkyl group.
R ^a and R ^b more preferably each independently represent a C _1-4 alkyl group, and R ^a and R ^b together with the nitrogen atom to which they are attached form a monocyclic non-aromatic heterocyclic group More preferably, each independently represents a C _1-2 alkyl group, and R ^a and R ^b together with the nitrogen atom to which they are attached form a 5-6 membered non-aromatic heterocyclic group. Also good.
[1-6] In the compound of the formula (I) of the embodiment [1], the substituents RI are preferably each independently a halogen atom.

[2] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt thereof or a solvate thereof, a preferred embodiment is represented by the formula (I):
Ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in Ring A may each be substituted with 1 to 5 R ¹ ;
Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R ² ;
L is, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxyl group, a halogenated C _{1 ~ 6} alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L Each heteroaryl group may be substituted with 1 to 5 R ³ , or when L and R ² are substituents adjacent to each other on ring B, L is bonded to R ^2. A condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), the definition and preferred range of ring A, ring B, L, R ¹ , R ² , R ³ , R ^a , R ^b and substituent RI are as described in the above embodiments [1-2] to As described above in [1-6].

[2-1] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt or solvate thereof, another preferred embodiment is represented by the following formula (I) -1 :

(In the formula (I) -1, the definitions of n, R ¹ , R ² , R ³ , R ^a , R ^b and the substituent RI are the same as those defined in the above embodiment [1];
Ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in Ring A may each be substituted with 1 to 5 R ¹ ;
Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R ² ;
L is, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxyl group, a halogenated C _{1 ~ 6} alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L Each heteroaryl group may be substituted with 1 to 5 R ³ , or when L and R ² are substituents adjacent to each other on ring B, L is bonded to R ^2. A condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom, L on B is a substituent adjacent to the bonding position of ring A-bicycloring-CO-).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I) -1, n is preferably 2.
In the compound of the formula (I) -1, the definition and preferred range of the ring A, ring B, L, R ¹ , R ² , R ³ , R ^a , R ^b and the substituent RI are as defined in the above embodiment [1-2 ] To [1-6] as described above.

[3] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt or solvate thereof, a more preferred embodiment is that in the formula (I), the ring A is The following partial structural formula (a1), (a2), (a3) or (a4):

(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A3 is composed of 1 to 2 halogen atoms May be replaced,
X ₁ represents a nitrogen atom, C—H or C—R ^1a ,
X ₂ represents a nitrogen atom, C—H or C—R ^1d , provided that when X ₁ is a nitrogen atom, X ₂ is C—H or C—R ^1d ,
R ^1a represents C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, a C _{2 ~ 7} alkanoyl group or a cyano group,
R ^1b and R ^1c each independently represents a hydrogen atom or a C _1-6 alkyl group,
R ^1d represents a halogen atom, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{1 ~ 6} alkylthio group, a -NR ^a R ^b group or an oxo group, provided that, When R ^1d is an oxo group, X ₁ is a nitrogen atom which may be substituted with a C _1-6 alkyl group,
R ^1e and R ^1f each independently represents a hydrogen atom or a C _1-6 alkyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R ^1a , R ^1b , R ^1c , R ^1d , R ^1e and R ^1f is each substituted with 1 to 5 substituents RI. May represent)
Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R ² ,
L represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in L may be substituted with one R ³ .
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compounds of the formula (I), ring A, ring A1, ring A2, ring A3, X _1, X _2, ring ^{B, L, R 1, R} 1a, R 1b, R 1c, R 1d, R 1e, The definitions and preferred ranges of R ^1f , R ² , R ³ , R ^a , R ^b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].

[3-1] In the compound of the above formula (I) of the above embodiment [1], or a pharmaceutically acceptable salt thereof or a solvate thereof, another more preferable embodiment is represented by the following formula (II):

(In the formula (II), the definitions of n, R ² , R ³ , R ^a and R ^b are the same as defined in the above embodiment [1];
Ring A has the following partial structural formula (a1), (a2), (a3) or (a4):

(In the formula (a1), (a2), (a3) or (a4),
Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced,
Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced,
Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A3 is composed of 1 to 2 halogen atoms May be replaced,
X ₁ represents a nitrogen atom, C—H or C—R ^1a ,
X ₂ represents a nitrogen atom, C—H or C—R ^1d , provided that when X ₁ is a nitrogen atom, X ₂ is C—H or C—R ^1d ,
R ^1a represents C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, a C _{2 ~ 7} alkanoyl group or a cyano group, further R ^1a is preferably C _{1 ~ 4} alkyl group, C _{3 ~ 6} cycloalkyl group, C _{1 ~ 4} alkoxyl group, a C _{2 ~ 5} alkanoyl group or a cyano group, more preferably C _{1 ~ 2} alkyl group, C _{3 ~ 4} cycloalkyl group, C _{1 ~ A 2} alkoxyl group, a C _2-3 alkanoyl group or a cyano group, more preferably a C _1-2 alkyl group or a cyano group,
R ^1b and R ^1c each independently represents a hydrogen atom or a C _1-6 alkyl group, and R ^1b and R ^1c are preferably a hydrogen atom or a C _1-4 alkyl group, more preferably a hydrogen atom. Or a C _1-2 alkyl group, more preferably R ^1b is a hydrogen atom, R ^1c is a hydrogen atom or a C _1-2 alkyl group,
R ^1d represents a halogen atom, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{1 ~ 6} alkylthio group, a -NR ^a R ^b group or an oxo group, further R ^1d is preferably a halogen atom, C _{1 ~ 4} alkyl group, C _{3 ~ 6} cycloalkyl group, C _{1 ~ 4} alkoxyl group, C _{1 ~ 4} alkylthio group, -NR ^a R ^b group or an oxo group, more Preferred are a halogen atom, a C _1-2 alkyl group, a C _3-4 cycloalkyl group, a C _1-2 alkoxyl group, a C _1-2 alkylthio group, a —NR ^a R ^b group or an oxo group, and more preferred is C _{1 to 2} alkoxyl group, provided that when R ^1d is an oxo group, X ₁ is a nitrogen atom which may be substituted with a C _1-6 alkyl group;
R ^1e and R ^1f each independently represents a hydrogen atom or a C _1-6 alkyl group, and R ^1e and R ^1f are each independently preferably a C _1-4 alkyl group, more preferably C 1 _{1 to 2} alkyl groups,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R ^1a , R ^1b , R ^1c , R ^1d , R ^1e and R ^1f is each substituted with 1 to 5 substituents RI. May represent)
Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R ² ,
Ring C represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring C may be substituted with one R ³ ,
On ring B, ring C is a substituent adjacent to the bonding position of ring A-bicycloring-CO—.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (II), n is preferably 2.
In the compounds of above-mentioned formula (II), ring A, ring A1, ring A2, ring A3, X _1, X _2, ring ^{B, R 1, R 1a,} R 1b, R 1c, R 1d, R 1e, R 1f , R ² , R ³ , R ^a , R ^b and the substituent RI are as defined above and in the preferred embodiments [1-2] to [1-6].

[4] In the compound of the above formula (I) of the above embodiment [3], or a pharmaceutically acceptable salt or solvate thereof, a further preferred embodiment is that in the formula (I), the ring A is In the partial structural formula (a1), X ₁ is C—R ^1a , X ₂ is a nitrogen atom, C—H or C—R ^1d , R ^1d is a halogen atom, C _1-6 alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{1 ~ 6} alkylthio group or -NR ^a R ^b group;
Ring B has the following partial structural formula (b1) or (b2):

(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R ^2b ,
R ^2a represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom And
R ^2b represents a halogen atom,
R ^2c represents a hydrogen atom, a C _1-6 alkyl group or a cyano group,
Each of the alkyl group and alkoxyl group in R ^2a and R ^2c may be substituted with 1 to 5 substituents RI;
R ³ represents a C _1-6 alkyl group, a C _1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R ³ is each substituted with 1 to 5 substituents RI. May be;
R ^a and R ^b each independently represent a C _1-6 alkyl group, R ^a and R ^b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group; The monocyclic non-aromatic heterocyclic group for R ^a and R ^b is a nitrogen in which at least one of the carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C _1-6 alkyl group It may be replaced with an atom arbitrarily selected from atoms,
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), ring A, X ₁ , X ₂ , ring B, Y, L, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ^2a , R ^2b , R The definitions and preferred ranges of ^2c , R ³ , R ^a , R ^b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].

[4-1] The compound of the formula (I) of the embodiment [3] or the compound of the formula (II) of the embodiment [3-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof In the product, another preferred embodiment is the following formula (III):

(In formula (III), the definitions of n, R ³ , R ^a and R ^b are the same as those in the above embodiment [1], and the definition of ring C is the same as the definition of formula (II) above;
X is a nitrogen atom, C—H or C—R ^1d ,
R ^1a represents C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, a C _{2 ~ 7} alkanoyl group or a cyano group, further R ^1a is preferably C _{1 ~ 4} alkyl group, C _{3 ~ 6} cycloalkyl group, C _{1 ~ 4} alkoxyl group, a C _{2 ~ 5} alkanoyl group or a cyano group, more preferably C _{1 ~ 2} alkyl group, C _{3 ~ 4} cycloalkyl group, C _{1 ~ A 2} alkoxyl group, a C _2-3 alkanoyl group or a cyano group, more preferably a C _1-2 alkyl group or a cyano group,
R ^1b and R ^1c each independently represents a hydrogen atom or a C _1-6 alkyl group, and R ^1b and R ^1c are preferably a hydrogen atom or a C _1-4 alkyl group, more preferably a hydrogen atom. Or a C _1-2 alkyl group, more preferably R ^1b is a hydrogen atom, R ^1c is a hydrogen atom or a C _1-2 alkyl group,
R ^1d represents a halogen atom, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, a C _{1 ~ 6} alkylthio group or -NR ^a R ^b group, further R ^1d is preferably a halogen atom, C _{1 ~ 4} alkyl group, C _{3 ~ 6} cycloalkyl group, C _{1 ~ 4} alkoxyl group, C _{1 ~ 4} alkylthio group or -NR ^a R ^b group, more preferably a halogen atom, C _{A 1-2} alkyl group, a C _3-4 cycloalkyl group, a C _1-2 alkoxyl group, a C _1-2 alkylthio group, or a —NR ^a R ^b group, more preferably a C _1-2 alkoxyl group,
The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R ^1a , R ^1b , R ^1c and R ^1d may each be substituted with 1 to 5 substituents RI;
Ring B has the following partial structural formula (b1) or (b2):

(In the formula (b1) or (b2),
Y represents a nitrogen atom, C—H or C—R ^2b ,
R ^2a represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxyl group or a monocyclic heteroaryl group, and the monocyclic heteroaryl group in R ^2a is preferably a phenyl group Or a 5- to 6-membered heteroaryl group is suitably located in the para position of ring C, and R ^2a is preferably a hydrogen atom, a halogen atom, a C _1-4 alkyl group, or a C _1-4 alkoxyl group. Or a 5- or 6-membered heteroaryl group, more preferably a hydrogen atom, a halogen atom, a C _1-2 alkyl group, a C _1-2 alkoxyl group or a 5- or 6-membered heteroaryl group, and more preferably a hydrogen atom. Is suitably an atom or a halogen atom, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom;
R ^2b represents a halogen atom,
R ^2c represents a hydrogen atom, a C _1-6 alkyl group or a cyano group, and R ^2c is preferably a hydrogen atom, a C _1-4 alkyl group or a cyano group, more preferably a hydrogen atom, C _{1- 2} is suitably an alkyl group or a cyano group,
Each of the alkyl group and alkoxyl group in R ^2a and R ^2c may be substituted with 1 to 5 substituents RI;
R ³ represents a C _1-6 alkyl group, a C _1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R ³ is each substituted with 1 to 5 substituents RI. R ³ is preferably a C _1-4 alkyl group, a C _1-4 alkoxyl group or a cyano group, more preferably a C _1-2 alkyl group, a C _1-2 alkoxyl group or a cyano group. More preferably a C _1-2 alkyl group or a cyano group;
R ^a and R ^b each independently represent a C _1-6 alkyl group, R ^a and R ^b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group; The monocyclic non-aromatic heterocyclic group for R ^a and R ^b is a nitrogen in which at least one of the carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C _1-6 alkyl group R ^a and R ^b may be optionally substituted with atoms arbitrarily selected from atoms, and more preferably each independently represents a C _1-4 alkyl group, and R ^a and R ^b are bonded to each other. May form a monocyclic non-aromatic heterocyclic group with the nitrogen atom
The substituents RI each independently represent a halogen atom or a hydroxyl group, preferably a halogen atom.
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (III), n is preferably 2.
In the compound of the above formula (III), ring B, Y, R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ^2a , R ^2b , R ^2c , R ³ , R ^a , R ^b and The definition and preferred range of the substituent RI are as described above in the above embodiments [1-2] to [1-6].

[5] In the compound of the above formula (I) of the above embodiment [4], or a pharmaceutically acceptable salt thereof or a solvate thereof, a particularly preferred embodiment is represented by the formula (I):
R ^1a represents a C _1-6 alkyl group or a cyano group, R ^1b represents a hydrogen atom, R ^1c represents a hydrogen atom or a C _1-6 alkyl group, and R ^1d represents a C _1-6 alkoxyl. Each of the alkyl group or alkoxyl group in R ^1a , R ^1b , R ^1c and R ^1d may be substituted with 1 to 5 halogen atoms,
R ^2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom, and R ^2c is preferably a hydrogen atom, a C _1-4 alkyl group, a halogenated group. A C _1-4 alkyl group or a cyano group, more preferably a hydrogen atom, a C _1-2 alkyl group, a halogenated C _1-2 alkyl group or a cyano group,
L is the following partial structural formula (c1), (c2) or (c3):

(In the formula (c1), (c2) or (c3),
Z ₁ , Z ₂ , and Z ₃ each independently represent a nitrogen atom or C—H, provided that when Z ₂ is C—H, Z ₁ is C—H;
Z ₄ represents an oxygen atom or a sulfur atom,
R ^3a , R ^3b and R ^3c each independently represents a hydrogen atom, a C _1-6 alkyl group or a cyano group)
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (I), more preferably, n is 2.
In the compound of the above formula (I), ring A, X ₁ , X ₂ , ring B, Y, L, Z ₁ , Z ₂ , Z ₃ , Z ₄ , R ¹ , R ^1a , R ^1b , R ^1c , R Definitions and preferred ranges of ^1d , R ² , R ^2a , R ^2b , R ^2c , R ³ , R ^3a , R ^3b , R ^3c , R ^a , R ^b and the substituent RI are the above-mentioned embodiments [1-2] to As described above in [1-6].

[5-1] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof In the product, another particularly preferred embodiment is represented by the following formula (III) -1:

(In formula (III) -1, the definitions of n and X are the same as those in formula (III) above,
R ^1a represents a C _1-6 alkyl group or a cyano group, and R ^1a is preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group, and R ^1b represents a hydrogen atom R ^1c represents a hydrogen atom or a C _1-6 alkyl group, and R ^1c is preferably a hydrogen atom or a C _1-4 alkyl group, more preferably a hydrogen atom or a C _1-2 alkyl group. R ^1d represents a C _1-6 alkoxyl group, and R ^1d is preferably a C _1-4 alkoxyl group, more preferably a C _1-2 alkoxyl group, and R ^1a , R ^1b , Each of the alkyl group or alkoxyl group in R ^1c and R ^1d may be substituted with 1 to 5 halogen atoms,
Ring B has the following partial structural formula (b1) -1 or (b2) -1:

(In the formula (b1) -1 or (b2) -1,
Y represents a nitrogen atom, C—H or C—R ^2b ,
R ^2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom;
R ^2b represents a halogen atom,
R ^2c represents a hydrogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a cyano group,
Ring C has the following partial structural formula (c1), (c2) or (c3):

(In the formula (c1), (c2) or (c3),
Z ₁ , Z ₂ , and Z ₃ each independently represent a nitrogen atom or C—H, provided that when Z ₂ is C—H, Z ₁ is C—H;
Z ₄ represents an oxygen atom or a sulfur atom,
R ^3a , R ^3b and R ^3c each independently represents a hydrogen atom, a C _1-6 alkyl group or a cyano group, and R ^3a , R ^3b and R ^3c are each independently preferably a hydrogen atom or C _{1 to 4} alkyl group, more preferably a hydrogen atom or C _1-2 alkyl group, and still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (III) -1, n is preferably 2.
In the compound of the above formula (III) -1, rings B, Y, Z ₁ , Z ₂ , Z ₃ , Z ₄ , R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ^2a , R The definitions and preferred ranges of ^2b , R ^2c , R ³ , R ^3a , R ^3b , R ^3c , R ^a , R ^b and the substituent RI are as described above in the above embodiments [1-2] to [1-6]. It is.

[5-1-a] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a salt thereof In the solvate, another particularly preferable embodiment is the following formula (IV):

(In formula (IV), the definition of n and X is the same as the definition of said formula (III),
R ^1a represents a C _1-6 alkyl group or a cyano group, and R ^1a is preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group, and R ^1b represents a hydrogen atom R ^1c represents a hydrogen atom or a C _1-6 alkyl group, and R ^1c is preferably a hydrogen atom or a C _1-4 alkyl group, more preferably a hydrogen atom or a C _1-2 alkyl group. R ^1d represents a C _1-6 alkoxyl group, and R ^1d is preferably a C _1-4 alkoxyl group, more preferably a C _1-2 alkoxyl group, and R ^1a , R ^1b , Each of the alkyl group or alkoxyl group in R ^1c and R ^1d may be substituted with 1 to 5 halogen atoms,
Y represents a nitrogen atom, C—H or C—R ^2b ,
R ^2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom;
R ^2b represents a halogen atom,
Ring C has the following partial structural formula (c1), (c2) or (c3):

(In the formula (c1), (c2) or (c3),
Z ₁ , Z ₂ , and Z ₃ each independently represent a nitrogen atom or C—H, provided that when Z ₂ is C—H, Z ₁ is C—H;
Z ₄ represents an oxygen atom or a sulfur atom,
R ^3a , R ^3b and R ^3c each independently represents a hydrogen atom, a C _1-6 alkyl group or a cyano group, and R ^3a , R ^3b and R ^3c are each independently preferably a hydrogen atom or C _{1 to 4} alkyl group, more preferably a hydrogen atom or C _1-2 alkyl group, and still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (IV), n is preferably 2.
In the compound of the above formula (IV), Y, Z ₁ , Z ₂ , Z ₃ , Z ₄ , R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ^2a , R ^2b , R ³ , The definitions and preferred ranges of R ^3a , R ^3b , R ^3c , R ^a , R ^b and the substituent RI are as described above in the above embodiments [1-2] to [1-6].

[5-1-b] The compound of the formula (I) of the embodiment [4], the compound of the formula (III) of the embodiment [4-1], or a pharmaceutically acceptable salt thereof, or a compound thereof In the solvate, another particularly preferable embodiment is represented by the following formula (V):

(In formula (V), the definitions of n and X are the same as the definitions of formula (III) above,
R ^1a represents a C _1-6 alkyl group or a cyano group, and R ^1a is preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group, and R ^1b represents a hydrogen atom R ^1c represents a hydrogen atom or a C _1-6 alkyl group, and R ^1c is preferably a hydrogen atom or a C _1-4 alkyl group, more preferably a hydrogen atom or a C _1-2 alkyl group. R ^1d represents a C _1-6 alkoxyl group, and R ^1d is preferably a C _1-4 alkoxyl group, more preferably a C _1-2 alkoxyl group, and R ^1a , R ^1b , Each of the alkyl group or alkoxyl group in R ^1c and R ^1d may be substituted with 1 to 5 halogen atoms,
R ^2c represents a hydrogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a cyano group, and R ^2c is preferably a hydrogen atom, a C _1-4 alkyl group, a halogenated C _{1- 4} alkyl group or cyano group, more preferably a hydrogen atom, C _1-2 alkyl group, halogenated C _1-2 alkyl group or cyano group,
Ring C has the following partial structural formula (c1) or (c3):

(In the formula (c1) or (c3),
Z ₁ and Z ₂ each independently represents a nitrogen atom or C—H, provided that when Z ₂ is C—H, Z ₁ is C—H;
Z ₄ represents an oxygen atom or a sulfur atom,
R ^3a and R ^3c each independently represent a hydrogen atom, a C _1-6 alkyl group or a cyano group, and R ^3a and R ^3c each independently preferably represent a hydrogen atom or a C _1-4 alkyl group. More preferably a hydrogen atom or a C _1-2 alkyl group, still more preferably a hydrogen atom).
A compound, or a pharmaceutically acceptable salt or solvate thereof.
In the compound of the above formula (V), n is preferably 2.
In the compound of the above formula (V), Z ₁ , Z ₂ , Z ₄ , R ¹ , R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ^2c , R ³ , R ^3a , R ^3c , R ^a , R ^b and the substituent RI are as defined above and in the preferred embodiments [1-2] to [1-6].

As described above, each of the embodiments [1] to [5] of the present invention and preferred embodiments thereof, and further by appropriately combining the definitions of substituents, the compound represented by the formula (I) of the embodiment [1] The preferred embodiments can be arbitrarily formed.
In the above-mentioned embodiments [1] to [5] and sub-embodiments thereof, more preferred substituents in the above formula (I) or a combination thereof are in accordance with the explanation described in the first embodiment.

[6] The sixth aspect of the present invention is the compound of the formula (I) of the aspect [1], wherein the preferred compounds are the compounds listed below, or pharmaceutically acceptable salts thereof, or those: Solvates thereof, or optical isomers thereof. The names of the compounds shown below are based on English names obtained according to the compound name naming program of ChemBioDraw (registered trademark) Ultra 14 (CambridgeSoft).

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 1);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1,2,4-oxadi Azol-5-yl) phenyl) methanone (Example 2);
(2- (1H-pyrazol-1-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 3);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrimidin-2-yl) phenyl) methanone (Examples) 4);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (trifluoromethoxy) phenyl) methanone (Example 5) ;

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-phenoxyphenyl) methanone (Example 6);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (6-methoxy-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 7);
(3- (2H-1,2,3-triazol-2-yl) pyridin-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 8);
(3- (1H-pyrazol-1-yl) pyridazin-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 9);
(4-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 10);

2- (3- (4-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 11);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrimidin-2-yl) Phenyl) methanone (Example 12);
3-methoxy-2- (3- (2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 13);
2- (3- (3- (2H-1,2,3-triazol-2-yl) isonicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 14);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (pyrimidin-2-yl) phenyl) Methanone (Example 15);

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (1H-1,2,3- Triazol-1-yl) phenyl) methanone (Example 16);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methyl-2- (pyrimidin-2-yl) phenyl) Methanone (Example 17);
(2,2-difluorobenzo [d] [1,3] dioxol-4-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 18);
(2-cyclopropylphenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 19);
(2,6-diethoxyphenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 20);

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2-phenylfuran-3-yl) methanone ( Example 21);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-methyl-4-phenylthiazol-5-yl) methanone ( Example 22);
(2-Cyclopropyl-4-phenylthiazol-5-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 23);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3-methyl-1-phenyl-1H-pyrazol-5-yl ) Methanone (Example 24);
3- (5- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -3-methyl-1H-pyrazole-1- Yl) benzonitrile (Example 25);

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (pyridin-2-yl) -1H-pyrazol-5 -Yl) methanone (Example 26);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (pyridin-2-yl) -3- (trifluoro Methyl) -1H-pyrazol-5-yl) methanone (Example 27);
5- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -1- (pyridin-2-yl) -1H-pyrazole -3-carbonitrile (Example 28);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (pyridin-2-yl) -1H -Pyrazol-4-yl) methanone (Example 29);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 30);

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1-methyl-1H-pyrazol-3-yl) Pyridin-3-yl) methanone (Example 31);
[2,2′-bipyridin] -3-yl (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Examples) 32);
(5 ″ -chloro- [2,2 ′: 5 ′, 3 ″ -terpyridin] -3′-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [ 3.2.1] octane-3-yl) methanone (Example 33);
2- (3- (1- (Pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Examples) 34);
3-methoxy-2- (3- (1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 35);

(3-Methyl-1- (pyridin-2-yl) -1H-pyrazol-5-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 36);
(8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octan-3-yl) (3-methyl-1- (pyridine- 2-yl) -1H-pyrazol-5-yl) methanone (Example 37);
2- (3- (3-Methyl-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 38);
3-Methoxy-2- (3- (3-methyl-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl ) Isonicotinonitrile (Example 39);
3-methoxy-2- (3- (1- (pyridin-2-yl) -3- (trifluoromethyl) -1H-pyrazole-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane -8-yl) isonicotinonitrile (Example 40);

1- (Pyridin-2-yl) -5- (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) -1H -Pyrazole-3-carbonitrile (Example 41);
2- (3- (3-Cyano-1- (pyridin-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- Methoxyisonicotinonitrile (Example 42);
3-methoxy-2- (3- (1- (pyridazin-3-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 43);
(8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (pyridine- 2-yl) -1H-pyrazol-4-yl) methanone (Example 44);
2- (3- (2,6-diethoxybenzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 45);

(2-Fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 46);
2- (3- (2-Fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 47);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (Example 48) );
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Example 49) );
2- (3- (2- (1- (1, H-1,2,3-triazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 50);

[2,2′-bipyridin] -3-yl (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 51);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl-2,2,4,4-d4) (1- (pyridine- 2-yl) -1H-pyrazol-5-yl) methanone (Example 52);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl-2,2,4,4-d4) methanone (Example 53);
(2-Methyl-4-phenylthiazol-5-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) Methanone (Example 54);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1-methyl-3- (thiazol-2-yl) -1H -Pyrazol-4-yl) methanone (Example 55);

(3-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 56);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 57);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 58);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 59);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 60);

(2-Chloro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 61);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methyl-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 62);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-methoxy-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 63);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 64);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-fluoro-2- (pyrimidin-2-yl) phenyl) Methanone (Example 65);

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) pyridin-3-yl) Methanone (Example 66);
(2- (1H-1,2,3-triazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 67);
(2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 68);
(2-Methoxy-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 69);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile Example 70);

2- (3- (2-Methoxy-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicoti Nononitrile (Example 71);
2- (3- (3-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 72);
3-Methoxy-2- (3- (2-methoxy-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) isonicotinonitrile (Example 73);
2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 74);
2- (3- (2- (thiazol-2-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 75);

(2- (2H-tetrazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 76);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 77);
[1,1′-biphenyl] -2-yl (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Examples) 78);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 79);
(4-Chloro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 80);

(4-Methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8- Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 81);
2- (3- (4-Chloro-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3 -Methoxyisonicotinonitrile (Example 82);
3-methoxy-2- (3- (4-methoxy-2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) isonicotinonitrile (Example 83);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 84);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 85);

2- (3- (2- (1- (1-H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 86);
2- (3-([2,2′-bipyridine] -3-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 87) );
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1,1,2,2-tetrafluoroethoxy) Phenyl) methanone (Example 88);
2- (3- (2- (1,1,2,2-tetrafluoroethoxy) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 89) );
3-methoxy-2- (3- (4-methoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 90);

2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 91) );
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 92);
(2- (thiazol-2-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone (Example 93);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) Pyridin-3-yl) methanone (Example 94);
3-methoxy-2- (3- (2- (2- (thiazol-2-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Example 95);

(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 96);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 97);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-ethoxy-2- (1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 98);
2- (3- (4-Ethoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Example 99);
(4-Ethoxy-2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2. 1] Octane-3-yl) methanone (Example 100);

(4-Chloro-2- (pyrimidin-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) Methanone (Example 101);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-fluoro-3- (pyrimidin-2-yl) pyridine- 2-yl) methanone (Example 102);
(5-Fluoro-3- (pyrimidin-2-yl) pyridin-2-yl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 103);
2- (3- (5-Fluoro-3- (pyrimidin-2-yl) picolinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile Example 104);
(4-Fluoro-2- (pyrimidin-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 105);

2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile Example 106);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl) -1H-pyrazol-5 -Yl) methanone (Example 107);
3-methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazol-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Nitrile (Example 108);
(8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl) -1H-pyrazol-5-yl) methanone (Example 109);
(8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Example 110);

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (oxazol-2-yl) phenyl) methanone (Examples) 111);
(2- (1H-pyrazol-3-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 112);
(2- (1H-pyrazol-4-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone ( Example 113);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4′-fluoro- [1,1′-biphenyl] -2 -Yl) methanone (Example 114);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (3′-methoxy- [1,1′-biphenyl] -2 -Yl) methanone (Example 115);

(3 ′-(Difluoromethoxy)-[1,1′-biphenyl] -2-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 116);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (isothiazol-4-yl) phenyl) methanone Example 117);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methylisothiazol-5-yl) phenyl) Methanone (Example 118);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-4-yl) phenyl) methanone (Examples) 119);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-5-yl) phenyl) methanone (Examples) 120);

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (thiazol-2-yl) phenyl) methanone (Examples) 121);
2- (2- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) phenyl) thiazole-4-carbonitrile (Examples) 122);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyridin-2-yl) phenyl) methanone (Examples) 123);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (6-methylpyridin-2-yl) phenyl) methanone (Example 124);
6- (2- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) phenyl) picolinonitrile (Example 125);

(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (6-methoxypyridin-2-yl) phenyl) methanone (Example 126);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 127);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 128);
(8- (4,5-Dimethylthiazol-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 129);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -6-methylisonicoti Nononitrile (Example 130);

(8- (3,5-Dimethylphenyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3-triazole-2- Yl) phenyl) methanone (Example 131);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (difluoromethoxy) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 132);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 133);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 134);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] ] Octane-3-yl) methanone (Example 135);

(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (furo [2,3-c] pyridin-7-yl) -3,8-diazabicyclo [3.2.1] ] Octane-3-yl) methanone (Example 136);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 137);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 138);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2.1] octane-3 -Yl) methanone (Example 139);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [4,3-b] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 140);

(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [4,3-c] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 141);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-1H-pyrazolo [3,4-c] pyridin-3-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 142);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (1-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl) -3,8 -Diazabicyclo [3.2.1] octane-3-yl) methanone (Example 143);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methylimidazo [1,5-a] pyrazin-1-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 144);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (6-fluoro-1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 145);

(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (5-fluoro-1-methyl-1H-indazol-3-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 146);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicoti Nononitrile (Example 147);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methylisonicoti Nononitrile (Example 148);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-ethoxyisonicoti Nononitrile (Example 149);
2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methoxy- d3) Isonicotinonitrile (Example 150);

(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (2,2,2-trifluoro-1-hydroxyethyl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 151);
2- (3- (2- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinate methyl Example 152);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methoxy-d3) isonicotinonitrile (Example 153);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-ethoxyisonicotinonitrile (Example 154) );
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-ethyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 155);

(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,5-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane- 3-yl) methanone (Example 156);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,5,6-trimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] Octan-3-yl) methanone (Example 157);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-cyclopropyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1 ] Octane-3-yl) methanone (Example 158);
(2-Fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-methoxy-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3. 2.1] octane-3-yl) methanone (Example 159);
1- (2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) pyridine-4 -Yl) ethane-1-one (Example 160);

2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicoti Nononitrile (Example 161);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1H-pyrazol-1-yl) Pyridin-3-yl) methanone (Example 162);
1- (3- (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carbonyl) pyridin-2-yl) -1H-pyrazole- 3-carbonitrile (Example 163);
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-morpholinopyridin-3-yl) methanone (Example 164) ;
(8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (pyrrolidin-1-yl) pyridin-3-yl) Methanone (Example 165);

(2,5-di (1H-pyrazol-1-yl) pyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane -3-yl) methanone (Example 166);
(2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3 2.1] octan-3-yl) methanone (Example 167);
(2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2 .1] octane-3-yl) methanone (Example 168);
3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -1,5-dimethyl Pyrazin-2 (1H) -one (Example 169);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Examples) 170);

2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropyliso Nicotinonitrile (Example 171);
2- (3- (2- (1 (H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (pyrrolidin-1-yl) isonicoti Nononitrile (Example 172);
2- (3- (2- (1- (1-H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methylthio) isonicotinonitrile Example 173);
2- (3- (2- (1 (H) pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (dimethylamino) isonicotinonitrile ( Example 174);
(6- (4,6-Dimethylpyrimidin-2-yl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) (2-fluoro-6- (2H-1,2,3- Triazol-2-yl) phenyl) methanone (Example 175);
2- (3- (2- (1 (H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptan-6-yl) -3-methoxyisonicotinonitrile (Example 176) ).

[7] A seventh aspect of the present invention contains at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. It is a pharmaceutical composition characterized by these.

[8] An eighth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. Is a prophylactic and / or therapeutic agent for a disease involving orexin receptor.
Diseases involving orexin receptors include sleep disorders such as insomnia, circadian rhythm sleep disorder, and sleep-related sleep disorder; depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism Spectrum disorders, mental disorders such as drug dependence; neurodegenerative diseases such as Alzheimer's disease; memory disorders such as dementia; and eating disorders such as bulimia.

[9] A ninth aspect of the present invention contains at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. A prophylactic and / or therapeutic agent for sleep disorders, mental disorders, neurodegenerative diseases, memory disorders or eating disorders.
Preferably, at least one of the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof is contained as an active ingredient, thereby preventing sleep disorder And / or a therapeutic agent, more preferably a prophylactic and / or therapeutic agent for insomnia.
In the present specification, unless otherwise specified, examples of the “sleep disorder” include insomnia, circadian rhythm sleep disorder, and sleep-related complications. More specific examples of insomnia include primary insomnia, insomnia due to mental illness, insomnia due to physical disease, insomnia due to drugs, and the like. However, it is not limited to these.
In this specification, unless otherwise specified, as a “mental disorder”, specifically, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug Addiction etc. are mentioned. However, it is not limited to these.
In the present specification, unless otherwise specified, examples of the “neurodegenerative disease” include Alzheimer's disease. However, it is not limited to these.
In the present specification, unless otherwise specified, the “memory disorder” specifically includes dementia and the like. However, it is not limited to these.
Unless otherwise specified, in this specification, “eating disorders” specifically includes bulimia and the like. However, it is not limited to these.

[10] A tenth aspect of the present invention is an orexin receptor antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. It is.
Another aspect of the present invention is an orexin 2 receptor selective antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
Another aspect of the present invention is an orexin receptor dual antagonist comprising one or more of the compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there. Here, the “orexin receptor dual antagonist” means an orexin receptor antagonist having an orexin 1 receptor antagonistic action and an orexin 2 receptor antagonistic action.

[11] An eleventh aspect of the present invention is the use of at least one pharmaceutical composition of a compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. is there.
[12] A twelfth aspect of the present invention is the use of a compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as at least one orexin receptor antagonist. is there.

[13] A thirteenth aspect of the present invention is a method for treating a disease selected from sleep disorder, mental disorder, neurodegenerative disorder, memory disorder and eating disorder, and is represented by the above formula (I) Administering at least one of a compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject in need of treatment of said disease or condition.
Preferably, a method for treating a sleep disorder, wherein at least one of the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof is administered in the disease or condition. A method comprising administering to a subject in need of treatment, more preferably a method of treating insomnia.
In this specification, unless stated otherwise, “treatment” as in “treatment of a disease or condition” refers to the progression of a “disease or condition” or one or more “diseases or conditions”. Means to mitigate, or suppress. Further, in the present specification, “treatment” refers to “disease” including preventing the onset of “disease or condition” or any symptoms related to “disease or condition” depending on the condition of the patient. Or prevention of “a condition” as well as reducing the severity of a “disease or condition” or any symptom thereof before onset. As used herein, “treating” is intended to include preventing and ameliorating the recurrence of a “disease or condition”.

[14] In a fourteenth aspect of the present invention, the disease is insomnia, circadian rhythm sleep disorder, parasomnia, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism A prophylactic and / or therapeutic agent according to aspect [9] or a method according to aspect [13], selected from the group of: autism spectrum disorder, drug dependence, Alzheimer's disease, dementia, bulimia.
The compound of the present invention has an IC ₅₀ value of 1 μM or less for the orexin receptor when measured by a method in which orexin receptor antagonism is appropriately selected, for example, Pharmacological Experiment Example 1 (orexin receptor antagonism evaluation) described later. Compounds are preferred. More preferred is a compound having an IC ₅₀ value for the orexin receptor of 200 nM or less, more preferably ₄₀ nM or less. Further, as a compound having a orexin 2 receptor antagonism is preferably a compound an IC ₅₀ value is less than 1μM for the orexin 2 receptor, more preferably 200nM or less, more preferably a compound or less 40 nM. The compound having such an activity is a compound having an orexin receptor antagonistic action, particularly an orexin 2 receptor antagonistic action, and can be used as an orexin receptor antagonist, particularly an orexin 2 receptor antagonist or a pharmaceutical composition It is. In addition, diseases involving orexin receptors, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity disorder, self Autism, autism spectrum disorder, drug dependence, etc.), neurodegenerative diseases (such as Alzheimer's disease), memory disorders (such as dementia) or eating disorders (such as bulimia), especially diseases involving the orexin 2 receptor Or as an agent for preventing and / or treating sleep disorders such as insomnia.

The compounds of the present invention include compounds having orexin 2 receptor antagonistic activity but not having orexining orexin 1 receptor antagonistic activity. Such compounds include orexin 2 receptor. It can be used as a compound having a selective antagonism or an orexin 2 receptor selective antagonist. For example, a compound having an IC ₅₀ value for orexin 1 receptor of 10 times or more, 20 times or more, 50 times or more, or 100 times or more of the IC ₅₀ value for orexin 2 receptor can be mentioned. A compound having an orexin 2 receptor selective antagonism is useful as a pharmaceutical composition having no side effects due to orexin 1 receptor antagonism. In addition, diseases involving orexin 2 receptor, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, Autism, autism spectrum disorder, drug addiction, etc.), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) or eating disorders (eg, bulimia), especially sleep disorders such as insomnia It can be used as a preventive and / or therapeutic agent.
The compounds of the present invention include compounds having orexin 2 receptor antagonism as well as orexin 1 receptor antagonism, and such compounds are compounds having orexin receptor dual antagonism, It can be used as an orexin receptor dual antagonist or a pharmaceutical composition. Moreover, it can utilize as a preventive and / or therapeutic agent of the disease in which the above orexin receptor is involved.

In all of the above embodiments, when the term “compound” is used, “a pharmaceutically acceptable salt thereof” is also referred to.
In addition, unless otherwise specified in this specification, “a compound of formula (I)”, “a compound represented by formula (I)”, etc. ”,“ Compounds of formula (II) ”and so on, which are subordinate concepts of“ compounds of formula (I) ”.

The compound of the present invention may form an acid addition salt or a salt with a base depending on the type of substituent. Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basics, Or the salt with an acidic amino acid etc. are mentioned. Preferable examples of the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt. (For example, besides a mono salt, a disodium salt and a dipotassium salt are also included). Preferable examples of the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine. Ethanolamine, piperidine, morpholine, pyridine, picoline, lysine, arginine, ornithine, ethylenediamine, N-methylglucamine, glucosamine, phenylglycine alkyl ester, guanidine, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, N , N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc. Salt with organic carboxylic acid, salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like. Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), In the case where the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.

According to a conventional method, for example, the salt is formed by mixing the compound of the present invention with a solution containing an appropriate amount of acid or base to form the desired salt, and then separated by filtration, or the mixed solvent is distilled off. Can be obtained. In addition, the compound of the present invention or a salt thereof can form a solvate with a solvent such as water, ethanol or glycerol.

Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl & Wermuth (Wiley-VCH, 2002) are published as detailed reviews on salts, and are described in detail in this document.
The compounds of the invention can exist in unsolvated or solvated forms. As used herein, “solvate” means a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is specifically called “hydrate”.
Hereinafter, the description relating to the compound of the present invention includes the description relating to the salt, solvate, and solvate of the salt.

“Prodrugs” of the compounds of the present invention are also encompassed by the compounds of the present invention. A “prodrug” is, for example, when a certain derivative of a compound of the invention, which may exhibit little or no desired pharmacological activity, is administered in or on the body, eg, hydrolysis. When converted to the compound of the present invention having the desired pharmacological activity by the like, the compound before administration is called “prodrug”.
“Prodrugs” of the compounds of the present invention may be prepared, for example, by combining suitable functional groups present in the compounds of the present invention with methods known in the literature, such as Design of Prodrugs, H. et al. It can be produced according to the method described in Bundgaard (Elsevier, 1985).
Specific examples of the “prodrug” of the compound of the present invention include the following (1) to (3), but are not limited thereto.

(1) When the compound of the present invention is substituted with a carboxy group: an ester thereof, that is, a compound in which a hydrogen atom of the carboxy group is substituted with a “C _1-6 alkyl group”.
(2) When the hydroxyl group in the compounds of the present invention is substituted: Part alkanoyloxy or ethers, i.e., hydrogen atoms of the hydroxyl groups in the "C _{2 ~ 6} alkanoyl group" or "C _{2 ~ 6} alkanoyloxymethyl group" Substituted compound.
(3) When the compound of the present invention is substituted with an amino group (—NH ₂ or —NHR ′ (where R ′ ≠ H)): the amide, that is, one or both hydrogen atoms of the amino group There compounds substituted by "C _{2 ~ 6} alkanoyl group".

When the compound of the present invention has isomers such as geometric isomers, configuration isomers, tautomers, optical isomers, stereoisomers, positional isomers, rotational isomers, etc., any one isomer And mixtures thereof are encompassed by the compounds of the present invention. Furthermore, when an optical isomer exists in the compound of the present invention, the optical isomer resolved from the racemate is also encompassed in the compound of the present invention.
When the compound of the present invention has one or more asymmetric carbon atoms, two or more stereoisomers can exist. Further, the compounds of the present invention, if it contains "C _{2 ~ 6} alkenyl group", geometric isomers (cis / trans or Z / E,) can be present. Also, tautomerism can occur when structural isomers can be interconverted by a low energy barrier. Examples of tautomerism include proton tautomerism in compounds having an imino, keto, or oxime group.

When there are geometrical isomers, configurational isomers, stereoisomers, conformational isomers and the like in the compound of the present invention, each can be isolated by known means.
In addition, when the compound of the present invention is an optically active substance, the racemate may be separated into a (+) form or a (−) form [(D) form or (L) form] by a conventional optical resolution means. it can.
When the compound of the present invention contains optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, each isomer is converted to a single isomer by a known synthesis method or separation method. It can be obtained as a compound. For example, examples of the optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like.

(1) Fractionation recrystallization method: After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. This is a method for obtaining a free optically pure compound. Examples of the optical resolution agent include (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine, Examples include cinchonine, (−)-cinchonidine, brucine and the like.
(2) Diastereomer method: An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , High-performance liquid chromatography (HPLC), etc.) and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. To obtain an optical isomer. For example, when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound of the present invention has a carboxyl group, an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.

(3) Chiral column method: A method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column). For example, in the case of high performance liquid chromatography, a mixture of optical isomers is added to a chiral column such as CHIRAL series (Daicel), water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol) , Isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution, the optical isomers can be separated by development. Further, for example, in the case of gas chromatography, separation can be performed using a chiral column such as CP-Chirasil-DeX CB (GL Science).
The compound of the present invention may be a crystal, and a single crystal form or a crystal form mixture is included in the compound of the present invention.
The compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.

Compounds of the present invention include isotopes (eg, hydrogen isotopes, ² H and ³ H, carbon isotopes, ¹¹ C, ¹³ C, and ¹⁴ C, chlorine isotopes, ³⁶ Cl, etc., fluorine Isotopes, ¹⁸ F, iodine isotopes, ¹²³ I and ¹²⁵ I, nitrogen isotopes, ¹³ N and ¹⁵ N, oxygen isotopes, ¹⁵ O, ¹⁷ O, and ¹⁸ O, phosphorus Also included are compounds labeled or substituted with isotopes, ³² P and the like, as well as sulfur isotopes, ³⁵ S and the like.
Compounds of the invention labeled or substituted with certain isotopes (eg, positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be synthesized, for example, by Positron Emission Tomography; PET ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
Compounds of the invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies. For example, ³ H and ¹⁴ C are useful for this research purpose because they are easy to label or displace and easy to detect.

A compound labeled or substituted with ² H (or sometimes referred to as D or deuterium) (D compound, deuterated compound) is expected to have high stability and is useful as an active compound itself. is there. For example, a compound in which a hydrogen atom at a position to undergo metabolism is substituted with ² H can be mentioned, and the metabolic reaction rate can be reduced with little influence on the properties of the compound. In addition, a compound in which the position of irreversibly binding to a metabolic enzyme is substituted with ² H can suppress the inhibition of the action of the metabolic enzyme, and can reduce the drug interaction at the time of combined use.
Isotopically-labeled compounds of the invention can be obtained by conventional techniques known to those skilled in the art or by methods analogous to the synthetic methods described in the examples below. In addition, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.

[Method for producing compound of the present invention]
Below, the manufacturing method of the compound represented by Formula (I) of this invention is demonstrated. Compounds of the present invention represented by formula (I), salts thereof and solvates thereof are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or intermediates of synthesis. As a body, it can be easily produced by combining known general chemical production methods, and can be produced according to the following typical production methods. Further, the present invention is not limited to the manufacturing method described below.

Definitions appearing in formula (I) such as L, ring A, ring B, R ^a , and R ^b in each formula of the following production methods are those of formula (I) described in the above embodiment unless otherwise specified. Each definition is the same. The definitions of L ′ and L ″ in the production method are included in the definition of L in formula (I) and are defined in each production method. The definition of M in the production method is a metal such as lithium, sodium and potassium unless otherwise specified. The definition of X in the production method is a halogen atom or trifluoromethanesulfonate (OTf) unless otherwise specified. The definition of B in the production method is boronic acid ester, boronic acid, trifluoroborate salt, or boronic acid N-methyliminodiacetic acid ester unless otherwise specified. Unless otherwise specified, the definitions of P ¹ and P ² in the production method are a protecting group for a hydrogen atom or an imino group. Definition of R ^A in the manufacturing method, unless otherwise specified, is a C _{1 ~ 6} alkyl group, C _{6 ~ 14} aryl group or a C _{7 ~ 20} aralkyl group. Definition of R ^B in the production process, unless otherwise specified, is a C _{1 ~ 6} alkyl group or a C _{3 ~ 8} cycloalkyl group. The definition of R ^C during manufacturing process, unless otherwise specified, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{1 ~ 6} alkylthio group, non-aromatic heterocyclic group or -NR ^a R ^b, It is a group.

In each of the following production methods, each raw material compound used for the production of formula (I) may form a salt, and as such a salt, the same salts as those of the aforementioned formula (I) can be mentioned. Can be mentioned. Each raw material compound used in the production of formula (I) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from a reaction mixture according to a conventional method. It can be easily purified by known means, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.

Examples of the solvent used for the recrystallization include water; alcohols such as methanol, ethanol, 2-propanol and butanol; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; n-hexane, cyclohexane and heptane. Hydrocarbons such as benzene, toluene, xylene, etc .; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; chloroform , Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; nitriles such as acetonitrile; ketones such as acetone and diphenyl ketone; esters such as methyl acetate and ethyl acetate; sulfoxides such as dimethyl sulfoxide; , Trifluoroacetic acid, methanesulfur Phosphate, organic acids such as p- toluenesulfonic acid; and the like. These solvents can be used alone, or two or more kinds of solvents can be mixed at an appropriate ratio, for example, a ratio of 1: 1 to 1:10. Moreover, when the compound in a formula is marketed, a commercial item can also be used as it is, and what was manufactured by the method known per se or a method according to it can also be used.

In substituent having the formula (I) is transformable functional group (e.g., carboxyl group, an amino group, a hydroxyl group, a carbonyl group, a mercapto groups, C _{1 ~ 6} alkoxycarbonyl groups, C _{6 ~ 14} aryloxycarbonyl groups, C _{In the} case of containing 7-20 aralkyloxycarbonyl groups, sulfo groups (—SO ₂ OH), halogen atoms, etc.), various compounds can be produced by converting these functional groups by a method known per se or a method analogous thereto. Can do.
In the case of a “carboxy group”, it can be converted by a reaction such as esterification, reduction, amidation, or a conversion reaction to an optionally protected amino group.
In the case of an “amino group”, it can be converted by a reaction such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.

In the case of “hydroxyl group”, it can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation and the like.
In the case of a “carbonyl group”, it can be converted by a reaction such as reduction, oxidation, imination (including oximation and hydrazone formation), (thio) ketalization, alkylidene formation, thiocarbonylation and the like.
In the case of a “mercapto group”, it can be converted by a reaction such as alkylation or oxidation.
If the "C _{1 ~ 6} alkoxycarbonyl group", "C _{6 ~ 14} aryloxycarbonyl group", or "C _{7 ~ 20} aralkyloxycarbonyl group", for example, the reduction can be converted by reaction such as hydrolysis.
In the case of a “sulfo group”, it can be converted by a reaction such as sulfonamidation or reduction.

In the case of “halogen atom”, it can be converted by, for example, various nucleophilic substitution reactions, various coupling reactions and the like.
In each of the above reactions, when the compound is obtained in a free state, it may be converted into a salt according to a conventional method. When it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also
These functional groups can be converted in accordance with, for example, the method described in the book of Larock et al., Comprehensive Organic Transformations, 2nd edition, October 1999, Wiley-VCH.
Moreover, in each reaction of the manufacturing method of a compound represented by the formula (I) of this invention and each reaction of a raw material compound synthesis, a hydroxyl group (an alcoholic hydroxyl group, a phenolic hydroxyl group, a heterocyclic hydroxyl group, etc.), an amino group as a substituent When there are reactive groups such as carboxy group and thiol group, these groups can be appropriately protected in each reaction step, and the protecting group can be removed at an appropriate stage.

Examples of the protective group for the hydroxyl group (alcoholic hydroxyl group, phenolic hydroxyl group, heterocyclic hydroxyl group, etc.) include C _1-6 represented by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like. Alkyl group; alkoxylalkyl group represented by methoxymethyl, methoxyethoxymethyl, etc .; tetrahydropyranyl group; aralkyl group represented by benzyl, triphenylmethyl, etc .; trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyl A silyl group typified by diphenylsilyl and the like; an alkanoyl group typified by acetyl, ethylcarbonyl, pivaloyl and the like; an aralkylcarbonyl group typified by benzylcarbonyl and the like; an aroyl group typified by benzoyl and the like; methoxycarbonyl, ethoxycarbonyl, - alkoxycarbonyl groups typified butoxycarbonyl; aralkyloxycarbonyl group represented by benzyloxycarbonyl and the like are used.

Examples of the protecting group for the amino group (—NH ₂ group) or imino group (—NH— group) include alkanoyl groups represented by acetyl, ethylcarbonyl, pivaloyl, etc .; methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl Allyloxycarbonyl group; fluorenylmethoxycarbonyl group; phenyloxycarbonyl; aralkyloxycarbonyl group represented by benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and the like; Aralkyl groups typified by benzyl, triphenylmethyl, etc .; aroyl groups typified by benzoyl, etc .; aralkylcarbonyl groups typified by benzylcarbonyl, etc .; methanesulfonyl, p-toluenesulfonate , 2,4-nitrobenzenesulfonyl, a sulfonyl group represented by benzenesulfonyl; 2- (trimethylsilyl) ethoxymethyl group; phthaloyl group; N, N-dimethylaminomethylene group, etc. are used.

Examples of the protecting group for the carboxy group (—COOH group) include alkyl groups typified by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc .; alkenyl groups typified by allyl; An aryl group typified by phenyl or the like; an aralkyl group typified by benzyl, triphenylmethyl or the like; a silyl group typified by trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or the like is used.
Examples of the protecting group for the thiol group (—SH group) include alkyl groups typified by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and the like; benzyl, triphenylmethyl and the like. Aralkyl groups represented by acetyl, ethylcarbonyl, pivaloyl and the like; aroyl groups represented by benzoyl and the like are used.
Such a method for introducing / removing a protecting group is appropriately performed depending on the group to be protected or the type of protecting group. For example, Greene et al., Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley & Sons. It can be performed by the method described in the book.

Examples of the deprotection method of the protecting group include alkanoyl groups represented by acetyl, ethylcarbonyl, pivaloyl, etc .; alkoxylcarbonyl groups represented by methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc .; benzoyl, etc. An acyl-type protecting group such as an aroyl group can be hydrolyzed and deprotected by using an appropriate base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
Alkoxylalkyl-type protecting groups represented by methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, etc .; Alkoxylcarbonyl-type protecting groups represented by t-butoxycarbonyl, etc .; benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, etc. Aralkyloxycarbonyl-type protecting groups; silyl-type protecting groups represented by trimethylsilyl, triethylsilyl, t-butyldimethylsilyl and the like include, for example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethane Deprotection can be achieved by using an appropriate acid such as sulfonic acid or a combination thereof.

The silyl-type protecting group can also be deprotected by using a suitable fluorine ion (F ⁻ ) generating reagent such as a reagent such as tetrabutylammonium fluoride and hydrogen fluoride.
Aralkyloxycarbonyl groups typified by benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and the like and aralkyl groups typified by benzyl are, for example, hydrogenolysis using a palladium-carbon (Pd-C) catalyst. Can be deprotected.
The benzyl group can also be deprotected by, for example, Birch reduction using metallic sodium in liquid ammonia.
The triphenylmethyl group can be deprotected by using an appropriate acid, for example, an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or a combination thereof. . It can also be deprotected by liquid Birch reduction using metallic sodium or metallic lithium or hydrogenolysis using a palladium carbon catalyst.

The sulfonyl group can be deprotected by, for example, one-electron reduction using Na / anthracene or Na / naphthalene at low temperature or Birch reduction using metallic sodium or metallic lithium in liquid ammonia.
Among the sulfonyl groups, the 2-nitrobenzenesulfonyl group can be deprotected under mild conditions in which a thiol is reacted in the presence of a basic reagent such as potassium carbonate or triethylamine.
The protecting group deprotection method shown here is only one example. For example, the method described in the book of Greene et al., "Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley &Sons" or publicly known Deprotection is possible by applying various papers published in.
The reaction conditions in the production method described below are as follows unless otherwise specified. The reaction temperature is in the range from −78 ° C. to the temperature at which the solvent is refluxed. When the temperature is not described, it is room temperature (0 to 35 ° C.), and the reaction time is the time for which the reaction proceeds sufficiently. .

In addition, each step in the production method can be performed without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction. Specific examples of solvents that do not participate in the reaction include water; saturated hydrocarbon solvents such as cyclohexane and hexane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, and xylene; methanol, ethanol, 1-propanol, 2 Alcohol solvents such as propanol, tert-butyl alcohol, 2-methoxyethanol; N, N-dimethylformamide (DMF), N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2- Polar amide solvents such as imidazolidinone: sulfoxide solvents such as dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether Ether solvents such as tellurium, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; ketone solvents such as acetone and methyl ethyl ketone; dichloromethane, Halogenated hydrocarbon solvents such as chloroform, carbon tetrachloride and 1,2-dichloroethane; basic solvents such as triethylamine, N, N-diisopropylethylamine, pyridine and lutidine; acid anhydrides such as acetic anhydride; formic acid, acetic acid, An organic acid such as propionic acid, trifluoroacetic acid, methanesulfonic acid, etc .; an inorganic acid such as hydrochloric acid, sulfuric acid, etc., but one kind of solvent may be used alone, or two or more kinds of solvents may be appropriately selected according to reaction conditions May be mixed and used at an appropriate ratio.

Specific examples of the base (or deoxidizer) used in the production method of the compound of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and carbonate. Inorganic bases such as cesium, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine (DIPEA), tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N-dimethyl Aniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1, 8-Diazabicyclo [5.4.0] -7-undecene Organic bases such as imidazole; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide; alkali metal hydrides such as sodium hydride and potassium hydride; sodium amide, lithium diisopropylamide ( LDA), metal amides such as lithium hexamethyldisilazide; organolithium reagents such as methyllithium, n-butyllithium (n-BuLi), sec-butyllithium, and tert-butyllithium. Further, as the acid or acid catalyst used in the method for producing the compound of the present invention, specifically, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid; acetic acid, trifluoroacetic acid, oxalic acid, Organic acids such as phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid; boron trifluoride ether complex, zinc iodide, anhydrous chloride Lewis acids such as aluminum, anhydrous zinc chloride, and anhydrous iron chloride. However, it is not necessarily limited to those described above.

The salt of the formula (I) is prepared according to a method known per se. For example, when the formula (I) is a basic compound, an inorganic acid (mineral acid) such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Or add organic acids such as formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Or when formula (I) is an acidic compound, ammonia, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N -Diisopropylethylamine, N, N'-dibenzylethylenediamine, N, N-dialkyl It can be produced by adding an organic base such as ruaniline or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate.

The compound represented by the formula (I) of the present invention is prepared by using the amine derivative represented by the formula (AM) as a starting material and the production method A (when P ¹ = H: introduction of the ring A group, followed by the P ² group Deprotection of carboxylic acid derivative represented by formula (CA), or production method B (when P ² = H: condensation reaction of carboxylic acid derivative represented by formula (CA), followed by P ¹ Group deprotection, introduction of ring A group).

Formula (I), Formula (I-1) [in the formula (I) where L = monocyclic non-aromatic heterocycle, phenyl or monocyclic heteroaryl], formula (I-2) [formula In the case of (I) ring A = 3-substituted-4-cyano-2-pyridine], and formula (CA) [formula (CA-3), formula (CA-4), formula (CA-5-1) , Formula (CA-5-2), and formula (CA-5-3)].

[Production Method A]

<Step 1>
[Ring A = 5 to 14-membered heteroaryl group; X = halogen atom]
A compound represented by formula (AM-1) (P ¹ = H in formula (AM)), and a compound represented by formula (AR-1) (in formula (AM-1) and formula (AR-1) The compound represented is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature). The compound of formula (AM-3) can be produced by carrying out the reaction at a reaction temperature of 120 to 150 ° C. without solvent in accordance with the method described in “Year” and the like.

Further, using a compound represented by the formula (AM-1) (P ¹ = H in the formula (AM)) and a compound represented by the formula (AR-1), methods known in the literature, for example, “Journal of Organic Chemistry, 70 (13), 5164-5173, 2005 ”and the like, a Cu catalyst such as copper iodide (CuI), and (S) -proline, and potassium carbonate, carbonate In the presence of a base such as sodium, cesium carbonate, triethylamine, N, N-diisopropylethylamine, potassium phosphate, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, 1,4-dioxane, tetrahydrofuran, Solvents that do not participate in the reaction, such as toluene, xylene, and acetonitrile, or these Using a solvent mixture, the reaction was carried out in the temperature at which the solvent refluxes from 0 ° C., it is possible to produce a compound represented by the formula (AM-3).
Further, using a compound represented by the formula (AM-1) (P ¹ = H in the formula (AM)) and a compound represented by the formula (AR-1), methods known in the literature, for example, “WO2012 / P76 catalyst such as tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ) and 4,5′-bis (diphenylphosphino) -9 , 9'-dimethylxanthene (XANTPHOS) and the like, and toluene, xylene, N, N in the presence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate -Dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, acetonitrile (acetonitrile / water) Using a solvent that does not participate in the reaction such as dioxane (dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. The compounds represented can be produced.

[Ring A = 5 to 14-membered heteroaryl group; when X = OTf]
Using a compound represented by formula (AM-1) (P ¹ = H in formula (AM)) and a compound represented by formula (AR-1), methods known in the literature, for example, “Synlett, ( 12) 1400-1402, 1997 ”and the like, halogen solvents such as dichloromethane and chloroform, ether systems such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like. Solvent, solvent such as benzene, toluene, polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc., or a mixed solvent of these solvents are used. The reaction can be performed at a refluxing temperature to produce a compound represented by the formula (AM-3).

[; When X = halogen atom ring A = C _{6 ~ 14} aryl group]
Using a compound represented by formula (AM-1) (P ¹ = H in formula (AM)) and a compound represented by formula (AR-1), methods known in the literature, for example, “WO2009 / 059112” Tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), palladium acetate (Pd (OAc) ₂ ), chloro (2-dicyclohexylphosphino-2 ′) , 6′-diisopropoxy-1,1′-biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II) (RuPhos Pd G2) and the like, and 2-dicyclohexyl Phosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (X-phos), 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene (XANTP OS), (Ph ₂ P) 2-binaphthyl, 2 ', 2-bis (diphenylphosphino) -1', 1 binaphthyl (BINAP), 2-dicyclohexyl phosphino-2 ', 6'-diisopropoxy - Phosphine reagents such as 1,1′-biphenyl (RuPhos), [1 ′, 1-biphenyl] -2-yl di-tert-butylphosphine (JohnPhos), and cesium carbonate, potassium carbonate, potassium phosphate, tert- In the presence of an organic or inorganic base such as BuONa, triethylamine, N, N-diisopropylethylamine, etc., toluene, N, N-dimethylformamide, N-methylpyrrolidone (NMP), N, N-dimethylacetamide, acetonitrile, acetonitrile / water, Dioxane, dioxane / water, tetrahydrofuran, tetrahydro A compound represented by the formula (AM-3) can be produced by performing a reaction at a temperature at which the solvent is refluxed from a room temperature using a solvent such as furan / water that does not participate in the reaction or a mixed solvent thereof. .

<Step 2>
[Production Method A] Using a compound represented by the formula (AM-3) obtained in <Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Greene” In accordance with the method described in the book of the et al., The P ² group is deprotected by reacting the protecting group P ² with a method according to the type of the protecting group, and the formula (AM-4) Can be produced.

<Step 3>
[Production Method A] The amine of formula (AM-4) obtained in <Step 2> and the compound of formula (CA) (the compound of formula (CA) is a commercially available compound or a commercially available compound from a known method in the literature. A compound that can be produced, or a compound that can be produced by the method of [Production Method E], [Production Method F], [Production Method G], [Production Method H] or [Production Method J] described later), In accordance with a known method, for example, a method described in “Experimental Chemistry Course 4th edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 191-309, 1992, Maruzen” and the like, 1,3-dicyclohexylcarbodiimide ( DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), benzotriazol -1-Iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium Hexafluorophosphate (CIP), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (DMTMM), polyphosphoric acid (PPA), 2- ( 1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy ) Dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) In the presence of a condensing agent such as propylphosphonic anhydride (T3P), halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, N, In the presence or absence of a base such as triethylamine, N, N-diisopropylethylamine, or pyridine in a solvent that does not participate in the reaction, such as a polar solvent such as N-dimethylformamide, or an alcohol solvent such as methanol, ethanol, or 2-propanol. The compound represented by the formula (I) can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C.

In addition, the compound of formula (CA) can be prepared according to methods known in the literature, for example, “Journal of the American Chemical Society, 109 (24), p7488-7494, 1987”. Halogenation of thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide in the presence or absence of bases such as N-diisopropylethylamine and N, N-dimethylaminopyridine The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using an agent and a solvent inert to the reaction such as dioxane, tetrahydrofuran, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, or a mixed solvent thereof. The resulting acid halide, And [Production Method A] using the amine of the formula (AM-4) obtained in <Step 2>, for example, “Experimental Chemistry Course, 4th Edition, 22. Organic Synthetic IV Acid / Amino Acid / Peptide, 144-146, 1992, In the presence of bases such as triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, In a solvent that does not participate in the reaction, such as an ether solvent such as diethyl ether, tetradrofuran, or 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as N, N-dimethylformamide, 0 By reacting at a temperature at which the solvent refluxes from 0 ° C., the compound of formula (I) can be similarly produced.

[Production Method B]

<Step 1>
Compounds of formula (AM-2) (P ² = H in formula (AM)) and compounds of formula (CA) (formula (AM-2) and compounds of formula (CA) are commercially available compounds or commercially available compounds) A compound that can be produced by a production method known in the literature, and the compound of the formula (CA) is [Production Method E], [Production Method F], [Production Method G], [Production Method H], or [Production Method J] described later. The compound of formula (AM-5) can be produced by carrying out a reaction according to [Production Method A] <Step 3>.

<Step 2>
[Production Method B] Using a compound of formula (AM-5) obtained in <Step 1>, a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Green et al.” A compound represented by the formula (AM-6), wherein the P ¹ group is deprotected by reacting the protecting group P ¹ according to the method according to the type of the protecting group in accordance with the method described in the document Can be manufactured.

<Step 3>
[Production Method B] The compound of formula (AM-6) obtained in <Step 2> and the compound of formula (AR-1) (this compound is a commercially available compound or can be produced from a commercially available compound by a method known in the literature) The compound of formula (I) can be produced by carrying out a reaction according to [Production Method A] <Step 1>.

[Production Method C] Formula (I-1) [In Formula (I), ring B ≠ 1-substituted-1H-pyrazole ring; L = L ′ = monocyclic non-aromatic heterocycle, phenyl or monocyclic heteroaryl In the case of

<Step 1>
[Production Method A] Compound of formula (AM-4) obtained in <Step 2> and formula (CA-1) The compound of formula (IM-1) can be produced by carrying out a reaction according to [Production method A] <Step 3>.

<Step 2>
[Production Method C] The compound of formula (IM-1) obtained in <Step 1> and the halogenated compound of formula (RG-1) (this compound is a commercially available compound or a commercially available compound from a known method in the literature). And the methods known in the literature, such as “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI —Organic synthesis using metals—327-352, 2004, Maruzen” and “Journal” of Medicinal Chemistry, 48 (20), p 6326-6339, 2005 ”, palladium (II) acetate (Pd (OAc) ₂ ), tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) _3), bis (Jibenjiri N'aseton) palladium (Pd (dba) _2), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ (dppf)) or the like of a palladium catalyst, triphenylphosphine, tris (tert- Phosphine reagents such as butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl In the presence of an organic or inorganic base such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate, etc., toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, Acetonitrile ( Using a solvent that does not participate in the reaction, such as cetonitrile / water), dioxane (dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. The compound represented by I-1) can be produced. Or it can manufacture by the same method using tetramethylammonium chloride, tetrabutylammonium chloride, etc. instead of a phosphine-type reagent.

<Step 3>
[Production Method A] Compound of formula (AM-4) obtained in <Step 2> and formula (CA-2) The compound of formula (IM-2) can be produced by carrying out a reaction according to [Production Method A] <Step 3>.

<Step 4>
[When using a boronic acid reagent of the formula (RG-2)]
[Production Method C] Compound of formula (IM-2) obtained in <Step 3> and formula (RG-2) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. The compound of formula (I-1) can be produced by carrying out a reaction according to [Production Method C] <Step 2> using the compound of (A).
[When using a tin reagent of the formula (RG-3)]
[Production Method C] Compound of formula (IM-2) obtained in <Step 3> and formula (RG-3) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. A compound known in the literature, for example, “Synlett, 25 (5), pages 653-656, 2014”, “European Journal of Organic Chemistry, 2013 (28), pages 6404-6419, 2013”. In accordance with the method described in "Chemical Communication, 48 (71), 8907-8909, 2012", "Bioorganic & Medicinal Chemistry, 21 (8), pages 2370-2378, 2013", etc. Triphenylphosphie Palladium (Pd (PPh _{3) 4),} bis (triphenylphosphine) palladium (II) dichloride (Pd ₂ (PPh _{3) 2)} the presence of a palladium catalyst such as (tetrakis triphenylphosphine palladium (Pd (PPh _{3) 4} In the presence or absence of a copper reagent such as copper iodide (CuI), in the presence or absence of a salt such as cesium fluoride and lithium chloride, toluene, tetrahydrofuran, N, N-dimethyl Using a solvent such as formamide, 1,4-dioxane, or a solvent not involved in the reaction, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. to produce the compound of formula (I-1). it can.

<Step 5>
[In the formula (IM-1) where B = boronic acid ester]
[Production Method C] The compound of formula (IM-2) obtained in <Step 3> is used and described in a method known in the literature, for example, “The Journal of Organic Chemistry, 60, 7508-2665, 1995”. According to the method, palladium (II) acetate, tetrakistriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, [1] in the presence of diboron esters such as bis (pinacolato) diboron and bis (neopentylglycolate) diboron , 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in the presence of a palladium catalyst such as triphenylphosphine, tris (tert-butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino -2 ', 6' Phosphine reagents such as dimethoxybiphenyl, and in the presence or absence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium acetate, or tetramethylammonium chloride, tetrabutylammonium chloride instead of phosphine reagents The temperature at which the solvent refluxs from 0 ° C. using a solvent that does not participate in the reaction, such as toluene, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, or a mixed solvent thereof in the presence or absence of To give a boronic ester of formula (IM-1)

[In the formula (IM-1) where B = boronic acid]
[Production Method C] Using a compound of the formula (IM-2) obtained in <Step 3>, according to a method known in the literature, for example, a method described in “Chemische Berichte, 42, 3090, 1909”, etc. , Toluene, tetrahydrofuran, 1,4-dioxane and the like, or a mixed solvent thereof, alkyl lithium such as n-butyllithium and sec-butyllithium, Grignard such as isopropylmagnesium chloride, etc. Trialkylborate such as trimethylborate and triisopropylborate is added in the presence of a reagent or magnesium metal, and the reaction is carried out at −78 ° C. to room temperature, then an acid such as hydrochloric acid and sulfuric acid is added, and the solvent is refluxed from 0 ° C. Reaction at a temperature to produce a boronic acid of formula (IM-1) Can.

[In the formula (IM-1) where B = trifluoroborate salt]
Using boronic acid ester obtained by the above-mentioned method or boronic acid, according to a method known in the literature, for example, a method described in “Chemical Reviews, 108, 288-325, 2008” or the like, In the presence of potassium, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction such as methanol, ethanol, water or the like, or a mixed solvent thereof, and the trifluoroborate salt of the formula (IM-1) Can be manufactured.

[In the formula (IM-1), B = boronic acid N-methyliminodiacetic acid ester]
[Production Method C] Using a compound represented by the formula (IM-2) obtained in <Step 3>, a method known in the literature, for example, “Journal of Organometallic Chemistry, 307 (1), 1-6, 1986” In the presence of N-methyliminodiacetic acid, a solvent not involved in the reaction such as benzene, toluene, xylene or dimethyl sulfoxide, or a mixed solvent thereof is used from 0 ° C. By reacting at the refluxing temperature, the boronic acid N-methyliminodiacetic acid ester of the formula (IM-1) can be produced.

<Step 6>
[Production Method A] [Production Method A] using the compound of formula (AM-4) obtained in <Step 2> and the compound of formula (CA-3) (see [Production Method E] described later) A reaction according to <Step 3> can be carried out to produce a compound of formula (I-1).

[Production Method D] Production method of formula (I-2) [in the case of formula A, ring A = 3-substituted-4-cyano-2-pyridine]

<Step 1>
[Production Method B] Compound of formula (AM-6) obtained in <Step 2> and formula (AR-2) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. A compound of formula (IM-3) can be produced by carrying out a reaction according to [Production method B] <Step 3>.
<Step 2>
[For R ^C = ^C _{3 ~ 8} cycloalkyl radical
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-4) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. In accordance with a method known in the literature, for example, a method described in “WO2014 / 066196 pamphlet” or the like, tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), bis [tris In the presence of a Pd catalyst such as (1,1-dimethylethyl) phosphine] palladium, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction, such as tetrahydrofuran and 2,2-dimethoxyethane, Compounds of formula (I-2) can be prepared.

[In the case of R ^C = —NR ^a R ^b group (including the case where R ^a and R ^b form a monocyclic non-aromatic heterocyclic group)]
[Production Method D] The compound of the formula (IM-3) obtained in <Step 1> and the compound of the formula (RG-5) (the compound of the formula (RG-5) are commercially available compounds or known productions from the commercially available compounds. And a known method such as “WO2005 / 111003 pamphlet”, “Journal of Medicinal Chemistry, 48 (23), 7374-7388, 2005”, etc. According to the described method, using a solvent that does not participate in the reaction, such as water, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, in the presence or absence of a base such as diisopropylethylamine or triethylamine. The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. It can be produced compound.
[When R ^C = C _1-6 alkylthio group]
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-6) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. And a solvent that does not participate in the reaction, such as N, N-dimethylformamide, N-methylpyrrolidone, etc., in accordance with a method known in the literature, for example, the method described in “WO2011 / 049222 pamphlet” or the like. The compound of formula (I-2) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C.

[In the case of R ^C = C _1-6 alkoxyl group]
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-7) (This compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature. In accordance with the method described in “Journal of Medicinal Chemistry, 55 (22), pages 10118-10129, 2012” and the like, N, N-dimethylformamide, N-methylpyrrolidone etc. A compound of formula (I-2) can be produced by carrying out the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction.
The formula (IM-3-1) (X ′ = Cl or F) when X = Cl or F in the formula (IM-3) is described in [Manufacturing Method D] <Step 3> to <Step 7 > Can also be produced.
<Step 3>
Compounds of formula (AR-2-1) and formula (AM-1) (formula (AR-2-1) and compound of formula (AM-1) are commercially available compounds, or commercially available compounds from the literature by known production methods) The compound of formula (AM-3-1) (X ′ = Cl) can be produced by carrying out a reaction according to [Production method A] <Step 1>.
<Step 4>
The compound of formula (AR-2-2), and the compound of formula (AM-1) (formula (AR-2-2) and compound of formula (AM-1) are commercially available compounds, or prepared from commercially available compounds in the literature The compound of formula (AM-3-2) can be produced by carrying out a reaction according to [Production Method A] <Step 1> using a compound of (a compound that can be produced by the method).
<Step 5>
[Production Method D] Using the compound of formula (AM-3-2) obtained in <Step 4> and trifluoroacetic anhydride (TFAA), a method known in the literature, for example, “WO2007 / 043677 pamphlet”. In the presence of a base such as triethylamine, the reaction is performed at a temperature at which the solvent refluxes from 0 ° C. in the presence of a base such as triethylamine. ) (X ′ = F) can be produced.
<Step 6>
[Production Method D] <Step 3> or [Production Method D] Using the compound of formula (AM-3-1) (X ′ = Cl or F) obtained in <Step 5>, [Production Method A] A compound of formula (AM-4-1) can be produced by performing a reaction according to <Step 2>.
<Step 7>
[Production Method D] Using the compound of formula (AM-4-1) obtained in <Step 6> and the compound of formula (CA), a reaction according to [Production Method A] <Step 3> is performed. A compound of formula (IM-3-1) can be prepared.

[Production Method E] Formula (CA-3) [In Formula (CA), ring B ≠ 1-substituted-1H-pyrazole ring; L = L ′ = monocyclic non-aromatic heterocycle, phenyl or monocyclic heteroaryl In the case of

<Step 1>
A compound of formula (E-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature), and a compound of formula (RG-2) or formula (RG-3) The compound of formula (E-2) can be produced by carrying out a reaction according to [Production method C] <Step 4>.

<Step 2>
[In the case of R ^A = C _1-6 alkyl group (for example, methyl, ethyl group, etc.)]
Using a compound of the formula (E-2), it is described in literature known methods such as “Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 1-43, 1992, Maruzen”. According to the method, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, water and methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1, The compound of the formula (CA-3) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent inert to the reaction such as 4-dioxane and tetrahydrofuran, or a mixed solvent thereof. .

[In the case of R ^A = tert-butyl group]
According to a method known in the literature using a compound of the formula (E-2), for example, a method of deprotection described in the book of Protective Groups in Organic Synthesis 4th, 2007, John Wiley & Sons, Green et al. The compound of the formula (CA-3) can be produced by performing a reaction with an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like at a temperature at which the solvent is refluxed from 0 ° C.

[For R ^A = C _{7 ~ 20} aralkyl group (e.g., benzyl group)]
A method known in the literature using a compound of formula (E-2), for example, “Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, Maruzen” In the presence of a catalyst such as palladium-carbon (Pd—C), Raney nickel (Raney-Ni), platinum oxide (PtO ₂ ), dichlorotritriphenylphosphine ruthenium, etc. in a hydrogen gas atmosphere. Alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, polar solvents such as ethyl acetate, methyl acetate, etc. The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not react or a mixture thereof. -3) can be produced.

<Step 3>
Using a compound of formula (E-3) (this compound is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature) and a compound of formula (RG-1), [Production Method C The compound of formula (E-2) can be produced by carrying out a reaction according to <Step 2>.

[Production Method F] Production method of formula (CA-4) [in formula (CA), ring B ≠ 1-substituted-1H-pyrazole ring; L = L ″ = in the case of a monocyclic heterocycle containing a nitrogen atom]

The compound of formula (CA-2) and the compound of formula (F-1) (the compounds of formula (CA-2) and formula (F-1) are commercially available compounds or produced from commercially available compounds by methods known in the literature) In accordance with a method known in the literature, for example, “Angewandte Chemie, International Edition, 50, 48, 11511-11515, 2011”, etc., copper iodide (CuI In the presence of a copper catalyst such as sodium carbonate, potassium carbonate, cesium carbonate, etc., the solvent is refluxed from 0 ° C. using a solvent not involved in the reaction such as acetonitrile, tetrahydrofuran, dimethylformamide, or a mixed solvent thereof. The compound of formula (CA-4) can be produced by carrying out the reaction at a temperature at which

[Production Method G] Production Method of Formula (CA-5-1) [In Formula (CA) Ring B = Pyrazole; L = 2-Pyridine (1)]

<Step 1>
Using a compound of the formula (G-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a method known in the literature) and 2-hydrazinopyridine, a method known in the literature, for example, In accordance with the method described in “WO2007 / 043677 pamphlet” and the like, the reaction is performed in the presence of acetic acid using a solvent that does not participate in the reaction, such as tetrahydrofuran and 2-methoxyethanol, at a temperature at which the solvent refluxes from 0 ° C. A compound of the formula (G-2) can be produced.

<Step 2>
[Production Method G] Using the compound of formula (G-2) obtained in <Step 1>, a reaction according to [Production Method E] <Step 2> is carried out to give a compound of formula (CA-5-1). Can be manufactured.

[Production Method H] Production Method of Formula (CA-5-2) [In Formula (CA), Ring B = Pyrazole; L = 2-Pyridine (2)]

<Step 1>
Using the compound of formula (H-1) (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature) and 2-hydrazinopyridine, [Production Method G] <Step The compound of the formula (H-2) can be produced by performing a reaction according to 1>.

<Step 2>
[Production Method H] Using the compound of formula (H-2) obtained in <Step 1>, a reaction according to [Production Method E] <Step 2> is carried out to give a compound of formula (CA-5-2). Can be manufactured.

[Production Method J] Production Method of Formula (CA-5-3) [In Formula (CA), Ring B = Pyrazole; L = 2-Pyridine (3)]

In accordance with a method known in the literature, for example, the method described in “Bioorganic & Medicinal Chemistry Letters, 23, 23, pages 6341-6345, 2013”, diisopropylamine in a solvent such as tetrahydrofuran at −78 ° C. , And n-butyllithium to prepare lithium diisopropylamide, and the compound of formula (J-1) at the same temperature (the compound is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method in the literature) The reaction solution is added with excess dry ice (solid piece) or excess carbon dioxide gas at the same temperature, and reacted, and acidified with an acid such as hydrochloric acid in the post-treatment stage, the formula ( A compound of CA-5-3) can be produced.

[Combination agent containing the compound of the present invention]
The compound and pharmaceutical composition of the present invention can be used in combination with other drugs or drugs by a general method performed in the medical field. Examples of the drug that can be combined or used in combination with the compound of the present invention include (A) a sleep disorder-related drug, (B) a therapeutic drug for a disease that easily causes sleep disorder, and the like.

Examples of the drug (A) include: (1) a sleep inducer ((i) a benzodiazepine sleep inducer [specifically, nitrazepam, estazolam, flurazepam hydrochloride, nimetazepam, flurazepam, haloxazolam, flunitrazepam, rilmazapine hydrochloride, Lormetazepam, triazolam, etc.], (ii) thienodiazepine sleep inducer [specifically, brotizolam, etc.], (iii) non-benzodiazepine sleep inducer [specifically, zolpidem, etc.], (iv) melatonin receptor operation Drugs (specifically, ramelteon, etc.), (v) cyclopyrrolone sleep inducers [specifically, zopiclone, etc.], (vi) orexin receptor antagonists [specifically, suvorexant, etc.], ( 2) Drugs prescribed for sleep apnea syndrome [specifically, acetazolamide, etc.], (3) Drugs prescribed for Treslegs syndrome ((i) benzodiazepine sleep inducers [specifically, clonazepam, etc.], (ii) dopamine agonists [specifically, levodopa, amantadine hydrochloride, bromocriptine mesylate, mesylate] Pergolide, cabergoline, talipexol hydrochloride, pramipexole hydrochloride hydrate, selegiline hydrochloride, ropinirole hydrochloride, etc.], (iii) opioid preparations [specifically, codeine etc.]) and the like.

Examples of the drug of (B) include (4) atypical antipsychotic drugs [specifically, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, paliperidone, perospirone, blonanserin, lurasidone, aripiprazole, sertindole, amisulpride, Iloperidone, bifeprunox, asenapine, melperone, brexpiprazole, zotepine, etc.], (5) typical antipsychotics [specifically, chlorpromazine, pchlorperazine, perphenazine, levomepromazine, fluphenazine, thioridazine, propericazine, spiperone] , Moperon, haloperidol, timiperone, bromperidol, pimozide, fluropipamide, sulpiride, thioprid, sultopride, nemonapride, oxypertin, etc.], (6) selection Serotonin reuptake inhibitor (SSRI) [specifically, escitalopram, citalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, etc.], (7) selective serotonin / noradrenaline reuptake inhibitor (SNRI) [specifically, MIL Nasiplan, duloxetine, venlafaxine, nefazodone, etc.], (8) selective noradrenaline / dopamine reuptake inhibitor (NDRI) [specifically, bubropine, etc.], (9) noradrenergic / specific serotonergic Antidepressant (NaSSA) [specifically, mirtazapine and the like], (10) Triazolopyridine antidepressant (SARI) [specifically, trazodone and the like], (11) Tetracyclic antidepressant [specifically In particular, cetiptiline, mianserin, maprotiline, etc.], ( 2) Tricyclic antidepressants [specifically, amitriptyline, trimipramine, imipramine, nortriptyline, clomipramine, lofepramine, amoxapine, dosrepin, etc.], (13) other antidepressants [specifically, NS-2359, Lu AA21004, DOV21947 etc.], (14) α7 nicotinic receptor agonist, (15) α7 nicotinic receptor activity modulator, (16) α7 nicotinic receptor partial modulator [specifically, SSR-180711, PNU-120596] Etc.], (17) PDE inhibitors [PDE1 inhibitors, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, PDE7 inhibitors, PDE9 inhibitors, PDE10 inhibitors, etc.], (18) NK2 antagonists, (19) NK3 antagonist,

(20) Muscarinic M1 acetylcholine receptor activity modulator, (21) Muscarinic M2 acetylcholine receptor activity modulator, (22) Adenosine receptor modulator, (23) Muscarinic M4 acetylcholine receptor activity regulator, (24 ) Muscarinic M5 acetylcholine receptor activity modulator, (25) adenosine receptor modulator, (26) glycine transporter 1 (GlyT1) inhibitor [specifically, ALX5407, SSR504734, etc.], (27) glutamate enhancer [Specifically, ampakine], (28) NMDA receptor inhibitor [specifically, memantine hydrochloride and the like], (29) metabolic glutamate receptor modulator (mGlu) [specifically, CDPPB, MPEP Etc.], (30) Anti-anxiety drugs ((i) benzodiazepine anxiolytic drugs [specifically Chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, lorazepam, dipotassium chlorazepate, prazepam, bromazepam, fludiazepam, mexazolam, alprazolam, fltoprazepam, flutazolam, ethyl loflazepate, etc. Ethiram, clothiazepam, etc.], (iii) serotonin 5-HT1A agonist [specifically, tandospirone, etc.)), (31) β-amyloid vaccine, (32) β-amyloid degrading enzyme, etc., (33) activation of brain function Drug [specifically, aniracetam, nicergoline, etc.], (34) cannabinoid modulator, (35) cholinesterase inhibitor [specifically, donepezil hydrochloride, rivastigmine, galantamine hydrobromide, etc.], (36) AO-B inhibitors [specifically, lasalidine, etc.], (37) Parkinson's disease therapeutic agent ((i) dopamine receptor agonists [specifically, levodopa, amantadine hydrochloride, bromocriptine mesylate, pergolide mesylate, Cabergoline, talipexol hydrochloride, pramipexole hydrochloride hydrate, selegiline hydrochloride, ropinirole hydrochloride, etc.], (ii) monoamine oxidase inhibitors [specifically, deprenyl, sergiline (selegiline), remasemide, riluzole, etc.], (iii) anti Choline agents [specifically, trihexyphenidyl, prophenamine, biperidene, pyroheptin hydrochloride, methixene hydrochloride, masaticol hydrochloride, etc.], (iv) COMT inhibitors [specifically, entacapone, etc.], (v) muscle atrophy Drugs for lateral sclerosis [specifically, riluzole and other neurotrophic factors Etc.], (vi) Apoptosis inhibitors [specifically CPI-1189, IDN-6556, CEP-1347, etc.], (vii) Neural differentiation / regeneration promoters [Specifically, leteprinim, xaliproden (Xaliproden; SR-57746-A], SB-216763 etc.),

(38) Antidiabetic agent ((i) PPARγ agonist (agonist, inhibitor) [specifically, pioglitazone, rosiglitazone, troglitazone, siglitazone, darglitazone, englitazone, netoglitazone, etc.], (ii) insulin Secretion enhancer [(a) sulfonylurea (specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glipentide, glyquidone, glisolamide, tolazamide, etc.), (b) non-sulfonylurea Agents, etc.], (iii) fast-acting insulin secretagogues (specifically, nateglinide, mitiglinide, repaglinide, etc.), (iv) α-glucosidase inhibitors [specifically, acarbose, voglibose, miglitol, camiglibose, adiposine, Emigli Tate, pradimicin-Q, sarvostatin, etc.], (v) insulin sensitizers [specifically, (a) PPAR-γ agonists, (b) PTP-1B inhibitors, (c) DPP-4 inhibition Drugs [specifically sitagliptin, vildagliptin, alogliptin, saxagliptin, NVP-DPP-728, etc.], (d) GLP-1 and GLP-1 agonists [specifically, exenatide, liraglutide, etc.], (e) 11β-HSD inhibitors, etc. (f) GPR40 agonists, (g) GPR119 agonists, (h) GPR120 agonists], (vi) hepatic gluconeogenesis inhibitors [specifically, glucagon antagonists, etc.], vii) biguanides [specifically, metformin, buformin, phenformin, etc.], (viii) insulin or insulin derivatives [specifically, insulin Phosphorus zinc suspension, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, mixed insulin, etc.], (ix) α2 antagonist [specifically, midaglyzol, isagridol, deliglidol, idazoxan , Efaloxane, etc.]),

(39) anti-obesity drugs ((i) adrenergic β3 receptor agonists [specifically, KRP-204, TRK-380 / TAC-301, etc.], (ii) CB-1 receptor antagonists [specifically Rimonabant, SR-147778, BAY-65-2520 etc.], (iii) Neuropeptide Y (NPY) receptor antagonist [specifically, S-2367 etc.], (iv) Antifeedant [monoamine] Reuptake inhibitors [specifically sibutramine, mazindol, etc.]], (v) lipase inhibitors [specifically, orlistat, cetiristat, etc.], (vi) peptide YY (PYY) receptor antagonists, etc.), (40) Antihyperlipidemic drugs such as cholesterol-lowering drugs ((i) ω3 fatty acids [specifically, ethyl icosapentate (EPA-E preparation, for example, product name: Epadale (registered trademark) ), Docosahexaenoic acid (DHA), ethyl icosapentate and ethyl docosahexaenoate (eg, product name: Lovaza (registered trademark), omacol (registered trademark), etc.), etc.], (ii) HMG-CoA reductase inhibitor [Specifically, atorvastatin, simvastatin, pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, etc.] (iii) HMG-CoA synthase inhibitor, (iv) cholesterol absorption inhibitor [specifically , Ezetimibe], (v) acyl-CoA / cholesterol acyltransferase inhibitor, (vi) CETP inhibitor, (vii) squalene synthase inhibitor, (viii) antioxidant [specifically, probucol and the like], (Ix) PPARα agonist [specifically, black Ibrate, etofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrozil, KRP-101, etc.], (x) PPARδ agonist, (xi) LXR agonist, (xii) FXR agonist [specifically, INT-747 Etc.], (xiii) MTTP inhibitor, (xiv) squalene eposidase inhibitor, etc.)

(41) Antihypertensive agent ((i) diuretic [specifically, trichlormethiazide, hydrochlorothiazide, mefluside, indapamide, methiclan, chlorthalidone, tripamide, furosemide, torasemide, bumetanide, ethacrynic acid, spironolactone, triamterene, eplerenone, etc.] (Ii) Calcium receptor antagonists [specifically, amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, nilvadipine, alanidipine, azelnidipine, manidipine, varnidipine, efonidipine, cilnidipine, benidipine, diltiazem etc.], (synten) Converting enzyme inhibitors [specifically, captopril, lisinopril, enalapril, delapril, perindopril, benazepril, trandolapril, Napril, alacepril, imidapril, temocapril, cilazapril, etc.], (iv) angiotensin receptor antagonist [specifically, losartan, olmesartan, telmisartan, valsartan, candesartan cilexetil, irbesartan, etc.], (v) direct renin inhibition Drugs [specifically, aliskiren, etc.], (vi) α receptor blockers [specifically, tolazoline, phentolamine, doxazosin, prazosin, bunazosin, terazosin, urapidil, etc.], (vii) β receptor blockers [ Specifically, bopindolol, pindolol, timolol, dichloroisoprenalin, alprenolol, carteolol, indenolol, bunitrolol, penbutolol, propranolol, nadolol, nipradilol, chilisolol, acebutol Lumpur, celiprolol, metoprolol, atenolol, bisoprolol, betaxolol, practolol, bevantolol, butoxamine, carvedilol, amosulalol, arotinolol, labetalol, etc.], the (viii) α ₁ β-blockers [specifically, carvedilol, labetalol, Arotinolol, bevantolol, etc.], (ix) α ₂ receptor stimulants [specifically, clonidine, methyldopa, guanfacine, etc.]),

(42) Non-steroidal anti-inflammatory drugs [specifically, meloxicam, teoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.], (43) disease-modifying anti-rheumatic drugs, (44) anti-cytokine drugs [44] Specifically, TNF inhibitors, MAP kinase inhibitors], (45) steroid drugs [specifically, dexamethasone, hexestrol, cortisone acetate, etc.], (46) sex hormones or derivatives thereof [specifically, , Progesterone, estradiol, estradiol benzoate, etc.], (47) parathyroid hormone, (48) opioid agonist [specifically, morphine, pentazocine, tramadol], (49) pilin antipyretic analgesic [specifically, Sulpyrine], (50) non-pyrine antipyretic analgesics [specific Acetaminophen (paracetamol)], (51) non-steroidal anti-inflammatory drugs (NSAIDs) [specifically, aspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, Zaltoprofen, piroxicam, lornoxicam, epirisol, thiaramide], (52) COX-2 selective inhibitor [specifically, celecoxib], (53) peripheral neuropathic pain / fibromyalgia agent [specifically , Pregabalin]. In addition, the following drugs that have been diverted to neuropathic pain and are prescribed (54) antiepileptic drugs [specifically, gabapentin, phenytoin, carbamazepine] and the like can be mentioned.

By using in combination with existing drugs for the above diseases, the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced. Of course, the combination method using the said drug is not limited to the said disease, and the drug used together is not limited to the compound illustrated above.
When the compound of the present invention is used in combination with a drug used in combination, it may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.

The compounds of the present invention can be administered either alone or in combination with a pharmaceutically acceptable carrier, either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution, and various organic solvents. The pharmaceutical composition thereby formed can then be easily administered in various dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injection solutions and the like. These pharmaceutical compositions can optionally contain additional ingredients such as flavoring agents, binders, excipients and the like. Accordingly, the compounds of the present invention may be used for oral, buccal, nasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), transdermal (eg, patch), or rectal administration, or by inhalation or insufflation. Can be formulated in a form suitable for administration by.

[Combination / Combination / Combination dosage form]
The administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Such dosage forms include, for example,
(1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug,
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug,
(3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference,
(4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention → the concomitant drug) Or administration in the reverse order). Hereinafter, these administration forms are collectively abbreviated as the combination agent of the present invention.

When administering the concomitant drug of the present invention, the concomitant drug and the compound of the present invention may be administered at the same time, but after administering the concomitant drug, the compound of the present invention may be administered. A concomitant drug may be administered after administration of the compound of the invention. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering the concomitant drug first, preferably within 1 minute to 3 days after administering the concomitant drug. Includes a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. The method of doing is mentioned.

Any amount of the concomitant drug can be set as long as side effects are not a problem. The daily dose as a concomitant drug varies depending on the administration subject, administration route, target disease, symptom, etc., for example, when orally administered to a patient with schizophrenia (adult, body weight about 60 kg), Usually, the dose is about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer once to several times (eg, 2, 3, 4 or 8 times).
When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet. (Including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, and the like, which can be oral or parenteral (Eg, topical, rectal, intravenous, etc.).

As the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention, the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.
The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by mass of the concomitant drug may be used per 1 part by mass of the compound of the present invention.
For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0, based on the whole preparation. The range is from 1 to 50% by mass, and more preferably from about 0.5 to 20% by mass.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by mass, preferably about 0.1 to about It is in the range of 50% by weight, more preferably in the range of about 0.5 to about 20% by weight.
The content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by mass, preferably about 10 to about 90% with respect to the whole preparation. It is the range of mass%.
The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and it may be necessary to administer beyond the range.

[Formulation of the preventive / therapeutic agent of the present invention]
The medicament of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the present invention only needs to contain at least one of the compounds represented by the formula (I) of the present invention, and is optionally combined with a pharmaceutically acceptable additive. More particularly, excipients (eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricants (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrants (eg; starches (corn starch, potato starch), carboxymethyl starch sodium, potassium Lumellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer LD), plastic) Agents (e.g. triethyl citrate, macrogol), masking agents (e.g. titanium oxide), colorants, flavoring agents, preservatives (e.g. benzalkonium chloride, paraoxybenzoate), isotonic agents (e.g .; Glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH adjuster (eg; buffer solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stabilizer (eg; Sugar, sugar alcohol, xanthan gum), dispersant, antioxidant (eg Asco Binic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffer, preservative (eg, paraben, benzyl alcohol, benzalkonium chloride), fragrance (eg, vanillin, l-menthol) , Rose oil), solubilizers (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancers (eg, sodium glycolate, sodium edetate, sodium caprate) , Acylcarnitines, limonene), gelling agents, suspending agents, or emulsifiers, commonly used suitable additives or solvents, and various combinations of the compounds of the present invention. I can do it.

Various dosage forms include, for example, tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, troches, liquids, spirits, suspensions Agents, extracts, elixirs and the like. The medicament of the present invention is, for example, oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration. It can be administered to patients by intraventricular administration, rectal administration, inhalation and the like.

The compounds of the present invention can be formulated for parenteral administration by injection, including using conventional catheter techniques or infusion. Injectable formulations may be presented as unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives. These formulations can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulation agents such as suspending, stabilizing, and / or dispersing agents. be able to. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

If a product solution is required, the product solution is isolated and included in water (or other aqueous medium) in an amount sufficient to produce a solution of the strength required for oral or parenteral administration to the patient. It can be produced by dissolving the complex. These compounds can be formulated into rapidly dispersed dosage forms (fddf) that are designed to release the active ingredient in the oral cavity. These formulations are often formulated using a matrix based on fast dissolving gelatin. These dosage forms are well known and can be used to deliver a wide range of drugs. Most rapid dispersion dosage forms utilize gelatin as a carrier or structure-forming agent. Gelatin is typically used to give a dosage form sufficient strength to prevent breakage when removed from the package, but once in the mouth, gelatin allows the dosage form to break down immediately. . Alternatively, various starches are used to achieve the same effect.

The compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, the compounds of the invention may be administered in the form of a solution or suspension from a pump spray container which is squeezed or pumped by the patient, or a suitable propellant such as dichloromethane. Conveniently delivered as an aerosol spray presentation from a pressurized container or nebulizer using difluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a metered amount. A pressurized container or nebulizer can contain a solution or suspension of the active compound. Capsules and cartridges (eg, made from gelatin) for use in an inhaler or insufflator should be formulated containing a mixed powder of a compound of the invention and a suitable powder base such as lactose or starch. Can do.

Aerosol formulations for treating the above-described conditions (eg, migraine) in the average adult preferably each metered dose or “puff” of the aerosol contains from about 20 mg to about 1000 mg of the compound of the invention. Is set as follows. The total daily dose with an aerosol will be within the range of about 100 mg to about 10 mg. Administration can be several times daily, for example 2, 3, 4 or 8 times, for example 1, 2 or 3 doses each time.

Proposed daily doses of the compounds of the invention administered orally, parenterally, rectally, or buccally to the average adult to treat the above conditions are, for example, units that can be administered 1 to 4 times daily From about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg, of the active ingredient of formula (I) per dose.

[Pharmacological experiment example]
Hereinafter, the present invention will be specifically described with reference to experimental examples, but the present invention is not limited to these examples.
The following Pharmacological Examples 1 to 11 provide methods for testing the effectiveness of the compounds of the present invention.

Pharmacological Experiment Example 1: Evaluation of orexin receptor antagonistic activity Evaluation of antagonistic activity against human orexin 1 receptor (hOX1R) and human orexin 2 receptor (hOX2R) was performed by the following method. CHO-DXB11 cells stably expressing hOX1R and hOX2R were seeded at 40,000 cells / well in a 96-well black bottom plate (Greiner), 100 units / mL penicillin-0.1 mg / mL streptomycin solution (Invitrogen), In Ham's F-12 medium (SIGMA) containing 0.4 mg / mL G418 (Invitrogen), 10% non-immobilized fetal calf serum (Cell Culture Bioscience or SIGMA) under conditions of 37 ° C. and 5% CO ₂ Incubated overnight. After removing the extracellular fluid, a buffer containing 1.25 mmol / L probenecid (SIGMA) and FLIPR Calcium 5 assay kit (Molecular Devices) (20 mmol / L HEPES (SIGMA), Hank's balanced salt solution (HBSS) ( 200 μL of Invitrogen)) was added and incubated for 60 minutes. Prepare a dimethyl sulfoxide (Wako Pure Chemicals) solution so that the test compound is 10 mM, and assay buffer (0.1%) to a final concentration of 10-10000 nM (hOX1R) or a final concentration of 3-3000 nM (hOX2R). After dilution with bovine serum albumin (BSA), 20 mmol / L HEPES (SIGMA), HBSS (Invitrogen)), 25 μL was added and incubated for 5 minutes. The agonist orexin-A (Tocris bioscience) was prepared in assay buffer so that the final concentration was the same as EC80 measured in advance on the same day, and the reaction was started by adding 25 μL to each well. Using a Functional Drug Screening System (FDSS: Hamamatsu Photonics) for 3 minutes from the start of the reaction, the fluorescence value (Ex. 480 nm / Em. 540 nm), which is an index of intracellular Ca ²⁺ concentration, was measured over time.
Orexin receptor antagonistic activity of the test compounds are expressed as an IC ₅₀ value, an IC ₅₀ value is +++ The following compounds 40 nmol / L, an IC ₅₀ value greater than 40nmol / L 200nmol / L following compounds of the present invention ++, the IC ₅₀ values are 200 nmol / L a greater than 1000 nmol / L or less of compound +, an IC ₅₀ value is the 1000 nmol / L is greater than compounds - shown as in Table 1.

Pharmacological Experiment Example 2: Evaluation of [Ala ¹¹ , D-Leu ¹⁵ ] -Orexin B-Induced Locomotor Activity After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals were subjected to an experiment with an acclimatization period of at least one week. use. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water.
[Ala ¹¹ , D-Leu ¹⁵ ] -Orexin B (ADL-OXB) (Tocris bioscience) induction using rats to confirm the antagonism of test compounds against the interaction of orexin and orexin 2 receptor in the brain Perform spontaneous exercise test. ADL-OXB is a peptide in which two amino acids of human orexin B are substituted, and has a 400 times higher affinity for OX2R than OX1R. In order to administer ADL-OXB intracerebroventricularly, rats are cannulated and kept for at least 1 week as a recovery period. In order to confirm whether the cannula is implanted at the correct position after the recovery period, 100 ng / 5 μL of angiotensin 2 (Peptide Institute) is administered intraventricularly as a preliminary test, and the amount of water consumed for 30 minutes after the administration is measured. Only rats that have reached 5 g of drinking water are used in this study. Rats are acclimated for at least 120 minutes in the measurement cage until this test. After acclimatization, either vehicle or test compound is administered and immediately returned to the measurement cage. 30 to 120 minutes after administration of the test compound, the rat is again taken out from the housing cage, and the solvent (saline) or ADL-OXB (3 nmol / 5 μL / rat) is administered into the ventricle and immediately returned to the measurement cage. Spontaneous momentum is measured in a spontaneous momentum measurement chamber (Muromachi Kikai) equipped with an infrared sensor. Spontaneous exercise is counted every 10 minutes, and cumulative counts for 30, 60, 120 minutes after ADL-OXB administration are calculated for each treatment group. All data are expressed as mean and standard error of the mean. For statistical analysis, comparison between the control group and ADL-OXB single administration group was performed using Student's t-test (significant difference at p <0.05), and comparison between ADL-OXB single administration group and test compound administration group Uses Dunnett's test (significantly different at p <0.05).

Pharmacological experiment example 3: Sleep EEG measurement test
After purchasing male Sprague-Dawley rats and arriving at the breeding facility, the animals are used for experiments with an acclimatization period of at least one week. Animals are housed in a laboratory with controlled temperature and humidity under a 12 hour light / dark cycle, with free access to food and water.
In order to confirm the effect on sleep, a sleep electroencephalogram test in rats is performed. Rats are subjected to EEG and EMG electrode implantation surgery for electroencephalogram (EEG) and electromyogram (EMG) measurement, and are kept for at least 1 week as a recovery period. After administration of vehicle or test compound, EEG and EMG signals are recorded for 6-12 hours.
The analysis is performed by using an automatic analysis software SleepSign (registered trademark) (Kissei Comtech) to analyze an electroencephalogram frequency and an electromyogram activity signal to classify one of three stages of arousal, REM sleep, and NREM sleep. The cumulative time of each stage is calculated, and the sleep action of the test compound is confirmed from the decrease in the awakening time and the increase in the total sleep time (REM sleep + NREM sleep). Moreover, the percentage of REM sleep with respect to the total sleep time is calculated, and it is examined whether a physiological sleep pattern is shown by comparing with the result of the control group.

Pharmacological Experiment Example 4: Solubility Test (1) DMSO Precipitation Solubility (Kinetic Solubility)
A 10 mM DMSO solution of the compound of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 μM. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, then filtered through a filter plate (MultiScreen _HTS- PCF filter plate (Merck Millipore)), and using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength. At the same time, the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 μM) of the test compound is added as a calibration curve standard solution, and a calibration curve is created. The solubility (μM) of the compound is calculated from the absorbance values of the filtrate and standard solution.
(2) Crystal solubility (Thermodynamic Solubility)
The compound of the present invention is added to a solvent (for example, water, buffer) so as to be 1 mg / mL. The solution is incubated with stirring at 1000 rpm for 24 hours at 25 ° C. or 37 ° C. and then filtered through a filter plate. The filtrate is analyzed by HPLC, the peak is detected at the maximum absorption wavelength, and the peak area is measured. Similarly, a solution (eg, DMSO solution, 1,4-dioxane solution) to which a known concentration of the test compound (eg, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 μg / mL) is added. , Methanol solution) is used as a standard curve standard solution to measure each peak area, and the solubility (μg / mL) of the compound is calculated from the peak area of the standard curve.

Pharmacological experiment example 5: Metabolic stability test (1) Metabolic stability test 1
Liver microsome solution (human, rat, mouse, dog or monkey; XenoTech), NADPH generating solution (β-NADP, Glucose-6-phosphate, G-6) -PDH (Y), water containing MgCl ₂ ). The solution is incubated at 37 ° C. for 5, 10, 20 or 30 minutes and then quenched with acetonitrile. The reaction solution is centrifuged through a filter plate (MultiScreen _HTS- HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and the residual rate (%) at each time point is calculated. The reaction time is plotted on the horizontal axis and the residual ratio is plotted on the vertical axis, and the clearance (μL / min / mg protein) is calculated from the slope.
(2) Metabolic stability test 2
A 10 mM DMSO solution of the compound of the present invention is added to a hepatocyte suspension (human; GIBCO, rat, dog, monkey; XenoTech) to a final concentration of 1 μM. The solution is incubated at 37 ° C. for 5, 15, 30, 45, 60, 120 minutes and then quenched with acetonitrile. The reaction solution is centrifuged through a filter plate (MultiScreenHTS-HV plate (Merck Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and the residual rate (%) at each time point is calculated from the ratio of the hepatocyte reaction sample and the control. The reaction time is plotted on the horizontal axis and the residual ratio is plotted on the vertical axis, and the clearance (μL / min / mg protein) is calculated from the slope.

Pharmacological Experiment Example 6 hERG Inhibition Test by Patch Clamp Method The effect on hERG (human ether-a-go related gene) channels is measured using a fully automatic patch clamp system (QPatch HT (Sophion Bioscience)). To confirm the hERG I _Kr current of the cells (CHO hERG DUO (B'SYS)), the membrane potential is held at −80 mV, followed by a depolarization pulse of −50 mV, 0.02 seconds and 20 mV, 4.8 seconds. -50 mV, 5 seconds of repolarization pulse given once every 15 seconds. The effect of the test compound on the hERG channel is confirmed by the tail current change induced by the repolarization pulse. The measurement is performed at room temperature. The hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 4 minutes after the addition relative to the tail current peak value before the addition of the test compound.
By calculating this suppression rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.

Pharmacological Experiment Example 7: Pharmacokinetics (PK) test (1) Rat cassette PK test 1 mg / kg of the present compound in 7 or 8 weeks old male CD (SD) IGS Jcl (administration solvent is DMSO: Tween 80: over (Pure water = 1: 1: 8, 10 mL / kg), and the blood is collected from the abdominal vena cava 0.5, 1, 2, and 4 hours later. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added was measured, and a calibration curve was prepared. The plasma concentration (μg / mL) is calculated, and the maximum plasma concentration is defined as Cmax (μg / mL).
(2) PK test 1 mg of the compound of the present invention in an animal (male Crl: CD (SD) rat, about 7 to 8 weeks old, male beagle dog about 4 years old, or male cynomolgus monkey about 6 years old) / Kg (administration solvent is dimethylacetamide: Tween 80: ultrapure water = 4: 4: 2, 1 mL / kg) or intravenous administration or 10 mg / kg (administration solvent is 0.5% methylcellulose, 5 mL / kg) After administration, blood is collected from the jugular vein 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours later. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, known concentrations of test compounds (0.001, 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 10 μg / (mL) is measured, the plasma concentration (μg / mL) is calculated from the prepared calibration curve, and the maximum plasma concentration is defined as Cmax (μg / mL).

Pharmacological Experiment Example 8: Protein Binding Test A 10 mM DMSO solution of the compound of the present invention is added to normal plasma (human, rat, dog, monkey) to a final concentration of 10 μM. After dialyzing for 4 hours at 37 ° C. with a simple equilibrium dialysis machine (HTD96b Complete Unit (HTDialissis)), the test compound concentrations in the inner (plasma side) solution and outer (PBS side) solution of the dialysis membrane were measured using a high-performance liquid chromatogram. / Measure using mass spectrometry. The non-binding fraction (%) is calculated from the ratio between the PBS side and the plasma side, and the protein binding rate (%) is calculated from 100−non-binding fraction (%).
Pharmacological experiment example 9: Calculation of various parameters in pharmacokinetics test Model-independent analysis of time course of plasma concentration obtained by PK test in rat, dog and monkey animal species (pharmacological experiment example 7) Systemic clearance CLtot (L / kg / hr), distribution volume Vdss in steady state (L / kg), plasma concentration-time curve area AUC (μg · hr / mL), half-life T1 / 2 (hr) Is calculated. In addition, the bioavailability is calculated by comparing the AUC at the time of intravenous administration with the AUC at the time of oral administration.

Pharmacological experiment example 10: Prediction of pharmacokinetic parameters in humans Various parameters in animal pharmacokinetic tests, metabolic stability in in vitro tests, proteins obtained by the method described in pharmacological experiment examples 5, 7 or 8 Using parameters such as binding rate, pharmacokinetic parameters in humans are predicted by methods known to those skilled in the art such as allometric scaling or IVIVE (in vitro / in vivo extrapolation).

Pharmacological Experiment Example 11: Safety test The compound of the present invention is orally administered to a mouse or rat once, and no deaths are observed, and no remarkable behavioral abnormality is observed, indicating the safety of the compound of the present invention.

From the above results, it was shown that the compound of the present invention has an excellent orexin receptor antagonistic action. Furthermore, orexin antagonism is shown by an antagonism test against [Ala ¹¹ , D-Leu ¹⁵ ] -orexin B-induced locomotor activity enhancement using rats, and sleep action is shown by a sleep electroencephalogram measurement test. In addition, no abnormality is observed in the safety test, indicating the low toxicity of the present invention. Furthermore, it is confirmed that the compound of the present invention is good in one point such as solubility, metabolic stability, pharmacokinetics, and avoidance of hERG channel inhibitory effect by conducting the above test.

Therefore, the compounds of the present invention are orexin receptor antagonists, such as sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorders, attention deficit hyperactivity) Prevention of diseases such as sexual disorders, autism, autism spectrum disorder, drug dependence), neurodegenerative diseases (Alzheimer's disease, etc.), memory disorders (dementia, etc.) and eating disorders (eg, bulimia) It is expected to be used as a therapeutic agent.
The compound of the present invention is expected to show promising preventive or therapeutic effects for various diseases shown below. Specifically, insomnia, circadian rhythm sleep disorder, sleep-related comorbidities, depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum disorder, drug addiction, Promising therapeutic effects can be expected for Alzheimer's disease, dementia, bulimia and the like.

Next, in order to describe the present invention in more detail, examples and production examples will be given. However, these examples are merely implementations, and do not limit the present invention, and do not depart from the scope of the present invention. It may be changed with.

For the measurement of nuclear magnetic resonance spectrum (NMR), JEOL JNM-ECX400 FT-NMR (JEOL) or JEOL JNM-ECX300 FT-NMR (JEOL) was used.
Liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by one of the following methods. [UPLC] Waters UPLC-ZQ MS system (Waters) and MGIII-H column (2.1 mm × 5 cm, 3 μm) (Shiseido) were used, and the mobile phase was methanol: 0.05% trifluoroacetic acid aqueous solution = 5: 95. Gradient conditions from (0 minutes) to 100: 0 (1 minute) to 100: 0 (2 minutes) were used. [LCMS] Waters FractionLynx MS system (Waters) and SunFire column (4.6 mm × 5 cm, 5 μm) (Waters) were used, and the mobile phase was [Method A] methanol: 0.05% aqueous trifluoroacetic acid = 10: 90 (0 min) to 100: 0 (5 min) to 100: 0 (7 min), or [Method B] methanol: 0.05% aqueous acetic acid solution = 10: 90 (0 min) to 100: 0 (5 min) Gradient conditions of ˜100: 0 (7 minutes) were used. For the preparative system, gradient conditions appropriately changed depending on the compound were used.
For the synthesis using the microwave, a microwave synthesizer Initiator (registered trademark) Sixty (Biotage) was used.

¹ H-NMR data, NMR signal pattern, s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad, J is coupling constant, Hz is Hertz, CDCl ₃ Represents deuterated chloroform, DMSO-d ₆ represents deuterated dimethyl sulfoxide, and CD3OD represents deuterated methanol. ^{In the 1} H-NMR data, signals that cannot be confirmed due to broadband, such as protons of hydroxyl groups, amino groups, and carboxyl groups, are not described in the data.
The LC-Mass data was indicated as “UPLC”, “LCMS [Method A]” or “LCMS [Method B]” in each example. In the LC-Mass data, [M + H] ⁺ , [M + Na] ⁺ and [M-CO ₂ ] ⁺ mean molecular ion peaks.
“Room temperature” in the examples and production examples represents the temperature in the laboratory, usually 20 ± 15 ° C.

Production Example 1 Synthesis of 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) <Step 1> tert-Butyl 8- ( Synthesis of 4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 1-1) tert-butyl 3,8-diazabicyclo [3. 2.1] Add 2-chloro-4,6-dimethylpyrimidine (0.86 g) to a mixture of NMP (5.0 mL) of octane-3-carboxylate (1.1 g) and potassium carbonate (1.7 g). The mixture was stirred at 100 ° C. for 16 hours in a nitrogen atmosphere. The reaction solution was cooled to room temperature, ethyl acetate was added, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 70:30) to obtain the title compound (1.6 g) as a colorless liquid. .
UPLC: 319 [M + H] ⁺ (retention time 1.00 min)

<Step 2> Synthesis of 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) tert-butyl 8- (4,6-dimethyl Pyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 1-1) (1.6 g) in dichloromethane (5.0 mL) in trifluoroacetic acid ( 5.0 mL) was added and stirred at room temperature for 1 hour under a nitrogen atmosphere. The residue obtained by evaporating the reaction solution under reduced pressure was dissolved in 1N hydrochloric acid (20 mL) and washed with an ethyl acetate-heptane mixed solvent (1: 1). A 1N aqueous sodium hydroxide solution (30 mL) and sodium chloride were added to the obtained aqueous layer, followed by extraction five times with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.0 g) as a white solid.
UPLC: 219 [M + H] ⁺ (retention time 0.59 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 6.26 (1H, s), 4.75-4.70 (2H, m), 3.13-3.07 (2H, m), 2.73-2.67 (2H, m), 2.28 (6H, s), 2.05-1.87 (4H, m).

Production Example 2 Synthesis of 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 2) <Step 1> Synthesis of 2-chloro-4-iodo-3-methoxypyridine (intermediate 2-1) A solution of 2-chloro-3-methoxypyridine (4.0 g) in THF (80 mL) was cooled to −78 ° C., then 1 .6M n-BuLi hexane solution (19 mL) was gradually added and stirred for 1 hour. Thereafter, iodine (7.8 g) was added to the reaction solution, and the mixture was further stirred for 30 minutes. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (6.0 g) as a colorless solid. .
UPLC: 270 [M + H] ⁺ (retention time 0.99 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.78 (1H, d, J = 5 Hz), 7.66 (1H, d, J = 5 Hz), 3.92 (3H, s).

<Step 2> Synthesis of 2-chloro-3-methoxy-4- (trifluoromethyl) pyridine (intermediate 2-2) 2-chloro-4-iodo-3-methoxypyridine (intermediate 2-1) (3) (Trifluoromethyl) trimethylsilane (8.3 mL) was added to a DMF (20 mL) mixture of potassium fluoride (2.1 g) and copper (I) iodide (3.4 g) under a nitrogen atmosphere. The mixture was heated to reflux in an oil bath at 85 ° C. for 4 hours. The reaction solution was cooled to room temperature, added with 10% aqueous ammonia, extracted with diethyl ether, and then washed with water and saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 92: 8) to give the title compound (1.2 g) was obtained as a pale yellow liquid.
UPLC: 212 [M + H] ⁺ (retention time 1.01 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.31 (1H, d, J = 5 Hz), 7.44 (1H, d, J = 5 Hz), 4.01 (3H, s).

<Step 3> tert-Butyl 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 2) -3) Synthesis of tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.89 g), 2-chloro-3-methoxy-4- (trifluoromethyl) pyridine (intermediate) Body 2-2) (0.88 g), sodium tert-butoxide (0.48 g), RuPhos (60 mg) in THF (10 mL) was added RuPhos Pd G2 (0.10 g), and the mixture was heated at 90 ° C. under a nitrogen atmosphere. For 3.5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 85:15) to obtain the title compound (0.85 g) as a yellow liquid. .
UPLC: 410 [M + Na] ⁺ (retention time 1.24 minutes)

<Step 4> Synthesis of 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) tert-butyl 8- To (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 2-3) (0.85 g) Trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction solution was evaporated under reduced pressure, an ethyl acetate-heptane mixed solvent (1: 1) was added to the resulting residue, and the mixture was extracted 3 times with 1N hydrochloric acid. A 1N aqueous sodium hydroxide solution and sodium chloride were added to the resulting aqueous layer, followed by extraction five times with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.56 g) as a pale purple liquid.
UPLC: 288 [M + H] ⁺ (retention time 0.83 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.03 (1H, d, J = 5 Hz), 6.86 (1H, d, J = 5 Hz), 4.59-4.52 (2H, m), 3.78 (3H, s ), 3.21-3.15 (2H, m), 2.74-2.68 (2H, m), 2.00-1.87 (4H, m).

Production Example 3 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Intermediate 3) <Step 1> 2-Chloro-3 Synthesis of -methoxyisonicotinic acid (intermediate 3-1) A solution of 2-chloro-3-methoxypyridine (5.2 g) in THF (100 mL) was cooled to -78 ° C, and then 1.6 M n-BuLi hexane The solution (25 mL) was added slowly and stirred for 1 hour. Thereafter, dry ice was added to the reaction solution, and the temperature was gradually raised to room temperature. A saturated aqueous ammonium chloride solution was added to adjust to pH = 6, and then back extraction was performed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer to adjust to pH = 2, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (6.3 g) as a colorless solid.
UPLC: 188 [M + H] ⁺ (retention time 0.71 minutes)
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 8.26 (1H, d, J = 5 Hz), 7.62 (1H, d, J = 5 Hz), 3.87 (3H, s).

<Step 2> Synthesis of 2-chloro-3-methoxyisonicotinamide (Intermediate 3-2) 2-Chloro-3-methoxyisonicotinic acid (Intermediate 3-1) (6.8 g), pyridine (15 mL) To a mixed solution of ammonium hydrogen carbonate (14 g) in 1,4-dioxane (100 mL) was added di-tert-butyl dicarbonate (13 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 0.1N aqueous hydrochloric acid solution, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (7.5 g) of the title compound as a colorless solid.
UPLC: 187 [M + H] ⁺ (retention time 0.61 minutes)

<Step 3> Synthesis of 2-chloro-3-methoxyisonicotinonitrile (Intermediate 3-3) 2-Chloro-3-methoxyisonicotinamide (Intermediate 3-2) obtained in Step 2 of Production Example 3 After cooling a mixed solution of crude product (7.4 g) and triethylamine (15 mL) in dichloromethane (66 mL) to 0 ° C., trifluoroacetic anhydride (7.5 mL) was gradually added, and the reaction solution was stirred at 0 ° C. for 30 minutes. Stir for minutes. After returning the reaction solution to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with diethyl ether. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 100: 0 to 90:10), The title compound (4.8 g) was obtained as a colorless solid.
UPLC: 169 [M + H] ⁺ (retention time 0.83 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz), 4.17 (3H, s).

<Step 4> of tert-butyl 8- (4-cyano-3-methoxypyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 3-4) Synthesis 2-chloro-3-methoxyisonicotinonitrile (intermediate 3-3) (0.87 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (1.0 g ), RuPhos (0.22 g) and cesium carbonate (2.3 g) in a tetrahydrofuran (10 mL) mixed solution were added RuPhos Pd G2 (0.37 g), and the mixture was stirred at 90 ° C. for 15 hours in a nitrogen atmosphere. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 84:16) Compound (1.1 g) was obtained as a yellow liquid.
UPLC: 367 [M + Na] ⁺ (retention time 1.15 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.99 (1H, d, J = 5 Hz), 6.83 (1H, d, J = 5 Hz), 4.73-4.61 (2H, m), 3.92 (3H, s ), 3.91-3.66 (2H, m), 3.27-3.08 (2H, m), 1.99-1.76 (4H, m), 1.46 (9H, s).

<Step 5> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (Intermediate 3) The same method as in Step 4 of Production Example 2 Alternatively, tert-butyl 8- (4-cyano-3-methoxypyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 3- 4) The title compound (0.75 g) was obtained as a yellow liquid using (1.1 g).
UPLC: 245 [M + H] ⁺ (retention time 0.66 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.00 (1H, d, J = 5 Hz), 6.85 (1H, d, J = 5 Hz), 4.70-4.64 (2H, m), 3.92 (3H, s ), 3.28-3.18 (2H, m), 2.93-2.81 (2H, m), 2.13-2.00 (4H, m).

Production Example 4 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Intermediate 4) <Step 1> tert-Butyl 8- (4-cyano Synthesis of Pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 4-1) 2-fluoroisonicotinonitrile (1.0 g), tert-butyl A mixed solution of 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (2.1 g) and DIPEA (4.3 mL) in 1-propanol (8.2 mL) at 100 ° C. under a nitrogen atmosphere. Stir for 23 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 94: 6 to 50:50) to give the title compound (1. 6 g) was obtained as a pale yellow liquid.
UPLC: 337 [M + Na] ⁺ (retention time 1.08 minutes)

<Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (intermediate 4) tert-butyl 8- (4-cyanopyridin-2-yl ) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 4-1) (1.6 g) and 4M hydrogen chloride-ethyl acetate (25 mL) in a nitrogen atmosphere. Stir at room temperature for 10 minutes. The residue obtained by evaporating the solvent under reduced pressure was adjusted to pH = 10-12 with 2N aqueous sodium hydroxide solution, and then extracted five times with a dichloromethane-isopropanol mixed solvent (3: 1). The collected extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.38 g) as a yellow solid.
UPLC: 215 [M + H] ⁺ (retention time 0.61 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.24 (1H, dd, J = 5, 1 Hz), 6.69-6.68 (1H, m), 6.67 (1H, dd, J = 5, 1 Hz), 4.45 -4.40 (2H, m), 3.08 (2H, dd, J = 12, 1 Hz), 2.71-2.64 (2H, m), 2.08-1.95 (4H, m).

Production Example 5 Synthesis of 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 5) <Step 1> tert-Butyl 8 Synthesis of — (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 5-1) tert-butyl 3,8- Diazabicyclo [3.2.1] octane-3-carboxylate (2.1 g), 2-bromo-4- (trifluoromethyl) pyridine (2.3 g), sodium tert-butoxide (1.9 g), Pd ₂ A toluene (30 mL) mixed solution of (dba) ₃ (0.46 g) and BINAP (0.62 g) was deaerated and then stirred at 90 ° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 95: 5 to 85:15) to give the title compound (2.9 g) as yellow. Obtained as a liquid.
UPLC: 380 [M + Na] ⁺ (retention time 1.18 minutes)

<Step 2> Synthesis of 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 5) Similar to step 2 of Production Example 1 Tert-Butyl 8- (4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 5) -1) The title compound (2.0 g) was obtained as a yellow solid using (2.9 g).
UPLC: 258 [M + H] ⁺ (retention time 0.74 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.26 (1H, d, J = 5 Hz), 6.69 (1H, d, J = 5 Hz), 6.67 (1H, s), 4.53-4.42 (2H, m ), 3.15-3.07 (2H, m), 2.72-2.64 (2H, m), 2.11-1.94 (4H, m).

Production Example 6 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (Intermediate 6) <Step 1> tert-Butyl 8- Synthesis of (3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) 2,3-dichloroisonicotinic acid (0.41 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.42 g) in DMSO (10 mL) mixed solution was added potassium carbonate (1.1 g). , And stirred at 150 ° C. for 3 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.0 g) of the title compound as a brown solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.18 (1H, d, J = 5 Hz), 7.00 (1H, d, J = 5 Hz), 4.66-4.33 (2H, m), 3.97-3.63 (2H , m), 3.53-2.85 (2H, m), 1.98-1.62 (4H, m), 1.51-1.42 (9H, m).

<Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile (intermediate 6) tert obtained in Step 1 of Production Example 6 -Butyl 8- (3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) crude product (1 The crude product of the title compound (0.16 g) was obtained as a brown liquid in the same manner as in Step 4 of Production Example 2 or a method analogous thereto.
UPLC: 249 [M + H] ⁺ (retention time 0.69 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.17 (1H, d, J = 5 Hz), 6.95 (1H, d, J = 5 Hz), 4.55-4.49 (2H, m), 3.24-3.16 (2H , m), 2.80-2.72 (2H, m), 2.02-1.86 (4H, m).

Production Example 7 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Intermediate 7) <Step 1> 2,3-Difluoro Synthesis of isonicotinamide (intermediate 7-1) To a solution of 2,3-difluoroisonicotinic acid (1.3 g) in 1,4-dioxane (15 mL), di-tert-butyl dicarbonate (2.8 g), carbonic acid Ammonium hydrogen (3.3 g) and pyridine (3.4 mL) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was stopped by adding a 0.1 M aqueous hydrochloric acid solution, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.2 g) as a white solid.
UPLC: 159 [M + H] ⁺ (retention time 0.51 minutes)
¹ H-NMR (CD ₃ OD, 400 MHz) δ: 8.07-8.03 (1H, m), 7.54-7.49 (1H, m).

<Step 2> of tert-butyl 8- (4-carbamoyl-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7-2) Synthesis The mixture was stirred at 120 ° C. for 15 hours using 2,3-difluoroisonicotinamide (intermediate 7-1) (0.27 g) in the same manner as in Step 1 of Production Example 6 or a method analogous thereto. The title compound (0.15 g) was obtained as a yellow liquid.
UPLC: 373 [M + Na] ⁺ (retention time 1.01 minutes)

<Step 3> of tert-butyl 8- (4-cyano-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7-3) Synthesis In the same manner as in Step 3 of Production Example 3 or a method analogous thereto, tert-butyl 8- (4-carbamoyl-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] Octane-3-carboxylate (Intermediate 7-2) (0.15 g) was used to give the title compound (0.15 g) as a yellow liquid.
UPLC: 355 [M + Na] ⁺ (retention time 1.16 minutes)

<Step 4> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicotinonitrile (Intermediate 7) The same method as in Step 4 of Production Example 2 Alternatively, tert-butyl 8- (4-cyano-3-fluoropyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 7- 3) The title compound (0.10 g) was obtained as a yellow liquid using (0.15 g).
UPLC: 233 [M + H] ⁺ (retention time 0.67 minutes)

(Production Example 8) 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d ₄ (Intermediate 8) Synthesis <Step 1> Synthesis of 3-benzyl-3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d ₄ (intermediate 8-1) 3-benzyl-3,8- To a solution of diazabicyclo [3.2.1] octane-2,4-dione (0.20 g) in diethyl ether (2.0 mL) was slowly added dropwise a 1.0 M LiAlD ₄ -diethyl ether solution (2.6 mL). In addition, the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. Water was added to stop the reaction, and the resulting precipitate was removed by filtration. The residue obtained by evaporating the solvent from the filtrate under reduced pressure was purified by column chromatography (silica gel, dichloromethane: methanol = 90: 10) to obtain the title compound (92 mg) as a yellow liquid.
UPLC: 207 [M + H] ⁺ (retention time 0.56 minutes)
¹ H-NMR (CD ₃ OD, 300 MHz) δ: 7.32-7.16 (5H, m), 3.45 (2H, s), 3.38-3.33 (2H, m), 1.95-1.85 (2H, m), 1.76-1.68 (2H, m).

<Step 2> 3-Benzyl-8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d ₄ (intermediate) 8-2) Synthesis 3-Benzyl-3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d ₄ (Intermediate 8-1) (92 mg), 2-chloro-4 DMAP (5.5 mg) and DIPEA (0.23 mL) were added to a solution of 1,6-dimethylpyrimidine (64 mg) in ethanol (1.0 mL), and the mixture was heated at 160 ° C. for 1 hour in a microwave reactor. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (0.12 g) as a white solid. .
UPLC: 313 [M + H] ⁺ (retention time 0.77 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.34-7.19 (5H, m), 6.24 (1H, s), 4.77-4.72 (2H, m), 3.44 (2H, s), 2.27 (6H, s) , 2.07-1.80 (4H, m).

<Step 3> 8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d ₄ (Intermediate 8)
3-Benzyl-8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-2,2,4,4-d ₄ (Intermediate 8-2) 10% Pd—C (40 mg) was added to a methanol solution of (0.12 g) and stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the solvent was evaporated under reduced pressure to obtain the title compound (78 mg) as a white solid.
UPLC: 223 [M + H] ⁺ (retention time 0.59 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 6.25 (1H, s), 4.72-4.68 (2H, m), 2.27 (6H, s), 2.03-1.84 (4H, m).

Production Example 9 Synthesis of 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 9) <Step 1> of tert-butyl 8- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 9-1) Synthesis 2,6-dichloro-4- (trifluoromethyl) pyridine (0.56 g), tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (0.50 g) in DMSO ( (2.0 mL) To the mixed solution, triethylamine (1.6 mL) was added and stirred at 120 ° C. for 1 hour under microwave conditions. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.96 g) of the title compound as an orange solid.
UPLC: 414 [M + Na] ⁺ (retention time 1.29 minutes)

<Step 2> tert-Butyl 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (Intermediate 9) -2) Synthesis of tert-butyl 8- (6-chloro-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] obtained in Step 1 of Production Example 9 To a mixed solution of crude product (0.95 g) of octane-3-carboxylate (intermediate 9-1) and tetrakis (triphenylphosphine) palladium (0.56 g) in THF (16 mL) was added trimethylaluminum (1.8 M (Toluene solution, 2.6 mL) was added, and the mixture was stirred at 100 ° C. for 15 hours. After returning the reaction solution to room temperature, water and 1N aqueous sodium hydroxide solution were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (2.3 g) as a red liquid.
UPLC: 394 [M + Na] ⁺ (retention time 1.23 minutes)

<Step 3> Synthesis of 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 9) Tert-butyl 8- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 9) -2) Using the crude product (2.3 g), the title compound (0.68 g) was obtained as a yellow liquid in the same manner as in Step 4 of Production Example 2 or a method analogous thereto.
UPLC: 272 [M + H] ⁺ (retention time 0.83 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 6.67 (1H, s), 6.51 (1H, s), 4.62-4.56 (2H, m), 3.25-3.18 (2H, m), 2.96-2.88 (2H, m), 2.44 (3H, s), 2.17-2.11 (4H, m).

Production Example 10 Synthesis of 8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10) <Step 1> 3-Benzyl- Synthesis of 8- (6-bromo-3-methoxypyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-1) 3,5-dibromo-2-methoxypyrazine ( 0.50 g), 3-benzyl-3,8-diazabicyclo [3.2.1] octane (0.45 g), potassium carbonate (0.77 g), cesium fluoride (0.28 g) in DMSO (1.9 mL) ) The mixture was stirred at 130 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with a heptane-ethyl acetate (2: 1) mixture (150 mL). The extract was washed successively with water (40 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 97 : 3 to 60:40) to obtain the title compound (0.41 g) as a pale yellow liquid.
UPLC: 389, 391 [M + H] ⁺ (retention time 0.89 minutes)

<Step 2> 3-Benzyl-8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10-2)
3-benzyl-8- (6-bromo-3-methoxypyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-1) (0.40 g), trimethylboroxine (0.26 g), PdCl ₂ (dppf) (38 mg), potassium carbonate (0.43 g) in DME (5.1 mL) was stirred at 90 ° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL). The extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 97: 3 to 60:40). The title compound (0.31 g) was obtained as a pale yellow liquid.
UPLC: 325 [M + H] ⁺ (retention time 0.84 minutes)

<Step 3> Synthesis of 8- (3-methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 10) 3-Benzyl-8- (3- Methoxy-6-methylpyrazin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 10-2) (0.30 g) and 10% Pd—C (18 mg) in methanol (9 .2 mL) The mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.24 g) as a brown liquid.
UPLC: 235 [M + H] ⁺ (retention time 0.74 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.27-7.24 (1H, m), 4.73-4.67 (2H, m), 3.91 (3H, s), 3.21-3.11 (2H, m), 2.70-2.60 ( 2H, m), 2.27 (3H, s), 2.06-1.83 (4H, m).

Production Example 11 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (4,4,5,5 Synthesis of -tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (intermediate 11) 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl) HATU (2.3 g) was added to a mixed solution of benzoic acid (1.2 g) and DIPEA (2.6 mL) in DMF (10 mL), and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. 6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (1.1 g) was added, and the mixture was further stirred for 17 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed successively with water (30 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was reduced in pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to obtain the title compound (1.5 g) as a pale yellow amorphous.
UPLC: 449 [M + H] ⁺ (retention time 1.13 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.82-7.76 (1H, m), 7.48-7.39 (1H, m), 7.38-7.30 (1H, m), 7.27-7.20 (1H, m), 6.31 ( 1H, s), 4.94-4.86 (1H, m), 4.68-4.61 (1H, m), 4.49-4.39 (1H, m), 3.42-3.33 (1H, m), 3.20-3.04 (2H, m), 2.27 (6H, s), 2.09-1.77 (4H, m), 1.33-1.10 (12H, m).

Production Example 12 Synthesis of 2- (pyrimidin-2-yl) benzoic acid (intermediate 12) <Step 1> Synthesis of methyl 2- (pyrimidin-2-yl) benzoate (intermediate 12-1) 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) methyl benzoate (3.0 g), 2-chloropyrimidine (2.0 g), PdCl ₂ (dppf) dichloromethane complex (0.47 g) and sodium carbonate (3.6 g) in 2-methyltetrahydrofuran (57 mL) -water (11 mL) were stirred at 80 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through celite with ethyl acetate (100 mL), water (100 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 2). The collected extract was washed with saturated brine (50 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (1.9 g) as a brown liquid.
UPLC: 237 [M + Na] ⁺ (retention time 0.79 minutes)

<Step 2> Synthesis of 2- (pyrimidin-2-yl) benzoic acid (intermediate 12) Methyl 2- (pyrimidin-2-yl) benzoate (intermediate 12-1) (1.9 g) and lithium hydroxide A mixed solution of (0.63 g) in THF (22 mL) -water (22 mL) was stirred at room temperature for 62 hours. The reaction solution was acidified with concentrated hydrochloric acid (pH = 1 to 2) and extracted with ethyl acetate (100 mL × 6). The collected extract was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.3 g) as a pale orange solid.
UPLC: 223 [M + Na] ⁺ (retention time 0.68 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.85 (2H, d, J = 5 Hz), 7.84 (1H, dd, J = 8, 1 Hz), 7.69-7.52 (3H, m), 7.45 (1H, t, J = 5 Hz).

(Production Example 13) Synthesis of 6-methoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 13) <Step 1> 6-Methoxy-2- (1H-pyrazol-1-yl) nicotinic acid Synthesis of methyl (intermediate 13-1) To a mixed solution of methyl 2-chloro-6-methoxynicotinate (0.50 g) and 1H-pyrazole (0.51 g) in DMF (5.0 mL) was added potassium carbonate (2.1 g). ) And stirred at 100 ° C. for 69 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 80:20) to obtain the title compound (0.12 g) as a colorless liquid. .
UPLC: 256 [M + Na] ⁺ (retention time 0.93 minutes)

<Step 2> Synthesis of 6-methoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 13) 6-methoxy-2- (1H-pyrazol-1-yl) methyl nicotinate (intermediate 13) -1) Sodium hydroxide (62 mg) was added to a methanol-water (1.0 mL, 1: 1) mixed solution of (0.12 g), and the mixture was stirred at 50 ° C. for 1 hour. After cooling the reaction solution to room temperature, the solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was extracted 3 times with 1N aqueous sodium hydroxide solution. 1N Hydrochloric acid was added to the obtained aqueous layer, and the mixture was extracted 5 times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (88 mg) as a white solid.
UPLC: 242 [M + Na] ⁺ (retention time 0.83 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.77-8.73 (1H, m), 7.92-7.80 (2H, m), 6.83-6.77 (1H, m), 6.61-6.57 (1H, m), 4.04 ( 3H, s).

Production Example 14 Synthesis of 3- (2H-1,2,3-triazol-2-yl) isonicotinic acid (Intermediate 14) 3-Bromoisonicotinic acid (0.50 g), cesium carbonate (1.6 g) ) 1H-1,2,3-triazole (0.29 mL), copper (I) iodide (24 mg), trans-N, N′-dimethylcyclohexane-1,2-diamine (70 mg) in DME (3. Water (45 μL) was added to the mixed solution and stirred at 100 ° C. for 4 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate, and then the resulting organic layer was extracted three times with a 1N aqueous sodium hydroxide solution. 1N Hydrochloric acid was added to the obtained aqueous layer, and the mixture was extracted 5 times with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.18 g) as a white solid.
UPLC: 191 [M + H] ⁺ (retention time 0.41 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 9.07 (1H, s), 8.79 (1H, d, J = 5 Hz), 8.19 (2H, s), 7.72 (1H, d, J = 5 Hz ).

(Production Example 15) Synthesis of 4-methyl-2- (pyrimidin-2-yl) benzoic acid (Intermediate 15) 4-Methyl-2- (4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) methyl benzoate (3.6 g) gave the title compound (0.98 g) as a light brown solid.
UPLC: 237 [M + Na] ⁺ (retention time 0.77 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.87 (2H, d, J = 5 Hz), 8.05 (1H, d, J = 8 Hz), 7.94 (1H, s), 7.41-7.33 (2H, m ), 2.48 (3H, s).

(Production Example 16) Synthesis of 4-chloro-2- (pyrimidin-2-yl) benzoic acid (Intermediate 16) 4-Chloro-2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid ethyl ester (3.5 g) to give the title compound (1.6 g) as a colorless solid.
UPLC: 257 [M + Na] ⁺ (retention time 0.88 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.81 (2H, d, J = 5 Hz), 7.79 (1H, d, J = 2 Hz), 7.69 (1H, d, J = 8 Hz), 7.61 (1H, dd, J = 8, 2 Hz), 7.45 (1H, t, J = 5 Hz).

(Production Example 17) Synthesis of 5-fluoro-3- (pyrimidin-2-yl) picolinic acid (intermediate 17) <Step 1> Methyl 5-fluoro-3- (pyrimidin-2-yl) picolinate (intermediate) 17-1) Synthesis of methyl 3-bromo-5-fluoropicolinate (0.30 g), 2- (tributyltin) pyrimidine (0.47 g), tetrakis (triphenylphosphine) palladium (0.15 g), copper iodide A mixed solution of (I) (24 mg) and cesium fluoride (0.39 g) in DMF (1.3 mL) was stirred at 100 ° C. for 18 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (10 mL) and ethyl acetate (30 mL) were added, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate (30 mL × 2). The collected extract was washed with saturated brine (20 mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 0: 100) to give the title compound (0.17 g) as an orange solid.
UPLC: 256 [M + Na] ⁺ (retention time 0.76 minutes)

<Step 2> Synthesis of 5-fluoro-3- (pyrimidin-2-yl) picolinic acid (intermediate 17) 5-Fluoro-3-yl by the same method as in Step 2 of Production Example 12 or a method analogous thereto. Using (pyrimidin-2-yl) methyl picolinate (intermediate 17-1) (0.17 g), the title compound (0.17 g) was obtained as a pale yellow amorphous product.
UPLC: 176 [M-CO ₂ ] ⁺ (retention time 0.63 minutes)
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 8.95 (2H, d, J = 5 Hz), 8.74 (1H, d, J = 3 Hz), 8.30 (1H, dd, J = 10, 3 Hz ), 7.57 (1H, t, J = 5 Hz).

(Production Example 18) Synthesis of methyl 1- (thiazol-2-yl) -1H-pyrazole-5-carboxylate (intermediate 18) Method of literature (J. Med. Chem. 2001, 44, 566-578.) The title compound (43 mg) was obtained as a yellow liquid using 2-hydrazinylthiazole hydrochloride (1.0 g).
UPLC: 210 [M + H] ⁺ (retention time 0.77 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.73 (1H, d, J = 2 Hz), 7.68 (1H, d, J = 4 Hz), 7.33 (1H, d, J = 3 Hz), 6.94 ( 1H, d, J = 2 Hz), 3.88 (3H, s).

Production Example 19 (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (intermediate) 19) Synthesis <Step 1> tert-Butyl 3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8- Synthesis of carboxylate (intermediate 19-1) To a solution of 2- (2H-1,2,3-triazol-2-yl) benzoic acid (2.1 g) in dichloromethane (25 mL) was added oxalyl chloride (1.9 mL). A catalytic amount of DMF was added, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and then the solvent was distilled off under reduced pressure. This residue was dissolved in dichloromethane (10 mL), and tert-butyl 3,8-diazabicyclo [3.2.1] octane-8-carboxylate (2.3 g) and triethylamine (6.0 mL) were mixed in dichloromethane (25 mL). The reaction vessel was added dropwise to the solution while cooling the reaction vessel with a water bath. The reaction mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30 to 40:60) to give the title compound. (3.9 g) was obtained as a white amorphous.
UPLC: 384 [M + H] ⁺ (retention time 1.05 minutes)

<Step 2> (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (Intermediate 19 ) Tert-butyl 3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-carboxylate (intermediate) 19-1) (3.9 g) was dissolved in dichloromethane (40 mL), 4M hydrogen chloride-1,4-dioxane solution (38 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure to obtain the title compound (3.3 g) as a white solid.
UPLC: 284 [M + H] ⁺ (retention time 0.58 minutes)
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 9.33 (2H, brs), 8.11 (2H, s), 7.99-7.90 (1H, m), 7.70-7.62 (1H, m), 7.59-7.43 ( 2H, m), 4.38-4.20 (1H, m), 4.15-4.08 (1H, m), 3.93-3.80 (1H, m), 3.70-2.94 (3H, m), 2.05-1.66 (4H, m).

(Production Example 20) (3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl) methanone hydrochloride Synthesis of salt (intermediate 20) 2-Fluoro-6- (2H-1,2,3-triazol-2-yl) benzoic acid (1.0 g) by the same method as in Production Example 19 or a method analogous thereto To give the title compound (1.4 g) as a colorless solid.
UPLC: 302 [M + H] ⁺ (retention time 0.59, 0.61 min, rotamer)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 9.35 (2H, brs), 8.18-8.15 (2H, m), 7.90-7.84 (1H, m), 7.74-7.67 (1H, m), 7.50- 7.43 (1H, m), 4.34-4.11 (2H, m), 3.94-3.86 (1H, m), 3.70-3.50 (1H, m), 3.39-3.13 (2H, m), 2.06-1.70 (4H, m ).

Production Example 21 (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (Intermediate 21) The title compound (3.0 g) was prepared using 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) (2.2 g) in the same manner as in Production Example 19 or a method analogous thereto. Obtained as a colorless solid.
UPLC: 284 [M + H] ⁺ (retention time 0.53 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 9.50-9.12 (2H, brm), 8.58-8.52 (2H, m), 8.02-7.87 (1H, m), 7.76 (1H, dd, J = 6 , 1 Hz), 7.51-7.44 (1H, m), 6.60-6.56 (1H, m), 4.40-4.09 (2H, m), 3.88-3.79 (1H, m), 3.64-3.04 (3H, m), 2.06-1.67 (4H, m).

Production Example 22 Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 22) <Step 1> Methyl 1- (pyridin-2-yl) -1H-pyrazole-5 Synthesis of carboxylate (Intermediate 22-1) Acetic acid of 2-hydrazinylpyridine (1.0 g), (E) -methyl 4- (dimethylamino) -2-oxobut-3-enoate (2.9 g) (10 mL) The mixture was stirred at 110 ° C. overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 70:30) to obtain the title compound (0.72 g) as an orange liquid. .
UPLC: 204 [M + H] ⁺ (retention time 0.75 minutes)

<Step 2> Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (intermediate 22) Methyl 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylate (intermediate) Lithium hydroxide monohydrate (0.11 g) was added to a THF (2.0 mL) -water (0.50 mL) mixed solution of compound 22-1) (0.35 g), and the mixture was added at 60 ° C. under a nitrogen atmosphere. Stir for 2 hours. 1N Hydrochloric acid aqueous solution was added to stop the reaction, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.33 g) as a white solid.
UPLC: 212 [M + Na] ⁺ (retention time 0.67 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.41-8.37 (1H, m), 8.36-8.32 (1H, m), 8.10-8.03 (1H, m), 7.76 (1H, d, J = 2 Hz) , 7.45-7.39 (2H, m).

Production Example 23 Synthesis of 3-cyano-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 23) Diisopropylamine (0.67 mL) in THF (5 mL) A solution of 1- (pyrimidin-2-yl) -1H-pyrazole-3-carbonitrile (0.23 g) in THF (5.0 mL) was added to an LDA solution prepared from a 6M n-BuLi-hexane solution (2.5 mL). Was added at −78 ° C. and stirred for 1 hour while allowing the temperature to rise naturally to 0 ° C. Dry ice was added to the reaction solution to stop the reaction, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.22 g) as a yellow solid.
UPLC: 215 [M + H] ⁺ (retention time 0.72 minutes)

(Production Example 24) Synthesis of 5-fluoro-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 24) 2,5-difluoronicotinic acid (0.30 g), 1H-pyrazole (0.13 g) Was added to a DMSO (3.0 mL) solution, and the mixture was stirred at 120 ° C. for 30 minutes and further at 160 ° C. for 2 hours. Water was added to the reaction solution and filtered, and then concentrated hydrochloric acid was added to the filtrate to pH = 2, followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure to obtain the title compound (0.12 g) as a yellow liquid.
UPLC: 208 [M + H] ⁺ (Retention time 0.70 minutes)

Production Example 25 Synthesis of Lithium 2- (1-Methyl-1H-pyrazol-3-yl) nicotinate (Intermediate 25) <Step 1> 2- (1-Methyl-1H-pyrazol-3-yl) nicotine Synthesis of methyl acid (intermediate 25-1) 3-Bromo-1-methyl-1H-pyrazole (0.70 g), bis (pinacolato) diboron (1.2 g), PdCl ₂ (dppf) dichloromethane adduct (0. 18 g) and potassium acetate (1.3 g) in 1,4-dioxane (8.7 mL) were degassed and then stirred at 110 ° C. for 6 hours under a nitrogen atmosphere. After filtering the reaction solution with a cotton plug, methyl 2-bromonicotinate (0.94 g), tripotassium phosphate (2.8 g) and PdCl 2 (dppf) dichloromethane adduct (0.18 g) were added to the filtrate, and nitrogen was added. The mixture was stirred at 110 ° C. for 1 hour and at room temperature for 16 hours. The reaction solution is diluted with ethyl acetate, washed with water, the organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is subjected to column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 0: 100) to give the title compound (0.29 g) as a brown liquid.
UPLC: 218 [M + H] ⁺ (retention time 0.69 minutes)

<Step 2> Synthesis of lithium 2- (1-methyl-1H-pyrazol-3-yl) nicotinate (intermediate 25) 2- (1-methyl-1H-pyrazol-3-yl) methyl nicotinate (intermediate) 25-1) (0.28 g) in methanol (1.0 mL) -THF (1.0 mL) was added an aqueous solution (0.50 mL) of lithium hydroxide monohydrate (60 mg) and stirred at 50 ° C. for 6 hours. Heated. A part of the solvent was distilled off, and the mixture was cooled to 0 ° C. and collected by filtration. The obtained solid was washed with cold THF-methanol (3: 1) to obtain the title compound (0.11 g) as a white solid. .
UPLC: 204 [M + H] ⁺ (retention time 0.36 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.32 (1H, dd, J = 5, 2 Hz), 7.59 (1H, d, J = 2 Hz), 7.45 (1H, dd, J = 7, 2 Hz), 7.13 (1H, dd, J = 7, 5 Hz), 6.71 (1H, d, J = 2 Hz), 3.84 (3H, s).

Production Example 26 Synthesis of 3-methyl-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 26) <Step 1> 3-Methyl-1- (pyridin-2-yl) ) Synthesis of ethyl 1H-pyrazole-5-carboxylate (intermediate 26-1) Acetic acid of ethyl 2-methoxyimino-4-oxopentanoate (0.40 g) and 2-hydrazinylpyridine (0.35 g) The (3.0 mL) solution was stirred at 110 ° C. for 2 hours under a nitrogen atmosphere. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 90:10) to obtain the title compound (0.15 g) as a colorless liquid. .
UPLC: 232 [M + H] ⁺ (retention time 0.90 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.48-8.44 (1H, m), 7.87-7.80 (1H, m), 7.64-7.59 (1H, m), 7.31-7.26 (1H, m), 6.70 ( 1H, s), 4.28 (2H, q, J = 7 Hz), 2.37 (3H, s), 1.25 (3H, t, J = 7 Hz).

<Step 2> Synthesis of 3-methyl-1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (intermediate 26) 3-methyl-1- (pyridin-2-yl) -1H-pyrazole Lithium hydroxide monohydrate (25 mg) was added to a mixed solution of ethyl 5-carboxylate (intermediate 26-1) (0.11 g) in THF (1.5 mL) -water (0.5 mL), and a nitrogen atmosphere was added. The mixture was stirred overnight at room temperature. The reaction solution was back-extracted with ethyl acetate, 1.0 M hydrochloric acid aqueous solution was added to the obtained aqueous layer, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (73 mg).
UPLC: 226 [M + Na] ⁺ (retention time 0.78 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.36-8.32 (1H, m), 8.30-8.26 (1H, m), 8.06-7.99 (1H, m), 7.39-7.33 (1H, m), 7.21 ( 1H, s), 2.37 (3H, s).

(Production Example 27) Synthesis of 1- (pyrazin-3-yl) -1H-pyrazole-5-carboxylic acid (intermediate 27) Pyridazine hydrochloride (1.0 g) was used to give the title compound (0.48 g) as a yellow solid.
UPLC: 191 [M + H] ⁺ (retention time 0.52 minutes)

(Production Example 28) Synthesis of 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) <Step 1> Ethyl 2- (1H-pyrazol-1-yl) nicotinate (intermediate 28-1) Synthesis of DMSO (140 mL) mixture of ethyl 2-chloronicotinate (25 g), 1H-pyrazole (18 g), potassium carbonate (56 g), cesium fluoride (20 g) at 120 ° C. (internal temperature) under nitrogen atmosphere Heated for 3 hours. The reaction mixture was cooled to room temperature, water (300 mL) was added, and the mixture was extracted with a mixed solvent (600 mL) of heptane-ethyl acetate (2: 1). The extract was washed successively with water (300 mL × 2) and saturated brine (200 mL), then the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (20 g).
UPLC: 218 [M + H] ⁺ (retention time 0.86 minutes)

<Step 2> Synthesis of 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) Ethyl 2- (1H-pyrazol-1-yl) nicotinate (intermediate 28-1) (20 g) and water A mixed solution of sodium oxide (7.3 g) in THF (150 mL) -water (150 mL) was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure to remove THF, and the aqueous layer was washed with MTBE (100 mL). The aqueous layer was adjusted to pH = 1 with concentrated hydrochloric acid, and extracted with ethyl acetate (450 mL × 2). The collected extract was washed with saturated brine (90 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (17 g).
UPLC: 190 [M + H] ⁺ (retention time 0.64 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 13.18 (1H, brs), 8.57 (1H, dd, J = 5, 2 Hz), 8.48-8.46 (1H, m), 8.07 (1H, dd, J = 8, 2 Hz), 7.77-7.75 (1H, m), 7.48 (1H, dd, J = 8, 5 Hz), 6.56 (1H, dd, J = 3, 2 Hz).

Production Example 29 2- (1H-1,2,3-triazol-1-yl) nicotinic acid (intermediate 29-1) and 2- (2H-1,2,3-triazol-2-yl) nicotine Synthesis of acid (intermediate 29-2) 2-chloronicotinic acid (5.0 g), copper (I) iodide (0.30 g), cesium carbonate (21 g), 1H-1,2,3-triazole (4 .4 g), a mixture of trans-N, N′-dimethylcyclohexane-1,2-diamine (0.90 g) in 1,4-dioxane (40 mL) -water (0.50 mL) at 100 ° C. under a nitrogen atmosphere. Stir for 4 hours. The reaction mixture was cooled to room temperature, acidified with 2N hydrochloric acid (10 mL), and extracted with ethyl acetate (50 mL × 3). The collected extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was triturated with a mixed solvent of ethyl acetate-petroleum ether (1: 2). Intermediate 29-1 (0.90 g) was obtained as a white solid. Thereafter, intermediate 29-2 (0.44 g) was obtained as a white solid by recrystallization from the filtrate with a mixed solvent of ethyl acetate-petroleum ether.
(Intermediate 29-1) UPLC: 191 [M + H] ⁺ (retention time 0.53 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz): δ: 8.77-8.68 (2H, m), 8.37-8.30 (1H, m), 7.95 (1H, s), 7.75-7.68 (1H, m).
(Intermediate 29-2) UPLC: 191 [M + H] ⁺ (retention time 0.51 min)
¹ H-NMR (DMSO-d ₆ , 400 MHz): δ: 8.76-8.69 (1H, m), 8.31-8.25 (1H, m), 8.13 (2H, s), 7.74-7.67 (1H, m).

Production Example 30 2-Chloro-6- (2H-1,2,3-triazol-2-yl) benzoic acid (Intermediate 30)
The title compound (0.80 g) was obtained as an orange amorphous form from 2-bromo-6-chlorobenzoic acid (2.0 g) by the same method as in Production Example 14 or a method analogous thereto.
UPLC: 179 [M-CO ₂ ] ⁺ (retention time 0.80 minutes)
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 13.68 (1H, brs), 8.16 (2H, s), 7.96-7.91 (1H, m), 7.66-7.62 (2H, m).

Production Example 31 Synthesis of 2- (thiazol-2-yl) nicotinic acid (Intermediate 31) In the same manner as in Production Example 17 or a method analogous thereto, The title compound (57 mg) was obtained as a pale yellow solid from-(tributyltin) thiazole (0.43 g).
UPLC: 229 [M + Na] ⁺ (retention time 0.72 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.70 (1H, dd, J = 5, 2 Hz), 8.01-7.89 (3H, m), 7.55 (1H, dd, J = 8, 5 Hz) .

Production Example 32 Synthesis of 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinic acid (Intermediate 32) <Step 1> Ethyl 2-chloro-4-ethoxynicotinate (Intermediate 32-1) A 20% sodium ethoxide-ethanol solution (1.4 mL) was added to a solution of ethyl 2,4-dichloronicotinate (1.0 g) in ethanol (15 mL), and the mixture was stirred at 40 ° C. for 13 hours under a nitrogen atmosphere. . A saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The extract was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92: 8-30: 70) to give the title compound (0.75 g) as an orange liquid.
UPLC: 230, 232 [M + H] ⁺ (retention time 0.93 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.26 (1H, d, J = 6 Hz), 6.79 (1H, d, J = 6 Hz), 4.43 (2H, q, J = 7 Hz), 4.14 ( 2H, q, J = 7 Hz), 1.46-1.37 (6H, m).

<Step 2> Ethyl 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 32-2)
DMSO of ethyl 2-chloro-4-ethoxynicotinate (intermediate 32-1) (0.75 g), 1H-pyrazole (0.44 g), potassium carbonate (1.4 g), cesium fluoride (0.50 g) The (3.3 mL) mixture was stirred at 130 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with a mixed solution of heptane-ethyl acetate (2: 1) (100 mL). The extract was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92: 8 to 30:70) to obtain the title compound (0.31 g) as a pale yellow liquid.
UPLC: 284 [M + Na] ⁺ (retention time 0.94 minutes)

<Step 3> Synthesis of 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 32) Ethyl 4-ethoxy-2- (1H-pyrazol-1-yl) nicotinate (intermediate 32) -2) A mixed solution of (0.30 g) and lithium hydroxide (0.14 g) in THF (2.9 mL) -water (2.9 mL) was stirred at 50 ° C. for 3 days in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove THF, and the aqueous layer was washed with MTBE (30 mL). The aqueous layer was adjusted to pH = 1 with 2N hydrochloric acid, and extracted with ethyl acetate (30 mL × 2). The collected extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.25 g) as a pale yellow solid.
UPLC: 256 [M + Na] ⁺ (retention time 0.69 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 12.97 (1H, brs), 8.53-8.49 (1H, m), 8.36 (1H, d, J = 6 Hz), 7.74-7.70 (1H, m) , 7.14 (1H, d, J = 6 Hz), 6.54-6.52 (1H, m), 4.23 (2H, q, J = 7 Hz), 1.33 (3H, t, J = 7 Hz).

Production Example 33 Synthesis of Lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33) <Step 1> Ethyl 2-chloro-4-methoxynicotinate (Intermediate 33-1) ) To a methanol solution (15 mL) of ethyl 2,4-dichloronicotinate (1.0 g) was added sodium tert-butoxide (0.87 g), and the mixture was stirred at 50 ° C. for 13 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (150 mL). The collected extract was washed successively with water (30 mL) and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 92 : 8 to 30:70) to obtain the title compound (0.84 g) as a colorless liquid.
UPLC: 216, 218 [M + H] ⁺ (retention time 0.87 minutes)

<Step 2> Synthesis of ethyl 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33-2) The title compound (30 mg) was obtained as a pale yellow liquid from ethyl chloro-4-methoxynicotinate (intermediate 33-1) (0.84 g).
UPLC: 270 [M + Na] ⁺ (retention time 0.89 minutes)

<Step 3> Synthesis of lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33) 4-methoxy-2- The title compound (27 mg) was obtained as a pale yellow solid from ethyl -2- (1H-pyrazol-1-yl) nicotinate (Intermediate 33-2) (30 mg).
UPLC: 242 [M + Na] ⁺ (retention time 0.62 minutes)

Production Example 34 Synthesis of 3-bromo-1-methyl-1H-pyrazolo [4,3-b] pyridine (intermediate 34) 3-bromo-1H-pyrazolo [4,3-b] pyridine (0.50 g ), Iodomethane (0.24 mL) was added to a DMF (5.0 mL) mixture of cesium carbonate (1.7 g), and the reaction vessel was stirred for 2 hours while cooling in a water bath. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The extract was washed successively with water (10 mL × 2) and saturated brine (5.0 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.34 g) as a brown solid. It was.
UPLC: 212 [M + H] ⁺ (retention time 0.76 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.66-8.63 (1H, m), 7.78-7.74 (1H, m), 7.40-7.35 (1H, m), 4.09 (3H, s).

Production Example 35 3-Bromo-1-methyl-1H-pyrazolo [4,3-c] pyridine (Intermediate 35)
The title compound (39 mg) was obtained as a pale yellow solid using 3-bromo-1H-pyrazolo [4,3-c] pyridine (0.25 g) in the same manner as in Production Example 34 or a method analogous thereto. .
UPLC: 212, 214 [M + H] ⁺ (retention time 0.47 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.97 (1H, d, J = 1 Hz), 8.49 (1H, d, J = 6 Hz), 7.28 (1H, dd, J = 6, 1 Hz), 4.06 (3H, s).

Production Example 36 3-Bromo-1-methyl-1H-pyrazolo [3,4-c] pyridine (Intermediate 36)
The title compound (0.11 g) was prepared as a pale yellow solid using 3-bromo-1H-pyrazolo [3,4-c] pyridine (0.50 g) in the same manner as in Production Example 34 or a method analogous thereto. Obtained.
UPLC: 212, 214 [M + H] ⁺ (retention time 0.60 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.96 (1H, d, J = 1 Hz), 8.38 (1H, d, J = 6 Hz), 7.51 (1H, dd, J = 6, 1 Hz), 4.18 (3H, s).

(Production Example 37) Synthesis of 2-chloro-3-ethoxyisonicotinonitrile (Intermediate 37) 2-Chloro-3-ethoxypyridine (5.1 g) by the same method as in Production Example 3 or a method analogous thereto To give the title compound (2.9 g) as a colorless solid.
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.41 (1H, d, J = 5 Hz), 4.39 (2H, q, J = 7 Hz), 1.53 ( (3H, t, J = 7 Hz).

Production Example 38 Synthesis of 2-chloro-3- (methoxy-d ₃ ) isonicotinonitrile (Intermediate 38) <Step 1> 2-Chloro-3- (methoxy-d ₃ ) pyridine (Intermediate 38- Synthesis of 1) To a mixed solution of 2-chloropyridin-3-ol (10 g) and potassium carbonate (32 g) in DMSO (100 mL) was added iodomethane-d ₃ (5.0 mL), and the mixture was stirred at 50 ° C. for 3 days. . The reaction solution was returned to room temperature, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of the title compound (10 g) as a colorless liquid.
UPLC: 147 [M + H] ⁺ (retention time 0.76 minutes)

<Step 2> Synthesis of 2-chloro-3- (methoxy-d ₃ ) isonicotinonitrile (Intermediate 38) 2-Chloro-3- (methoxy-d ₃ ) pyridine obtained in Step 1 of Production Example 38 ( Using the crude product of Intermediate 38-1) (5.0 g), the title compound (2.3 g) was obtained as a colorless solid in the same manner as in Production Example 3 or a method analogous thereto.
UPLC: 172 [M + H] ⁺ (retention time 0.83 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.24 (1H, d, J = 5 Hz), 7.42 (1H, d, J = 5 Hz).

Production Example 39 (2-Chloropyridin-3-yl) (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone Synthesis of (Intermediate 39) The title compound (0.49 g) was obtained as a brown liquid using 2-chloronicotinic acid (0.24 g) in the same manner as in Production Example 11 or a method analogous thereto.
UPLC: 358 [M + H] ⁺ (retention time 0.82 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.46-8.40 (1H, m), 7.77-7.43 (1H, m), 7.37-7.22 (1H, m), 6.36-6.31 (1H, m), 4.99- 4.90 (1H, m), 4.80-4.69 (1H, m), 4.54-4.42 (1H, m), 3.67-3.38 (1H, m), 3.27-3.02 (2H, m), 2.82-2.78 (6H, m ), 2.12-1.86 (2H, m), 1.53-1.40 (2H, m).

Production Example 40 (2-Chloro-5-fluoropyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of —yl) methanone (intermediate 40) The title compound (0.17 g) was obtained as a yellow solid using 2-chloro-5-fluoronicotinic acid (88 mg) in the same manner as in Production Example 11 or a method analogous thereto. Got as.
UPLC: 376, 378 [M + H] ⁺ (retention time 0.86 minutes)
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 8.56-8.51 (1H, m), 8.22-7.90 (1H, m), 6.50-6.47 (1H, m), 4.84-4.74 (1H, m), 4.64-4.55 (1H, m), 4.33-4.19 (1H, m), 3.45-2.94 (3H, m), 2.24 (6H, s), 2.06-1.67 (4H, m).

Production Example 41 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 5-bromo-1-methylpyrazin-2 (1H) -one (Intermediate 41) In the same manner as in Step 1 of Production Example 1 or a method analogous thereto, (2- (2H-1,2, 3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride (intermediate 19) (0.10 g) and 3,5-dibromo-1 Using -methylpyrazin-2 (1H) -one (0.16 g), the title compound (0.12 g) was obtained as a white amorphous.
UPLC: 470, 472 [M + H] ⁺ (retention time 1.06 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.04-7.98 (1H, m), 7.85-7.74 (2H, m), 7.57-7.19 (3H, m), 6.73-6.67 (1H, m), 4.54- 4.40 (1H, m), 3.45-2.34 (8H, m), 2.09-1.67 (4H, m).

(Production Example 42) tert-butyl 3- (2-fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,6-diazabicyclo [3.1.1] heptane-6 Synthesis of carboxylate (intermediate 42) tert-butyl 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (99 mg), 2-fluoro-6- (2H-1,2,3- EDCI (0.12 g) was added to a solution of triazol-2-yl) benzoic acid (0.11 g) and triethylamine (0.21 mL) in dichloromethane (0.50 mL), and the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 90: 10-0: 100) to obtain the title compound (39 mg) as a white amorphous.
UPLC: 388 [M + H] ⁺ (retention time 1.01 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.93-7.85 (1H, m), 7.80-7.72 (2H, m), 7.53-7.45 (1H, m), 7.19-7.10 (1H, m), 4.34- 3.79 (4H, m), 3.44-3.24 (1H, m), 2.66-2.56 (1H, m), 1.66-1.58 (2H, m), 1.49 (9H, s).

Production Example 43 Synthesis of (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptan-3-yl) methanone (Intermediate 43) <Step 1> of tert-butyl 3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 43-1) Synthesis In the same manner as in Production Example 11 or a method analogous thereto, tert-butyl 3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (0.10 g) and 2- (1H-pyrazole-1 -Ill) The title compound (0.19 g) was obtained as a yellow liquid using nicotinic acid (0.11 g).
UPLC: 392 [M + Na] ⁺ (retention time 0.96 minutes)

<Step 2> Synthesis of (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptan-3-yl) methanone (intermediate 43) tert -Butyl 3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 43-1) (0.19 g) 2N Hydrochloric acid-ethyl acetate solution (4.0 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. After evaporating the solvent under reduced pressure, water was added and back extraction was performed with ethyl acetate. After neutralization with a saturated sodium bicarbonate solution, extraction with a mixed solvent of dichloromethane-isopropanol (9: 1) was followed by drying over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (0.14 g) in orange Obtained as amorphous.
UPLC: 270 [M + H] ⁺ (retention time 0.50 minutes)

Production Example 44 Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Intermediate 44) <Step 1> tert-Butyl 8 Synthesis of — (4-cyano-3-cyclopropylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 44-1) tert-butyl 8- ( 3-chloro-4-cyanopyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 6-1) (76 mg), cyclopropylzinc bromide (0. Tetrakis (triphenylphosphine) palladium (0.10 g) was added to a mixed solution of 5N THF solution) (2.6 mL) in THF (0.73 mL), and a nitrogen atmosphere at 100 ° C. Stir for 3 days. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (77 mg) of the title compound as an orange liquid.

<Step 2> Synthesis of 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicotinonitrile (Intermediate 44) Obtained in Step 1 of Preparation Example 44 Crude product of tert-butyl 8- (4-cyano-3-cyclopropylpyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-carboxylate (intermediate 44-1) (77 mg) was added with trifluoroacetic acid and stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, 1N aqueous hydrochloric acid solution was added, and back extraction was performed with ethyl acetate. The mixture was neutralized with 1N aqueous sodium hydroxide solution, extracted with a mixed solvent of dichloromethane-isopropanol (9: 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (50 mg) as a yellow liquid. Got as.
UPLC: 255 [M + H] ⁺ (retention time 0.75 minutes)

Example 1 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (5-methyl-2- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) 22 mg), 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (20 mg), triethylamine (42 μL) in DMF (0.50 mL) mixed with HATU (46 mg). In addition, the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction solution was subjected to preparative purification by HPLC to obtain the title compound (29 mg).
UPLC: 404 [M + H] ⁺ (retention time 0.99 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 7.89-7.66 (3H, m), 7.35-6.99 (2H, m), 6.33-6.29 (1H, m), 4.98-4.39 (3H, m), 3.49- 2.66 (3H, m), 2.47-2.24 (9H, m), 2.06-1.60 (4H, m).

* Examples 2 to 15 are the same as in Example 1 using any one of Intermediates 1 to 3 and any of Intermediates 12 to 14 or commercially available or known compounds, or It was synthesized by a method according to this.

Example 16 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4-methoxy-2- (1H-1 , 2,3-Triazol-1-yl) phenyl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) 22 mg), 4-methoxy-2- (1H-1,2,3-triazol-1-yl) benzoic acid (22 mg), DIPEA (52 μL) in DMF (0.20 mL) mixed with HATU (46 mg). In addition, the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, washed with water, the organic layer was evaporated under reduced pressure to remove the solvent, and the resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 90: 10 to 0: 100). Purification gave the title compound (36 mg) as a white amorphous.
UPLC: 420 [M + H] ⁺ (retention time 0.85 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.23-6.98 (5H, m), 6.30 (1H, s), 4.86-4.76 (1H, m), 4.63-4.57 (1H, m), 4.40-4.26 ( 1H, m), 3.91-3.87 (3H, m), 3.40-2.60 (7H, m), 2.02-0.97 (6H, m).

* Example 17 to Example 55 were prepared using any of Intermediate 1 to Intermediate 8 and any of Intermediate 15, Intermediate 22 to Intermediate 28, Intermediate 29-1, or commercially available compounds or known compounds. This was synthesized by the same method as in Example 16 or a method analogous thereto.

Example 56 (3-Fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) Synthesis of 3,8-diazabicyclo [3.2.1] octane-3-yl) methanone 3-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (40 mg) in dichloromethane (0.97 mL) To the solution were added oxalyl chloride (51 μL) and a catalytic amount of DMF, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere, and the solvent was distilled off under reduced pressure. This residue was dissolved in dichloromethane (0.60 mL) and 8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate) 2) To a mixed solution of 55 mg) and triethylamine (0.11 mL) in dichloromethane (0.97 mL) was added dropwise at 0 ° C. The reaction solution was stirred at 0 ° C. for 1 hour under a nitrogen atmosphere and then purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (42 mg) as a colorless solid. It was.
UPLC: 477 [M + H] ⁺ (retention time 1.13 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.10-7.75 (3H, m), 7.57-7.04 (3H, m), 6.96-6.92 (1H, m), 4.77-4.27 (3H, m), 3.80- 3.70 (3H, m), 3.67-2.80 (3H, m), 2.18-1.62 (4H, m).

* Example 57 to Example 76 are any of Intermediate 1, Intermediate 3 to Intermediate 5, Intermediate 29-1, Intermediate 29-2, Intermediate 30, and Intermediate 31 or commercially available compounds. Alternatively, synthesis was performed using a known compound by the same method as in Example 56 or a method analogous thereto.

Example 77 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2 .1] Synthesis of octan-3-yl) methanone 2- (2H-1,2,3-triazol-2-yl) benzoic acid (45 mg) in DME (0.50 mL) solution with oxalyl chloride (42 μL) and catalyst An amount of DMF was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. This residue was dissolved in DME (0.10 mL) and 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (44 mg) was combined with The mixture was added dropwise to a mixed solution of triethylamine (56 μL) in DME (0.50 mL) at room temperature. The reaction solution was stirred at room temperature for 30 minutes under a nitrogen atmosphere and then filtered. The obtained filtrate was purified by column chromatography (silica gel, heptane: ethyl acetate = 60: 40 to 40:60) to give the title compound. (53 mg) was obtained as a colorless amorphous.
UPLC: 390 [M + H] ⁺ (retention time 0.94 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.02-7.99 (1H, m), 7.84 (1H, s), 7.70 (1H, s), 7.56-7.42 (2H, m), 7.40-7.18 (1H, m), 6.33-6.30 (1H, m), 4.98-4.89 (1H, m), 4.69-4.64 (1H, m), 4.48-4.41 (1H, m), 3.49-2.75 (3H, m), 2.29- 2.25 (6H, m), 2.04-1.62 (4H, m).

* Example 78 to Example 87 are the same as or similar to Example 77, using any of Intermediate 1 to Intermediate 5, Intermediate 9 and Intermediate 28, or a commercially available or known compound. It was synthesized by the method.

Example 88 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (1,1,2,2 Synthesis of -tetrafluoroethoxy) phenyl) methanone 2- (1,1,2,2-tetrafluoroethoxy) benzoic acid (28 mg) in dichloromethane (0.20 mL) in 1-chloro-N, N, 2-trimethyl -1-Propenylamine (17 μL) was added at room temperature under a nitrogen atmosphere. After stirring the reaction solution at room temperature for 30 minutes, 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (22 mg) and triethylamine ( 28 μL) was added and the reaction was stirred at room temperature for 30 minutes. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 100: 0 to 60:40) to obtain the title compound (35 mg) as a colorless gum.
UPLC: 439 [M + H] ⁺ (retention time 1.01 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.53-7.14 (4H, m), 6.34 (1H, s), 6.14-5.64 (1H, m), 4.98-4.89 (1H, m), 4.78-4.68 ( 1H, m), 4.58-4.45 (1H, m), 3.52-3.37 (1H, m), 3.23-3.08 (2H, m), 2.30 (6H, s), 2.10-1.80 (4H, m).

Example 89 2- (3- (2- (1,1,2,2-tetrafluoroethoxy) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotino Synthesis of nitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (intermediate 4) (22 mg) was used in the same manner as in Example 88 or To give the title compound (24 mg) as a colorless gum.
UPLC: 435 [M + H] ⁺ (retention time 1.04 minutes)

Example 90 3-Methoxy-2- (3- (4-methoxy-2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl ) Synthesis of isonicotionitrile Lithium 4-methoxy-2- (1H-pyrazol-1-yl) nicotinate (intermediate 33) (27 mg) and 2- (3,8-diazabicyclo [3.2.1] octane- EDCI (34 mg) was added to a mixed solution of 8-yl) -3-methoxyisonicotinonitrile (intermediate 3) (29 mg) and HOBT (28 mg) in DMF (0.60 mL), and the reaction solution was added at 50 ° C. Stir for days. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution (10 mL × 2) and a saturated aqueous ammonium chloride solution (10 mL), and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (8.7 mg) as a pale yellow solid. It was.
UPLC: 446 [M + H] ⁺ (retention time 1.01, 1.04 min, rotamer)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.47-8.32 (2H, m), 8.01-7.96 (1H, m), 7.72-7.50 (1H, m), 6.86-6.75 (2H, m), 6.45- 6.34 (1H, m), 4.88-4.36 (3H, m), 3.99-3.85 (6H, m), 3.50-3.04 (3H, m), 2.20-1.70 (4H, m).

Example 91 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotino Synthesis of nitrile 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 28) (0.55 g) and 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3 EDCI (0.60 g) was added to a mixed solution of methoxyisonicotinonitrile (intermediate 3) (0.64 g) and HOBT (80 mg) in dichloromethane (7.0 mL), and the reaction solution was stirred at room temperature for 2 hours. . A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (30 mL), the organic layer was washed successively with water (20 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 45: 55) to obtain the title compound (0.54 g) as a white amorphous.
UPLC: 416 [M + H] ⁺ (retention time 1.03 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.49-8.45 (2H, m), 8.02-7.95 (1H, m), 7.80-7.72 (1H, m), 7.55-7.51 (1H, m), 7.31- 7.20 (1H, m), 6.87-6.85 (1H, m), 6.49-6.36 (1H, m), 4.86-4.81 (1H, m), 4.58-4.34 (2H, m), 3.92-3.89 (3H, m ), 3.55-2.96 (3H, m), 2.20-1.64 (4H, m).

* Example 92 to Example 100 are any of Intermediate 1 to Intermediate 3, Intermediate 5, and Intermediate 10, and any of Intermediate 28, Intermediate 31, and Intermediate 32, or commercially available compounds or known compounds. And synthesized by the same method as in Example 91 or a method analogous thereto.

Example 101 (4-Chloro-2- (pyrimidin-2-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane Synthesis of 3-yl) methanone 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 1) (28 mg), 4-chloro-2 A mixed solution of-(pyrimidin-2-yl) benzoic acid (intermediate 16) (30 mg), COMU (82 mg) and 2,6-lutidine (30 μL) in dichloromethane (0.64 mL) at room temperature under a nitrogen atmosphere Stir for hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 mL × 2), and the collected organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (20 mg) as a colorless amorphous.
UPLC: 435 [M + H] ⁺ (retention time 1.06 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.85-8.62 (2H, m), 8.44-8.29 (1H, m), 7.54-7.08 (3H, m), 6.35-6.29 (1H, m), 5.04- 4.38 (3H, m), 3.55-2.92 (3H, m), 2.31-2.23 (6H, m), 2.12-1.66 (4H, m).

* Example 102 to Example 104 were synthesized using any one of Intermediate 1 to Intermediate 3 and Intermediate 17 by the same method as in Example 101 or a method analogous thereto.

Example 105 (4-Fluoro-2- (pyrimidin-2-yl) phenyl) (8- (3-methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3 2.1] Synthesis of Octan-3-yl) methanone 4-Fluoro-2- (pyrimidin-2-yl) benzoic acid (40 mg), 8- (3-methoxy-4- (trifluoromethyl) pyridine-2 -Il) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) (53 mg), T3P (0.11 mL), DIPEA (80 μL) in DMF (0.92 mL) mixed solution under nitrogen atmosphere And stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 mL × 2), and the collected organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (16 mg) as a brown solid.
UPLC: 488 [M + H] ⁺ (retention time 1.19 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.85-8.62 (2H, m), 8.16-7.96 (2H, m), 7.44-7.09 (3H, m), 7.00-6.88 (1H, m), 4.83- 4.34 (3H, m), 3.83-3.70 (3H, m), 3.66-3.00 (3H, m), 2.10-1.70 (4H, m).

Example 106 2- (3- (4-Fluoro-2- (pyrimidin-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyiso Synthesis of nicotinonitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-methoxyisonicotinonitrile (in the same manner as in Example 105 or a method analogous thereto) Intermediate 3) (45 mg) was used to give the title compound (13 mg) as an orange solid.
UPLC: 445 [M + H] ⁺ (retention time 1.10 minutes)

Example 107 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazol-2-yl)- Synthesis of 1H-pyrazol-5-yl) methanone Methyl 1- (thiazol-2-yl) -1H-pyrazole-5-carboxylate (Intermediate 18) (14 mg) in methanol (0.10 mL) -THF (0. 10 mL) To the mixed solution was added 8N aqueous sodium hydroxide solution (13 μL), and the mixture was stirred at 50 ° C. for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was dissolved in DMF (0.15 mL) to give 8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1]. Octane (Intermediate 1) (15 mg), DIPEA (35 μL) and HATU (28 mg) were added, and the reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (1 mL). The organic layer was washed successively with water (0.5 mL × 2) and saturated brine (0.5 mL), and dried over anhydrous sodium sulfate. . The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative TLC (silica gel, heptane: ethyl acetate = 50: 50) to obtain the title compound (4.8 mg) as a colorless amorphous.
UPLC: 396 [M + H] ⁺ (retention time 0.88 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.68 (1H, d, J = 2 Hz), 7.46 (1H, d, J = 4 Hz), 7.10 (1H, d, J = 4 Hz), 6.43 ( 1H, d, J = 2 Hz), 6.33 (1H, s), 4.99-4.91 (1H, m), 4.78-4.71 (1H, m), 4.51-4.45 (1H, m), 3.45-3.38 (1H, m), 3.27-3.20 (2H, m), 2.28 (6H, s), 2.06-1.72 (4H, m).

Example 108 3-Methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazole-5-carbonyl) -3,8-diazabicyclo [3.2.1] octane-8- Yl) Synthesis of isonicotinonitrile 3-methoxy-2- (3- (1- (thiazol-2-yl) -1H-pyrazole-5-carbonyl) in the same manner as in Example 107 or a method analogous thereto ) -3,8-diazabicyclo [3.2.1] octane-8-yl) isonicotinonitrile (Intermediate 3) (16 mg) was used to obtain the title compound (7.0 mg) as a colorless amorphous.
UPLC: 422 [M + H] ⁺ (retention time 1.01 minutes)

Example 109 (8- (3-Methoxy-4- (trifluoromethyl) pyridin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (1- (thiazole Synthesis of -2-yl) -1H-pyrazol-5-yl) methanone By a method similar to that in Example 107 or a method analogous thereto, 8- (3-methoxy-4- (trifluoromethyl) pyridine-2- Yl) -3,8-diazabicyclo [3.2.1] octane (intermediate 2) (19 mg) to give the title compound (10 mg) as a colorless amorphous.
UPLC: 465 [M + H] ⁺ (retention time 1.13 minutes)

Example 110 Synthesis of (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone 8- DME (2.0 mL) of (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane (Intermediate 1) (0.20 g) and triethylamine (0.19 mL) 2-Iodobenzoyl chloride (0.24 g) was added to the mixed solution in several portions at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by column chromatography (silica gel, heptane: ethyl acetate = 65: 35-50: 50) to obtain the title compound (0.31 g) as a white solid.
UPLC: 449 [M + H] ⁺ (retention time 1.01 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.90-7.77 (1H, m), 7.45-6.98 (3H, m), 6.33 (1H, s), 4.97-4.91 (1H, m), 4.76-4.68 ( 1H, m), 4.53-4.46 (1H, m), 3.57-3.35 (1H, m), 3.24-3.05 (2H, m), 2.29 (6H, s), 2.17-1.90 (4H, m).

Example 111 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (oxazol-2-yl) phenyl ) Synthesis of Methanone (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Example 110) (42 mg), 2- (tributyltin) oxazole (34 mg) and cesium fluoride (28 mg) in a mixed solution of DMF (0.50 mL) with tetrakis (triphenylphosphine) palladium (11 mg) and copper (I) iodide (1. 8 mg), and the mixture was stirred at 110 ° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel, heptane: ethyl acetate = 50: 50 to 25:75) and preparative TLC (NH-silica gel, heptane: ethyl acetate). The title compound (3.8 mg) was obtained as a colorless amorphous.
UPLC: 390 [M + H] ⁺ (retention time 0.89 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.13-8.03 (1H, m), 7.76-7.26 (4H, m), 7.20-7.10 (1H, m), 6.31 (1H, s), 5.02-4.90 ( 1H, m), 4.72-4.60 (1H, m), 4.56-4.47 (1H, m), 3.42-3.05 (3H, m), 2.29-2.24 (6H, m), 2.06-1.65 (4H, m).

Example 112 (2- (1H-pyrazol-3-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of (-yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-iodophenyl) methanone (Examples) 110) (45 mg), (1H-pyrazol-3-yl) boronic acid (17 mg), PdCl ₂ (dppf) (15 mg), potassium carbonate (41 mg) in DME (0.50 mL) -water (0.20 mL) The solution was stirred at 85 ° C. for 6 hours under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was purified by HPLC to obtain the title compound (5.7 mg) as a colorless amorphous.
UPLC: 389 [M + H] ⁺ (retention time 0.86 minutes)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.77-7.62 (2H, m), 7.50-7.14 (3H, m), 6.59-6.30 (2H, m), 4.83-4.72 (1H, m), 4.54-4.42 (1H, m), 4.33-4.18 (1H, m), 3.20-2.65 (3H, m), 2.24-2.20 (6H, m), 1.94-1.42 (4H, m).

Example 113 (2- (1H-pyrazol-4-yl) phenyl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3 Synthesis of -yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane) was carried out in the same manner as in Example 112 or a method analogous thereto. -3-yl) (2-iodophenyl) methanone (Example 110) (45 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- The title compound (3.4 mg) was obtained as a colorless amorphous using pyrazole (29 mg).
UPLC: 389 [M + H] ⁺ (retention time 0.87 minutes)

Example 114 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (4′-fluoro- [1,1 ′ Synthesis of -biphenyl] -2-yl) methanone (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octan-3-yl) (2- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanone (intermediate 11) (22 mg), 1-bromo-4-fluorobenzene (9.0 mg), PdCl ₂ A mixture of (dppf) (7.3 mg) and potassium carbonate (21 mg) in DME (0.50 mL) -water (0.15 mL) was stirred at 80 ° C. for 1 hour under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was purified by HPLC to obtain the title compound (7.6 mg).
UPLC: 417 [M + H] ⁺ (retention time 1.10 minutes)

* Example 115 to Example 126 were synthesized by the same method as in Example 114 or a method analogous thereto, using Intermediate 11 and a commercially available compound.

Example 127 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4,6-dimethylpyridin-2-yl) -3,8-diazabicyclo [3.2 .1] Synthesis of octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl ) Methanone hydrochloride (intermediate 19) (38 mg), 2-bromo-4,6-dimethylpyridine (22 mg), sodium tert-butoxide (29 mg), (±) -BINAP (7.5 mg) in toluene (1. 0 mL) Pd ₂ (dba) ₃ (5.5 mg) was added to the mixture, and the mixture was stirred at 85 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to give the title compound ( 39 mg) as a white solid.
UPLC: 389 [M + H] ⁺ (retention time 0.73 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.03-7.97 (1H, m), 7.88-7.64 (2H, m), 7.57-7.17 (3H, m), 6.37-6.31 (1H, m), 6.24- 6.14 (1H, m), 4.64-4.33 (3H, m), 3.54-2.76 (3H, m), 2.36-2.17 (6H, m), 2.07-1.59 (4H, m).

* Example 128 to Example 129 were synthesized in the same manner as in Example 127 or a method analogous thereto, using any of Intermediate 19 to Intermediate 20 and commercially available compounds.

Example 130 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 6-methylisonicotinonitrile (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride Salt (intermediate 19) (42 mg), 2-chloro-6-methylisonicotinonitrile (20 mg), sodium tert-butoxide (31 mg), XPhos (6.8 mg) in toluene (1.0 mL) mixed with Pd ₂ (dba) ₃ (6.0 mg) was added, and the mixture was stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 75: 25-50: 50) to give the title compound ( 3.7 mg) was obtained as a colorless amorphous.
UPLC: 400 [M + H] ⁺ (retention time 1.07 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.04-7.99 (1H, m), 7.86-7.68 (2H, m), 7.57-7.19 (3H, m), 6.65-6.47 (2H, m), 4.70- 4.34 (3H, m), 3.51-2.72 (3H, m), 2.43-2.35 (3H, m), 2.09-1.70 (4H, m).

Example 131 (8- (3,5-dimethylphenyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-6- (2H-1,2,3 Synthesis of -triazol-2-yl) phenyl) methanone (3,8-diazabicyclo [3.2.1] octane-3-yl) (2-fluoro-) by the same method as in Example 130 or a method analogous thereto Using 6- (2H-1,2,3-triazol-2-yl) phenyl) methanone hydrochloride (intermediate 20) (34 mg) and 1-bromo-3,5-dimethylbenzene (19 mg), the title compound ( 8.1 mg) was obtained as a colorless amorphous.
UPLC: 406 [M + H] ⁺ (retention times 1.16, 1.18 min, rotamer)

Example 132 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4- (difluoromethoxy) pyridin-2-yl) -3,8-diazabicyclo [3. 2.1] Synthesis of octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3- Yl) methanone hydrochloride (intermediate 19) (64 mg), 2-chloro- (4-difluoromethoxy) pyridine (36 mg), sodium tert-butoxide (48 mg) in THF (1.5 mL) mixed with RuPhos Pd G2 ( 7.8 mg) was added, and the mixture was stirred at 85 ° C. for 1.5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 40:60) to obtain the title compound (56 mg) as a colorless amorphous.
UPLC: 427 [M + H] ⁺ (retention time 0.81 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.14-7.98 (2H, m), 7.87-7.65 (2H, m), 7.58-7.18 (3H, m), 6.79-6.15 (3H, m), 4.62- 4.31 (3H, m), 3.53-2.75 (3H, m), 2.10-1.69 (4H, m).

* Example 133 to Example 146 are the same as Example 132 using any of Intermediate 2-2, Intermediate 34 to Intermediate 36, or a commercially available compound or a known compound and Intermediate 19 or Intermediate 21. It was synthesized by the method or a method analogous thereto.

Example 147 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 3-methoxyisonicotinonitrile (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3-yl) methanone hydrochloride RuPhos Pd G2 was added to a THF (1.0 mL) mixture of a salt (intermediate 19) (32 mg), 2-chloro-3-methoxyisonicotinonitrile (intermediate 3-3) (17 mg), and cesium carbonate (81 mg). (3.9 mg) was added, and the mixture was stirred at 85 ° C. for 6 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography (silica gel, heptane: ethyl acetate = 70: 30-50: 50) to obtain the title compound (7.4 mg) as a colorless amorphous.
UPLC: 416 [M + H] ⁺ (retention time 1.06 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.05-7.93 (2H, m), 7.87-7.70 (2H, m), 7.59-7.20 (3H, m), 6.88-6.82 (1H, m), 4.86- 4.35 (3H, m), 3.94-3.86 (3H, m), 3.58-2.79 (3H, m), 2.07-1.58 (4H, m).

* Example 148 to Example 154 are the same as or similar to Example 147, using any of Intermediate 37 to Intermediate 38, commercially available compounds or known compounds, and Intermediate 19 or Intermediate 21. It was synthesized by the method.

Example 155 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (4-ethyl-6-methylpyrimidin-2-yl) -3,8-diazabicyclo [3 Of 2.2.1] octan-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (3,8-diazabicyclo [3.2.1] octane-3 2-yl-4-ethyl-6-methylpyrimidine in a mixed solution of -yl) methanone hydrochloride (intermediate 19) (40 mg), DIPEA (0.11 mL), DMAP (1.5 mg) in ethanol (1.0 mL) (20 mg) was added, and the mixture was stirred at 170 ° C. for 1 hour under microwave conditions. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative purification by HPLC to obtain the title compound (19 mg).
LCMS [Method B]: 404 [M + H] ⁺ (Retention time 5.75 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.04-7.97 (1H, m), 7.86-7.67 (2H, m), 7.57-7.19 (3H, m), 6.38-6.26 (1H, m), 5.07- 4.37 (3H, m), 3.52-2.72 (3H, m), 2.63-2.47 (2H, m), 2.38-2.21 (3H, m), 2.08-1.64 (4H, m), 1.29-1.14 (3H, m ).

* Examples 156 to 161 were synthesized by the same method as in Example 155 or a method analogous thereto, using Intermediate 19 or Intermediate 20, and commercially available compounds or known compounds.

Example 162 (8- (4,6-Dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) (2- (3-methyl-1H-pyrazole Synthesis of (1-yl) pyridin-3-yl) methanone (2-chloropyridin-3-yl) (8- (4,6-dimethylpyrimidin-2-yl) -3,8-diazabicyclo [3.2. 1] Potassium carbonate (77 mg) was added to a mixed solution of octan-3-yl) methanone (intermediate 39) (50 mg) and 3-methyl-1H-pyrazole (34 mg) in DMSO (1.0 mL) at 200 ° C. Stir for 30 minutes. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 83: 17 to 50:50), The title compound (19 mg) was obtained as a colorless gum.
UPLC: 404 [M + H] ⁺ (retention time 0.96 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.44-8.27 (2H, m), 7.78-7.11 (2H, m), 6.37-6.05 (2H, m), 5.00-4.90 (1H, m), 4.73- 4.63 (1H, m), 4.54-4.28 (1H, m), 3.49-2.90 (3H, m), 2.37-2.25 (9H, m), 2.14-1.60 (4H, m).

* Examples 163 to 166 were synthesized in the same manner as in Example 162, or a method analogous thereto, using Intermediate 39 or Intermediate 40 and commercially available compounds.

Example 167 (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3, Synthesis of 8-diazabicyclo [3.2.1] octane-3-yl) methanone (2- (2H-1,2,3-triazol-2-yl) phenyl) (8- (fur [3,2-c ] Pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 135) (30 mg) in ethanol (4.0 mL) was added to a flow hydrogenation reactor. Operation of passing 10% Pd-C CatCart (registered trademark) using [H-Cube (registered trademark), manufactured by Theles Nano Co., Ltd.] [hydrogen pressure; 3.0 bar, flow rate; 1.0 mL / min, temperature; 50 ° C] was repeated twice. The obtained reaction solution was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 40:60) to give the title compound (12 mg) as a colorless amorphous product. Obtained.
UPLC: 403 [M + H] ⁺ (retention time 0.69 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.04-7.67 (4H, m), 7.57-7.19 (3H, m), 6.34-6.27 (1H, m), 4.64-4.33 (5H, m), 3.60- 2.81 (5H, m), 2.11-1.63 (4H, m).

Example 168 (2- (1H-pyrazol-1-yl) pyridin-3-yl) (8- (2,3-dihydrofuro [3,2-c] pyridin-4-yl) -3,8- Synthesis of diazabicyclo [3.2.1] octane-3-yl) methanone In the same manner as in Example 167 or a method analogous thereto, (2- (1H-pyrazol-1-yl) pyridin-3-yl) Using (8- (furo [3,2-c] pyridin-4-yl) -3,8-diazabicyclo [3.2.1] octane-3-yl) methanone (Example 137) (30 mg) Compound (11 mg) was obtained as colorless amorphous.
UPLC: 403 [M + H] ⁺ (retention time 0.67 minutes)

Example 169 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 1,5-dimethylpyrazin-2 (1H) -one 3- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2 .1] Octane-8-yl) -5-bromo-1-methylpyrazin-2 (1H) -one (intermediate 41), tetrakis (triphenylphosphine) palladium (23 mg), trimethylboroxine (63 mg), carbonic acid A mixture of cesium (0.16 g) in 1,4-dioxane (1.0 mL) -water (0.10 mL) was degassed under reduced pressure, and then stirred at 100 ° C. for 8 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was concentrated and purified by column chromatography (silica gel, heptane: ethyl acetate = 80: 20 to 0: 100) to obtain the title compound (24 mg) as a pale yellow gum.
UPLC: 406 [M + H] ⁺ (retention time 0.95 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.04-7.98 (1H, m), 7.85-7.72 (2H, m), 7.57-7.18 (3H, m), 6.42-6.38 (1H, m), 5.48- 5.00 (2H, m), 4.49-4.37 (1H, m), 3.58-2.85 (6H, m), 2.20-1.64 (7H, m).

Example 170 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropylisonicoti Synthesis of nononitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotinonitrile Example 48 Tetrakis (triphenylphosphine) palladium (33 mg) was added to a mixed solution of (30 mg), cyclopropylzinc bromide (0.5N THF solution) (0.84 mL) in THF (0.4 mL), and nitrogen was added. It stirred for 30 minutes at 100 degreeC under atmosphere. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 75: 25 to 33:67), The title compound (19 mg) was obtained as a colorless solid.
UPLC: 426 [M + H] ⁺ (retention time 1.09 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.50-8.44 (2H, m), 8.15-8.08 (1H, m), 7.82-7.20 (3H, m), 6.97-6.93 (1H, m), 6.50- 6.39 (1H, m), 4.76-4.33 (3H, m), 3.64-2.95 (3H, m), 2.21-1.58 (5H, m), 1.34-0.71 (4H, m).

Example 171 2- (3- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl)- Synthesis of 3-cyclopropylisonicotinonitrile 2- (3,8-diazabicyclo [3.2.1] octane-8-yl) -3-cyclopropyl by a method similar to that of Example 16 or a method analogous thereto. Isonicotinonitrile (intermediate 44) (12 mg) was used to give the title compound (12 mg) as a colorless solid.
UPLC: 426 [M + H] ⁺ (retention time 1.09 minutes)

Example 172 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (pyrrolidine-1 Synthesis of -yl) isonicotinonitrile 2- (3- (2- (1 (H) -pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- Pyrrolidine (8.9 μL) was added to a mixed solution of chloroisonicotinonitrile (Example 48) (30 mg) and DIPEA (20 μL) in NMP (0.5 mL), and the mixture was stirred at 150 ° C. for 30 minutes under microwave conditions. . After returning the reaction solution to room temperature, pyrrolidine (0.5 mL) was added, and the mixture was stirred at 90 ° C. for 15 hours. The residue obtained by evaporating the reaction solution under reduced pressure was subjected to preparative purification by HPLC to obtain the title compound (2.4 mg) as a colorless solid.
LCMS [Method B]: 455 [M + H] ⁺ (retention time 5.83 minutes)

Example 173 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (methylthio) iso Synthesis of nicotinonitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-chloroisonicotino Sodium thiomethoxide (6.7 mg) was added to a solution of nitrile (Example 48) (27 mg) in DMF (2.0 mL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the precipitated solid was collected by filtration using a Kiriyama funnel, and then the solid was dried under reduced pressure to obtain the title compound (12 mg) as a yellow solid.
UPLC: 432 [M + H] ⁺ (retention time 1.07 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.49-8.45 (2H, m), 8.21-8.14 (1H, m), 7.81-7.71 (1H, m), 7.61-7.56 (1H, m), 7.31- 7.21 (1H, m), 7.03-6.99 (1H, m), 6.49-6.39 (1H, m), 4.95-4.83 (1H, m), 4.61-4.36 (2H, m), 3.64-3.00 (3H, m ), 2.49-2.43 (3H, m), 2.15-1.50 (4H, m).

Example 174 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3- (dimethylamino) Synthesis of isonicotinonitrile 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,8-diazabicyclo [3.2.1] octane-8-yl) -3-fluoroisonicoti 9.5 M dimethylamine aqueous solution (1.0 mL) was added to nononitrile (Example 49) (15 mg), and the mixture was stirred at room temperature for 1 day. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (NH silica gel, heptane: ethyl acetate = 75: 25 to 33:67), The title compound (5.4 mg) was obtained as an orange solid.
UPLC: 429 [M + H] ⁺ (retention time 1.08 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.49-8.44 (2H, m), 7.94-7.71 (2H, m), 7.61-7.51 (1H, m), 7.31-7.19 (1H, m), 6.86- 6.81 (1H, m), 6.50-6.36 (1H, m), 4.83-4.74 (1H, m), 4.55-4.28 (2H, m), 3.60-2.95 (3H, m), 2.96-2.91 (6H, m ), 1.88-1.62 (4H, m).

Example 175 (6- (4,6-Dimethylpyrimidin-2-yl) -3,6-diazabicyclo [3.1.1] heptan-3-yl) (2-fluoro-6- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone tert-butyl 3- (2-fluoro-6- (2H-1,2,3-triazol-2-yl) benzoyl) -3,6- To a solution of diazabicyclo [3.1.1] heptane-6-carboxylate (intermediate 42) (39 mg) in dichloromethane (0.40 mL) was added trifluoroacetic acid (0.20 mL) at room temperature. After stirring the reaction solution for 30 minutes, the solvent was distilled off under reduced pressure. The residue was dissolved in NMP (0.20 mL), potassium carbonate (42 mg) and 2-chloro-4,6-dimethylpyrimidine (15 mg) were added, and the mixture was stirred at 100 ° C. for 16 hr. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, and the residue obtained by concentrating the organic layer under reduced pressure is subjected to column chromatography (silica gel, heptane: ethyl acetate = 70: 30-0). : 100) The product was purified twice, and the title compound (13 mg) was obtained as a white amorphous.
UPLC: 394 [M + H] ⁺ (retention time 0.86, 0.89 min, rotamer)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.87-7.83 (1H, m), 7.80 (1H, s), 7.50-7.42 (1H, m), 7.29 (1H, s), 7.16-7.03 (1H, m), 6.45 (1H, s), 4.64-4.14 (3H, m), 3.97-3.60 (2H, m), 3.31-3.23 (1H, m), 2.82-2.72 (1H, m), 2.44-2.04 ( 6H, m), 1.74-1.63 (1H, m).

Example 176 2- (3- (2- (1H-pyrazol-1-yl) nicotinoyl) -3,6-diazabicyclo [3.1.1] heptane-6-yl) -3-methoxyisonicotino Synthesis of Nitrile (2- (1H-pyrazol-1-yl) pyridin-3-yl) (3,6-diazabicyclo [3.1.1] heptane) was prepared in the same manner as in Example 147 or a method analogous thereto. The title compound (7.6 mg) was obtained as a colorless solid using -3-yl) methanone (intermediate 43) (72 mg).
UPLC: 402 [M + H] ⁺ (retention time 0.90 minutes)
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 8.56-8.42 (2H, m), 8.07-8.01 (1H, m), 7.94-7.76 (1H, m), 7.48-7.34 (1H, m), 7.18-7.11 (1H, m), 6.67-6.33 (2H, m), 4.60-4.49 (1H, m), 4.36-4.28 (1H, m), 4.05-3.62 (5H, m), 3.43-3.04 (2H , m), 2.79-2.68 (1H, m), 1.80-1.60 (1H, m).

The structure of the final compound synthesized in the above (Example 1) to (Example 176) is shown in the following figures (Chemical Formulas 13 to 22). The structure of the intermediate compound synthesized in (Production Example 1) to (Production Example 44) is shown in the following figures (Chemical Formulas 23 to 25). As for the intermediate compound, for example, the compound obtained in (Preparation Example 1) is designated as (Intermediate 1), the compound obtained in (Preparation Example 1) <Step 1> as (Intermediate 1-1) Indicated.

Claims (10)

1. The following formula (I):
   
   

   

   
   (Where
   n represents 1 or 2;
   Ring A represents a C _{6 ~ 14} aryl group or a 5-14 membered heteroaryl group, in the ring A, the C _{6 ~ 14} aryl group or a 5-14 membered heteroaryl group, respectively, 1-5 R Optionally substituted by ¹ ;
   Ring B represents a phenyl group or a monocyclic heteroaryl group, and the phenyl group or the monocyclic heteroaryl group in Ring B may each be substituted with 1 to 4 R ² ;
   L is a halogen atom, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxyl group, a halogenated C _{1 ~ 6} alkoxy group, a phenoxy group, a monocyclic non-aromatic heterocyclic group, a phenyl group or a monocyclic heteroaryl Represents an aryl group, and the phenoxy group, monocyclic non-aromatic heterocyclic group, phenyl group or monocyclic heteroaryl group in L may each be substituted with 1 to 5 R ³ , or , L may be bonded to R ² to form a condensed ring group together with a part of ring B, and the condensed ring group is a 5- to 7-membered heterocyclic group which may be substituted with a halogen atom. ;
   L on ring B is a substituent adjacent to the bond position of ring A-bicycloring-CO—;
   R ¹ is, each independently, a halogen atom, C _{1 ~ 6} alkyl group, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy group, C _{2 ~ 6} alkynyloxy group, C _{2 ~ 7} alkanoyl group, C _{1 ~ 6} alkoxycarbonyl group, C _{1 ~ 6} alkylthio group, -NR ^a R ^b group, optionally cyano group and oxo group represents a group selected, the C _{1 ~ 6} alkyl group in R ^1, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy group, C _{2 ~ 6} alkynyloxy group, C _{2 ~ 7} alkanoyl group, C _{1 ~ 6} alkoxycarbonyl group, or a C _{1 ~ 6} alkylthio group, respectively, substituted with 1 to 5 substituents RI Well;
   R ² are each independently a halogen atom, C _{1 ~ 6} alkyl group, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy groups, C _{2 ~ 6} alkynyloxy group, a chosen group optionally cyano group and a monocyclic heteroaryl group, wherein the R ² C _{1 ~ 6} alkyl groups, C _{2 ~ 6} alkenyl groups, C _2-6 alkynyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _2-6 alkenyloxy group, C _2-6 alkynyloxy group or a monocyclic heteroaryl group, respectively, 1-5 Optionally substituted by one substituent RI;
   R ³ are each independently a halogen atom, C _{1 ~ 6} alkyl group, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{1 ~ 6} alkoxy group, C _{2 ~ 6} alkenyloxy group, C _{2 ~} It represents ₆ alkynyloxy group and chosen group optionally cyano group, wherein in R ³ C _{1 ~ 6} alkyl group, C _{2 ~ 6} alkenyl group, C _{2 ~ 6} alkynyl group, C _{1 ~ 6} alkoxy group, C _{2 1-6} alkenyloxy group or a C _{2 - 6} alkynyloxy groups may each be substituted with 1 to 5 substituents RI;
   R ^a and R ^b represent each independently, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group, a chosen group optionally from C _{2 ~ 6} alkenyl group and C _{2 ~ 6} alkynyl radical, R ^a and R ^b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group, and the monocyclic non-aromatic heterocyclic group in R ^a and R ^b At least one of the carbon atoms may be replaced with an atom or carbonyl group arbitrarily selected from an oxygen atom, a sulfur atom and a nitrogen atom optionally substituted with a C _1-6 alkyl group;
   Each of the substituents RI independently represents a halogen atom or a hydroxyl group)
   Or a pharmaceutically acceptable salt or solvate thereof.
2. In formula (I), ring A represents a phenyl group or a 5- to 10-membered heteroaryl group, and the phenyl group or heteroaryl group in ring A may be substituted with 1 to 5 R ^{1 s} , respectively. Often;
   Ring B represents a phenyl group or a 5- to 6-membered monocyclic heteroaryl group, and the phenyl group or heteroaryl group in Ring B may each be substituted with 1 to 4 R ² ;
   L is, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxyl group, a halogenated C _{1 ~ 6} alkoxy group, a monocyclic heteroaryl group phenyl group or a 5-6-membered, or the phenyl group in L Each heteroaryl group may be substituted with 1 to 5 R ³ , or when L and R ² are substituents adjacent to each other on ring B, L is bonded to R ^2. A condensed ring group may be formed together with a part of ring B, and the condensed ring group is a 5- to 7-membered monocyclic non-aromatic heterocyclic group which may be substituted with a halogen atom.
   The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.
3. In formula (I), ring A is the following partial structural formula (a1), (a2), (a3) or (a4):
   
   

   

   
   (In the formula (a1), (a2), (a3) or (a4),
   Ring A1 together with the adjacent pyridine ring forms a 9-10 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A1 is composed of 1 to 2 halogen atoms May be replaced,
   Ring A2 together with the adjacent pyrazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A2 is composed of 1 to 2 halogen atoms May be replaced,
   Ring A3 together with the adjacent imidazole ring forms an 8-9 membered condensed heteroaryl group or a partially hydrogenated condensed heteroaryl group, wherein said ring A3 is composed of 1 to 2 halogen atoms May be replaced,
   X ₁ represents a nitrogen atom, C—H or C—R ^1a ,
   X ₂ represents a nitrogen atom, C—H or C—R ^1d , provided that when X ₁ is a nitrogen atom, X ₂ is C—H or C—R ^1d ,
   R ^1a represents C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, a C _{2 ~ 7} alkanoyl group or a cyano group,
   R ^1b and R ^1c each independently represents a hydrogen atom or a C _1-6 alkyl group,
   R ^1d represents a halogen atom, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, C _{1 ~ 6} alkylthio group, a -NR ^a R ^b group or an oxo group, provided that, When R ^1d is an oxo group, X ₁ is a nitrogen atom which may be substituted with a C _1-6 alkyl group,
   R ^1e and R ^1f each independently represents a hydrogen atom or a C _1-6 alkyl group,
   The alkyl group, cycloalkyl group, alkoxyl group, alkanoyl group or alkylthio group in R ^1a , R ^1b , R ^1c , R ^1d , R ^1e and R ^1f is each substituted with 1 to 5 substituents RI. May represent)
   Ring B represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in Ring B may be substituted with one R ² ,
   L represents a phenyl group or a 5- to 6-membered heteroaryl group, and each of the phenyl group or heteroaryl group in L may be substituted with one R ³ .
   The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.
4. In formula (I), ring A is the partial structural formula (a1), wherein X ₁ is C—R ^1a , X ₂ is a nitrogen atom, C—H or C—R ^1d , R ^1d represents a halogen atom, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, C _{1 ~ 6} alkoxy group, a C _{1 ~ 6} alkylthio group or -NR ^a R ^b group;
   Ring B has the following partial structural formula (b1) or (b2):
   
   

   

   
   (In the formula (b1) or (b2),
   Y represents a nitrogen atom, C—H or C—R ^2b ,
   R ^2a represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxyl group or a monocyclic heteroaryl group, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom And
   R ^2b represents a halogen atom,
   R ^2c represents a hydrogen atom, a C _1-6 alkyl group or a cyano group,
   Each of the alkyl group and alkoxyl group in R ^2a and R ^2c may be substituted with 1 to 5 substituents RI;
   R ³ represents a C _1-6 alkyl group, a C _1-6 alkoxyl group or a cyano group, wherein the alkyl group or alkoxyl group in R ³ is each substituted with 1 to 5 substituents RI. May be;
   R ^a and R ^b each independently represent a C _1-6 alkyl group, R ^a and R ^b together with the nitrogen atom to which they are attached may form a monocyclic non-aromatic heterocyclic group; The monocyclic non-aromatic heterocyclic group for R ^a and R ^b is a nitrogen in which at least one of carbon atoms in the ring may be substituted with an oxygen atom, a sulfur atom and a C _1-6 alkyl group. It may be replaced with an atom arbitrarily selected from atoms,
   The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof.
5. In formula (I), R ^1a represents a C _1-6 alkyl group or a cyano group, R ^1b represents a hydrogen atom, R ^1c represents a hydrogen atom or a C _1-6 alkyl group, and R ^1d represents Represents a C _1-6 alkoxyl group, and the alkyl group or alkoxyl group in R ^1a , R ^1b , R ^1c and R ^1d may be substituted with 1 to 5 halogen atoms,
   R ^2a represents a hydrogen atom or a halogen atom, provided that when Y is C—R ^2b , R ^2a is a hydrogen atom;
   R ^2c represents a hydrogen atom, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group or a cyano group,
   L is the following partial structural formula (c1), (c2) or (c3):
   
   

   

   
   (In the formula (c1), (c2) or (c3),
   Z ₁ , Z ₂ , and Z ₃ each independently represent a nitrogen atom or C—H, provided that when Z ₂ is C—H, Z ₁ is C—H;
   Z ₄ represents an oxygen atom or a sulfur atom,
   R ^3a , R ^3b and R ^3c each independently represents a hydrogen atom, a C _1-6 alkyl group or a cyano group)
   The compound according to claim 4, or a pharmaceutically acceptable salt or solvate thereof.
6. A pharmaceutical composition comprising as an active ingredient at least one of the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof or a solvate thereof. .
7. 6. An orexin receptor comprising as an active ingredient at least one of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof. Preventive and / or therapeutic agent for diseases involving
8. A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising as an active ingredient, the sleep disorder characterized by Prophylactic and / or therapeutic agent.
9. An orexin receptor antagonist comprising one or more of the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof.
10. The compound according to any one of claims 1 to 5, or one or more of a pharmaceutically acceptable salt thereof or a solvate thereof, and a disorder easily associated with a sleep disorder-related drug or sleep disorder. A pharmaceutical composition comprising at least one therapeutic agent.