WO2016088813A1

WO2016088813A1 - Novel diazabicyclo[2.2.2]octane derivative

Info

Publication number: WO2016088813A1
Application number: PCT/JP2015/083926
Authority: WO
Inventors: 大道堀田; 勲櫻田
Original assignee: 持田製薬株式会社
Priority date: 2014-12-03
Filing date: 2015-12-02
Publication date: 2016-06-09
Also published as: JP2018016544A

Abstract

Provided are: a compound having an antagonistic activity on an orexin receptor, a pharmaceutically acceptable salt of the compound, or a solvate of the compound or the pharmaceutically acceptable salt; a pharmaceutical composition characterized by containing the compound, the pharmaceutically acceptable salt or the solvate as an active ingredient; and a use of the compound or the pharmaceutical composition for medical purposes, specifically a use of the compound or the pharmaceutical composition as a prophylactic and/or therapeutic agent for diseases associated with an orexin receptor, such as sleep disorders, mental diseases, neurodegenerative diseases, memory impairments and eating disorders, particularly insomnia (an insomniac symptom) which is one of sleep disorders. Specifically provided is a compound represented by formula (I), a pharmaceutically acceptable salt of the compound, or a solvate of the compound or the pharmaceutically acceptable salt.

Description

Novel diazabicyclo [2.2.2] octane derivatives

The present invention relates to a compound having an orexin receptor antagonistic action, particularly a compound having a 2,5-diazabicyclo [2.2.2] octane structure represented by the following formula (I), or a compound thereof: The present invention relates to a pharmaceutically acceptable salt, or a solvate thereof, and a pharmaceutical composition characterized by containing them as an active ingredient.

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. OX receptors (hereinafter sometimes abbreviated as “OXR”), which are specific receptors for these peptides, are OX1 receptor (hereinafter sometimes abbreviated as “OX1R”), and OX2 receptor (hereinafter, abbreviated as “OXR”). Two subtypes have been reported (sometimes abbreviated as “OX2R”). All receptors are 7-transmembrane G protein-coupled receptors (GPCRs) expressed in the central nervous system, but the tissue distribution varies depending on the subtype and has various effects on various nerves. This suggests that orexin has complex physiological activities.

Insomnia (insomnia symptoms), which is one of the sleep disorders, is a disease that is said to affect one out of five Japanese people. Long-term insomnia not only interferes with daily life and work during the day, but also may cause mental and physical distress, so that sufficient qualitative and quantitative sleep can be ensured. Treatment (such as drug therapy or non-drug therapy) is required. Currently, drugs with high prescription frequency for insomnia pharmacotherapy include benzodiazepines (hereinafter sometimes abbreviated as “BZ”), etc., but tolerance, rebound insomnia, withdrawal symptoms in long-term use , Abuse and other problems tend to occur. In Europe and the United States, long-term use of BZ drugs (including ultra-short-time BZ drugs zolpidem, zopiclone, etc.) from institutions such as NIH should be avoided. Recommendations have been made. Therefore, in order to solve the side effects and problems of existing hypnotic drugs, development of hypnotic drugs having a new mechanism of action is required.

At the beginning of the identification of OX, attention was paid to the control and regulation function of feeding behavior, but in recent years, the relationship between OX and the regulation and regulation of sleep / wakefulness has attracted attention. When OX is administered into the rat ventricle, OXR is activated, and as a result, monoamine / cholinergic neurons are dominant, and arousal promoting effects such as increased spontaneous momentum and prolonged awakening time are recognized (Non-Patent Document). 1 and Non-Patent Document 2). Moreover, in OX knockout mice and OX2R knockout mice, inhibition of arousal is observed (Non-patent Document 3). From such knowledge, it is considered that the OXR antagonist is an excellent therapeutic agent for insomnia as a sleep induction agent that induces sleep by suppressing the arousal state.

As OXR antagonists, suvorexant (trade name: Bersomura (registered trademark)) and almorexant (ACT-0778573, clinical trial number NCT00608985) are known. These OXR antagonists are substances (dual orexin receptor antagonists (DORA)) that antagonize OX1R and OX2R to the same extent, and improvement of insomnia has been reported (Non-patent Documents 4 and 5). ).

Suvorexant has already been approved for manufacture and sale as a treatment for insomnia in Japan and the United States. However, as an important basic precaution for its precautions, `` Because the effect of this drug extends after the morning after taking it, drowsiness, attention / concentration / reflex ability etc. may occur. ”Be careful not to engage in the operation of dangerous machinery such as driving a car” (Non-Patent Document 6), and there are concerns about its side effects.

From the results of experiments using knockout mice, it has been reported that the arousal action and non-REM sleep inhibitory action by OX are mainly mediated by OX2R (Non-patent Document 7). Therefore, an OX2R selective antagonist may be a therapeutic agent for insomnia that induces physiological sleep and reduces the risk of side effects. As OX2R selective antagonists, MIN-202 (Minerva Neurosciences. Inc. (http://www.minerneunosciences.com)) and MK-1064 (Merck Sharp & Dohm Corp.) (non-patent documents) are currently available. It has been clinically developed as a treatment for insomnia.

International Publication No. 2008/008517 pamphlet (Patent Document 1) discloses a compound having a cross-linked structure in the molecule as an OXR antagonist.

WO 2011/050198 pamphlet (Patent Document 2) and WO 2012/145581 pamphlet (Patent Document 3) include octahydropyrrolo [3,4-c] pyrrole in the molecule as an OXR regulator. A compound having a structure is disclosed.

In WO 2011/050200 (Patent Document 4) and WO 2011/050202 (Patent Document 5), as an OXR regulator, 3,8-diaza-bicyclo [4. Compounds having 2.0] octane and 3,6-diazabicyclo [3.2.0] heptane structures are disclosed. However, the compounds disclosed therein are different in basic skeleton from the compounds having a diazabicyclo [2.2.2] octane structure, and the compounds having a diazabicyclo [2.2.2] octane structure are also disclosed. Nor.

In WO 2011/034741 (Patent Document 6), a 5-substituted-2,5-diazabicyclo [2.2.2] octane-2-carbonyl structure is partially used as a potentiator of metabotropic glutamate receptors. Although a compound having a structure is disclosed, there is no disclosure of a specific compound of the present invention as shown below.

International Publication No. 2011/090935 (Patent Document 7) discloses a partial 5-substituted-2,5-diazabicyclo [2.2.2] octane-2-carbonyl structure as an mTOR (mammalian target of rapamycin) inhibitor. Although a compound having a structure is disclosed, there is no disclosure of a specific compound 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.

International Publication No. 2008/008517 Pamphlet International Publication No. 2011/050198 Pamphlet International Publication No. 2012/145581 Pamphlet International Publication No. 2011/050200 Pamphlet International Publication No. 2011/050202 Pamphlet International Publication No. 2011/034741 Pamphlet International Publication No. 2011/090935 Pamphlet

Currently, various insomnia drugs including BZ drugs are available for pharmacotherapy of insomnia (insomnia symptoms), which is one of sleep disorders. On the other hand, however, the patient's treatment satisfaction is low due to side effects caused by the drug, and the development of a new insomnia drug having a better drug profile than that of existing drugs is required.

There are multiple reports of compounds with OXR antagonistic activity, but there are always comprehensive issues in the above drug development. 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 OXR antagonist that is highly safe and / or excellent in effectiveness, and as a result, is represented by the formula (I). That a compound having a 2,5-diazabicyclo [2.2.2] octane structure, or a pharmaceutically acceptable salt thereof, or a solvate thereof has an OXR antagonistic action. I found it. The compound of the present invention has an OXR antagonistic action, and has an action of improving psychiatric and neurological disorders including sleep disorders such as insomnia.

The present invention relates to a compound having a 2,5-diazabicyclo [2.2.2] octane structure represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a A solvate and a pharmaceutical composition characterized by containing them as active ingredients.

The compound of the present invention has an OXR antagonistic action, and has an action of improving psychological and neurological disorders including sleep disorders such as insomnia. In addition, the pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally, and OXR antagonists, diseases involving OXR, psychiatric and neurological disorders, particularly sleep disorders such as insomnia It is expected as a preventive and / or therapeutic agent. Furthermore, the compound group of the present invention has at least one or more of such properties as good solubility, high metabolic stability, excellent oral absorption, and little hERG channel inhibitory action. Since it has characteristics, it is highly useful.

The present invention relates to a compound having a 2,5-diazabicyclo [2.2.2] octane structure represented by the following formula (I) shown in the following embodiments, or a pharmaceutically acceptable product thereof: Or a solvate thereof, and a pharmaceutical composition characterized by containing them as an active ingredient, and their pharmaceutical use, an OXR antagonist.

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

[In formula (I), m is an integer from 0 to 4; n is an integer of 0-4; ring A represents a C _{6 ~ 14} aryl group or a 5-7 membered heteroaryl group, ; ring B represents a C _{6 ~ 14} aryl group or a 5-7 membered heteroaryl group,; Q (the Q is diazabicyclo [2.2.2] amide bond at the adjacent position to couple the octane ring and ring B (o-position) to always replace: the substitution position of Q is also the same defined during each aspect described below), the C _{3 ~ 8} cycloalkyl group, or -OR ^c or partial structural formula,, (SF- Group represented by 1):

Wherein (SF-1), ring C is C _{6 ~ 14} aryl group, 5- to 7-membered heteroaryl group or 3-8 represents a non-aromatic heterocyclic group,; p is an integer of 0 to 5 Yes; each R ³ independently represents a halogen atom, a cyano group, —R ^d , or —OR ^d , where R ^d is a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, or C _{3 And} R ¹ each independently represents a halogen atom, a cyano group, —R ^a , —OR ^a , —C (O) R ^a , —C (O) OR ^a , — SR ^{a represents} —SO ₂ R ^a , —NR ^A R ^B group, 3- to 8-membered non-aromatic heterocyclic group, or oxo group; R ² each independently represents a halogen atom, a cyano group, —R ^b represents -OR ^b or 5-7 membered heteroaryl group, the 5- to 7-membered heteroaryl group optionally substituted with one to five halogen atoms or hydroxyl, At best, the and R ^A in -NR ^A R ^B group in R ¹ R ^B are each ^{independently, -R a, -C (O)} R a, -C (O) OR a , or -SO, ₂ R ^a represents; R ^a in the R ¹ and in -NR ^a R ^B group, a hydrogen atom, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group, hydroxy C _{1 ~ 6} alkyl group, hydroxy halogenated C _{1 ~ 6} alkyl group or an C _{3 ~ 8} cycloalkyl group; R ^b in the R ² represents a C _{1 ~ 6} alkyl group or halogenated C _{1 ~ 6} alkyl group; the Q R ^c in the, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group or C _{6 ~ 14} compounds are represented by an aryl group, or a pharmaceutically acceptable salt thereof, or, The solvate.

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 of the above “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, pentyl, isopentyl, neopentyl, Hexyl, isohexyl and the like can be 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, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.

In the present specification, unless otherwise specified, the term “hydroxyhalogenated C _1-6 alkyl group” means that the above “halogenated C _1-6 alkyl group” is optionally substituted with 1 to 5 hydroxyl groups. Means a group such as 2,2,2-trifluoro-1-ethanol group.

Herein, unless otherwise specified, as the "C _{3 ~ 8} cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 It may be 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 above “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 above-mentioned “heteroaryl group” means 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 condensed ring”. Formula heteroaryl group ".

In the present specification, unless otherwise specified, the above “monocyclic heteroaryl group” is preferably one having 5 to 7 ring members (5 to 7 membered heteroaryl group), such as 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, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2, 4-triazinyl, 1,3,5-triazinyl, 2H-1,2,3-thiadiazinyl, H-1,2,4-thiadiazinyl, 6H-1,3,4-thiadiazinyl, 1,4 diazepinyl, 1,4-oxazepinyl and the like.

In the present specification, unless otherwise specified, the above-mentioned “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 above-mentioned “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, phenothiadi 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 this specification, unless otherwise specified, the “monocyclic non-aromatic heterocyclic group (3- to 8-membered non-aromatic heterocyclic group)” is a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Represents a monovalent group formed by removing any hydrogen atom from a saturated or unsaturated heterocyclic ring, which is a 3- to 8-membered monocycle containing 1 to 4.

In the present specification, unless otherwise specified, examples of the “monocyclic non-aromatic heterocyclic group (3- to 8-membered non-aromatic heterocyclic group)” include aziridinyl, azetidinyl, oxiranyl, thiranyl, oxetanyl, thietanyl, and the like. , Pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, thiolanyl, pyrazolinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl (oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolidinyl, isoxazolinyl, 1,3-oxazolidinyl, iso Xazolidinyl, thiazolinyl, isothiazolinyl, 1,3-thiazolidinyl, isothiazolidinyl, oxadiazolinyl, 1,3,4-oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinu Lysinyl, azepanyl, diazepinyl, oxepanyl, and the like.

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” means that two hydrogen atoms on the nitrogen atom of “amino group” are each independently “hydrogen atom”, “C _1-6 alkyl group”, “halogenated C”. _1-6 alkyl group "," C _{2 ~ 6} alkenyl group "," C _{2 ~ 6} alkynyl group "," _{- C (O) -C 1 ~} 6 alkyl group ", -C (O) O-C 1 ~ ₆ alkyl group ", -SO ₂ -C _{1 ~ 6} alkyl group", "- C (O) - halogenated C _{1 ~ 6} alkyl group" -SO ₂ - optionally halogenated C _{1 ~ 6} alkyl group "such as Means a group substituted by a group selected by

[1-1]
In the formula (I) of the above embodiment [1], preferably m = 0 to 3.
[1-1-1]
In the formula (I) of the above embodiment [1], m = 2 is more preferable.

[1-2]
In the formula (I) of the above embodiment [1], preferably n = 0 to 2.
[1-2-1]
In the formula (I) of the above embodiment [1], n = 0 or 1 is more preferable.

[1-3]
In the formula (I) of the above embodiment [1], the ring A is preferably a group selected from a phenyl group, a pyridinyl group, a pyrimidinyl group, a pyrazinyl group, a thiazolyl group, or an oxazolyl group.
[1-3-1]
In the formula (I) of the above embodiment [1], the ring A is more preferably ring A is a phenyl group, a pyridin-2-yl group, a pyrimidin-2-yl group, a pyrazin-2-yl group, a thiazole-2 -A group selected from an yl group and an oxazol-2-yl group.
[1-3-2]
In the formula (I) of the above embodiment [1], the ring A is particularly preferably a pyridin-2-yl group or a pyrimidin-2-yl group.

[1-4]
In the formula (I) of the above embodiment [1], the ring B is preferably a group selected from a phenyl group, a pyridinyl group, a pyridazinyl group, a furanyl group, a 1H-pyrazolyl group, and a thiazolyl group.
[1-4-1]
In the formula (I) of the above embodiment [1], the ring B is more preferably the formula (B-1), the formula (B-2), the formula (B-3), the formula (B-4) or the formula (B -5) [in the formula (B-1), X ₄ , X ₅ , X ₆ and X ₇ each independently represents N or C—H] (provided that the formula (B— 1) to (B-5), the —C (O) — group and the Q group are not included in the ring B).

Wherein (B-1), X ₄ represents N or C-R ^2a, where the R ^2a represents a hydrogen atom, a halogen atom or -O-C _{1 ~ 6} alkyl group,; X ₅ Represents C—R ^2b , where R ^2b is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, or a 5- to 7-membered heteroaryl group (the 5- to 7-membered heteroaryl group is a halogen atom X ₁ represents N or C—R ^2c , where R ^2C represents a hydrogen atom, a halogen atom, a C atom, or a C _1-6 alkyl group (which may be substituted with 1 to 4 alkyl groups). _1-6 alkyl group or -O-C _{1 ~} represents an _alkyl group,; X ₇ represents N or C-R ^2d, wherein said R ^2d represents a hydrogen atom or a halogen atom. ]

[1-4-2]
In formula (I) of the above embodiment [1], ring B is particularly preferably a group selected from formula (B-1-1), formula (B-1-2), or formula (B-3). (However, in formula (B-1-1), formula (B-1-2) and formula (B-3), the —C (O) — group and Q group are not included in ring B).

[1-5]
In the formula (I) of the above embodiment [1], preferably the Q, C _{3 ~ 8} cycloalkyl group, -OR ^c1 (the R ^c1 is, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group, or C _{6 ~ 14} aryl group), or a partial structural formula (SF-1) a group represented by:

[In Formula (SF-1), Ring C is a phenyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, triazolyl group, oxadiazolyl group, thiazolyl group, oxazolyl group, isothiazolyl group, tetrazolyl group, pyrrolidinyl group, piperazinyl group A group or a group selected from morpholyl groups; p is an integer of 0 to 2; R ³ is independently a halogen atom, a cyano group, —R ^d1 , or —OR ^d1 (wherein R ^d1 is Represents a C _1-6 alkyl group or a halogenated C _1-6 alkyl group].

[1-5-1]
In the formula (I) of the above embodiment [1], is more preferably Q, C _{3 ~ 8} cycloalkyl group, -OR ^c1 (the R ^c1 is, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group , or C _{6 ~ 14} aryl group), or a partial structural formula (SF-1) a group represented by:

[In the formula (SF-1), ring C represents a phenyl group, a pyridin-2-yl group, a pyrimidin-2-yl group, a pyridazin-3-yl group, a 1H-pyrazol-1-yl group, 1-methyl- 1H-pyrazol-3-yl group, 1H-pyrazol-3-yl group, 1H-pyrazol-4-yl group, 1H-1,2,3-triazol-1-yl group, 2H-1,2,3- Triazol-2-yl group, 1,2,4-oxadiazol-5-yl group, thiazol-2-yl group, thiazol-4-yl group, thiazol-5-yl group, oxazol-2-yl group, Isothiazol-4-yl group, isothiazol-5-yl group, 2H-tetrazol-2-yl group, morpholin-1-yl group, pyrrolidin-1-yl group, pyrrolidin-1-yl group, piperazin-1- Il group or morpho It represents a group selected from the down-1-yl group; p is an integer of 0 or 1; R ³ is, each independently, a halogen atom, a cyano group, -C _{1 ~ 6} alkyl group or -O-, Represents a C _1-6 alkyl group].

[1-5-2]
In the formula (I) of the above embodiment [1], more preferably, Q is —O-halogenated C _1-6 alkyl group (more specifically, 1,1,2,2-tetrafluoroethoxy group, and 2,2,2-trifluoroethoxy), and a group represented by the partial structural formula (SF-1):

[In the formula (SF-1), ring C represents a pyridin-2-yl group, a 1H-pyrazol-1-yl group, a 2H-1,2,3-triazol-2-yl group, or 1,2,4. Represents a group selected from -oxadiazol-5-yl group; p is an integer of 0 or 1; R ³ is a C _1-6 alkyl group (more specifically, R ³ is a methyl group) Represents).

[1-6]
In the formula (I) of the above embodiment [1], R ¹ is preferably a halogen atom, a cyano group, —R ^a1 , —OR ^a1 , —C (O) R ^a1 , —C (O) OR ^a1 , —SR ^a1 , —NR ^A R ^B group, 3- to 8-membered non-aromatic heterocyclic group, or oxo group (R ^A and R ^B in the —NR ^A R ^B group are each independently a hydrogen atom, or C _1- It represents an _alkyl group; the R ^a1 is a C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group, hydroxy halogenated C _{1 ~ 6} alkyl group or an C _{3 ~ 8} cycloalkyl group) .
[1-6-1]
In the formula (I) of the above embodiment [1], and more preferably as R ^1, a cyano group, C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, or -O-C _{1 ~ 6} alkyl group, More specifically, R ¹ is a cyano group, a methyl group, a cyclopropyl group, and a methoxy group.

[1-7]
In the formula (I) of the above embodiment [1], R ² is preferably a halogen atom, a cyano group, —R ^b1 , —OR ^b1 (where R ^b1 is a C _1-6 alkyl group, or a halogenated C ₁ Represents a _6- alkyl group), a pyrazolyl group, or a pyridyl group (the pyrazolyl group and the pyridyl group may be substituted with 1 to 4 halogen atoms or a C _1-6 alkyl group).
[1-7-1]
In the formula (I) of the above embodiment [1], R ² is more preferably a halogen atom or a C _1-6 alkyl group, and more specifically, R ² is fluorine and a methyl group.

[1-8]
In the formula (I) of the above embodiment [1], the combination of the ring A and (R ¹ ) _m is preferably the following partial structural formula (A-1) or (A-2):

[In the formula (A-1), X ₁ represents N or C—H; X ₂ represents N or C—R ^1a (wherein R ^1a represents a hydrogen atom, a halogen atom, C _1-6 alkyl group, C _{3 ~ 8} cycloalkyl group, -O-C _{1 ~ 6} alkyl group, -S-C _{1 ~ 6} alkyl group, -NR ^A R ^B group (said -NR ^A R in R ^B groups ^A and R ^B Each independently represents a hydrogen atom and a C _1-6 alkyl group), or a 3- to 8-membered non-aromatic heterocyclic group); X ₃ represents N or C—R ^1b (the R ^1b is a hydrogen atom, a cyano group, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group, C _{3 ~ 8} cycloalkyl group, -O-C _{1 ~ 6} alkyl group, -O- halogenated C _{1 1-6} alkyl group, a hydroxy halogenated C _{1 ~ 6} alkyl _{group, -C (O) -C 1 ~} 6 alkyl group, or _{-C (O) O-C 1} ~ 6 alkyl group,); R ^1c Each independently represent a hydrogen atom or a C _{1 ~ 6} alkyl group; wherein (A-2), Y ₁ represents O, S or N-R ^1d,, the R ^1d are each independently, Represents a hydrogen atom or a C _1-6 alkyl group].

[1-8-1]
In the formula (I) of the above embodiment [1], the combination of the ring A and (R ¹ ) _m is more preferably a formula (A-1) or a formula (A) which is a partial structural formula in the above embodiment [1-8]. A-2) [in the formula (A-1), X ₁ represents N or C—H; X ₂ represents N or C—R ^1a (wherein R ^1a represents a hydrogen atom, a fluorine atom, chlorine) An atom, a methyl group, a methoxy group, an ethoxy group, a (methoxy-d ₃ ) group, a cyclopropyl group, a pyrrolidin-1-yl group, a methylthio group, or a dimethylamino group); X ₃ is N or C—R ^1b (wherein R ^1b represents a hydrogen atom, a cyano group, a methyl group, an ethyl group, a cyclopropyl group, an acetyl group, a methoxy group, a difluoromethoxy group, a trifluoromethyl group, 1-hydroxy-2,2,2- Trifluoroethyl group or methoxycarbonyl group R ^1c each independently represents a hydrogen atom or a methyl group: In Formula (A-2), Y ₁ represents O, S, or N—R ^1d , and each R ^1d represents each independently And represents a hydrogen atom or a methyl group.

[1-8-2]
In the formula (I) of the above embodiment [1], the combination of the ring A and (R ¹ ) _m is more preferably a 3,5-dimethylphenyl group, a 3-chloro-4-cyano-pyridin-2-yl group, 3-methyl-4- (trifluoromethyl) pyridin-2-yl group, 3-methoxy-4- (trifluoromethyl) pyridin-2-yl group, 4-acetylpyridin-2-yl group, 4-cyano- Pyridin-2-yl group, 4-cyano-3-cyclopropyl-pyridin-2-yl group, 4-cyano-3-methoxy-pyridin-2-yl group, 4-cyano-3-ethoxy-pyridine-2- Yl group, 4-cyano-3- (methoxy-d3) -pyridin-2-yl group, 4-cyano-6-methyl-pyridin-2-yl group, 4-cyano-3-fluoro-pyridin-2-yl Group 4-cyano-3- Cyclopropyl-pyridin-2-yl group, 4-cyano-3- (pyrrolidin-1-yl) -pyridin-2-yl group, 4-cyano-3- (methylthio) -pyridin-2-yl group, 4- Cyano-3- (dimethylamino) -pyridin-2-yl group, 4- (difluoromethoxy) pyridin-2-yl group, 4- (1-hydroxy-2,2,2-trifluoroethyl) -pyridine-2 -Yl group, 4- (trifluoromethyl) pyridin-2-yl group, 4- (methoxycarbonyl) -pyridin-2-yl group, 6-methyl-4- (trifluoromethyl) pyridin-2-yl group, 4,6-dimethylpyridin-2-yl group, 1,5-dimethylpyrazin-2 (1H) -one-3-yl group, 4,5-dimethylpyrimidin-2-yl group, 4,6-dimethylpyrimidine- 2-I Group, 4-ethyl-6-methylpyrimidin-2-yl group, 4,5,6-trimethylpyrimidin-2-yl group, 4-cyclopropyl-6-methylpyrimidin-2-yl group, 4-methoxy-6 -A group selected from a methylpyrimidin-2-yl group, a 3-methoxy-6-methylpyrazin-2-yl group, and a 4,5-dimethylthiazol-2-yl group.

[1-8-3]
In the formula (I) of the above embodiment [1], the combination of the ring A and (R ¹ ) _m is particularly preferably a 4-cyano-3-methoxy-pyridin-2-yl group, 4-cyano-3-cyclopropyl -Pyridin-2-yl group or 4,6-dimethylpyrimidin-2-yl group.

[1-9]
In the formula (I) of the above embodiment [1], the combination of the rings B, Q and (R ² ) _n is preferably a partial structural formula of the formula (BQ-1), formula (BQ-2), formula (BQ -3), formula (BQ-4), or formula (BQ-5) (wherein, in formulas (BQ-1) to (BQ-5), the —C (O) — group represents ring B, Q and (R ² ) Not included in the combination of _n ):

Wherein (BQ-1), X ₄ represents N or C-R ^2a (the R ^2a represents a hydrogen atom, a halogen atom or -O-C _{1 ~ 6} alkyl group,); X ₅ is C—R ^2b (wherein R ^2b is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, or a 5- to 7-membered heteroaryl group (the 5- to 7-membered heteroaryl group is a halogen atom, or C represents a may be one to four substituents) at _1-6 alkyl group); X ₆ represents N or C-R ^2c (the R ^2C is hydrogen atom, halogen atom, C _1-6 alkyl X ₇ represents N or C—R ^2d (wherein R ^2d represents a hydrogen atom or a halogen atom); Q ′ represents a halogen atom, or —O—C _1-6 alkyl group; , C _{3 ~ 8} cycloalkyl group, -OR ^c1 (the R ^c1 is, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl group, Oyo Fine C _{6 ~ 14} represents a group selected from aryl group optionally), or 3-8 membered represents a non-aromatic heterocyclic ring: wherein (BQ-2), formula (BQ-3), formula (BQ-4) And in formula (BQ-5), p and R ³ are the same as defined in the above embodiment [1-5]; X ₄ , X ₅ , X ₆ and X ₇ are the same as those in formula (BQ-1) X represents N or C—H; Y ₂ represents O, S, N—H or N—CH ₃ ].

[1-9-1]
In the formula (I) of the embodiment [1], the combination of the rings B, Q and (R ² ) _n is more preferably a formula (BQ-1) which is a partial structural formula in the embodiment [1-9], Formula (BQ-2), Formula (BQ-3), Formula (BQ-4), or Formula (BQ-5) [In the above formula (BQ-1), X ₄ represents N or C—R ^2a R ^2a represents a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group, or an ethoxy group; X ₅ represents C—R ^2b (wherein R ^2b represents a hydrogen atom, a fluorine atom, a methyl group, 1H— X ₆ is N or C—R ^2c (wherein R ^2C is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl atom), or a pyrazol-1-yl group or a 5-chloro-pyridin-3-yl group; X ₇ represents N or C—R ^2d (wherein R ^2d represents a hydrogen atom or fluorine) Q ′ represents an ethoxy group, phenoxy group, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy group, cyclopropyl group, pyrrolidin-1-yl group, or morpholine-1- In the above formula (BQ-2), formula (BQ-3), formula (BQ-4) and formula (BQ-5), p is an integer of 0 or 1; R ³ is X ₄ , X ₅ , X ₆ and X ₇ are the same as defined in the above formula (BQ-1) in the embodiment [1-9-1]. X represents N or C—H; Y ₂ represents O, S, N—H or N—CH ₃ ].

[1-9-2]
In the formula (I) of the above embodiment [1], the combination of rings B, Q and (R ² ) _n is more preferably a 5-fluoro-3- (pyrimidin-2-yl) pyridin-2-yl group, 2,2′-bipyridin) -3-yl group, 2- (1H-1,2,3-triazol-1-yl) pyridin-3-yl group, 2- (1H-pyrazol-1-yl) pyridine- 3-yl group, 2- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl group, 2- (2H-1,2,3-triazol-2-yl) pyridin-3-yl group 2- (3-cyano-1H-pyrazol-1-yl) pyridin-3-yl group, 2- (3-methyl-1H-pyrazol-1-yl) pyridin-3-yl group, 2- (thiazol- 2-yl) pyridin-3-yl group, 2,5- (1H-pyrazole 1-yl) pyridin-3-yl group, 4-ethoxy-2- (1H-pyrazol-1-yl) pyridin-3-yl group, 4-methoxy-2- (1H-pyrazol-1-yl) pyridine- 3-yl group, 5 ″ -chloro- [2,2 ′: 5 ′, 3 ″ -terpyridine] -3′-yl group, 5-fluoro-2- (1H-pyrazol-1-yl) pyridine -3-yl group, 6-methoxy-2- (1H-pyrazol-1-yl) pyridin-3-yl group, 2- (2H-1,2,3-triazol-2-yl) pyridin-4-yl Group, 3- (1H-pyrazol-1-yl) pyridazin-4-yl group, [1,1′-biphenyl] group, 2- (1H-pyrazol-1-yl) phenyl group, 2- (2H-1 , 2,3-Triazol-2-yl) phenyl group, 2- (2H-tetrazole-2- Yl) phenyl group, 2- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl group, 2- (3-methylisothiazol-5-yl) phenyl group, 2- (4- Cyanothiazol-2-yl) phenyl group, 2- (6-cyanopyridin-2-yl) phenyl group, 2- (6-methylpyridin-2-yl) phenyl group, 2- (6-methoxypyridine-2- Yl) phenyl group, 2- (isothiazol-4-yl) phenyl group, 2- (oxazol-2-yl) phenyl group, 2- (thiazol-2-yl) phenyl group, 2- (thiazol-4-yl) ) Phenyl group, 2- (thiazol-5-yl) phenyl group, 2- (pyridin-2-yl) phenyl group, 2- (pyrimidin-2-yl) phenyl group, 2-chloro-6- (2H-1) , 2,3-Triazo Ru-2-yl) phenyl group, 2-fluoro-6- (pyrimidin-2-yl) phenyl group, 2-methoxy-6- (2H-1,2,3-triazol-2-yl) phenyl group, 3 '-(Difluoromethoxy)-[1,1'-biphenyl] -2-yl group, 3'-methoxy- [1,1'-biphenyl] -2-yl group, 3-fluoro-2- (2H-1 , 2,3-triazol-2-yl) phenyl group, 4′-fluoro- [1,1′-biphenyl] -2-yl group, 4-chloro-2- (2H-1,2,3-triazole- 2-yl) phenyl group, 4-chloro-2- (pyrimidin-2-yl) phenyl group, 4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl group, 4-fluoro -2- (pyrimidin-2-yl) phenyl group, 4-methyl-2- 2H-1,2,3-triazol-2-yl) phenyl group, 4-methyl-2- (pyrimidin-2-yl) phenyl group, 4-methoxy-2- (1H-1,2,3-triazole- 1-yl) phenyl group, 4-methoxy-2- (2H-1,2,3-triazol-2-yl) phenyl group, 5-fluoro-2- (2H-1,2,3-triazole-2- Yl) phenyl group, 5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl group, 2-cyclopropylphenyl group, 2,6-diethoxyphenyl group, 2- (trifluoro Methoxy) phenyl group, 2- (1,1,2,2-tetrafluoroethoxy) phenyl group, 2-phenoxyphenyl group, 2- (pyrrolidin-1-yl) pyridin-3-yl group, or 2-morpholinopyridine -3 -A group selected from yl groups.

[1-9-3]
In the formula (I) of the above embodiment [1], the combination of rings B, Q and (R ² ) _n is particularly preferably a 2- (2H-1,2,3-triazol-2-yl) phenyl group, 2 -Fluoro-6- (2H-1,2,3-triazol-2-yl) phenyl group, 5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl group, 2- ( 3-methyl-1,2,4-oxadiazol-5-yl) phenyl group, 2- (1H-pyrazol-1-yl) pyridin-3-yl group, 2- (2,2,2-trifluoro) An ethoxy) phenyl group or a 2- (1,1,2,2-tetrafluoroethoxy) phenyl group.

[1-10]
In the formula (I) of the above embodiment [1], the combination of the ring B, Q and (R ² ) _n is preferably the following partial structural formula (BQ-6) or (BQ-7) (provided that In the formulas (BQ-6) and (BQ-7), the —C (O) — group is not included in the combination of ring B, Q and (R ² ) _n ):

[In formula (BQ-6) and formula (BQ-7), p and R ³ are the same as defined in the above embodiment [1-5]; X represents N or C—H; Y ₂ Represents O, S, NH, or N—CH ₃ ; R ^2e represents a hydrogen atom, a cyano group, a C _1-6 alkyl group, or a halogenated C _1-6 alkyl group].

[1-10-1]
In the formula (I) of the embodiment [1], the combination of the rings B, Q and (R ² ) _n is more preferably a formula (BQ-6) which is a partial structural formula in the embodiment [1-10] or Formula (BQ-7) [In Formula (BQ-6) and Formula (BQ-7), p is an integer of 0 or 1; R ³ represents a cyano group; X is N or C—H. Y ₂ represents S; R ^2e represents a hydrogen atom, a cyano group, a methyl group, or a trifluoromethyl group.

[1-10-2]
In the formula (I) of the above embodiment [1], the combination of rings B, Q and (R ² ) _n is more preferably a 3-methyl-1- (3-cyanophenyl) -1H-pyrazol-5-yl group 1- (pyridin-2-yl) -1H-pyrazol-5-yl group, 3-cyano-1- (pyridin-2-yl) -1H-pyrazol-5-yl group, 3-methyl-1- ( Pyridin-2-yl) -1H-pyrazol-5-yl group, 3- (trifluoromethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl group, 1- (pyridazine-3- Yl) -1H-pyrazol-5-yl group or 1- (thiazol-2-yl) -1H-pyrazol-5-yl group.

[1-10-3]
In the formula (I) of the above embodiment [1], the combination of rings B, Q and (R ² ) _n is particularly preferably a 1- (pyridin-2-yl) -1H-pyrazol-5-yl group.

[1-11]
In the formula (I) of the above embodiment [1], preferably, m is the same as defined in the above embodiment [1-1]; n is the same as defined in the above embodiment [1-2]. Ring A is the same as defined in the above embodiment [1-3]; ring B is the same as defined in the above embodiment [1-4]; Q is defined in the above embodiment [1-5]. R ¹ is the same as defined in the above embodiment [1-6]; R ² is the same as defined in the above embodiment [1-7].

[1-11-1]
In the formula (I) of the embodiment [1], more preferably, m is the same as defined in the embodiment [1-1-1]; n is the same as in the embodiment [1-2-1]. Ring A is the same as defined in the above embodiment [1-3-2]; ring B is the same as defined in the above embodiment [1-4-2]; R ¹ is the same as defined in the above embodiment [1-6-1]; R ² is defined as in the above embodiment [1-7-]. 1] Same definition as in [1].

[1-12]
In the formula (I) of the embodiment [1], the combination of the ring A and (R ¹ ) _m is preferably the same as defined in the embodiment [1-8]; the rings B, Q and (R ² ) The combination of _n is the same as defined in the above embodiment [1-9] or the above embodiment [1-10].

[1-12-1]
In the formula (I) of the above embodiment [1], preferably, the combination of the ring A and (R ¹ ) _m is the same as defined in the above embodiment [1-8-3]; The combination of (R ² ) _n is the same as defined in the above embodiment [1-9-3] or the above embodiment [1-10-3].

[2] Among the compounds of the above formula (I) of the above embodiment [1], preferred compounds are those represented by the following formula (Ia):

[In the formula (Ia), m, n, Q, R ¹ and R ² are the same as defined in the above embodiment [1]; X ₁ , X ₂ and X ₃ in the ring A ′ are Each independently represents N or C—H; each of X ₄ , X ₅ , X ₆ , and X _{7 in} ring B ′ independently represents N or C—H]. A compound. Further, as a preferred embodiment of the present invention, a pharmaceutically acceptable salt of the compound of the above formula (Ia) or a solvate thereof can be mentioned.

[2-1]
In the formula (Ia) of the above embodiment [2], m is preferably an integer of 0 to 3.
[2-1-1]
In the formula (Ia) of the above embodiment [2], m = 2 is more preferable.

[2-2]
In the formula (Ia) of the above embodiment [2], n is preferably an integer of 0 to 2.
[2-2-1]
In the formula (Ia) of the above embodiment [2], n = 0 or 1 is more preferable.

[2-3]
In the formula (Ia) of the above embodiment [2], the combination of X ₁ , X ₂ and X ₃ in the ring A ′ is preferably (X ₁ = N, X ₂ = X ₃ = C—H) (X ₁ = X ₂ = N, X ₃ = C—H), (X ₁ = C—H, X ₂ = X ₃ = N), or (X ₁ = X ₂ = X ₃ = C—H) It is.

[2-3-1]
In the formula (Ia) of the embodiment [2], the combination of X ₁ , X ₂ and X ₃ in the ring A ′ is more preferably (X ₁ = N, X ₂ = X ₃ = C—H). Or (X ₁ = X ₂ = N, X ₃ = C—H).

[2-4]
In the formula (Ia) of the embodiment [2], the combination of X ₄ , X ₅ , X ₆ and X ₇ in the ring B ′ is preferably (X ₄ = N, X ₅ = X ₆ = X ₇ = C-H), (X 4 = X 5 = X 6 = C-H, X 7 = N), (X 4 = X 5 = X 7 = C-H, X 6 = N), (X 4 = X ₅ = C—H, X ₆ = X ₇ = N), or (X ₄ = X ₅ = X ₆ = X ₇ = C—H).

[2-4-1]
In the formula (Ia) of the above embodiment [2], the combination of X ₄ , X ₅ , X ₆ and X ₇ in ring B ′ is more preferably (X ₄ = N, X ₅ = X ₆ = X ₇ = C-H), a _{_{(X 4 = X 5 = X}} 6 = C-H, X 7 = N), or _{_{(X 4 = X 5 = X}} 6 = X 7 = C-H).

[2-5]
In the formula (I-a) of the above embodiment [2], preferably, C _{3 ~ 8} cycloalkyl group, -OR ^c2 (the R ^c2 is, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl as Q groups, and C _{6 ~ 14} represent optionally a chosen group aryl group), or a group represented by the partial structural formula (SF-1):

[In the formula (SF-1), rings C, p and R ³ are the same as defined in the above embodiment [1-5]].

[2-5-1]
In the formula (I-a) of the above embodiment [2], is more preferably Q, C _{3 ~ 8} cycloalkyl group, -OR ^c2 (the R ^c2 is, C _{1 ~ 6} alkyl group, a halogenated C _{1 ~ 6} alkyl groups, and C _{6 ~ 14} represent the chosen group optionally aryl group), or a partial structural formula (SF-1) a group represented by:

[In Formula (SF-1), Ring C is a phenyl group, a pyridin-2-yl group, a pyrimidin-2-yl group, a 1H-pyrazol-1-yl group, or a 1-methyl-1H-pyrazol-3-yl group. A group, 1H-pyrazol-3-yl group, 1H-pyrazol-4-yl group, 1H-1,2,3-triazol-1-yl group, 2H-1,2,3-triazol-2-yl group, 1,2,4-oxadiazol-5-yl group, thiazol-2-yl group, thiazol-4-yl group, oxazol-2-yl group, isothiazol-4-yl group, isothiazol-5-yl Or a group selected from 2H-tetrazol-2-yl group; p and R ³ are as defined in the above embodiment [1-5-1].

[2-5-2]
In the formula (Ia) of the above embodiment [2], Q is more preferably the same as defined in the above embodiment [1-5-2].

[2-6]
In the formula (Ia) of the above embodiment [2], R ¹ is preferably a halogen atom, a cyano group, —R ^a1 , —OR ¹ , —C (O) R ^a1 , —C (O) OR ^a1 , —SR ^a1 , —NR ^A R ^B group, or 3- to 8-membered non-aromatic heterocyclic group (the above R ^a1 , R ^A , and R ^B are the same as defined in the above embodiment [1-6]) It is.

[2-6-1]
In the formula (Ia) of the above embodiment [2], R ¹ is more preferably the same as defined in the above embodiment [1-6-1].

[2-7]
In the formula (Ia) of the above embodiment [2], R ² is preferably a halogen atom, —R ^b1 , —OR ^b1 (wherein R ^b1 has the same definition as in the above embodiment [1-7]). ), A pyrazolyl group, or a pyridyl group (the pyrazolyl group and the pyridyl group may be substituted with 1 to 4 halogen atoms and a C _1-6 alkyl group).

[2-7-1]
In the formula (Ia) of the above embodiment [2], R ^{2 represents} more preferably a halogen atom or a C _1-6 alkyl group, and more specifically a fluorine and a methyl group.

[2-8]
In the formula (Ia) of the above embodiment [2], the combination of the ring A ′ and (R ¹ ) _m is preferably the same as the definition of the ring A and (R ¹ ) _{m in} the above embodiment [1-8]. It is.

[2-8-1]
In the formula (Ia) of the embodiment [2], the combination of the ring A ′ and (R ¹ ) _m is more preferably a combination of the ring A and the (R ¹ ) _{m in} the embodiment [1-8-1]. Same as definition.

[2-8-2]
In the formula (Ia) of the embodiment [2], the combination of the ring A ′ and (R ¹ ) _m is more preferably a combination of the ring A and the (R ¹ ) _{m in} the embodiment [1-8-2]. Same as definition.

[2-8-3]
In the formula (Ia) of the embodiment [2], the combination of the ring A ′ and (R ¹ ) _m is particularly preferably a combination of the ring A and the (R ¹ ) _{m in} the embodiment [1-8-3]. Same as definition.

[2-9]
In the formula (Ia) of the embodiment [2], the combination of the rings B ′, Q and (R ² ) _n is preferably a ring B, Q and (R ² ) _{n in the} embodiment [1-9]. The definition is the same as

[2-9-1]
In the formula (Ia) of the embodiment [2], the combination of the rings B ′, Q and (R ² ) _n is more preferably a ring B, Q and (R) in the embodiment [1-9-1]. ² ) Same definition as _n .

[2-9-2]
In the formula (Ia) of the embodiment [2], the combination of the rings B ′, Q and (R ² ) _n is more preferably a combination of the rings B, Q and (R) in the embodiment [1-9-2]. ² ) Same definition as _n .

[2-9-3]
In the formula (Ia) of the above embodiment [2], the combination of the rings B ′, Q and (R ² ) _n is particularly preferably a ring B, Q and (R) in the above embodiment [1-9-3]. ² ) Same definition as _n .

[2-10]
In the formula (Ia) of the above embodiment [2], preferably, m is the same as defined in the above embodiment [2-1]; n is the same as defined in the above embodiment [2-2]. Ring A ′ is the same as defined in the above embodiment [2-3]; Ring B is the same as defined in the above embodiment [2-4]; Q is the above described embodiment [2-2]. 5] in the same definition as in; R ¹ are as defined in the above aspect [2-6]; R ² is the same as defined in the above aspect [2-7].

[2-10-1]
In the formula (Ia) of the above embodiment [2], more preferably, m is the same as defined in the above embodiment [2-1-1]; n is the above embodiment [2-2-1]. Ring A is the same as defined in the above embodiment [2-3-2]; ring B is the same as defined in the above embodiment [2-4-2]; Q is the same as defined in the above embodiment [2-5-2]; R ¹ is the same as defined in the above embodiment [2-6-1]; R ² is defined in the above embodiment [2-5-2]. 7-1] The same definition as in [7-1].

[2-11]
In the formula (Ia) of the above embodiment [2], the combination of the ring A ′ and (R ¹ ) _m is preferably the same as defined in the above embodiment [2-8]; And the combination of (R ² ) _n is the same as defined in the above embodiment [2-9].

[2-11-1]
In the formula (Ia) of the above embodiment [2], more preferably, the combination of the ring A ′ and (R ¹ ) _m is the same as defined in the above embodiment [2-8-3]; The combination of ', Q and (R ² ) _n is the same as defined in the above embodiment [2-9-3].

[3] Among the compounds of the above formula (I) of the above embodiment [1], preferred compounds are those represented by the following formula (Ib):

[In the formula (Ib), m, n, Q, R ¹ and R ² are the same as defined in the above embodiment [1]; X ₁ , X ₂ and X ₃ in the ring A ′ are Each independently represents N or C—H]. Further, as a preferred embodiment of the present invention, a pharmaceutically acceptable salt of the compound of the above formula (Ib) or a solvate thereof can be mentioned.

[3-1]
In the formula (Ib) of the above embodiment [3], m is preferably an integer of 0 to 3.
[3-1-1]
In the formula (Ib) of the above embodiment [3], m = 2 is more preferable.

[3-2]
In the formula (Ib) of the above embodiment [3], preferably n = 0 or 1.
[3-2-1]
In the formula (Ib) of the above embodiment [3], n = 0 is more preferable.

[3-3]
In the formula (Ib) of the embodiment [3], the combination of X ₁ , X ₂ and X ₃ in the ring A ′ is preferably the same as defined in the embodiment [2-3].

[3-3-1]
In the formula (Ib) of the above embodiment [3], the combination of X ₁ , X ₂ and X ₃ in the ring A ′ is more preferably (X ₁ = X ₂ = N, X ₃ = C—H ).

[3-4]
In the formula (I-b) of the above embodiment [3], is preferably a Q, represented by C _{3 ~ 8} cycloalkyl group or partial structural formula, (SF-1) group:

[3-4-1]
In the formula (Ib) of the above embodiment [3], more preferably, Q is a group represented by the partial structural formula (SF-1):

Wherein (SF-1), ring C is a phenyl group, pyridin-2-yl group, pyridazin-3-yl group or represents a group selected from thiazol-2-yl group,; p and R ³ are, It is the same as defined in the above embodiment [1-5-1].

[3-4-2]
In the formula (Ib) of the above embodiment [3], Q is more preferably a pyridin-2-yl group.

[3-5]
In the formula (Ib) of the above embodiment [3], R ¹ is preferably a halogen atom, a cyano group, —R ^a2 , or —OR ^a2 (wherein R ^a2 is a C _1-6 alkyl group, and a halogenated group). Represents a group arbitrarily selected from a C _1-6 alkyl group.

[3-5-1]
In the formula (Ib) of the above embodiment [3], R ¹ is more preferably a cyano group, a C _1-6 alkyl group, or an —O—C _1-6 alkyl group, and more specifically, A cyano group, a methyl group, and a methoxy group;

[3-6]
In the formula (Ib) of the above embodiment [3], R ² is preferably a cyano group, a C _1-6 alkyl group, or a halogenated C _1-6 alkyl group.

[3-7]
In the formula (Ib) of the embodiment [3], the combination of the ring A ′ and (R ¹ ) _m is preferably the same as the definition of the ring A and (R ¹ ) _{m in} the embodiment [1-8]. It is.

[3-7-1]
In the formula (Ib) of the embodiment [3], the combination of the ring A ′ and (R ¹ ) _m is more preferably a combination of the ring A and the (R ¹ ) _{m in} the embodiment [1-8-1]. Same as definition.

[3-7-2]
In the formula (Ib) of the above embodiment [3], the combination of the ring A ′ and (R ¹ ) _m is more preferably 4-cyano-pyridin-2-yl group, 4-trifluoromethyl-pyridine-2. -Yl group, 4-cyano-3-methoxy-pyridin-2-yl group, 4-cyano-3-cyclopropyl-pyridin-2-yl group, 3-methoxy-4-trifluoromethyl-pyridin-2-yl Or a group selected from a 4,6-dimethylpyrimidin-2-yl group.

[3-7-3]
In the formula (Ib) of the above embodiment [3], the combination of the ring A ′ and (R ¹ ) _m is particularly preferably a 4,6-dimethylpyrimidin-2-yl group.

[3-8]
In the formula (Ib) of the above embodiment [3], the combination of 1H-pyrazole ring, Q and (R ² ) _n is preferably the same as defined in the above embodiment [1-10].

[3-8-1]
In the formula (Ib) of the above embodiment [3], the combination of 1H-pyrazole ring, Q and (R ² ) _n is more preferably the same as the definition in the above embodiment [1-10-1].

[3-8-2]
In the formula (Ib) of the above embodiment [3], the combination of 1H-pyrazole ring, Q and (R ² ) _n is more preferably the same as defined in the above embodiment [1-10-2].

[3-8-3]
In the formula (Ib) of the above embodiment [3], the combination of 1H-pyrazole ring, Q and (R ² ) _n is particularly preferably the same as defined in the above embodiment [1-10-3].

[3-9]
In the formula (Ib) of the above embodiment [3], preferably, m is the same as defined in the above embodiment [3-1]; n is the same as defined in the above embodiment [3-2]. Ring A ′ is the same as defined in the above embodiment [3-3]; Q is the same as defined in the above embodiment [3-4]; R ¹ is the above defined embodiment [3- 5] is the same as defined in R; R ² is the same as defined in the above embodiment [3-6].

[3-9-1]
In the formula (Ib) of the above embodiment [3], more preferably, m is the same as defined in the above embodiment [3-1-1]; n is the above embodiment [3-2-1]. Ring A is the same as defined in the above embodiment [3-3-1]; Q is the same as defined in the above embodiment [3-4-2]; R ¹ is the same as defined in the above embodiment [3-5-1]; R ² is the same as defined in the above embodiment [3-6].

[3-10]
In the formula (Ib) of the above embodiment [3], preferably the combination of the ring A ′ and (R ¹ ) _m is the same as the definition of the ring A and (R ¹ ) _{m in} the above embodiment [3-7]. The combination of 1H-pyrazole ring, Q, and (R ² ) _n is the same as defined in the above embodiment [3-8].

[3-10-1]
In the formula (Ib) of the embodiment [3], more preferably, the combination of the ring A ′ and (R ¹ ) _m is the same as defined in the embodiment [3-7-3]; The combination of the pyrazole ring, Q, and (R ² ) _n is the same as defined in the above embodiment [3-8-3].

As described above, each of the embodiments [1] to [3] of the present invention and preferred embodiments thereof, and further by appropriately combining the definitions of substituents, the compound represented by the above formula (I) of the above embodiment [1] The preferred embodiments can be arbitrarily formed.

[4] The fourth aspect of the present invention is the compound of the above formula (I) of the above 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 14.0.0.117 (PerkinElmer Informations).

In the present specification, unless otherwise specified, when a cyclic group is substituted with a variable substituent, it means that the variable substituent is not bonded to a specific carbon atom of the cyclic group. For example, the variable substituent R ^x in the following formula A can be substituted on any of the carbon atoms i, ii, iii or iv in the formula A, and the variable substituent R ^y in the following formula B can be substituted with the formula B It can be substituted with either carbon atom v or vi.

[5] A fifth 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. It is a pharmaceutical composition characterized by these.

[6] A sixth 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 prophylactic and / or therapeutic agent for diseases involving OXR.

OXR is widely involved in biological functions. This suggests a potential role for OXR in the course of various diseases in humans or other species.

Diseases involving OXR include sleep disorders such as insomnia, circadian rhythm sleep disorder, and sleep-related disorders; depression, anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, autism, autism spectrum Mental disorders such as disorders, drug dependence; neurodegenerative diseases such as Alzheimer's disease; memory disorders such as dementia; and eating disorders such as bulimia.

[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. A prophylactic and / or therapeutic agent for sleep disorders, mental disorders, neurodegenerative diseases, memory disorders or eating disorders.

[8-1]
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.

Unless otherwise specified, in this specification, specific 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.

Unless otherwise specified, in this specification, specific examples of “neurodegenerative diseases” 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.

[9] A ninth aspect of the present invention is an OXR antagonist comprising one or more of the compounds represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. .

[10] A tenth aspect of the present invention is an OX2R selective antagonist comprising one or more of the compounds represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof. It is.
Another aspect of the present invention is an OXR dual antagonist comprising one or more of the compounds represented by formula (I) above, or a pharmaceutically acceptable salt or solvate thereof. Here, the “OXR 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 the disease or condition.

[13-1]
Preferably, there is provided 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 Or a prophylactic and / or therapeutic agent according to aspect [8] or [8-1] selected from the group consisting of: autism spectrum disorder, drug dependence, Alzheimer's disease, dementia, bulimia, or aspect [13] Or it is the method as described in [13-1].

The compound of the present invention is a compound having an IC ₅₀ value for OXR of 1 μM or less 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. preferable. More preferred is a compound having an IC ₅₀ value for the orexin receptor of 100 nM or less. Further, as a compound having a OX2R antagonism is preferably a compound an IC ₅₀ value is less than 1μM for OX2R, and more preferably not more than 100nM compound. The compound having such an activity is a compound having an OXR antagonistic action, particularly an OX2R antagonistic action, and can be used as an OXR antagonist, particularly an OX2R antagonist, or a pharmaceutical composition. In addition, diseases involving OXR, sleep disorders (insomnia, circadian rhythm sleep disorders, sleep-related complications, etc.), mental disorders (depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, autism , Autism spectrum disorders, drug addiction, etc.), neurodegenerative diseases (Alzheimer's disease etc.), memory disorders (dementia etc.) or eating disorders (eg bulimia), especially OX2R-related diseases, insomnia, etc. It can be used as a preventive and / or therapeutic agent for sleep disorders.

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 the present specification, unless otherwise specified, when “a compound of formula (I)”, “a compound represented by formula (I)” or the like is described, “a compound of formula (Ia)”, Reference is also made to compounds that are subordinate concepts of “compound of formula (Ib)” and “compound of formula (Ic)”.

In all of the above embodiments, when the term “compound” is used, “a pharmaceutically acceptable salt or the compound and a solvate of the salt” is also referred to.

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 salt, and are described in detail in this document.

The compounds of the present 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 particularly 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”.

The “prodrug” of the compound of the present invention can be prepared by, for example, converting an appropriate functional group present in the compound of the present invention into a method known in the literature, for example, Design of Products, H.P. 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 (—COOH): the ester, ie, the hydrogen atom of the carboxy group (—COOH) is substituted with a “C _1-6 alkyl group” Compound.
(2) When the hydroxyl group (-OH) to a compound of the present invention is substituted: Part alkanoyloxy or ethers, i.e., a hydrogen atom is "C _{2 ~ 7} alkanoyl group" in the hydroxyl group (-OH) or "C ₂ compounds substituted with _1-7 alkanoyloxymethyl group ".
(3) When the compound of the present invention is substituted with an amino group (—NH ₂ or —NHR ′ (where R ′ ≠ H)): its amide, that is, the amino group (—NH ₂ or —NHR) '(wherein, R' ≠ H)) one or both of the hydrogen atoms "C _{2 ~ 7} alkanoyl group" compounds substituted with a.

The compound of the present invention is a geometric isomer (geometric isomer), configurational isomer (configurational isomer), tautomer (tortomeric isomer), optical isomer (optical isomer), stereoisomer (diastereomer). , Positional isomers (Regio isomers), rotational isomers (rotational isomers) and the like, both isomers and mixtures are also included in the compound 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.

A diazabicyclo [2.2.2] octane skeleton (formula (OC) in the formula (I) of the compound of the present invention, wherein —C (O) — group is diazabicyclo [2.2.2] Not included in the octane skeleton):

May have optical isomers. In the present specification, unless otherwise specified, the formula (OC) includes both (1S, 4S) form (formula (OC-1)) and (1R, 4R) form (formula (OC-2)) isomers. It means that the body is included.

In the example compounds of the present invention, the compounds having * mark at the 1-position and 4-position of the formula (OC) have either steric configuration of the formula (OC-1) or the formula (OC-2). Meaning a compound.

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 a known means.

In addition, when the compound of the present invention is an optically active substance, the racemate can be separated into a (+) isomer or a (−) isomer [D isomer or L isomer] by an ordinary optical resolution means.

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). , HPLC (High Performance Liquid Chromatography, etc.) etc., and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. This is a method for obtaining 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 carboxy 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 to a chromatography on a chiral column (optical isomer separation column). For example, in the case of high performance liquid chromatography (High performance liquid chromatography: HPLC), a mixture of optical isomers is added to a chiral column such as Daicel's CHIRAL series, water, various buffers (eg, phosphate buffer), Optical isomers can be separated by developing using an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution. In addition, for example, in the case of gas chromatography, the separation can be performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

When the compound of the present invention is an optically active substance, it can be synthesized by asymmetric synthesis in which one of optical isomers is selectively synthesized. Optically active compounds are: (1) asymmetric synthesis reaction in which a racemic compound is enantioselectively reacted to lead to an optically active form, (2) diastereoselective from a naturally occurring optically active compound (sugar, amino acid, etc.). It can be synthesized by the synthesis method.

The compound of the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a crystal form mixture.

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.

The isotope-labeled compound of the present invention can be obtained by a common technique known to those skilled in the art or by a method similar to the synthesis method described in the Examples below. In addition, the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.

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.

[Method for producing compound of the present invention]
Below, the manufacturing method of the compound represented by Formula (I) of this invention is demonstrated. The compound of the present invention represented by the formula (I), a salt thereof, and a solvate 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 synthesis. As an intermediate, 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.

Unless otherwise specified, the definitions of Q, ring A, ring B, R ¹ , R ² , R ³ , m, n, p, and the like in each formula of the following production methods are the formulas ( It is the same as each definition of I). 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 trifluoromethanesulfonyloxy (OTf) unless otherwise specified. Definition of AR in the production process, unless otherwise specified, a C _{6 ~ 14} aryl group or 5- to 7-membered heteroaryl group. The definition of B in the production method is boronic acid ester, boronic acid, trifluoroborate salt, boronic acid, or 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. Defining R ^alpha in the production process, unless otherwise specified, is a C _{1 ~ 6} alkyl group, C _{6 ~ 14} aryl group or a benzyl group. Defining R ^beta 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 ^gamma in the manufacturing method, unless otherwise specified, C _3-8 cycloalkyl group, -O-C _{1 ~ 6} alkyl group, -S-C _{1 ~ 6} alkyl group, 3- to 8-membered non-aromatic A heterocyclic group, or a —NR ^A R ^B 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 group, -C (O) -O-C 1 ~ 6 alkyl group, -C ( O) -O-C _{6 ~ 14} aryl group, -C (O) -O- benzyl group, a sulfo group, when containing a halogen atom, etc.), is converted by a method analogous to these functional groups per se known methods or in As a result, various compounds can be produced.

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, iminization (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.

For - _{"C (O) -O-C 6} ~ 14 aryl group" or "-C (O) -O- benzyl group", _{"-C (O) -O-C 1} ~ 6 alkyl group", For example, it can be converted by a reaction such as reduction or hydrolysis.

"In the case of a sulfo group, it can be converted by a reaction such as sulfonamidation or reduction.

In the case of a “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 group transformations are described in, for example, Comprehensive Organic Transformations, 2nd edition, published in October 1999, by Richard C. Larock, et al. VCH) can be carried out according to the method described in the book.

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, for example, C _1-6 alkyl groups (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group). group, and tert- butyl group); - C _{1 ~ 6} alkyl -O-C _{1 ~ 6} alkyl group (methoxymethyl group, methoxyethoxymethyl group, etc.); a tetrahydropyranyl group; C _{7 ~ 20} aralkyl group (e.g. Silyl group (for example, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, and t-butyldiphenylsilyl group); —C (O) —C _{1- 6} alkyl group (e.g., acetyl group, ethylcarbonyl group, and pivaloyl group); - C (O) -C 7 ~ 20 aralkyl group (e.g., Ben Le carbonyl group); - C (O) -C 6 ~ 14 aryl group (e.g., benzoyl group); - C (O) -O -C 1 ~ 6 alkyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group , and t- butoxycarbonyl group or the like); - C (O) -O -C 7 ~ 20 aralkyl group (e.g., a benzyl oxycarbonyl group) and the like.

The protecting group of the amino group (-NH ₂ group) or an imino group (-NH- group), for _{example, -C (O) -C 1 ~} 6 alkyl group (e.g., acetyl group, ethylcarbonyl group, and pivaloyl group); - C (O) -O -C 1 ~ 6 alkyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, and t- butoxycarbonyl group or the like); - C (O) -O -C 6 ~ 14 an aryl group (e.g., phenyloxycarbonyl group); - C (O) -O -C 7 ~ 20 aralkyl group (e.g., fluorenyl methoxy carbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, and para nitro benzyloxycarbonyl group, etc.); - C (O) -O -C 2 ~ 7 alkenyl group (e.g., an allyloxycarbonyl group, etc.); - C _{7 ~ 20} aralkyl group (eg , Benzyl, and triphenylmethyl group and the like); - C (O) -C 6 ~ 14 aryl group (e.g., benzoyl group); - C (O) -C 7 ~ 20 aralkyl group (e.g., benzylcarbonyl group _{_{etc); - SO 2 -C 1 ~}} 6 alkyl group or -SO ₂ -C _{6 ~ 14} aryl group (e.g., methanesulfonyl group, p- toluenesulfonyl group, 2,4-nitrobenzenesulfonyl group, and a benzenesulfonyl group Etc.); 2- (trimethylsilyl) ethoxymethyl group; phthaloyl group; N, N-dimethylaminomethylene group and the like are used.

The protecting group of the carboxyl group, for example, C _{1 ~ 6} alkyl group (e.g., methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, and tert- butyl group); C _{2 ~ 7} alkenyl group (vinyl group, and allyl group, etc.); C _{6 ~ 14} aryl group (e.g., phenyl, etc.); C _{7 ~ 20} aralkyl group (e.g., benzyl, and triphenylmethyl group); a silyl group (e.g. , Trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc.).

Examples of the protecting group for the thiol group (—SH group) include C _1-6 alkyl groups (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, etc.) ); C _{7 ~ 20} aralkyl group (e.g., benzyl, and triphenylmethyl group and the like); - C (O) -C 1 ~ 6 alkyl group (e.g., acetyl group, ethylcarbonyl group, and pivaloyl group); -C (O) -C _{6 ~ 14} aryl group (e.g., benzoyl group) and the like.

Such protecting group introduction / removal method is appropriately carried out depending on the group to be protected or the type of protecting group. For example, Green, et al., Protective Groups in Organic Synthesis (Protective Groups in Organic). (Synthesis), 4th edition, 2007, John Wiley & Sons, can be performed by the method described in the book.

The deprotection methods of protecting groups, _{e.g., -C (O) -C 1 ~} 6 alkyl group (e.g., acetyl group, ethylcarbonyl group, and pivaloyl group); - C (O) -O -C 1 ~ ₆ alkyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, and t- butoxycarbonyl group or the like); - acyl type protecting groups such as C (O) -C _{6 ~ 14} aryl group (e.g., benzoyl group, etc.), For example, it can be hydrolyzed and deprotected by using a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.

-C _{1 ~ 6} alkyl -O-C _{1 ~ 6} alkyl group (methoxymethyl group, methoxyethoxymethyl group, etc.); a tetrahydropyranyl group; -C (O) -O-C 1 ~ 6 alkyl group (e.g., methoxy group, an ethoxycarbonyl group, and t- butoxycarbonyl group or the like); - C (O) -O -C 7 ~ 20 aralkyl group (e.g., benzyloxycarbonyl group, and para-methoxybenzyloxycarbonyl group, etc.); silyl groups Protecting groups such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group and the like are, for example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoro Deprotection can be achieved by using an appropriate acid such as acetic acid or trifluoromethanesulfonic acid, or a combination of these acids.

The silyl group can also be deprotected by using a suitable fluorine ion (F ⁻ ) generating reagent, for example, a reagent such as tetrabutylammonium fluoride or hydrogen fluoride.

_{-C (O) -O-C 7} ~ 20 aralkyl group (e.g., benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, and para-nitrobenzyloxycarbonyl group and the like); C _{7 ~ 20} aralkyl group (e.g., benzyl group And the like can be deprotected by hydrogenolysis using, for example, a palladium-carbon (Pd—C) catalyst.

The above C _{7 ~ 20} aralkyl group (e.g., benzyl group) protecting groups are, for example, in liquid ammonia, can be deprotected by Birch reduction using metal sodium.

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.

-SO ₂ -C _{1 ~ 6} alkyl group or -SO ₂ -C _{6 ~ 14} aryl group (e.g., methanesulfonyl group, p- toluenesulfonyl group, 2,4-nitrobenzenesulfonyl group, and a benzenesulfonyl group, etc.) For example, deprotection can be achieved by using 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 -SO ₂ -C _{6 ~ 14} aryl group, 2-nitrobenzenesulfonyl group and a 2,4-nitrobenzenesulfonyl group, for example, the presence of a basic reagent such as potassium carbonate or triethylamine, reacting the thiol, Can be deprotected under mild conditions.

The protecting group deprotection method shown here is only one example. For example, Green et al., “Protective Groups in Organic Synthesis, 4th Edition, 2007. Deprotection is possible by applying the method described in the book of John Wiley & Sons or various published papers.

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, N, N-dimethylacetamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone Polar amide solvents such as: sulfoxide solvents such as dimethyl sulfoxide; nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy Ether solvents such as tan; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; ketone solvents such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane Solvent; basic solvent such as triethylamine, N, N-diisopropylethylamine, pyridine, lutidine; acid anhydride such as acetic anhydride; organic acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid; hydrochloric acid, sulfuric acid However, one kind of solvent may be used alone, or two or more kinds of solvents may be mixed and used at an appropriate ratio depending on the reaction conditions.

Specific examples of the base (or deoxidizer) used in the method for producing the compound of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, Inorganic bases such as cesium carbonate, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine (DIPEA), tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N- Dimethylaniline, 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-undece Organic bases such as imidazole; sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide and other metal alkoxides; sodium hydride, potassium hydride and other alkali metal hydrides; sodium amide, lithium diisopropylamide And metal amides such as lithium hexamethyldisilazide; organolithium reagents such as methyllithium, n-butyllithium, sec-butyllithium, and tert-butyllithium. In addition, 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 Lewis acids such as aluminum chloride, 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).

The following formula (I), formula (I-1) [Formula (I) by ring B = phenyl (Ph), or 5-7 membered heteroaryl ring; in the case of Q = C _{6 ~ 14} aryl (Ar)] And formula (I-2) [in the case of ring A = 3-substituted-4-cyano-2-pyridine in formula (I)], 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 7-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, and a method known in the literature, for example, “Tetrahedron, 66 (13), 2398”. The compound of formula (AM-3) can be produced by carrying out the reaction at a reaction temperature of 120 to 150 ° C. in the absence of a solvent in accordance with the method described in “-2403, 2010”.
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), a method known in the literature, for example, “Journal According to the method described in Journal of Organic Chemistry, 70 (13), pages 5164-5173, 2005, etc., and (S)- Proline and potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, potassium phosphate and the like in the presence of dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, 1 , 4-dioxane, tetrahydrofuran, toluene, xylene, acetonito The compound represented by the formula (AM-3) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent such as ril, which does not participate in the reaction, or a mixed solvent thereof.

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), a method known in the literature, for example, “International In accordance with the method described in “Publication 2012/076430 pamphlet” and the like, a Pd catalyst such as tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), and 4,5′-bis (diphenylphosphino) In the presence of phosphine reagents such as -9,9'-dimethylxanthene (XANTPHOS) and organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate, toluene, xylene, N , N-dimethylformamide, N, N-dimethylacetamide, dimethoxyethane, acetonitrile (acetonitrile / ), Dioxane (dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a solvent not involved in the reaction, or a mixed solvent thereof, and the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. ) Can be produced.

[Ring A = 5 to 7-membered heteroaryl group; when X = OTf]
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, “Synlett ), (12), 1400-1402, 1997 ”, etc., halogen solvents such as dichloromethane and chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like 0 ° C. using a solvent that does not participate in the reaction, such as an ether solvent of the above, an aromatic hydrocarbon solvent such as benzene or toluene, a polar solvent such as acetonitrile, N, N-dimethylformamide, or dimethyl sulfoxide, or a mixed solvent thereof. The compound represented by the formula (AM-3) can be produced by reacting at a temperature at which the solvent is refluxed.

[; When X = halogen atom ring A = C _{6 ~ 14} aryl group]
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, “International Publication 2009” / 059112 pamphlet "or the like, tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), palladium acetate (Pd (OAc) ₂ ), chloro (2-dicyclohexylphosphino- A Pd catalyst such as 2 ′, 6′-diisopropoxy-1,1′-biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II) (RuPhos G2), and 2- Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (X-phos), 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene (XANT) HOS), (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-ylbis (1 ′, 1-dimethylethyl) -phosphine (JohnPhos), and cesium carbonate, potassium carbonate, In the presence of an organic or inorganic base such as potassium phosphate, tert-BuONa, triethylamine, N, N-diisopropylethylamine, etc., toluene, N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), N, N— Dimethylacetamide, acetonitrile, acetonitrile / water, dioxane, dioxane / water, tet Using a solvent that does not participate in the reaction, such as lahydrofuran (THF), tetrahydrofuran / water, or a mixed solvent thereof, the reaction is performed from room temperature to the temperature at which the solvent is refluxed, and the compound represented by the formula (AM-3) is obtained. Can be manufactured.

<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” 4ThEdition) 4th edition, 2007, John Wiley & Sons (John Wiley & Sons), in accordance with the method described in textbooks of green (Greene) et al ", in accordance with the type of the protecting group the protecting group P ² By reacting by the method, a compound represented by the formula (AM-4) in which the P ² group is deprotected can be produced.

<Step 3>
[Production Method A] Using the amine of formula (AM-4) obtained in <Step 2> and the carboxylic acid of formula (CA), a method known in the literature, for example, “Experimental Chemistry Course 4th Edition 22 Organic Synthesis” In accordance with the method described in IV Acid / Amino Acid / Peptide, 191-309, 1992, Maruzen, etc., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl) ) Carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), benzotriazole-1-iroxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic Chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium hexaf Olophosphate (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) Dichloromethane, chloroform, diethyl ether, tetrahydrofuran, toluene, benzene, N, N-dimethyl in the presence of condensing agents such as dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), propylphosphonic anhydride (T3P) Solvents that do not participate in the reaction, such as formamide, methanol, ethanol, 2-propanol , Triethylamine, N, N-diisopropylethylamine, pyridine and the like in the presence or absence of a reaction at a temperature at which the solvent is refluxed from 0 ° C. to produce the compound represented by formula (I). it can.

Further, the carboxylic acid of the formula (CA) is converted into a method known in the literature, for example, “Journal of the American Chemical Society, 109 (24), p7488-7494, 1987”. In the presence or absence of a base such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine, thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, trichloride. Use a halogenating agent such as phosphorus, phosphorus pentachloride or phosphorus tribromide and a solvent inert to the reaction such as dioxane, tetrahydrofuran, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, or a mixed solvent thereof. Using an acid halide obtained by reacting at a temperature at which the solvent refluxed from 0 ° C. and an amine of the formula (AM-4) obtained in [Production Method A] <Step 2>, for example, “Experimental Chemistry Course 4th Edition 22 Organic Synthetic IV Acids / Amino Acids / Peptides, 144-146, 1992, Maruzen ”etc., and bases such as triethylamine, N, N-disopropylethylamine, pyridine, 4-dimethylaminopyridine, etc. In the presence of dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, tetradrofuran, 1,4-dioxane, toluene, benzene, N, N-dimethylformamide and the like, or a mixed solvent thereof To react the compound of formula (I) in a similar manner by reacting from 0 ° C. to the temperature at which the solvent is refluxed. It is possible to elephants.

[Production Method B]

<Step 1>
Compound of formula (AM-2) (P ² = H in formula (AM)) and compound of formula (CA) (formula (AM-2) and compound of formula (CA) are commercially available compounds or commercially available compounds 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 Edition” 4th edition, 2007, according to the method described in the book of John Wiley & Sons, Greene et al., The protecting group P ¹ is reacted by a method according to the type of the protecting group. Thus, a compound represented by the formula (AM-6) in which the P ¹ group is deprotected can be produced.

<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 = Ph, or a 5- to 7-membered heteroaryl ring (provided that the 5- to 7-membered heteroaryl ring is diazabicyclo [2.2.2] ] Except for a ring such as a 1-substituted-1H-pyrazol-5-yl group that has a nitrogen atom adjacent to the amide bond of the octane ring and ring B (o-position); Q = AR (C _{6 To 14} aryl group or 5- to 7-membered heteroaryl group)]

[Production Method C]

<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>
[Method C] Compounds of <Step 1> In the resulting formula (IM-1), and halogenated C _{6 ~ 14} aryl compound of formula (RG-1) (the compound document from commercially available compounds, or commercially available compound The compound is a compound that can be produced by a known production method), and a method known in the literature, for example, “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI —Organic synthesis using metals—327-352, 2004, Maruzen And palladium (II) acetate (Pd (OAc) ₂ ) according to the methods described in Journal of Medicinal Chemistry, 48 (20), p 6326-6339, 2005. ), Tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), tris (dibenzylidene) Acetone) dipalladium (Pd ₂ (dba) ₃ ), bis (dibenzylideneacetone) palladium (Pd (dba) ₂ ), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (PdCl ₂ Palladium catalysts such as (dppf)), triphenylphosphine, tris (tert-butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino- In the presence of a phosphine reagent such as 2 ′, 4 ′, 6′-triisopropylbiphenyl, and an organic or inorganic base such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate, toluene, xylene, N, N-dimethylformamide, N Using a solvent that does not participate in the reaction such as N-dimethylacetamide, dimethoxyethane, acetonitrile (acetonitrile / water), dioxane (dioxane / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, The reaction can be carried out at a refluxing temperature to produce the compound represented by the formula (I-1). 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).
[C _{6 ~ 14} aryl tin reagent of formula (RG-3), when using a heteroaryl tin reagent]
[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), 653-656, 2014”, “European Journal of Organic Chemistry,” 2013 (28), 6404-6419, 2013 ”,“ Chemical Communication, 48 (71), 8907-8909, 2012 ”,“ Bioorgana and Medicinal Chemistry (Bioorga). ic & Medicinal Chemistry), 21 ( 8), pp. 2370-2378, in accordance with the method described in 2013 ", etc., tetrakis triphenylphosphine palladium (Pd (PPh ₃₎ _4), bis (triphenylphosphine) palladium (II) In the presence of a palladium catalyst such as dichloride (Pd ₂ (PPh ₃ ) ₂ ) (when tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ) is used, the presence of a copper reagent such as copper iodide (CuI) Or in the absence or presence of a salt such as cesium fluoride or lithium chloride, or a solvent not involved in the reaction, such as toluene, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, or the like The reaction is carried out at a temperature from 0 ° C. to the reflux of the solvent. , It is possible to produce a compound of formula (I-1).

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

[In the formula (IM-1) where B = boronic acid]
[Production Method C] Using a compound of formula (IM-2) obtained in <Step 3>, it is described in literature known methods, for example, “Chemiche Berichte, 42, 3090, 1909” and the like. In accordance with the above method, using a solvent such as toluene, tetrahydrofuran, 1,4-dioxane or the like, or a mixed solvent thereof, alkyllithium such as n-butyllithium and sec-butyllithium, isopropylmagnesium chloride, etc. In the presence of Grignard reagent or magnesium metal, trialkylborate such as trimethylborate and triisopropylborate was added, and the reaction was carried out at −78 ° C. at room temperature, and then acid such as hydrochloric acid and sulfuric acid was added. The reaction is carried out at a temperature at which the solvent refluxes from -1) boronic acids can be produced.

[In the formula (IM-1) where B = trifluoroborate salt]
Using the boronic acid ester obtained by the above-mentioned method or boronic acid, a method known in the literature, for example, the method described in “Chemical Reviews, 108, 288-325, 2008”, etc. Similarly, 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 in the presence of potassium hydrogen difluoride, or a mixed solvent thereof. ) Trifluoroborate salt can be produced.

[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 ”, etc., in the presence of N-methyliminodiacetic acid (MIDA), solvents such as benzene, toluene, xylene or dimethyl sulfoxide, or the like The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. using the mixed solvent of (1) to produce a boronic acid N-methyliminodiacetic acid (MIDA) ester of the formula (IM-1).

<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]

[Production Method D]

<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 γ ⁼ 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, the method described in “International Publication No. 2014/066196 Pamphlet”, etc., tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), bis In the presence of a Pd catalyst such as [tris (1,1-dimethylethyl) phosphine] palladium, the reaction is carried out at a temperature at which the solvent refluxes from 0 ° C. using a solvent that does not participate in the reaction, such as tetrahydrofuran and 2,2-dimethoxyethane. And the compound of formula (I-2) can be produced.

[In the case of R ^γ = non-aromatic heterocyclic group (aziridine, azetidine, pyrrolidine, piperidine, morpholine, etc.) or —NR ^a R ^b group]
[Production Method D] Compound of formula (IM-3) obtained in <Step 1>, and formula (RG-5) or formula (RG-6) (formula (RG-5) and formula (RG-6)) Is a commercially available compound or a compound that can be produced from a commercially available compound by a known production method), using known amines such as “International Publication No. 2005/111003 pamphlet”, “Journal of Medicinal”. According to the method described in Chemistry (Journal of Medicinal Chemistry), 48 (23), pages 7374-7388, 2005, etc., in the presence or absence of a base such as diisopropylethylamine, triethylamine, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydroph The solvent is not involved in the reaction, such as down, or by using a mixed solvent thereof, the reaction was carried out in the temperature at which the solvent refluxes from 0 ° C., can be prepared a compound of formula (I-2).

[In the case of R ^γ = C _1-6 alkylthio 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. And a compound known in the literature, for example, according to the method described in “International Publication No. 2011/049222 pamphlet” or the like, is involved in the reaction of N, N-dimethylformamide, N-methylpyrrolidone, etc. The 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 is not used or a mixed solvent thereof.

[In the case of R ^γ = C _1-6 alkoxy group]
[Production Method D] Compound of formula (IM-3) obtained in <Step 1> and formula (RG-8) (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. N, N-dimethylformamide, according to the method described in “Journal of Medicinal Chemistry, 55 (22), pages 10118-10129, 2012” and 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. using a solvent that does not participate in the reaction, such as N-methylpyrrolidone.

The formula (IM-3-1) when X = Cl in the formula (IM-3) can also be produced by the following [Production Method D] <Step 3> to [Production Method D] <Step 5>. I can do it.

<Step 3>
A compound of formula (AR-2-1) and a compound of formula (AM-1) (formula (AR-2-1) and compound of formula (AM-1) are commercially available compounds, or known production from literature The compound of formula (D-1) can be produced by carrying out a reaction according to [Production Method B] <Step 3> using a compound of (a compound that can be produced by the method).

<Step 4>
[Production Method D] Using the compound of formula (D-1) obtained in <Step 3>, a reaction according to [Production Method A] <Step 2> is carried out to produce a compound of formula (D-2) can do.

<Step 5>
[Production Method D] Using the compound of the formula (D-2) obtained in <Step 4> and the compound of the formula (CA), a reaction according to [Production Method A] <Step 3> is carried out to give a compound of the formula ( The compound of IM-3-1) can be produced.

The formula (IM-3-2) when X = F in the formula (IM-3) can also be produced by the following [Production Method D] <Step 6> to [Production Method D] <Step 9>. I can do it.

<Step 6>
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 (D-3) can be produced by carrying out a reaction according to [Production Method B] <Step 3>.

<Step 7>
[Production Method D] Using the compound of the formula (D-3) obtained in <Step 6> and trifluoroacetic anhydride (TFAA), a method known in the literature, for example, “Patent of International Publication No. WO 2007/043777. In the presence of a base such as triethylamine, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. in the presence of a base such as triethylamine. Compounds can be produced.

<Step 8>
[Production Method D] Using the compound of formula (D-4) obtained in <Step 7>, a reaction according to [Production Method A] <Step 2> is carried out to produce a compound of formula (D-5) can do.

<Step 9>
[Production Method D] Using the compound of formula (D-5) obtained in <Step 8> and the compound of formula (CA), a reaction according to [Production Method A] <Step 3> is carried out to give a compound of formula ( The compound of IM-3-2) can be produced.

[Production Method E] Formula (CA-3) [In formula (CA), ring B = Ph, or a 5- to 7-membered heteroaryl ring (provided that the 5- to 7-membered heteroaryl ring is diazabicyclo [2.2.2] ] Except for a ring such as a 1-substituted-1H-pyrazol-5-yl group that has a nitrogen atom adjacent to the amide bond of the octane ring and ring B (o-position); Q = AR (C _{6 To 14} aryl group or 5- to 7-membered heteroaryl group)]

[Production Method E]

<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 ^α = C _1-6 alkyl group (eg, 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, 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 that does not participate in the reaction such as 4-dioxane and tetrahydrofuran, or a mixed solvent thereof.

[In the case of R ^α = tert-butyl group]
Using a compound of formula (E-2), a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition”, 4th edition, 2007, John Willy and Sons (John) The temperature at which the solvent is refluxed from 0 ° C. using an acid such as hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid according to the deprotection method described in the book of Wiley & Sons, Green et al. To produce a compound of formula (CA-3).

[In the case of R ^α = benzyl group, etc.]
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. , Methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, ethyl acetate, methyl acetate and the like, or a mixed solvent thereof, The reaction can be carried out at a temperature at which the solvent is refluxed from 0 ° C. to produce a compound of formula (CA-3).

<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] Formula (CA-4) [In formula (CA), ring B = Ph, or 5- to 7-membered heteroaryl (wherein the 5- to 7-membered heteroaryl ring is diazabicyclo [2.2.2] Q = imidazole, triazole, pyrrolidine, except for a ring such as a 1-substituted-1H-pyrazol-5-yl group having a nitrogen atom adjacent to the amide bond of the octane ring and ring B (o-position)) , A group such as piperazine, morpholine]

[Production Method F]
The compound of the formula (CA-2) and the compound of the formula (F-1) (the compound of the formula (CA-2) and the formula (F-1) are commercially available compounds or commercially available compounds from the literature by known production methods. A compound known in the literature, for example, the method described in “Angewandte Chemie, International Edition, 50, 48, 11511-11515, 2011”, etc. Similarly, using a copper catalyst such as copper iodide (CuI) and a solvent that does not participate in the reaction such as acetonitrile, tetrahydrofuran, dimethylformamide, or a mixed solvent thereof in the presence of a base such as sodium carbonate, potassium carbonate, or cesium carbonate. And react at a temperature at which the solvent refluxes from 0 ° C. To produce a compound of formula (CA-4).

[Production Method G] Production Method of Formula (CA-5-1) [In the Formula (CA) where Ring B = Pyrazole (1)]

[Production Method G]

<Step 1>
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 a hydrazine compound of the formula (G-2) (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), in the presence of acetic acid according to a method known in the literature, for example, the method described in “International Publication No. 2007/043777 pamphlet” or the like. Using a solvent that does not participate in the reaction, such as tetrahydrofuran, 2-methoxyethanol, or a mixed solvent thereof, at a temperature at which the solvent is refluxed from 0 ° C. to produce a compound of formula (G-3). it can.

<Step 2>
[Production Method G] Using the compound of formula (G-3) 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 the Formula (CA) where Ring B = Pyrazole (2)]

[Production Method H]

<Step 1>
Using the compound of the 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 a hydrazine compound of the formula (G-2), [Production Method G] A compound of formula (H-2) can be produced by carrying out a reaction according to <Step 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 the Formula (CA) where Ring B = Pyrazole (3)]

[Production Method J]
In a solvent such as tetrahydrofuran in accordance with a method known in the literature, for example, the method described in “Bioorganic & Medicinal Chemistry Letters, 23, 23, 6341-6345, 2013”, etc. , Diisopropylamine and n-butyllithium were reacted at −78 ° C. to prepare lithium diisopropylamide (LDA), and the compound of formula (J-1) (the compound was a commercially available compound or It is a compound that can be produced from a commercially available compound by a known production method in the literature), and at the same temperature, the reaction solution is added with excess dry ice (solid piece) or excess carbon dioxide gas to carry out the reaction. By acidification with an acid such as (CA-5-3) It can be prepared of compounds.

[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 used 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) sleep inducers ((i) benzodiazepine-based sleep inducers [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-mentioned diseases, it is possible to reduce the dosage of existing drugs and reduce the side effects of existing drugs. Of course, the combination method using the drug is not limited to the above diseases, and the drug used in combination is not limited to the compounds exemplified 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.
OXR antagonistic activity of the test compounds, OX2R and IC ₅₀ values of OXlR (an IC ₅₀ value is ++ with 100 nmol / L the following compounds, an IC ₅₀ value is the compound of greater than 1000 nmol / L or less of the present invention 100 nmol / L + The compounds with IC ₅₀ values greater than 1000 nmol / L are expressed as −).

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 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 (eg, 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 microsomal 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 The compound of the present invention was added to 7 or 8 weeks old male CD (SD) IGS Jcl at 1 mg / kg (administration solvent was DMSO: Tween 80: Ultrapure water = 1: 1: 8, 10 mL / kg), and 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 The compound of the present invention was applied to animals (male Crl: CD (SD) rats of about 7 to 8 weeks of age, male beagle dogs of about 4 years of age, or male cynomolgus monkeys of about 6 years of age). 1 mg / kg (administration solvent is Dimethylacetamide: Tween 80: Ultrapure water = 4: 4: 2, 1 mL / kg) or 10 mg / kg (administration solvent is 0.5% Methylcellulose, 5 mL / kg) After oral 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 the time course of plasma concentration obtained by PK test (the above pharmacological experiment example 7) in rat, dog and monkey animal species 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 above 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. It is.

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 deficits Prevention of diseases such as mobility disorders, autism, autism spectrum disorders, drug addiction, etc.), neurodegenerative diseases (such as Alzheimer's disease), memory disorders (such as dementia), and eating disorders (such as bulimia) And / or expected to be used in therapeutic agents.
The compounds of the present invention are 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] Using a Waters FractionLynx MS system (Waters) and a SunFire column (4.6 mm × 5 cm, 5 μm) (Waters), the mobile phase was methanol: 0.05% acetic acid aqueous solution = 10: 90 (0 min) to 100 : Gradient conditions from 0 (5 minutes) to 100: 0 (7 minutes) were used. For the preparative system, gradient conditions appropriately changed depending on the compound were 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 Means deuterated chloroform, DMSO-d ₆ means deuterated dimethyl sulfoxide. ^{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 is shown as “UPLC” and “LCMS” in each example. In the LC-Mass data, [M + H] ⁺ and [M + Na] ⁺ 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 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane hydrochloride (intermediate 1) <Step 1> tert-butyl 5 Synthesis of — (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 1-1) tert-butyl 2,5-diazabicyclo [ 2.2.2] 2-Chloro-4,6-dimethylpyrimidine (0.37 g) was added to a DMF (24 mL) mixture of octane-2-carboxylate (0.50 g) and cesium carbonate (1.5 g). , And stirred at 90 ° C. for 1 day. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water 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 = 87: 13 to 75:25) to obtain the title compound (0.50 g) as a colorless liquid. .
UPLC: 341 [M + Na] ⁺ (retention time 0.93 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 6.26 (1H, s), 5.08-5.01 (1H, m), 4.42-4.23 (1H, m), 3.84-3.75 (1H, m), 3.65-3.57 ( 2H, m), 3.51-3.43 (1H, m), 2.27 (6H, s), 2.10-1.95 (2H, m), 1.88-1.72 (2H, m), 1.47-1.44 (9H, m).

<Step 2> Synthesis of 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane hydrochloride (intermediate 1) tert-butyl 5- (4,6 -Dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 1-1) (0.50 g) in 4N hydrochloric acid-dioxane solution (3.0 mL) ) And stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure to obtain the title compound (0.40 g) as a white solid.
UPLC: 219 [M + H] ⁺ (retention time 0.51 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 10.42 (1H, br s), 10.09 (1H, br s), 6.56 (1H, s), 5.43-5.35 (1H, m), 4.66-4.57 (1H, m), 4.46-4.38 (1H, m), 4.24-4.13 (1H, m), 3.80-3.60 (2H, m), 2.78-2.54 (7H, m), 2.22-2.09 (2H, m), 2.02- 1.89 (1H, m).

Production Example 2 Synthesis of 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3-methoxyisonicotinonitrile (Intermediate 2) <Step 1> 2-Chloro-3 Synthesis of -methoxyisonicotinic acid (intermediate 2-1) 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 2-2) 2-Chloro-3-methoxyisonicotinic acid (Intermediate 2-1) (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 2-3) 2-Chloro-3-methoxyisonicotinamide (Intermediate 2-2) obtained in Step 2 of Production Example 2 A crude product of 7.4 g, triethylamine (15 mL) in dichloromethane (66 mL) mixed solution was cooled to 0 ° C., trifluoroacetic anhydride (7.5 mL) was gradually added, and the reaction solution was added at 0 ° C. to 30 ° C. Stir for minutes. The reaction solution was warmed to room temperature, 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 5- (4-cyano-3-methoxypyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 2-4) Synthesis 2-chloro-3-methoxyisonicotinonitrile (intermediate 2-3) (0.26 g), tert-butyl 2,5-diazabicyclo [2.2.2] octane-2-carboxylate (0.30 g) ), RuPhos (66 mg), and a mixed solution of cesium carbonate (0.69 g) in tetrahydrofuran (3.0 mL) were added with RuPhos Pd G2 (0.11 g) and stirred at 90 ° C. for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography (silica gel, heptane: ethyl acetate = 95: 5 to 80:20). The title compound (0.28 g) was obtained as a yellow gum.
UPLC: 367 [M + Na] ⁺ (retention time 1.13 minutes)

<Step 5> Synthesis of 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3-methoxyisonicotinonitrile (intermediate 2) tert-butyl 5- (4-cyano- 3-methoxypyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 2-4) (0.13 g) was added trifluoroacetic acid (1.0 mL). The mixture was further stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, 1N aqueous hydrochloric acid solution was added to the resulting residue, and the mixture was washed with an ethyl acetate-heptane mixed solvent (1: 1). The aqueous layer was basified with 1N aqueous sodium hydroxide solution, sodium chloride was added, and the mixture was extracted 5 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (21 mg) as a pale yellow gum.
UPLC: 245 [M + H] ⁺ (retention time 0.66 minutes)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.95 (1H, d, J = 5 Hz), 6.72 (1H, d, J = 5 Hz), 4.50-4.45 (1H, m), 3.88 (3H, s ), 3.86-3.80 (1H, m), 3.71-3.66 (1H, m), 3.44-3.39 (1H, 2m), 3.20-3.11 (2H, m), 2.17-1.76 (4H, m).

Production Example 3 Synthesis of 2- (1H-pyrazol-1-yl) nicotinic acid (Intermediate 3) <Step 1> Ethyl 2- (1H-pyrazol-1-yl) nicotinate (Intermediate 3-1) 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) as a pale yellow oil. It was.
UPLC: 218 [M + H] ⁺ (retention time 0.86 minutes)

<Step 2> Synthesis of 2- (1H-pyrazol-1-yl) nicotinic acid (intermediate 3) Ethyl 2- (1H-pyrazol-1-yl) nicotinate (intermediate 3-1) (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) as a colorless solid.
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 4 Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 4) <Step 1> Methyl 1- (pyridin-2-yl) -1H-pyrazole-5 Synthesis of carboxylate (intermediate 4-1) 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 4) 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 3-1) (0.35 g), and the mixture was heated 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 5 2- (4,6-Dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane optical isomer (Intermediate 5-A), (Intermediate 5- Synthesis of B) <Step 1> tert-Butyl 5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (Intermediate 1-1) ) Optical resolution of tert-butyl 5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 1-1) (0. 40 g) was subjected to optical resolution using supercritical fluid chromatography, whereby each optical isomer of the title compound was converted into the first fraction (intermediate 5-1-A): 0.14 g, orange gum ,> 99% ee, retention time (analysis) .44 minutes), the second fraction ((Intermediate 5-1-B): 0.13 g, orange gum,> 99% ee, was obtained by retention time 2.05 min and (analysis)).
Preparative conditions (column: CHIRALCEL OJ-H (20 mm × 250 mm), eluent: 3% isopropanol / CO ₂ , flow rate: 15 mL / min)
Analysis conditions (column: CHIRALCEL OJ-H (4.6 mm × 150 mm), eluent: 3% isopropanol / CO ₂ , flow rate: 3 mL / min)

<Step 2> Synthesis of 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane optical isomer (intermediate 5-A) Step of Production Example 5 Tert-butyl 5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate obtained in 1 above (intermediate 5- To 1-A) (0.14 g) was added 4N hydrochloric acid-ethyl acetate solution (2.2 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 2N aqueous sodium hydroxide solution was added to adjust the pH to 12-13, and extraction was performed 10 times with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (97 mg) as an orange liquid.
UPLC: 219 [M + H] ⁺ (retention time 0.51 minutes)

<Step 3> Synthesis of 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane optical isomer (intermediate 5-B) Step of Production Example 5 2 or a method analogous thereto, tert-butyl 5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2] obtained in Step 1 of Production Example 5 was used. .2] The title compound (85 mg) was obtained as a pale yellow solid from the optical isomer of Octane-2-carboxylate (Intermediate 5-1-B) (0.13 g).
UPLC: 219 [M + H] ⁺ (retention time 0.51 minutes)

Production Example 6 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3-methoxyisonicotinonitrile optical isomer (Intermediate 6-A), (Intermediate 6) Synthesis of -B) <Step 1> tert-Butyl 5- (4-cyano-3-methoxypyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate) 2-4) optical resolution of tert-butyl 5- (4-cyano-3-methoxypyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 2- 4) By optically resolving (0.15 g) using supercritical fluid chromatography, each optical isomer of the title compound was converted into the first fraction ((intermediate 6-1-A): 63 mg, colorless Gum-like material,> 99% ee, retention Time (analysis) 1.76 minutes), second fraction ((intermediate 6-1-B): 60 mg, colorless gum,> 99% ee, retention time (analysis) 2.07 minutes) .
Preparative conditions (column: CHIRALPAK OD-H (20 mm × 250 mm), eluent: 10% isopropanol / CO ₂ , flow rate: 15 mL / min)
Analysis conditions (column: CHIRALCEL OD-H (4.6 mm × 150 mm), eluent: 10% isopropanol / CO ₂ , flow rate: 3 mL / min)

<Step 2> Synthesis of 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3-methoxyisonicotinonitrile optical isomer (intermediate 6-A) In the same manner as in Step 2 or a method analogous thereto, tert-butyl 5- (4-cyano-3-methoxypyridin-2-yl) -2,5-diazabicyclo [O] obtained in Step 1 of Production Example 6 2.2.2] The title compound (40 mg) was obtained as an orange gum from the optical isomer of the octane-2-carboxylate (6-1-A) (60 mg).
UPLC: 245 [M + H] ⁺ (retention time 0.67 minutes)

<Step 3> Synthesis of optical isomer of 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotinonitrile (intermediate 6-B) In the same manner as in Step 2 or a method analogous thereto, tert-butyl 5- (4-cyano-3-methoxypyridin-2-yl) -2,5-diazabicyclo [O] obtained in Step 1 of Production Example 6 2.2.2] The title compound (41 mg) was obtained as an orange gum from the optical isomer of the octane-2-carboxylate (6-1-B) (58 mg).
UPLC: 245 [M + H] ⁺ (retention time 0.67 minutes)

(Production Example 7) 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicotinonitrile optical isomer (Intermediate 7-A), (Intermediate) Synthesis of 7-B) <Step 1> tert-butyl 5- (3-chloro-4-cyanopyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate) Synthesis of Compound 7-1) 3-Chloro-2-fluoroisonicotinonitrile (0.19 g), tert-butyl 2,5-diazabicyclo [2.2.2] octane-2-carboxylate (0.20 g) Then, a mixed solution of potassium carbonate (0.39 g) in DMSO (3 mL) was stirred at 100 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The collected extract was dried over anhydrous sodium sulfate, and 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 75:25). The compound (0.26 g) was obtained as a yellow solid.
UPLC: 371, 373 [M + Na] ⁺ (retention time 1.16 minutes)

<Step 2> tert-butyl 5- (4-cyano-3-cyclopropylpyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-2) Synthesis of tert-butyl 5- (3-chloro-4-cyanopyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-1) (0. 26 g), tetrakis (triphenylphosphine) palladium (0.35 g) was added to a THF (2.5 mL) mixed solution of cyclopropyl zinc bromide (0.5 N THF solution) (9 mL), and the mixture was heated to 100 ° C. under a nitrogen atmosphere. And stirred for 15 hours. The reaction solution was returned to room temperature, saturated aqueous ammonium chloride solution 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 (NH silica gel, heptane: ethyl acetate = 100: 0 to 80:20) The compound (0.13 g) was obtained as a colorless oily substance.
UPLC: 377 [M + Na] ⁺ (retention time 1.16 minutes)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.10 (1H, d, J = 5 Hz), 6.88 (1H, d, J = 5 Hz), 4.59-4.48 (1H, m), 4.33-4.13 (1H , m), 3.94-3.68 (3H, m), 3.57-3.45 (1H, m), 2.30-1.68 (5H, m), 1.48 (9H, s), 1.19-1.10 (2H, m), 0.76-0.69 (2H, m).

<Step 3> tert-butyl 5- (4-cyano-3-cyclopropylpyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-2) Optical resolution of tert-butyl 5- (4-cyano-3-cyclopropylpyridin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-2) 0.13 g) was optically resolved using supercritical fluid chromatography, whereby each optical isomer of the title compound was converted into the first fraction (intermediate 7-3-A): 50 mg, colorless oily substance ,> 99% ee, retention time (analysis) 1.62 minutes), second fraction ((intermediate 7-3-B): 52 mg, colorless oily substance,> 99% ee, retention time (analysis) 2 22 minutes) Obtained.
Preparative conditions (column: CHIRALPAK OD-H (20 mm × 250 mm), eluent: 10% methanol / CO ₂ , flow rate: 15 mL / min)
Analysis conditions (column: CHIRALCEL OD-H (4.6 mm × 150 mm), eluent: 10% methanol / CO ₂ , flow rate: 3 mL / min)

<Step 4> Synthesis of 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicotinonitrile optical isomer (intermediate 7-A) Production Example 5 Tert-Butyl 5- (4-cyano-3-cyclopropylpyridin-2-yl) -2,5- The title compound (44 mg) was obtained as a yellow oil from the optical isomer of diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-3-A) (50 mg).
UPLC: 255 [M + H] ⁺ (retention time 0.73 minutes)

<Step 5> Synthesis of optical isomer of 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicotinonitrile (intermediate 7-B) Production Example 5 Tert-Butyl 5- (4-cyano-3-cyclopropylpyridin-2-yl) -2,5- obtained in Step 3 of Production Example 7 in the same manner as in Step 2 above or a method analogous thereto. The title compound (42 mg) was obtained as a yellow oil from the optical isomer of diazabicyclo [2.2.2] octane-2-carboxylate (intermediate 7-3-B) (52 mg).
UPLC: 255 [M + H] ⁺ (retention time 0.72 minutes)

Example 1 (5- (4,6-Dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-yl) (5-methyl-2- (2H-1 , 2,3-Triazol-2-yl) phenyl) methanone tert-butyl 5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2- Trifluoroacetic acid (0.88 mL) was added to a dichloromethane solution of carboxylate (intermediate 1-1) (0.11 g), and the reaction solution was stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was azeotroped with toluene and diluted with DMF to give 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (70 mg). ), HATU (0.16 g) and triethylamine (0.19 mL) were sequentially added, and the mixture was stirred at room temperature. After 1 hour, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water 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 = 50: 50 to 0: 100) to obtain the title compound (74 mg) as a white solid.
UPLC: 404 [M + H] ⁺ (retention time 0.91, 0.95 min, rotamer)
¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 7.95-7.68 (3H, m), 7.43-7.33 (1H, m), 7.28-7.20 (1H, m), 6.39-6.33 (1H, m), 5.05-3.24 (6H, m), 2.70 (3H, s), 2.44-2.35 (2H, m), 2.26-2.18 (6H, m), 1.93-1.76 (2H, m).

Example 2 (2- (2H-1,2,3-triazol-2-yl) phenyl) (5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2 .2] Synthesis of octan-2-yl) methanone 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane hydrochloride (intermediate 1) (50 mg) Triethylamine (70 μL) was added to a mixed solution of 2- (2H-1,2,3-triazol-2-yl) benzoic acid (32 mg) and HATU (76 mg) in DMF (1.0 mL) at room temperature for 18 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively 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 = 60: 40 to 25:75) to obtain the title compound (37 mg) as a white solid.
UPLC: 390 [M + H] ⁺ (retention time 0.83, 0.87 min, rotamer)
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.10-7.83 (2H, m), 7.66-7.42 (4H, m), 6.40-6.35 (1H, m), 5.06-3.26 (6H, m), 2.90-2.67 (2H, m), 2.23 (6H, s), 1.94-1.75 (2H, m).

The following (Example 3) to (Example 6) were synthesized by the same method as (Example 2) or a method analogous thereto using the above (Intermediate 1) or a commercially available compound.

Example 7 2- (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of 3-methoxyisonicotinonitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotinonitrile (intermediate 2) (11 mg), 2- ( To a mixed solution of 2H-1,2,3-triazol-2-yl) benzoic acid (9.5 mg) and HATU (21 mg) in DMF (1.0 mL) was added triethylamine (9.5 μL), and the mixture was stirred at room temperature for 64 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively 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 = 70: 30 to 25:75) to obtain the title compound (13 mg) as a colorless amorphous.
UPLC: 416 [M + H] ⁺ (retention time 1.02, 1.03 min, rotamer)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.05-7.62 (3H, m), 7.59-7.49 (1H, m), 7.48-7.36 (2H, m), 7.30-7.21 (1H, m), 6.82- 6.73 (1H, m), 4.95-3.23 (10H, m), 2.39-1.67 (3H, m).

Example 8 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino Synthesis of nitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotinonitrile (intermediate 2) (25 mg), 2- (1H-pyrazole-1- Il) 2,6-lutidine (36 μL) was added to a mixed solution of nicotinic acid (23 mg) and HATU (58 mg) in dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (20 mL). 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 (NH silica gel, heptane: ethyl acetate = 88: 12 to 0: 100) to obtain the title compound (23 mg) as a colorless amorphous.
UPLC: 416 [M + H] ⁺ (retention time 0.97, 1.00 min, rotamer)
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.52-8.37 (2H, m), 8.01-7.80 (1H, m), 7.76-7.20 (3H, m), 6.83-6.70 (1H, m), 6.51- 6.22 (1H, m), 5.00-4.79 (1H, m), 4.66-3.19 (9H, m), 2.59-1.68 (3H, m).

Example 9 (2- (2H-1,2,3-triazol-2-yl) phenyl) (5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2 .2] Synthesis of Octan-2-yl) methanone optical isomer 3- (2H-1,2,3-triazol-2-yl) benzoic acid (30 mg) in dichloromethane (0.80 mL) in oxalyl chloride (42 μL) And a catalytic amount of DMF were 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 (0.60 mL), and the optical isomer of 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane (intermediate 5- A) (35 mg) and triethylamine (0.11 mL) were added dropwise to a mixed solution of dichloromethane (10 mL) 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 = 90: 10 to 0: 100) to obtain the title compound (57 mg) as a colorless amorphous. It was.
UPLC: 390 [M + H] ⁺ (retention time 0.83, 0.87 min, rotamer)
¹ H-NMR was consistent with (Example 1).

Example 10 (2- (2H-1,2,3-triazol-2-yl) phenyl) (5- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2 .2] Synthesis of octan-2-yl) methanone optical isomer 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo The title compound (35 mg) was obtained as a colorless amorphous form from the optical isomer of [2.2.2] octane (Intermediate 5-B) (35 mg).
UPLC: 390 [M + H] ⁺ (retention time 0.83, 0.87 min, rotamer)
¹ H-NMR was consistent with (Example 1).

Example 11 (5- (4,6-Dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane-2-yl) (1- (pyridin-2-yl)- Synthesis of 1H-pyrazol-5-yl) methanone optical isomer 2- (4,6-dimethylpyrimidin-2-yl) -2,5-diazabicyclo [2.2.2] octane optical isomer (intermediate 5 -B) (35 mg), 1- (pyridin-2-yl) -1H-pyrazole-5-carboxylic acid (Intermediate 4) (31 mg), in a mixed solution of DMF (1.0 mL), HATU (63 mg), diisopropyl Ethylamine (72 μL) was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (5.0 mL). 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 = 80: 20 to 40:60) to obtain the title compound (14 mg) as a white solid.
UPLC: 390 [M + H] ⁺ (retention time 0.80, 0.84 min, rotamer)
¹ H-NMR (CDCl ₃ , 300 MHz) δ: 8.28-8.22 (1H, m), 7.94-7.65 (3H, m), 7.20-7.09 (1H, m), 6.49-6.43 (1H, m), 6.31- 6.25 (1H, m), 5.25-3.38 (7H, m), 2.32-2.20 (6H, m), 2.16-1.66 (3H, m).

Example 12 2- (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of 3-methoxyisonicotinonitrile optical isomer 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3 in the same manner as in Example 7 or a method analogous thereto The title compound (13 mg) was obtained as a colorless amorphous form from the optical isomer of 2-methoxyisonicotinonitrile (Intermediate 6-A) (14 mg).
UPLC: 416 [M + H] ⁺ (retention time 1.02 minutes)
¹ H-NMR was consistent with (Example 7).

Example 13 2- (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of 3-methoxyisonicotinonitrile optical isomer 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) -3 in the same manner as in Example 7 or a method analogous thereto The title compound (7.7 mg) was obtained as a colorless amorphous form from the optical isomer of 2-methoxyisonicotinonitrile (intermediate 6-B) (18 mg).
UPLC: 416 [M + H] ⁺ (retention time 1.02 minutes)
¹ H-NMR was consistent with (Example 7).

Example 14 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino Synthesis of optical isomer of nitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino by the same method as in Example 7 or a method analogous thereto The title compound (6.2 mg) was obtained as a colorless amorphous form from the optical isomer of nitrile (Intermediate 6-A) (12 mg).
UPLC: 416 [M + H] ⁺ (retention time 0.99, 1.01 min, rotamer)
¹ H-NMR was consistent with (Example 8).

Example 15 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino Synthesis of optical isomer of nitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-methoxyisonicotino by the same method as in Example 7 or a method analogous thereto The title compound (9.6 mg) was obtained as a colorless amorphous form from the optical isomer of nitrile (Intermediate 6-B) (12 mg).
UPLC: 416 [M + H] ⁺ (retention time 0.99, 1.01 min, rotamer)
¹ H-NMR was consistent with (Example 8).

Example 16 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicoti Synthesis of optical isomers of nononitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicotinonitrile optical isomer (intermediate 7-A) ( 22 mg), 2- (1H-pyrazol-1-yl) nicotinic acid (16 mg), and HATU (40 mg) in dichloromethane (2 mL) were added with 2,6-lutidine (20 μL), and a nitrogen atmosphere at room temperature was added. Stir for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried 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 = 2: 1 to 1: 2) to obtain the title compound (24 mg) as a colorless amorphous.
UPLC: 426 [M + H] ⁺ (retention time 1.03, 1.07 min, rotamer)
¹ H-NMR (DMSO-D ₆ , 400 MHz) δ: 8.57-8.42 (2H, m), 8.19-7.18 (4H, m), 7.11-6.98 (1H, m), 6.60-6.35 (1H, m), 4.63-3.40 (6H, m), 2.30-0.98 (7H, m), 0.65-0.51 (2H, m).

Example 17 2- (5- (2- (1H-pyrazol-1-yl) nicotinoyl) -2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropylisonicoti Synthesis of optical isomers of nononitrile 2- (2,5-diazabicyclo [2.2.2] octan-2-yl) -3-cyclopropyliso-isolated by a method similar to or equivalent to that in Example 16. The title compound (26 mg) was obtained as a colorless amorphous form from the optical isomer of nicotinonitrile (Intermediate 7-B) (21 mg).
UPLC: 426 [M + H] ⁺ (retention time 1.02, 1.06 min, rotamer)

Example 18 2- (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of optical isomers of 3-cyclopropylisonicotinonitrile 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) in the same manner as in Example 16 or a method analogous thereto The title compound (26 mg) was obtained as a colorless amorphous form from the optical isomer of -3-cyclopropylisonicotinonitrile (Intermediate 7-A) (22 mg).
UPLC: 426 [M + H] ⁺ (retention time 1.05, 1.09 min, rotamer)

Example 19 2- (5- (2- (2H-1,2,3-triazol-2-yl) benzoyl) -2,5-diazabicyclo [2.2.2] octane-2-yl)- Synthesis of optical isomers of 3-cyclopropylisonicotinonitrile 2- (2,5-diazabicyclo [2.2.2] octane-2-yl) in the same manner as in Example 16 or a method analogous thereto The title compound (23 mg) was obtained as a colorless amorphous form from the optical isomer of -3-cyclopropylisonicotinonitrile (Intermediate 7-B) (21 mg).
UPLC: 426 [M + H] ⁺ (retention time 1.05, 1.08 min, rotamer)

The structures of the final compounds synthesized in the above (Example 1) to (Example 19) are shown in the following [Chemical Formula 32] and [Chemical Formula 33]. The structures of the intermediate compounds obtained in the above production examples are shown in the following [Chemical Formula 34] and [Chemical Formula 35].

Claims

The following formula (I):

[In formula (I), m is an integer from 0 to 4; n is an integer of 0-4; ring A represents a C 6 ~ 14 aryl group or a 5-7 membered heteroaryl group, ; ring B is C 6 ~ 14 aryl group, or represents a 5- to 7-membered heteroaryl group,; Q is Table with C 3 ~ 8 cycloalkyl group, or -OR c or partial structural formula,, (SF-1) Group:

Wherein (SF-1), ring C is C 6 ~ 14 aryl group, 5- to 7-membered heteroaryl group or 3-8 represents a non-aromatic heterocyclic group,; p is an integer of 0 to 5 Yes; each R 3 independently represents a halogen atom, a cyano group, —R d , or —OR d , where R d is a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, or C 3 represents ~ represents an 8 cycloalkyl group]; R 1 is each independently a halogen atom, a cyano group, -R a, -OR a, -C (O) R a, -C (O) OR a, - SR a represents —SO 2 R a , —NR A R B group, 3- to 8-membered non-aromatic heterocyclic group, or oxo group; R 2 each independently represents a halogen atom, a cyano group, —R b represents -OR b or 5-7 membered heteroaryl group, the 5-7 membered heteroaryl group, optionally substituted with 1-5 halogen atoms or a hydroxyl group Ku; R A and R B in -NR A R B group in the R 1 are each independently, -R a, -C (O) R a, -C (O) OR a or -SO 2 R, It represents a; R a in the R 1 and -NR a R B group, a hydrogen atom, C 1 ~ 6 alkyl group, a halogenated C 1 ~ 6 alkyl group, hydroxy C 1 ~ 6 alkyl group, hydroxy halides C 1 ~ 6 alkyl group or an C 3 ~ 8 cycloalkyl group; R b in the R 2 represents a C 1 ~ 6 alkyl group or halogenated C 1 ~ 6 alkyl group; in the Q R c is, C 1 ~ 6 alkyl group, a halogenated C 1 ~ 6 alkyl group or a compound represented by the representative] a C 6 ~ 14 aryl group, or a pharmaceutically acceptable salt thereof or their solvent, Japanese products.
A pharmaceutical composition comprising at least one of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
The prevention of a disease involving orexin receptor comprising at least one of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient / Or therapeutic agent.
A prophylactic and / or therapeutic agent for sleep disorders, comprising at least one of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
An orexin receptor antagonist comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.
The orexin receptor antagonist according to claim 5, which is an orexin 2 receptor selective antagonist.
One or more of the compounds according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and (1) a sleep-inducing agent and (2) a drug prescribed for sleep apnea syndrome , (3) drugs prescribed for restless legs syndrome, (4) atypical antipsychotics, (5) typical antipsychotics, (6) selective serotonin reuptake inhibitors (SSRI), (7) selective Serotonin / noradrenaline reuptake inhibitor (SNRI), (8) Selective noradrenaline / dopamine reuptake inhibitor (NDRI), (9) Noradrenergic / specific serotonergic antidepressant (NaSSA), (10) Tria Zolopyridine antidepressants (SARI), (11) tetracyclic antidepressants, (12) tricyclic antidepressants, (13) other antidepressants, (14) α7 nicotine receptor production (15) α7 nicotinic receptor activity modulator, (16) α7 nicotinic receptor partial modulator, (17) PDE inhibitor, (18) NK2 antagonist, (19) NK3 antagonist, (20) muscarinic type M1 acetylcholine receptor activity modulator, (21) muscarinic M2 acetylcholine receptor activity regulator, (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, (27) glutamate enhancer, (28) NMDA receptor inhibitor, (29) metabolic glutamate Receptor modulator (mGlu), (30) anxiolytic, (31) β-amyloid vaccine, (32) β-amyloid (33) brain function activator, (34) cannabinoid modulator, (35) cholinesterase inhibitor, (36) MAO-B inhibitor, (37) Parkinson's disease treatment, (38) diabetes treatment, (39) anti-obesity drugs, (40) anti-hyperlipidemic drugs such as cholesterol-lowering drugs, (41) antihypertensive drugs, (42) non-steroidal anti-inflammatory drugs, (43) disease-modifying anti-rheumatic drugs, (44 ) Anti-cytokine drugs, (45) steroid drugs, (46) sex hormones or derivatives thereof, (47) parathyroid hormone, (48) opioid agonists, (49) pilin antipyretic analgesics, (50) non-pyrine antipyretic analgesics , (51) non-steroidal anti-inflammatory drugs (NSAIDs), (52) COX-2 selective inhibitors, (53) peripheral neuropathic pain / fibromyalgia drugs, and (54) antiepileptic drugs Pharmaceutical composition characterized by containing a one or more agents selected from Ranaru group.