JP2020193176A - Novel biaryl derivative and pharmaceutical use thereof - Google Patents

Abstract

To provide an agent for preventing and/or treating disease associated with group II mGlu receptor.SOLUTION: The present invention provides a compound of formula (1) or a pharmaceutically acceptable salt thereof (R1, R2: H, halogen or the like. Ring A: C6-10 aromatic carbocycle, 4-10 membered saturated heterocycle or the like. R3, R4: H, halogen or the like. Ring B: C6-10 aromatic carbocycle, 4-10 membered saturated heterocycle, 5-10 membered heteroaromatic ring. R5, R6: H, a halogen atom or the like. X: N, CRe (Re: H, halogen or the like)).SELECTED DRAWING: None

Description

The present invention contains a novel biaryl derivative having a negative regulatory effect on the Group II metabotropic glutamate (mGlu) receptor or a pharmaceutically acceptable salt thereof, as well as an active ingredient thereof. , And / or prophylactic and / or therapeutic agents for diseases involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3).

Glutamate is a major excitatory neurotransmitter in the central nervous system and is an ion channel receptor (ie, N-methyl-D-asparamate (NMDA)) glutamate receptor, α-amino-3-hydroxy-5-5. It acts on the methyl-4-isooxazole propionic acid (AMPA) receptor and the kainic acid receptor) and the metabolic glutamate receptor (mGlu receptor), which is a G protein-conjugated receptor (GPCR). The mGlu receptor is classified as a GPCR class C and has a large extracellular ligand binding site in addition to the 7 transmembrane site (TMD) that GPCRs have in common. Due to the high homology of the orthosteric ligand binding site of the mGlu receptor, it has been difficult to develop subtype-selective orthosteric ligands. On the other hand, the allosteric modulator exhibits subtype selectivity by binding to TMD (Non-Patent Documents 1 to 3).
There are eight subtypes 1 to 8 (mGluR1 to 8) of mGlu receptors, group I (mGluR1, mGluR5), group II (mGluR2, mGluR3) based on the signal transduction system and pharmacological characteristics that are conjugate to homology. ) And Group III (mGluR4, mGluR6, mGluR7, mGluR8). Group II mGlu receptors (mGluR2, mGluR3) are predominantly present at presynapses and suppressively regulate glutamate release. Therefore, it has been reported that the mGlu2 / 3 receptor negative allosteric modulator (NAM) may be an antidepressant (Non-Patent Document 4) and a cognitive function enhancer (Non-Patent Document 5).

Recently, compounds acting as mGlu2 / 3 receptor NAM have been reported in Patent Documents 1 to 6 and the like. However, these patent documents do not disclose or suggest any compound represented by the formula (1) described later in the present application.

WO2014 / 195311 WO2016 / 016382 WO2016 / 0163383 WO2016 / 087487 WO2017 / 018475 WO2018 / 079628

Hemstapat et al, Pharmacology and Experimental Therapeutics, 2007, 322, 254-264 Lungstrom et al, British Journal of Pharmacology, 2011,164,521-537 Dore et al, Nature, 2014, 511,557-562 Chaki et al, Neuropharmacology, 2013, 66, 40-52 Higgins et al, Neuropharmacology, 2004, 46, 907-917

The problem to be solved by the present invention is to find a novel compound having a negative regulatory effect on the group II mGlu receptor, and to find a group II mGlu receptor (that is, metabotropic glutamate receptor subtype 2 (mGluR2)) and / Or to provide a prophylactic and / or therapeutic agent useful for the treatment of diseases involving the metabotropic glutamate receptor subtype 3 (mGluR3)).

The present inventors have found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, may be referred to as “compound of the present invention”) solves the above-mentioned problems. , The present invention has been completed.

That is, the present invention includes the following aspects.

［式中、
Ｒ^１及びＲ^２は、各々独立して、水素原子、ハロゲン原子、シアノ、Ｃ_１−４アルキル又はＣ_３−６飽和炭素環基（該アルキル及び該飽和炭素環基は、各々独立して、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表し；
あるいは、Ｒ^１及びＲ^２は、それらが結合する炭素原子と一緒になってＣ_３−４飽和炭素環基（該飽和炭素環基は、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を形成していてもよく；
環Ａは、Ｃ_６−１０芳香族炭素環基、４〜１０員の飽和複素環基又は５〜１０員の芳香族複素環基を表し；
Ｒ^３及びＲ^４は、各々独立して、水素原子、ハロゲン原子、シアノ、ヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−４アルコキシ、Ｃ_１−４アルキルチオ、Ｃ_２−４アルケニル、４〜６員の飽和複素環基又は５又は６員の芳香族複素環基（該アルキル、該アルコキシ、該アルキルチオ、該飽和複素環基及び該芳香族複素環基は、各々独立して、同一又は異なる１〜５個のハロゲン原子で置換されていてもよい）、Ｃ_３−６飽和炭素環基、又はＣ_３−６シクロアルコキシ（該飽和炭素環基及び該シクロアルコキシは、各々独立して、ハロゲン原子及びＣ_１−４アルキルからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表し；
環Ｂは、Ｃ_６−１０芳香族炭素環基、４〜１０員の飽和複素環基又は５〜１０員の芳香族複素環基を表し；
Ｒ^５及びＲ^６は、各々独立して、水素原子、ハロゲン原子、シアノ、ヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_１−６アルキルチオ、４〜６員の飽和複素環基（該アルキル、該アルコキシ、該アルキルチオ及び該飽和複素環基は、各々独立して、ハロゲン原子、ヒドロキシ、及び同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、Ｃ_３−６シクロアルコキシ、Ｃ_３−６飽和炭素環基（該シクロアルコキシ及び該飽和炭素環基は、各々独立して、ハロゲン原子、ヒドロキシ、Ｃ_１−４アルキル、及び同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、−ＮＲ^ａＲ^ｂ、−ＮＲ^ｄ−Ｃ（Ｏ）−Ｒ^ｃ、−ＮＲ^ｄ−Ｃ（Ｏ）−ＯＲ^ｃ、−ＮＲ^ｄ−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−ＮＲ^ｄ−ＳＯ_２−Ｒ^ｃ、−ＣＨ_２−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−Ｃ（Ｏ）−Ｒ^ｄ、−Ｃ（Ｏ）−ＯＲ^ｄ、又は−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂを表し；
Ｒ^ａ及びＲ^ｂは、各々独立して、またＮＲ^ａＲ^ｂが複数ある場合のＲ^ａ又はＲ^ｂの各々は独立して、水素原子、Ｃ_１−４アルキル（該アルキルは、各々独立して、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、Ｃ_３−６飽和炭素環基又は４〜６員の飽和複素環基（該飽和炭素環基及び該飽和複素環基は、各々独立して、ハロゲン原子、ヒドロキシ、Ｃ_１−４アルキル及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表し；
あるいは、Ｒ^ａ及びＲ^ｂは、それらが結合する窒素原子と一緒になって４〜６員の含窒素飽和複素環基（該含窒素飽和複素環基は、ハロゲン原子、ヒドロキシ、Ｃ_１−４アルキル及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を形成していてもよく；
Ｒ^ｃは、複数ある場合は各々独立して、Ｃ_１−４アルキル、Ｃ_３−６飽和炭素環基又は４〜６員の飽和複素環基（該アルキル、該飽和炭素環基及び該飽和複素環基は、各々独立して、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表し；
Ｒ^ｄは、複数ある場合は各々独立して、水素原子、Ｃ_１−４アルキル、Ｃ_３−６飽和炭素環基又は４〜６員の飽和複素環基（該アルキル、該飽和炭素環基及び該飽和複素環基は、各々独立して、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表し；
Ｘは窒素原子又はＣＲ^ｅを表し；
Ｒ^ｅは、水素原子、ハロゲン原子、シアノ、ヒドロキシ、Ｃ_１−４アルキル、Ｃ_１−４アルコキシ又は−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ（該アルキル及び該アルコキシは同一又は異なる１〜５個のハロゲン原子又はヒドロキシで置換されていてもよい）であり；
ただし、Ｘが窒素原子であるとき、環Ｂは、アゼチジン、ピロリジン、ジヒドロピロール、ピペリジン、テトラヒドロピリジン、ピリジン、イソオキサゾール、イミダゾール、又はオキサジアゾールではない] [Item 1]
A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.

[During the ceremony,
R ¹ and R ² are independently hydrogen atom, halogen atom, cyano, C _1-4 alkyl or C _3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are each independently, respectively. Represents (may be substituted with the same or different 1-5 substituents, selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy);
Alternatively, R ¹ and R ² may be combined with the carbon atom to which they are attached to form a C _3-4 saturated carbocyclic group (the saturated carbocyclic group comprises a group consisting of halogen atoms, hydroxy and C _1-4 alkoxy. It may be substituted with the same or different 1 to 5 substituents of choice);
Ring A represents a C _6-10 aromatic carbocyclic group, a 4-10 member saturated heterocyclic group or a 5-10 member aromatic heterocyclic group;
R ³ and R ⁴ are independently hydrogen atom, halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-4 alkoxy, C _1-4 alkyl thio, C _2-4 alkenyl, 4 to 6 members. Saturated heterocyclic groups or 5- or 6-membered aromatic heterocyclic groups (the alkyl, the alkoxy, the alkylthio, the saturated heterocyclic group and the aromatic heterocyclic group are independently the same or different 1- It may be substituted with 5 halogen atoms), a C _3-6 saturated carbocyclic group, or a C _3-6 cycloalkoxy (the saturated carbocyclic group and the cycloalkoxy are independently each of the halogen atom and the halogen atom and the cycloalkoxy. C (may be substituted with the same or different 1-5 substituents selected from the group consisting of _1-4 alkyl);
Ring B represents a C _6-10 aromatic carbocyclic group, a 4-10 member saturated heterocyclic group or a 5-10 member aromatic heterocyclic group;
R ⁵ and R ⁶ are independently hydrogen atom, halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, 4- to 6-membered saturated heterocyclic group ( The alkyl, the alkoxy, the alkylthio and the saturated heterocyclic group are each independently from C _1-4 alkoxy which may be substituted with halogen atom, hydroxy and 1 to 5 halogen atoms which are the same or different. C _3-6 cycloalkoxy, C _3-6 saturated carbocyclic group (the cycloalkoxy and the saturated carbocyclic ring), which may be substituted with the same or different 1 to 5 substituents selected from the group Each group is independently selected from the group consisting of halogen atoms, hydroxy, C _1-4 alkyl, and C _1-4 alkoxy optionally substituted with the same or different 1-5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents), -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d- C (O) -OR ^c ,- NR ^d- C (O) -NR ^a R ^b , -NR ^d -SO _2- R ^c , -CH _2- C (O) -NR ^a R ^b , -C (O) -R ^d , -C (O) ) -OR ^d , or -C (O) -NR ^a R ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom and C _1-4 alkyl (the alkyl is independent of each other). It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), C _3-6 saturated carbocyclic groups or 4 to 4 to A 6-membered saturated heterocyclic group (the saturated carbocyclic group and the saturated heterocyclic group are each independently selected from the group consisting of halogen atom, hydroxy, C _1-4 alkyl and C _1-4 alkoxy. It may be substituted with the same or different 1 to 5 substituents);
Alternatively, ^Ra and R ^b may be a 4- to 6-membered nitrogen-containing saturated heterocyclic group together with the nitrogen atom to which they are bonded (the nitrogen-containing saturated heterocyclic group is a halogen atom, hydroxy, C _1-4. It may be substituted with the same or different 1-5 substituents selected from the group consisting of alkyl and C _1-4 alkoxy);
If there are a plurality of ^Rc , each of them is independently C _1-4 alkyl, C _3-6 saturated carbocyclic group or 4- to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and the saturated heterocyclic group). The ring groups each independently represent (may be optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy);
R ^d may be a hydrogen atom, a C _1-4 alkyl, a C _3-6 saturated carbocyclic group or a 4- to 6-membered saturated heterocyclic group (the alkyl, the saturated carbon ring group and Each of the saturated heterocyclic groups independently represents the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C _1-4 alkoxy). ;
X represents a nitrogen atom or CR ^e ;
^Re is a hydrogen atom, a halogen atom, a cyano, a hydroxy, a C _1-4 alkyl, a C _1-4 alkoxy or -C (O) -NR ^a R ^b (the alkyl and the alkoxy are the same or different 1 to 5). May be replaced with a halogen atom or hydroxy);
However, when X is a nitrogen atom, ring B is not azetidine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, pyridine, isoxazole, imidazole, or oxadiazole]

[Item 2]
R ¹ and R ² are independently selected from the group consisting of hydrogen atom or C _1-4 alkyl (the alkyl is a halogen atom, hydroxy and C _1-4 alkoxy, 1 to 5 identical or different). , Or R ¹ and R ² together with the carbon atoms to which they are attached to form a cyclopropane or cyclobutane ring.
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[Item 3]
Ring A is benzene, naphthalene, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isooxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indridin, imidazopyridine, triazolopyridine, 1,3 -Benzodioxol, chromane, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-inden or 2,3-dihydro-1H-inden-1-one,
Item 1 or Item 2 or a pharmaceutically acceptable salt thereof.

[Item 4]
R ³ and R ⁴ are independent of each other
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl, which may be substituted with the same or different 1 to 5 halogen atoms,
(6) C _1-4 alkoxy, which may be substituted with the same or different 1 to 5 halogen atoms,
(7) C _3-6 cycloalkoxy (the cycloalkoxy may be substituted with the same or different 1-5 substituents selected from the group consisting of C _1-4 alkyl and halogen atoms), Or (8) C _1-4 alkylthio, which may be substituted with the same or different 1-5 halogen atoms.
The compound according to any one of Items 1 to 3 or a pharmaceutically acceptable salt thereof.

[Item 5]
Item 4. The compound according to any one of Items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring B is benzene or a 5- to 10-membered aromatic heterocyclic group.

[Item 6]
R ⁵ and R ⁶ are independent of each other
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl (the alkyl is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(6) C _1-4 Alkoxy (The alkoxy is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(7) 4- to 6-membered saturated heterocyclic group (the saturated heterocyclic group consists of a halogen atom, hydroxy, and C _1-4 alkoxy which may be substituted with the same or different 1 to 5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents selected from the group), or (8) -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d. -C (O) -OR ^c , -NR ^d -C (O) -NR ^a R ^b , -NR ^d -SO _2- R ^c , -CH _2- C (O) -NR ^a R ^b , -C ( O) -R ^d , -C (O) -OR ^d , or -C (O) -NR ^a R ^b ,
Item 2. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.

[Item 7]
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom or C _1-4 alkyl (the alkyl is independent of each other). It may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), or ^Ra and R ^b are them. A group of 4 to 6-membered nitrogen-containing saturated heterocyclic groups (the nitrogen-containing saturated heterocyclic group consists of a halogen atom, hydroxy, C _1-4 alkyl and C _1-4 alkoxy) together with the nitrogen atom to which is bonded. (May be substituted with the same or different 1 to 5 substituents) selected from
Item 2. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.

[Item 8]
If there are a plurality of R ^cs , they are independently C _1-4 alkyl or C _3-6 saturated carbocyclic groups (the alkyl and the saturated carbocyclic groups are independently halogen atoms, hydroxy and C _{1). -4} Substituents may be substituted with the same or different 1-5 substituents selected from the group consisting of alkoxy).
Item 2. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.

[Item 9]
If there are multiple R ^ds , they are independent of each other.
(1) Hydrogen atom,
(2) C _1-4 alkyl (the alkyl may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), Or (3) C _3-6 saturated carbocyclic group (the saturated carbocyclic group is substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C _1-4 alkoxy. May have been),
Item 2. The compound according to any one of Items 1 to 8 or a pharmaceutically acceptable salt thereof.

[Item 10]
^Re
(1) Hydrogen atom,
(2) a halogen atom, or (3) a C _1-4 alkyl which may be substituted with 1 to 5 halogen atoms which are the same or different.
Item 2. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

［式中、
Ｒ^１及びＲ^２は、各々独立して、水素原子又はＣ_１−４アルキル（該アルキルは、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）であり、あるいは、Ｒ^１及びＲ^２はそれらが結合する炭素原子と一緒になって、シクロプロパン環又はシクロブタン環を形成していてもよく；
環Ａは、ベンゼン、ナフタレン、ピリジン、ピリダジン、ピリミジン、ピラジン、チオフェン、チアゾール、イソチアゾール、オキサゾール、イソオキサゾール、キノリン、イソキノリン、ベンゾチオフェン、ベンゾフラン、インドリジン、イミダゾピリジン、トリアゾロピリジン、１，３−ベンゾジオキソール、クロマン、２，３−ジヒドロベンゾフラン、１，３−ジヒドロイソベンゾフラン、２，３−ジヒドロ−１Ｈ−インデン又は２，３−ジヒドロ−１Ｈ−インデン−１−オンを表し；
Ｒ^３及びＲ^４は、各々独立して、
（１）水素原子、
（２）ハロゲン原子、
（３）シアノ、
（４）ヒドロキシ、
（５）同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルキル、
（６）同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシ、
（７）Ｃ_３−６シクロアルコキシ（該シクロアルコキシは、Ｃ_１−４アルキル及びハロゲン原子からなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、又は
（８）同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルキルチオを表し；
環Ｂは、５〜１０員の芳香族複素環基（ただし、環Ｂは、ピリジン、イソオキサゾール、イミダゾール、又はオキサジアゾールではない）を表し；
Ｒ^５及びＲ^６は、各々独立して、
（１）水素原子、
（２）ハロゲン原子、
（３）シアノ、
（４）ヒドロキシ、
（５）Ｃ_１−４アルキル（該アルキルは、ハロゲン原子、ヒドロキシ、及び同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、
（６）Ｃ_１−４アルコキシ（該アルコキシは、ハロゲン原子、ヒドロキシ、及び同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、
（７）４〜６員の飽和複素環基（該飽和複素環基は、ハロゲン原子、ヒドロキシ、及び同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、又は
（８）−ＮＲ^ａＲ^ｂ、−ＮＲ^ｄ−Ｃ（Ｏ）−Ｒ^ｃ、−ＮＲ^ｄ−Ｃ（Ｏ）−ＯＲ^ｃ、−ＮＲ^ｄ−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−ＮＲ^ｄ−ＳＯ_２−Ｒ^ｃ、−ＣＨ_２−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−Ｃ（Ｏ）−Ｒ^ｄ、−Ｃ（Ｏ）−ＯＲ^ｄ、又は−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂを表し；
Ｒ^ａ及びＲ^ｂは、各々独立して、またＮＲ^ａＲ^ｂが複数ある場合のＲ^ａ又はＲ^ｂの各々は独立して、水素原子又はＣ_１-４アルキル（該アルキルは、各々独立して、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）であり、あるいは、Ｒ^ａ及びＲ^ｂはそれらが結合する窒素原子と一緒になって４〜６員の含窒素飽和複素環基（該含窒素飽和複素環基は、ハロゲン原子、ヒドロキシ、Ｃ_１−４アルキル及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を形成し；
Ｒ^ｃは、複数ある場合は各々独立して、Ｃ_１−４アルキル又はＣ_３−６飽和炭素環基（該アルキル及び該飽和炭素環基は、各々独立して、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表し；
Ｒ^ｄは、複数ある場合は各々独立して、
（１）水素原子、
（２）Ｃ_１−４アルキル（該アルキルは、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、又は
（３）Ｃ_３−６飽和炭素環基（該飽和炭素環基は、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表す］ [Item 11]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is represented by the following formula (1a).

[During the ceremony,
R ¹ and R ² are each independently selected from the group consisting of a hydrogen atom or a C _1-4 alkyl (the alkyl is a halogen atom, a hydroxy and a C _1-4 alkoxy, the same or different 1 to 5). a of which may be substituted with a substituent), or, R ¹ and R ² together with the carbon atoms to which they are attached, may form a cyclopropane ring or a cyclobutane ring;
Ring A is benzene, naphthalene, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isooxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indridin, imidazopyridine, triazolopyridine, 1,3. -Represents benzodioxol, chromane, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-inden or 2,3-dihydro-1H-inden-1-one;
R ³ and R ⁴ are independent of each other.
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl, which may be substituted with the same or different 1 to 5 halogen atoms,
(6) C _1-4 alkoxy, which may be substituted with the same or different 1 to 5 halogen atoms,
(7) C _3-6 cycloalkoxy (the cycloalkoxy may be substituted with the same or different 1-5 substituents selected from the group consisting of C _1-4 alkyl and halogen atoms), Or (8) represents a C _1-4 alkylthio which may be substituted with the same or different 1-5 halogen atoms;
Ring B represents a 5- to 10-membered aromatic heterocyclic group, where ring B is not pyridine, isooxazole, imidazole, or oxadiazole;
R ⁵ and R ⁶ are independent of each other.
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl (the alkyl is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(6) C _1-4 Alkoxy (The alkoxy is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(7) 4- to 6-membered saturated heterocyclic group (the saturated heterocyclic group consists of a halogen atom, hydroxy, and C _1-4 alkoxy which may be substituted with the same or different 1 to 5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents selected from the group), or (8) -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d. -C (O) -OR ^c , -NR ^d -C (O) -NR ^a R ^b , -NR ^d -SO _2- R ^c , -CH _2- C (O) -NR ^a R ^b , -C ( Represents O) -R ^d , -C (O) -OR ^d , or -C (O) -NR ^a R ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom or C _1-4 alkyl (the alkyl is independent of each other). It may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), or ^Ra and R ^b are them. A group of 4 to 6-membered nitrogen-containing saturated heterocyclic groups (the nitrogen-containing saturated heterocyclic group consists of a halogen atom, hydroxy, C _1-4 alkyl and C _1-4 alkoxy) together with the nitrogen atom to which is bonded. It may be substituted with the same or different 1 to 5 substituents selected from);
If there are a plurality of ^Rc , each of them is independent of C _1-4 alkyl or C _3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are independently each of a halogen atom, hydroxy and C _{1). Represents} (may be substituted with the same or different 1-5 substituents, selected from the group consisting of _-4 alkoxy);
If there are multiple R ^d , each is independent.
(1) Hydrogen atom,
(2) C _1-4 alkyl (the alkyl may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), Or (3) C _3-6 saturated carbocyclic group (the saturated carbocyclic group is substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C _1-4 alkoxy. Represents (may be)]

[Item 12]
Ring B is pyrimidine, pyrazine, pyridazine, imidazole pyridine, imidazole pyrimidine, imidazole pyridazine, indolizine, indazole, benzoimidazole, benzoxazole, benzothiazole, triazolopyridine, triazolopyrimidine, triazolopyrazine, pyrazolopyridine, pyra Item 2. The compound according to Item 11 or a pharmaceutically acceptable salt thereof, which is zolopyrimidine, pyrazolopyrazine, quinoline, isoquinoline, quinoxaline, quinazoline, dihydrobenzoxazine, dihydropyranopyridine or tetrahydroquinolin.

[Item 13]
Ring B is imidazole pyridine, imidazole pyrimidine, imidazole pyridazine, indazole, benzoimidazole, benzoxazole, triazolopyridine, pyrazolopyridine, pyrazolopyrimidine, quinoline, quinoxalin, dihydrobenzoxazine, dihydropyranopyridine or tetrahydroquinoline. , Item 11 or Item 12, or a pharmaceutically acceptable salt thereof.

［式中、
Ｗ^１、Ｗ^２及びＷ^３は、各々独立して、窒素原子又はＣＲ^ｆを表し（ただし、Ｗ^１、Ｗ^２及びＷ^３の少なくとも２つ以上はＣＲ^ｆである）、
Ｗ^４及びＷ^５は、各々独立して、窒素原子又はＣＲ^ｆを表し（ただし、Ｗ^４及びＷ^５の少なくともいずれか一つは窒素原子である）、
Ｒ^ｆは、各々独立して、水素原子、フッ素原子又はメチルを表す］
で表される置換基からなる群から選択される、いずれか一つの置換基である、
項１１から項１３のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 14]
Ring B is from the following formula (1a-1) to (1a-17):

[During the ceremony,
W ¹ , W ² and W ³ each independently represent a nitrogen atom or CR ^f (where at least two or more of W ¹ , W ² and W ³ are CR ^f ).
W ⁴ and W ⁵ each independently represent a nitrogen atom or CR ^f (provided that at least one of W ⁴ and W ⁵ is a nitrogen atom).
R ^f independently represents a hydrogen atom, a fluorine atom or methyl]
Any one of the substituents selected from the group consisting of the substituents represented by.
Item 2. The compound according to any one of Items 11 to 13, or a pharmaceutically acceptable salt thereof.

[Item 15]
Ring B is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1a-1) to (1a-9).
R ^f is a hydrogen atom,
Item 4. The compound according to Item 14 or a pharmaceutically acceptable salt thereof.

[Item 16]
Ring B is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1a-1) to (1a-3).
R ^f is a hydrogen atom,
Item 4. The compound according to Item 14 or a pharmaceutically acceptable salt thereof.

［式中、
Ｒ^１及びＲ^２は、各々独立して、水素原子又はＣ_１−４アルキル（該アルキルは、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）であり、あるいは、Ｒ^１及びＲ^２はそれらが結合する炭素原子と一緒になって、シクロプロパン環又はシクロブタン環を形成していてもよく；
環Ａは、ベンゼン、ナフタレン、ピリジン、ピリダジン、ピリミジン、ピラジン、チオフェン、チアゾール、イソチアゾール、オキサゾール、イソオキサゾール、キノリン、イソキノリン、ベンゾチオフェン、ベンゾフラン、インドリジン、イミダゾピリジン、トリアゾロピリジン、１，３−ベンゾジオキソール、クロマン、２，３−ジヒドロベンゾフラン、１，３−ジヒドロイソベンゾフラン、２，３−ジヒドロ−１Ｈ−インデン又は２，３−ジヒドロ−１Ｈ−インデン−１−オンを表し；
Ｒ^３及びＲ^４は、各々独立して、
（１）水素原子、
（２）ハロゲン原子、
（３）シアノ、
（４）ヒドロキシ、
（５）同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルキル、
（６）同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシ、
（７）Ｃ_３−６シクロアルコキシ（該シクロアルコキシは、Ｃ_１−４アルキル及びハロゲン原子からなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、又は
（８）同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルキルチオを表し
環Ｂは、５〜１０員の芳香族複素環基を表し；
Ｒ^５及びＲ^６は、各々独立して、
（１）水素原子、
（２）ハロゲン原子、
（３）シアノ、
（４）ヒドロキシ、
（５）Ｃ_１−４アルキル（該アルキルは、ハロゲン原子、ヒドロキシ、及び同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、
（６）Ｃ_１−４アルコキシ（該アルコキシは、ハロゲン原子、ヒドロキシ、及び同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、
（７）４〜６員の飽和複素環基（該飽和複素環基は、ハロゲン原子、ヒドロキシ、及び同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、又は
（８）−ＮＲ^ａＲ^ｂ、−ＮＲ^ｄ−Ｃ（Ｏ）−Ｒ^ｃ、−ＮＲ^ｄ−Ｃ（Ｏ）−ＯＲ^ｃ、−ＮＲ^ｄ−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−ＮＲ^ｄ−ＳＯ_２−Ｒ^ｃ、−ＣＨ_２−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−Ｃ（Ｏ）−Ｒ^ｄ、−Ｃ（Ｏ）−ＯＲ^ｄ、又は−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂを表し；
Ｒ^ａ及びＲ^ｂは、各々独立して、またＮＲ^ａＲ^ｂが複数ある場合のＲ^ａ又はＲ^ｂの各々は独立して、水素原子又はＣ_１−４アルキル（該アルキルは、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）であり、あるいは、Ｒ^ａ及びＲ^ｂはそれらが結合する窒素原子と一緒になって４〜６員の含窒素飽和複素環基（該含窒素飽和複素環基は、ハロゲン原子、ヒドロキシ、Ｃ_１−４アルキル及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を形成し；
Ｒ^ｃは、複数ある場合は各々独立して、Ｃ_１−４アルキル又はＣ_３−６飽和炭素環基（該アルキル及び該飽和炭素環基は、各々独立して、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表し；
Ｒ^ｄは、複数ある場合は各々独立して、
（１）水素原子、
（２）Ｃ_１−４アルキル（該アルキルは、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）、又は
（３）Ｃ_３−６飽和炭素環基（該飽和炭素環基は、ハロゲン原子、ヒドロキシ及びＣ_１−４アルコキシからなる群から選択される、同一又は異なる１〜５個の置換基で置換されていてもよい）を表し；
Ｒ^ｅは、
（１）水素原子、
（２）ハロゲン原子、又は
（３）同一又は異なる１〜５個のハロゲン原子で置換されていてもよいＣ_１−４アルキルを表す］ [Item 17]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is represented by the following formula (1b).

[During the ceremony,
R ¹ and R ² are each independently selected from the group consisting of a hydrogen atom or a C _1-4 alkyl (the alkyl is a halogen atom, a hydroxy and a C _1-4 alkoxy, the same or different 1 to 5). a of which may be substituted with a substituent), or, R ¹ and R ² together with the carbon atoms to which they are attached, may form a cyclopropane ring or a cyclobutane ring;
Ring A is benzene, naphthalene, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isooxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indridin, imidazopyridine, triazolopyridine, 1,3. -Represents benzodioxol, chromane, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-inden or 2,3-dihydro-1H-inden-1-one;
R ³ and R ⁴ are independent of each other.
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl, which may be substituted with the same or different 1 to 5 halogen atoms,
(6) C _1-4 alkoxy, which may be substituted with the same or different 1 to 5 halogen atoms,
(7) C _3-6 cycloalkoxy (the cycloalkoxy may be substituted with the same or different 1-5 substituents selected from the group consisting of C _1-4 alkyl and halogen atoms), Or (8) represents a C _1-4 alkylthio which may be substituted with the same or different 1-5 halogen atoms, and ring B represents a 5-10 membered aromatic heterocyclic group;
R ⁵ and R ⁶ are independent of each other.
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl (the alkyl is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(6) C _1-4 Alkoxy (The alkoxy is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(7) 4- to 6-membered saturated heterocyclic group (the saturated heterocyclic group consists of a halogen atom, hydroxy, and C _1-4 alkoxy which may be substituted with the same or different 1 to 5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents selected from the group), or (8) -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d. -C (O) -OR ^c , -NR ^d -C (O) -NR ^a R ^b , -NR ^d -SO _2- R ^c , -CH _2- C (O) -NR ^a R ^b , -C ( Represents O) -R ^d , -C (O) -OR ^d , or -C (O) -NR ^a R ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom or C _1-4 alkyl (the alkyl is a halogen atom, It may be substituted with the same or different 1-5 substituents selected from the group consisting of hydroxy and C _1-4 alkoxy), or ^Ra and R ^b are the nitrogen atoms to which they are attached. Together with a 4- to 6-membered nitrogen-containing saturated heterocyclic group, the nitrogen-containing saturated heterocyclic group is selected from the group consisting of halogen atoms, hydroxy, C _1-4 alkyl and C _1-4 alkoxy. It may be substituted with the same or different 1 to 5 substituents);
If there are a plurality of ^Rc , each of them is independent of C _1-4 alkyl or C _3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are independently each of a halogen atom, hydroxy and C _{1). Represents} (may be substituted with the same or different 1-5 substituents, selected from the group consisting of _-4 alkoxy);
If there are multiple R ^d , each is independent.
(1) Hydrogen atom,
(2) C _1-4 alkyl (the alkyl may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), Or (3) C _3-6 saturated carbocyclic group (the saturated carbocyclic group is substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C _1-4 alkoxy. Represents (may be);
^Re is
(1) Hydrogen atom,
(2) Represents a halogen atom, or (3) C _1-4 alkyl which may be substituted with the same or different 1 to 5 halogen atoms]

[Item 18]
Ring B is pyridine, pyrimidine, pyrazine, pyridazine, imidazole pyridine, imidazole pyrimidine, imidazole pyridazine, indridin, indazole, benzoimidazole, benzoxazole, benzothiazole, triazolopyridine, triazolopyrimidine, triazolopyrazine, pyrazolopyridine , Pyrazolopyrimidine, pyrazolopyrazine, quinoline, isoquinolin, quinoxalin, quinazoline, dihydrobenzoxazine, dihydropyranopyridine or tetrahydroquinoline, item 17 or a pharmaceutically acceptable salt thereof.

[Item 19]
Ring B is pyridine, imidazole pyridine, imidazole pyrimidine, imidazole pyridazine, indazole, benzoimidazole, benzoxazole, triazolopyridine, pyrazolopyridine, pyrazolopyrimidine, quinoline, quinoxaline, dihydrobenzoxazine, dihydropyranopyridine or tetrahydroquinoline. The compound according to Item 17 or Item 18, or a pharmaceutically acceptable salt thereof.

［式中、
Ｗ^１、Ｗ^２及びＷ^３は、各々独立して、窒素原子又はＣＲ^ｆを表し（ただし、Ｗ^１、Ｗ^２及びＷ^３の少なくとも２つ以上はＣＲ^ｆである）、
Ｗ^４及びＷ^５は、各々独立して、窒素原子又はＣＲ^ｆを表し（ただし、Ｗ^４及びＷ^５の少なくともいずれか一つは窒素原子である）、
Ｒ^ｆは、各々独立して、水素原子、フッ素原子又はメチルを表す］
で表される置換基からなる群から選択される、いずれか一つの置換基である、
項１７から項１９のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 20]
Ring B is from the following formula (1b-1) to (1b-19):

[During the ceremony,
W ¹ , W ² and W ³ each independently represent a nitrogen atom or CR ^f (where at least two or more of W ¹ , W ² and W ³ are CR ^f ).
W ⁴ and W ⁵ each independently represent a nitrogen atom or CR ^f (provided that at least one of W ⁴ and W ⁵ is a nitrogen atom).
R ^f independently represents a hydrogen atom, a fluorine atom or methyl]
Any one of the substituents selected from the group consisting of the substituents represented by.
Item 4. The compound according to any one of Items 17 to 19, or a pharmaceutically acceptable salt thereof.

[Item 21]
Ring B is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1b-1) to (1b-9).
R ^f is a hydrogen atom,
Item 2. The compound according to Item 20 or a pharmaceutically acceptable salt thereof.

[Item 22]
Ring B is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1b-1) to (1b-4).
R ^f is a hydrogen atom,
Item 2. The compound according to Item 20 or a pharmaceutically acceptable salt thereof.

[Item 23]
^Re
(1) Hydrogen atom,
Item 2. The compound according to any one of Items 17 to 22, wherein there is (2) a fluorine atom, or (3) C _1-4 alkyl which may be substituted with 1 to 5 halogen atoms which are the same or different. Pharmaceutically acceptable salt.

[Item 24]
Item 4. The compound according to any one of Items 17 to 23, or a pharmaceutically acceptable salt thereof, wherein ^Re is a hydrogen atom or a fluorine atom.

[Item 25]
Item 4. The compound according to any one of Items 17 to 24, or a pharmaceutically acceptable salt thereof, wherein ^Re is a hydrogen atom or a fluorine atom.

[Item 26]
R ¹ and R ² are independently hydrogen atoms, methyl, ethyl, isopropyl, cyclopropyl, methoxymethyl, hydroxymethyl, difluoromethyl or trifluoromethyl, or R ¹ and R ² are bound together. Item 5. The compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof, which forms a cyclopropane ring or a cyclobutane ring together with a carbon atom.

[Item 27]
Item 3. The compound described or a pharmaceutically acceptable salt thereof.

[Item 28]
R ³ and R ⁴ are independent of each other
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) C _1-4 alkyl, which may be substituted with the same or different 1 to 5 halogen atoms,
(5) C _1-4 alkoxy which may be substituted with the same or different 1 to 5 halogen atoms, or (6) C _3-6 cycloalkoxy (the cycloalkoxy is C _1-4 alkyl and a halogen atom). Item 5. The compound according to any one of Items 1 to 27, which is selected from the group consisting of (may be substituted with the same or different 1 to 5 substituents), or pharmaceutically acceptable thereof. Salt to be done.

[Item 29]
R ⁵ and R ⁶ are independent of each other
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl (the alkyl is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(6) C _1-4 Alkoxy (The alkoxy is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(7) 4- to 6-membered saturated heterocyclic group (the saturated heterocyclic group consists of halogen atoms, hydroxy, and C _1-4 alkoxy which may be substituted with 1 to 5 halogen atoms which are the same or different. Item 2. The item 1 to item 28, which is selected from the group and may be substituted with the same or different 1 to 5 substituents) or (8) -NR ^{a Rb} . A compound or a pharmaceutically acceptable salt thereof.

[Item 30]
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom or C _1-4 alkyl (the alkyl is a halogen atom, Item 2. The compound according to any one of Items 1 to 29, which is selected from the group consisting of hydroxy and C _1-4 alkoxy and may be substituted with the same or different 1 to 3 substituents). Or its pharmaceutically acceptable salt.

[Item 31]
Item 6. The compound according to any one of Items 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently a hydrogen atom, methyl, ethyl or trifluoromethyl.

[Item 32]
Item 4. The compound according to any one of Items 1 to 31, or a pharmaceutically acceptable salt thereof, wherein ring A is benzene, pyridine or thiophene.

[Item 33]
Item 2. The compound according to any one of Items 1 to 32, wherein R ³ and R ⁴ are independently hydrogen atom, fluorine atom, chlorine atom, cyano, methyl, trifluoromethyl, methoxy or cyclopropoxy. Or its pharmaceutically acceptable salt.

[Item 34]
R ⁵ and R ⁶ are independently substituted with hydrogen atom, halogen atom, cyano, hydroxy, 1 to 5 halogen atoms which are the same or different, C _1-4 alkyl, or -NR ^a R. ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independently substituted with a hydrogen atom or the same or different 1 to 3 halogen atoms. Item 5. The compound according to any one of Items 1 to 33 or a pharmaceutically acceptable salt thereof, which is C _1-4 alkyl which may be used.

[Item 35]
Item 4. The compound according to any one of Items 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl and R ² is a hydrogen atom.

[Item 36]
Item 4. The compound according to any one of Items 1 to 35, or a pharmaceutically acceptable salt thereof, wherein ring A is benzene.

[Item 37]
Item 4. The compound according to any one of Items 1 to 36, wherein R ³ and R ⁴ are independently hydrogen atom, fluorine atom, chlorine atom, methyl, trifluoromethyl or methoxy, or the pharmaceutical science thereof. Allowable salt for.

[Item 38]
Item 4. The compound according to any one of Items 1 to 37, or a pharmaceutical product thereof, wherein R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, C _1-4 alkyl or -NH _2. Allowable salt.

[Item 39]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
Example 1: (4S) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 2: (4S) -4-methyl-8- (1-methyl-1H-indazole-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1, 2-a] Pyrazine-1 (2H) -on;
Example 4: (4S) -8- (imidazole [1,5-a] pyridin-7-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 5: (4S) -4-methyl-8- (pyrazolo [1,5-a] pyridin-5-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 6: (4S) -8- (imidazole [1,5-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 11: (4S) -4-methyl-8- (quinoline-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine- 1 (2H) -on;
Example 13: (4S) -6-fluoro-8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4 -Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on;
Example 14: (4S) -6-fluoro-4-methyl-8- (quinoline-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
Example 16: (4S) -2- (3,4-dichlorophenyl) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2] -A] Pyrazine-1 (2H) -on;
Example 17: (4S) -2- [3-fluoro-4- (trifluoromethyl) phenyl] -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4 -Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on;
Example 18: (4S) -2- (3-chloro-4-fluorophenyl) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 21: (4S) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [5- (trifluoromethyl) thiophen-2-yl] -3,4 -Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on;
Example 22: (4S) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [6- (trifluoromethyl) pyridin-3-yl] -3,4 -Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on;
Example 25: (4S) -8- (imidazole [1,2-a] pyrazine-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 26: (4S) -8- (3-fluoroimidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4- Dihydropyrro [1,2-a] pyrazine-1 (2H) -on;
Example 27: (4S) -2- [4- (1,1-difluoroethyl) phenyl] -4-methyl-8- (3-methylimidazo [1,2-a] pyridin-6-yl) -3 , 4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; and Example 28: (4S) -8- (3-ethylimidazo [1,2-a] pyridin-6-yl) -4-Methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one.

[Item 40]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
Example 1: (4S) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 4: (4S) -8- (imidazole [1,5-a] pyridin-7-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 6: (4S) -8- (imidazole [1,5-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 13: (4S) -6-fluoro-8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4 -Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on;
Example 16: (4S) -2- (3,4-dichlorophenyl) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2] -A] Pyrazine-1 (2H) -on;
Example 17: (4S) -2- [3-fluoro-4- (trifluoromethyl) phenyl] -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4 -Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on;
Example 18: (4S) -2- (3-chloro-4-fluorophenyl) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 25: (4S) -8- (imidazole [1,2-a] pyrazine-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
Example 26: (4S) -8- (3-fluoroimidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4- Dihydropyrro [1,2-a] pyrazine-1 (2H) -on;
Example 27: (4S) -2- [4- (1,1-difluoroethyl) phenyl] -4-methyl-8- (3-methylimidazo [1,2-a] pyridin-6-yl) -3 , 4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one; and Example 28: (4S) -8- (3-ethylimidazo [1,2-a] pyridin-6-yl) -4-Methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one.

[Item 41]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
Example 29: (4S) -2- [3-Methoxy-4- (trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1 , 2-a] Pyrazine-1 (2H) -on;
Example 30: (4S) -2- [3-fluoro-4- (trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1 , 2-a] Pyrazine-1 (2H) -on;
Example 36: (4S) -2- [3-chloro-4- (trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1] , 2-a] Pyrazine-1 (2H) -on;
Example 37: (4S) -4-methyl-8- (2-methylpyridine-4-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a ] Pyrazine-1 (2H) -on;
Example 38: (4S) -4-methyl-8- (2-methylpyridine-4-yl) -2- [3-methyl-4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1 , 2-a] Pyrazine-1 (2H) -one; and Example 39: (4S) -6-fluoro-4-methyl-8- (2-methylpyridine-4-yl) -2- [4-( Trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one.

[Item 42]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
Example 40: (7S) -7-methyl-3- (pyrazolo [1,5-a] pyridin-5-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on;
Example 44: (7S) -3- (Imidazo [1,2-a] pyrimidine-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on;
Example 46: (7S) -7-methyl-3- (quinoxaline-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine -4 (5H) -on;
Example 49: (7S) -3- (imidazole [1,5-a] pyridin-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on;
Example 50: (7S) -7-methyl-3- (1-methyl-1H-pyrazolo [4,3-b] pyridin-6-yl) -5- [4- (trifluoromethyl) phenyl] -6 , 7-Dihydropyrazolo [1,5-a] pyrazine-4 (5H) -on;
Example 52: (7S) -3- (imidazole [1,2-b] pyridazine-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on;
Example 53: (7S) -3- (imidazole [1,5-a] pyridine-7-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on;
Example 55: (7S) -7-methyl-3- (3-methylimidazole [1,5-a] pyridin-7-yl) -5- [4- (trifluoromethyl) phenyl] -6,7- Dihydropyrazolo [1,5-a] pyrazine-4 (5H) -on;
Example 61: (7S) -7-methyl-3- (quinoline-6-yl) -5- [5- (trifluoromethyl) thiophen-2-yl] -6,7-dihydropyrazolo [1,5] -A] Pyrazine-4 (5H) -on;
Example 63: (7S) -7-methyl-3- (1H-pyrazolo [4,3-b] pyridin-5-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydro Pyrazolo [1,5-a] pyrazine-4 (5H) -on; and Example 64: (7S) -7-methyl-3- (1,2,3,4-tetrahydroquinolin-6-yl)- 5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one.

[Item 43]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
Example 44: (7S) -3- (Imidazo [1,2-a] pyrimidine-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on;
Example 46: (7S) -7-methyl-3- (quinoxaline-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine -4 (5H) -on;
Example 49: (7S) -3- (imidazole [1,5-a] pyridin-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on;
Example 52: (7S) -3- (imidazole [1,2-b] pyridazine-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on;
Example 53: (7S) -3- (Imidazo [1,5-a] Pyridine-7-yl) -7-Methyl-5- [4- (Trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -on; and Example 55: (7S) -7-methyl-3- (3-methylimidazo [1,5-a] pyridin-7-yl)- 5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one.

[Item 44]
Item 5. A pharmaceutical composition containing the compound according to any one of Items 1 to 43 or a pharmaceutically acceptable salt thereof.

[Item 45]
A therapeutic agent and / or a prophylactic agent for a disease involving a Group II mGlu receptor, which comprises the compound according to any one of Items 1 to 43 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Item 46]
Item 4. Therapeutic and / or prophylactic agents according to Item 45, wherein the Group II mGlu receptor is a metabotropic glutamate receptor subtype 2 (mGluR2).

[Item 47]
The therapeutic and / or prophylactic agent according to Item 45 or Item 46, wherein the disease involving the Group II mGlu receptor is a psychiatric disorder or a neurodegenerative disease.

[Item 48]
Psychiatric or neurodegenerative disorders include depressive disorder, depressive disorder, bipolar disorder and related disorders, anxiety disorder, post-traumatic stress disorder, compulsive disorder, acute stress disorder, schizophrenia, autism spectrum disorder The therapeutic and / or prophylactic agent according to Item 47, which is Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, convulsions, tremor, pain or sleep disorder.

[Item 49]
Use of the compound according to any one of Items 1 to 43 or a pharmaceutically acceptable salt thereof for producing a therapeutic agent and / or a preventive agent for a disease involving the Group II mGlu receptor.

[Item 50]
Item 5. The compound according to any one of Items 1 to 43 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving the Group II mGlu receptor.

[Item 51]
A group II mGlu receptor comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items 1-43 or a pharmaceutically acceptable salt thereof. Methods for treating and / or preventing the diseases involved.

[Item 52]
A drug containing the compound according to any one of Items 1 to 43 or a pharmaceutically acceptable salt thereof, and depressive disorder, depressive disorder, bipolar disorder and related disorders, anxiety disorder, and psychological disorder. Treatments for post-traumatic stress disorder, compulsive disorder, acute stress disorder, schizophrenia, autism spectrum disorder, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, spasm, tremor, pain or sleep disorders A drug that is a combination of one or more drugs selected from.

[Item 53]
Containing the compound according to any one of Items 1 to 43 or a pharmaceutically acceptable salt thereof for treating a psychiatric disorder or a neurodegenerative disease in combination with one or more antipsychotic agents. Medicine to do.

The compounds of the present invention exhibit a negative regulatory effect on Group II metabotropic glutamate (mGlu) receptors. Thus, the compounds of the invention are therapeutic agents and agents for diseases involving group II mGlu receptors (ie, metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3)). / Or useful as a prophylactic agent.

The terms used herein will be described below.

The term "group" means a monovalent group. In addition, the term "base" may be omitted in the present specification.

The number of substituents in the group defined as "may be substituted" or "substituted" is not particularly limited as long as it can be substituted. Unless otherwise indicated, the description of each group also applies when the group is part of another group or a substituent.

"C _1-4 alkyl" means an aliphatic hydrocarbon group having 1 to 4 carbon atoms, and "C ₄ alkyl" means an aliphatic hydrocarbon group having 4 carbon atoms. The same applies to other numbers. Specific examples of "C _1-4 alkyl" include, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl and the like. Can be mentioned.

“C _1-6 alkyl” means an aliphatic hydrocarbon group having 1 to 6 carbon atoms. As the "C _1-6 alkyl", preferably "C _1-4 alkyl" is mentioned. Specific examples of "C _1-6 alkyl" include, for example, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-, in addition to those listed as specific examples of "C _1-4 alkyl". Examples thereof include methylpentyl and n-hexyl.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. It is preferably a fluorine atom or a chlorine atom.

The “C _1-4 alkoxy” means an oxy group substituted with the “C _1-4 alkyl”. Specific examples of "C _1-4 alkoxy" include, for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, and 2-methylpropoxy. Be done. Preferably, methoxy or ethoxy is used.

"C _1-6 alkoxy" means an oxy group substituted with the "C _1-6 alkyl". As the "C _1-6 alkoxy", preferably "C _1-4 alkoxy" can be mentioned. Specific examples of "C _1-6 alkoxy" include, for example, n-pentyroxy, 3-methylbutoxy, 2-methylbutoxy, 2,2, in addition to those listed as specific examples of "C _1-4 alkoxy". -Dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, n-hexyloxy, 4-methylpentyroxy, 3-methylpentyroxy, 2-methylpentyroxy, 1-methylpentyroxy, 3,3-dimethylbutoxy , 2,2-Dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy and the like.

"C _3-6 cycloalkoxy" means an oxy group substituted with a cyclic alkyl having 3 to 6 carbon atoms. Specific examples of "C _3-6 cycloalkoxy" include cyclopropoxy, cyclobutoxy, cyclopentyroxy, cyclohexyloxy and the like. Preferably, cyclopropoxy or cyclobutoxy is mentioned.

The "C _1-4 alkyl thio" means a thiol group substituted with the "C _1-4 alkyl". Specific examples of "C _1-4 alkylthio" include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, s-butylthio, t-butylthio and the like.

The "C _1-6 alkyl thio" means a thiol group substituted with the "C _1-6 alkyl". As the "C _1-6 alkyl thio", preferably "C _1-4 alkyl thio" is mentioned. Specific examples of "C _1-6 alkylthio" include, for example, 1-ethylpropylthio, n-pentylthio, neopentylthio, and n-hexylthio, in addition to those listed as specific examples of "C _1-4 alkylthio". , Isohexylthio and the like.

“C _2-4 alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having 2 to 4 carbon atoms contained in the chain. Specific examples of "C _2-4 alkenyl" include vinyl, allyl, 1-propenyl, 1-butenyl and the like.

The “C _3-6 saturated carbocycle” means a monocyclic saturated or partially unsaturated hydrocarbon ring having 3 to 6 carbon atoms. As the "C _3-6 saturated carbocycle", preferably, "C _3-4 saturated carbocycle" is mentioned. Specific examples of the "C _3-6 saturated carbocycle" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene and the like. Preferably, cyclopropane or cyclobutane is mentioned.

The "C _3-4 saturated carbocyclic group" means a monovalent group of the "C _3-4 saturated carbocyclic ring" among the above "C _3-6 saturated carbocyclic rings".

A "4- to 10-membered saturated heterocycle" is composed of 4 to 10 atoms, including the same or different 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. It means a monocyclic or bicyclic saturated heterocycle to be used, and includes those having a partially unsaturated bond, those having a partially crosslinked structure, and those partially spoiled. Bicyclic saturated heterocycles include those in which a monocyclic saturated heterocycle and a benzene or a monocyclic 5- to 6-membered aromatic heterocycle are fused. Further, one or two carbonyls, thiocarbonyls, sulfinyls or sulfonyls may be contained in the saturated heterocycle, and for example, lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate, etc. Cyclic groups such as cyclic thiocarbamates are also included in the saturated heterocycle. Here, the oxygen atom of carbonyl, sulfinyl and sulfonyl and the sulfur atom of thiocarbonyl are not included in the number of 4 to 10 members (ring size) and the number of heteroatoms constituting the ring. Examples of the "4 to 10-membered saturated heterocycle" include a monocyclic or bicyclic "4 to 8-membered saturated heterocycle", and more preferably a monocyclic "4 to 6-membered saturated heterocycle". "Heterocycle" is mentioned, and more preferably, a monocyclic "5- or 6-membered saturated heterocycle" is mentioned. Specific examples of the "4- to 10-membered saturated heterocycle" include, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran, 1,3-benzodioxol, 1,3. − Dihydroisobenzofuran and the like, preferably pyrrolidine, piperidine, piperazine, morpholine, 1,3-benzodioxol, 1,3-dihydroisobenzofuran and the like.

The "4 to 6-membered saturated heterocyclic group" means a monovalent group of "4 to 6-membered saturated heterocycle" among the above-mentioned "4 to 10-membered saturated heterocycle". Preferred examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

The "4- to 6-membered nitrogen-containing saturated heterocyclic group" means a monovalent saturated heterocyclic group containing at least one nitrogen atom in the above-mentioned "4- to 6-membered saturated heterocycle". Preferably, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like can be mentioned.

The "C _6-10 aromatic carbocycle" means a monocyclic or bicyclic aromatic hydrocarbon ring having 6 to 10 carbon atoms. Bicyclic aromatic hydrocarbon rings include those obtained by condensing a monocyclic aromatic carbocycle and a monocyclic saturated carbocycle as exemplified by 2,3-dihydro-1H-indene. Specific examples of the "C _6-10 aromatic carbocycle" include benzene, 1-naphthalene, 2-naphthalene and the like, and benzene is preferable.

A "5- to 10-membered aromatic heterocycle" is from 5 to 10 atoms, including the same or different 1-3 heteroatoms, selected from the group consisting of oxygen, nitrogen and sulfur atoms. It means a monocyclic or bicyclic aromatic heterocycle, and the ring may be appropriately substituted with an oxo group. Bicyclic aromatic heterocycles include those obtained by condensing monocyclic aromatic carbocycles and monocyclic saturated heterocycles as exemplified by Chroman, and 5,6,7,8-tetrahydroquinoline. It includes a condensate of a monocyclic aromatic heterocycle and a monocyclic saturated carbocycle as exemplified. Examples of the "5 to 10-membered aromatic heterocycle" include a monocyclic or bicyclic "5 to 9-membered aromatic heterocycle", and more preferably a monocyclic "5 to 8 member". The aromatic heterocycle of the above is mentioned, and more preferably, the monocyclic "5- or 6-membered aromatic heterocycle" is mentioned. Specific examples of the "5- to 10-membered aromatic heterocycle" include, for example, pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isooxazole, oxal. Diazol, thiazazole, triazole, tetrazole, quinoline, isoquinoline, quinoxalin, naphthylidine, quinazoline, benzofuran, benzothiophene, indol, benzoxazole, benzoisoxazole, benzothiazole, 1H-indazole, 2H-indazole, benzoimidazole, benzoxazil Azol, benzothiaziazole, indidine, benzofurazine, thienopyrimidine, pyrazolopyridine, imidazolepyridine, imidazolopyrazine, imidazolopyrazine, imidazolopyrazine, pyrazolopyrimidine, pyrazolopyrazine, triazolopyridine, triazolopyrimidine, triazolopyrazine, thieno Thiophen, imidazoliazole, chromane, dihydrobenzoxazine, dihydropyranopyridine, 2,3-dihydrobenzofuran, 1,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-inden, 2, 3-Dihydro-1H-inden-1-one, 2,3-dihydro-1H-pyrrolopyridine, 2,3-dihydro-1H-pyrrolopyridine-1-one, 1,2-dihydro-3H-pyrrolopyridine-3 -On, tetrahydroquinolin, 5,6,7,8-tetrahydroimidazolipyrazine and the like.

Examples of the "5-membered aromatic heterocycle" include thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole and the like. Preferred are thiophene, thiazole or isothiazole.

Examples of the "6-membered aromatic heterocycle" include pyridine, pyridazine, pyrimidine, pyrazine and the like. Pyridine is preferred.

The "5- or 6-membered aromatic heterocyclic group" means a monovalent group of the above-mentioned "5-membered aromatic heterocycle" or "6-membered aromatic heterocycle".

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^a , R ^b , R ^c , R ^d , ^Re , R ^f , Ring A, Ring B, X, W ¹ , W ² , Preferred embodiments of W ³ , W ⁴ and W ⁵ are illustrated below, but the technical scope of the present invention is not limited to the preferred embodiments shown below, and these may be combined as appropriate.

Preferably R ¹ and R ² , respectively, are 1 to 5 substitutions independently selected from the group consisting of a hydrogen atom or a C _1-4 alkyl (the alkyl is a fluorine atom and a C _1-4 alkoxy). It may be substituted with a group). More preferably, R ¹ and R ² are each independently a hydrogen atom, methyl, ethyl, methoxymethyl or trifluoromethyl. More preferably, it is a hydrogen atom or methyl. Particularly preferably, R ¹ is methyl and R ² is a hydrogen atom.

Preferably as R ³ and R ⁴ , each independently has a hydrogen atom, a halogen atom, a C _1-4 alkyl or a C _1-4 alkoxy (the alkyl and the alkoxy each independently have 1 to 5 fluorines. It may be replaced with an atom). More preferably, R ³ and R ⁴ are independently hydrogen atom, fluorine atom, chlorine atom, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy. More preferably, it is a hydrogen atom, a fluorine atom, a chlorine atom, methyl or trifluoromethyl. Particularly preferred is a hydrogen atom or trifluoromethyl.

Preferably as R ⁵ and R ⁶ , each independently has a hydrogen atom, a halogen atom, a C _1-4 alkyl, and a C _1-4 alkoxy (the alkyl and the alkoxy each independently have 1 to 5 fluorines. It may be substituted with an atom) or -NR ^a R ^b . More preferably, R ⁵ and R ⁶ are independently hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, propyl, methoxy or -NR ^a R ^b . More preferably, it is a hydrogen atom, a fluorine atom, methyl, ethyl or -NH ₂ . Particularly preferred are a hydrogen atom, a fluorine atom or methyl.

The R ^a and R ^b are preferably independent hydrogen atoms or C _1-4 alkyl (the alkyl may be substituted with 1 to 5 fluorine atoms). More preferably, ^Ra and R ^b are each independently a hydrogen atom or methyl. More preferably, both are hydrogen atoms.

The R ^c is preferably C _1-4 alkyl, even if the alkyl is substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy. Good). More preferably, it is methyl or ethyl. More preferably, it is methyl.

Preferred examples of R ^d include a hydrogen atom or C _1-4 alkyl. More preferably, it is a hydrogen atom or methyl.

Preferably the R ^e is hydrogen _atom, a _{C 1-4} alkyl or halogen atoms. More preferably, it is a hydrogen atom or a fluorine atom. As one aspect of R ^e, include hydrogen atom, in another embodiment, it includes a fluorine atom.

Preferred examples of R ^f include a hydrogen atom and methyl. More preferably, it is a hydrogen atom.

Benzene, pyridine, thiophene, 1,3-benzodioxole, benzothiophene, benzofuran or quinoline are preferable as the ring A. More preferably, it is benzene, thiophene, pyridine or 1,3-benzodioxole. More preferably, it is benzene or pyridine. Particularly preferred is benzene.

When X is a nitrogen atom, the ring B is preferably imidazopyridine, imidazopyrimidine, imidazopyridazine, indazole, pyrazolopyridine, pyrazolopyrimidine, quinoline, quinoxaline or tetrahydroquinoline. More preferably, it is any one substituent selected from the group consisting of substituents represented by the formulas (1a-1) to (1a-8), wherein W ¹ , W ² and W ³ are. each independently a nitrogen atom or CH (with the proviso ^that at least two or more W 1, ^{W 2} and ^{W 3} are CH), ^{W 4} and ^{W 5} are each independently a nitrogen atom or a CH it is (provided that at least one of W ⁴ and W ⁵ is a nitrogen atom). More preferably, it is any one substituent selected from the group consisting of substituents represented by the formulas (1a-1) to (1a-8), wherein W ¹ , W ² and W ³ are. CH, one of W ⁴ and W ⁵ is CH and the other is a nitrogen atom. Particularly preferred is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1a-1) to (1a-3), wherein W ¹ , W ² and W ³ are. , it is CH, ^{W 4} and ^{W 5} is any one is CH, the other is a nitrogen atom.

When X is CR ^e , the ring B is preferably pyridine, imidazopyridine, imidazopyrimidine, imidazopyridazine, indazole, triazolopyridine, pyrazolopyridine, pyrazolopyrimidine, quinoline or quinoxalin. More preferably, it is any one substituent selected from the group consisting of substituents represented by the formulas (1b-1) to (1b-10), wherein W ¹ , W ² and W ³ are. each independently a nitrogen atom or CH (with the proviso ^that at least two or more W 1, ^{W 2} and ^{W 3} are CH), ^{W 4} and ^{W 5} are each independently a nitrogen atom or a CH it is (provided that at least one of W ⁴ and W ⁵ is a nitrogen atom). More preferably, it is any one substituent selected from the group consisting of substituents represented by the formulas (1b-1) to (1b-9), wherein W ¹ , W ² and W ³ are. CH, one of W ⁴ and W ⁵ is CH and the other is a nitrogen atom. Particularly preferred is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1b-1) to (1b-3), wherein W ¹ , W ² and W ³ are. It is CH. Further, one embodiment of the ring B is a substituent represented by the formula (1b-3), and W ¹ , W ² and W ³ are independently nitrogen atoms or CH (however, respectively). At least two or more of W ¹ , W ² and W ³ are CH).

Preferably W ¹ , W ² and W ³ are each independently nitrogen atom or CH (however, at least two or more of W ¹ , W ² and W ³ are CH). One mode of W ¹ , W ² and W ³ is all CH, and another mode is a nitrogen atom or CH independently of each other (however, either W ¹ , W ^{2 or} W ³ ). One is the nitrogen atom).

Examples of the compound represented by the formula (1) include a compound represented by the formula (1a) and a compound represented by the formula (1b). One embodiment of the compound represented by the formula (1) includes a compound represented by the formula (1a), and another embodiment includes a compound represented by the formula (1b).

［式中、
Ｗ^１、Ｗ^２及びＷ^３は、各々独立して、窒素原子又はＣＨであり（ただし、Ｗ^１、Ｗ^２及びＷ^３の少なくとも２つ以上はＣＨである）、
Ｗ^４及びＷ^５は、各々独立して、窒素原子又はＣＨである（ただし、Ｗ^４及びＷ^５の少なくともいずれか一つは窒素原子である）］
からなる群から選択されるいずれか一つの置換基である、
式（１ａ）で表される化合物、又はその製薬学的に許容される塩。 One embodiment of the compound represented by the formula (1a) includes the following (A).
(A)
R ¹ and R ² are each independently a hydrogen atom or methyl;
R ³ and R ⁴ are independently substituted with hydrogen atom, halogen atom, cyano, 1 to 5 halogen atoms of the same or different C _1-4 alkyl, 1 to 5 of the same or different. C _1-4 alkoxy, which may be substituted with a halogen atom of, or C _3-6 cycloalkoxy (the cycloalkoxy is selected from the group consisting of C _1-4 alkyl and halogen atoms, the same or different 1 to It may be substituted with 5 substituents);
R ⁵ and R ⁶ are independently substituted with hydrogen atom, halogen atom, cyano, hydroxy, 1 to 5 halogen atoms which are the same or different, C _1-4 alkyl, or -NR ^a R. ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independently replaced with a hydrogen atom or 1 to 5 halogen atoms which are the same or different. _May be C _1-4 alkyl;
Ring A is benzene, pyridine or thiophene;
Ring B is from the following formula (1a-1) to (1a-8):

[During the ceremony,
W ¹ , W ² and W ³ are independently nitrogen atoms or CH (provided that at least two or more of W ¹ , W ² and W ³ are CH).
W ⁴ and W ⁵ are independently nitrogen atoms or CH (provided that at least one of W ⁴ and W ⁵ is a nitrogen atom)]
Any one of the substituents selected from the group consisting of,
A compound represented by the formula (1a) or a pharmaceutically acceptable salt thereof.

［式中、
Ｗ^１、Ｗ^２及びＷ^３は、各々独立して、窒素原子又はＣＨであり（ただし、Ｗ^１、Ｗ^２及びＷ^３の少なくとも２つ以上はＣＨである）、
Ｗ^４及びＷ^５は、各々独立して、窒素原子又はＣＨである（ただし、Ｗ^４及びＷ^５の少なくともいずれか一つは窒素原子である）］
で表される置換基から選択されるいずれか一つの置換基である、
式（１ｂ）で表される化合物、又はその製薬学的に許容される塩。 One embodiment of the compound represented by the formula (1b) includes the following (B).
(B)
R ¹ and R ² are each independently a hydrogen atom or methyl;
R ³ and R ⁴ are independently substituted with hydrogen atom, halogen atom, cyano, 1 to 5 halogen atoms of the same or different C _1-4 alkyl, 1 to 5 of the same or different. C _1-4 alkoxy, which may be substituted with a halogen atom of, or C _3-6 cycloalkoxy (the cycloalkoxy is selected from the group consisting of C _1-4 alkyl and halogen atoms, the same or different 1 to It may be substituted with 5 substituents);
R ⁵ and R ⁶ are independently substituted with hydrogen atom, halogen atom, cyano, hydroxy, 1 to 5 halogen atoms which are the same or different, C _1-4 alkyl, or -NR ^a R. ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independently replaced with a hydrogen atom or 1 to 5 halogen atoms which are the same or different. _May be C _1-4 alkyl;
^Re is a hydrogen atom or a fluorine atom;
Ring A is benzene, pyridine or thiophene;
Ring B is from the following formulas (1b-1) to (1b-3) and (1b-5) to (1b-9):

[During the ceremony,
W ¹ , W ² and W ³ are independently nitrogen atoms or CH (provided that at least two or more of W ¹ , W ² and W ³ are CH).
W ⁴ and W ⁵ are independently nitrogen atoms or CH (provided that at least one of W ⁴ and W ⁵ is a nitrogen atom)]
Any one of the substituents selected from the substituents represented by,
A compound represented by the formula (1b) or a pharmaceutically acceptable salt thereof.

で表される置換基である、
式（１ｂ）で表される化合物、又はその製薬学的に許容される塩。 Another embodiment of the compound represented by the formula (1b) includes the following (C).
(C)
R ¹ and R ² are each independently a hydrogen atom or methyl;
R ³ and R ⁴ are independently substituted with hydrogen atom, halogen atom, cyano, 1 to 5 halogen atoms of the same or different C _1-4 alkyl, 1 to 5 of the same or different. C _1-4 alkoxy, which may be substituted with a halogen atom of, or C _3-6 cycloalkoxy (the cycloalkoxy is selected from the group consisting of C _1-4 alkyl and halogen atoms, the same or different 1 to It may be substituted with 5 substituents);
R ⁵ and R ⁶ are independently substituted with hydrogen atom, halogen atom, cyano, hydroxy, 1 to 5 halogen atoms which are the same or different, C _1-4 alkyl, or -NR ^a R. ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independently replaced with a hydrogen atom or 1 to 5 halogen atoms which are the same or different. _May be C _1-4 alkyl;
^Re is a hydrogen atom or a fluorine atom;
Ring A is benzene, pyridine or thiophene;
Ring B is the following formula (1b-4) or (1b-10):

It is a substituent represented by,
A compound represented by the formula (1b) or a pharmaceutically acceptable salt thereof.

Examples of the "pharmaceutically acceptable salt" include acid addition salts, base addition salts and amino acid addition salts. For example, as the acid addition salt, an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, phthalate, etc. Fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonic acid Examples thereof include organic acid salts such as salts and camphor sulfonates. Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt and aluminum salt, or trimethylamine, triethylamine, pyridine, picoline, 2,6-rutidine, ethanolamine, diethanolamine and tri. Examples thereof include organic base salts such as ethanolamine, trimethylamine, tris (hydroxymethyl) methylamine, tert-butylamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylamine and the like. Examples of the amino acid salt include amino acid salts with basic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid, or acidic amino acids.

Suitable salts of raw material compounds and intermediates and acceptable salts as raw materials for pharmaceuticals are conventional non-toxic salts, such as organic acid salts (eg, acetates, trifluoroacetates, maleates, fumaric acids). Salts, citrates, tartrates, methanesulfonates, benzenesulfonates, formates or para-toluenesulfonates, etc.) and inorganic acid salts (eg hydrochlorides, hydrobromide, hydroiodide) , Sulfates, nitrates or phosphates, etc.), salts with amino acids (eg, arginine, aspartic acid or glutamate, etc.), alkali metal salts (eg, sodium or potassium salts, etc.) and alkaline earth metals Metal salts such as salts (eg calcium salt or magnesium salt), ammonium salts, or organic base salts (eg trimethylamine salt, triethylamine salt, pyridine salt, picolin salt, dicyclohexylamine salt or N, N'-dibenzylethylenediamine salt, etc. ), Etc., can be appropriately selected by those skilled in the art.

When it is desired to obtain a salt of the compound of the present invention, when the compound of the present invention is obtained in the form of a salt, the salt may be purified as it is, and when it is obtained in the free form, the free form is appropriately organic. It may be dissolved or suspended in a solvent, and an acid or a base may be added to form a salt by a usual method.

The present invention includes a compound represented by the formula (1), or a pharmaceutically acceptable salt or co-crystal thereof. Further, since the compound of the present invention may exist in the form of a hydrate and / or a solvate with various solvents (for example, an ethanol solvate), these hydrates and / or solvates may also be present. Included in the compounds of the present invention.

Some of the compounds of the invention are optical isomers based on the chiral center, atropisomers based on axial or planar chirality caused by the constraint of intramolecular rotation, other steric isomers, tautomers, and geometry. All possible isomers and mixtures thereof, including these, are included in the scope of the invention, although some isomers and the like may be present. Furthermore, in addition to the above isomers, the present invention also includes crystalline forms of all modes, as well as mixtures thereof.

In particular, the optical isomer and the atrop isomer can be obtained as a mixture having a different three-dimensional structure such as a racemate, or as an optically active substance when a starting material or an intermediate for optical activity is used. If necessary, at the appropriate stage of the following production method, the corresponding raw material, intermediate or final racemate is physically separated by a known separation method such as a method using an optically active column or a fractional crystallization method. It can be divided into their optical racemics either or chemically. Specifically, for example, in the diastereomer method, two types of diastereomers are formed from a racemate by a reaction using an optical resolution agent. Since these different diastereomers generally have different physical properties, they can be separated by a known method such as fractional crystallization.

In addition to the above isomers, the compound of the present invention includes a prodrug of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof. Furthermore, the compounds of the invention are the compounds obtained by converting some or all of the atoms constituting the compound of the formula (1) in isotope (e.g., deuterated hydrogen ^{(2 H,} 3 ^H) and compound Also includes compounds in which ¹² C is converted to ¹⁴ C).

In the present specification, the term "prodrug of a compound represented by the formula (1)" is a compound that is converted into a compound of the formula (1) by a reaction with an enzyme, gastric acid, etc. under physiological conditions in vivo. It means a compound that enzymatically undergoes oxidation, reduction, hydrolysis, etc. to change to a compound of formula (1), or a compound that undergoes hydrolysis due to a pH change due to gastric acid or the like to change to a compound of formula (1).

Method for Producing Compound of the Present Invention The method for producing a compound of the present invention will be described below with reference to examples, but the present invention is not limited thereto.
The compound of the present invention can be produced, for example, by the methods shown in the following production methods 1 to 13. These production methods can be appropriately improved based on the knowledge of those who are familiar with synthetic organic chemistry. As the compound used as a raw material, a salt thereof or a compound having a protected functional group may be used, if necessary.

In the following production method, even when the use of protecting groups is not specifically specified, when any functional group other than the reaction site changes depending on the reaction conditions, or when it is inappropriate to carry out post-reaction treatment. The desired product can be obtained by protecting other than the reaction point as necessary and deprotecting after the reaction is completed or after a series of reactions are carried out. Protecting groups include TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, Inc., New (19), Inc., New. The usual protecting groups that have been used can be used, and the introduction and removal of the protecting groups can be carried out by a method commonly used in synthetic organic chemistry (for example, the method described in the above document) or a method similar thereto. Specifically, examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like, and examples of the hydroxy protecting group include trialkylsilyl, acetyl, benzyl and the like. Can be done.

The starting materials and intermediates in each of the following production methods can be purchased as commercial products, or can also be obtained by synthesizing a commercially available compound or a known compound by a method known to those skilled in the art or a method similar thereto. Further, as the starting material and the intermediate, if necessary, salts thereof or those in which functional groups are protected may be used.

The intermediate and the target compound in the following production method are appropriately converted in their functional groups, and in particular, various side chains are extended from amino, hydroxyl group, carbonyl, halogen atom, etc., and if necessary at that time. By performing the above protection and deprotection, it can be converted into another compound contained in the present invention. Functional group conversion and side chain extension are commonly performed by conventional methods (eg, RC Larock, "Comprehensive Organic Transitions", 2nd Ed., John Wiley and Sons Inc., NY, NY). It can be performed by the method described above) or a method similar thereto.

The inert solvent in the following production method means a solvent that does not react with the raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction.

（式中、Ｘは項１と同義であり、Ｒ^７はメチル又はエチルを表し、Ｙは水素原子、ヨウ素原子、臭素原子又は塩素原子を表す） Manufacturing method 1
Compound (3) is produced, for example, by the method shown below.

(In the formula, X is synonymous with item 1, R ⁷ represents methyl or ethyl, and Y represents hydrogen atom, iodine atom, bromine atom or chlorine atom).

Step 1: Compound (2) is subjected to a known method (eg, RC Larock, "Comprehensive Organic Transfers", 2nd Ed., John Wiley and Sons Inc., New York (1999), etc.). The compound (3) can be produced by esterification. Here, as the compound (2), a commercially available compound or a compound synthesized by a known method can be used.

（式中、Ｒ^１、Ｒ^２及びＸは項１と同義であり、Ｒ^７及びＹは前記と同義であり、ＰＧは保護基（ｔｅｒｔ−ブトキシカルボニル基、ベンジルオキシカルボニル基等）を表し、ＬＧは脱離基（ヨウ素原子、臭素原子、塩素原子、置換スルホニルオキシ基（例えば、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基等）を表す） Manufacturing method 2
Compound (6) is produced, for example, by the method shown below.

(In the formula, R ¹ , R ² and X are synonymous with Item 1, R ⁷ and Y are synonymous with the above, and PG represents a protecting group (tert-butoxycarbonyl group, benzyloxycarbonyl group, etc.). LG represents a leaving group (iodine atom, bromine atom, chlorine atom, substituted sulfonyloxy group (for example, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, etc.))

Step 2: Compound (6) can be produced by a Mitsunobu reaction between compound (3) and compound (4) by a conventional method in a suitable inert solvent. Specifically, it is carried out in the presence of triphenylphosphine or tributylphosphine and a Mitsunobu reaction reagent such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or N, N, N', N'-tetramethylazodicarboxamide, or , Cyamethylenephosphoran reagent can be used. The reaction temperature in this step is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days. Here, as the compounds (3) and (4), a commercially available compound or a compound synthesized by a known method can be used.
Specific examples of the inert solvent used in this step include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether-based solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane. Solvents; and mixed solvents thereof.

Step 3: Compound (6) can also be produced by reacting compound (3) and compound (5) in a suitable inert solvent by a conventional method in the presence of a suitable base. The reaction may be carried out in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature in this step is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days. Here, as the compounds (3) and (5), a commercially available compound or a compound synthesized by a known method can be used.
Specific examples of the base used in this step include organic bases such as triethylamine, N, N-diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, and dipotassium phosphate. Inorganic bases such as potassium, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; sodium methoxyde, potassium tert -Metal alkoxides such as butoxide can be mentioned.
Specific examples of the phase transfer catalyst used in this step include tetrabutylammonium hydrogen sulfate and the like.
Specific examples of the inert solvent used in this step include halogenated hydrocarbons such as chloroform and dichloromethane; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran, diethyl ether, 1 , 4-Dioxane, 1,2-Dimethoxyethane and other ether solvents; Lower alcohols such as methanol, ethanol and 2-propanol; Aprotic such as acetonitrile, N, N-dimethylformamide and N-methyl-2-pyrrolidone. Polar solvents; water; and mixed solvents thereof can be mentioned.

（式中、環Ａ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＸは項１と同義であり、ＰＧ、Ｒ^７及びＹは前記と同義であり、Ｘ^１は、ヨウ素原子、臭素原子又は塩素原子を表す） Manufacturing method 3
Compound (9) is produced, for example, by the method shown below.

(In the formula, rings A, R ¹ , R ² , R ³ , R ⁴ and X are synonymous with item 1, PG, R ⁷ and Y are synonymous with the above, and X ¹ is an iodine atom and a bromine atom. Or represents a chlorine atom)

Step 4: Compound (7) is prepared by various methods (TW Greene and PG) known to those skilled in the art for protecting the amine protecting group PG of compound (6) by a conventional method in a suitable inert solvent. After removal using M. Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)), in the presence of a suitable base or acid. It can be manufactured by allowing it to be produced. In this step, deprotection and cyclization reaction can be simultaneously carried out in the same system in the presence of a suitable base or acid by a conventional method in a suitable inert solvent. The reaction temperature in this step is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days.
Specific examples of the base used in this step include organic bases such as triethylamine and pyridine; inorganic bases such as cesium carbonate, potassium carbonate and sodium carbonate; and metal alkoxides such as potassium tert-butoxide.
Specific examples of the acid used in this step include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid and trifluoroacetic acid, and the like.
Specific examples of the inert solvent used in this step include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2. Ether-based solvents such as -dimethoxyethane; lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and N-methyl-2-pyrrolidone; organic acids such as acetic acid ; And a mixed solvent thereof.

Step 5: Compound (9) is produced by subjecting compound (7) and compound (8) to a coupling reaction in the presence of a suitable transition metal catalyst and base in a suitable inert solvent by a conventional method. be able to. The reaction may be carried out in the presence of a suitable ligand, if necessary. The reaction temperature in this step is usually in the range from room temperature to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days. Here, as the compound (8), a commercially available compound or a compound synthesized by a known method can be used.
Specific examples of the transition metal catalyst used in this step include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0), and iodide. Examples thereof include copper (I) and copper (II) oxide.
Specific examples of the ligand used in this step include, for example, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl, 4,5-bis (diphenylphos). Fino) -9,9-dimethylxanthene, N, N'-dimethylethylenediamine and the like can be mentioned.
Specific examples of the base used in this step include metal alkoxides such as sodium tert-butoxide and inorganic bases such as tripotassium phosphate and potassium carbonate.
Specific examples of the inert solvent used in this step include aromatic hydrocarbons such as benzene and toluene; ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane; N. , N-dimethylformamide, N, N-dimethylacetamide and other aprotic polar solvents; and mixed solvents thereof.

（式中、環Ａ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＸは項１と同義であり、Ｒ^７、Ｙ及びＸ^１は前記と同義である） Manufacturing method 4
Compound (9) is also produced, for example, by the method shown below.

(In the equation, rings A, R ¹ , R ² , R ³ , R ⁴ and X are synonymous with item 1, and R ⁷ , Y and X ¹ are synonymous with the above).

Step 6: Compound (13) can be produced by reacting compound (10) with compound (11) in a suitable inert solvent according to a conventional method. The reaction may be carried out in the presence of a suitable additive, base or acid, and further in the presence of a suitable phase transfer catalyst, if necessary. The reaction temperature in this step is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time of this step is from 1 minute to 10 days. Here, as the compounds (10) and (11), a commercially available compound or a compound synthesized by a known method can be used.
Specific examples of the additive used in this step include lithium bromide and the like.
Specific examples of the base used in this step include organic bases such as triethylamine and pyridine; and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.
Specific examples of the acid used in this step include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as p-toluenesulfonic acid and trifluoroacetic acid, and the like.
Specific examples of the inert solvent used in this step include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran, diethyl ether, 1,4-dioxane, 1, 2 and so on. Ether-based solvents such as -dimethoxyethane; lower alcohols such as methanol, ethanol and 2-propanol, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and N-methyl-2-pyrrolidone; and mixed solvents thereof. Can be mentioned.

Step 7: Compound (13) is prepared by subjecting compound (8) and compound (12) to a coupling reaction in the presence of a suitable transition metal catalyst and base in a suitable inert solvent or under solvent-free conditions. Can also be manufactured. The reaction temperature in this step is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days. Here, as the compound (8) and the compound (12), a commercially available compound or a compound synthesized by a known method can be used.
Specific examples of the transition metal catalyst used in this step include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0), and copper chloride. (I), copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) oxide and the like can be mentioned.
Specific examples of the base used in this step include organic bases such as triethylamine and pyridine; and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide and sodium hydroxide.
Specific examples of the inert solvent used in this step include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran, diethyl ether, 1,4-dioxane, 1, 2 and so on. Ether-based solvents such as −dimethoxyethane; lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone and dimethylsulfoxide; water; And a mixed solvent thereof.

Step 8: Compound (14) can be produced by the same method as in Step 2 using compound (3) and compound (13).

Step 9: Compound (9) can be produced by subjecting compound (14) to a cyclization reaction in the presence of a suitable base or acid according to a conventional method in a suitable inert solvent. The reaction temperature in this step is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days.
Specific examples of the base used in this step include organic bases such as triethylamine and pyridine; inorganic bases such as potassium carbonate and sodium carbonate; and metal alkoxides such as potassium tert-butoxide.
Specific examples of the acid used in this step include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as p-toluenesulfonic acid monohydrate, acetic acid and trifluoroacetic acid.
Specific examples of the inert solvent used in this step include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; tetrahydrofuran, diethyl ether, 1,4-dioxane, 1, 2 and so on. Ether-based solvents such as -dimethoxyethane; lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and N-methyl-2-pyrrolidone; and mixed solvents thereof. Can be mentioned.

（式中、環Ａ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＸは項１と同義であり、Ｘ^１は前記と同義である） Manufacturing method 5
Compound (16) is produced, for example, by the method shown below.

(In the equation, rings A, R ¹ , R ² , R ³ , R ⁴ and X are synonymous with item 1, and X ¹ is synonymous with the above).

Step 10: Compound (16) can be produced by reacting compound (15) with a suitable halogenating agent according to a conventional method in a suitable inert solvent. Here, the compound (15) is a compound (9) in which Y is a hydrogen atom. The reaction may be carried out in the presence of a suitable additive or acid, if necessary. The reaction temperature in this step is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days.
Specific examples of the halogenating agent used in this step include N-iodosuccinate imide, N-bromosuccinimide, N-chlorosuccinate imide, iodine, iodine monochloride, bromine, 1,3-diiodo-5, and so on. 5-Dimethyl hydantin and the like can be mentioned.
Specific examples of the additive used in this step include cerium (IV) nitrate ammonium, sodium acetate, iron and the like.
Specific examples of the acid used in this step include hydrochloric acid, sulfuric acid, acetic acid, paratoluenesulfonic acid, pyridinium paratoluenesulfonate and the like.
Specific examples of the inert solvent used in this step include halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride; aprotic polar solvents such as N, N-dimethylformamide and ethyl acetate; and acetic acid and the like. Protic and aprotic solvents; and mixed solvents thereof.

（式中、環Ａ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＸは項１と同義であり、Ｘ^１は前記と同義である） Manufacturing method 6
Compound (16) is also produced, for example, by the method shown below.

(In the equation, rings A, R ¹ , R ² , R ³ , R ⁴ and X are synonymous with item 1, and X ¹ is synonymous with the above).

Step 11: Compound (18) can be produced by the same method as in Step 10 using compound (17). Here, the compound (17) is a compound (7) in which Y is a hydrogen atom.

Step 12: Compound (16) can be produced by using compound (18) and compound (8) in the same manner as in Step 5.

（式中、Ｒ^１及びＲ^２は項１と同義であり、Ｘ^１は前記と同義であり、Ｘ^２はハロゲン原子を表す） Manufacturing method 7
Compound (20) is produced, for example, by the method shown below.

(In the equation, R ¹ and R ² are synonymous with item 1, X ¹ is synonymous with the above, and X ² represents a halogen atom).

Step 13: Compound (20) can be produced by reacting compound (19) with a halogenating agent by a conventional method in a suitable inert solvent. Here, the compound (19) is the compound (18) in which X is CH. The reaction may be carried out in the presence of additives or acids, if necessary. The reaction temperature usually ranges from −20 ° C. to the boiling point of the solvent used. The reaction time is from 1 minute to 5 days.
Specific examples of the halogenating agent include 1-fluoro-4-methyl-1,4-diazoniabicyclo [2,2,2] octanebis (tetrafluoroborate) and 1-fluoropyridinium trifluoromethanesulfonate. , N-fluorobenzenesulfonimide, N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, iodine, iodine monochloride, bromine, 1,3-diiodo-5,5-dimethylhydantoin and the like. ..
Specific examples of the additive include, for example, cerium (IV) nitrate ammonium, sodium acetate, iron and the like.
Specific examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, paratoluenesulfonic acid, pyridinium paratoluenesulfonate and the like.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and ethyl acetate; and protic polarities such as acetic acid. Solvents; and mixed solvents thereof.

（式中、環Ａ、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は項１と同義であり、Ｘ^１及びＸ^２は前記と同義である） Manufacturing method 8
Compound (22) is produced, for example, by the method shown below.

(In the equation, rings A, R ¹ , R ² , R ³ and R ⁴ are synonymous with item 1, and X ¹ and X ² are synonymous with the above).

Step 14: Compound (22) can be produced using compound (21) by the same method as in Step 13. Here, the compound (21) is the compound (16) in which X is CH.

（式中、環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６及びＸは項１と同義であり、Ｘ^１は前記と同義であり、Ｒ^Ａはボロン酸、ボロン酸エステル又はトリアルキルスズを表す） Manufacturing method 9
Compound (1) is produced, for example, by the method shown below.

(In the formula, ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are synonymous with item 1, X ¹ is synonymous with the above, and ^RA is boron. Represents acid, boronic acid ester or trialkyltin)

Step 15: Compound (1) is produced by subjecting compound (16) and compound (23) to a coupling reaction in the presence of a suitable transition metal catalyst and base according to a conventional method in a suitable inert solvent. be able to. This step can also be performed in the coexistence of a suitable ligand, if necessary. The reaction temperature in this step is usually from room temperature to the boiling point of the solvent used, preferably from 50 ° C to 150 ° C. The reaction time of this step is usually 1 minute to 5 days, preferably 1 minute to 2 days. This step may be performed under microwave irradiation. Here, as the compound (23), a commercially available compound or a compound synthesized by a known method can be used.
Specific examples of the transition metal catalyst used in this step include tetrakis (triphenylphosphine) palladium (0), palladium acetate (II), palladium chloride (II), and tris (dibenzylideneacetone) dipalladium (0). , Dichlorobis (triphenylphosphine) palladium (II), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct, dichloro [1,1'-bis (diphenylphosphino) ferrocene] Palladium (II), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) and the like can be mentioned.
Specific examples of the base used in this step include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate and the like.
Specific examples of the ligand used in this step include, for example, triphenylphosphine, tri-tert-butylphosphine, 2-dicyclohexylphosphine-2', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2'. , 4', 6'-triisopropylbiphenyl and the like.
Specific examples of the inert solvent used in this step include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethylformamide, N, N-. Examples thereof include aprotic polar solvents such as dimethylacetamide, N-methyl-2-pyrrolidone and acetonitrile; aromatic hydrocarbons such as benzene and toluene; water; and mixed solvents thereof.

（式中、環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６及びＸは項１と同義であり、Ｘ^１及びＲ^Ａは前記と同義である） Manufacturing method 10
Compound (1) is also produced, for example, by the method shown below.

(In the equation, ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are synonymous with item 1, and X ¹ and ^RA are synonymous with the above).

Step 16: Compound (24) can be produced by using compound (18) and compound (23) in the same manner as in step 15.

Step 17: Compound (1) can be produced by using compound (24) and compound (8) in the same manner as in Step 5.

（式中、環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６及びＸは項１と同義であり、Ｘ^１は前記と同義であり、Ｒ^Ｂはボロン酸エステルを表し、Ｒ^８はＣ_１−４アルキルを表す） Manufacturing method 11
Compound (1) is also produced, for example, by the method shown below.

(Wherein ring A, ring ^{B, R 1, R 2,} R 3, R 4, R 5, R 6 and X have the same meanings as defined in claim 1, ^{X 1} are as defined above, ^{R B} is boron Represents an acid ester, R ⁸ represents C _1-4 alkyl)

Step 18: Compound (26) can be produced by reacting compound (16) with compound (25) or trialkyl borate in the presence of a suitable base according to a conventional method in a suitable inert solvent. .. The reaction temperature in this step is usually from −78 ° C. to the boiling point of the solvent used, preferably from −78 ° C. to room temperature. The reaction time of this step is usually 1 minute to 5 days, preferably 1 minute to 2 days. Here, as the compound (25), a commercially available compound or a compound synthesized by a known method can be used.
Specific examples of the base used in this step include, for example, isopropylmagnesium chloride-lithium chloride complex, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium tetramethylpiperidide, and lithium hexa. Examples thereof include methyldisilazide, sodium hexamethyldisiradide, potassium hexamethyldisiradide and the like.
Specific examples of the inert solvent used in this step include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane; n-hexane, n-heptane, cyclohexane and the like. Saturated hydrocarbons; and mixed solvents thereof.
Alternatively, compound (26) is prepared by conventionally in a suitable inert solvent with compound (16) and a boron reagent such as bis (pinacolato) diborane in the presence of a suitable transition metal catalyst and base. It can also be produced by subjecting it to a coupling reaction. The reaction may be carried out in the presence of a suitable ligand, if necessary. The reaction temperature in this step is usually in the range from room temperature to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days.
Specific examples of the transition metal catalyst used in this step include tetrakis (triphenylphosphine) palladium (0), palladium acetate (II), palladium chloride (II), and tris (dibenzylideneacetone) dipalladium (0). , Dichlorobis (triphenylphosphine) palladium (II), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct, dichloro [1,1'-bis (diphenylphosphino) ferrocene] Examples thereof include palladium (II), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II), and bis- (tri-tert-butylphosphine) palladium (0).
Specific examples of the ligand used in this step include 1,1'-bis (diphenylphosphino) ferrocene and the like.
Specific examples of the base used in this step include acetates such as potassium acetate and sodium acetate; metal alkoxides such as sodium tert-butoxide; and inorganic bases such as tripotassium phosphate and potassium carbonate.
Specific examples of the inert solvent used in this step include aromatic hydrocarbons such as benzene and toluene; ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane; N. , N-dimethylformamide, N, N-dimethylacetamide and other aprotic polar solvents; and mixed solvents thereof.

Step 19: Compound (1) can be produced by using compound (26) and compound (27) in the same manner as in step 15. Here, as the compound (27), a commercially available compound or a compound synthesized by a known method can be used.

（式中、環Ａ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４及びＲ^６は項１と同義であり、Ｘ^２は前記と同義である） Manufacturing method 12
When X is CH and ring B is imidazopyridine in compound (1), compound (29) is also produced, for example, by the method shown below.

(In the equation, rings A, R ¹ , R ² , R ³ , R ⁴ and R ⁶ are synonymous with item 1, and X ² is synonymous with the above).

Step 20: Compound (29) can be produced by the same method as in Step 13 using compound (28) produced according to the above production method.

（式中、環Ａ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^６は項１と同義であり、Ｘ^２は前記と同義であり、Ｒ^９はビニル又はアリルを表す） Manufacturing method 13
When X is CH and ring B is imidazopyridine in compound (1), compound (31) is also produced, for example, by the method shown below.

(In the formula, rings A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are synonymous with item 1, X ² is synonymous with the above, and R ⁹ represents vinyl or allyl).

Step 21: Compound (31) is produced by coupling compound (29) with a boronic acid reagent or an alkylzinc reagent in the presence of a suitable transition metal catalyst by a conventional method in a suitable inert solvent. can do. This step can also be carried out in the presence of a suitable base and / or a suitable ligand, if desired. The reaction temperature in this step is usually from room temperature to the boiling point of the solvent used. The reaction time of this step is usually 1 minute to 5 days, preferably 1 minute to 2 days. This step may be performed under microwave irradiation.
Specific examples of the boronic acid used in this step are not limited to these, and examples thereof include methylboronic acid, ethylboronic acid, and trimethylboronic acid.
Specific examples of the alkyl zinc reagent used in this step are not limited to these, and examples thereof include methyl zinc chloride and ethyl zinc chloride.
Specific examples of the transition metal catalyst used in this step are not limited to these, but for example, tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, palladium (II) chloride, and tris (dibenzylideneacetone). ) Dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct, dichloro [1,1'-bis (1,1'-bis) Diphenylphosphino) ferrocene] palladium (II), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II), bis- (tri-tert-butylphosphine) palladium (0) and the like. ..
Specific examples of the base used in this step include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate and the like.
Specific examples of the ligand used in this step are not limited to these, but for example, triphenylphosphine, tri-tert-butylphosphine, 2-dicyclohexylphosphine-2', 6'-dimethoxybiphenyl, 2-. Examples thereof include dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl and the like.
Specific examples of the inert solvent used in this step are not limited to these, but for example, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethyl. Examples thereof include aprotic polar solvents such as formamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and acetonitrile; aromatic hydrocarbons such as benzene and toluene; water; and mixed solvents thereof.

Step 22: Compound (30) is produced by coupling compound (29) and a boronic acid reagent in a suitable inert solvent in the presence of a suitable transition metal catalyst and a suitable base by a conventional method. can do. This step can also be performed in the coexistence of a suitable ligand, if necessary. The reaction temperature in this step is usually from room temperature to the boiling point of the solvent used, preferably from 50 ° C to 150 ° C. The reaction time of this step is usually 1 minute to 5 days, preferably 1 minute to 2 days. This step may be performed under microwave irradiation.
Specific examples of the boronic acid used in this step are not limited to these, but for example, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaboronic acid, cis-propenylboronic acid, and the like. Examples thereof include trans-propenylboronic acid and allylboronic acid pinacol ester.
Specific examples of the transition metal catalyst used in this step are not limited to these, but for example, tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone). ) Dipalladium (0), dichlorobis (triphenylphosphine) palladium (II), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct, dichloro [1,1'-bis (1,1'-bis) Diphenylphosphino) ferrocene] palladium (II), dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) and the like.
Specific examples of the base used in this step include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate and the like.
Specific examples of the ligand used in this step are not limited to these, but for example, triphenylphosphine, tri-tert-butylphosphine, 2-dicyclohexylphosphine-2', 6'-dimethoxybiphenyl, 2-. Examples thereof include dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl and the like.
Specific examples of the inert solvent used in this step are not limited to these, but for example, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; N, N-dimethyl. Examples thereof include aprotic polar solvents such as formamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and acetonitrile; aromatic hydrocarbons such as benzene and toluene; water; and mixed solvents thereof.

Step 23: Compound (31), by conventional methods in a suitable inert solvent, various methods an unsaturated carbon bond in the substituent ^{R 9} of the compound (30) are known to those skilled in the art (R.C.Larock , "Complihensive Organic Transformations", 2nd Ed., John Wiley and Sons, Inc., New York (1999), etc.) can be used for hydrogenation reaction. The reaction temperature in this step is usually in the range from room temperature to the boiling point of the solvent used. The reaction time of this step is 1 minute to 5 days.

The base used in each step of each of the above production methods should be selected in a timely manner depending on the reaction, the type of raw material compound, etc., but unless otherwise specified, for example, sodium hydroxide, potassium bicarbonate, etc. Alkali bicarbonate; Alkali carbonates such as sodium carbonate, potassium carbonate; Metal hydrides such as sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; Sodium methoxy Alkali metal alkoxides such as sodium tert-butoxide; organic metal bases such as butyllithium and lithium diisopropylamide; triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [ 5.4.0] -7-Organic bases such as undecene (DBU) can be mentioned.

The solvent used in each step of each of the above production methods should be selected in a timely manner depending on the reaction, the type of raw material compound, etc., but unless otherwise specified, alcohols such as methanol, ethanol, and isopropanol are used. Ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran (THF) and 1,4-dioxane; aromatic hydrocarbons such as toluene and benzene Aliper hydrocarbons such as hexane, heptane; esters such as ethyl acetate, propyl acetate; amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone; dimethyl sulfoxide ( Examples include sulfoxides such as DMSO); nitriles such as acetonitrile, and these solvents can be used alone or in admixture of two or more. Further, depending on the type of reaction, organic bases may be used as a solvent.

The intermediates and target compounds in each of the above production methods are purified by purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography (for example, silica gel column chromatography, etc.). It can be isolated and purified by ion exchange column chromatography or preparative liquid chromatography). Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as benzene and toluene; acetone. Etc. Ketone-based solvent; Halogen-based solvent such as dichloromethane and chloroform; Hydrocarbon-based solvent such as hexane; Aprotonic solvent such as N, N-dimethylformamide and acetonitrile; Water; or a mixed solvent thereof and the like can be used. it can. As another purification method, the method described in Volume 1 of the Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen) can be used. Further, the molecular structure of the compound of the present invention is determined by a spectroscopic method such as nuclear magnetic resonance method, infrared absorption method, circular dichroism spectrum analysis method, etc., with reference to the structure derived from each raw material compound. And it can be easily done by mass spectrometry. In addition, the intermediate can be used in the next reaction without any particular purification.

The compounds of the present invention may be asymmetric or have substituents having asymmetric carbons, and such compounds have optical isomers. The compounds of the present invention also include mixtures and isolated compounds of each of these isomers and can be produced according to conventional methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing an asymmetry in an intermediate stage. For example, in the case of an optical isomer, the optical isomer can be obtained by using an optically active raw material or by performing optical resolution or the like at an appropriate stage in the manufacturing process. Examples of the optical resolution method include HPLC using a column for separating optical isomers. When the compound represented by the formula (1) or an intermediate thereof has a basic functional group, it is contained in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, 2-propanol; diethyl ether or the like). Ether solvent; ester solvent such as ethyl acetate; hydrocarbon solvent such as toluene; aprotonic solvent such as acetonitrile; or a mixed solvent of two or more selected from the above solvents), an optically active acid (for example, Monocarboxylic acids such as mandelic acid, N-benzyloxyalanine and lactic acid; dicarboxylic acids such as tartaric acid, o-diisopropyridene tartaric acid and malic acid; sulfonic acids such as camphor sulfonic acid and bromo camphor sulfonic acid). The diastereomer method to form is mentioned. When the compound of the present invention or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (for example, an organic amine such as 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strikinine) is used. It is also possible to perform optical resolution by forming a salt.

The temperature at which the salt is formed is selected from the range of −50 ° C. to the boiling point of the solvent, preferably the range of 0 ° C. to the boiling point, and more preferably the range of room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled if necessary to improve the yield. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably around 1 equivalent with respect to the substrate. If necessary, the crystals are placed in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, 2-propanol; an ether solvent such as diethyl ether; an ester solvent such as ethyl acetate; a hydrocarbon solvent such as toluene; It can also be recrystallized in an aproton solvent such as acetonitrile; or a mixed solvent of two or more selected from the above solvents) to obtain a highly pure optically active salt. Further, if necessary, the optically resolved salt can be treated with an acid or a base by a usual method to obtain a free form.

The compounds of the present invention have mGlu2 receptor negative allosteric modulator (NAM) activity and thus have a negative regulatory effect on Group II mGlu receptors, group II mGlu receptors (ie, metabotropic glutamate receptor subtypes). It can be a novel therapeutic and / or prophylactic agent for diseases involving 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3), preferably mGluR2). Diseases involving the Group II mGlu receptor include mental illness and neurodegenerative diseases, and specific examples include depressive disorder and depressive disorder (major depression, treatment-resistant depression, chronic depression, etc.). , Bipolar disorder and related disorders (bipolar depression, etc.), anxiety disorder (general anxiety disorder, panic disorder, social anxiety disorder, specific phobia, etc.), post-traumatic stress disorder, compulsive disorder, acute stress Disorders, schizophrenia, autism spectrum disorders, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, spasm, tremor, pain, sleep disorders and the like.
Among these mental and neurodegenerative diseases, the preferred target diseases are depressive disorder, depressive disorder (major depression, treatment-resistant depression, chronic depression, etc.), bipolar disorder and related disorders (bipolar depression). Diseases, etc.), anxiety disorders (general anxiety disorder, panic disorder, social anxiety disorder, specific fears, etc.), post-traumatic stress disorder, compulsive disorder, acute stress disorder, Alzheimer's disease, cognitive dysfunction, dementia , Drug dependence, obesity, convulsions, tremor, pain, and sleep disorders.

The administration route of the compound of the present invention may be oral administration, parenteral administration or rectal administration, and the daily dose thereof varies depending on the type of compound, administration method, patient's symptom, age and the like. For example, in the case of oral administration, about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per day can be administered to an adult in 1 to several divided doses.

The compound of the present invention can be directly administered by oral administration or parenteral administration, or can be formulated and administered using an appropriate dosage form. Examples of the dosage form include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. Formulations are made by known methods using pharmaceutically acceptable additives. Additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , Perfume and the like can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, stearate. Examples thereof include magnesium acid, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium oxide and talc.

The compounds of the present invention may be used in combination with one or more antipsychotic agents to treat one or more of the psychiatric or neurodegenerative diseases described herein. Antipsychotic drugs include, for example, depressive disorder, depressive disorder (major depression, treatment-resistant depression, chronic depression, etc.), bipolar disorder and related disorders (bipolar depression, etc.), anxiety disorder (general). Sexual anxiety disorder, panic disorder, social anxiety disorder, certain fears, etc.), post-traumatic stress disorder, obsessive disorder, acute stress disorder, schizophrenia, autism spectrum disorder, Alzheimer's disease, cognitive dysfunction, Examples include therapeutic agents for depression, drug dependence, obesity, convulsions, tremors, pain or sleep disorders. The administration time of the compound of the present invention and these therapeutic agents is not limited, and these may be administered to the administration subject at the same time or at different times. Further, it may be a mixture containing the compound of the present invention and a therapeutic agent thereof. The dose of these therapeutic agents can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and these therapeutic agents can be appropriately selected depending on the administration target, administration route, target disease, symptom, combination thereof and the like.

When the compound of the present invention is used as an active ingredient of a medicine, it is not intended to be used only for humans, but also for other animals other than humans (cats, dogs, cows, chickens, fish, etc.). Is possible.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited to this. The compound names shown in the following reference examples and examples do not necessarily follow the IUPAC nomenclature. Abbreviations may also be used for the sake of brevity.

The compounds were identified using proton nuclear magnetic resonance spectra ( ¹ H-NMR), LC-MS, and the like. Tetramethylsilane was used as an internal standard for the nuclear magnetic resonance spectrum.

For the column chromatography and amino chromatography in Reference Examples and Examples, silica gel columns and amino columns manufactured by Yamazen Corporation were used. Silica gel 60F254 (Merck) was used for TLC (silica gel plate) when purified using TLC, and TLC plate NH (FujiSilicasia) was used for TLC (NH silica gel plate).

The following reactors were used in Reference Examples and Examples. Various data described in the reference example and the example were acquired by the following devices.
Microwave reactor: Biotage AB Initiator
NMR spectrum: [ ¹ H-NMR] 400 MHz: JEOL JNM-AL series AL400
LC-MS spectrum: Waters ACQUITYTM UltraPerformance LC
The compound names in Reference Examples and Examples were named by ACD / Name (ACD / Labs12.0, Advanced Chemistry Development Inc.).

For the LC-MS data in the reference example and the example, the values measured under the conditions shown below were used. The observed mass spectrometric value [MS (m / z)] is indicated by [M + H] ⁺ . In each measured value, the measurement conditions used for the measurement are added with A or B.
Measurement condition A
Column: ACQUITY UPLC BEH C18 1.7 μm 2.1 × 30 mm volume
Solvent: Solution A: 0.05% HCOOH / H ₂ O, Solution B: CH ₃ CN
Gradient condition:
0.0-1.3 minutes; A / B = 90 / 10-5 / 95 (linear gradient)
1.3-1.5 minutes; A / B = 90/10
Flow velocity: 0.80 mL / min
UV: 220nm, 254nm
Column temperature: 40 ° C
In the following reference examples and examples, LC-MS data is measured under measurement condition A unless otherwise specified.
Measurement condition B
Column: ACQUITY UPLC BEH C18 1.7 μm 2.1 × 30 mm volume
Solvent: Solution A: 0.05% HCOOH / H ₂ O, Solution B: CH ₃ CN
Gradient condition:
0.0-1.3 minutes; A / B = 99/1 to 5/95 (linear gradient)
1.3-1.5 minutes; A / B = 99/1
Flow velocity: 0.80 mL / min
UV: 220nm, 254nm
Column temperature: 40 ° C

The following abbreviations may be used in Reference and Examples.
CDCl ₃ : Deuterated chloroform CD ₃ OD: Deuterated methanol DMSO-d ₆ : Deuterated dimethyl sulfoxide s: Single line d: Double line t: Triple line q: Quadruple line m: Multiple line br: Wide dd: Double double Deuterated line td: Triple double line J: Coupling constant
Hz: Hertz
min: min atm: barometric HPLC: high performance liquid chromatograph THF: tetrahydrofuran TFA: trifluoroacetic acid DMF: N, N-dimethylformamide X-phos: 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl S-phos: 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl RLU: Reactive Light Unit

合成法−１：Ｒ−（＋）−プロピレンオキシド（３．６５ｇ）および４−アミノベンゾトリフルオリド（７．７８ｍＬ）のエタノール（１０ｍＬ）溶液を室温で４時間撹拌した後、臭素化リチウム（１．６４ｇ）およびＲ−（＋）−プロピレンオキシド（１．６６ｇ）を加えて室温で９日間撹拌した。反応液を減圧濃縮し、得られた残渣を、シリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル）で精製し、表題化合物（１０．５ｇ）を得た。
合成法−２：ヨウ化銅のジメチルスルホキシド/水（２：１）混合溶液（１９ｍＬ）に炭酸セシウム（６．５ｇ）、（Ｒ）−１−アミノプロパン−２−オール（８．０ｍＬ）および１−ヨード−４−（トリフルオロメタン）ベンゼン（１．５ｍＬ）を加えて、９０℃まで昇温し、７．５時間撹拌した。反応液に水（２０ｍＬ）を加えて、酢酸エチル（３０ｍＬ）で３回抽出した。有機層を無水硫酸ナトリウムで乾燥し、ろ過した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル）で精製し、表題化合物（６．７ｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；２２０［Ｍ＋Ｈ］^＋ Ｒｔ：０．８７７ｍｉｎ．（測定条件Ａ） Reference Example 1: (2R) -1-{[4- (trifluoromethyl) phenyl] amino} propan-2-ol

Synthesis Method-1: A solution of R- (+)-propylene oxide (3.65 g) and 4-aminobenzotrifluoride (7.78 mL) in ethanol (10 mL) was stirred at room temperature for 4 hours, and then lithium bromide (1). .64 g) and R- (+)-propylene oxide (1.66 g) were added and stirred at room temperature for 9 days. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (10.5 g).
Synthesis Method-2: Cesium carbonate (6.5 g), (R) -1-aminopropan-2-ol (8.0 mL) and cesium carbonate (6.5 g) in a mixed solution of copper iodide in dimethyl sulfoxide / water (2: 1) (19 mL). 1-Iodo-4- (trifluoromethane) benzene (1.5 mL) was added, the temperature was raised to 90 ° C., and the mixture was stirred for 7.5 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (6.7 g).
LC-MS, m / z; 220 [M + H] ⁺ Rt: 0.877 min. (Measurement condition A)

参考例１の化合物（１１．８ｇ）、メチル ３−ブロモ−１Ｈ−ピロール−２−カルボキシレート（１０．０ｇ）、ｎ−トリブチルホスフィン（１４．９ｇ）のトルエン（１６０ｍＬ）溶液に氷冷下にて１，１’−アゾビス（Ｎ，Ｎ−ジメチルホルムアミド）（１２．７ｇ）を加えた。反応液を室温まで昇温し、３日間撹拌した後、ｎ−トリブチルホスフィン（９．９１ｇ）と１，１’−アゾビス（Ｎ，Ｎ−ジメチルホルムアミド）（８．４４ｇ）を氷冷下追加し、室温でさらに６時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル）で精製することにより、表題化合物（１７．７ｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；４０５［Ｍ＋Ｈ］^＋ Ｒｔ：１．１５２ｍｉｎ．（測定条件Ａ） Reference Example 2: Methyl 3-bromo-1-[(2S) -1-{[4- (trifluoromethyl) phenyl] amino} propan-2-yl] -1H-pyrrole-2-carboxylate

The compound of Reference Example 1 (11.8 g), methyl 3-bromo-1H-pyrrole-2-carboxylate (10.0 g), n-tributylphosphine (14.9 g) in a toluene (160 mL) solution under ice-cooling. 1,1'-Azobis (N, N-dimethylformamide) (12.7 g) was added. The reaction mixture was heated to room temperature, stirred for 3 days, and then n-tributylphosphine (9.91 g) and 1,1'-azobis (N, N-dimethylformamide) (8.44 g) were added under ice cooling. , Stirred for an additional 6 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (17.7 g).
LC-MS, m / z; 405 [M + H] ⁺ Rt: 1.152 min. (Measurement condition A)

参考例２の化合物（１２．４ｇ）のＮ，Ｎ−ジメチルホルムアミド（１００ｍＬ）溶液に炭酸セシウム（１５．０ｇ）を加え、９０℃にて２時間撹拌した。反応液を室温まで放冷し、水（２００ｍＬ）を加え、生じた固体を濾取し、減圧乾燥することにより、表題化合物（９．４４ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.63 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 6.80 (1H, d, J = 2.8 Hz), 6.36 (1H, d, J = 2.8 Hz), 4.51-4.41 (1H, m), 4.08 (1H, dd, J = 12.5, 4.0 Hz), 3.87 (1H, dd, J = 12.4, 7.3 Hz), 1.58 (3H, d, J = 6.1 Hz). Reference Example 3: (4S) -8-bromo-4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one

Cesium carbonate (15.0 g) was added to a solution of the compound (12.4 g) of Reference Example 2 in N, N-dimethylformamide (100 mL), and the mixture was stirred at 90 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, water (200 mL) was added, the resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (9.44 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.63 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 6.80 (1H, d, J = 2.8 Hz), 6.36 (1H, d, J = 2.8 Hz), 4.51-4.41 (1H, m), 4.08 (1H, dd, J = 12.5, 4.0 Hz), 3.87 (1H, dd, J = 12.4, 7.3 Hz), 1.58 ( 3H, d, J = 6.1 Hz).

参考例３の化合物（５６０ｍｇ）のアセトニトリル（１５ｍＬ）溶液にＮ−フルオロ−Ｎ’−(クロロメチル)トリエチレンジアミンビス(テトラフルオロボラート)（６３８ｍｇ）を加え、８０℃にて４時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル）で精製することにより、表題化合物（１２５ｍｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；３９１［Ｍ＋Ｈ］^＋ Ｒｔ：１．００４ｍｉｎ．（測定条件Ａ） Reference Example 4: (4S) -8-bromo-6-fluoro-4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 ( 2H) -On

N-fluoro-N'-(chloromethyl) triethylenediaminebis (tetrafluoroborate) (638 mg) was added to a solution of the compound (560 mg) of Reference Example 3 in acetonitrile (15 mL), and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (125 mg).
LC-MS, m / z; 391 [M + H] ⁺ Rt: 1.004 min. (Measurement condition A)

ｔｅｒｔ−ブチル （Ｒ）−（２−ヒドロキシプロピル）カルバメート（３０．４ｇ）とメチル ３−ブロモ−１Ｈ−ピロール−２−カルボキシレート（２７．２ｇ）、１，１’−アゾビス（Ｎ，Ｎ−ジメチルホルムアミド）（４６．０ｇ）のトルエン（３３４ｍＬ）溶液に３５℃以下でｎ−トリブチルホスフィン（６５．９ｍＬ）を滴下した。反応液を４５℃で２時間撹拌し、１，１’−アゾビス（Ｎ，Ｎ−ジメチルホルムアミド）（４６．０ｇ）とｎ−トリブチルホスフィン（６５．９ｍＬ）を加え、４５℃でさらに１時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、濾過し、減圧濃縮し、茶色油状物（２０４ｇ）を得た。茶色油状物（２０４ｇ）のジエチルエーテル（１００ｍＬ）溶液に、４ｍｏｌ／Ｌ塩酸/酢酸エチル溶液（２９０ｍＬ）を加え、室温で３時間撹拌した。反応溶液に水（５００ｍＬ）を加え、分液した。有機層を１ｍｏｌ／Ｌ塩酸（２５０ｍＬ）で２回分液した。水層を合わせ６ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加え、液性をアルカリ性とした（ｐＨ＞９）。水層をクロロホルム/エタノール（４/１）で３回抽出し、合わせた有機層を無水硫酸マグネシウムで乾燥、ろ過し、減圧濃縮した。残渣にジエチルエーテル/ヘキサン（１/４）を加え、生じた固体をろ取し、表題化合物（１３．４ｇ）を得た。
¹H-NMR (DMSO-d₆) δ: 7.73 (1H, br s), 7.10 (1H, d, J = 2.8 Hz), 6.26 (1H, d, J = 2.8 Hz), 4.34-4.24 (1H, m), 3.54-3.47 (1H, m), 3.23-3.15 (1H, m), 1.37 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；２２９［Ｍ＋Ｈ］^＋ Ｒｔ：０．４６１ｍｉｎ．（測定条件Ａ） Reference Example 5: (4S) -8-bromo-4-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one

tert-Butyl (R)-(2-Hydroxypropyl) carbamate (30.4 g) and methyl 3-bromo-1H-pyrrole-2-carboxylate (27.2 g), 1,1'-azobis (N, N-) N-Tributylphosphine (65.9 mL) was added dropwise to a solution of dimethylformamide (46.0 g) in toluene (334 mL) at 35 ° C. or lower. The reaction mixture is stirred at 45 ° C. for 2 hours, 1,1'-azobis (N, N-dimethylformamide) (46.0 g) and n-tributylphosphine (65.9 mL) are added, and the mixture is further stirred at 45 ° C. for 1 hour. did. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil (204 g). A 4 mol / L hydrochloric acid / ethyl acetate solution (290 mL) was added to a solution of brown oil (204 g) in diethyl ether (100 mL), and the mixture was stirred at room temperature for 3 hours. Water (500 mL) was added to the reaction solution to separate the solutions. The organic layer was separated twice with 1 mol / L hydrochloric acid (250 mL). The aqueous layers were combined and a 6 mol / L sodium hydroxide aqueous solution was added to make the liquid alkaline (pH> 9). The aqueous layer was extracted 3 times with chloroform / ethanol (4/1), and the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Diethyl ether / hexane (1/4) was added to the residue, and the resulting solid was collected by filtration to give the title compound (13.4 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.73 (1H, br s), 7.10 (1H, d, J = 2.8 Hz), 6.26 (1H, d, J = 2.8 Hz), 4.34-4.24 (1H, m), 3.54-3.47 (1H, m), 3.23-3.15 (1H, m), 1.37 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 229 [M + H] ⁺ Rt: 0.461 min. (Measurement condition A)

参考例５の化合物（３．９５ｇ）とＮ−フルオロ−Ｎ’−（クロロメチル）トリエチレンジアミンビス（テトラフルオロボラート）（７．３３ｇ）を用いて、参考例４に記載の方法に準じ、表題化合物（１．０４ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 6.64 (1H, br s), 5.72 (1H, d, J = 3.7 Hz), 4.43-4.35 (1H, m), 3.77 (1H, dd, J = 12.8, 4.3 Hz), 3.33-3.25 (1H, m), 1.39 (3H, d, J = 6.7 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；２４７［Ｍ＋Ｈ］^＋ Ｒｔ：０．３５１ｍｉｎ．（測定条件Ａ） Reference Example 6: (4S) -8-bromo-6-fluoro-4-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one

Using the compound of Reference Example 5 (3.95 g) and N-fluoro-N'-(chloromethyl) triethylenediaminebis (tetrafluoroborate) (7.33 g), according to the method described in Reference Example 4. The title compound (1.04 g) was obtained.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 6.64 (1H, br s), 5.72 (1H, d, J = 3.7 Hz), 4.43-4.35 (1H, m), 3.77 (1H, dd, J = 12.8, 4.3 Hz), 3.33-3.25 (1H, m), 1.39 (3H, d, J = 6.7 Hz).
LC-MS, m / z; 247 [M + H] ⁺ Rt: 0.351 min. (Measurement condition A)

６−ブロモイミダゾ［１，２−ａ］ピリジン（１５１．７２ｇ）、ビス（ピナコレート）ジボロン（２３５ｇ）、１，１’−ビス（ジフェニルホスフィノ）フェロセンパラジウム（ＩＩ）クロライドジクロロメタン付加物（６２．９ｇ）、酢酸カリウム（１８９ｇ）の１，２−ジメトキシエタン（１．５９Ｌ）混合物を４．５時間加熱還流下撹拌した。反応混合物を室温まで放冷後、析出した固体をろ取し、１，２−ジメトキシエタン（２００ｍＬ）で洗浄した。得られた固体に水（５００ｍＬ）、ヘキサン（５００ｍＬ）を加え、室温で、３０分、懸濁撹拌した。固体をろ取し、１，２−ジメトキシエタン（４００ｍＬ）で３回洗浄することで表題化合物（１４５．１ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 8.55 (1H, t, J = 1.2 Hz), 7.62-7.56 (3H, m), 7.44 (1H, dd, J = 9.2, 1.2 Hz), 1.35 (13H, s). Reference Example 7: 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazole [1,2-a] pyridine

6-Bromoimidazo [1,2-a] pyridine (151.72 g), bis (pinacholate) diboron (235 g), 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride dichloromethane adduct (62. A mixture of 1,2-dimethoxyethane (1.59 L) of 9 g) and potassium acetate (189 g) was stirred under heating and reflux for 4.5 hours. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration and washed with 1,2-dimethoxyethane (200 mL). Water (500 mL) and hexane (500 mL) were added to the obtained solid, and the mixture was suspended and stirred at room temperature for 30 minutes. The solid was collected by filtration and washed 3 times with 1,2-dimethoxyethane (400 mL) to give the title compound (145.1 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 8.55 (1H, t, J = 1.2 Hz), 7.62-7.56 (3H, m), 7.44 (1H, dd, J = 9.2, 1.2 Hz), 1.35 ( 13H, s).

参考例５の化合物（５．０ｇ）、参考例７の化合物（８．５ｇ）、酢酸パラジウム（４９０ｍｇ）、Ｓ−ｐｈｏｓ（１．８ｇ）、炭酸カリウム（６．０ｇ）の１，２−ジメトキシエタン（４９ｍＬ）／水（２４ｍＬ）混合物を加熱還流下３時間撹拌した。反応混合物を室温まで放冷後、クロロホルム／メタノール（９／１、３０ｍＬ）で希釈しセライトろ過を行い、ろ液に水を加え分液した。有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）により精製することで表題の化合物（５．１ｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.94-8.91 (1H, m), 7.89 (1H, s), 7.74 (1H, s), 7.52 (1H, d, J = 1.2 Hz), 7.49-7.46 (2H, m), 7.17 (1H, d, J = 2.4 Hz), 6.42 (1H, d, J = 2.4 Hz), 4.39-4.29 (1H, m), 3.60-3.52 (1H, m), 3.28-3.20 (1H, m), 1.43 (3H, d, J = 6.7 Hz). Reference Example 8: (4S) -8- (Imidazo [1,2-a] Pyridine-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H)- on

1,2-Dimethoxy of the compound of Reference Example 5 (5.0 g), the compound of Reference Example 7 (8.5 g), palladium acetate (490 mg), S-phos (1.8 g), and potassium carbonate (6.0 g). The ethane (49 mL) / water (24 mL) mixture was stirred under heating under reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted with chloroform / methanol (9/1, 30 mL), filtered through Celite, and water was added to the filtrate to separate the solutions. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (ethyl acetate / methanol) to give the title compound (5.1 g).
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.94-8.91 (1H, m), 7.89 (1H, s), 7.74 (1H, s), 7.52 (1H, d, J = 1.2 Hz), 7.49-7.46 (2H, m), 7.17 (1H, d, J = 2.4 Hz), 6.42 (1H, d, J = 2.4 Hz), 4.39-4.29 (1H, m), 3.60-3.52 (1H, m) , 3.28-3.20 (1H, m), 1.43 (3H, d, J = 6.7 Hz).

Reference example 9-10
Using the compound of Reference Example 5 or 6 as a starting material, the reaction, post-treatment, and purification were carried out according to the same method as described in Reference Example 8 to obtain the compounds shown in the table below.

The compound names of Reference Examples 9 to 10 are described below.
Reference Example 9: (4S) -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Reference Example 10: (4S) -6-fluoro-4-methyl-8- (1-methyl-1H-indazole-6-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one

Ｎ−［（２Ｒ）−２−ヒドロキシプロピル］カルバミン酸ｔｅｒｔ−ブチル（１８．３ｇ）のＴＨＦ（１３０ｍＬ）溶液に室温でエチル １Ｈ−ピラゾール−３−カルボキシレート（１６．１ｇ）、トリフェニルホスフィン（３０．２ｇ）を加えた後、アゾジカルボン酸ジイソプロピル（６０．６ｍＬ，１．９ｍｏｌ／Ｌ トルエン溶液）を３０分かけて滴下した。さらに室温で２時間撹拌した後、水（１３０ｍＬ）を加えて３０分間撹拌した。混合物を酢酸エチルで２回抽出し、合わせた有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣にヘキサン：ジエチルエーテル（１：１、２００ｍＬ）を加え、生じた固体をろ別し、ろ液を減圧濃縮することで粗生成物を得た。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）により精製することで表題の化合物（２６．５ｇ）を得た。
¹H-NMR (400 MHz,CDCl₃) δ: 7.52 (1H, d, J = 1.8 Hz), 6.83 (1H, d, J = 1.8 Hz), 5.58-5.48 (1H, m), 4.88 (1H, s), 4.34 (2H, q, J = 7.1 Hz), 3.66-3.49 (2H, m), 1.47-1.33 (15H, m). Reference Example 11: 1-{(2S) -1-[(tert-butoxycarbonyl) amino] propan-2-yl} -1H-ethyl pyrazolo-5-carboxylate

Ethyl 1H-pyrazole-3-carboxylate (16.1 g) in a solution of tert-butyl N-[(2R) -2-hydroxypropyl] carbamic acid (18.3 g) in THF (130 mL) at room temperature, triphenylphosphine (16.1 g). After adding 30.2 g), diisopropyl azodicarboxylate (60.6 mL, 1.9 mol / L toluene solution) was added dropwise over 30 minutes. After further stirring at room temperature for 2 hours, water (130 mL) was added and the mixture was stirred for 30 minutes. The mixture was extracted twice with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Hexane: diethyl ether (1: 1, 200 mL) was added to the obtained residue, the resulting solid was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (26.5 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.52 (1H, d, J = 1.8 Hz), 6.83 (1H, d, J = 1.8 Hz), 5.58-5.48 (1H, m), 4.88 (1H, 1H, s), 4.34 (2H, q, J = 7.1 Hz), 3.66-3.49 (2H, m), 1.47-1.33 (15H, m).

参考例１１の化合物（２６．５ｇ）のトルエン（９０ｍＬ）溶液に氷浴下、ＴＦＡ（２７．８ｍＬ）を加え室温で終夜撹拌した。反応混合物を減圧濃縮し、残渣をＤＭＦ（１５０ｍＬ）に溶解させ、トリエチルアミン（３７．９ｍＬ）を室温にて滴下した。反応混合物を７時間加熱還流した後、水（３００ｍＬ）を加え、さらに１０分間撹拌した。混合物をクロロホルム：メタノール（４：１）で１４回抽出した後、合わせた有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣にジエチルエーテル（１００ｍＬ）を加え撹拌し、生じた固体をろ取した（６．５１ｇ）。ろ液を減圧濃縮し、得られた残渣にジエチルエーテル（１００ｍＬ）を加え撹拌し、生じた固体をろ取した（２．５１ｇ）。得られた固体を合わせることで表題の化合物（８．６６ｇ）を得た。
¹H-NMR (400 MHz,CDCl₃) δ: 7.57 (1H, d, J = 2.4 Hz), 6.88 (1H, d, J = 2.4 Hz), 6.88-6.82 (1H, m), 4.60-4.50 (1H, m), 3.80 (1H, ddd, J = 7.6, 4.8, 3.6 Hz), 3.49 (1H, ddd, J = 10.4, 7.6, 2.8 Hz), 1.62 (3H, d, J = 6.1 Hz). Reference Example 12: (7S) -7-methyl-6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -on

TFA (27.8 mL) was added to a toluene (90 mL) solution of the compound (26.5 g) of Reference Example 11 under an ice bath, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DMF (150 mL), and triethylamine (37.9 mL) was added dropwise at room temperature. The reaction mixture was heated to reflux for 7 hours, water (300 mL) was added, and the mixture was further stirred for 10 minutes. The mixture was extracted 14 times with chloroform: methanol (4: 1), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Diethyl ether (100 mL) was added to the obtained residue, and the mixture was stirred, and the resulting solid was collected by filtration (6.51 g). The filtrate was concentrated under reduced pressure, diethyl ether (100 mL) was added to the obtained residue, and the mixture was stirred, and the resulting solid was collected by filtration (2.51 g). The obtained solids were combined to give the title compound (8.66 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.57 (1H, d, J = 2.4 Hz), 6.88 (1H, d, J = 2.4 Hz), 6.88-6.82 (1H, m), 4.60-4.50 ( 1H, m), 3.80 (1H, ddd, J = 7.6, 4.8, 3.6 Hz), 3.49 (1H, ddd, J = 10.4, 7.6, 2.8 Hz), 1.62 (3H, d, J = 6.1 Hz).

１−ブロモ−４−（トリフルオロメチル）ベンゼン（６０．６ｇ）、参考例１２の化合物（３３．９２ｇ）、炭酸カリウム（６２ｇ）のトルエン（７４６ｍＬ）懸濁液に、Ｎ，Ｎ’−ジメチルエチレンジアミン（１１．８７ｇ）、ヨウ化銅（８．５５ｇ）を加え、６時間加熱還流した。反応溶液を室温まで放冷後、１４％アンモニア水（７５０ｍＬ）と酢酸エチル（７５０ｍＬ）を加え室温で３０分撹拌した。混合物を分液後、有機層を１４％アンモニア水（７５０ｍＬ）、飽和食塩水（４００ｍＬ）の順で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。残渣にイソプロパノール（７６０ｍＬ）、活性炭（７．６ｇ）、シリカゲル（２４ｇ）を加え、室温で１時間撹拌した。混合物をセライトろ過し、酢酸エチル（２００ｍＬ）で３回洗浄した後、濾液を減圧濃縮することにより表題の化合物（７１．８ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.68 (2H, d, J = 8.5 Hz), 7.60 (1H, d, J = 1.8 Hz), 7.49 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 1.8 Hz), 4.75-4.67 (1H, m), 4.21 (1H, dd, J = 12.5, 4.3 Hz), 3.95 (1H, dd, J = 12.5, 7.6 Hz), 1.69 (3H, d, J = 6.7 Hz). Reference Example 13: (7S) -7-methyl-5-[4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one

N, N'-dimethyl in a suspension of 1-bromo-4- (trifluoromethyl) benzene (60.6 g), compound of Reference Example 12 (33.92 g), potassium carbonate (62 g) in toluene (746 mL). Ethylenediamine (11.87 g) and copper iodide (8.55 g) were added, and the mixture was heated under reflux for 6 hours. The reaction solution was allowed to cool to room temperature, 14% aqueous ammonia (750 mL) and ethyl acetate (750 mL) were added, and the mixture was stirred at room temperature for 30 minutes. After separating the mixture, the organic layer was washed with 14% aqueous ammonia (750 mL) and saturated brine (400 mL) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Isopropanol (760 mL), activated carbon (7.6 g) and silica gel (24 g) were added to the residue, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through Celite, washed 3 times with ethyl acetate (200 mL), and the filtrate was concentrated under reduced pressure to give the title compound (71.8 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.68 (2H, d, J = 8.5 Hz), 7.60 (1H, d, J = 1.8 Hz), 7.49 (2H, d, J = 8.5 Hz), 6.97 (1H, d, J = 1.8 Hz), 4.75-4.67 (1H, m), 4.21 (1H, dd, J = 12.5, 4.3 Hz), 3.95 (1H, dd, J = 12.5, 7.6 Hz), 1.69 ( 3H, d, J = 6.7 Hz).

参考例１３の化合物（１０４．９ｇ）と１，３−ジヨード−５，５−ジメチルヒダントイン（８８ｇ）の酢酸（６６２ｍＬ）懸濁液を１００℃で１時間撹拌した。反応懸濁液を室温まで放冷後、水（３３０ｍＬ）を滴下し、３０分間撹拌した。反応混合物にヘキサン（２００ｍＬ）と水（９９０ｍＬ）を滴下し、３０分間撹拌した。生じた固体をろ取し、ヘキサン（１５０ｍＬ）で３回洗浄することにより粗生成物（１４６ｇ）を得た。得られた粗生成物にイソプロパノール（４３８ｍＬ）を加え７５℃で撹拌後、５５℃まで徐々に放冷し、水（６５７ｍＬ）を滴下した。混合物を１時間撹拌後、３時間かけ１５℃まで冷却した。生じた固体をろ取し、イソプロパノール：水（１：２）で２回洗浄し、減圧乾燥することにより表題の化合物（１３３ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.68-7.66 (3H, m), 7.49 (2H, d, J = 8.5 Hz), 4.75-4.71 (1H, m), 4.22 (1H, dd, J = 12.5, 4.3 Hz), 3.95 (1H, dd, J = 12.5, 7.6 Hz), 1.67 (3H, d, J = 6.1 Hz). Reference Example 14: (7S) -3-iodo-7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H)- on

A suspension of compound (104.9 g) of Reference Example 13 and acetic acid (662 mL) of 1,3-diiodo-5,5-dimethylhydantoin (88 g) was stirred at 100 ° C. for 1 hour. The reaction suspension was allowed to cool to room temperature, water (330 mL) was added dropwise, and the mixture was stirred for 30 minutes. Hexane (200 mL) and water (990 mL) were added dropwise to the reaction mixture, and the mixture was stirred for 30 minutes. The resulting solid was collected by filtration and washed 3 times with hexane (150 mL) to give a crude product (146 g). Isopropanol (438 mL) was added to the obtained crude product, and the mixture was stirred at 75 ° C., gradually allowed to cool to 55 ° C., and water (657 mL) was added dropwise. The mixture was stirred for 1 hour and then cooled to 15 ° C. over 3 hours. The resulting solid was collected by filtration, washed twice with isopropanol: water (1: 2), and dried under reduced pressure to give the title compound (133 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.68-7.66 (3H, m), 7.49 (2H, d, J = 8.5 Hz), 4.75-4.71 (1H, m), 4.22 (1H, dd, J) = 12.5, 4.3 Hz), 3.95 (1H, dd, J = 12.5, 7.6 Hz), 1.67 (3H, d, J = 6.1 Hz).

参考例１４の化合物（１０．００ｇ）、２−イソプロポキシ−４，４，５，５−テトラメチル−１，３，２−ジオキザボロラン（９．６０ｍL）のＴＨＦ（１００ｍL）溶液に−２５℃でイソプロピルマグネシウムクロライド−塩化リチウム錯体（４２．７ｍL）を滴下した。反応混合物を−２５℃で３０分間撹拌後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）により精製することで表題の化合物（９．１２ｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；３４０［Ｍ＋Ｈ］^＋ 保持時間；０．８６５ｍｉｎ（測定条件Ａ） Reference Example 15: {(7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine- 3-yl} boronic acid

Compound (10.00 g) of Reference Example 14, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.60 mL) in THF (100 mL) solution at -25 ° C. Isopropylmagnesium chloride-lithium chloride complex (42.7 mL) was added dropwise. The reaction mixture was stirred at −25 ° C. for 30 minutes, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (9.12 g).
LC-MS, m / z; 340 [M + H] ⁺ retention time; 0.865 min (measurement condition A)

参考例１２の化合物（８．０３ｇ）の酢酸（１１０ｍＬ）溶液にＮ−クロロスクシンイミド（７．４５ｇ）を加えた。反応溶液を１００℃で５時間撹拌した後、減圧濃縮した。残渣に水を加え、室温で１５分間撹拌、固体をろ取し、水とヘキサンで洗浄することにより表題の化合物（９．１３ｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.28 (1H, brs), 7.70 (1H, s), 4.50-4.45 (1H, m), 3.67-3.62 (1H, m), 3.36-3.30 (1H, m), 1.43 (3H, d, J = 6.7 Hz). Reference Example 16: (7S) -3-chloro-7-methyl-6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one

N-Chlorosuccinimide (7.45 g) was added to a solution of the compound (8.03 g) of Reference Example 12 in acetic acid (110 mL). The reaction solution was stirred at 100 ° C. for 5 hours and then concentrated under reduced pressure. Water was added to the residue, the mixture was stirred at room temperature for 15 minutes, the solid was collected by filtration, and washed with water and hexane to give the title compound (9.13 g).
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.28 (1H, brs), 7.70 (1H, s), 4.50-4.45 (1H, m), 3.67-3.62 (1H, m), 3.36-3.30 (1H, m), 1.43 (3H, d, J = 6.7 Hz).

参考例１６の化合物（９．１２ｇ）、２−ブロモ−５−（トリフルオロメチル）チオフェン（１４．７６ｇ）、炭酸カリウム（１３．５８ｇ）、トルエン（１００ｍＬ）懸濁液に、Ｎ，Ｎ’−ジメチルエチレンジアミン（３．９０ｇ）、ヨウ化銅（２．８１ｇ）を加え、６時間加熱還流した。反応溶液を室温まで放冷後、１４％アンモニア水と酢酸エチルを加え室温で３０分撹拌した。混合物を分液後、有機層を飽和塩化アンモニウム水溶液、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）により精製することで表題の化合物（９．１３ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (1H, s), 7.26 (1H, d, J = 4.3 Hz), 6.66 (1H, d, J = 4.3 Hz), 4.74-4.66 (1H, m), 4.34 (1H, dd, J = 12.8, 4.3 Hz), 4.01 (1H, dd, J = 12.8, 7.9 Hz), 1.69 (3H, d, J = 6.7 Hz). Reference Example 17: (7S) -3-chloro-7-methyl-5- [5- (trifluoromethyl) thiophen-2-yl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -On

N, N'in a suspension of compound (9.12 g), 2-bromo-5- (trifluoromethyl) thiophene (14.76 g), potassium carbonate (13.58 g), toluene (100 mL) of Reference Example 16 -Dimethylethylenediamine (3.90 g) and copper iodide (2.81 g) were added, and the mixture was heated under reflux for 6 hours. The reaction solution was allowed to cool to room temperature, 14% aqueous ammonia and ethyl acetate were added, and the mixture was stirred at room temperature for 30 minutes. After separating the mixture, the organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (9.13 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.55 (1H, s), 7.26 (1H, d, J = 4.3 Hz), 6.66 (1H, d, J = 4.3 Hz), 4.74-4.66 (1H, m), 4.34 (1H, dd, J = 12.8, 4.3 Hz), 4.01 (1H, dd, J = 12.8, 7.9 Hz), 1.69 (3H, d, J = 6.7 Hz).

実施例１の化合物（６００ｍｇ）と１，３−ジヨード−５，５−ジメチルヒダントイン（３３２ｍｇ）の酢酸（１０ｍＬ）溶液を室温で１時間撹拌した。反応溶液に飽和チオ硫酸ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル）により精製することで表題の化合物（２００ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.47 (s, 1 H), 7.95 (s, 1 H), 7.73 (d, J = 8.8 Hz, 2 H), 7.56-7.58 (m, 4 H), 7.50 (d, J = 9.2 Hz, 1 H), 7.12-7.14 (m, 1 H), 4.65-4.67 (m, 1 H), 4.22-4.26 (m, 1 H), 3.97-4.02 (m, 1 H), 1.55 (d, J = 6.4 Hz, 3 H). Reference Example 18: (4S) -8- (3-iodoimidazo [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4- Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on

A solution of the compound of Example 1 (600 mg) and 1,3-diiodo-5,5-dimethylhydantoin (332 mg) in acetic acid (10 mL) was stirred at room temperature for 1 hour. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the title compound (200 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.47 (s, 1 H), 7.95 (s, 1 H), 7.73 (d, J = 8.8 Hz, 2 H), 7.56-7.58 (m, 4 H), 7.50 (d, J = 9.2 Hz, 1 H), 7.12-7.14 (m, 1 H), 4.65-4.67 (m, 1 H), 4.22-4.26 (m, 1 H), 3.97-4.02 (m, 1 H), 1.55 (d, J = 6.4 Hz, 3 H).

参考例１８の化合物（１００ｍｇ）、４，４，５，５−テトラメチル−２−ビニル−１，３，２−ジオキサボロラン（５７．４ｍｇ）、ジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）（２７．２ｍｇ）、炭酸カリウム（５１．４ｍｇ）の１，４−ジオキサン（５ｍＬ）と水（１ｍＬ）の混合物を、アルゴン雰囲気下、８０℃で終夜撹拌した。反応混合物を室温まで放冷後、減圧濃縮し得られた残渣を逆相カラムクロマトグラフィーにより精製することで表題の化合物（７０ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.91 (s, 1 H), 7.85 (s, 1 H), 7.75-7.77 (m, 2 H), 7.61-7.63 (m, 2 H), 7.50 (s, 2 H), 7.31 (d, J = 2.4 Hz, 1 H), 6.99-7.06 (m, 1 H), 6.58 (d, J = 2.8 Hz, 1 H), 5.81 (d, J = 18.0 Hz, 1 H), 5.27 (d, J = 12.0 Hz, 1 H), 4.61-4.65 (m, 1 H), 4.24-4.28 (m, 1 H), 3.91-3.98 (m, 1 H), 1.54 (d, J = 6.4 Hz, 3 H). Reference Example 19: (4S) -8- (3-ethenylimidazo [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydro Pyrrolo [1,2-a] Pyrazine-1 (2H) -on

Compound of Reference Example 18 (100 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (57.4 mg), dichloro [1,1'-bis (diphenylphosphino)) Ferrocene] A mixture of 1,4-dioxane (5 mL) of palladium (II) (27.2 mg) and potassium carbonate (51.4 mg) and water (1 mL) was stirred overnight at 80 ° C. under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography to give the title compound (70 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.91 (s, 1 H), 7.85 (s, 1 H), 7.75-7.77 (m, 2 H), 7.61-7.63 (m, 2 H) , 7.50 (s, 2 H), 7.31 (d, J = 2.4 Hz, 1 H), 6.99-7.06 (m, 1 H), 6.58 (d, J = 2.8 Hz, 1 H), 5.81 (d, J = 18.0 Hz, 1 H), 5.27 (d, J = 12.0 Hz, 1 H), 4.61-4.65 (m, 1 H), 4.24-4.28 (m, 1 H), 3.91-3.98 (m, 1 H) , 1.54 (d, J = 6.4 Hz, 3 H).

参考例１４の化合物（３０３ｍｇ）、（１−（ｔｅｒｔ−ブトキシカルボニル）−１，２，３，４−テトラヒドロキノリン−６−イル）ボロン酸（２７７ｍｇ）、酢酸パラジウム（１６．２ｍｇ）、Ｘ−ｐｈｏｓ（６８．６ｍｇ）、炭酸カリウム（１９９ｍｇ）の１，２−ジメトキシエタン（１ｍＬ）／水（０．５ｍＬ）混合物を加熱還流下３時間撹拌した。反応混合物を室温まで放冷後、酢酸エチルで希釈しセライトろ過を行い、ろ液に水を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）により精製することで表題の化合物（３２０．１ｍｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；５２７［Ｍ＋Ｈ］^＋ 保持時間；１．２４７ｍｉｎ（測定条件Ｂ） Reference Example 20: tert-Butyl 6-{(7S) -7-methyl-4-oxo-5-[4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5] -A] Pyrazine-3-yl} -3,4-dihydroquinoline e-1 (2H) -carboxylate

Compound of Reference Example 14 (303 mg), (1- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroquinoline-6-yl) boronic acid (277 mg), palladium acetate (16.2 mg), X- A mixture of 1,2-dimethoxyethane (1 mL) / water (0.5 mL) of phos (68.6 mg) and potassium carbonate (199 mg) was stirred under heating and reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, filtered through Celite, and water was added to the filtrate to separate the mixture. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (hexane / ethyl acetate) to give the title compound (320.1 mg).
LC-MS, m / z; 527 [M + H] ⁺ retention time; 1.247 min (measurement condition B)

６−ブロモイミダゾ［１，２−ａ］ピリジン（５００ｍｇ）のアセトニトリル（１０ｍｌ）混合物に水素化ナトリウム（１５２ｍｇ）を０℃で加え、アルゴン雰囲気下、室温に昇温して１５分間撹拌した。反応混合物を０℃に冷却し、１−クロロメチル−４−フルオロ−１，４−ジアゾニアビシクロ［２．２．２］オクタンビス（テトラフルオロボラート）（１．９６ｇ）を徐々に加えた後、室温で３時間撹拌した。反応混合物に飽和チオ硫酸ナトリウム水溶液を加えた後に酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル＝５：１）により精製することで６−ブロモ−３−フルオロイミダゾ［１，２−ａ］ピリジン（４０ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.74 (s, 1 H), 7.56 (d, J = 10.4 Hz, 1H), 7.49 (d, J = 6.8 Hz, 1 H), 7.41 (d, J = 9.6 Hz, 1 H). Reference Example 21: 6-Bromo-3-fluoroimidazole [1,2-a] pyridine

Sodium hydride (152 mg) was added to a mixture of 6-bromoimidazole [1,2-a] pyridine (500 mg) in acetonitrile (10 ml) at 0 ° C., the temperature was raised to room temperature under an argon atmosphere, and the mixture was stirred for 15 minutes. After cooling the reaction mixture to 0 ° C. and gradually adding 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octanebis (tetrafluoroborate) (1.96 g). , Stirred at room temperature for 3 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5: 1) to obtain 6-bromo-3-fluoroimidazole [1,2-a] pyridine (40 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.74 (s, 1 H), 7.56 (d, J = 10.4 Hz, 1H), 7.49 (d, J = 6.8 Hz, 1 H), 7.41 ( d, J = 9.6 Hz, 1 H).

参考例３の化合物（５００ｍｇ）、参考例７の化合物（５２３ｍｇ）、酢酸パラジウム（３０．１ｍｇ）、Ｓ−ｐｈｏｓ（１１０ｍｇ）、炭酸カリウム（３７０ｍｇ）の１，２−ジメトキシエタン（３ｍL）／水（１．５ｍL）混合物を加熱還流下３時間撹拌した。反応混合物を室温まで放冷後、クロロホルム／メタノール（９／１、２０ｍＬ）で希釈しセライトろ過を行い、ろ液に水を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）により精製した。得られた残渣のジエチルエーテル（２ｍL）溶液を室温で３０分懸濁撹拌し、ろ取することで表題の化合物（４８３ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 8.71 (1H, s), 7.67 (2H, d, J = 8.5 Hz), 7.60-7.54 (3H, m), 7.51-7.40 (3H, m), 6.96 (1H, d, J = 2.4 Hz), 6.48-6.46 (1H, m), 4.61-4.51 (1H, m), 4.18 (1H, dd, J = 12.5, 4.0 Hz), 3.95 (1H, dd, J = 12.5, 7.3 Hz), 1.67 (3H, d, J = 6.7 Hz). Example 1: (4S) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on

Compound of Reference Example 3 (500 mg), Compound of Reference Example 7 (523 mg), Palladium acetate (30.1 mg), S-phos (110 mg), Potassium carbonate (370 mg) 1,2-dimethoxyethane (3 mL) / water The (1.5 mL) mixture was stirred under heating under reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted with chloroform / methanol (9/1, 20 mL), filtered through Celite, and water was added to the filtrate to separate the solutions. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol). A solution of the obtained residue in diethyl ether (2 mL) was suspended and stirred at room temperature for 30 minutes and collected by filtration to give the title compound (483 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 8.71 (1H, s), 7.67 (2H, d, J = 8.5 Hz), 7.60-7.54 (3H, m), 7.51-7.40 (3H, m), 6.96 (1H, d, J = 2.4 Hz), 6.48-6.46 (1H, m), 4.61-4.51 (1H, m), 4.18 (1H, dd, J = 12.5, 4.0 Hz), 3.95 (1H, dd, J = 12.5, 7.3 Hz), 1.67 (3H, d, J = 6.7 Hz).

参考例３の化合物（３２４ｍｇ）、１−メチル−１Ｈ−インダゾール−６−ボロン酸（１９９ｍｇ）、酢酸パラジウム（１９．５ｍｇ）、Ｘ−ｐｈｏｓ（８３ｍｇ）、炭酸カリウム（２４０ｍｇ）の１，２−ジメトキシエタン（１ｍL）／水（０．５ｍL）混合物を加熱還流下３時間撹拌した。反応混合物を室温まで放冷後、酢酸エチルで希釈しセライトろ過を行い、ろ液に水を加え分液した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）により精製することで表題の化合物（１９４．７ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.90 (1H, s), 7.65-7.59 (4H, m), 7.46 (2H, d, J = 8.5 Hz), 7.38 (1H, dd, J = 8.5, 1.2 Hz), 6.93 (1H, d, J = 2.4 Hz), 6.46 (1H, d, J = 2.4 Hz), 4.53-4.52 (1H, m), 4.19-4.13 (1H, m), 4.04 (3H, s), 3.97-3.94 (1H, m), 1.64 (3H, d, J = 6.1 Hz). Example 2: (4S) -4-methyl-8- (1-methyl-1H-indazole-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1, 2-a] Pyrazine-1 (2H) -on

1,2- of the compound of Reference Example 3 (324 mg), 1-methyl-1H-indazole-6-boronic acid (199 mg), palladium acetate (19.5 mg), X-phos (83 mg), potassium carbonate (240 mg). The dimethoxyethane (1 mL) / water (0.5 mL) mixture was stirred under heating and reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, filtered through Celite, and water was added to the filtrate to separate the mixture. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (194.7 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.90 (1H, s), 7.65-7.59 (4H, m), 7.46 (2H, d, J = 8.5 Hz), 7.38 (1H, dd, J = 8.5) , 1.2 Hz), 6.93 (1H, d, J = 2.4 Hz), 6.46 (1H, d, J = 2.4 Hz), 4.53-4.52 (1H, m), 4.19-4.13 (1H, m), 4.04 (3H) , s), 3.97-3.94 (1H, m), 1.64 (3H, d, J = 6.1 Hz).

Examples 3-14
Using Reference Example 3 or 4 as a starting material, the reaction, post-treatment, and purification were carried out according to the same method as described in Example 1 to obtain the compounds shown in the table below.

The compound names of Examples 3 to 14 are described below.
Example 3: (4S) -4-methyl-8- (pyrazolo [1,5-a] pyridin-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] pyrazine-1 (2H) -on Example 4: (4S) -8- (Imidazo [1,5-a] Pyridine-7-yl) -4-methyl-2- [4-( Trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 5: (4S) -4-methyl-8- (pyrazolo [1,5-a] ] Pyridine-5-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on Example 6: (4S)- 8- (Imidazo [1,5-a] Pyridine-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine- 1 (2H) -one Example 7: (4S) -8- (1H-indazole-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -one Example 8: (4S) -4-methyl-8- (1-methyl-1H-indazole-5-yl) -2- [4- (trifluoro) Methyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 9: (4S) -8- (1H-indazole-5-yl) -4-methyl- 2- [4- (Trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 10: (4S) -4-methyl-8- (2) -Methyl-2H-Indazole-5-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 11: (4S) -4-methyl-8- (quinolin-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -On Example 12: (4S) -4-methyl-8- (quinoxalin-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] Pyrazine-1 (2H) -one Example 13: (4S) -6-fluoro-8- (imidazo [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoro) Methyl) phenyl] -3,4-dihydropyrrolo [1,2-a] Pyrazine-1 (2H) -one Example 14: (4S) -6-fluoro-4-methyl-8- (quinoline-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4 -Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on

参考例１０の化合物（３４１．６ｍｇ）、４−ヨードベンゼントリフルオリド（４３６ｍｇ）、ヨウ化銅（６５．４ｍｇ）、Ｎ，Ｎ’−ジメチルエチレンジアミン（０．１１１ｍＬ）、炭酸カリウム（３１７ｍｇ）のトルエン（４ｍＬ）懸濁液を６時間加熱還流化撹拌した。反応溶液を室温まで放冷後、１４％アンモニア水と酢酸エチルを加え室温で３０分撹拌した。混合物を分液後、有機層を飽和塩化アンモニウム水溶液、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）により精製することで表題の化合物（２８５ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.91 (1H, s), 7.67-7.60 (4H, m), 7.44 (2H, d, J = 7.9 Hz), 7.36 (1H, dd, J = 8.5, 1.2 Hz), 5.91 (1H, d, J = 3.7 Hz), 4.64-4.60 (1H, m), 4.47 (1H, dd, J = 12.2, 3.7 Hz), 4.04 (3H, s), 3.77 (1H, dd, J = 12.2, 2.4 Hz), 1.59 (3H, d, J = 6.7 Hz). Example 15: (4S) -6-fluoro-4-methyl-8- (1-methyl-1H-indazole-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydro Piloro [1,2-a] pyrazine-1 (2H) -on

Toluene of the compound of Reference Example 10 (341.6 mg), 4-iodobenzenetrifluoride (436 mg), copper iodide (65.4 mg), N, N'-dimethylethylenediamine (0.111 mL), potassium carbonate (317 mg). The (4 mL) suspension was heated under reflux and stirred for 6 hours. The reaction solution was allowed to cool to room temperature, 14% aqueous ammonia and ethyl acetate were added, and the mixture was stirred at room temperature for 30 minutes. After separating the mixture, the organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (285 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.91 (1H, s), 7.67-7.60 (4H, m), 7.44 (2H, d, J = 7.9 Hz), 7.36 (1H, dd, J = 8.5) , 1.2 Hz), 5.91 (1H, d, J = 3.7 Hz), 4.64-4.60 (1H, m), 4.47 (1H, dd, J = 12.2, 3.7 Hz), 4.04 (3H, s), 3.77 (1H) , dd, J = 12.2, 2.4 Hz), 1.59 (3H, d, J = 6.7 Hz).

Examples 16-24
Using the compound of Reference Example 8 as a starting material, the reaction, post-treatment, and purification were carried out according to the same method as described in Example 15 to obtain the compounds shown in the table below.

The compound names of Examples 16 to 24 are described below.
Example 16: (4S) -2- (3,4-dichlorophenyl) -8- (Imidazo [1,2-a] Pyridine-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2] -A] Pyrazine-1 (2H) -one Example 17: (4S) -2- [3-Fluoro-4- (trifluoromethyl) phenyl] -8- (Imidazo [1,2-a] Pyridine-6 -Il) -4-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 18: (4S) -2- (3-chloro-4-fluorophenyl)- 8- (Imidazo [1,2-a] Pyridine-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 19: (4S) -2- (4-Chloro-3-fluorophenyl) -8- (Imidazo [1,2-a] Pyridine-6-yl) -4-Methyl-3,4-dihydropyrrolo [1,2-a] pyrazine -1 (2H) -on Example 20: (4S) -2- (4-fluoro-3-methylphenyl) -8- (Imidazo [1,2-a] Pyridine-6-yl) -4-methyl- 3,4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 21: (4S) -8- (Imidazo [1,2-a] Pyridine-6-yl) -4-methyl -2- [5- (trifluoromethyl) thiophen-2-yl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 22: (4S) -8-( Imidazo [1,2-a] Pyridine-6-yl) -4-Methyl-2- [6- (trifluoromethyl) Pyridine-3-yl] -3,4-dihydropyrrolo [1,2-a] pyrazine -1 (2H) -on Example 23: (4S) -8- (Imidazo [1,2-a] Pyridine-6-yl) -4-Methyl-2- [5- (Trifluoromethyl) Pyridine-2 -Il] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 24: (4S) -2- (3,4-difluorophenyl) -8- (Imidazo [1] , 2-a] Pyridine-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one

６−ブロモイミダゾ［１，２−ａ］ピラジン（１００ｍｇ）、ヘキサメチルジスタナン（１６５ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（５８．３ｍｇ）の１，４−ジオキサン（５ｍｌ）混合物を、アルゴン雰囲気下、８０℃で１０時間撹拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィーにより精製することで６−（トリメチルスタニル）イミダゾ［１，２−ａ］ピラジン（３０ｍｇ）を得た。この工程を複数回行い、得られた６−（トリメチルスタニル）イミダゾ［１，２−ａ］ピラジン（９８．１ｍｇ）、参考例３（１３０ｍｇ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（４８．８ｍｇ）の１，４−ジオキサン（５ｍｌ）混合物を、アルゴン雰囲気下、８０℃で６時間撹拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィーにより精製することで表題の化合物（９ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 9.58 (d, J = 1.6 Hz, 1 H), 9.06 (d, J = 1.2 Hz, 1 H), 8.17 (s, 1 H), 7.77-7.80 (m, 3 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 2.8 Hz, 1 H), 6.89 (d, J = 2.8 Hz, 1 H), 4.64-4.68 (m, 1 H), 4.26-4.31 (m, 1 H), 3.95-4.00 (m, 1 H), 1.55 (d, J = 6.4 Hz, 3 H). Example 25: (4S) -8- (imidazole [1,2-a] pyrazine-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on

A mixture of 1,4-dioxane (5 ml) of 6-bromoimidazole [1,2-a] pyrazine (100 mg), hexamethyldistanan (165 mg), tetrakis (triphenylphosphine) palladium (0) (58.3 mg) , Stirred at 80 ° C. for 10 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography to obtain 6- (trimethylstanyl) imidazole [1,2-a] pyrazine (30 mg). This step was repeated multiple times to obtain 6- (trimethylstanyl) imidazole [1,2-a] pyrazine (98.1 mg), Reference Example 3 (130 mg), dichlorobis (triphenylphosphine) palladium (II) ( A mixture of 48.8 mg) of 1,4-dioxane (5 ml) was stirred at 80 ° C. for 6 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography to give the title compound (9 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 9.58 (d, J = 1.6 Hz, 1 H), 9.06 (d, J = 1.2 Hz, 1 H), 8.17 (s, 1 H), 7.77 -7.80 (m, 3 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 2.8 Hz, 1 H), 6.89 (d, J = 2.8 Hz, 1 H), 4.64- 4.68 (m, 1 H), 4.26-4.31 (m, 1 H), 3.95-4.00 (m, 1 H), 1.55 (d, J = 6.4 Hz, 3 H).

参考例２１の化合物（４０ｍｇ）、ジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）（２７．２ｍｇ）、ビス（ピナコレート）ジボロン（６１．４ｍｇ）、酢酸カリウム（５４．６ｍｇ）の１，４−ジオキサン（５ｍｌ）混合物を、アルゴン雰囲気下、８５℃で３時間撹拌した。反応混合物を室温に冷却し、３−フルオロ−６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）イミダゾ［１，２−ａ］ピリジンの粗体（５０ｍｇ）を得た。３−フルオロ−６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）イミダゾ［１，２−ａ］ピリジンの粗体（４８．６ｍｇ）と参考例３（５７．８ｍｇ）の１，４−ジオキサン（５ｍｌ）混合物に、ジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）（２２．６ｍｇ）、炭酸カリウム（６４ｍｇ）、水（１ｍｌ）を加えた。反応混合物を、アルゴン雰囲気下、８０℃で６時間撹拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィーにより精製することで表題の化合物（１０ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.63 (s, 1 H), 7.77 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.43-7.50 (m, 2 H), 7.31-7.33 (m, 2 H), 6.59 (d, J = 2.4 Hz, 1 H), 4.61-4.65 (m, 1 H), 4.24-4.28 (m, 1 H), 3.94-3.99 (m, 1 H), 1.53 (d, J = 6.8 Hz, 3 H). Example 26: (4S) -8- (3-fluoroimidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4- Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on

Reference Example 21 compound (40 mg), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (27.2 mg), bis (pinacolate) diboron (61.4 mg), potassium acetate (54. A mixture of 6 mg) of 1,4-dioxane (5 ml) was stirred at 85 ° C. for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and crude of 3-fluoro-6- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazole [1,2-a] pyridine. (50 mg) was obtained. 3-Fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazole [1,2-a] pyridine crude (48.6 mg) and reference example A mixture of 3 (57.8 mg) 1,4-dioxane (5 ml), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (22.6 mg), potassium carbonate (64 mg), water. (1 ml) was added. The reaction mixture was stirred at 80 ° C. for 6 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography to give the title compound (10 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.63 (s, 1 H), 7.77 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.43 -7.50 (m, 2 H), 7.31-7.33 (m, 2 H), 6.59 (d, J = 2.4 Hz, 1 H), 4.61-4.65 (m, 1 H), 4.24-4.28 (m, 1 H) ), 3.94-3.99 (m, 1 H), 1.53 (d, J = 6.8 Hz, 3 H).

参考例１８の化合物（１００ｍｇ）、メチルボロン酸（３３．４ｍｇ）、ジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）（２７．２ｍｇ）、炭酸カリウム（７７．１ｍｇ）の 1，4‐ジオキサン（５ｍｌ）／水（１ｍｌ）混合物を８５℃で加熱還流下、６時間撹拌した。反応混合物を室温まで放冷後、水（１０ｍｌ）に加え、酢酸エチル（３０ｍｌ）で３回抽出した。有機層を無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィーにより精製することで、表題の化合物（３ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.53 (s, 1 H), 7.76 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.43 (s, 2 H), 7.30-7.32 (m, 2 H), 6.56 (d, J = 2.4 Hz, 1 H), 4.61-4.65 (m, 1 H), 4.24-4.28 (m, 1 H), 3.94-3.99 (m, 1 H), 2.42 (s, 3 H), 1.54 (d, J = 6.8 Hz, 3 H). Example 27: (4S) -2- [4- (1,1-difluoroethyl) phenyl] -4-methyl-8- (3-methylimidazole [1,2-a] pyridin-6-yl) -3 , 4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on

Reference Example 18 compound (100 mg), methylboronic acid (33.4 mg), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (27.2 mg), potassium carbonate (77.1 mg) The 1,4-dioxane (5 ml) / water (1 ml) mixture was stirred at 85 ° C. under heating and reflux for 6 hours. The reaction mixture was allowed to cool to room temperature, added to water (10 ml), and extracted 3 times with ethyl acetate (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography to give the title compound (3 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.53 (s, 1 H), 7.76 (d, J = 8.8 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 7.43 (s, 2 H), 7.30-7.32 (m, 2 H), 6.56 (d, J = 2.4 Hz, 1 H), 4.61-4.65 (m, 1 H), 4.24-4.28 (m, 1 H), 3.94-3.99 (m, 1 H), 2.42 (s, 3 H), 1.54 (d, J = 6.8 Hz, 3 H).

参考例１９の化合物（６０ｍｇ）と１０％パラジウム／炭素（１２０ｍｇ）のメタノール（４ｍｌ）混合物を、水素雰囲気下、室温で撹拌した。その後、反応混合物をセライトろ過し、メタノールで洗浄した。得られた混合物を減圧濃縮し、残渣を逆相カラムクロマトグラフィーにより精製することで表題の化合物（５ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.61 (s, 1 H), 7.77 (d, J = 8.8 Hz, 2 H), 7.63 (d, J = 8.4 Hz, 2 H), 7.47 (s, 2 H), 7.37 (s, 1 H), 7.32 (d, J = 2.4 Hz, 1 H), 6.58 (d, J = 2.8 Hz, 1 H), 4.62-4.66 (m, 1 H), 4.25-4.29 (m, 1 H), 3.95-4.00 (m, 1 H), 2.81-2.87 (m, 2 H), 1.55 (d, J = 6.8 Hz, 3 H), 1.31 (t, J = 7.4 Hz, 3 H). Example 28: (4S) -8- (3-ethylimidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4- Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on

A mixture of compound (60 mg) of Reference Example 19 and methanol (4 ml) of 10% palladium / carbon (120 mg) was stirred at room temperature under a hydrogen atmosphere. The reaction mixture was then filtered through Celite and washed with methanol. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography to give the title compound (5 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.61 (s, 1 H), 7.77 (d, J = 8.8 Hz, 2 H), 7.63 (d, J = 8.4 Hz, 2 H), 7.47 (s, 2 H), 7.37 (s, 1 H), 7.32 (d, J = 2.4 Hz, 1 H), 6.58 (d, J = 2.8 Hz, 1 H), 4.62-4.66 (m, 1 H) , 4.25-4.29 (m, 1 H), 3.95-4.00 (m, 1 H), 2.81-2.87 (m, 2 H), 1.55 (d, J = 6.8 Hz, 3 H), 1.31 (t, J = 7.4 Hz, 3 H).

Examples 29-38
Using the compound of Reference Example 9 as a starting material, the reaction, post-treatment, and purification were carried out in the same manner as in the method described in Reference Example 13 to obtain the compounds shown in the table below.

The compound names of Examples 29 to 38 are described below.
Example 29: (4S) -2- [3-methoxy-4- (trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1 , 2-a] Pyrazine-1 (2H) -one Example 30: (4S) -2- [3-Fluoro-4- (trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-) 4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 31: 5-[(4S) -4-methyl-8- (2-methylpyridine-4) -Il) -1-oxo-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -yl] -2- (trifluoromethyl) benzonitrile Example 32: (4S) -2- (4-Chloro-3-methoxyphenyl) -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 33: (4S) -2- (4-fluoro-3-methoxyphenyl) -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1,2-a] Pyrazine-1 (2H) -one Example 34: (4S) -2- [4-chloro-3- (cyclopropyloxy) phenyl] -4-methyl-8- (2-methylpyridine-4-yl)- 3,4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 35: (4S) -2- [2-fluoro-4- (trifluoromethyl) phenyl] -4-methyl- 8- (2-Methylpyridine-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 36: (4S) -2- [3-chloro-4 -(Trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one Example 37 : (4S) -4-methyl-8- (2-methylpyridine-4-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine- 1 (2H) -one Example 38: (4S) -4-methyl-8- (2-methylpyridine-4-yl) -2- [3-methyl-4- (trifluoromethyl) phenyl] -3, 4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one

参考例４の化合物（３７５ｍｇ）、（２−メチルピリジン−４−イル）ボロン酸（２６３ｍｇ）の１，２−ジメトキシエタン（５．０ｍＬ）溶液に、２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（２．４ｍＬ）とジクロロビス［ジ−ｔｅｒｔ−ブチル（４−ジメチルアミノフェニル）ホスフィノ］パラジウム（ＩＩ）（３４ｍｇ）を加え、４時間加熱還流した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、濾過した。濾液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（アミノシリカゲル、ヘキサン／酢酸エチル）にて精製した。得られた残渣に４ｍｏｌ／Ｌ塩酸−酢酸エチル（５ｍＬ）を加え、室温で３０分撹拌した後、反応混合物を減圧濃縮した。得られた残渣にジエチルエーテルを加え、懸濁撹拌し、ろ取することにより表題の化合物（２２８ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 8.67-8.62 (1H, m), 8.15 (2H, s), 7.79 (2H, d, J = 8.5 Hz), 7.63 (2H, d, J = 8.5 Hz), 6.55 (1H, d, J = 2.4 Hz), 4.87-4.78 (1H, m), 4.53 (1H, dd, J = 13.1, 4.0 Hz), 3.92 (1H, dd, J = 13.1, 2.1 Hz), 2.68 (3H, s), 1.50 (3H, d, J = 6.1 Hz). Example 39: (4S) -6-fluoro-4-methyl-8- (2-methylpyridine-4-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1 , 2-a] Pyrazine-1 (2H) -one hydrochloride

A 2 mol / L sodium carbonate aqueous solution (2.4 mL) in a solution of compound (375 mg) and (2-methylpyridine-4-yl) boronic acid (263 mg) of Reference Example 4 in 1,2-dimethoxyethane (5.0 mL). And dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (34 mg) were added, and the mixture was heated under reflux for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (amino silica gel, hexane / ethyl acetate). 4 mol / L hydrochloric acid-ethyl acetate (5 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes, and then the reaction mixture was concentrated under reduced pressure. Diethyl ether was added to the obtained residue, the mixture was suspended and stirred, and collected by filtration to give the title compound (228 mg).
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.67-8.62 (1H, m), 8.15 (2H, s), 7.79 (2H, d, J = 8.5 Hz), 7.63 (2H, d, J) = 8.5 Hz), 6.55 (1H, d, J = 2.4 Hz), 4.87-4.78 (1H, m), 4.53 (1H, dd, J = 13.1, 4.0 Hz), 3.92 (1H, dd, J = 13.1, 2.1 Hz), 2.68 (3H, s), 1.50 (3H, d, J = 6.1 Hz).

Examples 40-63
Using the compounds of Reference Example 14, Reference Example 15 or Reference Example 17 as starting materials, the reaction, post-treatment and purification were carried out according to the same method as described in Example 1 to obtain the compounds shown in the table below.

The compound names of Examples 40 to 63 are described below.
Example 40: (7S) -7-methyl-3- (pyrazolo [1,5-a] pyridin-5-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -one Example 41: (7S) -7-methyl-3- (1-methyl-1H-benzoimidazol-5-yl) -5- [4- ( Trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 42: (7S) -7-methyl-3- (3-methyl [1,3-methyl] 2,4] Triazolo [4,3-a] Pyridine-7-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 ( 5H) -on Example 43: (7S) -7-methyl-3- (1-methyl-1H-pyrazolo [3,4-b] pyridin-5-yl) -5- [4- (trifluoromethyl) Phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -on Example 44: (7S) -3- (Imidazo [1,2-a] pyrimidin-6-yl) -7-Methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 45: (7S) -7- Methyl-3- (1-methyl-1H-pyrazolo [3,4-b] Pyridine-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -one Example 46: (7S) -7-methyl-3- (quinoxalin-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7- Dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 47: (7S) -3- (Imidazo [1,5-a] Pyridine-7-yl) -7-Methyl-5- [4- (Trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 48: (7S) -3- (1,4-dimethyl-) 1H-Indazole-5-yl) -7-methyl-5-[4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 49: (7S) -3- (Imidazo [1,5-a] Pyridine-6-yl) -7-Methyl-5- [4- (Trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1 , 5-a] Pyrazine-4 (5H) -on Example 50: (7S)- 7-Methyl-3- (1-methyl-1H-pyrazolo [4,3-b] Pyridine-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1 , 5-a] Pyrazine-4 (5H) -on Example 51: (7S) -7-methyl-3- (1H-pyrazolo [3,4-b] pyridin-5-yl) -5- [4- (Trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -on Example 52: (7S) -3- (Imidazo [1,2-b] pyridazine -6-yl) -7-methyl-5-[4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 53: ( 7S) -3- (Imidazo [1,5-a] Pyridine-7-yl) -7-Methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5- a] Pyrazine-4 (5H) -one Example 54: (7S) -7-methyl-3- (pyrazolo [1,5-a] pyridin-6-yl) -5- [4- (trifluoromethyl) Phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 55: (7S) -7-methyl-3- (3-methylimidazo [1,5-a] ] Pyridine-7-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 56: (7S) -3- (Imidazo [1,5-a] pyrimidine-3-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -one Example 57: (7S) -7-methyl-3- (2-methyl-2H-indazole-4-yl) -5- [5- (trifluoromethyl) thiophen-2- Il] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 58: (7S) -3- (1,3-benzoxazole-5-yl) -7- Methyl-5- [5- (trifluoromethyl) thiophen-2-yl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 59: (7S) -7 -Methyl-3- (4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-yl) -5- [5- (trifluoromethyl) thiophen-2-yl] -6,7 -Dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -On fruit Example 60: (7S) -3- (3,4-dihydro-2H-pyrano [2,3-b] pyridin-6-yl) -7-methyl-5- [5- (trifluoromethyl) thiophene- 2-Il] -6,7-dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on Example 61: (7S) -7-Methyl-3- (quinolin-6-yl) -5 -[5- (Trifluoromethyl) thiophen-2-yl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one Example 62: (7S) -7-methyl- 3- (Pyrazine [1,5-a] pyrimidin-5-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) ) -On Example 63: (7S) -7-methyl-3- (1H-pyrazolo [4,3-b] pyridin-5-yl) -5- [4- (trifluoromethyl) phenyl] -6, 7-Dihydropyrazolo [1,5-a] Pyrazine-4 (5H) -on

参考例２０の化合物（３２０．１ｍｇ）に４ｍｏｌ／Ｌ塩酸−酢酸エチル（４．６ｍＬ）を加え室温で撹拌した。３時間後、反応混合物を減圧濃縮することにより表題の化合物（２６９．７ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 7.90 (1H, s), 7.80 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.61-7.60 (2H, m), 7.20-7.18 (1H, m), 4.83-4.78 (1H, m), 4.36 (1H, dd, J = 12.8, 4.3 Hz), 4.09 (1H, dd, J = 12.8, 7.9 Hz), 3.33 (2H, t, J = 5.8 Hz), 2.81 (2H, t, J = 6.4 Hz), 2.02-1.96 (2H, m), 1.57 (3H, d, J = 6.7 Hz).CDCl₃). Example 64: (7S) -7-methyl-3- (1,2,3,4-tetrahydroquinoline-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazine Zoro [1,5-a] pyrazine-4 (5H) -one hydrochloride

4 mol / L hydrochloric acid-ethyl acetate (4.6 mL) was added to the compound of Reference Example 20 (320.1 mg), and the mixture was stirred at room temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure to give the title compound (269.7 mg).
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ: 7.90 (1H, s), 7.80 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.61-7.60 ( 2H, m), 7.20-7.18 (1H, m), 4.83-4.78 (1H, m), 4.36 (1H, dd, J = 12.8, 4.3 Hz), 4.09 (1H, dd, J = 12.8, 7.9 Hz) , 3.33 (2H, t, J = 5.8 Hz), 2.81 (2H, t, J = 6.4 Hz), 2.02-1.96 (2H, m), 1.57 (3H, d, J = 6.7 Hz). CDCl ₃ ).

Test Examples The pharmacological test methods for the compounds of the present invention and their results are shown below, but the present invention is not limited to these test examples.

（４）時間依存的なｍＧｌｕ２受容体ネガティブアロステリックモジュレーター活性評価
ヒトｍＧｌｕ２受容体安定発現細胞を作製し、培養に供する。ｍＧｌｕ２受容体刺激による発光シグナルの検出にはＦＤＳＳ７０００（浜松ホトニクス）を用いる。細胞及び発光基質を添加したプレートに、上記（２）で調製した試験化合物溶液を添加する（１０μｌ／ｗｅｌｌ）。添加２分後、１５分後、３０分後、６０分後及び１２０分後にそれぞれＥＣ_８０のＧｌｕｔａｍａｔｅ含有溶液を添加し（１０μｌ／ｗｅｌｌ）、添加後３００秒間発光シグナル（中心波長：４６５ｎｍ）を測定してＲＬＵ（Ｉｎｔｅｇｒａｔｉｏｎ）を算出する。化合物各添加時間のｍＧｌｕ２受容体のネガティブアロステリックモジュレーター活性は、（１００−１００×（各化合物の各濃度のＲＬＵ／ＤＭＳＯ群のＲＬＵ））にて算出する。 Test Example 1: Examination using human mGlu2 receptor stable expression cells (1) Human mGlu2 receptor stable expression cells Human mGlu2 receptor stable expression cells were prepared and used for culturing. Specifically, the human mGlu2 receptor gene was inserted into pcDNA4 / TO (K1020-01, Life Technologies, Carlsbad, CA, USA), and TR-expressing human kidney-derived HEK cells (cat # CCL-82.2, ATCC, USA) were inserted. ) Was introduced. Then, the cells were sorted by Geneticin (cat # 10131-027, Lifetechnologies, Carlsbad, CA, USA) to obtain human mGlu2 receptor stable expression cells.
Medium 10% Diarysed-FBS (cat # 26400-044, Lifetechnologies, Carlsbad, CA, USA), 50 μg / mL Blasticidin S (cat # ANT-BL-1, Lifetechnologies, Carlsbad), Carlsbad Cell culture flask using High glucos-DMEM medium (cat # 11995-065, Lifetechnologies, Carlsbad, CA, USA) containing G418 (cat # 16513-84, nacalai tesque, Kyoto, Japan). , AGC Thechno Glass, Shizuoka, Japan). During culturing, cells were collected by TrypLE Express (cat # 12604-013, Lifetechnologies, Carlsbad, CA, USA) treatment every 3 to 4 days, and subcultured.
After 3 to 4 days from passage, cells were collected by TrypLE Express treatment in a state of about 80% confluence, and 0.1% BSA (cat # 12604-013, Lifetechnologies, Carlsbad, CA, USA), 0.1 μg / Hanks (cat # 14065-056, Life Technologies, Carlsbad, CA, USA) / 20 mmol / L HEPES (cat # 14065-056, Carlsbad, CA, USA) / 20 mmol / L HEPES Under CA, USA) Buffer (pH 7.4) medium, Gα16, apoaequourin was transiently introduced, followed by 1,500 cells / 30 μL on a 384-well plate (cat # 781090, Greener bio-one, Frickenhausen, Germany). It was sown so as to be well.
The day after sowing, Coelentorazine h (cat # S2011, Promega, Madison, WI, USA) was added to a final concentration of 1 μmol / L (10 μl / well), and the mixture was allowed to stand at room temperature for 4 hours or more after centrifugation.
(2) Preparation of test compound The test compound was dissolved using DMSO so as to have a concentration 1000 times the evaluation concentration. This DMSO solution was diluted with medium (Hanks, 20 mmol / L HEPES, 0.1% BSA) to a concentration 6 times the evaluation concentration. Glutamate was diluted in Hanks / 20 mmol / L HEPES / 0.1% BSA medium to a concentration 6 times the EC ₈₀ concentration.
(3) Evaluation of mGlu2 Receptor Negative Allosteric Modulator Activity Human mGlu2 receptor stable expression cells were prepared and used for culturing. FDSS7000 (Hamamatsu Photonics) was used to detect the luminescence signal stimulated by the mGlu2 receptor. The compound solution prepared above was added to the plate to which the cells and the luminescent substrate were added (10 μl / well). 120 seconds after the addition, a Glutamic acid-containing solution of EC ₈₀ was added (10 μl / well), and the emission signal (center wavelength: 465 nm) was measured for 300 seconds after the addition to calculate RLU (Integration). The negative allosteric modulator activity of the mGlu2 receptor of the compound was calculated by (100-100 × (RLU of each concentration of each compound / RLU of the DMSO group)).
When the compound of the present invention was evaluated in the above-mentioned biological test, a compound showing mGlu2 receptor negative allosteric modulator activity was found. MGlu2 receptor negative allosteric modulator activity of each compound is shown _{(IC 50} values (nmol / L)) in the following Table.

(4) Evaluation of time-dependent mGlu2 receptor negative allosteric modulator activity Human mGlu2 receptor stable expression cells are prepared and used for culturing. FDSS7000 (Hamamatsu Photonics) is used to detect the luminescence signal stimulated by the mGlu2 receptor. The test compound solution prepared in (2) above is added to the plate to which the cells and the luminescent substrate have been added (10 μl / well). 2 minutes, 15 minutes, 30 minutes, 60 minutes, and 120 minutes after the addition, a Glutamic acid-containing solution of EC ₈₀ was added (10 μl / well), and the emission signal (center wavelength: 465 nm) was measured for 300 seconds after the addition. Then, RLU (Integration) is calculated. The negative allosteric modulator activity of the mGlu2 receptor at each compound addition time is calculated as (100-100 × (RLU of each concentration of each compound / RLU of the DMSO group)).

Test Example 2: Rat forced swimming test In the rat forced swimming test, existing antidepressants (tricyclic antidepressants, serotonin reuptake inhibitors, etc.) are known to reduce immobility time. Therefore, using this test system, the antidepressant effect of the compound of the present invention will be examined using the immobility time as an index.
A rat forced swimming test is performed using 7-week-old male Wistar rats. That is, after putting the animal in a water tank filled with tap water (water temperature 25 ± 1 ° C.) of 5.8 L, the animal is allowed to swim for 15 minutes (swimming training). Immediately after the swimming training, wipe off the water droplets on the animal and return it to the home cage. The day after the swimming training, the swimming test is carried out by allowing the animals to swim for 5 minutes in the same manner as the swimming training. The swimming behavior of each individual is photographed with a video camera from the side of the aquarium. After the swimming test was completed, the water droplets adhering to the animals were immediately wiped off and returned to the home cage. The test compound, imipramine, which is a positive control, is suspended in a 0.5% methylcellulose solution and orally administered. Administration of the vehicle and test compound is performed 15 minutes after the end of swimming training and 2 hours before the swimming test. Administration of imipramine is performed 15 minutes after the end of swimming training and 1 hour before the swimming test. The state in which an animal is floating in a water tank without moving its forelimbs and torso is defined as akinesia, and the cumulative value of the time showing immobility in a 5-minute swimming test is measured as the akinesia time of the individual. .. Student's t-test and Dunnett's multiplex comparison are used for statistical processing.

Test Example 3: Rat cortical EEG γ frequency band power enhancing effect γ frequency band power change in cortical EEG is considered to be an index of cortical activity, and is an antagonist of mGluR2, NAM, or an antagonist of NMDA receptor (Ketamine, etc.). Is known to enhance the γ frequency band power. Whether or not the compound of the present invention also exhibits a γ frequency band enhancing effect will be examined.
The test is performed in the dark period using male Wistar rats that have undergone electroencephalography electrode placement surgery. The compound is suspended in a 0.5% methylcellulose solution and administered orally. The electroencephalogram measurement and frequency analysis follow the method described in Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 6-13. The frequency analysis of the brain wave is performed between 0.5 and 80 Hz, and the power value is calculated with the frequency band of 30 to 80 Hz as the γ frequency band. With the pre-administration value as 100%, the power change up to 2 hours after administration is totaled every hour. For statistical processing, Dunnett's multiple comparison is performed after two-way ANOVA in consideration of repeated measurements.

Test Example 4: CYP3A4 MBI and enzyme inactivation clearance assessment Cytochrome P450 (hereafter CYP) is the most important group of enzymes involved in drug metabolism, and most of the pharmacokinetic interactions are based on inhibition of these CYP activities. There are multiple molecular species of CYP, and in particular, CYP3A4 is most involved in the metabolism of pharmaceuticals in the oxidation reaction by CYP, and accounts for most of the CYP present in the liver.
There are two major types of CYP inhibition modes, "reversible inhibition" and "mechanism-based inhibition (MBI)". In particular, MBI-based CYP inhibition is not only a drug interaction but also a serious side effect (liver). It is known to cause toxicity (Curr Opin Drug Discov Devel. 2010 Journal, 13 (1), 66-77, Therapeutics and Clinical Risk Management, 2005, 1 (1), 3-13).
Human liver microsomes are used as the enzyme source, and midazolam or testosterone is used as the substrate, and the inhibitory effect and inhibitory mode of the test compound on CYP3A4 are evaluated. After the metabolic reaction at 37 ° C. for 30 minutes, the substrate-derived metabolic products of the test compound-added group (4 concentrations) and the substrate-derived metabolic products of the non-added group were measured by LC-MS / MS, and the inhibition rate was measured from the ratio. To calculate. Further, _{IC 50} values are calculated from the density plot. When the test compound has an MBI effect, it is known that the IC ₅₀ is lowered by adding a substrate after preincubation in the presence of NADPH (cofactor) and initiating the reaction (Xenobiotica, 2009). , 39 (2), 99-112), variation of _{an IC 50} value by preincubation determines that there MBI effect if more than twice.
If MBI effect was observed, k _{inact (maximum} enzyme inactivation rate constant) and K _{I (concentration} of inhibitor resulting in 50% of the speed of the maximum enzyme inactivation rate) is calculated by a nonlinear least square method .. Furthermore, Drug Metabolism and Disposition, 2011,39 ( 7), according to the method described in 1247-1254, to calculate the enzyme inactivation clearance _{(CL int = k inact / K} I (ml / min / mmol) × CYP contents (pmol / mg protein)).

As described above, the compounds of the present invention exhibit a negative regulatory effect on Group II metabotropic glutamate (mGlu) receptors. Therefore, the compounds of the present invention are useful as therapeutic and / or prophylactic agents for diseases involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3).

Claims (53)

A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.

[During the ceremony,
R ¹ and R ² are independently hydrogen atom, halogen atom, cyano, C _1-4 alkyl or C _3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are each independently, respectively. Represents (may be substituted with the same or different 1-5 substituents, selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy);
Alternatively, R ¹ and R ² may be combined with the carbon atom to which they are attached to form a C _3-4 saturated carbocyclic group (the saturated carbocyclic group comprises a group consisting of halogen atoms, hydroxy and C _1-4 alkoxy. It may be substituted with the same or different 1 to 5 substituents of choice);
Ring A represents a C _6-10 aromatic carbocyclic group, a 4-10 member saturated heterocyclic group or a 5-10 member aromatic heterocyclic group;
R ³ and R ⁴ are independently hydrogen atom, halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-4 alkoxy, C _1-4 alkyl thio, C _2-4 alkenyl, 4 to 6 members. Saturated heterocyclic groups or 5- or 6-membered aromatic heterocyclic groups (the alkyl, the alkoxy, the alkylthio, the saturated heterocyclic group and the aromatic heterocyclic group are independently the same or different 1- It may be substituted with 5 halogen atoms), a C _3-6 saturated carbocyclic group, or a C _3-6 cycloalkoxy (the saturated carbocyclic group and the cycloalkoxy are independently each of the halogen atom and the halogen atom and the cycloalkoxy. C (may be substituted with the same or different 1-5 substituents selected from the group consisting of _1-4 alkyl);
Ring B represents a C _6-10 aromatic carbocyclic group, a 4-10 member saturated heterocyclic group or a 5-10 member aromatic heterocyclic group;
R ⁵ and R ⁶ are independently hydrogen atom, halogen atom, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, 4- to 6-membered saturated heterocyclic group ( The alkyl, the alkoxy, the alkylthio and the saturated heterocyclic group are each independently from C _1-4 alkoxy which may be substituted with halogen atom, hydroxy and 1 to 5 halogen atoms which are the same or different. C _3-6 cycloalkoxy, C _3-6 saturated carbocyclic group (the cycloalkoxy and the saturated carbocyclic ring), which may be substituted with the same or different 1 to 5 substituents selected from the group Each group is independently selected from the group consisting of halogen atoms, hydroxy, C _1-4 alkyl, and C _1-4 alkoxy optionally substituted with the same or different 1-5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents), -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d- C (O) -OR ^c ,- NR ^d- C (O) -NR ^a R ^b , -NR ^d -SO _2- R ^c , -CH _2- C (O) -NR ^a R ^b , -C (O) -R ^d , -C (O) ) -OR ^d , or -C (O) -NR ^a R ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom and C _1-4 alkyl (the alkyl is independent of each other). It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), C _3-6 saturated carbocyclic groups or 4 to 4 to A 6-membered saturated heterocyclic group (the saturated carbocyclic group and the saturated heterocyclic group are each independently selected from the group consisting of halogen atom, hydroxy, C _1-4 alkyl and C _1-4 alkoxy. It may be substituted with the same or different 1 to 5 substituents);
Alternatively, ^Ra and R ^b may be a 4- to 6-membered nitrogen-containing saturated heterocyclic group together with the nitrogen atom to which they are bonded (the nitrogen-containing saturated heterocyclic group is a halogen atom, hydroxy, C _1-4. It may be substituted with the same or different 1-5 substituents selected from the group consisting of alkyl and C _1-4 alkoxy);
If there are a plurality of ^Rc , each of them is independently C _1-4 alkyl, C _3-6 saturated carbocyclic group or 4- to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and the saturated heterocyclic group). The ring groups each independently represent (may be optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy);
R ^d may be a hydrogen atom, a C _1-4 alkyl, a C _3-6 saturated carbocyclic group or a 4- to 6-membered saturated heterocyclic group (the alkyl, the saturated carbon ring group and Each of the saturated heterocyclic groups independently represents the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C _1-4 alkoxy). ;
X represents a nitrogen atom or CR ^e ;
^Re is a hydrogen atom, a halogen atom, a cyano, a hydroxy, a C _1-4 alkyl, a C _1-4 alkoxy or -C (O) -NR ^a R ^b (the alkyl and the alkoxy are the same or different 1 to 5). May be replaced with a halogen atom or hydroxy);
However, when X is a nitrogen atom, ring B is not azetidine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, pyridine, isoxazole, imidazole, or oxadiazole] R ¹ and R ² are independently selected from the group consisting of hydrogen atom or C _1-4 alkyl (the alkyl is a halogen atom, hydroxy and C _1-4 alkoxy, 1 to 5 identical or different). , Or R ¹ and R ² together with the carbon atoms to which they are attached to form a cyclopropane or cyclobutane ring.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Ring A is benzene, naphthalene, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isooxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indridin, imidazopyridine, triazolopyridine, 1,3 -Benzodioxol, chromane, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-inden or 2,3-dihydro-1H-inden-1-one,
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. R ³ and R ⁴ are independent of each other
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl, which may be substituted with the same or different 1 to 5 halogen atoms,
(6) C _1-4 alkoxy, which may be substituted with the same or different 1 to 5 halogen atoms,
(7) C _3-6 cycloalkoxy (the cycloalkoxy may be substituted with the same or different 1-5 substituents selected from the group consisting of C _1-4 alkyl and halogen atoms), Or (8) C _1-4 alkylthio, which may be substituted with the same or different 1-5 halogen atoms.
The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring B is benzene or a 5- to 10-membered aromatic heterocyclic group. R ⁵ and R ⁶ are independent of each other
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl (the alkyl is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(6) C _1-4 Alkoxy (The alkoxy is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(7) 4- to 6-membered saturated heterocyclic group (the saturated heterocyclic group consists of a halogen atom, hydroxy, and C _1-4 alkoxy which may be substituted with the same or different 1 to 5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents selected from the group), or (8) -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d. -C (O) -OR ^c , -NR ^d -C (O) -NR ^a R ^b , -NR ^d -SO _2- R ^c , -CH _2- C (O) -NR ^a R ^b , -C ( O) -R ^d , -C (O) -OR ^d , or -C (O) -NR ^a R ^b ,
The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom or C _1-4 alkyl (the alkyl is independent of each other). It may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), or ^Ra and R ^b are them. A group of 4 to 6-membered nitrogen-containing saturated heterocyclic groups (the nitrogen-containing saturated heterocyclic group consists of a halogen atom, hydroxy, C _1-4 alkyl and C _1-4 alkoxy) together with the nitrogen atom to which is bonded. (May be substituted with the same or different 1 to 5 substituents) selected from
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. If there are a plurality of R ^cs , they are independently C _1-4 alkyl or C _3-6 saturated carbocyclic groups (the alkyl and the saturated carbocyclic groups are independently halogen atoms, hydroxy and C _{1). -4} Substituents may be substituted with the same or different 1-5 substituents selected from the group consisting of alkoxy).
The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. If there are multiple R ^ds , they are independent of each other.
(1) Hydrogen atom,
(2) C _1-4 alkyl (the alkyl may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), Or (3) C _3-6 saturated carbocyclic group (the saturated carbocyclic group is substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C _1-4 alkoxy. May have been),
The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof. ^Re
(1) Hydrogen atom,
(2) a halogen atom, or (3) a C _1-4 alkyl which may be substituted with 1 to 5 halogen atoms which are the same or different.
The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is represented by the following formula (1a).

[During the ceremony,
R ¹ and R ² are each independently selected from the group consisting of a hydrogen atom or a C _1-4 alkyl (the alkyl is a halogen atom, a hydroxy and a C _1-4 alkoxy, the same or different 1 to 5). a of which may be substituted with a substituent), or, R ¹ and R ² together with the carbon atoms to which they are attached, may form a cyclopropane ring or a cyclobutane ring;
Ring A is benzene, naphthalene, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isooxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indridin, imidazopyridine, triazolopyridine, 1,3. -Represents benzodioxol, chromane, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-inden or 2,3-dihydro-1H-inden-1-one;
R ³ and R ⁴ are independent of each other.
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl, which may be substituted with the same or different 1 to 5 halogen atoms,
(6) C _1-4 alkoxy, which may be substituted with the same or different 1 to 5 halogen atoms,
(7) C _3-6 cycloalkoxy (the cycloalkoxy may be substituted with the same or different 1-5 substituents selected from the group consisting of C _1-4 alkyl and halogen atoms), Or (8) represents a C _1-4 alkylthio which may be substituted with the same or different 1-5 halogen atoms;
Ring B represents a 5- to 10-membered aromatic heterocyclic group, where ring B is not pyridine, isooxazole, imidazole, or oxadiazole;
R ⁵ and R ⁶ are independent of each other.
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl (the alkyl is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(6) C _1-4 Alkoxy (The alkoxy is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(7) 4- to 6-membered saturated heterocyclic group (the saturated heterocyclic group consists of a halogen atom, hydroxy, and C _1-4 alkoxy which may be substituted with the same or different 1 to 5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents selected from the group), or (8) -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d. -C (O) -OR ^c , -NR ^d -C (O) -NR ^a R ^b , -NR ^d -SO _2- R ^c , -CH _2- C (O) -NR ^a R ^b , -C ( Represents O) -R ^d , -C (O) -OR ^d , or -C (O) -NR ^a R ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom or C _1-4 alkyl (the alkyl is independent of each other). It may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), or ^Ra and R ^b are them. A group of 4 to 6-membered nitrogen-containing saturated heterocyclic groups (the nitrogen-containing saturated heterocyclic group consists of a halogen atom, hydroxy, C _1-4 alkyl and C _1-4 alkoxy) together with the nitrogen atom to which is bonded. It may be substituted with the same or different 1 to 5 substituents selected from);
If there are a plurality of ^Rc , each of them is independent of C _1-4 alkyl or C _3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are independently each of a halogen atom, hydroxy and C _{1). Represents} (may be substituted with the same or different 1-5 substituents, selected from the group consisting of _-4 alkoxy);
If there are multiple R ^d , each is independent.
(1) Hydrogen atom,
(2) C _1-4 alkyl (the alkyl may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), Or (3) C _3-6 saturated carbocyclic group (the saturated carbocyclic group is substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C _1-4 alkoxy. Represents (may be)] Ring B is pyrimidine, pyrazine, pyridazine, imidazole pyridine, imidazole pyrimidine, imidazole pyridazine, indolizine, indazole, benzoimidazole, benzoxazole, benzothiazole, triazolopyridine, triazolopyrimidine, triazolopyrazine, pyrazolopyridine, pyra The compound according to claim 11, or a pharmaceutically acceptable salt thereof, which is zolopyridazine, pyrazolopyrazine, quinoline, isoquinoline, quinoxaline, quinazoline, dihydrobenzoxazine, dihydropyranopyridine or tetrahydroquinolin. Ring B is imidazole pyridine, imidazole pyrimidine, imidazole pyridazine, indazole, benzimidazole, benzoxazole, triazolopyridine, pyrazolopyridine, pyrazolopyrimidine, quinoline, quinoxalin, dihydrobenzoxazine, dihydropyranopyridine or tetrahydroquinoline. , The compound according to claim 11 or claim 12, or a pharmaceutically acceptable salt thereof. Ring B is from the following formula (1a-1) to (1a-17):

[During the ceremony,
W ¹ , W ² and W ³ each independently represent a nitrogen atom or CR ^f (where at least two or more of W ¹ , W ² and W ³ are CR ^f ).
W ⁴ and W ⁵ each independently represent a nitrogen atom or CR ^f (provided that at least one of W ⁴ and W ⁵ is a nitrogen atom).
R ^f independently represents a hydrogen atom, a fluorine atom or methyl]
Any one of the substituents selected from the group consisting of the substituents represented by.
The compound according to any one of claims 11 to 13, or a pharmaceutically acceptable salt thereof. Ring B is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1a-1) to (1a-9).
R ^f is a hydrogen atom,
The compound according to claim 14 or a pharmaceutically acceptable salt thereof. Ring B is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1a-1) to (1a-3).
R ^f is a hydrogen atom,
The compound according to claim 14 or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is represented by the following formula (1b).

[During the ceremony,
R ¹ and R ² are each independently selected from the group consisting of a hydrogen atom or a C _1-4 alkyl (the alkyl is a halogen atom, a hydroxy and a C _1-4 alkoxy, the same or different 1 to 5). a of which may be substituted with a substituent), or, R ¹ and R ² together with the carbon atoms to which they are attached, may form a cyclopropane ring or a cyclobutane ring;
Ring A is benzene, naphthalene, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isooxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indridin, imidazopyridine, triazolopyridine, 1,3. -Represents benzodioxol, chromane, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, 2,3-dihydro-1H-inden or 2,3-dihydro-1H-inden-1-one;
R ³ and R ⁴ are independent of each other.
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl, which may be substituted with the same or different 1 to 5 halogen atoms,
(6) C _1-4 alkoxy, which may be substituted with the same or different 1 to 5 halogen atoms,
(7) C _3-6 cycloalkoxy (the cycloalkoxy may be substituted with the same or different 1-5 substituents selected from the group consisting of C _1-4 alkyl and halogen atoms), Or (8) represents a C _1-4 alkylthio which may be substituted with the same or different 1-5 halogen atoms, and ring B represents a 5-10 membered aromatic heterocyclic group;
R ⁵ and R ⁶ are independent of each other.
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl (the alkyl is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(6) C _1-4 Alkoxy (The alkoxy is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(7) 4- to 6-membered saturated heterocyclic group (the saturated heterocyclic group consists of a halogen atom, hydroxy, and C _1-4 alkoxy which may be substituted with the same or different 1 to 5 halogen atoms. It may be substituted with the same or different 1 to 5 substituents selected from the group), or (8) -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d. -C (O) -OR ^c , -NR ^d -C (O) -NR ^a R ^b , -NR ^d -SO _2- R ^c , -CH _2- C (O) -NR ^a R ^b , -C ( Represents O) -R ^d , -C (O) -OR ^d , or -C (O) -NR ^a R ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom or C _1-4 alkyl (the alkyl is a halogen atom, It may be substituted with the same or different 1-5 substituents selected from the group consisting of hydroxy and C _1-4 alkoxy), or ^Ra and R ^b are the nitrogen atoms to which they are attached. Together with a 4- to 6-membered nitrogen-containing saturated heterocyclic group, the nitrogen-containing saturated heterocyclic group is selected from the group consisting of halogen atoms, hydroxy, C _1-4 alkyl and C _1-4 alkoxy. It may be substituted with the same or different 1 to 5 substituents);
If there are a plurality of ^Rc , each of them is independent of C _1-4 alkyl or C _3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are independently each of a halogen atom, hydroxy and C _{1). Represents} (may be substituted with the same or different 1-5 substituents, selected from the group consisting of _-4 alkoxy);
If there are multiple R ^d , each is independent.
(1) Hydrogen atom,
(2) C _1-4 alkyl (the alkyl may be substituted with the same or different 1-5 substituents selected from the group consisting of halogen atoms, hydroxy and C _1-4 alkoxy), Or (3) C _3-6 saturated carbocyclic group (the saturated carbocyclic group is substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy and C _1-4 alkoxy. Represents (may be);
^Re is
(1) Hydrogen atom,
(2) Represents a halogen atom, or (3) C _1-4 alkyl which may be substituted with the same or different 1 to 5 halogen atoms] Ring B is pyridine, pyrimidine, pyrazine, pyridazine, imidazole pyridine, imidazole pyrimidine, imidazole pyridazine, indridin, indazole, benzoimidazole, benzoxazole, benzothiazole, triazolopyridine, triazolopyrimidine, triazolopyrazine, pyrazolopyridine , Pyrazolopyrimidine, pyrazolopyrazine, quinoline, isoquinolin, quinoxaline, quinazoline, dihydrobenzoxazine, dihydropyranopyridine or tetrahydroquinoline, the compound of claim 17 or a pharmaceutically acceptable salt thereof. Ring B is pyridine, imidazole pyridine, imidazole pyrimidine, imidazole pyridazine, indazole, benzoimidazole, benzoxazole, triazolopyridine, pyrazolopyridine, pyrazolopyrimidine, quinoline, quinoxalin, dihydrobenzoxazine, dihydropyranopyridine or tetrahydroquinoline. The compound according to claim 17 or claim 18, or a pharmaceutically acceptable salt thereof. Ring B is from the following formula (1b-1) to (1b-19):

[During the ceremony,
W ¹ , W ² and W ³ each independently represent a nitrogen atom or CR ^f (where at least two or more of W ¹ , W ² and W ³ are CR ^f ).
W ⁴ and W ⁵ each independently represent a nitrogen atom or CR ^f (provided that at least one of W ⁴ and W ⁵ is a nitrogen atom).
R ^f independently represents a hydrogen atom, a fluorine atom or methyl]
Any one of the substituents selected from the group consisting of the substituents represented by.
The compound according to any one of claims 17 to 19, or a pharmaceutically acceptable salt thereof. Ring B is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1b-1) to (1b-9).
R ^f is a hydrogen atom,
The compound according to claim 20 or a pharmaceutically acceptable salt thereof. Ring B is any one of the substituents selected from the group consisting of the substituents represented by the formulas (1b-1) to (1b-4).
R ^f is a hydrogen atom,
The compound according to claim 20 or a pharmaceutically acceptable salt thereof. ^Re
(1) Hydrogen atom,
The compound according to any one of claims 17 to 22, which comprises (2) a fluorine atom or (3) a C _1-4 alkyl which may be substituted with 1 to 5 halogen atoms which are the same or different. Or its pharmaceutically acceptable salt. The compound according to any one of claims 17 to 23, or a pharmaceutically acceptable salt thereof, wherein ^Re is a hydrogen atom or a fluorine atom. The compound according to any one of claims 17 to 24, or a pharmaceutically acceptable salt thereof, wherein ^Re is a hydrogen atom or a fluorine atom. R ¹ and R ² are independently hydrogen atoms, methyl, ethyl, isopropyl, cyclopropyl, methoxymethyl, hydroxymethyl, difluoromethyl or trifluoromethyl, or R ¹ and R ² are bound together. The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, which forms a cyclopropane ring or a cyclobutane ring together with a carbon atom. Any one of claims 1 to 26, wherein ring A is benzene, naphthalene, pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, quinoline, isoquinoline, benzothiophene or benzofuran. The compound according to the section or a pharmaceutically acceptable salt thereof. R ³ and R ⁴ are independent of each other
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) C _1-4 alkyl, which may be substituted with the same or different 1 to 5 halogen atoms,
(5) C _1-4 alkoxy which may be substituted with the same or different 1 to 5 halogen atoms, or (6) C _3-6 cycloalkoxy (the cycloalkoxy is C _1-4 alkyl and a halogen atom). The compound according to any one of claims 1 to 27, which is selected from the group consisting of (may be substituted with the same or different 1 to 5 substituents), or the pharmaceuticals thereof. Tolerant salt. R ⁵ and R ⁶ are independent of each other
(1) Hydrogen atom,
(2) Halogen atom,
(3) Cyano,
(4) Hydroxy,
(5) C _1-4 alkyl (the alkyl is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(6) C _1-4 Alkoxy (The alkoxy is selected from the group consisting of halogen atoms, hydroxys, and C _1-4 alkoxys which may be substituted with the same or different 1-5 halogen atoms, the same. Alternatively, it may be substituted with 1 to 5 different substituents),
(7) 4- to 6-membered saturated heterocyclic group (the saturated heterocyclic group consists of halogen atoms, hydroxy, and C _1-4 alkoxy which may be substituted with 1 to 5 halogen atoms which are the same or different. 1 to 5 of claims 1 to 28, which are selected from the group and may be substituted with the same or different 1 to 5 substituents) or (8) -NR ^{a Rb.} The compound described or a pharmaceutically acceptable salt thereof. R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independent of a hydrogen atom or C _1-4 alkyl (the alkyl is a halogen atom, The one according to any one of claims 1 to 29, which is selected from the group consisting of hydroxy and C _1-4 alkoxy and may be substituted with the same or different 1 to 3 substituents). Compound or pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 30, wherein R ¹ and R ² are each independently a hydrogen atom, methyl, ethyl or trifluoromethyl, or a pharmaceutically acceptable compound thereof. salt. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein ring A is benzene, pyridine or thiophene. R ³ and R ⁴ are each independently hydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl, trifluoromethyl, methoxy or cyclopropoxy, claimed in any of claims 32 Compound or a pharmaceutically acceptable salt thereof. R ⁵ and R ⁶ are independently substituted with hydrogen atom, halogen atom, cyano, hydroxy, 1 to 5 halogen atoms which are the same or different, C _1-4 alkyl, or -NR ^a R. ^b ;
R ^a and R ^b are independent of each other, and when there are a plurality of NR ^a R ^b , each of R ^a or R ^b is independently replaced with a hydrogen atom or the same or different 1 to 3 halogen atoms. The compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, which is a C _1-4 alkyl which may be used. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl and R ² is a hydrogen atom. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein ring A is benzene. The compound according to any one of claims 1 to 36, or a pharmaceutical product thereof, wherein R ³ and R ⁴ are independently hydrogen atom, fluorine atom, chlorine atom, methyl, trifluoromethyl or methoxy. Physically acceptable salt. The compound according to any one of claims 1 to 37, or a pharmaceutical product thereof, wherein R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, C _1-4 alkyl or -NH _2. Tolerable salt. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
(4S) -8- (Imidazo [1,2-a] Pyrazine-6-yl) -4-Methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -4-Methyl-8- (1-methyl-1H-indazole-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] Pyrazine-1 (2H) -on;
(4S) -8- (Imidazo [1,5-a] Pyrazine-7-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -4-methyl-8- (pyrazolo [1,5-a] pyridin-5-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -8- (Imidazo [1,5-a] Pyrazine-6-yl) -4-Methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -4-methyl-8- (quinoline-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -On;
(4S) -6-fluoro-8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
(4S) -6-fluoro-4-methyl-8- (quinoline-6-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine- 1 (2H) -on;
(4S) -2- (3,4-dichlorophenyl) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine -1 (2H) -on;
(4S) -2- [3-Fluoro-4- (trifluoromethyl) phenyl] -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
(4S) -2- (3-Chloro-4-fluorophenyl) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -8- (Imidazo [1,2-a] Pyrazine-6-yl) -4-methyl-2- [5- (trifluoromethyl) thiophen-2-yl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
(4S) -8- (Imidazo [1,2-a] Pyrazine-6-yl) -4-Methyl-2- [6- (trifluoromethyl) Pyrazine-3-yl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
(4S) -8- (Imidazo [1,2-a] pyrazine-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -8- (3-fluoroimidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1 , 2-a] Pyrazine-1 (2H) -on;
(4S) -2- [4- (1,1-difluoroethyl) phenyl] -4-methyl-8- (3-methylimidazo [1,2-a] pyridin-6-yl) -3,4-dihydro Pyrrolo [1,2-a] pyrazine-1 (2H) -one; and (4S) -8- (3-ethylimidazo [1,2-a] pyridin-6-yl) -4-methyl-2- [ 4- (Trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
(4S) -8- (Imidazo [1,2-a] Pyrazine-6-yl) -4-Methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -8- (Imidazo [1,5-a] Pyrazine-7-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -8- (Imidazo [1,5-a] Pyrazine-6-yl) -4-Methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -6-fluoro-8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
(4S) -2- (3,4-dichlorophenyl) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2-a] pyrazine -1 (2H) -on;
(4S) -2- [3-Fluoro-4- (trifluoromethyl) phenyl] -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [ 1,2-a] Pyrazine-1 (2H) -on;
(4S) -2- (3-Chloro-4-fluorophenyl) -8- (imidazole [1,2-a] pyridin-6-yl) -4-methyl-3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -8- (Imidazo [1,2-a] pyrazine-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2- a] Pyrazine-1 (2H) -on;
(4S) -8- (3-fluoroimidazole [1,2-a] pyridin-6-yl) -4-methyl-2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1 , 2-a] Pyrazine-1 (2H) -on;
(4S) -2- [4- (1,1-difluoroethyl) phenyl] -4-methyl-8- (3-methylimidazo [1,2-a] pyridin-6-yl) -3,4-dihydro Pyrrolo [1,2-a] pyrazine-1 (2H) -one; and (4S) -8- (3-ethylimidazo [1,2-a] pyridin-6-yl) -4-methyl-2- [ 4- (Trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -one. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
(4S) -2- [3-Methoxy-4- (trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1,2-a ] Pyrazine-1 (2H) -on;
(4S) -2- [3-Fluoro-4- (trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1,2-a ] Pyrazine-1 (2H) -on;
(4S) -2- [3-Chloro-4- (trifluoromethyl) phenyl] -4-methyl-8- (2-methylpyridine-4-yl) -3,4-dihydropyrrolo [1,2-a ] Pyrazine-1 (2H) -on;
(4S) -4-methyl-8- (2-methylpyridine-4-yl) -2- [4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a] pyrazine-1 (2H) -On;
(4S) -4-Methyl-8- (2-Methylpyridine-4-yl) -2- [3-Methyl-4- (trifluoromethyl) phenyl] -3,4-dihydropyrrolo [1,2-a ] Pyrazine-1 (2H) -one; and (4S) -6-fluoro-4-methyl-8- (2-methylpyridine-4-yl) -2- [4- (trifluoromethyl) phenyl] -3 , 4-Dihydropyrrolo [1,2-a] pyrazine-1 (2H) -on. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
(7S) -7-Methyl-3- (pyrazolo [1,5-a] pyridin-5-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5] -A] Pyrazine-4 (5H) -on;
(7S) -3- (Imidazo [1,2-a] pyrimidin-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -on;
(7S) -7-Methyl-3- (quinoxaline-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) ) -On;
(7S) -3- (Imidazo [1,5-a] Pyridine-6-yl) -7-Methyl-5- [4- (Trifluoromethyl) Phenyl] -6,7-Dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -on;
(7S) -7-Methyl-3- (1-methyl-1H-pyrazolo [4,3-b] Pyridine-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydro Pyrazolo [1,5-a] Pyrazine-4 (5H) -on;
(7S) -3- (Imidazo [1,2-b] pyridazine-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -on;
(7S) -3- (Imidazo [1,5-a] Pyridine-7-yl) -7-Methyl-5- [4- (Trifluoromethyl) Phenyl] -6,7-Dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -on;
(7S) -7-Methyl-3- (3-methylimidazole [1,5-a] pyridine-7-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [ 1,5-a] Pyrazine-4 (5H) -on;
(7S) -7-Methyl-3- (quinoline-6-yl) -5- [5- (trifluoromethyl) thiophen-2-yl] -6,7-dihydropyrazolo [1,5-a] pyrazine -4 (5H) -on;
(7S) -7-Methyl-3- (1H-pyrazolo [4,3-b] pyridin-5-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1] , 5-a] Pyrazine-4 (5H) -one; and (7S) -7-methyl-3- (1,2,3,4-tetrahydroquinolin-6-yl) -5- [4- (trifluoro) Methyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
(7S) -3- (Imidazo [1,2-a] pyrimidin-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -on;
(7S) -7-Methyl-3- (quinoxaline-6-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) ) -On;
(7S) -3- (Imidazo [1,5-a] Pyridine-6-yl) -7-Methyl-5- [4- (Trifluoromethyl) Phenyl] -6,7-Dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -on;
(7S) -3- (Imidazo [1,2-b] pyridazine-6-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -on;
(7S) -3- (Imidazo [1,5-a] Pyridine-7-yl) -7-Methyl-5- [4- (Trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5 -A] Pyrazine-4 (5H) -one; and (7S) -7-methyl-3- (3-methylimidazo [1,5-a] pyridin-7-yl) -5- [4- (trifluoro) Methyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H) -one. A pharmaceutical composition containing the compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof. A therapeutic agent and / or a prophylactic agent for a disease involving a Group II mGlu receptor, which comprises the compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof as an active ingredient. .. The therapeutic and / or prophylactic agent according to claim 45, wherein the group II mGlu receptor is a metabotropic glutamate receptor subtype 2 (mGluR2). The therapeutic and / or prophylactic agent according to claim 45 or 46, wherein the disease involving the Group II mGlu receptor is a psychiatric disorder or a neurodegenerative disease. Psychiatric or neurodegenerative disorders include depressive disorders, depressive disorders, bipolar disorders and related disorders, anxiety disorders, post-traumatic stress disorders, compulsive disorders, acute stress disorders, schizophrenia, autism spectrum disorders The therapeutic and / or prophylactic agent according to claim 47, which is Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, convulsions, tremor, pain or sleep disorder. The compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof for producing a therapeutic agent and / or a preventive agent for a disease involving the Group II mGlu receptor. use. The compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving the Group II mGlu receptor. Group II mGlu acceptance comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof. A method for treating and / or preventing a disease involving the body. A drug containing the compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, and depressive disorder, depressive disorder, bipolar disorder and related disorders, anxiety disorder, Post-traumatic stress disorder, obsessive disorder, acute stress disorder, schizophrenia, autism spectrum disorder, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, spasm, tremor, pain or sleep disorder A drug that is a combination of one or more drugs selected from therapeutic agents. The compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof for treating a psychiatric disorder or a neurodegenerative disease in combination with one or more antipsychotic agents. A drug containing.