JP2021035911A - Annelated pyrazole derivative and medicinal use thereof - Google Patents

Abstract

To provide a compound useful as a therapeutic agent for diseases associated with metabotropic glutamate receptor subtype 2 (mGluR2) and/or metabotropic glutamate receptor subtype 3 (mGluR3), and a pharmaceutical composition containing the compound.SOLUTION: The present invention provides: a compound represented by formula (1); and a pharmaceutical composition containing the compound. (In the formula, R1 and R2 represent H, C1-4 alkyl, or the like; n represents 1 or 2; ring A represents a C6-10 aromatic carbon ring or the like; R3, R4 and R5 each represent H, C1-6 alkyl, C1-4 alkoxy, or the like; ring B represents a 5- to 10-membered heteroaromatic ring; and R6, R7 and R8 each represent H, C1-6 alkyl, or the like.)SELECTED DRAWING: None

Description

The present invention contains a fused pyrazole derivative having a negative regulatory effect on the Group II metabolic glutamate (mGlu) receptor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof, as an active ingredient. Depressive disorder / depressive disorder (major depression, treatment-resistant depression, chronic depression, etc.), bipolar and related disorders (bipolar depression, etc.), anxiety disorder (generalized anxiety disorder, panic disorder, etc.) Social anxiety disorder, certain fears, etc.), post-traumatic stress disorder, compulsive disorder, acute stress disorder, schizophrenia, autism spectrum disorder, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity , Convulsions, tremors, pain, sleep disorders and other preventive or therapeutic agents.

Glutamate is a major excitatory neurotransmitter in the central nervous system, an ion channel-type receptor (N-methyl-D-aspartic acid (NMDA) -type glutamate receptor, α-amino-3-hydroxy-5-methyl- It acts on 4-isoxazolepropionic acid (AMPA) receptor, kainic acid receptor) and metabotropic glutamate receptor (mGlu receptor), which is a G protein-conjugated receptor. The mGlu receptor is classified as a G protein-coupled (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, and they are group I (mGluR1 and mGluR5) and group II (mGluR2 and mGluR3) based on the signal transduction system and pharmacological characteristics that are conjugate with homology. ) And Group III (mGluR4, mGluR6, mGluR7, mGluR8). Group II mGlu receptors (mGluR2 and 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 and 2. However, these patent documents do not disclose or suggest any compound having a fused pyrazole skeleton of the present application.

WO2014 / 133022 WO2016 / 027844

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 Group II mGlu receptor, and to find depressive disorder / depressive disorder (major depression, treatment-resistant depression, chronic depression). Diseases, etc.), bipolar and related disorders (bipolar depression, etc.), anxiety disorders (generalized anxiety disorder, panic disorder, social anxiety disorder, specific fears, etc.), post-traumatic stress disorder, compulsive disorder, Useful prevention or prevention for the treatment of diseases such as acute stress disorder, schizophrenia, autism spectrum disorder, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, spasm, tremor, pain, sleep disorders, etc. To provide a therapeutic agent.

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 is as follows.

［式（１）中、
Ｒ^１及びＲ^２は、各々独立して、水素原子、ハロゲン、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、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から５個の置換基で置換されていてもよい）を表し；
ここにおいて、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_３−６飽和炭素環（該飽和炭素環は、ハロゲン、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から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；
ｎは、１又は２であり；
環Ａは、Ｃ_３−１０飽和炭素環、３から１０員の飽和複素環、Ｃ_６−１０芳香族炭素環又は５から１０員の芳香族複素環であり；
Ｒ^３、Ｒ^４及びＲ^５は、各々独立して、水素原子、ハロゲン、シアノ、ヒドロキシ、Ｃ_１−６アルキル、Ｃ_３−６飽和炭素環基、Ｃ_１−４アルコキシ、Ｃ_３−６シクロアルコキシ、Ｃ_１−４アルキルチオ、Ｃ_２−４アルケニル、３から６員の飽和複素環基又は５もしくは６員の芳香族複素環基（該アルキル、該飽和炭素環基、該アルコキシ、該シクロアルコキシ、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から５個のハロゲンで置換されていてもよい）であり；
環Ｂは、Ｃ_６−１０芳香族炭素環又は５から１０員の芳香族複素環であり；
Ｒ^６、Ｒ^７及びＲ^８は、各々独立して、水素原子、ハロゲン、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、Ｃ_３−６飽和炭素環基、３から６員の飽和複素環基、−ＣＨ_２−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−Ｃ（Ｏ）−Ｒ^ｃ、−Ｃ（Ｏ）−ＯＲ^ｄ、−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−ＮＲ^ａＲ^ｂ、−ＮＲ^ｄ−Ｃ（Ｏ）−Ｒ^ｃ、−ＮＲ^ｄ−Ｃ（Ｏ）−ＮＲ^ａＲ^ｂ、−ＮＲ^ｄ−Ｓ（Ｏ）_２−Ｒ^ｃ、−ＮＲ^ｄ−Ｓ（Ｏ）_２−ＮＲ^ａＲ^ｂ、―Ｓ（Ｏ）―Ｒ^ｃ、−Ｓ（Ｏ）_２−Ｒ^ｃ、−Ｓ（Ｏ）_２−ＯＨ、−Ｓ（Ｏ）_２−ＮＲ^ａＲ^ｂ又は−Ｓ（Ｏ）（＝ＮＲ^ｄ）―Ｒ^ｃ（該アルキル、該アルコキシ、該アルキルチオ、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、シアノ、−ＮＲ^ａＲ^ｂ、ヒドロキシ及び１から５個のハロゲン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から５個の置換基で置換されていてもよい）を表し、
Ｒ^ａ及びＲ^ｂは、各々独立して、またＲ^ａ又はＲ^ｂが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３から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、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から５個の置換基で置換されていてもよい）を表し、
ここにおいて、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３から６員の飽和複素環基（該飽和複素環基は、ハロゲン、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から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３から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、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から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３から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、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から５個の置換基で置換されていてもよい）である] [Item 1] A compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.

[In equation (1),
R ¹ and R ² are independent of hydrogen atom, halogen, cyano, C _1-4 alkyl or C _3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are each independently halogen. , Which may be substituted with the same or different 1 to 5 substituents, selected from the group consisting of hydroxy and C _{1-4 alkoxy);}
Here, R ¹ and R ² are selected from the group consisting of _{C 3-6} saturated carbon rings (the saturated carbon rings are halogen, hydroxy and C _1-4 alkoxy) together with the carbon atoms to which they are bonded. , Which may be substituted with the same or different 1 to 5 substituents);
n is 1 or 2;
Ring A is a C _3-10 saturated carbocycle, a 3-10 member saturated heterocycle, a C _6-10 aromatic carbocycle or a 5-10 membered aromatic heterocycle;
R ³ , R ⁴ and R ⁵ are independently hydrogen atom, halogen, cyano, hydroxy, C _1-6 alkyl, C _3-6 saturated carbocyclic group, C _1-4 alkoxy, C _3-6 cyclo. Alkoxy, C _1-4 alkylthio, C _2-4 alkenyl, 3 to 6-membered saturated heterocyclic group or 5 or 6-membered aromatic heterocyclic group (the alkyl, the saturated carbocyclic group, the alkoxy, the cycloalkoxy). , The alkylthio, the saturated heterocyclic group and the aromatic heterocyclic group may be independently substituted with the same or different 1 to 5 halogens);
Ring B is a C _6-10 aromatic carbocycle or a 5- to 10-membered aromatic heterocycle;
R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, halogens, cyanos, hydroxys, C _1-6 alkyls, C _1-6 alkoxys, C _1-6 alkylthios and C _3-6 saturated carbocyclic groups. 3- to 6-membered saturated heterocyclic groups, -CH _2- C (O) -NR ^a R ^b , -C (O) -R ^c , -C (O) -OR ^d , -C (O) -NR ^a R ^b , -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d- C (O) -NR ^a R ^b , -NR ^d- S (O) _2- R ^c ,- NR ^d- S (O) _2- NR ^a R ^b , -S (O) -R ^c , -S (O) _2- R ^c , -S (O) _2- OH, -S (O) _2- NR ^a R ^b or -S (O) (= NR ^d ) -R ^c (the alkyl, the alkoxy, the alkylthio, the saturated carbocyclic group and the saturated heterocyclic group are independently halogen, cyano,- NR a ^{R b,} optionally substituted by hydroxy and 1 to five halogens are also selected from the group consisting of optionally C _1-4 alkoxy, optionally substituted by the same or different one to five substituents )
R ^a and R ^b are independent ^{of each other, and if there are a plurality of Ra} or R ^b , they are independent of each other, such as hydrogen atom, C _1-4 alkyl, C _3-6 saturated carbocyclic group or 3 to 6 members. (The alkyl, the saturated carbocyclic group and the saturated heterocyclic group are each independently selected from the group consisting of _{halogen, hydroxy, C 1-4} alkyl and C _{1-4 alkoxy.} It may be substituted with the same or different 1 to 5 substituents).
Here, ^Ra and R ^b are 3 to 6-membered saturated heterocyclic groups together with the nitrogen atom to which they are bonded (the saturated heterocyclic groups are halogen, hydroxy, C _1-4 alkyl and C _{1). -4} It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of alkoxy).
^{If there are a plurality of Rc} , each of them is independently C _1-4 alkyl, C _3-6 saturated carbocyclic group or 3 to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and the saturated complex). The ring groups each independently represent the same or different 1 to 5 substituents selected from the group consisting of halogens, hydroxys and C _{1-4 alkoxys).}
R ^d _{may be a hydrogen atom, a C 1-4} alkyl, a C _3-6 saturated carbocyclic group or a 3 to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and each of them independently, if there are a plurality of them. The saturated heterocyclic groups may be independently substituted with the same or different 1 to 5 substituents _{, each independently selected from the group consisting of halogen, hydroxy and C 1-4 alkoxy)].}

[Item 2]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

[Item 3]
Item 2. The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein n is 2.

[Item 4]
Ring A is a C _6-10 aromatic carbocycle or a 5- to 10-membered aromatic heterocycle.
Item 2. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 5]
Ring A is benzene, pyridine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indrine, imidazole pyridine, chromane, 2,3-dihydrobenzofuran, 1, 3-Dihydrobenzofuran, 2,3-dihydro-1H-indene or 2,3-dihydro-1H-inden-1-one,
Item 4. The compound according to any one of Items 1 to 4, or a pharmaceutically acceptable salt thereof.

[Item 6]
Ring A is benzene, pyridine, thiophene or quinoline,
Item 2. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 7]
Ring A is benzene,
Item 2. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 8]
Ring B is benzene, pyridine, pyrimidine, pyrazine, imidazole, pyrazole, thiophene, thiazole, isothazole, oxazole, isooxazole, oxadiazol, quinoline, isoquinoline, benzoimidazole, azabenzoimidazole, indazole, azaindazole, indolidin. , Imidazopyridine, 2,3-dihydro-1H-pyrrolopyridine, 2,3-dihydro-1H-pyrrolopyridine-1-one, 1,2-dihydro-3H-pyrrolopyridine-3-one or 5,6,7 , 8-Tetrahydroimidazolipyrazine,
Item 2. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.

[Item 9]
Ring B is benzene, pyridine, pyrimidine, imidazolepyridine, 2,3-dihydro-1H-pyrrolopyridine, 2,3-dihydro-1H-pyrrolopyridine-1-one, 1,2-dihydro-3H-pyrrolopyridine- 3-one or 5,6,7,8-tetrahydroimidazolipyrazine,
Item 2. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.

[Item 10]
Ring B is pyridine,
Item 2. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.

[Item 11]
R ¹ and R ² _{are C 1-4} alkyl, which may be independently substituted with hydrogen atoms or 1 to 5 halogens, respectively, where R ¹ and R ² are the carbons to which they are attached. Together with the atom, it may form a cyclopropane ring or a cyclobutane ring,
Item 2. The compound according to any one of Items 1 to 10 or a pharmaceutically acceptable salt thereof.

[Item 12]
R ¹ is methyl and R ² is a hydrogen atom,
Item 2. The compound according to any one of Items 1 to 10 or a pharmaceutically acceptable salt thereof.

[Item 13]
R ³ , R ⁴ and R ⁵ are each independently hydrogen atom, halogen, cyano, hydroxy, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 alkyl thio (the alkyl, the alkoxy and the alkyl thio). May be independently substituted with the same or different 1 to 5 halogens).
Item 2. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[Item 14]
R ³ , R ⁴ and R ⁵ are independently hydrogen atoms, fluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
Item 2. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[Item 15]
R ⁶ , R ⁷ and R ⁸ are independent hydrogen atoms, halogens, cyanos, hydroxys, C _1-6 alkyls, C _1-6 alkoxys, 3- to 6-membered saturated heterocyclic groups, -CH _2- C (O) -NR ^a R ^b , -C (O) -R ^c , -C (O) -OR ^d , -C (O) -NR ^a R ^b , -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d- C (O) -NR ^a R ^b , -NR ^d- S (O) _2- R ^c , -S (O) _2- NR ^a R ^b or -S (O) ) (= NR ^d ) -R ^c (Even if the alkyl, the alkoxy and the saturated heterocyclic group are independently ^{substituted with halogen, -NR a} R ^b , hydroxy and 1 to 5 halogens, respectively. It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of _{good C 1-4 alkoxy).}
Item 2. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.

[Item 16]
R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, halogens, cyanos, hydroxys, C _1-6 alkyls, C _1-6 alkoxys, 3- to 6-membered saturated heterocyclic groups, -C (O). ) -NR ^a R ^b , -NR ^a R ^b , -NR ^d- S (O) _2- R ^c , -S (O) _2- NR ^a R ^b or -S (O) (= NR ^d ) -R ^c (The alkyl, the alkoxy and the saturated heterocyclic group each independently consist of halogen, -NR ^a R ^b _{, hydroxy and C 1-4} alkoxy optionally substituted with 1 to 5 halogens. It may be substituted with the same or different 1 to 5 substituents selected from the group).
Item 2. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.

[Item 17]
R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, fluorine, chlorine, cyano, hydroxymethyl, methyl, ethyl, methoxy, ethoxy, 3- to 6-membered saturated heterocyclic groups, -NR ^a R ^b. , -NR ^d- S (O) _2- R ^c , -S (O) _2- NR ^a R ^b or -S (O) (= NR ^d ) -R ^c ,
Item 2. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.

[Item 18]
R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, fluorine, chlorine, cyano, hydroxymethyl, methyl, ethyl, methoxy, ethoxy or -NR ^a R ^b .
Item 2. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.

[Item 19]
R ^a and R ^b are independent of each other, and if there are multiple ^Ra or R ^b, _{each is independent of hydrogen atom, C 1-4} alkyl, C _3-6 saturated carbocyclic group or 3 to 6 members. Saturated heterocyclic groups (the alkyl, the saturated carbocyclic groups and the saturated heterocyclic groups are each independently _{selected from the group consisting of halogens, hydroxys and C 1-4} alkoxys, the same or different 1 to 5 It may be substituted with 11 substituents),
Item 2. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.

[Item 20]
R ^a and R ^b are independent of each other, and if there are multiple ^Ra or R ^b, _{each is independent of hydrogen atom or C 1-4} alkyl (the alkyl is halogen, hydroxy and C _1-4 alkoxy). It may be substituted with the same or different 1 to 3 substituents selected from the group consisting of).
Item 2. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.

[Item 21]
R ^c are each independently when a plurality of a 5 substituents C _1-4 alkyl optionally substituted with halogen from 1,
Item 2. The compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof.

[Item 22]
If there are a plurality of R ^d _{, they are C 1-4} alkyl which may be independently substituted with a hydrogen atom or 1 to 5 halogens.
Item 2. The compound according to any one of Items 1 to 21, or a pharmaceutically acceptable salt thereof.

[Item 23]
A pharmaceutical composition containing the compound according to any one of Items 1 to 22 or a pharmaceutically acceptable salt thereof.

[Item 24]
Metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor containing the compound according to any one of Items 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for diseases associated with subtype 3 (mGluR3).

[Item 25]
A therapeutic agent for a disease involving metabotropic glutamate receptor subtype 2 (mGluR2), which comprises the compound according to any one of Items 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient. / Or a preventive agent.

[Item 26]
Item 24. The therapeutic agent and / or the therapeutic agent according to Item 24, wherein the disease involving the metabotropic glutamate receptor subtype 2 (mGluR2) and / or the metabotropic glutamate receptor subtype 3 (mGluR3) is a psychiatric disorder or a neurodegenerative disease. Preventive agent.

[Item 27]
Mental or neurodegenerative disorders include depressive / depressive disorders, bipolar and related disorders, anxiety disorders, post-traumatic stress disorders, compulsive disorders, acute stress disorders, schizophrenia, autism spectrum disorders, Item 26. The therapeutic and / or prophylactic agent according to Item 26, which is Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, convulsions, tremor, pain or sleep disorder.

[Item 28]
Any of Items 1 to 22 for producing a therapeutic agent and / or a preventive agent for a disease involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3). Use of the compound according to paragraph 1 or a pharmaceutically acceptable salt thereof.

[Item 29]
Any one of Items 1 to 22 for use in the treatment and / or prevention of diseases involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3). The compound described in the section, or a pharmaceutically acceptable salt thereof.

[Item 30]
Metabotropic glutamate acceptance, characterized in that a therapeutically effective amount of the compound according to any one of Items 1 to 22 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment. A method for treating and / or preventing a disease involving body subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3).

[Item 31]
A drug obtained by combining the drug according to any one of Items 1 to 22 and at least one or more drugs selected from drugs classified as psychotic drugs.

[Item 32]
Item 6. The item according to any one of Items 1 to 22, for treating a nervous system disease, a psychiatric disease or a neurodegenerative disease in combination with at least one drug selected from the drugs classified as an antipsychotic drug. Medicine.

The compounds of the present invention exhibit a strong negative regulatory effect on Group II metabotropic glutamate (mGlu) receptors. Therefore, the compounds of the present invention include depressive disorders / depressive disorders (major depression, treatment-resistant depression, chronic depression, etc.), bipolar and related disorders (bipolar depression, etc.), and anxiety disorders (generalized anxiety disorder). Anxiety disorder, panic disorder, social anxiety disorder, certain fears, etc.), post-traumatic stress disorder, compulsive disorder, acute stress disorder, schizophrenia, autism spectrum disorder, Alzheimer's disease, cognitive dysfunction, cognition It is useful as a therapeutic and / or preventive agent for depression, drug dependence, obesity, convulsions, tremor, pain, sleep disorders, etc.

The terms used herein will be described below.

The term "group" means a monovalent group. In addition, the term "group" may be omitted in the following description of substituents and the like.

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 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. 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" include fluorine, chlorine, bromine and iodine. Fluorine or chlorine is preferred.

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

The “C _1-6 alkoxy” means an oxy group substituted with the _{“C 1-6 alkyl”.} As the "C _1-6 alkoxy group", "C _1-4 alkoxy" is preferably 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”.} The same applies to other numbers. 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, and 1-butenyl.

The "C _3-10 saturated carbocycle" means a monocyclic or bicyclic saturated hydrocarbon ring having 3 to 10 carbon atoms, which has a partially unsaturated bond and a partially crosslinked structure. Includes those that are partially spirozed and those that have one or two carbonyl structures. Here, the oxygen atom of the carbonyl is not included in the number of 3 to 10 members (ring size). As _{- 'C} 3 ₁₀ saturated carbocycle ", preferably" _{C 3} - ₈ saturated carbocycle ", and more preferably include - it includes" _{C 3 6} saturated carbocycle ", more preferably" _{C 4} - ₆ saturated carbon ring "can be mentioned, particularly preferably" C ₅ or C ₆ saturated carbocycle ". Specific examples of the - "C _{3 10} saturated carbon ring", but are not limited to, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, Cyclooctene, cyclohexadiene, cycloheptadiene, cyclooctane and the like can be mentioned.

The "C _3-6 saturated carbocyclic group" means a substituent in which the "C _3-6 saturated carbocyclic ring" is a monovalent group _{among the above "C 3-10 saturated carbocyclic rings".}

A "3- to 10-membered saturated heterocycle" is composed of 3 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. 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 3 to 10 members (ring size) and the number of heteroatoms constituting the ring. Examples of the "3 to 10-membered saturated heterocycle" include a monocyclic or bicyclic "3 to 8-membered saturated heterocycle", and more preferably a monocyclic "3- 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 "3- to 10-membered saturated heterocycle" include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran and the like.

The "3- to 6-membered saturated heterocyclic group" means a substituent in which the "3- to 6-membered saturated heterocycle" is a monovalent group among the above-mentioned "3 to 10-membered saturated heterocycle". To do.

The "C _6-10 aromatic carbocycle" means a monocyclic or bicyclic aromatic hydrocarbon ring having 6 to 10 carbon atoms. Bicyclic aromatic carbocycles also include those in which a monocyclic aromatic carbocycle and a monocyclic saturated carbocycle (cyclohexane or the like) or a saturated heterocycle (piperidine or the like) are fused. Further, one or two carbonyls or thiocarbonyls may be contained to form a monocyclic saturated carbocyclic ring which is fused with a monocyclic aromatic carbocycle. On the other hand, the same or different 1 or different one selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom to form a monocyclic saturated heterocycle fused with a monocyclic aromatic carbon ring. It may contain two heteroatoms and one or two carbonyls, thiocarbonyls, sulfinyls or sulfonyls. Here, the oxygen atoms of carbonyl, sulfinyl and sulfonyl and the sulfur atom of thiocarbonyl are not included in the number of heteroatoms constituting the saturated heterocycle fused with the monocyclic aromatic carbocycle. .. Benzene is preferably mentioned as the "C _{6-10 aromatic carbocycle".} Specific examples of the "C _6-10 aromatic carbocycle" include, but are not limited to, benzene, 1-naphthalene, 2-naphthalene and the like, and benzene is preferable.

A "5- to 10-membered aromatic heterocycle" consists of 5 to 10 atoms, including the same or different 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. It means a monocyclic or bicyclic aromatic heterocycle. Bicyclic aromatic heterocycles also include those in which a monocyclic aromatic heterocycle and a monocyclic saturated carbocycle (cyclohexane or the like) or a saturated heterocycle (piperidine or the like) are fused. Further, one or two carbonyls or thiocarbonyls may be contained to form a saturated carbocycle fused with a monocyclic aromatic heterocycle. Here, the oxygen atom of carbonyl and the sulfur atom of thiocarbonyl are not included in the number of 5 to 10 members (ring size). On the other hand, in a bicyclic aromatic heterocycle, one or two carbonyls, thiocarbonyls, sulfinyls or sulfonyls are used to form a saturated heterocycle fused with a monocyclic aromatic heterocycle. It may be included. Here, the oxygen atoms of carbonyl, sulfinyl and sulfonyl and the sulfur atom of thiocarbonyl are not included in the number of 5 to 10 members (ring size) and the number of heteroatoms constituting the ring. 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-membered". 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, but are not limited to, pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiophene, pyrrol, thiazole, isothiazole, pyrazole, imidazole, furan, and the like. Oxazole, isooxazole, oxadiazol, thiazazole, triazole, tetrazole, quinoline, isoquinoline, naphthylidine, quinazoline, benzofuran, benzothiophene, indol, benzoxazole, benzoisoxazole, 1H-indazole, 2H-indazole, benzoimidazole, benzoxa Diazol, benzothiaziazole, indridin, benzofurazine, thienopyrimidine, pyrazolopyridine, imidazolopyridine, imidazolopyrazine, pyrazolopyrimidine, triazolopyrimidine, thienothiophene, imidazolothiazole, chromane, 2,3-dihydrobenzofuran, 1,3 -Dihydrobenzofuran, 2,3-dihydro-1H-inden, 2,3-dihydro-1H-inden-1-one, 2,3-dihydro-1H-pyrrolopyridine, 2,3-dihydro-1H-pyrrolopyridine- Examples thereof include 1-one, 1,2-dihydro-3H-pyrrolopyridine-3-one, 5,6,7,8-tetrahydroimidazolipyrazine.

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

Examples of the "6-membered aromatic heterocyclic group" include pyridine, pyridazine, pyrimidine, pyrazine and the like. Pyridine or pyrimidines are preferred.

The "5- or 6-membered aromatic heterocyclic group" means a substituent in which the above-mentioned "5-membered aromatic heterocycle" or "6-membered aromatic heterocycle" is a monovalent group.

In the compound of the present invention represented by the formula (1), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , n, R ^a , R ^b , R ^c , R. ^{The preferred ones of d} , ring A and ring B are as follows, but the technical scope of the present invention is not limited to the range of the compounds shown below.

Preferable examples of R ¹ and R ² _{include C 1-4} alkyl which may be independently substituted with a hydrogen atom or 1 to 5 halogens. More preferably, each independently includes a hydrogen atom, methyl, ethyl or trifluoromethyl. More preferably, a hydrogen atom or methyl is used. Particularly preferably, R ¹ is methyl and R ² is a hydrogen atom.

Preferably R ³ , R ⁴ and R ⁵ respectively, each independently has a hydrogen atom, a halogen, a cyano, a C _1-4 alkyl or a C _1-4 alkoxy (the alkyl and the alkoxy are from 1 to 3 halogens). It may be replaced). More preferably, hydrogen atom, fluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy can be mentioned.

Preferably as R ⁶ , R ⁷ and R ⁸ , each independently has a hydrogen atom, a halogen, a cyano, a hydroxy, a C _1-6 alkyl, a C _1-6 alkoxy, and a 3- to 6-membered saturated heterocyclic group (the alkyl). , The alkoxy and the saturated heterocycle ^{may be substituted with hydroxy, -NR a} R ^b and 1 to 3 halogens), -C (O) -NR ^a R ^b , -NR ^a R ^b , Examples thereof include ^{−NR d} −S (O) _2- R ^c , −S (O) _2- NR ^a R ^b or −S (O) (= NR ^d ) −R ^c. More preferably, each independently includes a hydrogen atom, fluorine, chlorine, cyano, hydroxymethyl, methyl, ethyl, methoxy, ethoxy or -NR ^a R ^b . More preferably, each independently includes a hydrogen atom, fluorine, chlorine, hydroxymethyl, methyl, methoxy, ethoxy or -NR ^a R ^b .

2 is mentioned as a preferable embodiment of n.

Preferably as R ^a and R ^b , respectively, independently, a hydrogen atom, a C _1-4 alkyl, a C _3-6 saturated carbocyclic group or a 3 to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group). And the saturated heterocyclic group may be independently substituted with the same or different 1 to 5 substituents selected from the group consisting of _{halogen, hydroxy and C 1-4 alkoxy).} Be done. More preferably, they are hydrogen atoms or C _1-4 alkyl, each independently selected from the group consisting of halogen, hydroxy and C _1-4 alkoxy, with the same or different 1 to 3 substituents. It may be replaced). More preferably, a hydrogen atom or methyl can be mentioned. Particularly preferably, both are hydrogen atoms.

Preferred as R ^c _{is C 1-4} alkyl which may be substituted with 1 to 3 halogens. More preferably, it is methyl.

Preferred as R ^d _{is C 1-4} alkyl which may be substituted with a hydrogen atom or 1 to 3 halogens. More preferably, a hydrogen atom or methyl is used.

Benzene or a 5- to 10-membered aromatic heterocycle is preferably used as the ring A. More preferably, benzene, pyridine, thiophene, benzothiophene, benzofuran or quinoline can be mentioned. More preferably, benzene and pyridine are mentioned. Benzene is particularly preferable.

Benzene or a 5- to 10-membered aromatic heterocycle is preferably used as the ring B. More preferably, benzene, pyridine, pyrimidine, pyrazine or imidazopyridine can be mentioned. More preferably, it is pyridine.

One embodiment of the compound represented by the formula (1) includes the following (A).
(A)
R ¹ is methyl;
R ² is a hydrogen atom;
n is 2;
Ring A is benzene or a 5- to 10-membered aromatic heterocycle;
R ³ , R ⁴ and R ⁵ are independently hydrogen atoms, halogens, cyanos, C _1-6 alkyls, C _1-4 alkoxys or C _3-6 cycloalkoxys (the alkyls, the alkoxys and the cycloalkoxys). May be independently substituted with the same or different 1 to 5 halogens);
Ring B is benzene or a 5- to 10-membered aromatic heterocycle;
R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, halogens, cyanos, hydroxys, C _1-6 alkyls, C _1-6 alkoxys, C _3-6 saturated carbocyclic groups, 3 to 6 members. Saturated heterocyclic group, -C (O) -NR ^a R ^b , -NR ^a R ^b , -NR ^d- S (O) 2-R ^c , -S (O) _2- NR ^a R ^b or -S ( O) (= NR ^d ) -R ^c (the alkyl, the alkoxy, the saturated carbocyclic group and the saturated heterocyclic group are independently halogen, cyano, -NR ^a R ^b , hydroxy and 1 to 5 respectively. It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of _{C 1-4} alkoxy which may be substituted with 1 halogen;
R ^a and R ^b are independent of each other, and if there are multiple ^Ra or R ^b, _{each is independent of hydrogen atom, C 1-4} alkyl, C _3-6 saturated carbocyclic group or 3 to 6 members. (The alkyl, the saturated carbocyclic group and the saturated heterocyclic group are each independently selected from the group consisting of _{halogen, 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 independently C _1-4 alkyl, C _3-6 saturated carbocyclic group or 3 to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and the saturated complex). The ring groups are each independently substituted with the same or different 1 to 3 substituents selected from the group consisting of halogens, hydroxys and C _{1-4 alkoxys);}
If there are a plurality of R ^ds _{, each of them is independently selected from the group consisting of hydrogen atom or C 1-4} alkyl (the alkyl is a _{group consisting of halogen, hydroxy and C 1-4} alkoxy, the same or different 1 to 3). It may be substituted with a substituent of),
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by the formula (1) includes the following (B) .
(B)
R ¹ is methyl;
R ² is a hydrogen atom;
n is 2;
Ring A is benzene or a 5- to 10-membered aromatic heterocycle;
R ³ , R ⁴ and R ⁵ are independent of hydrogen atom, halogen, cyano, C _1-6 alkyl, C _1-4 alkoxy (the alkyl and the alkoxy are each independently the same or different 1). May be replaced with 5 halogens);
Ring B is benzene or a 5- to 10-membered aromatic heterocycle;
R ⁶ , R ⁷ and R ⁸ are independent hydrogen atoms, halogens, cyanos, C _1-6 alkyls, C _1-6 alkoxys, C _3-6 saturated carbocyclic groups, 3 to 6-membered saturated complex. Ring group, -C (O) -NR ^a R ^b or -NR ^a R ^b (the alkyl, the alkoxy, the saturated carbon ring group and the saturated heterocyclic group are independently halogen, cyano, -NR, respectively. ^It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of a R ^b _{, hydroxy, and C 1-4} alkoxy which may be substituted with 1 to 5 halogens. ) And;
R ^a and R ^b are independent of each other, and if there are multiple ^Ra or R ^b, _{each is independent of hydrogen atom, C 1-4} alkyl, C _3-6 saturated carbocyclic group or 3 to 6 members. (The alkyl, the saturated carbocyclic group and the saturated heterocyclic group are each independently selected from the group consisting of _{halogen, hydroxy, C 1-4} alkyl and C _{1-4 alkoxy.} It may be substituted with the same or different 1 to 5 substituents).
A compound or a pharmaceutically acceptable salt thereof.

Examples of the "pharmaceutically acceptable salt" include acid addition salts and base addition salts. For example, as the acid addition salt, an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate or the like, citrate, oxalate, phthalate, fumal Acid, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonate , Organic acid salts such as camphor sulfonate. 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 and diethanolamine. Examples thereof include triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and organic base salts of N, N-dibenzylethylamine. Further, examples of the "pharmaceutically acceptable 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., 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, if the compound of the present invention is obtained in the form of a salt, it may be purified as it is, or if it is obtained in the free form, it is dissolved in an appropriate organic solvent. Alternatively, it may be suspended and an acid or 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 thereof. Further, since the compound of the present invention may exist in the form of a hydrate and / or a solvate with various solvents (such as an ethanol solvate), these hydrates and / or solvates are also present. Included in the compounds of the invention.

Among the compounds (1) of the present invention are optical isomers based on optically active centers, atropisomers based on axial or planar chirality generated by the constraint of intramolecular rotation, other stereoisomers, and mutual mutations. All possible isomers and mixtures thereof, including these, are included in the scope of the present invention, although there may be sexes, geometric isomers and the like. Further, 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 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 optically active dividing 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 (I) or a pharmaceutically acceptable salt thereof. Further, the compound of the present invention is a compound obtained by converting a part or all of the atoms constituting the compound represented by the formula (I) into isotopes (for example, a compound obtained by deuterating hydrogen or ¹² C to ¹⁴ C). Compounds converted to) are also included.

The term "prodrug of a compound of formula (I)" as used herein refers to a compound that is converted into a compound of formula (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, enzymatically oxidized. , A compound that changes to a compound of formula (I) by causing reduction, hydrolysis, etc., and a compound that changes to a compound of formula (I) by causing hydrolysis by gastric acid or the like.

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.

Production Method The compound of the present invention represented by the formula (1) can be produced, for example, by the methods shown in the following production methods 1 to 3. These production methods can be appropriately improved based on the knowledge of those who are proficient in organic synthesis. As the raw material compound, if necessary, a compound whose salt or functional group is protected may be used.

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 those described in the literature (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, those in which their salts or functional groups are protected may be used, if necessary.

The intermediates and target compounds in the following production methods are appropriately converted in their functional groups, and in particular, various side chains are extended from aminos, hydroxyl groups, carbonyls, halogens, 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., New York). It can be done by the method that has been done) or a method similar to it.

The Inactive 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、Ｒ^１、Ｒ^２及びｎは項１と同義であり、Ｒ^９はＣ_１−４アルキル又はベンジルを表し、Ｘはヨウ素、臭素又は塩素を表す） Manufacturing method 1
Compound (6) is produced, for example, by the method shown below.

(In the formula, R ¹ , R ² and n are synonymous with item 1, R ⁹ represents C _1-4 alkyl or benzyl, and X represents iodine, bromine or chlorine).

Step 1: Compound (4) can be produced by reacting compound (2) with formate ester (3) in the presence of an appropriate base in a suitable inert solvent by a conventional method. 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. Here, as the compounds (2) and (3), 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 metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, and organometallic bases such as lithium hexamethyldisilazane and lithium diisopropylamide.
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 and 1,4-dioxane, N, N-dimethylformamide and N-. Examples thereof include an aprotic polar solvent such as methyl-2-pyrrolidone, and a mixed solvent thereof.

Step 2: Compound (5) can be produced by reacting compound (4) with hydrazine hydrate by a conventional method in a suitable inert solvent. 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 inert solvent used in this step include lower alcohols such as methanol, ethanol and 2-propanol, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, and mixed solvents thereof. Can be mentioned.

Step 3: Compound (6) can be produced by reacting compound (5) with a halogenating agent in the presence of an appropriate base in a suitable inert solvent by a conventional method. 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 used in this step include iodine, bromine, iodine monochloride, N-iodosuccinate imide, N-bromosuccinimide, N-chlorosuccinimide, 1,3-diiodo-5, and so on. 5-Dimethyl hydantin and the like can be mentioned.
Specific examples of the base used in this step include potassium hydroxide, sodium hydroxide and the like.
Specific examples of the inert solvent used in this step include aprotic polar solvents such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, tetrahydrofuran, diethyl ether, 1,4-dioxane and the like. Examples thereof include ether solvents and mixed solvents thereof.

（式中、Ｒ^１、Ｒ^２及びｎは項１と同義であり、ＰＧ^１は水酸基の保護基（トリアルキルシリル基、ベンジル基、ベンゾイル基等）を表し、ＰＧ^２は窒素原子の保護基（Ｎ，Ｎ−ジメチルスルファモイル基等）を表し、ＬＧ^１は脱離基（ヨウ素原子、臭素原子、塩素原子、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 (5) is also produced, for example, by the method shown below.

(In the formula, R ¹ , R ² and n are synonymous with Item 1, PG ¹ represents a hydroxyl protecting group (trialkylsilyl group, benzyl group, benzoyl group, etc.), and PG ² is a nitrogen atom protecting group. (N, N-dimethylsulfamoyl group, etc.), LG ¹ is a leaving group (iodine atom, bromine atom, chlorine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, etc.) Represents)

Step 4: Compound (8) is added to the hydroxyl group of compound (7) by a known method (eg, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John. It can be produced by introducing a protecting group by the method described in Wiley and Sons, inc., New York (1999), etc.). Here, as the compound (7), a commercially available compound or a compound synthesized by a known method can be used.

Step 5: Compound (9) is applied to the nitrogen atom of compound (8) by a known method (eg, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., It can be produced by introducing a protecting group by the method described in John Wiley and Sons, inc., New York (1999), etc.).

Step 6: Compound (11) can be produced by reacting compound (9) with compound (10) in the presence of a suitable base in a suitable inert solvent according to a conventional method. 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 (10), 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, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium tetrapetylpiperidide, lithium hexamethyldisilazide, and sodium hexamethyl. Examples thereof include disilamide and potassium hexamethyldisilazide.
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-heptan, cyclohexane and the like. Saturated hydrocarbons and mixed solvents thereof can be mentioned.

Step 7: Compound (12) uses known methods (eg, TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed) to protect the hydroxyl groups of compound (11). It can be produced by removing it by a method described in John Wiley and Sons, inc., New York (1999), etc.).

Step 8: Compound (13) is described in more conventional manner than compound (12) (eg, RC Larock, “Comprehensive Organic Transitions”, 2nd Ed., John Wiley and Sons, inc., New York). It can be manufactured according to the method described).

Step 9: Compound (14) can be produced by reacting compound (13) with 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 10 days, preferably 1 minute to 3 days.

Specific examples of the base used in this step include inorganic bases such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate and cesium carbonate, natrimmethoxyd and potassium tert-butoxide. Metal alkoxide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium tetrapetyl piperidide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, Triethylamine, pyridine, 1,8-diazabicyclo [5.4.0. ] -7-Organic bases such as undecene and the like can be mentioned.
Specific examples of the inert solvent used in this step include aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrroloridone, and acetonitrile, tetrahydrofuran and diethyl. Examples thereof include ether solvents such as ether, 1,4-dioxane and 1,2-dimethoxyethane, saturated hydrocarbons such as n-hexane, n-heptane and cyclohexane, and mixed solvents thereof.

Step 10: Compound (5) uses known methods (eg, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd) to protect the nitrogen atom protecting group of compound (14). It can be produced by removing it by Ed., John Wiley and Sons, inc., The method described in New York (1999), etc.).

（式中、環Ａ、環Ｂ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８及びｎは項１と同義であり、Ｒ^Ａはボロン酸又はボロン酸エステルを表し、Ｘは、ヨウ素、臭素又は塩素を表す） Manufacturing method 3
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 , R ⁷ , R ⁸ and n are synonymous with item 1, and ^RA is boronic acid or boron. Represents an acid ester, where X represents iodine, bromine or chlorine)

Step 11: Compound (16) is prepared by subjecting compound (6) and compound (15) to a coupling reaction in the presence of a suitable transition metal catalyst and a suitable base according to a conventional method in a suitable inert solvent. Can be manufactured. This step can also be carried out by coexistence of an appropriate ligand, if necessary. The reaction temperature in this step is usually from room temperature to 200 ° C., preferably 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 (15), 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 (II) acetate, palladium (II) chloride, and tris (dibenzylideneacetone) dipalladium (0). , Dichlorobis (triphenylphosphine) palladium (II), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct, 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 and 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-. Examples thereof include aprotonic polar solvents such as dimethylacetamide, N-methyl-2-pyrroloridone and acetonitrile, aromatic hydrocarbons such as benzene and toluene, water and a mixed solvent thereof.

Step 12: Compound (1) is prepared from compound (16) and compound (17) in the presence of a suitable copper catalyst and a suitable base in the presence of a suitable copper catalyst and a suitable base, in the air or in an oxygen atmosphere, according to a conventional method in a suitable inert solvent. It can be produced by a coupling reaction. The reaction temperature in this step is usually from 0 ° C. to the boiling point of the solvent used, preferably from room temperature to 100 ° C. The reaction time of this step is usually 1 minute to 10 days, preferably 1 minute to 3 days. Here, as the compound (17), a commercially available compound or a compound synthesized from a known compound can be used.

Specific examples of the copper catalyst used in this step include copper (II) acetate, copper (II) chloride and the like.
Specific examples of the base used in this step include pyridine, triethylamine and the like.
Specific examples of the inert solvent used in this step include aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrroloridone and acetonitrile, and dichloromethane, chloroform and the like. Examples thereof include a halogenated hydrocarbon solvent and a mixed solvent thereof.

Step 13: Compound (18) can be produced by reacting compound (6) with compound (17) by a method according to step 12 above.

Step 14: Compound (1) can be produced by reacting compound (15) with compound (18) by a method according to step 11 above.

The room temperature in the above production method specifically means 10 ° C. to 30 ° C.

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 the raw material compound, etc., and for example, sodium hydroxide, alkali hydroxides such as potassium hydroxide, sodium carbonate, etc. , Alkali carbonates such as potassium carbonate, sodium hydride, metal hydrides such as potassium hydride, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium methoxydo, sodium t-butoxide Alkali metal alkoxides such as, butyllithium, organic metal bases such as 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., and for example, alcohols such as methanol, ethanol and isopropanol, acetone, methyl ketone and the like. Ketones, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane. Classes, esters such as ethyl acetate, propyl acetate, amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide (DMSO), such as acetonitrile. Nitriles can be mentioned, and these solvents can be used alone or in combination 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 (eg, 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 an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, an aromatic hydrocarbon solvent such as benzene or toluene, and acetone. A ketone solvent such as, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aproton solvent such as dimethylformamide or acetonitrile, water, or a mixed solvent thereof and the like can be used. 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 a nuclear magnetic resonance method, an infrared absorption method, a 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 compound of the present invention represented by the formula (1) may have an asymmetry or have a substituent having an asymmetric carbon, and such a compound has an optical isomer. 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 manufacturing method include a method using a raw material having an asymmetric point, or a method of introducing an asymmetric point 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 performing optical resolution or the like at an appropriate stage in the manufacturing process. As an optical division method, for example, 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 or the like). , Ether solvent such as diethyl ether, ester solvent such as ethyl acetate, hydrocarbon solvent such as toluene, aproton solvent such as acetonitrile, or a mixed solvent of two or more selected from the above solvents), optically active. Acids (eg, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartrate, dicarboxylic acids such as o-diisopropyridene tartrate, malic acid, sulfonic acids such as camphorsulfonic acid and bromocamparsulfonic acid) A diastereomer method in which a salt is formed by using it can be mentioned. When the compound of the present invention represented by the formula (1) or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, etc.) Optical resolution can also be performed by forming a salt using an organic amine such as strikinine).

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 appropriately in the range of about 0.5 to about 2.0 equivalents, preferably about 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, etc. It can also be recrystallized in an aproton solvent such as acetonitrile or a mixed solvent of two or more kinds 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 compound of the present invention is a compound having mGlu2 receptor negative allosteric modulator (NAM) activity. Therefore, it can be a novel therapeutic agent for psychiatric or neurodegenerative diseases having a negative regulatory effect on Group II mGlu receptors. Specific examples of these mental and neurodegenerative diseases include depressive disorders / depressive disorders (major depression, treatment-resistant depression, chronic depression, etc.), bipolar and related disorders (bipolar depression, etc.). , Anxiety disorders (general anxiety disorder, panic disorder, social anxiety disorder, specific fears, etc.), post-traumatic stress disorder, compulsive disorder, acute stress disorder, schizophrenia, autism spectrum disorder, Alzheimer's disease , Cognitive dysfunction, dementia, drug dependence, obesity, convulsions, tremor, pain, sleep disorders, etc.
Among these mental and neurodegenerative diseases, the preferred target diseases are depressive disorder / depressive disorder (major depression, treatment-resistant depression, chronic depression, etc.), bipolar 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, sleep disorders, etc.

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 prepared and administered directly or by using an appropriate dosage form by oral administration or parenteral administration. Dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices and the like. Formulations are prepared 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, hydroxypropylmethyl cellulose, polyvinyl alcohol, stear. Examples thereof include magnesium acid, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

The compounds of the present invention are depressive disorders / depressive disorders (major depression, treatment-resistant depression, chronic depression, etc.) for treating one or more psychiatric disorders or neurodegenerative disorders described herein. , Bipolar and related disorders (bipolar depression, etc.), anxiety disorders (generalized 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, spasm, tremor, pain or sleep disorder may be used in combination with at least one agent selected from the therapeutic agents. 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 of the compound of the present invention and these therapeutic agents. 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 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 be used for the sake of brevity.

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
Optical Purity Measurement: Shimadzu LC-20AT HPLC System 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] +.}
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 gradation)
1.3-1.5 minutes; A / B = 90/10
Flow velocity: 0.80 mL / min
UV: 220nm, 254nm
Column temperature: 40 ° C

For the optical purity in the reference example and the example, the values measured under the conditions shown below were used. Further, ee (Enantiomeric excess) is used as a symbol indicating the enantiomeric excess.
Measurement condition A
Column: CHIRALPAK IC 0.46 cm I. D. × 25 cm L.
Solvent: n-hexane / 2-propanol / methanol = 80/15/5
Flow velocity: 1.0 mL / min
UV: 220 nm
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 pressure HATU: O- (7-aza-1H-benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate THF: tetrahydrofuran DME: dimethoxyethane THF: Trifluoroacetate DMF: N, N-dimethylformamide HBTU: O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate

Reference Example 1: 3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole

a) Production of 5- (Hydroxymethylidene) -2-methyltetrahydro-4H-pyran-4-one (Reference Example 1-1) 2-Methyltetrahydro-4H-pyran-4-one (5.25 g) and formic acid Ethyl (5.62 mL) was dissolved in toluene (150 mL), a 28% sodium methoxide / methanol solution (13.3 g) was added dropwise at room temperature, and the reaction solution was stirred for 5 hours. 1 mol / L hydrochloric acid (100 mL) 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 then the filtrate was concentrated under reduced pressure to obtain a crude product of Reference Example 1-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 8.35 (1H, s), 4.50 (1H, d, J = 12.8 Hz), 4.45-4.37 (1H, m), 3.84-3.66 (1H, m), 2.45-2.23 (2H, m), 1.31 (3H, d, J = 6.1 Hz).

b) Production of 6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole (Reference Example 1-2) The crude product of the compound of Reference Example 1-1 was added to ethanol (100 mL). Hydrazine monohydrate (2.30 g) was added dropwise at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol). The obtained crystals were washed with diisopropyl ether, filtered, and dried under reduced pressure to obtain Reference Example 1-2 (2.07 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.30 (1H, s), 4.84 (1H, d, J = 13.2 Hz), 4.73-4.66 (1H, m), 3.83-3.71 (1H, m), 2.77 (1H, dd, J = 15.5, 3.2 Hz), 2.59 (1H, d, J = 10.5 Hz), 1.39 (3H, d, J = 6.4 Hz).

c) Production of 3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole (Reference Example 1) Compound (2.07 g) of Reference Example 1-2 was added to DMF. It was dissolved in (20 mL), potassium hydroxide (1.68 g) was added at room temperature, and the mixture was stirred for 10 minutes. After that, iodine (5.70 g) was added, and the mixture was stirred overnight at room temperature. An aqueous sodium thiosulfate solution was added to the reaction solution until the brown color of iodine disappeared, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 1 (2.87 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 4.57 (1H, d, J = 14.0 Hz), 4.53-4.46 (1H, m), 3.80-3.66 (1H, m), 2.80-2.72 (1H, m) ), 2.56 (1H, dd, J = 16.2, 10.1 Hz), 1.38 (3H, d, J = 6.7 Hz).

Reference Example 2: (6R) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole

The compound of Reference Example 1 was optically resolved under the same conditions as the measurement condition A to obtain Reference Example 2 (holding time: 5.727 min, 99.4% ee).

Reference Example 3: (6S) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole

The compound of Reference Example 1 was optically resolved under the same conditions as the measurement condition A to obtain Reference Example 2 (holding time: 7.423 min, 99.5% ee).

参考例１の化合物（５００ｍｇ）、２，６−ジメチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ピリジン（５３０ｍｇ）及び２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（４．７３ｍＬ）のＤＭＥ（１５ｍＬ）溶液に、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）（６７．０ｍｇ）を加え、８時間加熱還流した。反応液を室温に冷却後、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（ＮＨシリカゲル、ヘキサン／酢酸エチル）にて精製することにより、参考例４（２７１ｍｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；２４４［ｍ＋Ｈ］^＋ 保持時間；０．３０７ｍｉｎ Reference Example 4: 3- (2,6-dimethylpyridin-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole

Compound of Reference Example 1 (500 mg), 2,6-dimethyl-4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (530 mg) and 2 mol / L carbonate. Dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (67.0 mg) was added to a DME (15 mL) solution of an aqueous sodium solution (4.73 mL), and the mixture was heated under reflux for 8 hours. The reaction mixture was cooled to room temperature, water was added, 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 (NH silica gel, hexane / ethyl acetate) to obtain Reference Example 4 (271 mg).
LC-MS, m / z; 244 [m + H] ⁺ retention time; 0.307 min

Reference examples 5-7
The compounds of Reference Examples 1 to 3 were used as starting materials, and the reaction, post-treatment, and purification were carried out according to the same method as described in Reference Example 4 to obtain the compounds shown in the table below.

The compound names of Reference Examples 5 to 7 are described below.
Reference Example 5: 6-Methyl-3- (2-Methylpyridine-4-yl) -1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole Reference Example 6: (6S) -3- (2,6-Dimethylpyridin-4-yl) -6-Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] Pyrazole Reference Example 7: (6R) -3- (2,6) -Dimethylpyridin-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole

参考例１の化合物（２１１ｍｇ）、３−メトキシ−４−（トリフルオロメチル）フェニルボロン酸（２６４ｍｇ）及びピリジン（０．１９４ｍＬ）のＤＭＦ（５ｍＬ）溶液に、酢酸銅（ＩＩ）（４３．５ｍｇ）を加え、室温で１週間撹拌した。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（ヘキサン／酢酸エチル）にて精製することにより、参考例８（２００ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.60 (1H, d, J = 8.5 Hz), 7.28-7.22 (1H, m), 7.03-6.97 (1H, m), 4.61 (1H, d, J = 14.0 Hz), 4.57-4.50 (1H, m), 3.95 (3H, s), 3.73-3.62 (1H, m), 2.77-2.65 (2H, m), 1.39 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；４３９［ｍ＋Ｈ］^＋ 保持時間；１．１５６ｍｉｎ Reference Example 8: 3-iodo-1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole

Copper acetate (II) (43.5 mg) in a solution of compound (211 mg), 3-methoxy-4- (trifluoromethyl) phenylboronic acid (264 mg) and pyridine (0.194 mL) of Reference Example 1 in DMF (5 mL). ) Was added, and the mixture was stirred at room temperature for 1 week. 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 (hexane / ethyl acetate) to give Reference Example 8 (200 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.60 (1H, d, J = 8.5 Hz), 7.28-7.22 (1H, m), 7.03-6.97 (1H, m), 4.61 (1H, d, J) = 14.0 Hz), 4.57-4.50 (1H, m), 3.95 (3H, s), 3.73-3.62 (1H, m), 2.77-2.65 (2H, m), 1.39 (3H, d, J = 6.1 Hz) ..
LC-MS, m / z; 439 [m + H] ⁺ retention time; 1.156 min

Reference examples 9-28
Using Reference Examples 1 to 3 as starting materials, 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 28 are described below.
Reference Example 9: 1- (4-Chloro-3-methoxyphenyl) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 10: 3- Iodo-1- [3-methoxy-4- (trifluoromethoxy) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 11: 1- [3 −ethoxy-4- (trifluoromethyl) phenyl] -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 12: (6R) -3- Iodo-1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 13: (6S)- 3-Iodo-1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 14: (6S ) -3-Iodo-1- [3-methoxy-4- (trifluoromethoxy) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 15: (6S) -1- (4-Fluorophenyl) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 16: (6S) -3- Iodo-6-methyl-1- [4- (trifluoromethyl) phenyl] -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 17: (6S) -3-iodo- 1- (4-Methylphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 18: (6S) -1- (4-fluoro-3-methoxy) Phenyl) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference Example 19: 1- (4-fluorophenyl) -3-iodo-6-methyl -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Reference example 20: 1- (4-fluoro-3-methoxyphenyl) -3-iodo-6-methyl-1,4,6 , 7-Tetrahydropyrano [4,3-c] Pyrazole Reference Example 21: 1- (4-fluoro-3-methylphenyl) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole Reference Example 22: (6S) -1- (4-fluoro-3-methylphenyl) -3-iodo-6-me Chill-1,4,6,7-Tetrahydropyrano [4,3-c] Pyrazole Reference Example 23: (6S) -1- (4-chlorophenyl) -3-iodo-6-methyl-1,4,6 , 7-Tetrahydropyrano [4,3-c] Pyrazole Reference Example 24: (6S) -1- (4-Chloro-3-methylphenyl) -3-iodo-6-methyl-1,4,6,7 -Tetrahydropyrano [4,3-c] Pyrazole Reference Example 25: (6S) -1- (4-chloro-3-methoxyphenyl) -3-iodo-6-methyl-1,4,6,7-tetrahydro Pyrazole [4,3-c] Pyrazole Reference Example 26: (6S) -1- (3-Chloro-4-fluorophenyl) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole Reference Example 27: (6S) -1- (4-chloro-3-fluorophenyl) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4] , 3-c] Pyrazole Reference Example 28: (6S) -1- (3,4-difluorophenyl) -3-iodo-6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] ] Pyrazole

Reference Example 29: 1- [3-ethoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylic acid

a) Production of ethyl (6-methyl-4-oxotetrahydro-2H-pyran-3-yl) (oxo) acetate (Reference Example 29-1) 2-Methyldihydro-2H-pyran-4 (3H) -one ( To a solution of 1.0 g) in ethanol (22 mL) was added diethyl oxalate (1.78 mL) and sodium ethoxide (4.47 g), and the mixture was stirred at room temperature for 4 hours. 1 mol / L hydrochloric acid was added to the reaction mixture to adjust the pH to 2-3, and then the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 29-1 (1.16 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.85 (1H, d, J = 15.3 Hz), 4.55 (1H, d, J = 14.6 Hz), 4.32 (2H, q, J = 7.1 Hz), 3.84 -3.72 (1H, m), 2.52 (1H, dd, J = 18.9, 3.7 Hz), 2.39 (1H, dd, J = 18.9, 10.4 Hz), 1.36 (3H, t, J = 7.1 Hz), 1.29 ( 3H, d, J = 6.7 Hz).

b) Production of ethyl 6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylate (Reference Example 29-2) Compound of Reference Example 29-1 (161 mg) Was dissolved in ethanol (3.8 mL), hydrazine hydrate (0.04 mL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution to adjust the pH to 3 to 4, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 29-2 (136 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 10.65 (1H, br s), 5.00 (1H, d, J = 15.3 Hz), 4.74 (1H, d, J = 15.3 Hz), 4.35 (2H, q) , J = 7.1 Hz), 3.80-3.68 (1H, m), 2.77 (2H, dd, J = 15.9, 3.1 Hz), 2.55 (2H, dd, J = 15.9, 10.4 Hz), 1.41-1.32 (6H, m).

c) Ethyl 1- [3-ethoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylate (reference) Production of Example 29-3) Pyridine (0.231 mL) and pyridine (0.231 mL) in a DMF (50 mL) solution of the compound (200 mg) of Reference Example 29-2 and 3-ethoxy-4- (trifluoromethyl) phenylboronic acid (334 mg). Copper (II) acetate (52 mg) was added, and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 29-3 (342 mg).
LC-MS, m / z; 399 [m + H] ⁺ retention time; 1.176 min

d) 1- [3-ethoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylic acid (reference example) 29) A 2 mol / L aqueous sodium hydroxide solution (0.82 mL) was added to a solution of the compound (327 mg) of Reference Example 29-3 in ethanol (4 mL), and the mixture was stirred at 70 ° C. for 1 hour. The reaction mixture was cooled to room temperature, neutralized by adding 2 mol / L hydrochloric acid, and concentrated under reduced pressure. Ethanol was added to the obtained residue, and the precipitated insoluble matter was filtered off. Reference Example 29 (302 mg) was obtained by concentrating the filtrate under reduced pressure.
LC-MS, m / z; 371 [m + H] ⁺ retention time; 0.937 min

Reference Example 30: 1- (4-chloro-3-methoxyphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylic acid

a) Ethyl 1- (4-chloro-3-methoxyphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylate (Reference Example 30-1) ), The compound (200 mg) of Reference Example 29-2 was used as a starting material, and the reaction, post-treatment, and purification were carried out according to the same method as described in Reference Example 29c). Got
LC-MS, m / z; 351 [m + H] ⁺ retention time; 1.036 min

b) Production of 1- (4-chloro-3-methoxyphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-carboxylic acid (Reference Example 30) Using the compound of Reference Example 30-1 (288 mg) as a starting material, the reaction, post-treatment and purification were carried out according to the same method as described in Reference Example 29d) to obtain Reference Example 30 (312 mg).
LC-MS, m / z; 323.20 [m + H] ⁺ retention time; 0.766 min

Reference Example 31: 3- (2,6-dimethylpyridin-4-yl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole

Using 3-iodo-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole (150 mg), Reference Example 31 (143 mg) was obtained according to the method described in Reference Example 4.
LC-MS, m / z; 230 [m + H] + retention time; 0.220 min

Reference Example 32: 3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole

a) Production of 4- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -1H-pyrazole (Reference Example 32-1) 2- (1H-pyrazole-4-yl) ethanol (10 g) Tert-Butyldimethylchlorosilane (15 g) was added to a solution of imidazole (6.7 g) in N, N-dimethylformamide (200 mL) at room temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (22 g) of Reference Example 32-1.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.45 (2H, s), 3.75 (2H, t, J = 6.7 Hz), 2.71 (2H, t, J = 6.7 Hz), 0.89 (9H, s) , 0.03 (6H, s).

b) Production of 4- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -N, N-dimethyl-1H-pyrazole-1-sulfonamide (Reference Example 32-2) Reference Example 32-1 To a solution of crude product (22 g) and 1,4-diazabicyclo [2.2.2] octane in acetonitrile (300 mL), add N, N-dimethylsulfamoyl chloride (12.4 mL) at room temperature and stir overnight. 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 dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 32-2 (28 g).
LC-MS, m / z; 334 [m + H] ⁺ retention time; 1.200 min

c) 4- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5- (2-hydroxypropyl) -N, N-dimethyl-1H-pyrazole-1-sulfonamide (Reference Example 32- The compound (10 g) of Production Reference Example 32-2 of 3) was dissolved in THF (150 mL), cooled to −78 ° C., and n-butyllithium (1.55 mol / L hexane solution, 29 mL) was added dropwise. The reaction mixture was heated to room temperature, stirred for 30 minutes, and then cooled to −78 ° C. again. After adding propylene oxide (6.4 mL), the temperature was raised to room temperature and the mixture was stirred overnight. 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 (hexane / ethyl acetate) to obtain Reference Example 32-3 (4.7 g).
LC-MS, m / z; 392 [m + H] ⁺ retention time; 1.133 min

d) Production of 4- (2-Hydroxyethyl) -5- (2-Hydroxypropyl) -N, N-dimethyl-1H-pyrazole-1-sulfonamide (Reference Example 32-4) Compound of Reference Example 32-3 (6.0 g) was dissolved in THF (80 mL), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 18 mL) was added at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain Reference Example 32-4 (3.4 g).
LC-MS, m / z; 278 [m + H] ⁺ retention time; 0.426 min

e) Production Reference Example of 2- [1- (Dimethylsulfamoyl) -5- (2-Hydroxypropyl) -1H-Pyrazole-4-yl] Ethyl 4-Methylbenzene Sulfonate (Reference Example 32-5) Compound 32-4 (3.3 g) was dissolved in pyridine (48 mL) and 4-toluenesulfonyl chloride (2.3 g) was added at 0 ° C. The reaction mixture was heated to room temperature and stirred overnight. 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 dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 32-5 (2.1 g).
LC-MS, m / z; 432 [m + H] ⁺ retention time; 0.847 min

f) Production of N, N, 7-trimethyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-1-sulfonamide (Reference Example 32-6) 55% sodium hydride A suspension of (303 mg) in tetrahydrofuran (20 mL) was cooled to 0 ° C., and a solution of the compound (2.0 g) of Reference Example 32-5 in tetrahydrofuran (10 mL) was added dropwise. The reaction solution was gradually warmed to room temperature and stirred for 3 days. 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 (hexane / ethyl acetate) to give Reference Example 32-6 (0.89 g).
LC-MS, m / z; 260 [m + H] ⁺ retention time; 0.679 min

g) Production of 7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole (Reference Example 32-7) tetrahydrofuran of the compound (0.89 g) of Reference Example 32-6 6 mol / L hydrochloric acid (8.58 mL) was added to the (8 mL) solution, and the mixture was stirred at 50 ° C. for 6 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain Reference Example 32-7 (0.58 g).
LC-MS, m / z; 153 [m + H] ⁺ retention time; 0.288 min

h) Production of 3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole (Reference Example 32) Compound of Reference Example 32-7 (0.58 g) Iodine (1.45 g) was added to a solution of potassium hydroxide (0.43 g) in DMF (8 mL) at room temperature, and the mixture was stirred overnight. Then, potassium hydroxide (0.43 g) and iodine (1.45 g) were added, and the mixture was stirred at room temperature for 6 hours. Then, potassium hydroxide (0.43 g) and iodine (1.45 g) were added, and the mixture was stirred at room temperature for 2 hours. Then, potassium hydroxide (0.43 g) and iodine (1.45 g) were added, and the mixture was stirred at room temperature for 2 hours. After confirming the disappearance of the raw materials, an aqueous sodium thiosulfate solution was added to the reaction solution until the brown color of iodine disappeared, 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 (hexane / ethyl acetate) to obtain Reference Example 32 (0.39 g).
LC-MS, m / z; 279 [m + H] ⁺ retention time; 0.565 min

参考例３２の化合物（５００ｍｇ）、２，６−ジメチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ピリジン（５３０ｍｇ）及び２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（４．７３ｍＬ）のＤＭＥ（１５ｍＬ）溶液に、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）（６７．０ｍｇ）を加え、８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（ＮＨシリカゲル、ヘキサン／酢酸エチル）にて精製することにより、参考例３３（２７１ｍｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；２５８［ｍ＋Ｈ］^＋ 保持時間；０．３３２ｍｉｎ Reference Example 33: 3- (2,6-dimethylpyridin-4-yl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole

Compound of Reference Example 32 (500 mg), 2,6-dimethyl-4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (530 mg) and 2 mol / L carbonate. Dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (67.0 mg) was added to a DME (15 mL) solution of an aqueous sodium solution (4.73 mL), and the mixture was heated under reflux for 8 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 (NH silica gel, hexane / ethyl acetate) to obtain Reference Example 33 (271 mg).
LC-MS, m / z; 258 [m + H] ⁺ retention time; 0.332 min

Reference Example 34: (7R) -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole

a) 4- (2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) -5-[(2R) -2-hydroxypropyl] -N, N-dimethyl-1H-pyrazol-1-sulfonamide ( Production of Reference Example 34-1) The compound (33.4 g) of Reference Example 32-2 was dissolved in THF (500 mL), cooled to −78 ° C., and n-butyllithium (2.66 mol / L hexane solution, 58. 2 mL) was added dropwise. The reaction mixture was heated to room temperature, stirred for 30 minutes, and then cooled to −78 ° C. again. After adding (R) -propylene oxide (21.7 mL), the temperature was raised to room temperature and the mixture was stirred overnight. 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 (hexane / ethyl acetate) to give Reference Example 34-1 (30.9 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.55 (1H, s), 4.17-4.04 (1H, m), 3.89-3.73 (2H, m), 3.19-3.11 (1H, m), 3.04 (6H) , s), 2.97-2.84 (1H, m), 2.76-2.60 (2H, m), 1.27 (3H, d, J = 6.1 Hz), 0.85 (9H, s), 0.03-0.00 (6H, m).
LC-MS, m / z; 392 [m + H] ⁺ retention time; 1.150 min

b) Production of 4- (2-Hydroxyethyl) -5-[(2R) -2-hydroxypropyl] -N, N-dimethyl-1H-pyrazole-1-sulfonamide (Reference Example 34-2) Reference Example 34 The compound of -1 (30.9 g) was dissolved in THF (395 mL), tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 118 mL) was added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain Reference Example 34-2 (21.0 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.54 (1H, s), 4.27-4.16 (1H, m), 3.94-3.83 (1H, m), 3.81-3.71 (1H, m), 3.16 (1H) , dd, J = 14.6, 3.1 Hz), 2.86 (1H, dd, J = 14.6, 9.2 Hz), 2.72-2.66 (2H, m), 1.31 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 278 [m + H] ⁺ retention time; 0.442 min

c) 2- {1- (Dimethylsulfamoyl) -5-[(2R) -2-hydroxypropyl] -1H-pyrazole-4-yl} ethyl 4-methylbenzene-1-sulfonate (Reference Example 34-3) ) Was dissolved in pyridine (306 mL), and 4-toluenesulfonyl chloride (14.4 g) was added at 0 ° C. The reaction solution was heated to room temperature and stirred for 5 hours. 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 dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 34-3 (16.7 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.77-7.71 (2H, m), 7.47 (1H, s), 7.36-7.31 (2H, m), 4.23-4.03 (4H, m), 3.04 (6H) , s), 2.88-2.73 (3H, m), 2.44 (3H, s), 1.66 (1H, d, J = 4.9 Hz), 1.25 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 432 [m + H] ⁺ retention time; 0.864 min

d) Production of (7R) -N, N, 7-trimethyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-1-sulfonamide (Reference Example 34-4) 55 A suspension of% sodium hydride (2.53 g) in tetrahydrofuran (221 mL) was cooled to 0 ° C., and a solution of the compound (16.7 g) of Reference Example 34-3 in tetrahydrofuran (110 mL) was added dropwise. The reaction solution was gradually warmed to room temperature and stirred for 3 days. 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 (hexane / ethyl acetate) to obtain Reference Example 34-4 (3.5 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.36 (1H, s), 4.21-4.14 (1H, m), 3.75-3.67 (1H, m), 3.62-3.52 (2H, m), 3.04 (6H) , s), 2.90-2.81 (2H, m), 2.65-2.58 (1H, m), 1.32 (3H, d, J = 6.7 Hz).
LC-MS, m / z; 260 [m + H] ⁺ retention time; 0.692 min

e) Production of (7R) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole (Reference Example 34-5) Compound of Reference Example 34-4 (3. 6 mol / L hydrochloric acid (60.7 mL) was added to a solution of 5 g) in tetrahydrofuran (79 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain Reference Example 34-5 (1.9 g).
^{1 1} H-NMR (400 MHz, CD ₃ OD) δ: 7.88 (1H, s), 4.26-4.17 (1H, m), 3.81-3.71 (1H, m), 3.62-3.52 (1H, m), 3.02- 2.74 (4H, m), 1.32 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 153 [m + H] ⁺ retention time; 0.317 min

f) Preparation of (7R) -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole (Reference Example 34) Compound of Reference Example 34-5 (Reference Example 34) Iodine (15.2 g) was added to a solution of 1.9 g) and potassium hydroxide (4.0 g) in DMF (92 mL) at room temperature, and the mixture was stirred for 3 hours. An aqueous sodium thiosulfate solution was added to the reaction solution until the brown color of iodine disappeared, 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 (hexane / ethyl acetate) to obtain Reference Example 34 (2.26 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 4.29-4.21 (1H, m), 3.74-3.63 (1H, m), 3.57-3.47 (1H, m), 2.91-2.77 (3H, m), 2.53 -2.44 (1H, m), 1.31 (3H, d, J = 6.7 Hz).
LC-MS, m / z; 279 [m + H] ⁺ retention time; 0.584 min

参考例３４の化合物（５００ｍｇ）、２，６−ジメチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ピリジン（６２９ｍｇ）、炭酸ナトリウム（５７２ｍｇ）及び水（０．９２ｍL）のＤＭＥ（２．３ｍＬ）溶液に、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）（２５５ｍｇ）を加え、２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）にて精製することにより、参考例３５（２７１ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.08 (2H, s), 4.29-4.20 (1H, m), 3.76-3.65 (1H, m), 3.53 (1H, t, J = 11.9 Hz), 3.04-2.82 (3H, m), 2.82-2.73 (1H, m), 2.56 (6H, s), 1.31 (3H, d, J = 5.5 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；２５８［ｍ＋Ｈ］^＋ 保持時間；０．３２７ｍｉｎ Reference Example 35: (7R) -3- (2,6-dimethylpyridin-4-yl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole

Compound of Reference Example 34 (500 mg), 2,6-dimethyl-4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (629 mg), sodium carbonate (572 mg). ) And water (0.92 mL) in a DME (2.3 mL) solution, dichlorobis [di-tert-butyl (4-dimethylaminophenyl) phosphino] palladium (II) (255 mg) was added, and the mixture was heated under reflux for 2 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) to obtain Reference Example 35 (271 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.08 (2H, s), 4.29-4.20 (1H, m), 3.76-3.65 (1H, m), 3.53 (1H, t, J = 11.9 Hz), 3.04-2.82 (3H, m), 2.82-2.73 (1H, m), 2.56 (6H, s), 1.31 (3H, d, J = 5.5 Hz).
LC-MS, m / z; 258 [m + H] ⁺ retention time; 0.327 min

参考例３２−２の化合物（５ｇ）と（Ｓ）−プロピレンオキシド（２．６ｇ）を用いて、参考例３４に記載の方法に準じ、参考例３６の化合物（２６０ｍｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；２７９［ｍ＋Ｈ］^＋ 保持時間；０．５８７ｍｉｎ Reference Example 36: (7S) -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole

Using the compound (5 g) of Reference Example 32-2 and (S) -propylene oxide (2.6 g), the compound of Reference Example 36 (260 mg) was obtained according to the method described in Reference Example 34.
LC-MS, m / z; 279 [m + H] ⁺ retention time; 0.587 min

Reference example 37-44
Using Reference Example 34 or 36 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 37 to 44 are described below.
Reference Example 37: (7R) -3-iodo-1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5 -C]
Pyrazole Reference Example 38: (7S) -3-iodo-1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4, 5-c] Pyrazole Reference Example 39: (7R) -1- (3-chloro-4-fluorophenyl) -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4, 5-c] Pyrazole Reference Example 40: (7R) -1- (4-fluoro-3-methylphenyl) -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4, 5-c] Pyrazole Reference Example 41: (7R) -1- (4-fluoro-3-methoxyphenyl) -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4, 5-c] Pyrazole Reference Example 42: (7R) -1- (4-chloro-3-methoxyphenyl) -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4, 5-c] Pyrazole Reference Example 43: (7R) -1- [4-fluoro-3- (trifluoromethyl) phenyl] -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H- Oxepino [4,5-c] Pyrazole Reference Example 44: (7R) -1- (4-fluorophenyl) -3-iodo-7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4, 5-c] Pyrazole

Reference example 45-47
Using Reference Example 34 as a starting material, the reaction, post-treatment, and purification were carried out according to the same method as described in Reference Example 35 to obtain the compounds shown in the table below.

The compound names of Reference Examples 45 to 47 are described below.
Reference Example 45: 5-[(7R) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] pyridin-2-amine Reference Example 46: 3-Methyl-5-[(7R) -7-Methyl-4,5,7,8-Tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] Pyridine-2-amine Reference Example 47: 4-[(7R) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] pyridin-2-amine

参考例６の化合物（１４１ｍｇ）、［３−メトキシ−４−（トリフルオロメチル）フェニル）ボロン酸（１８１ｍｇ）及びピリジン（１３８ｍｇ）のＤＭＦ（５ｍＬ）溶液に、酢酸銅（ＩＩ）（３１．８ｍｇ）を加え、反応液を室温にて終夜撹拌した。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（ヘキサン／酢酸エチル）で精製することにより、実施例１の化合物（１０４ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.60 (1H, d, J = 8.5 Hz), 7.26 (1H, s), 7.24-7.13 (2H, m), 7.05 (1H, d, J = 7.9 Hz), 4.99 (1H, d, J = 14.0 Hz), 4.95-4.86 (1H, m), 3.93 (3H, s), 3.77-3.65 (1H, m), 2.81-2.67 (2H, m), 2.54 (6H, d, J = 3.7 Hz), 1.38 (3H, d, J = 6.1 Hz). Example 1: (6S) -3- (2,6-dimethylpyridin-4-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6 7-Tetrahydropyrano [4,3-c] pyrazole

Copper acetate (II) (31.8 mg) in a solution of compound (141 mg) of Reference Example 6, [3-methoxy-4- (trifluoromethyl) phenyl) boronic acid (181 mg) and pyridine (138 mg) in DMF (5 mL). ) Was added, and the reaction solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the compound of Example 1 (104 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.60 (1H, d, J = 8.5 Hz), 7.26 (1H, s), 7.24-7.13 (2H, m), 7.05 (1H, d, J = 7.9) Hz), 4.99 (1H, d, J = 14.0 Hz), 4.95-4.86 (1H, m), 3.93 (3H, s), 3.77-3.65 (1H, m), 2.81-2.67 (2H, m), 2.54 (6H, d, J = 3.7 Hz), 1.38 (3H, d, J = 6.1 Hz).

Examples 2-32
Using the corresponding reference example compound 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 2-32 are described below.
Example 2: 3- (2,6-dimethylpyridine-4-yl) -6-methyl-1- [4- (trifluoromethoxy) phenyl] -1,4,6,7-tetrahydropyrano [4, 3-c] Pyrazole Example 3: 3- (2,6-dimethylpyridine-4-yl) -6-methyl-1- [3-methyl-4- (trifluoromethoxy) phenyl] -1,4,6 , 7-Tetrahydropyrano [4,3-c] pyrazole Example 4: 6-Methyl-3- (2-methylpyridine-4-yl) -1- [3-Methyl-4- (trifluoromethoxy) phenyl ] -1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole Example 5: 3- (2,6-dimethylpyridine-4-yl) -6-methyl-1- [4-( Trifluoromethyl) phenyl] -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 6: 1- (3,4-difluorophenyl) -3- (2,6-dimethylpyridine) -4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 7: 1- (3,4-dichlorophenyl) -3- (2,6-) Dimethylpyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 8: 1- (3-chloro-4-fluorophenyl) -3- (2,6-Dimethylpyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 9: 1- (3-chloro-4-methoxy) Phenyl) -3- (2,6-dimethylpyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 10: 3- (2,2) 6-Dimethylpyridine-4-yl) -1- (4-fluoro-3-methylphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 11: 3- (2,6-Dimethylpyridine-4-yl) -1- (3-ethoxy-4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole Example 12: 5- [3- (2,6-dimethylpyridine-4-yl) -6-methyl-6,7-dihydropyrano [4,3-c] pyrazole-1 (4H) -yl] -2 -Fluorobenzonitrile Example 13: 3- (2,6-dimethylpyridine-4-yl) -6-methyl-1- [2-methyl-4- (trifluoromethyl) phenyl]- 1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole Example 14: 3- (2,6-dimethylpyridine-4-yl) -6-methyl-1- [3- (trifluoro) Methyl) phenyl] -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 15: 1- [4- (difluoromethoxy) -3-methylphenyl] -3- (2,6) -Dimethylpyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 16: (6S) -3- (2,6-dimethylpyridine- 4-yl) -1- (3-ethoxy-4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 17: (6S) -3 -(2,6-Dimethylpyridine-4-yl) -1- [3-ethoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3 -C] Pyrazole Example 18: (6S) -3- (2,6-dimethylpyridine-4-yl) -1- [3-methoxy-4- (trifluoromethoxy) phenyl] -6-methyl-1, 4,6,7-Tetrahydropyrano [4,3-c] pyrazole Example 19: (6S) -1- (4-chloro-3-methoxyphenyl) -3- (2,6-dimethylpyridine-4-) Il) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 20: (6S) -1- (4-chloro-3-fluorophenyl) -3-( 2,6-Dimethylpyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 21: (6S) -1- [4- (difluoro) Methoxy) -3-methylphenyl] -3- (2,6-dimethylpyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 22 : (6S) -1- (3-chloro-4-fluorophenyl) -3- (2,6-dimethylpyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4] , 3-c] Pyrazole Example 23: (6R) -3- (2,6-dimethylpyridine-4-yl) -1- (3-ethoxy-4-fluorophenyl) -6-methyl-1,4 6,7-Tetrahydropyrano [4,3-c] pyrazole Example 24: (6R) -1- (3-chloro-4-fluorophenyl) -3- (2,6-dimethylpyridi) N-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 25: (6R) -3- (2,6-dimethylpyrididine-4-4) Il) -1- [3-ethoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 26: (6R) -3- (2,6-dimethylpyridin-4-yl) -1- [3-methoxy-4- (trifluoromethoxy) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4] , 3-c] Pyrazole Example 27: (6R) -1- (4-chloro-3-methoxyphenyl) -3- (2,6-dimethylpyridin-4-yl) -6-methyl-1,4 6,7-Tetrahydropyrano [4,3-c] pyrazole Example 28: (6R) -1- (4-chloro-3-fluorophenyl) -3- (2,6-dimethylpyridin-4-yl) -6-Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] Pyrazole Example 29: (6R) -1- [4- (difluoromethoxy) -3-methylphenyl] -3- (2,6-Dimethylpyridin-4-yl) -6-Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] Pyrazole Example 30: 5-[(6S) -3-( 2,6-Dimethylpyridin-4-yl) -6-methyl-6,7-dihydropyrano [4,3-c] pyrazole-1 (4H) -yl] -2- (trifluoromethyl) benzonitrile Example 31 : (6S) -3- (2,6-dimethylpyridin-4-yl) -6-methyl-1- [3-methyl-4- (trifluoromethyl) phenyl] -1,4,6,7-tetrahydro Pyrano [4,3-c] Pyrazole Example 32: (6S) -1- (4-chloro-3-methylphenyl) -3- (2,6-dimethylpyridin-4-yl) -6-methyl- 1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole

参考例８の化合物（０．７ｇ）、２，６−ジメチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボラン−２−イル）ピリジン（０．４４７ｇ）及び２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（３．９９ｍＬ）のＤＭＥ（１５ｍＬ）溶液に、テトラキストリフェニルホスフィンパラジウム（０）（０．１８５ｇ）を加え、反応液を５時間加熱還流した。反応液を室温に冷却後、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、ろ過して、ろ液を減圧濃縮した。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）で精製することにより、実施例３３（０．２９ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.60 (1H, d, J = 8.5 Hz), 7.30-7.13 (3H, m), 7.05 (1H, d, J = 7.9 Hz), 4.99 (1H, d, J = 14.0 Hz), 4.96-4.84 (1H, m), 3.93 (3H, s), 3.79-3.64 (1H, m), 2.83-2.66 (2H, m), 2.55 (6H, s), 1.38 (3H, d, J = 6.1 Hz). Example 33: 3- (2,6-dimethylpyridin-4-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyra No [4,3-c] pyrazole

Reference Example 8 compound (0.7 g), 2,6-dimethyl-4- (4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) pyridine (0.447 g) and Tetrakistriphenylphosphine palladium (0) (0.185 g) was added to a DME (15 mL) solution of a 2 mol / L sodium carbonate aqueous solution (3.99 mL), and the reaction solution was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Example 33 (0.29 g).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.60 (1H, d, J = 8.5 Hz), 7.30-7.13 (3H, m), 7.05 (1H, d, J = 7.9 Hz), 4.99 (1H, 1H, d, J = 14.0 Hz), 4.96-4.84 (1H, m), 3.93 (3H, s), 3.79-3.64 (1H, m), 2.83-2.66 (2H, m), 2.55 (6H, s), 1.38 (3H, d, J = 6.1 Hz).

参考例１５の化合物（１４２ｍｇ）、（４−アミノスルフォニルフェニル）ボロン酸（１２０ｍｇ）及びビス［ジ−ｔｅｒｔ−ブチル（４−ジメチルアミノフェニル）ホスフィン］ジクロロパラジウム（ＩＩ）（１４ｍｇｌ）のＤＭＥ（２ｍＬ）溶液に、２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０．９９ｍＬ）を加え、反応液を８５℃で２時間撹拌した。反応液を室温に冷却し、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、ろ過して、ろ液を減圧濃縮した。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）で精製した。得られた結晶をジイソプロピルエーテルで洗浄することにより、実施例３４（１３２ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.98-7.91 (2H, m), 7.81-7.73 (2H, m), 7.56-7.48 (2H, m), 7.22-7.13 (2H, m), 5.01 (1H, d, J = 14.0 Hz), 4.98-4.90 (1H, m), 4.83 (2H, s), 3.83-3.70 (1H, m), 2.76-2.66 (2H, m), 1.41 (3H, d, J = 6.1 Hz). Example 34: 4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] benzene sulfone Amide

DME (2 mL) of the compound of Reference Example 15 (142 mg), (4-aminosulfonylphenyl) boric acid (120 mg) and bis [di-tert-butyl (4-dimethylaminophenyl) phosphine] dichloropalladium (II) (14 mgl). ), A 2 mol / L aqueous sodium carbonate solution (0.99 mL) was added, and the reaction solution was stirred at 85 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate). The obtained crystals were washed with diisopropyl ether to obtain Example 34 (132 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.98-7.91 (2H, m), 7.81-7.73 (2H, m), 7.56-7.48 (2H, m), 7.22-7.13 (2H, m), 5.01 (1H, d, J = 14.0 Hz), 4.98-4.90 (1H, m), 4.83 (2H, s), 3.83-3.70 (1H, m), 2.76-2.66 (2H, m), 1.41 (3H, d) , J = 6.1 Hz).

Examples 35-95
Using the corresponding reference compound as a starting material, the reaction, post-treatment, and purification were carried out according to the same methods as described in Examples 33 and 34 to obtain the compounds shown in the table below.

The compound names of Examples 35 to 96 are described below.
Example 35: 1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-3- (2-methylpyridine-4-yl) -1,4,6,7-tetrahydropyrano [ 4,3-c] Pyrazole Example 36: 1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-3- (pyridine-4-yl) -1,4,6,7- Tetrahydropyrano [4,3-c] pyrazole Example 37: 1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-3- (pyridine-3-yl) -1,4 6,7-Tetrahydropyrano [4,3-c] pyrazole Example 38: 1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-3- (6-methylpyridine-3-3) Il) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 39: 1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-3-( 5-Methylpyridine-3-yl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 40: 1- [3-methoxy-4- (trifluoromethyl) phenyl]- 6-Methyl-3- (1H-pyrazol-5-yl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 41: 1- [3-methoxy-4- (tri) Fluoromethyl) phenyl] -6-methyl-3- (1H-pyrazol-4-yl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 42: 1- [3- [3-] Methoxy-4- (trifluoromethyl) phenyl] -6-methyl-3-phenyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 43: 5- {1- [3 −Methyl-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl} pyridin-2-amine Example 44: 1- (4-Chloro-3-methoxyphenyl) -3- (2,6-dimethylpyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole Example 45: 1- (4-chloro-3-methoxyphenyl) -6-methyl-3- (2-methylpyridine-4-yl) -1,4,6,7-tetrahydropyrano [4,3] -C] Pyrazole Example 46: 3- (2,6-Dimethylpyridine-4-yl) -1- [3-Methyl-4- (trifluo) Lomethoxy) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 47: 1- [3-methoxy-4- (trifluoromethoxy) phenyl] -6 − Methyl-3- (2-methylpyridine-4-yl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 48: 3- (2,6-dimethylpyridine-4) -Il) -1- [3-ethoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 49: 1- [3-ethoxy-4- (trifluoromethyl) phenyl] -6-methyl-3- (2-methylpyridine-4-yl) -1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole Example 50: 4- {1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3 -Il} Pyridin-2-amine Example 51: 1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-3- [6- (morpholin-4-yl) pyridine-3-yl ] -1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole Example 52: 3- {1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1 , 4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl} benzamide Example 53: 4- {1- [3-methoxy-4- (trifluoromethyl) phenyl] -6- Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl} benzamide Example 54: 4- {1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl} benzenesulfonamide Example 55: (6R) -1- [3-methoxy-4-( Trifluoromethyl) phenyl] -6-methyl-3- (3-methylpyridine-4-yl) -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 56: 3-{ (6R) -1- [3-Methyl-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl} benzene Symphonamide Example 57: 4-{(6S) -1- [3-methoxy-4- (trifluoromethyl) Le) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl} pyridin-2-amine Example 58: 4-{(6S) -1 -[3-Methyl-4- (trifluoromethoxy) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl} pyridin-2-amine Example 59: (6S) -3- (2-methoxypyridine-4-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydro Pyrano [4,3-c] pyrazole Example 60: (4-{(6S) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7 -Tetrahydropyrano [4,3-c] pyrazole-3-yl} pyridin-2-yl) Methanol Example 61: 4-{(6S) -1- [3-methoxy-4- (trifluoromethyl) phenyl) ] -6-Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl} pyridine-2-carbonitrile Example 62: (6S) -1- (4-fluoro) Phenyl) -6-methyl-3- [4- (S-methylsulfonimideyl) phenyl] -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole Example 63: 4-[( 6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] -N- (propan-2-yl) Benzenesulfonamide Example 64: N-ethyl-4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole -3-yl] benzenesulfonamide Example 65: N-cyclopropyl-4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4] , 3-c] pyrazole-3-yl] benzenesulfonamide Example 66: 4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [ 4,3-c] Pyrazole-3-yl] -N-methylbenzenesulfonamide Example 67: 4-{(6S) -6-methyl-1- [4- (trifluoromethyl) phenyl] -1,4 , 6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl} -N- (propan-2-yl) benzene Sulphonamide Example 68: N- (bicyclo [1.1.1] penta-1-yl) -4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6 7-Tetrahydropyrano [4,3-c] pyrazole-3-yl] benzenesulfonamide Example 69: N- (3,3-difluorocyclobutyl) -4-[(6S) -1- (4-fluoro) Phenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] benzenesulfonamide Example 70: 5-{(6S) -6-methyl-1 -[4- (Trifluoromethyl) phenyl] -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl} pyridin-2-amine Example 71: 4-[(6S) ) -1- (4-Methylphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] -N- (propan-2-yl) benzene Symphonamide Example 72: N-Cyclopropyl-4-[(6S) -1- (4-methoxyphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole -3-yl] benzenesulfonamide Example 73: 4-[(6S) -1- (4-fluoro-3-methoxyphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4, 3-c] Pyrazole-3-yl] -N- (propan-2-yl) benzenesulfonamide Example 74: N-cyclopropyl-4-[(6S) -1- (4-fluoro-3-methoxyphenyl) ) -6-Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl] benzenesulfonamide Example 75: 4-[(6S) -1- (4-fluoro) Phenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] -N- (oxetan-3-yl) benzenesulfonamide Example 76: N- (2,2-Difluoroethyl) -4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3 -Il] benzenesulfonamide Example 77: 4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole- 3-Il] -N- (3-Methyloxetane-3-yl) benzenesulfonamide Example 78: 4-Il [(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] -N-methylbenzamide Example 79 : N-ethyl-4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] benzamide Example 80: 4-[(6S) -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] -N -(Propane-2-yl) benzamide Example 81: 1- (4-fluorophenyl) -3- (2-fluoropyridine-4-yl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole Example 82: 1- (4-fluoro-3-methoxyphenyl) -3- (2-fluoropyridine-4-yl) -6-methyl-1,4,6,7- Tetrahydropyrano [4,3-c] pyrazole Example 83: 1- (4-fluoro-3-methylphenyl) -3- (2-fluoropyridine-4-yl) -6-methyl-1,4,6 , 7-Tetrahydropyrano [4,3-c] pyrazole Example 84: 1- (4-fluorophenyl) -6-methyl-3- (2-methylpyridine-4-yl) -1,4,6 7-Tetrahydropyrano [4,3-c] pyrazole Example 85: 3- (2,6-dimethylpyridine-4-yl) -1- (4-fluorophenyl) -6-methyl-1,4,6 , 7-Tetrahydropyrano [4,3-c] pyrazole Example 86: 3- (2-fluoropyridine-4-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6- Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole Example 87: 4-[(6S) -1- (4-fluoro-3-methylphenyl) -6-methyl-1 , 4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl] benzenesulfonamide Example 88: 4-[(6S) -1- (4-fluoro-3-methoxyphenyl)- 6-Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl] benzenesulfonamide Example 89: 4-[(6S) -1- (4-chlorophenyl)- 6-Methyl-1,4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl] benzenesulfonamide Example 9 0: 4-[(6S) -1- (4-chloro-3-methylphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] Benzenesulfonamide Example 91: 4-[(6S) -1- (4-chloro-3-methoxyphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole -3-yl] benzenesulfonamide Example 92: 4-[(6S) -1- (3-chloro-4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4, 3-c] pyrazole-3-yl] benzenesulfonamide Example 93: 4-[(6S) -1- (4-chloro-3-fluorophenyl) -6-methyl-1,4,6,7-tetrahydro Pyrano [4,3-c] pyrazole-3-yl] benzenesulfonamide Example 94: 4-{(6S) -6-methyl-1- [4- (trifluoromethyl) phenyl] -1,4 6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl} benzenesulfonamide Example 95: 4-[(6S) -1- (3,4-difluorophenyl) -6-methyl-1 , 4,6,7-Tetrahydropyrano [4,3-c] pyrazole-3-yl] benzenesulfonamide Example 96: (6R) -3- (2,6-dimethylpyridine-4-yl) -1 -[3-Methyl-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole

参考例２９の化合物（８０ｍｇ）、ピリジン−３，４−ジアミン（２６ｍｇ）及びジイソプロピルエチルアミン（０．０４１ｍＬ）のＤＭＦ（１ｍＬ）溶液に、ＨＢＴＵ（９０ｍｇ）を室温にて加え、反応液を終夜撹拌した。反応液を酢酸エチルで希釈し、１ｍｏｌ／Ｌ炭酸ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、ろ過した。ろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製して得られた化合物を酢酸（０．３７１ｍＬ）に溶解し、１００℃にて１時間撹拌した。反応液を減圧濃縮し、得られた残渣に１ｍｏｌ／Ｌ炭酸ナトリウムを加え、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後、ろ過した。ろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、実施例９７（２０．５ｍｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；４４４［ｍ＋Ｈ］^＋ 保持時間；０．７９４ｍｉｎ Example 97: 1- [3-ethoxy-4- (trifluoromethyl) phenyl] -3- (3H-imidazole [4,5-c] pyridin-2-yl) -6-methyl-1,4,6 , 7-Tetrahydropyrano [4,3-c] pyrazole

HBTU (90 mg) is added to a solution of compound (80 mg), pyridine-3,4-diamine (26 mg) and diisopropylethylamine (0.041 mL) of Reference Example 29 in DMF (1 mL) at room temperature, and the reaction solution is stirred overnight. did. The reaction mixture was diluted with ethyl acetate and washed with 1 mol / L aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography, the obtained compound was dissolved in acetic acid (0.371 mL), and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, 1 mol / L sodium carbonate was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to give Example 97 (20.5 mg).
LC-MS, m / z; 444 [m + H] ⁺ retention time; 0.794 min

参考例３０の化合物（１００ｍｇ）にオキシ塩化リン（１．１５ｍＬ）を室温にて加え、５時間撹拌した。反応液にセミカルバジド 塩酸塩（３５ｍｇ）を加え、５時間加熱還流した。反応液を室温に冷却し、飽和炭酸水素ナトリウム水溶液で中和し、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、ろ過した。ろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製後、分取用薄層クロマトグラフィー（酢酸エチル）で精製することにより、実施例９８（６．７ｍｇ）を得た。
ＬＣ−ＭＳ，ｍ／ｚ；３６２［ｍ＋Ｈ］^＋ 保持時間；０．７５１ｍｉｎ Example 98: 5- [1- (4-chloro-3-methoxyphenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl] -1 , 3,4-Oxadiazole-2-amine

Phosphoryl oxychloride (1.15 mL) was added to the compound (100 mg) of Reference Example 30 at room temperature, and the mixture was stirred for 5 hours. Semicarbazide hydrochloride (35 mg) was added to the reaction mixture, and the mixture was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) and then purified by thin layer chromatography (ethyl acetate) for preparative use to obtain Example 98 (6.7 mg). Obtained.
LC-MS, m / z; 362 [m + H] ⁺ retention time; 0.751 min

Example 99: 3- (1H-benzimidazol-5-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [ 4,3-c] Pyrazole

a) tert-Butyl 5- {1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3 -Il} -1H-benzimidazole-1-carboxylate (Example 99-1) Production Reference Example 8 compound (70 mg), 2 mol / L sodium carbonate aqueous solution (0.399 mL) and tert-butyl 5- (4) , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-benzimidazole-1-carboxylate (110 mg) in a DME (2 mL) solution with tetrakis (triphenylphosphine) palladium (0) (18 mg) was added at room temperature, and the reaction solution was stirred at 80 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, 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 obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Example 99-1 (55 mg). This product was used as it was in the next reaction.

b) 3- (1H-benzimidazol-5-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4, 3-c] Production of pyrazole (Example 99) TFA (0.401 mL) was added to a solution of Example 99-1 (55 mg) in chloroform (0.5 mL), and the reaction solution was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate) to obtain Example 99 (21 mg).
LC-MS, m / z; 429 [m + H] ⁺ retention time; 0.894 min

Example 100: 3- (3H-imidazole [4,5-b] pyridin-6-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6 , 7-Tetrahydropyrano [4,3-c] pyrazole

a) 5- {1- [3-Methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl} Preparation of -3-Nitropyridine-2-amine (Example 100-1) Compound (101 mg) of Reference Example 8 and 2 mol / L sodium carbonate aqueous solution (0.574 mL) and (6-amino-5-nitropyridine-3). To a solution of −yl) boronic acid (84 mg) in DME (2 mL) was added tetraxtriphenylphosphine palladium (0) (26.5 mg), and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate) to obtain Example 100-1 (75 mg).

b) 5- {1- [3-Methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] pyrazole-3-yl} Production of Pyridine-2,3-Diamine (Example 100-2) A mixture of the compound of Example 100-1 (75 mg, 0.167 mmol) and 10% palladium carbon (89 mg) in methanol (1 mL) was added under a hydrogen atmosphere. , Stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained crude product of Example 100-2 was used as it was in the next reaction.

c) 3- (3H-imidazole [4,5-b] pyridin-6-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -6-methyl-1,4,6,7 -Production of tetrahydropyrano [4,3-c] pyrazole (Example 100) A mixture of the compound (67 mg) of Example 100-2 and formic acid (0.184 mL) was stirred at 100 ° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the obtained residue, saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate) and then purified by reverse phase column chromatography to obtain Example 100 (6.97 mg).
LC-MS, m / z; 430 [m + H] ⁺ retention time; 0.946 min

実施例６２の化合物（３５ｍｇ）のＤＭＥ（０．５ｍＬ）溶液に、水素化ナトリウム（６．５４ｍｇ）を０℃にて加えた。同温にて反応液を３０分間撹拌後、室温に昇温した。反応液にヨウ化メチル（０．０１７ｍＬ）を加え、８０℃に加熱し、４時間撹拌した。反応液を室温に冷却し、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、ろ過した。ろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、ヘキサン／酢酸エチル）にて精製した。得られた結晶をジイソプロピルエーテルで洗浄することにより、実施例１０１（３０ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-D₆) δ: 7.91-7.85 (4H, m), 7.74-7.67 (2H, m), 7.42-7.35 (2H, m), 5.07-4.87 (2H, m), 3.80-3.65 (1H, m), 3.13 (3H, s), 2.88-2.72 (2H, m), 2.54-2.44 (3H, m), 1.32 (3H, d, J = 6.1 Hz). Example 101: (6S) -3- [4- (N, S-dimethylsulfonimideyl) phenyl] -1- (4-fluorophenyl) -6-methyl-1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole

Sodium hydride (6.54 mg) was added to a solution of compound (35 mg) of Example 62 in DME (0.5 mL) at 0 ° C. The reaction solution was stirred at the same temperature for 30 minutes and then heated to room temperature. Methyl iodide (0.017 mL) was added to the reaction mixture, the mixture was heated to 80 ° C., and the mixture was stirred for 4 hours. The reaction mixture was cooled to room temperature, water was added, 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 obtained residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate). The obtained crystals were washed with diisopropyl ether to obtain Example 101 (30 mg).
^{1 1} H-NMR (400 MHz, DMSO-D ₆ ) δ: 7.91-7.85 (4H, m), 7.74-7.67 (2H, m), 7.42-7.35 (2H, m), 5.07-4.87 (2H, m) , 3.80-3.65 (1H, m), 3.13 (3H, s), 2.88-2.72 (2H, m), 2.54-2.44 (3H, m), 1.32 (3H, d, J = 6.1 Hz).

実施例７０の化合物（２０ｍｇ）及びピリジン（０．０３５ｍＬ）のＴＨＦ（１ｍＬ）溶液に、塩化アセチル（０．０１９ｍＬ）を室温にて加え、反応液を終夜撹拌した。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し、濾過した。濾液を減圧濃縮し、残渣を水で洗浄することにより、実施例１０２(１１ｍｇ)を得た。
¹H-NMR (400 MHz, DMSO-D₆) δ: 10.61 (1H, br s), 8.61-8.55 (1H, m), 8.21-8.12 (1H, m), 8.08-8.00 (1H, m), 7.97-7.85 (4H, m), 4.98 (1H, d, J = 14.0 Hz), 4.93-4.85 (1H, m), 3.78-3.65 (1H, m), 2.97-2.83 (2H, m), 2.11 (3H, s), 1.33 (3H, d, J = 6.1 Hz). Example 102: N-(5-{(6S) -6-methyl-1- [4- (trifluoromethyl) phenyl] -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole -3-yl} pyridin-2-yl) acetamide

Acetyl chloride (0.019 mL) was added to a solution of compound (20 mg) and pyridine (0.035 mL) in Example 70 in THF (1 mL) at room temperature, and the reaction solution was stirred overnight. 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 washed with water to obtain Example 102 (11 mg).
^{1 1} H-NMR (400 MHz, DMSO-D ₆ ) δ: 10.61 (1H, br s), 8.61-8.55 (1H, m), 8.21-8.12 (1H, m), 8.08-8.00 (1H, m), 7.97-7.85 (4H, m), 4.98 (1H, d, J = 14.0 Hz), 4.93-4.85 (1H, m), 3.78-3.65 (1H, m), 2.97-2.83 (2H, m), 2.11 ( 3H, s), 1.33 (3H, d, J = 6.1 Hz).

実施例７０の化合物（２０ｍｇ）及びトリエチルアミン（０．０２２ｍＬ）のＴＨＦ（１ｍＬ）溶液に塩化メタンスルホニル（０．０１２ｍＬ）を室温にて加え、反応液を終夜撹拌した。反応液に２ｍｏｌ／Ｌ塩酸を加え、析出した結晶をろ取、乾燥して、実施例１０３（２２ｍｇ）を得た。
¹H-NMR (400 MHz, DMSO-D₆) δ: 10.85 (1H, br s), 8.52-8.42 (1H, m), 8.06 (1H, dd, J = 8.5, 2.4 Hz), 7.96-7.84 (4H, m), 7.07 (1H, d, J = 8.5 Hz), 4.97 (1H, d, J = 14.0 Hz), 4.92-4.83 (1H, m), 3.77-3.63 (1H, m), 3.32 (3H, s), 2.97-2.83 (2H, m), 1.32 (3H, d, J = 6.1 Hz). Example 103: N-(5-{(6S) -6-methyl-1- [4- (trifluoromethyl) phenyl] -1,4,6,7-tetrahydropyrano [4,3-c] pyrazole -3-Il} Pyridine-2-yl) Methanesulfonamide

Methanesulfonyl chloride (0.012 mL) was added to a solution of compound (20 mg) and triethylamine (0.022 mL) in Example 70 in THF (1 mL) at room temperature, and the reaction solution was stirred overnight. 2 mol / L hydrochloric acid was added to the reaction solution, and the precipitated crystals were collected by filtration and dried to obtain Example 103 (22 mg).
^{1 1} H-NMR (400 MHz, DMSO-D ₆ ) δ: 10.85 (1H, br s), 8.52-8.42 (1H, m), 8.06 (1H, dd, J = 8.5, 2.4 Hz), 7.96-7.84 ( 4H, m), 7.07 (1H, d, J = 8.5 Hz), 4.97 (1H, d, J = 14.0 Hz), 4.92-4.83 (1H, m), 3.77-3.63 (1H, m), 3.32 (3H) , s), 2.97-2.83 (2H, m), 1.32 (3H, d, J = 6.1 Hz).

Examples 104-105
Using Reference Example 29 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 104 to 105 are described below.
Example 104: 3- (2,6-dimethylpyridin-4-yl) -1- [4- (trifluoromethyl) phenyl] -1,4,6,7-tetrahydropyrano [4,3-c] Pyrazole Example 105: 3- (2,6-dimethylpyridin-4-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -1,4,6,7-tetrahydropyrano [4] , 3-c] Pyrazole

参考例３１の化合物（２１５ｍｇ）、［３−メトキシ−４−（トリフルオロメチル）フェニル）ボロン酸（２７６ｍｇ）及びピリジン（１９８ｍｇ）のＤＭＦ（５ｍＬ）溶液に、酢酸銅（ＩＩ）（４５．５ｍｇ）を加え、反応液を室温にて３日間撹拌した。反応液を減圧濃縮し、得られた残渣を酢酸エチルに懸濁し、セライトろ過した。濾液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、実施例１０６の化合物（１３５ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.62 (1H, d, J = 7.9 Hz), 7.21 (2H, br s), 7.09 (1H, s), 6.94-6.89 (1H, m), 4.24-4.16 (1H, m), 3.91 (3H, s), 3.70-3.61 (1H, m), 3.60-3.52 (1H, m), 3.07-2.78 (4H, m), 2.59 (6H, s), 1.23 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；４３２［ｍ＋Ｈ］^＋ 保持時間；０．７１６ｍｉｎ Example 106: 3- (2,6-dimethylpyridin-4-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro- 1H-oxepino [4,5-c] pyrazole

Copper acetate (II) (45.5 mg) in a solution of compound (215 mg) of Reference Example 31, [3-methoxy-4- (trifluoromethyl) phenyl) boronic acid (276 mg) and pyridine (198 mg) in DMF (5 mL). ) Was added, and the reaction solution was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, the obtained residue was suspended in ethyl acetate, and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the compound of Example 106 (135 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.62 (1H, d, J = 7.9 Hz), 7.21 (2H, br s), 7.09 (1H, s), 6.94-6.89 (1H, m), 4.24 -4.16 (1H, m), 3.91 (3H, s), 3.70-3.61 (1H, m), 3.60-3.52 (1H, m), 3.07-2.78 (4H, m), 2.59 (6H, s), 1.23 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 432 [m + H] ⁺ retention time; 0.716 min

参考例３３の化合物（３５０ｍｇ）、［３−メトキシ−４−（トリフルオロメチル）フェニル）ボロン酸（４４９ｍｇ）及びピリジン（３２３ｍｇ）のＤＭＦ（６ｍＬ）溶液に、酢酸銅（ＩＩ）（７４．１ｍｇ）を加え、反応液を室温にて４日間撹拌した。反応液に塩化アンモニウム水を加え、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、得られた残渣をアミノカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、実施例１０７の化合物（３２６ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.68 (1H, d, J = 7.9 Hz), 7.21-7.15 (3H, m), 6.99 (1H, d, J = 9.2 Hz), 4.30-4.21 (1H, m), 3.97 (3H, s), 3.77-3.57 (2H, m), 3.13-2.84 (4H, m), 2.58 (6H, s), 1.30 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；４３２［ｍ＋Ｈ］^＋ 保持時間；０．７２０ｍｉｎ Example 107: (7R) -3- (2,6-dimethylpyridin-4-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7, 8-Tetrahydro-1H-oxepino [4,5-c] pyrazole

Copper acetate (II) (74.1 mg) in a solution of compound (350 mg) of Reference Example 33, [3-methoxy-4- (trifluoromethyl) phenyl) boronic acid (449 mg) and pyridine (323 mg) in DMF (6 mL). ) Was added, and the reaction solution was stirred at room temperature for 4 days. Ammonium chloride 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 obtained residue was purified by amino column chromatography (hexane / ethyl acetate) to obtain the compound of Example 107 (326 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.68 (1H, d, J = 7.9 Hz), 7.21-7.15 (3H, m), 6.99 (1H, d, J = 9.2 Hz), 4.30-4.21 ( 1H, m), 3.97 (3H, s), 3.77-3.57 (2H, m), 3.13-2.84 (4H, m), 2.58 (6H, s), 1.30 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 432 [m + H] ⁺ retention time; 0.720 min

参考例３５の化合物（７７．０ｍｇ）、（３−シアノ−４−フルオロフェニル）ボロン酸（７４．０ｍｇ）及びピリジン（７１．０ｍｇ）のＤＭＦ（１ｍＬ）溶液に、酢酸銅（ＩＩ）（１６．０ｍｇ）を加え、反応液を室温にて３日間撹拌した。反応液に塩化アンモニウム水を加え、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、得られた残渣をアミノカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、実施例１０８の化合物（５７．９ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.75-7.64 (2H, m), 7.39-7.32 (1H, m), 7.15 (2H, s), 4.28-4.17 (1H, m), 3.78-3.53 (2H, m), 3.12-2.91 (2H, m), 2.91-2.66 (2H, m), 2.56 (6H, s), 1.28 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；３７７［ｍ＋Ｈ］^＋ 保持時間；０．５７１ｍｉｎ Example 108: 5-[(7R) -3- (2,6-dimethylpyridin-4-yl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] Pyrazole-1-yl] -2-fluorobenzonitrile

Copper acetate (II) (16) in a solution of compound (77.0 mg), (3-cyano-4-fluorophenyl) boronic acid (74.0 mg) and pyridine (71.0 mg) of Reference Example 35 in DMF (1 mL). 0.0 mg) was added, and the reaction solution was stirred at room temperature for 3 days. Ammonium chloride 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 obtained residue was purified by amino column chromatography (hexane / ethyl acetate) to obtain the compound of Example 108 (57.9 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.75-7.64 (2H, m), 7.39-7.32 (1H, m), 7.15 (2H, s), 4.28-4.17 (1H, m), 3.78-3.53 (2H, m), 3.12-2.91 (2H, m), 2.91-2.66 (2H, m), 2.56 (6H, s), 1.28 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 377 [m + H] ⁺ retention time; 0.571 min

参考例３５の化合物（１．６０ｇ）、（４−フルオロ−３−メトキシフェニル）ボロン酸（１．５９ｇ）及びピリジン（１．４８ｇ）のＤＭＦ（２５ｍＬ）溶液に、酢酸銅（ＩＩ）（０．３３９ｇ）を加え、反応液を室温にて３日間撹拌した。反応液に塩化アンモニウム水を加え、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、得られた残渣をアミノカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、実施例１０９の化合物（１．３５ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.21-7.14 (3H, m), 7.11-7.07 (1H, m), 6.91-6.85 (1H, m), 4.30-4.20 (1H, m), 3.94 (3H, s), 3.78-3.55 (2H, m), 3.13-2.98 (1H, m), 2.99-2.78 (3H, m), 2.57 (6H, s), 1.28 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；３８２［ｍ＋Ｈ］^＋ 保持時間；０．６１２ｍｉｎ Example 109: (7R) -3- (2,6-dimethylpyridin-4-yl) -1- (4-fluoro-3-methoxyphenyl) -7-methyl-4,5,7,8-tetrahydro- 1H-oxepino [4,5-c] pyrazole

Copper (II) acetate (0) in a solution of compound (1.60 g), (4-fluoro-3-methoxyphenyl) boronic acid (1.59 g) and pyridine (1.48 g) of Reference Example 35 in DMF (25 mL). .339 g) was added, and the reaction solution was stirred at room temperature for 3 days. Ammonium chloride 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 obtained residue was purified by amino column chromatography (hexane / ethyl acetate) to obtain the compound of Example 109 (1.35 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.21-7.14 (3H, m), 7.11-7.07 (1H, m), 6.91-6.85 (1H, m), 4.30-4.20 (1H, m), 3.94 (3H, s), 3.78-3.55 (2H, m), 3.13-2.98 (1H, m), 2.99-2.78 (3H, m), 2.57 (6H, s), 1.28 (3H, d, J = 6.1 Hz) ).
LC-MS, m / z; 382 [m + H] ⁺ retention time; 0.612 min

参考例３５の化合物（６４ｍｇ）、（３−クロロ−４−フルオロフェニル）ボロン酸（６５ｍｇ）及びピリジン（５９ｍｇ）のＤＭＦ（１ｍＬ）溶液に、酢酸銅（ＩＩ）（１４ｍｇ）を加え、反応液を室温にて５日間撹拌した。反応液に塩化アンモニウム水を加え、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、得られた残渣をアミノカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、実施例１１０の化合物（４８．５ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.58-7.52 (1H, m), 7.31-7.24 (2H, m), 7.18 (2H, s), 4.31-4.19 (1H, m), 3.77-3.55 (2H, m), 3.15-2.68 (4H, m), 2.57 (6H, s), 1.29 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；３８６［ｍ＋Ｈ］^＋ 保持時間；０．７００ｍｉｎ Example 110: (7R) -1- (3-chloro-4-fluorophenyl) -3- (2,6-dimethylpyridin-4-yl) -7-methyl-4,5,7,8-tetrahydro- 1H-oxepino [4,5-c] pyrazole

Copper acetate (II) (14 mg) was added to a solution of compound (64 mg), (3-chloro-4-fluorophenyl) boronic acid (65 mg) and pyridine (59 mg) of Reference Example 35 in DMF (1 mL), and the reaction solution was added. Was stirred at room temperature for 5 days. Ammonium chloride 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 obtained residue was purified by amino column chromatography (hexane / ethyl acetate) to obtain the compound of Example 110 (48.5 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.58-7.52 (1H, m), 7.31-7.24 (2H, m), 7.18 (2H, s), 4.31-4.19 (1H, m), 3.77-3.55 (2H, m), 3.15-2.68 (4H, m), 2.57 (6H, s), 1.29 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 386 [m + H] ⁺ retention time; 0.700 min

Examples 111-129
Using the corresponding reference example compound as a starting material, the reaction, post-treatment, and purification were carried out according to the same method as described in Example 107 to obtain the compound shown in the table below.

The compound names of Examples 111 to 129 are described below.
Example 111: (7R) -1- (3,4-difluorophenyl) -3- (2,6-dimethylpyridin-4-yl) -7-methyl-4,5,7,8-tetrahydro-1H- Oxepino [4,5-c] pyrazole Example 112: (7R) -3- (2,6-dimethylpyridin-4-yl) -1- (3-ethoxy-4-fluorophenyl) -7-methyl-4 , 5,7,8-Tetrahydro-1H-oxepino [4,5-c] pyrazole Example 113: (7R) -3- (2,6-dimethylpyridin-4-yl) -1- (4-fluoro-) 3-Methylphenyl) -7-Methyl-4,5,7,8-Tetrahydro-1H-Oxepino [4,5-c] Pyrazole Example 114: (7R) -1- (4-chloro-3-methoxyphenyl) ) -3- (2,6-Dimethylpyridin-4-yl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole Example 115: 5-[( 7R) -3- (2,6-dimethylpyridin-4-yl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-1-yl] -2 −methoxybenzonitrile Example 116: 2-Chloro-5-[(7R) -3- (2,6-dimethylpyridin-4-yl) -7-methyl-4,5,7,8-tetrahydro-1H- Oxepino [4,5-c] pyrazole-1-yl] benzonitrile Example 117: (7R) -3- (2,6-dimethylpyridin-4-yl) -7-methyl-1- (quinolin-3-yl) Il) -4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole Example 118: (7R) -3- (2,6-dimethylpyridin-4-yl) -1- [ 3-methoxy-4- (trifluoromethoxy) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole Example 119: (7R) -3-( 2,6-Dimethylpyridin-4-yl) -7-methyl-1- [4- (trifluoromethoxy) phenyl] -4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole Example 120: (7R) -3- (2,6-dimethylpyridin-4-yl) -1- [3-fluoro-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7, 8-Tetrahydro-1H-Oxepino [4,5-c] Pyrazole Example 121: 4-[(7R) -1 -(4-Fluoro-3-methoxyphenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] pyridin-2-amine Example 122 : 5-[(7R) -1- (4-fluoro-3-methoxyphenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl ] Pyridin-2-amine Example 123: 5-[(7R) -1- (4-chloro-3-fluorophenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4, 5-c] pyrazole-3-yl] pyridin-2-amine Example 124: 5-[(7R) -3- (6-aminopyridine-3-yl) -7-methyl-4,5,7,8 -Tetrahydro-1H-oxepino [4,5-c] pyrazole-1-yl] -2-chlorobenzonitrile Example 125: 5-{(7R) -1- [3-methoxy-4- (trifluoromethoxy) Phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} pyridin-2-amine Example 126: 5-{(7R) -1 -[4- (Difluoromethoxy) -3-methylphenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} -3-methylpyridine -2-Amine Example 127: 5-[(7R) -1- (3-ethoxy-4-fluorophenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-amine] c] Pyrazole-3-yl] -3-methylpyridine-2-amine Example 128: 5-[(7R) -3- (6-amino-5-methylpyridine-3-yl) -7-methyl-4 , 5,7,8-Tetrahydro-1H-oxepino [4,5-c] pyrazole-1-yl] -2-chlorobenzonitrile Example 129: 3-Methyl-5-{(7R) -7-Methyl- 1- [4- (trifluoromethyl) phenyl] -4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} pyridin-2-amine

Examples 130-158
Using the corresponding reference example compound as a starting material, the reaction, post-treatment, and purification were carried out according to the same method as described in Example 34 to obtain the compounds shown in the table below.

The compound names of Examples 130 to 158 are described below.
Example 130: (7S) -3- (2,6-dimethylpyridine-4-yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7, 8-Tetrahydro-1H-oxepino [4,5-c] pyrazole Example 131: 5-{(7R) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5 , 7,8-Tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} pyridin-2-amine Example 132: (4-{(7R) -1- [3-methoxy-4- ( Trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} pyridin-2-yl) Methyl Example 133: (7R ) -1- [3-Methyl-4- (trifluoromethyl) phenyl] -7-methyl-3- [4- (4-methylpiperazin-1-yl) phenyl] -4,5,7,8-tetrahydro -1H-oxepino [4,5-c] pyrazole Example 134: 4-{(7R) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7, 8-Tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} pyridin-2-amine Example 135: 4-{(7R) -1- [3-methoxy-4- (trifluoromethyl) Phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} -6-methylpyridin-2-amine Example 136: (7R)- 3- (2-Methyl-6-methylpyridine-4-yl) -1- [3-Methyl-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H- Oxepino [4,5-c] pyrazole Example 137: 5-{(7R) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro -1H-oxepino [4,5-c] pyrazole-3-yl} -3-methylpyridine-2-amine Example 138: (7R) -3- (Imidazo [1,2-a] pyridine-7-yl ) -1- [3-Methyl-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole Example 139: (7R ) -3- (Imidazo [1,2-a] pyridine-6-yl) -1 -[3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole Example 140: 6-{(7R) ) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl}- 1-Methyl-1H-Indazole-3-amine Example 141: 4-[(7R) -1- (3-chloro-4-fluorophenyl) -7-methyl-4,5,7,8-tetrahydro-1H -Oxepino [4,5-c] pyrazole-3-yl] -6-methylpyridin-2-amine Example 142: 5-[(7R) -1- (3-chloro-4-fluorophenyl) -7- Methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] pyridin-2-amine Example 143: 5-[(7R) -1- (3-chloro) -4-fluorophenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] -3-methylpyridine-2-amine Example 144: (7R) -1- (3-Chloro-4-fluorophenyl) -3- (Imidazo [1,2-a] Pyrazole-6-yl) -7-Methyl-4,5,7,8-Tetrahydro-1H -Oxepino [4,5-c] Pyrazole Example 145: 6-[(7R) -1- (3-chloro-4-fluorophenyl) -7-methyl-4,5,7,8-tetrahydro-1H- Oxepino [4,5-c] pyrazole-3-yl] -1-methyl-1H-indazole-3-amine Example 146: 4-[(7R) -1- (3-chloro-4-fluorophenyl)- 7-Methyl-4,5,7,8-Tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] -6-methoxypyridin-2-amine Example 147: 4-[(7R)- 1- (4-fluoro-3-methylphenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] -6-methylpyridine-2 -Amine Example 148: 4-[(7R) -1- (4-fluoro-3-methoxyphenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] Pyrazole-3-yl] -6-methylpyridin-2-amine Example 149: 4-[(7R) -1- (4-Fluoro-3-methoxyphenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] benzene-1-sulfonamide Example 150: 5-[(7R) -1- (4-chloro-3-methoxyphenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole- 3-Il] Pyridin-2-amine Example 151: 4-[(7R) -1- (4-chloro-3-methoxyphenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] -6-methylpyridin-2-amine Example 152: 5-[(7R) -1- (4-chloro-3-methoxyphenyl) -7-methyl- 4,5,7,8-Tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl] -3-methylpyridin-2-amine Example 153: (7R) -1- (4-chloro-) 3-methoxyphenyl) -3- (imidazo [1,2-a] pyridine-6-yl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole implementation Example 154: (7R) -3- (2,6-dimethylpyridine-4-yl) -1- [4-fluoro-3- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8 -Tetrahydro-1H-oxepino [4,5-c] pyrazole Example 155: 5-{(7R) -1- [4-fluoro-3- (trifluoromethyl) phenyl] -7-methyl-4,5 7,8-Tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} pyridin-2-amine Example 156: 4-{(7R) -1- [4-fluoro-3- (trifluoro) Methyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-yl} -6-methylpyridin-2-amine Example 157: 5- {(7R) -1- [4-Fluoro-3- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole-3-3 Il} -3-methylpyridine-2-amine Example 158: 4-[(7R) -1- (4-fluorophenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4] , 5-c] pyrazole-3-yl] benzene-1-sulfonamide

参考例３７の化合物（８０ｍｇ）、２，３−ジヒドロ−１H−ピロロピリジン−１−オン（４４．６ｍｇ）、炭酸セシウム（１４４ｍｇ）、ヨウ化銅（Ｉ）（３３．７ｍｇ）のジオキサン（１．７７ｍL）溶液にＮ，Ｎ’−ジメチルエチレンジアミン（２８．５μL）を加え、２時間還流した。反応液を室温まで放冷後、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、ろ過した後、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）で精製し、実施例１５９の化合物（６２ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 9.18 (1H, s), 8.83 (1H, d, J = 4.9 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.51 (1H, t, J = 2.7 Hz), 7.13-7.09 (1H, m), 6.98-6.93 (1H, m), 5.02-4.97 (2H, m), 4.27-4.19 (1H, m), 3.95 (3H, s), 3.79-3.64 (2H, m), 3.05-2.84 (3H, m), 2.79-2.71 (1H, m), 1.29 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；４５９［ｍ＋Ｈ］^＋ 保持時間；０．８８０ｍｉｎ Example 159: 2-{(7R) -1- [3-Methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5- c] Pyrazole-3-yl} -2,3-dihydro-1H-pyrrolo [3,4-c] Pyridine-1-one

The compound of Reference Example 37 (80 mg), 2,3-dihydro-1H-pyrrolopyridine-1-one (44.6 mg), cesium carbonate (144 mg), copper (I) iodide (33.7 mg) dioxane (1). N, N'-dimethylethylenediamine (28.5 μL) was added to the .77 mL) solution, and the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature, water was added, 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 amino silica gel column chromatography (hexane / ethyl acetate) to obtain the compound of Example 159 (62 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 9.18 (1H, s), 8.83 (1H, d, J = 4.9 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.51 (1H, t, J = 2.7 Hz), 7.13-7.09 (1H, m), 6.98-6.93 (1H, m), 5.02-4.97 (2H, m), 4.27-4.19 (1H, m), 3.95 (3H, s), 3.79 -3.64 (2H, m), 3.05-2.84 (3H, m), 2.79-2.71 (1H, m), 1.29 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 459 [m + H] ⁺ retention time; 0.880 min

参考例３７の化合物（２０ｍｇ）を用いて実施例１５９に記載の方法に準じ、実施例１６０の化合物（１５ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 8.92 (1H, s), 8.84 (1H, d, J = 4.9 Hz), 7.83-7.79 (1H, m), 7.67 (1H, d, J = 7.9 Hz), 7.11 (1H, s), 6.99-6.94 (1H, m), 5.05 (2H, dd, J = 23.2, 17.1 Hz), 4.27-4.19 (1H, m), 3.95 (3H, s), 3.80-3.63 (2H, m), 3.04-2.84 (3H, m), 2.75-2.67 (1H, m), 1.29 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；４５９［ｍ＋Ｈ］^＋ 保持時間；０．８７５ｍｉｎ Example 160: 2-{(7R) -1- [3-Methoxy-4- (trifluoromethyl) phenyl] -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5- c] Pyrazole-3-yl} -1,2-dihydro-3H-pyrrolo [3,4-c] pyridine-3-one

Using the compound of Reference Example 37 (20 mg), the compound of Example 160 (15 mg) was obtained according to the method described in Example 159.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 8.92 (1H, s), 8.84 (1H, d, J = 4.9 Hz), 7.83-7.79 (1H, m), 7.67 (1H, d, J = 7.9) Hz), 7.11 (1H, s), 6.99-6.94 (1H, m), 5.05 (2H, dd, J = 23.2, 17.1 Hz), 4.27-4.19 (1H, m), 3.95 (3H, s), 3.80 -3.63 (2H, m), 3.04-2.84 (3H, m), 2.75-2.67 (1H, m), 1.29 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 459 [m + H] ⁺ retention time; 0.875 min

参考例３７の化合物（２０ｍｇ）、５，６，７，８−テトラヒドロイミダゾ[１，２−ａ]ピラジン（５４．５ｍｇ）、ナトリウム ｔｅｒｔ-ブトキシド（６．３８ｍｇ）、トリス（ジベンジリデンアセトン）ジパラジウム（８．１ｍｇ）、キサントホス（７．６８ｍｇ）のジオキサン（０．３６９ｍＬ）溶液を、１００℃にて２時間撹拌した。反応液を室温まで放冷後、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン/酢酸エチル）で精製し、実施例１６１の化合物（１.２ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 7.62 (1H, d, J = 8.5 Hz), 7.09 (1H, s), 7.05-7.02 (1H, m), 6.92-6.86 (2H, m), 4.52-4.43 (1H, m), 4.30 (1H, d, J = 15.8 Hz), 4.26-4.05 (3H, m), 3.95 (3H, s), 3.74-3.60 (2H, m), 3.60-3.53 (2H, m), 2.99-2.80 (3H, m), 2.68-2.59 (1H, m), 1.27 (3H, d, J = 6.7 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；４４８［ｍ＋Ｈ］^＋ 保持時間；０．７３４ｍｉｎ Example 161: (7R) -3- (5,6-dihydroimidazole [1,2-a] pyrazine-7 (8H) -yl) -1- [3-methoxy-4- (trifluoromethyl) phenyl] -7-Methyl-4,5,7,8-Tetrahydro-1H-oxepino [4,5-c] pyrazole

Compound of Reference Example 37 (20 mg), 5,6,7,8-tetrahydroimidazole [1,2-a] pyrazine (54.5 mg), sodium tert-butoxide (6.38 mg), tris (dibenzylideneacetone) di A solution of palladium (8.1 mg) and xantphos (7.68 mg) in dioxane (0.369 mL) was stirred at 100 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and the obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to obtain the compound of Example 161 (1.2 mg).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 7.62 (1H, d, J = 8.5 Hz), 7.09 (1H, s), 7.05-7.02 (1H, m), 6.92-6.86 (2H, m), 4.52-4.43 (1H, m), 4.30 (1H, d, J = 15.8 Hz), 4.26-4.05 (3H, m), 3.95 (3H, s), 3.74-3.60 (2H, m), 3.60-3.53 ( 2H, m), 2.99-2.80 (3H, m), 2.68-2.59 (1H, m), 1.27 (3H, d, J = 6.7 Hz).
LC-MS, m / z; 448 [m + H] ⁺ retention time; 0.734 min

実施例１２１の化合物（４７ｍｇ）のエタノール（０．４２５ｍL）溶液に、室温にてホルムアルデヒド溶液を加え、５０℃にて１時間撹拌した。反応溶液を室温まで放冷し、水素化ホウ素ナトリウム（２４ｍｇ）を加え、再び５０℃にて３０分間撹拌した。反応液を室温まで放冷後、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、ろ過した後、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）で精製し、実施例１６２の化合物（２４ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 8.13 (1H, d, J = 4.9 Hz), 7.21-7.13 (1H, m), 7.12-7.06 (1H, m), 6.90-6.84 (1H, m), 6.81-6.76 (1H, m), 6.63 (1H, s), 4.62-4.55 (1H, br m), 4.28-4.19 (1H, m), 3.93 (3H, s), 3.75-3.65 (1H, m), 3.65-3.55 (1H, m), 3.09-2.99 (1H, m), 2.96 (3H, d, J = 5.5 Hz), 2.93-2.76 (3H, m), 1.27 (3H, d, J = 6.1 Hz).
ＬＣ−ＭＳ，ｍ／ｚ；４１８［ｍ＋Ｈ］^＋ 保持時間；０．７６３ｍｉｎ Example 162: 4-[(7R) -1- (4-fluoro-3-methoxyphenyl) -7-methyl-4,5,7,8-tetrahydro-1H-oxepino [4,5-c] pyrazole- 3-Il] -N-methylpyridine-2-amine

A formaldehyde solution was added to a solution of the compound (47 mg) of Example 121 in ethanol (0.425 mL) at room temperature, and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was allowed to cool to room temperature, sodium borohydride (24 mg) was added, and the mixture was stirred again at 50 ° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, water was added, 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 amino silica gel column chromatography (hexane / ethyl acetate) to obtain the compound of Example 162 (24 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.13 (1H, d, J = 4.9 Hz), 7.21-7.13 (1H, m), 7.12-7.06 (1H, m), 6.90-6.84 (1H, m) ), 6.81-6.76 (1H, m), 6.63 (1H, s), 4.62-4.55 (1H, br m), 4.28-4.19 (1H, m), 3.93 (3H, s), 3.75-3.65 (1H, m), 3.65-3.55 (1H, m), 3.09-2.99 (1H, m), 2.96 (3H, d, J = 5.5 Hz), 2.93-2.76 (3H, m), 1.27 (3H, d, J = 6.1 Hz).
LC-MS, m / z; 418 [m + H] ⁺ retention time; 0.763 min

Pharmacological Tests The pharmacological test methods and results of the compounds of the present invention are shown below, but the present invention is not limited to these test examples.

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, Lifetechnologies, Carlsbad, CA, USA), and TR-expressing human kidney-derived HEK cells (cat # CCL-82.2, ATCC, USA) were inserted. ) Was introduced. Then, selection was performed 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 Blastidin S (cat # ANT-BL-1, Lifetechnologies, 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 3-4 days, and subcultured.
After 3-4 days from passage, cells were harvested by TrypLE Express treatment in a state of approximately 80% confluence, 0.1% BSA (cat # 12604-013, Lifetechnologies, Carlsbad, CA, USA), 0.1 μg / Hanks (cat # 14065-056, Carlsbad, CA, USA) / 20 mmol / L HEPES (cat # 14065-056, 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 in the RLU / 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. The mGlu2 receptor negative allosteric modulator activity (IC50 value (nmol / L) or inhibition rate (%) at 10 μmol / L) of each compound is shown in the table below.

As described above, the compounds of the present invention exhibit a strong negative regulatory effect on Group II metabotropic glutamate (mGlu) receptors. Therefore, the compounds of the present invention are depressive disorders / depressive disorders (major depression, treatment-resistant depression, chronic depression, etc.), bipolar and related disorders, and anxiety disorders (generalized anxiety disorder, panic disorder, social anxiety). Disorders, specific fears, etc.), post-traumatic stress disorder, compulsive disorder, acute stress disorder, cognitive dysfunction, dementia, obesity, etc. are useful as therapeutic and / or preventive agents.

Claims (32)

Equation (1):

[During the ceremony,
R ¹ and R ² are independent of hydrogen atom, halogen, cyano, C _1-4 alkyl or C _3-6 saturated carbocyclic group (the alkyl and the saturated carbocyclic group are each independently halogen. , Which may be substituted with the same or different 1 to 5 substituents, selected from the group consisting of hydroxy and C _{1-4 alkoxy).}
Here, R ¹ and R ² are selected from the group consisting of _{C 3-6} saturated carbon rings (the saturated carbon rings are halogen, hydroxy and C _1-4 alkoxy) together with the carbon atoms to which they are bonded. , Which may be substituted with the same or different 1 to 5 substituents).
n represents 1 or 2
Ring A represents a C _3-10 saturated carbocycle, a 3-10 member saturated heterocycle, a C _6-10 aromatic carbocycle or a 5-10 membered aromatic heterocycle.
R ³ , R ⁴ and R ⁵ are independently hydrogen atom, halogen, cyano, hydroxy, C _1-6 alkyl, C _3-6 saturated carbocyclic group, C _1-4 alkoxy, C _3-6 cyclo. Alkoxy, C _1-4 alkylthio, C _2-4 alkenyl, 3 to 6-membered saturated heterocyclic group or 5 or 6-membered aromatic heterocyclic group (the alkyl, the saturated carbocyclic group, the alkoxy, the cycloalkoxy). , The alkylthio, the saturated heterocyclic group and the aromatic heterocyclic group may be independently substituted with the same or different 1 to 5 halogens).
Ring B represents a C _6-10 aromatic carbocycle or a 5- to 10-membered aromatic heterocycle.
R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, halogens, cyanos, hydroxys, C _1-6 alkyls, C _1-6 alkoxys, C _1-6 alkylthios and C _3-6 saturated carbocyclic groups. 3- to 6-membered saturated heterocyclic groups, -CH _2- C (O) -NR ^a R ^b , -C (O) -R ^c , -C (O) -OR ^d , -C (O) -NR ^a R ^b , -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d- C (O) -NR ^a R ^b , -NR ^d- S (O) _2- R ^c ,- NR ^d- S (O) _2- NR ^a R ^b , -S (O) -R ^c , -S (O) _2- R ^c , -S (O) _2- OH, -S (O) _2- NR ^a R ^b or -S (O) (= NR ^d ) -R ^c (the alkyl, the alkoxy, the alkylthio, the saturated carbocyclic group and the saturated heterocyclic group are independently halogen, cyano,- NR a ^{R b,} optionally substituted by hydroxy and 1 to five halogens are also selected from the group consisting of optionally C _1-4 alkoxy, optionally substituted by the same or different one to five substituents )
R ^a and R ^b are independent ^{of each other, and if there are a plurality of Ra} or R ^b , they are independent of each other, such as hydrogen atom, C _1-4 alkyl, C _3-6 saturated carbocyclic group or 3 to 6 members. (The alkyl, the saturated carbocyclic group and the saturated heterocyclic group are each independently selected from the group consisting of _{halogen, hydroxy, C 1-4} alkyl and C _{1-4 alkoxy.} It may be substituted with the same or different 1 to 5 substituents).
Here, ^Ra and R ^b are 3 to 6-membered saturated heterocyclic groups together with the nitrogen atom to which they are bonded (the saturated heterocyclic groups are halogen, hydroxy, C _1-4 alkyl and C _{1). -4} It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of alkoxy).
^{If there are a plurality of Rc} , each of them is independently C _1-4 alkyl, C _3-6 saturated carbocyclic group or 3 to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and the saturated complex). The ring groups each independently represent the same or different 1 to 5 substituents selected from the group consisting of halogens, hydroxys and C _{1-4 alkoxys).}
R ^d _{may be a hydrogen atom, a C 1-4} alkyl, a C _3-6 saturated carbocyclic group or a 3 to 6-membered saturated heterocyclic group (the alkyl, the saturated carbocyclic group and each of them independently, if there are a plurality of them. The saturated heterocyclic groups may be independently substituted with the same or different 1 to 5 substituents _{, each independently selected from the group consisting of halogen, hydroxy and C 1-4 alkoxy)].}
A compound represented by or a pharmaceutically acceptable salt thereof. n is 1,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. n is 2,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Ring A is a C _6-10 aromatic carbocycle or a 5- to 10-membered aromatic heterocycle.
The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. Ring A is benzene, pyridine, pyrimidine, pyrazine, thiophene, thiazole, isothiazole, oxazole, isoxazole, quinoline, isoquinoline, benzothiophene, benzofuran, indrine, imidazole pyridine, chromane, 2,3-dihydrobenzofuran, 1, 3-Dihydrobenzofuran, 2,3-dihydro-1H-indene or 2,3-dihydro-1H-inden-1-one,
The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. Ring A is benzene, pyridine, thiophene or quinoline,
The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. Ring A is benzene,
The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. Ring B is benzene, pyridine, pyrimidine, pyrazine, imidazole, pyrazole, thiophene, thiazole, isothazole, oxazole, isooxazole, oxadiazol, quinoline, isoquinoline, benzoimidazole, azabenzoimidazole, indazole, azaindazole, indolidin. , Imidazopyridine, 2,3-dihydro-1H-pyrrolopyridine, 2,3-dihydro-1H-pyrrolopyridine-1-one, 1,2-dihydro-3H-pyrrolopyridine-3-one or 5,6,7 , 8-Tetrahydroimidazolipyrazine,
The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. Ring B is benzene, pyridine, pyrimidine, imidazolepyridine, 2,3-dihydro-1H-pyrrolopyridine, 2,3-dihydro-1H-pyrrolopyridine-1-one, 1,2-dihydro-3H-pyrrolopyridine- 3-one or 5,6,7,8-tetrahydroimidazolipyrazine,
The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. Ring B is pyridine,
The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. R ¹ and R ² _{are C 1-4} alkyl, which may be independently substituted with hydrogen atoms or 1 to 5 halogens, respectively.
Here, R ¹ and R ² may form a cyclopropane ring or a cyclobutane ring together with the carbon atom to which they are bonded.
The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. R ¹ is methyl and R ² is a hydrogen atom,
The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. R ³ , R ⁴ and R ⁵ are each independently hydrogen atom, halogen, cyano, hydroxy, C _1-4 alkyl, C _1-4 alkoxy or C _1-4 alkyl thio (the alkyl, the alkoxy and the alkyl thio). May be independently substituted with the same or different 1 to 5 halogens).
The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof. R ³ , R ⁴ and R ⁵ are independently hydrogen atoms, fluorine, chlorine, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof. R ⁶ , R ⁷ and R ⁸ are independent hydrogen atoms, halogens, cyanos, hydroxys, C _1-6 alkyls, C _1-6 alkoxys, 3- to 6-membered saturated heterocyclic groups, -CH _2- C (O) -NR ^a R ^b , -C (O) -R ^c , -C (O) -OR ^d , -C (O) -NR ^a R ^b , -NR ^a R ^b , -NR ^d- C (O) -R ^c , -NR ^d- C (O) -NR ^a R ^b , -NR ^d- S (O) _2- R ^c , -S (O) _2- NR ^a R ^b or -S (O) ) (= NR ^d ) -R ^c (Even if the alkyl, the alkoxy and the saturated heterocyclic group are independently ^{substituted with halogen, -NR a} R ^b , hydroxy and 1 to 5 halogens, respectively. It may be substituted with the same or different 1 to 5 substituents selected from the group consisting of _{good C 1-4 alkoxy).}
The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof. R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, halogens, cyanos, hydroxys, C _1-6 alkyls, C _1-6 alkoxys, 3- to 6-membered saturated heterocyclic groups, -C (O). ) -NR ^a R ^b , -NR ^a R ^b , -NR ^d- S (O) _2- R ^c , -S (O) _2- NR ^a R ^b or -S (O) (= NR ^d ) -R ^c (The alkyl, the alkoxy and the saturated heterocyclic group each independently consist of halogen, -NR ^a R ^b _{, hydroxy and C 1-4} alkoxy optionally substituted with 1 to 5 halogens. It may be substituted with the same or different 1 to 5 substituents selected from the group).
The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof. R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, fluorine, chlorine, cyano, hydroxymethyl, methyl, ethyl, methoxy, ethoxy, 3- to 6-membered saturated heterocyclic groups, -NR ^a R ^b. , -NR ^d- S (O) _2- R ^c , -S (O) _2- NR ^a R ^b or -S (O) (= NR ^d ) -R ^c ,
The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof. R ⁶ , R ⁷ and R ⁸ are independently hydrogen atoms, fluorine, chlorine, cyano, hydroxymethyl, methyl, ethyl, methoxy, ethoxy or -NR ^a R ^b .
The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof. R ^a and R ^b are independent of each other, and if there are multiple ^Ra or R ^b, _{each is independent of hydrogen atom, C 1-4} alkyl, C _3-6 saturated carbocyclic group or 3 to 6 members. Saturated heterocyclic groups (the alkyl, the saturated carbocyclic groups and the saturated heterocyclic groups are each independently _{selected from the group consisting of halogens, hydroxys and C 1-4} alkoxys, the same or different 1 to 5 It may be substituted with 11 substituents),
The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof. R ^a and R ^b are independent of each other, and if there are multiple ^Ra or R ^b, _{each is independent of hydrogen atom or C 1-4} alkyl (the alkyl is halogen, hydroxy and C _1-4 alkoxy). It may be substituted with the same or different 1 to 3 substituents selected from the group consisting of).
The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof. R ^c are each independently when a plurality of a 5 substituents C _1-4 alkyl optionally substituted with halogen from 1,
The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof. If there are a plurality of R ^d _{, they are C 1-4} alkyl which may be independently substituted with a hydrogen atom or 1 to 5 halogens.
The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof. Metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor containing the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and / or prophylactic agent for diseases associated with subtype 3 (mGluR3). A therapeutic agent for a disease involving metabotropic glutamate receptor subtype 2 (mGluR2), which comprises the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient. / Or a preventive agent. The therapeutic agent and / or the therapeutic agent according to claim 24, wherein the disease involving the metabotropic glutamate receptor subtype 2 (mGluR2) and / or the metabotropic glutamate receptor subtype 3 (mGluR3) is a psychiatric disorder or a neurodegenerative disease. Or a preventive agent. Mental or neurodegenerative disorders include depressive / depressive disorders, bipolar 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 26, which is Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, convulsions, tremor, pain or sleep disorder. Any of claims 1-22 for producing a therapeutic and / or prophylactic agent for a disease involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3). Use of the compound according to paragraph 1 or a pharmaceutically acceptable salt thereof. Any one of claims 1-22 for use in the treatment and / or prevention of diseases involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3). The compound described in the section, or a pharmaceutically acceptable salt thereof. Metabotropic glutamate acceptance, characterized in that a therapeutically effective amount of the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment. A method for treating and / or preventing a disease involving body subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3). A drug obtained by combining the drug according to any one of claims 1 to 22 with at least one drug selected from drugs classified as psychotic drugs. The invention according to any one of claims 1 to 22, for treating a nervous system disease, a psychiatric disease or a neurodegenerative disease in combination with at least one drug selected from the drugs classified as an antipsychotic drug. Medicine.