JP2019112307A - Pharmaceutical composition administered in combination with substituted dihydro pyrrolopyrazole compound and other psoriasis therapeutic agents - Google Patents

Abstract

To provide a pharmaceutical composition useful as an agent for treating and/or preventing psoriasis.SOLUTION: A pharmaceutical composition, which is administered in combination with other psoriasis therapeutic agents, contains a compound represented by general formula (I) or a pharmacologically acceptable salt thereof [where two R's independently represent a Calkyl group, or represent the groups bound to each other to form a Calkylene group, Lis a single bond or the like, Lis a single bond or the like, R, Rand Rindependently represent an optionally substituted linear or branched Calkyl group, Ris an optionally substituted linear or branched Calkyl group or the like, Ris a hydrogen atom or the like].SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition to which a substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof, or a prodrug thereof and another therapeutic agent for psoriasis are administered in combination.

  Psoriasis is a chronic skin keratosis disease, the symptoms of which manifest as a red rash and a rash with a white scale. Psoriasis is a disease that is thought to be caused by genetic or environmental factors, but its etiology has not yet been clearly identified, and there is no cure that can be completely cured.

  At present, steroids, vitamin D agents, or a combination thereof are mainly used for the treatment of psoriasis. Recently, the JAK inhibitor Tofacitinib and the PDE 4 inhibitor Apremilast have both been approved as oral treatments for psoriasis, and patient options are expanding. Under these circumstances, medicines showing a combination effect with these psoriasis therapeutic agents are considered to be useful from the viewpoint of being able to provide new options for the treatment of psoriasis.

  On the other hand, CDK7 (cyclin-dependent kinase 7) was initially identified as an mRNA transcription regulator in budding yeast, and then it became clear that it plays two roles of cell cycle control and mRNA transcription control. (See Non-Patent Document 1). The CDK family (CDKs), including CDK7, is known to be involved in the inflammatory response via the proliferation of inflammatory cells and immune cells, regulation of apoptosis, transcriptional control of inflammatory mediators, etc. Is considered promising for the disease of interest (see Non-Patent Document 2). In fact, compounds that inhibit CDKs are important for the pathogenesis of chronic obstructive pulmonary disease, etc., through the apoptosis of neutrophils etc., the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) in bleomycin-induced lung injury model It has been reported to show suppression of (see non-patent document 3). In addition, it has also been reported that expression of cyclin D1 / A / B, which is an activity regulator of CDKs, is enhanced in skin tissue of psoriasis patients (see Non-patent Document 4).

  To date, there has been no report specifically showing that a compound that specifically inhibits CDK7 is useful for psoriasis and that there is a combined effect of a compound that specifically inhibits CDK7 with other agents.

International Publication No. 2002/012242 WO 2004/056827 WO 2004/080457 WO 2007/068637 International Publication No. 2007/072153 International Publication No. 2007/099171 International Publication No. 2008/043745 WO 2008/125945 International Publication No. 2011/044264 International Publication No. 2008/151304 International Publication No. 2013/128028 International Publication No. 2013/128029 International Publication No. 2014/063068 WO2015 / 058126 International Publication No. 2015/058140 International Publication No. 2015/058163 International Publication No. 2015/124941 International Publication No. 2015/154022 WO 2015/154038 International Publication No. 2015/154039

Cell Cycle 2006, 5, 546-554 Br. J. Pharmacol. 2009, 158 (4), 1004-1016. Cell Death and Differentiation 2012, 19, 1950-1961. Br. J. Dermatol. 2008, 143 (5), 950-956. Nature 2014, 511, 616-620. Journal of Medicinal Chemistry 2012, 55 (10), 4728-4749. Bioorganic & Medicinal Chemistry 2010, 18 (5), 1844-1835. ChemMedChem 2007, 2, 841-852.

  The present invention is characterized in that it is a pharmaceutical composition comprising a novel substituted dihydropyrrolopyrazole compound having a specific structure or a pharmacologically acceptable salt thereof, which is administered in combination with another therapeutic agent for psoriasis. The present invention has been found to be useful as a therapeutic agent and / or a preventive agent (preferably, a therapeutic agent) for psoriasis, and a compound which can be a prodrug of the compound is also found to complete the present invention.

  Patent documents 1 to 9 and non-patent documents 8 to 10 describe compounds having a 6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole skeleton, There is no disclosure of the compound according to the present invention or the pharmacologically acceptable salt thereof.

  As compounds inhibiting CDK7, pyrazolopyrimidine derivatives are disclosed in Patent Document 10, pyrazolotriazine derivatives are disclosed in Patent Documents 11 and 12, and phenyl derivatives are disclosed in Patent Document 13 and Non-Patent Document 7, Patent Documents 14 The heterocyclic compounds are disclosed in to 20, but the compounds having a 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton are not disclosed.

The present invention is a pharmaceutical composition comprising a novel substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof, or a prodrug thereof, characterized in that it is administered in combination with another therapeutic agent for psoriasis. A pharmaceutical composition (preferably a pharmaceutical composition for the treatment or prevention of psoriasis);
A substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof, or a prodrug thereof, and other psoriasis therapeutic agents for producing a pharmaceutical composition for the treatment or prevention (preferably, treatment) of psoriasis; Combined use; and a pharmaceutically effective amount of a substituted dihydropyrrolopyrazole compound or a pharmacologically acceptable salt thereof, or a prodrug thereof and another therapeutic agent for psoriasis, in combination with a warm-blooded animal (preferably, Provided) a method for the treatment or prevention (preferably treatment) of psoriasis by being administered to a human.

［式中、
２つのＲは、それぞれ独立にＣ_１−３アルキル基を示す、または、互いに結合してＣ_２−５アルキレン基を形成している基を示し、
Ｌ^２は、単結合、酸素原子、または、−ＮＨ−で表される２価のアミノ基を示し、
Ｌ^３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示し、
Ｒ^１、Ｒ^２およびＲ^３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ_１−４アルキル基を示し、
Ｒ^４は、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示し、
Ｒ^５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ_１−１６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示す］
で表される化合物またはその薬理上許容される塩を含む医薬組成物であって、
他の乾癬治療薬と組み合わせて投与されることを特徴とする、医薬組成物。
［２］一般式（ＩＩ）：

［式中、
Ｌ^２は、単結合、酸素原子、または、−ＮＨ−で表される２価のアミノ基を示し、
Ｌ^３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示し、
Ｒ^１、Ｒ^２およびＲ^３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ_１−４アルキル基を示し、
Ｒ^４は、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示し、
Ｒ^５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ_１−１６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示す］
で表される化合物またはその薬理上許容される塩を含む医薬組成物であって、
他の乾癬治療薬と組み合わせて投与されることを特徴とする、医薬組成物。
［３］Ｌ^２およびＬ^３が、単結合を示す、［２］記載の医薬組成物。
［４］Ｌ^２が、−ＮＨ−で表される２価のアミノ基を示し、Ｌ^３が、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示す、［２］記載の医薬組成物。
［５］一般式（ＩＩＩ）：

［式中、
Ｌ^２は、単結合、酸素原子、または、−ＮＨ−で表される２価のアミノ基を示し、
Ｌ^３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示し、
Ｒ^１、Ｒ^２およびＲ^３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ_１−４アルキル基を示し、
Ｒ^４は、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示し、
Ｒ^５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ_１−１６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示す］
で表される化合物またはその薬理上許容される塩を含む医薬組成物であって、
他の乾癬治療薬と組み合わせて投与されることを特徴とする、医薬組成物。
［６］Ｌ^２およびＬ^３が、単結合を示す、［５］記載の医薬組成物。
［７］Ｌ^２が、−ＮＨ−で表される２価のアミノ基を示し、Ｌ^３が、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示す、［５］記載の医薬組成物。
［８］一般式（ＩＶ）：

［式中、
Ｌ^２は、単結合、酸素原子、または、−ＮＨ−で表される２価のアミノ基を示し、
Ｌ^３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示し、
Ｒ^１、Ｒ^２およびＲ^３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ_１−４アルキル基を示し、
Ｒ^４は、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示し、
Ｒ^５は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ_１−１６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示す］
で表される化合物またはその薬理上許容される塩を含む医薬組成物であって、
他の乾癬治療薬と組み合わせて投与されることを特徴とする、医薬組成物。
［９］Ｌ^２およびＬ^３が、単結合を示す、［８］記載の医薬組成物。
［１０］Ｌ^２が、−ＮＨ−で表される２価のアミノ基を示し、Ｌ^３が、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示す、［８］記載の医薬組成物。
［１１］一般式（Ｖ）もしくは（ＶＩ）：

［式中、
２つのＲは、それぞれ独立にＣ_１−３アルキル基を示す、または、互いに結合してＣ_２−５アルキレン基を形成している基を示し、
Ｌ^２は、単結合、酸素原子、または、−ＮＨ−で表される２価のアミノ基を示し、
Ｌ^３は、単結合、または、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示し、
Ｒ^１、Ｒ^２およびＲ^３は、それぞれ独立に、置換されていてもよい直鎖もしくは分岐Ｃ_１−４アルキル基を示し、
Ｒ^４は、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示し、
Ｒ^６は、水素原子、置換されていてもよい直鎖もしくは分岐Ｃ_１−１６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_１−６アルコキシ基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示し、
Ｒ^７は、置換されていてもよい直鎖もしくは分岐Ｃ_１−１６アルキル基、置換されていてもよいＣ_３−６シクロアルキル基、置換されていてもよいＣ_６−１０アリール基、または、置換されていてもよい複素環基を示し、
Ｒ^８およびＲ^９は、それぞれ独立に、水素原子またはＣ_１−４アルキル基を示す］
で表される化合物またはその薬理上許容される塩を含む医薬組成物であって、
他の乾癬治療薬と組み合わせて投与されることを特徴とする、医薬組成物。
［１２］Ｌ^２が、−ＮＨ−で表される２価のアミノ基を示し、Ｌ^３が、置換されていてもよい直鎖もしくは分岐Ｃ_１−６アルキレン基を示す、［１１］記載の医薬組成物。
［１３］［１］乃至［１２］のいずれかに記載の化合物またはその薬理上許容される塩を有効成分として含有する組成物、および、１以上の他の乾癬治療薬を有効成分として含有する組成物が、同時にまたは異なる時間に投与されることを特徴とする、医薬組成物。
［１４］［１］乃至［１２］のいずれかに記載の化合物またはその薬理上許容される塩、および、１以上の他の乾癬治療薬を有効成分として含有する、医薬組成物。
［１５］前記他の乾癬治療薬が、ビタミン誘導体、ステロイド剤、免疫抑制剤、免疫調節剤、非ステロイド性抗炎症剤、シクロオキシゲナーゼ抑制薬、ＰＤＥ４阻害薬、ＴＮＦ阻害薬、抗ヒスタミン薬、シグナル伝達に関係する分子の阻害薬、インターロイキン阻害薬、インターロイキン受容体拮抗薬、インターロイキン薬、ＭＡＰＫ阻害薬、チロシンキナーゼ阻害薬、サイトカイン産生抑制薬、ＪＡＫ阻害薬、Ｔ細胞阻害薬、Ｂ細胞阻害薬、代謝拮抗薬、金製剤、共刺激分子関連タンパク質製剤、および、ジヒドロオロト酸脱水素酵素（ＤＨＯＤＨ）阻害薬からなる群より選択される、［１］乃至［１４］のいずれかに記載の医薬組成物。
［１６］前記他の乾癬治療薬が、ビタミンＤ３誘導体、ビタミンＤ２誘導体、ビタミンＥ、レチノイド製剤、酢酸ジフロラゾン、プロピオン酸クロベタゾール、フランカルボン酸モメタゾン、酪酸プロピオン酸ベタメタゾン、フルオシノニド、ジプロピオン酸ベタメタゾン、ジフルプレドナート、アムシノニド、吉草酸ジフルコルトロン、リドカイン、酪酸プロピオン酸ヒドロコルチゾン、プロピオン酸デプロドン、プロピオン酸デキサメタゾン、ハルシノニド、吉草酸デキサメタゾン、吉草酸ベタメタゾン、硫酸ゲンタマイシン、硫酸フラジオマイシン、プロピオン酸ベクロメタゾン、フルオシノロンアセトニド、硫酸フラジオマイシン、吉草酸酢酸プレドニゾロン、メチルプレドニゾロン、トリアムシノロンアセトニド、ピバル酸フルメタゾン、プロピオン酸アルクロメタゾン、酪酸クロベタゾン、酪酸ヒドロコルチゾン、デキサメタゾン、グリチルレチン酸、ピリドキシン、プレドニゾロン、クロラムフェニコール・硫酸フラジオマイシン、酢酸ヒドロコルチゾン、塩酸ジフェンヒドラミン、クロタミトン、塩酸オキシテトラサイクリン、リン酸ベタメタゾンナトリウム、サラゾピリン、コルヒチン、サルファサラジン、アセチルサリチル酸、ジフルニサル、エテンザミド、メフェナム酸、ジクロフェナク、スリンダク、インドメタシン、フェルビナク、エトドラク、トルメチンナトリウム、ナプトメン、ロキソプロフェン、イブプロフェン、フルルビプロフェン、ケトプロフェン、ナプロキセン、フェノブロフェン、オキサブロジン、ザルトプロフェン、ケトロラク、ピロキシカム、メロキシカム、ロルノキシカムセレコキシブ、バルデコキシブ、パレコキシブナトリウム、ルミラコキシブ、エトリコキシブ、塩酸チアラミド、塩酸チノリジン、エピリゾール、エモルファゾン、アセトアミノフェン、オキシコドン、トラマドール塩酸塩、アセトアニリド、フェナセチン、フェニルブタゾン、アンチピリン、アミノピリン、スルピリン、イソプロピルアンチピリン、スルフィンピラゾン、ケトロラク、ケトロラクトロメタミン、ＳＣ−５６０、Ｎ−（５−アミノ−２−ピリジニル）−４−（トリフルオロメチル）ベンズアミド、エタネルセプト、アダリムマブ、インフリキシマブ、ウステキヌマブ、セクキヌマブ、トシリズマブ、ブリアキヌマブ、リツキシマブ、セルトリズマブ ペゴル、クロロキン、タクロリムス、Ｄ−ペニシラミン、アザチオプリン、ゴリムマブ、シクロスポリン、ベリムマブ、フマル酸ジメチル、デヒドロキシメチルエポキシキノマイシン、ＤＴＣＭ−グルタルイミド、サリドマイド、セスキテルペンラクトン、レスベラトロール、クルクミン、ジインドリルメタンノスカピン、パルテノライド、ボルテゾミブ、イキサゾミブ、カーフィルゾミブ、デランゾミブ、マリゾニブ、ＭＬＮ−４９２４、ＩＭＤ―２５６０、ＩＭＤ―０３５４、ＩＭＤ―１０４１、ＢＡＹ−１１−７０８２、ＢＡＹ−１１−７０８５、ＭＬＮ１２０Ｂ、ＢＭＳ−３４５５４１、ＳＣ−５１４、ＰＳ−１１４５、デノスマブ、ボリノスタット、ロミデプシン、ＳＮ−５０、Ｔ−５２２４、トファシチニブ、フォスタマチニブ、カナキヌマブ、サリルマブ、バリシチニブ、ＡＳＰ５０９４、ＡＳＰ０１５Ｋ、ＴＡＫ−０２０、ＡＢＴ−４９４、シルクマブ、デノスマブ、オゾラリズマブ、ナミルマブ、マブリリムマブ、アバタセプト、アタシセプト、ＪＴＥ−０５２、ＭＴ−１３０３、ＪＴＥ−０５１、ＪＴＥ−１５１、イブジラスト、フィンゴモリド、可溶性インターロイキン−１受容体抗体、アナキンラ、インターロイキン−１０、インターロイキン２製剤、インターロイキン１２製剤、ブリアキヌマブ、セクキヌマブ（ＡＩＮ−４５７）、イキセキズマブ（ＬＹ−２４３９８２１）、ＡＭＧ８２７、ＢＭＳ−５８２９４９、ＴＮＦ−αワクチン、ナタリズマブ、ベドリズマブ、エファリツマブ、ＳＣＩ０４６９、ＢＩＲＢ７９６、ＳＢ２０３５８０、ＶＸ−７０２、パラピモド、ＰＨ７９７８０４、ベムラフェニブ、ダブラフェニブ、トラメチニブ、コビメチニブ、ＣＣ−３５９、ＣＣ−９３０、ベンタマピモド、ＸＧ−１０４、サリチル酸軟膏、尿素軟膏、メトトレキサート、金チオリンゴ酸ナトリウム、オーラノフィン、ペニシラミン、ブシラミン、ロベンザリット二ナトリウム、サラゾスルファピリジン、アクタリット、ミゾリビン、イグラチモド、アプレミラスト、ロフルミラスト、ＡＮ２７２８、Ｍ５２００、ＤＲＭ０２、ＲＶＴ−０５１、ＯＰＡ−１５４０６、クロモグリク酸ナトリウム、トラニラスト、レピリナスト、アンレキサノン、イブジラスト、ケトチフェン、テルフェナジン、メキタジン、アゼラスチン、塩酸オザグレル、プランルカスト水和物、セラトロダスト、シクレソニド、マレイン酸クロルフェニラミン、アリメマジン酒石酸塩、フマル酸クレマスチン、塩酸ホモクロルシクリジン、フェキソフェナジン、フマル酸ケトチフェン、塩酸セチリジン、オキサトミド、エバスチン、エピナスチン塩酸塩、ロラタジン、トラマドール、プロメタジン、ヒドロキシジン、ホモクロルシクリジン、シプロヘプタジン、メキタジン、フマル酸エメダスチン、プソイドエフェドリン、ベシル酸ベポタスチンレボセチリジン、オロパタジン塩酸塩、ミコフェノール酸モフェチル、ダクリズマブ、ガリキシマブ、メトホルミン塩酸塩、ビジリズマブ、アミノプテリン、パゾパニブ塩酸塩、フェザキヌマブ、ルキソリチニブリン酸塩、イクセキズマブ、グセルクマブ、ＳＬｘ−２１１９、ＰＲＸ−１６７７００、および、レフルノミドからなる群より選択される、［１］乃至［１４］のいずれかに記載の医薬組成物。
［１７］前記他の乾癬治療薬が、トファシチニブである、［１］乃至［１４］のいずれかに記載の医薬組成物。
［１８］前記他の乾癬治療薬が、アプレミラストである、［１］乃至［１４］のいずれかに記載の医薬組成物。
［１９］乾癬を治療または予防するための、［１］乃至［１８］のいずれかに記載の医薬組成物。
［２０］［１］乃至［１２］のいずれかに記載の化合物、または、その薬理上許容される塩、および、１以上の他の乾癬治療薬を組み合わせて、それを必要とする対象に投与することを含む、乾癬の治療または予防方法。
［２１］乾癬の治療剤または予防剤である医薬組成物の製造のための、［１］乃至［１２］のいずれかに記載の化合物、または、その薬理上許容される塩、および、１以上の他の乾癬治療剤を組み合わせての使用。
［２２］乾癬を治療または予防するための、［１］乃至［１２］のいずれかに記載の化合物、または、その薬理上許容される塩、および、１以上の他の乾癬治療剤を組み合わせての使用。
［２３］乾癬の治療または予防に使用するための、［１］乃至［３３］のいずれかに記載の化合物、または、その薬理上許容される塩、および、１以上の他の乾癬治療剤の組み合わせ。 The present invention provides the following [1] to [23] from one aspect.
[1] General Formula (I):

[In the formula,
Two R's each independently represent a C _1-3 alkyl group, or represent a group bonded to each other to form a C _2-5 alkylene group;
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[2] General Formula (II):

[In the formula,
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[3] The pharmaceutical composition according to [2], wherein L ² and L ³ represent a single bond.
[4] ^{L 2} is a divalent group represented by -NH-, ^{L 3} indicates a straight chain may be substituted or branched _{C 1-6} alkylene group, [2] according Pharmaceutical composition.
[5] General Formula (III):

[In the formula,
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[6] The pharmaceutical composition according to [5], wherein L ² and L ³ represent a single bond.
[7] The method according to [5], wherein L ² represents a divalent amino group represented by -NH-, and L ³ represents a linear or branched C _1-6 alkylene group which may be substituted. Pharmaceutical composition.
[8] General Formula (IV):

[In the formula,
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[9] The pharmaceutical composition according to [8], wherein L ² and L ³ represent a single bond.
[10] The method according to [8], wherein L ² represents a divalent amino group represented by -NH-, and L ³ represents a linear or branched C _1-6 alkylene group which may be substituted. Pharmaceutical composition.
[11] General Formula (V) or (VI):

[In the formula,
Two R's each independently represent a C _1-3 alkyl group, or represent a group bonded to each other to form a C _2-5 alkylene group;
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁶ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _1-6 alkoxy group A C _6-10 aryl group which may be substituted, or a heterocyclic group which may be substituted,
R ⁷ represents a linear or branched C _1-16 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-4 alkyl group]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[12] The method according to [11], wherein L ² represents a divalent amino group represented by -NH-, and L ³ represents a linear or branched C _1-6 alkylene group which may be substituted. Pharmaceutical composition.
[13] A composition comprising the compound according to any one of [1] to [12] or a pharmacologically acceptable salt thereof as an active ingredient, and one or more other psoriasis therapeutic agents as an active ingredient Pharmaceutical composition, characterized in that the composition is administered simultaneously or at different times.
[14] A pharmaceutical composition comprising the compound according to any one of [1] to [12] or a pharmacologically acceptable salt thereof, and one or more other psoriasis therapeutic agents as an active ingredient.
[15] The other psoriasis therapeutic agents are vitamin derivatives, steroids, immunosuppressants, immunomodulators, non-steroidal anti-inflammatory agents, cyclooxygenase inhibitors, PDE4 inhibitors, TNF inhibitors, antihistamines, signal transduction Inhibitors related to cancer, interleukin inhibitors, interleukin receptor antagonists, interleukin drugs, MAPK inhibitors, tyrosine kinase inhibitors, cytokine production inhibitors, JAK inhibitors, T cell inhibitors, B cell inhibition The drug according to any one of [1] to [14], which is selected from the group consisting of a drug, antimetabolite, a gold preparation, a costimulatory molecule-related protein preparation, and a dihydroorotic acid dehydrogenase (DHODH) inhibitor Composition.
[16] The other psoriasis therapeutic agents are vitamin D3 derivatives, vitamin D2 derivatives, vitamin E, retinoid preparations, diflorazone acetate, clobetasol propionate, mometasone furoate, betamethasone butyrate propionate, fluocinonide, betamethasone dipropionate, difulf Predonato, amcinonide, diflucortorone valerate, lidocaine, hydrocortisone butyrate, deprodon propionate, dexamethasone propionate, harcinonide, dexamethasone valerate, betamethasone valerate, gentamycin sulfate, fradiomycin sulfate, beclomethasone propionate, fluocinolone propionate Acetonide, Fradromycin sulfate, Prednisolone valerate acetate, Methylprednisolone, Triamcinolone acetonide, Flume pivalate Zonate, alclomethasone propionate, clobetasone butyrate, hydrocortisone butyrate, dexamethasone butyrate, glycyrrhetinic acid, pyridoxine, prednisolone, chloramphenicol sulfate flavomycin, hydrocortisone acetate, diphenhydramine hydrochloride, crotamiton, oxytetracycline hydrochloride, betamethasone sodium phosphate, salazopyrine, colchicine , Sulfasalazine, acetylsalicylic acid, diflunisal, ethensamide, mefenamic acid, diclofenac, sulindac, indomethacin, felbinac, etodolac, tolmetin sodium, naptomen, loxoprofen, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenobrofen, oxbrozine, Zaltoprofen, ketorolac, piro Sicam, meloxicam, lornoxicam celecoxib, valdecoxib, parecoxib sodium, lumiracoxib, etoricoxib, tiaramide hydrochloride, tilolizine hydrochloride, epilizole, emorfazone, acetaminophen, oxycodone, tramadol hydrochloride, acetanilide, phenacetin, phenylbutazone, antipyrine Aminopyrine, sulpyrine, isopropylantipyrine, sulfinpyrazone, ketorolac, ketorolac tromethamine, SC-560, N- (5-amino-2-pyridinyl) -4- (trifluoromethyl) benzamide, etanercept, adalimumab, infliximab, Ustekinumab, secquinumab, tocilizumab, briaquinumab, rituximab, seltrizumab pegol, chloroquine, tacrolim , D-penicillamine, azathioprine, golimumab, cyclosporin, belimumab, dimethyl fumarate, dehydroxymethyl epoxy quinomycin, DTCM-glutarimide, thalidomide, sesquiterpene lactone, resveratrol, curcumin, diindolylmethanoscapine, parthenolide, bortezomib, Ixazomib, Carfilzomib, Delanzomib, Marizonib, MLN-4924, IMD-2560, IMD- 0354, IMD- 1041, BAY-11-7082, BAY-11-7085, MLN 120B, BMS-345541, SC-514, PS-1145, Denosumab, vorinostat, romidepsin, SN-50, T-5224, tofacitinib, fostamatinib, canakinumab, salilumab, Bali Citinib, ASP 5094, ASP 015 K, TAK-020, ABT-494, Cicumab, Denosumab, Ozolalizumab, Namilumab, Mabrilimumab, Abatacept, Atacicept, JTE-052, MT-1303, JTE-051, JTE-151, Ibudilast, Fingomolid, Soluble Inter Leukin-1 receptor antibody, anakinra, interleukin-10, interleukin 2 preparation, interleukin 12 preparation, biaquinumab, secquinumab (AIN-457), ixequizumab (LY-2439821), AMG 827, BMS-582 949, TNF-α vaccine , Natalizumab, vedolizumab, efalizumab, SCI 0469, BIRB 796, SB 203 580, VX-702, parapimod, PH79780 , Vemurafenib, Dabrafenib, Trametinib, Cobimetinib, CC-359, CC-930, Bentamapimod, XG-104, Salicylic Acid Ointment, Urea Ointment, Methotrexate, Gold Thiomalate Sodium, Auranophin, Penicillamine, Bucilamine, Lobenzarit Disodium, Salazosul Phapyridine, Actarit, Mizoribine, Igratimod, Apremilast, Roflumilast, AN2728, M5200, DRM02, RVT-051, OPA-15406, Sodium Cromoglycate, Tranilast, Repirinast, Anlexanone, Ibutilast, Ketotifen, Terfenadine, Mequitazine Azezerustine, Pranlukast hydrate, seratrodust, ciclesonide, chlorpheniramine maleate , Alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, fexofenadine, ketotifen fumarate, cetirizine hydrochloride, oxatomid, ebastine, evastine, epinastine hydrochloride, loratadine, tramadol, promethazine, hydroxyzine, homochlorcyclidine, cyproheptadine, Mequitadine, emedastine fumarate, pseudoephedrine, bepotastine levocetirizine besilate, olopatadine hydrochloride, mycophenolate mofetil, daclizumab, galiximab, galliximab, metformin hydrochloride, vigilzumab, aminopterin, pazopanib hydrochloride, fezakinumab It is selected from the group consisting of ixerkizumab, guselkmab, SLx-2119, PRX-167700, and leflunomide, [ ] Or a pharmaceutical composition according to any one of [14].
[17] The pharmaceutical composition according to any one of [1] to [14], wherein the other psoriasis therapeutic agent is tofacitinib.
[18] The pharmaceutical composition according to any one of [1] to [14], wherein the other psoriasis therapeutic agent is apremilast.
[19] The pharmaceutical composition according to any one of [1] to [18] for treating or preventing psoriasis.
[20] [1] to [12], or a pharmacologically acceptable salt thereof, and one or more other therapeutic agents for psoriasis, which are administered to a subject in need thereof A method of treating or preventing psoriasis, including:
[21] The compound according to any one of [1] to [12], or a pharmacologically acceptable salt thereof, and one or more of the compounds according to any one of [1] to [12] for producing a pharmaceutical composition that is a therapeutic agent or prophylactic agent for psoriasis Use in combination with other psoriasis treatments.
[22] A compound of any one of [1] to [12], or a pharmacologically acceptable salt thereof, and one or more other psoriasis therapeutic agents for treating or preventing psoriasis Use of.
[23] The compound according to any one of [1] to [33], or a pharmacologically acceptable salt thereof, and one or more other therapeutic agents for psoriasis, for use in the treatment or prevention of psoriasis combination.

The present invention provides the following [24] to [55] from another aspect.
[24] (S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c [Pyrazole-5 (1H) -carboxamide,
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
(S) -2-[(2-methoxypropan-2-yl) oxy] -1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxylate,
(S) -2-hydroxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
2-Methoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate,
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(R) -N- (4-hydroxy-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (5-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -N- (2-methoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- [2- (Difluoromethoxy) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c [Pyrazole-5 (1H) -carboxamide,
(S) -N- (2-Ethoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (3-methoxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4.5.6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 Sodium phenylacetate,
N- [1- (2-fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(S) -N- [1- (3-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
(S) -N- [1- (4-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- [2-hydroxy-1- (pyridin-2-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
N- [2-hydroxy-1- (pyridin-3-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -N- (1-Cyclohexyl-2-hydroxyethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (1-hydroxy-3-methylbutan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c [Pyrazole-5 (1H) -carboxamide,
(S) -N- (1-hydroxypropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl acetate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl propionate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl butanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pentanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl octanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl dodecanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl palmitate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl isobutanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pivalate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl 3-methylbutanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl benzoate,
(S) -4- (2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide } -2-Phenylethoxy) sodium 4-oxobutanoate,
(S)-(2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenylethoxy) methyl pivalate,
(S) -2-Acetoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
(S) -benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
(S) -Methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -N- [1- (2-chlorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -N- [2-hydroxy-1- (o-tolyl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -N- (1-hydroxy-3-phenylpropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
N- [5- (3-methoxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
N- [5- (4-methoxy-2-phenylbutanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclopropanecarboxamide,
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclopropanecarboxamide,
(R) -N- {5- [2- (difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -1- (ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] Pyrazol-3-yl] cyclobutanecarboxamide,
(R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [6,6-dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2- (4-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2- (3-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- {5- [2- (2-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole- 3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl } -1- (Trimethylsilyl) cyclobutanecarboxamide,
(-)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 ,, 4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- (3-ethyl-3-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (3-fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (2-fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- (5-hydroxy-2,5-dimethylhexan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
(-)-N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
(+)-N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (2-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
N- (1-hydroxy-2,2,4-trimethylpentan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c [Pyrazole-5 (1H) -carboxamide,
(-)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
(+)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [5- (2-butoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide, and N- (3-methoxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- A pharmaceutical composition comprising a compound selected from the group consisting of dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamides or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[25] (R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- A pharmaceutical composition comprising dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[26] (-)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropane-1-carboxamide] -4, A pharmaceutical composition comprising 6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[27] (R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3-3 A pharmaceutical composition comprising: [I] -l- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with one or more other psoriasis therapeutic agents.
[28] (R) -N- [6,6-Dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- A pharmaceutical composition comprising: [I] -l- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[29] (R) -N- {5- [2- (2-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] A pharmaceutical composition comprising pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[30] (R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- A pharmaceutical composition comprising: [I] -l- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[31] (R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 A pharmaceutical composition comprising: -yl] -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[32] (R) -N- [5- (2-Isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 A pharmaceutical composition comprising: -yl] -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[33] (+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-] c) pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, which is a pharmaceutical composition comprising:
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[34] (-)-N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4 6-Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[35] N- {5- [2- (3-Fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 A pharmaceutical composition comprising: -yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[36] N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydro A pharmaceutical composition comprising pyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[37] (R) -N- [1- (3-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- A pharmaceutical composition comprising dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with one or more other psoriasis therapeutic agents.
[38] (R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] A pharmaceutical composition comprising pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[39] (R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo A pharmaceutical composition comprising [3,4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof, which comprises:
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[40] (R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide or a pharmacologically acceptable salt thereof, which is a pharmaceutical composition comprising:
A pharmaceutical composition, which is administered in combination with one or more other psoriasis therapeutic agents.
[41] (R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- A pharmaceutical composition comprising: [I] -l- (trimethylsilyl) cyclopropanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[42] (R) -N- {5- [2- (Difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide or a pharmacologically acceptable salt thereof, which is a pharmaceutical composition comprising:
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[43] (R) -1- (ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3, A pharmaceutical composition comprising 4-c] pyrazol-3-yl] cyclobutanecarboxamide or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[44] N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-] c) pyrazol-5 (1H) -carboxamide or a pharmaceutical composition comprising the pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis.
[45] [24] A composition containing the compound of any of the above [44] or a pharmacologically acceptable salt thereof as an active ingredient, and a composition containing another therapeutic agent for psoriasis as an active ingredient A pharmaceutical composition, which is administered simultaneously or at different times.
[46] A pharmaceutical composition comprising, as an active ingredient, the compound according to any of [24] to [44] or a pharmacologically acceptable salt thereof, and another therapeutic agent for psoriasis.
[47] The other psoriasis therapeutic agents are vitamin derivatives, steroids, immunosuppressants, immunomodulators, non-steroidal anti-inflammatory agents, cyclooxygenase inhibitors, PDE4 inhibitors, TNF inhibitors, antihistamines, signal transduction Inhibitors related to cancer, interleukin inhibitors, interleukin receptor antagonists, interleukin drugs, MAPK inhibitors, tyrosine kinase inhibitors, cytokine production inhibitors, JAK inhibitors, T cell inhibitors, B cell inhibition The drug according to any of [24] to [46], which is selected from the group consisting of a drug, antimetabolite, a gold preparation, a costimulatory molecule-related protein preparation, and a dihydroorotic acid dehydrogenase (DHODH) inhibitor Composition.
[48] The other psoriasis therapeutic agents are vitamin D3 derivatives, vitamin D2 derivatives, vitamin E, retinoid preparations, diflorazone acetate, clobetasol propionate, mometasone furoate, betamethasone butyrate propionate, fluocinonide, betamethasone dipropionate, difulf Predonato, amcinonide, diflucortorone valerate, lidocaine, hydrocortisone butyrate, deprodon propionate, dexamethasone propionate, harcinonide, dexamethasone valerate, betamethasone valerate, gentamycin sulfate, fradiomycin sulfate, beclomethasone propionate, fluocinolone propionate Acetonide, Fradromycin sulfate, Prednisolone valerate acetate, Methylprednisolone, Triamcinolone acetonide, Flume pivalate Zonate, alclomethasone propionate, clobetasone butyrate, hydrocortisone butyrate, dexamethasone butyrate, glycyrrhetinic acid, pyridoxine, prednisolone, chloramphenicol sulfate flavomycin, hydrocortisone acetate, diphenhydramine hydrochloride, crotamiton, oxytetracycline hydrochloride, betamethasone sodium phosphate, salazopyrine, colchicine , Sulfasalazine, acetylsalicylic acid, diflunisal, ethensamide, mefenamic acid, diclofenac, sulindac, indomethacin, felbinac, etodolac, tolmetin sodium, naptomen, loxoprofen, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenobrofen, oxbrozine, Zaltoprofen, ketorolac, piro Sicam, meloxicam, lornoxicam celecoxib, valdecoxib, parecoxib sodium, lumiracoxib, etoricoxib, tiaramide hydrochloride, tilolizine hydrochloride, epilizole, emorfazone, acetaminophen, oxycodone, tramadol hydrochloride, acetanilide, phenacetin, phenylbutazone, antipyrine Aminopyrine, sulpyrine, isopropylantipyrine, sulfinpyrazone, ketorolac, ketorolac tromethamine, SC-560, N- (5-amino-2-pyridinyl) -4- (trifluoromethyl) benzamide, etanercept, adalimumab, infliximab, Ustekinumab, secquinumab, tocilizumab, briaquinumab, rituximab, seltrizumab pegol, chloroquine, tacrolim , D-penicillamine, azathioprine, golimumab, cyclosporin, belimumab, dimethyl fumarate, dehydroxymethyl epoxy quinomycin, DTCM-glutarimide, thalidomide, sesquiterpene lactone, resveratrol, curcumin, diindolylmethanoscapine, parthenolide, bortezomib, Ixazomib, Carfilzomib, Delanzomib, Marizonib, MLN-4924, IMD-2560, IMD- 0354, IMD- 1041, BAY-11-7082, BAY-11-7085, MLN 120B, BMS-345541, SC-514, PS-1145, Denosumab, vorinostat, romidepsin, SN-50, T-5224, tofacitinib, fostamatinib, canakinumab, salilumab, Bali Citinib, ASP 5094, ASP 015 K, TAK-020, ABT-494, Cicumab, Denosumab, Ozolalizumab, Namilumab, Mabrilimumab, Abatacept, Atacicept, JTE-052, MT-1303, JTE-051, JTE-151, Ibudilast, Fingomolid, Soluble Inter Leukin-1 receptor antibody, anakinra, interleukin-10, interleukin 2 preparation, interleukin 12 preparation, biaquinumab, secquinumab (AIN-457), ixequizumab (LY-2439821), AMG 827, BMS-582 949, TNF-α vaccine , Natalizumab, vedolizumab, efalizumab, SCI 0469, BIRB 796, SB 203 580, VX-702, parapimod, PH79780 , Vemurafenib, Dabrafenib, Trametinib, Cobimetinib, CC-359, CC-930, Bentamapimod, XG-104, Salicylic Acid Ointment, Urea Ointment, Methotrexate, Gold Thiomalate Sodium, Auranophin, Penicillamine, Bucilamine, Lobenzarit Disodium, Salazosul Phapyridine, Actarit, Mizoribine, Igratimod, Apremilast, Roflumilast, AN2728, M5200, DRM02, RVT-051, OPA-15406, Sodium Cromoglycate, Tranilast, Repirinast, Anlexanone, Ibutilast, Ketotifen, Terfenadine, Mequitazine Azezerustine, Pranlukast hydrate, seratrodust, ciclesonide, chlorpheniramine maleate , Alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, fexofenadine, ketotifen fumarate, cetirizine hydrochloride, oxatomid, ebastine, evastine, epinastine hydrochloride, loratadine, tramadol, promethazine, hydroxyzine, homochlorcyclidine, cyproheptadine, Mequitadine, emedastine fumarate, pseudoephedrine, bepotastine levocetirizine besilate, olopatadine hydrochloride, mycophenolate mofetil, daclizumab, galiximab, galliximab, metformin hydrochloride, vigilzumab, aminopterin, pazopanib hydrochloride, fezakinumab It is selected from the group consisting of ixerkizumab, guselkmab, SLx-2119, PRX-167700, and leflunomide, [ 4] or a pharmaceutical composition according to any one of [46].
[49] The pharmaceutical composition according to any of [24] to [46], wherein the other psoriasis therapeutic agent is tofacitinib.
[50] The pharmaceutical composition according to any of [24] to [46], wherein the other psoriasis therapeutic agent is apremilast.
[51] The pharmaceutical composition according to any one of [24] to [50] for treating or preventing psoriasis.
[52] [24] to [44], or a pharmacologically acceptable salt thereof, and other therapeutic agent for psoriasis combined and administered to a subject in need thereof Methods of treating or preventing psoriasis, including.
[53] The compound according to any of [24] to [44], or a pharmacologically acceptable salt thereof, and the like, for the manufacture of a pharmaceutical composition which is a therapeutic agent or prophylactic agent for psoriasis Use in combination with psoriasis treatment.
[54] Use of the compound according to any of [24] to [44], or a pharmacologically acceptable salt thereof, in combination with another therapeutic agent for psoriasis, for treating or preventing psoriasis.
[55] A combination of a compound according to any of [24] to [44], or a pharmacologically acceptable salt thereof, and another therapeutic agent for psoriasis, for use in the treatment or prevention of psoriasis.

As a specific example of a compound represented by general formula (I) of this invention, a compound as shown to the following Tables 1-20 can be mentioned, for example. In Tables 1 to 20, Me represents a methyl group, Et represents an ethyl group, nPr represents an n-propyl group, iPr represents an isopropyl group, cPr represents a cyclopropyl group, and nBu represents n IBu represents an isobutyl group, tBu represents a tert-butyl group, cHex represents a cyclohexyl group, Ph represents a phenyl group, and 2-F-Ph represents a 2-fluorophenyl group, 3-F-Ph represents a 3-fluorophenyl group, 4-F-Ph represents a 4-fluorophenyl group, 2-Cl-Ph represents a 2-chlorophenyl group, and 3-Cl-Ph represents 3-chlorophenyl. 4-Cl-Ph represents 4-chlorophenyl group, 2-Me-Ph represents 2-methylphenyl group, 3-Me-Ph represents 3-methylphenyl group, 4- e-Ph represents a 4-methylphenyl group, 2-Py represents a 2-pyridyl group, 3-Py represents a 3-pyridyl group, 4-Py represents a 4-pyridyl group, and Bn represents a benzyl group. In the formula,-represents a single bond, and "(R)-" and "(S)-" represent the following general formulas (II), (III), (IV), (Va), (Va), (Vb), The configuration of the carbon atom with “*” in (Vc), (VIa), (VIb), and (VIc) is shown, “racemic” is a racemate, and “(+)” Indicates that the compound is a dextrorotatory optically active substance, and "(-)" indicates that it is a levorotatory optically active substance. Further, in each chemical structure described as L ³ in the table, in the corresponding general formula, an atom located on the left side of the chemical structure is bonded to a carbon atom to which “*” is attached. For example, in the case of the compound of compound No. II-11, CH ₂ (CMe) ₂ corresponding to L ³ is bonded to a carbon atom to which a methylene carbon atom (CH ₂ ) is attached with “*” _{CMe) 2} is meant binding with an oxygen atom adjacent to ^{R 5.}

  The novel substituted dihydropyrrolopyrazole compound having a specific structure represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is excellent in CDK7 inhibitory activity and kinase inhibition in which the compound itself or a metabolite thereof is excellent. It has high selectivity for action and excellent safety. Therefore, a pharmaceutical composition comprising the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof, which is administered in combination with another therapeutic agent for psoriasis, is It is useful as a therapeutic and / or preventive agent for psoriasis.

  One embodiment of the present invention will be described below. In the present specification, the “compound represented by the general formula (I)” and the like are also referred to as “compound (I)” and the like for convenience. Various substituents defined or exemplified below can be arbitrarily selected and combined.

  As used herein, “prodrug” refers to a compound or a salt thereof which, upon administration into the animal, undergoes a metabolic reaction to produce a compound having CDK7 inhibitory activity.

  One embodiment of the present invention is a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which is administered in combination with another therapeutic agent for psoriasis , A pharmaceutical composition.

<1. Compound Represented by General Formula (I) or Pharmaceutically Acceptable Salt Thereof>

In the general formula (I),
Two R's each independently represent a C _1-3 alkyl group, or represent a group bonded to each other to form a C _2-5 alkylene group;
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted.

  In the present specification, the term "optionally substituted" means that the group may be unsubstituted or may be further substituted by a substituent.

The above substituents means a monovalent group, for example, a linear or branched _{C 1-6} alkyl _{group, C 3-6} cycloalkyl group, straight or branched _{C 2-6} alkenyl _{group, C 3-6} cycloalkyl Alkenyl group, linear or branched C _2-6 alkynyl group, C _1-6 alkoxy group, halogen atom, hydroxyl group, cyano group, oxo group (= O), amino group, C _1-6 alkylamino group, nitro group, carboxy group (-COOH), a carbamoyl group (-CONH _2), N- mono- _{C 1-6} alkylcarbamoyl group, N, _{N-di-C 1-6} alkylcarbamoyl _{group, C 1-6} alkanoyloxy group (-OCOR, R is _{C 1-6} alkyl _{group), C 6-10} aryl group, a heterocyclic _{group, C 6-10} aryloxy _{group, C 7-12} aralkyl groups, _{and, C 7-12} aralkyloxy group And the like. The substituent may be further substituted by a halogen atom, a hydroxyl group, an amino group, a cyano group, an oxo group (= O), a linear or branched C _1-6 alkyl group, or the like. When the substituent is an amino group or a carboxy group, it may be in the form of a salt thereof.

When the group has two or more substituents, two substituents may be bonded to each other to form a cyclic structure. Examples of the case where two substituents combine with each other to form a cyclic structure include a cyclopropyl group, a cyclobutyl group and a methylenedioxy group. Specifically, when a methylenedioxy group is bonded to a benzene ring, the substituent is a 1,3-benzodioxole group, and has two methyl groups at the same carbon atom of a 1,2-ethylene group. When the two groups are bonded to each other, the group is a group represented by the following formula (M-1) or (M-2), and the same carbon atom of the 1,2-ethylene group has a methyl group and an ethyl group. When the methyl group is bonded to the 2-position of the ethyl group, the group is a group represented by the following formula (N-1) or (N-2).

The linear or branched a C _1-6 alkyl group described herein means a straight or branched alkyl group having 1 to 6 carbon atoms. As a linear or branched C _1-6 alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl Group, tert-pentyl group, 1-ethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group Group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, or include _{C 1-6} alkyl groups such as 2,3-dimethylbutyl group, the Substituent is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, a tert- butyl group.

As a C _1-6 alkyl group substituted by a halogen atom, for example, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, dichloromethyl group, dibromomethyl group, diiodomethyl group, trifluoromethyl group, trichloromethyl group 1-fluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 2,2 -Dichloroethyl group, 2,2,2-trichloroethyl group, 1-fluoropropyl group, 2-fluoropropyl group, 3-fluoropropyl group, 3,3,3-trifluoropropyl group, perfluoropropyl group, 1 -Fluoromethylethyl group, 1-difluoromethylethyl group, 1-trifluoromethyl ether And tyl, 1-fluoro-1-methylethyl, 4-fluorobutyl, perfluorobutyl, 5-fluoropentyl, perfluoropentyl, 6-fluorohexyl or perfluorohexyl groups. .

The C _1-6 alkyl group substituted with an aryl group may be, for example, a C _7-11 aralkyl group. The C _7-11 aralkyl group means an alkyl group having an aryl group having 7 to 11 carbon atoms in total, and examples thereof include a benzyl group, a phenylethyl group and a naphthylmethyl group.

The _C3-6 cycloalkyl group described herein means a cyclic alkyl group having 3 to 6 carbon atoms. As _C3-6 cycloalkyl group, For example, monocyclic rings, such as a cyclopropyl group, cyclobutyl group, a cyclopentyl group, a cyclohexyl group; Condensed rings, such as a bicyclo [3.1.0] hexyl group; spiro [2.3] And spiro rings such as hexyl group. The substituent is preferably a cyclopropyl group or a cyclobutyl group.

The linear or branched C _2-6 alkenyl group described herein means a linear or branched alkenyl group having 2 to 6 carbon atoms. As a linear or branched C _2-6 alkenyl group, for example, vinyl group, propen-1-yl group, propen-2-yl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl -1-propenyl group, 2-methyl-1-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 5-pentenyl group, 1-methyl-1-butenyl group, 2 -Methyl-1-butenyl group, 3-methyl-1-butenyl group, 4-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group Butenyl group, 4-methyl-2-butenyl group, 1-methyl-3-butenyl group, 2-methyl-3-butenyl group, 3-methyl-3-butenyl group, 4-methyl-3-butenyl group, 1, 2-Dimethyl-l-p And alkenyl groups such as lopenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 6-hexenyl group and structural isomers thereof.

The _C3-6 cycloalkenyl group described in the present specification means a C3-C6 cycloalkenyl group. The C _3-6 cycloalkenyl group, for example, cyclopropenyl group, cyclobutenyl group, and a cyclopentenyl group and cyclohexenyl group.

The _C2-6 alkynyl group as described in the present specification means an alkynyl group having 2 to 6 carbon atoms. Examples of the C _2-6 alkynyl group include ethynyl group, propargyl group, butynyl group, pentynyl group and hexynyl group.

The C _1-6 alkoxy group described in the present specification includes an oxy group (—O—), a linear or branched C _1-6 alkyl group linked to the oxy group, or a C _3-6 cycloalkyl group. Means a group which As C _1-6 alkoxy group, for example, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, cyclopropyloxy group, butoxy group, cyclobutyloxy group, pentyloxy group, cyclopentyloxy group, hexyloxy group, A cyclohexyloxy group is mentioned.

The C _1-6 alkylamino group described in the present specification is substituted with one or two of the above-mentioned linear or branched C _1-6 alkyl groups selected independently or a C _3-6 cycloalkyl group. Means an amino group which is As C _1-6 alkylamino group, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, cyclopropylamino group, butoxy group, cyclobutylamino group, pentylamino group, cyclopentylamino group, hexyl Examples thereof include an amino group, a cyclohexylamino group, a dimethylamino group, a diethylamino group, an ethylmethylamino group, an isopropylmethylamino group and a cyclopropylmethylamino group.

  The halogen atom described herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The C _6-10 aryl group described herein means an aryl group having 6 to 10 carbon atoms. As a _C6-10 aryl group, a phenyl group, a naphthyl group, etc. are mentioned, for example.

  The heterocyclic group described in the present specification means a cyclic group having at least one nitrogen atom, oxygen atom or sulfur atom, and may be an aromatic heterocyclic group or non-aromatic heterocyclic group, It is also good. Examples of the aromatic heterocyclic group include pyridine group, pyrimidine group, pyridazine group, pyrazine group, triazine group, triazine group, pyrrole group, imidazole group, pyrazole group, indole group, indazole group, furan group, benzofuran group, thiophene group, benzo group Thiophene group, thiazole group, isothiazole group, oxazole group, isoxazole group and oxadiazole group can be mentioned. Examples of non-aromatic heterocyclic groups include pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group and thiomorpholinyl group.

The C _6-10 aryloxy group described in the present specification means a group consisting of an oxy group (-O-) and the above C _6-10 aryl group bonded to the oxy group. As a _C6-10 aryloxy group, a phenyloxy group, 1-naphthyloxy group, 2-naphthyloxy group etc. are mentioned.

The _{C 7-12} aralkyl group described herein means the above _{C 1-6} alkyl group substituted on the _{C 6-10} aryl group. _{Examples of the} C _7-12 aralkyl group include benzyl group, phenylethyl group, naphthylmethyl group, and naphthylethyl group.

The C _7-12 aralkyloxy group described in the present specification means a group consisting of an oxy group (—O—) and the above C _7-12 aralkyl group bonded to the oxy group. _{Examples of the} C _7-12 aralkyloxy group include benzyloxy group, phenylethyloxy group, naphthylmethyloxy group and naphthylethyloxy group.

The C _1-3 alkyl group as R is an alkyl group having 1 to 3 carbon atoms, and corresponds to one having 1 to 3 carbon atoms among the above C _1-6 alkyl groups. _{Examples of the} C _1-3 alkyl group include a methyl group, an ethyl group, a propyl group and an isopropyl group.

C ₂ bind two R each other - ₅ The groups form an alkylene group of the C _1-6 alkyl group, a C _2-5 alkyl group corresponds to that of 2 to 5 carbon atoms Further means a divalent group from which one hydrogen atom has been removed. As _C2-5 alkylene group, 1,2-ethylene group, 1,2-propylene group, 1,3-propylene group, 1,2-butylene group, 1,3-butylene group, 1,4-butylene group 2,3-butylene group, 1,2-pentylene group, 1,3-pentylene group, 1,4-pentylene group, 1,5-pentylene group, 2,3-pentylene group, 2,4-pentylene group It can be mentioned.

The linear or branched C _1-6 alkylene group as L ^3, means a divalent group obtained by removing one more hydrogen atom from the C _1-6 alkyl group. As the C _1-6 alkylene group, for example, methylene group, 1,1-ethylene group, 1,2-ethylene group, 1,1-propylene group, 1,2-propylene group, 2,2-propylene group, 1 And 3-propylene group.

The linear or branched C _1-4 alkyl group as R ¹ , R ² or R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms, and among the above C _1-6 alkyl groups, 1 carbon atom To 4 correspond.

A linear or branched _{C 1-6} alkyl group as R _{^4, C 3-6} cycloalkyl _{group, C 6-10} aryl group, and a heterocyclic group are defined as above substituents.

The linear or branched C _1-16 alkyl group as R ⁵ means an alkyl group having 1 to 16 carbon atoms. As a linear or branched C _1-16 alkyl group, for example, methyl group, ethyl group, propyl group, butyl group, isobutyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, nonyl group And C _1-16 alkyl groups such as decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl and the like.

_{C 3-6} cycloalkyl group as R _{^5, C 6-10} aryl group, and a heterocyclic group are defined as above substituents.

  The compound according to the present embodiment may be a compound represented by any one of chemical formula (II), general formula (III), or general formula (IV).

In the general formula (II), the general formula (III) and the general formula (IV), L ² , L ³ , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as in the general formula (I) Defined in

In the general formulas (I) to (IV), L ² may be an oxygen atom or a divalent amino group represented by —NH—. L ³ may be a single bond or a linear or branched C _1-6 alkylene group which may be substituted.

As L ² and L ³ in the general formulas (I) to (IV), preferably, L ² and L ³ are a single bond, or L ² is a divalent amino group represented by —NH— And L ³ is a linear or branched C _1-6 alkylene group which may be substituted.

In formulas (I) to (IV), R ¹ , R ² and R ³ may each independently be a linear or branched C _1-4 alkyl group which may be substituted. R ⁴ is a hydrogen atom, a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted Or a heterocyclic group which may be substituted. R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted.

In the general formulas (I) to (IV), preferably, L ² is a single bond or a divalent amino group represented by —NH—, and L ³ may be a single bond or substituted a linear or branched _{C 1-6} alkylene ^group, R 1, ^{R 2} and ^{R 3} are each independently an optionally substituted straight or branched _{C 1-4} alkyl group, ^{R 4} is, A linear or branched C _1-6 alkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or a heterocyclic group which may be substituted, R ⁵ is a hydrogen atom, a substituted group It may be a linear or branched C _1-16 alkyl group which may be substituted or a C _3-6 cycloalkyl group which may be substituted.

In the general formulas (I) to (IV), as another embodiment, preferably, L ² and L ³ are a single bond, and R ¹ , R ² and R ³ may be independently substituted. A linear or branched C _1-4 alkyl group, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or a substituted And R ⁵ is a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, or an optionally substituted C _3-6 cycloalkyl group.

In the general formulas (I) to (IV), in still another embodiment, preferably, L ² is a divalent amino group represented by —NH—, and L ³ is a linear which may be substituted. or a branched _{C 1-6} alkylene ^group, R 1, ^{R 2} and ^{R 3} are each independently an optionally substituted straight or branched _{C 1-4} alkyl group, ^{R 4} is substituted A linear or branched C _1-6 alkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or a heterocyclic group which may be substituted, and R ⁵ is a hydrogen atom, which is substituted It may be a linear or branched C _1-16 alkyl group which may be substituted, or a C _3-6 cycloalkyl group which may be substituted.

In the general formulas (I) to (IV), more preferably, L ² is a single bond or a divalent amino group represented by —NH—, and L ³ is a single bond or substituted R ¹ , R ² and R ³ are each independently a linear or branched C _1-4 alkyl group, and R ⁴ is a substituted or unsubstituted C _1-6 alkylene group. a good linear or branched C _1-6 alkyl group, optionally substituted C _6-10 aryl group or an optionally substituted heterocyclic group, R ⁵ is a hydrogen atom, a linear or branched C _{1 -16} alkyl group, halogen atom, oxo group, or linear or branched C _1-16 alkyl group substituted by linear or branched C _1-6 alkyl group, or C optionally substituted by halogen atom _3-6 cycloalkyl It is a group.

In the general formulas (I) to (IV), as another embodiment, more preferably, L ² and L ³ are single bonds, and R ¹ , R ² and R ³ are each independently a linear or branched C _1-4 alkyl group, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or a heterocyclic ring which may be substituted R ⁵ is a linear or branched C ₁ substituted with a hydrogen atom, a linear or branched C _1-16 alkyl group, a halogen atom, an oxo group, or a linear or branched C 1 to ₆ alkyl group _-16 alkyl group or a _C3-6 cycloalkyl group which may be substituted by a halogen atom.

In the general formulas (I) to (IV), as still another embodiment, more preferably, L ² is a divalent amino group represented by —NH—, and L ³ may be substituted R ¹ , R ² and R ³ are each independently a linear or branched C _1-4 alkyl group, and R ⁴ is an optionally substituted straight or branched C _1-6 alkylene group A chain or branched C _1-6 alkyl group, an optionally substituted C _6-10 aryl group or an optionally substituted heterocyclic group, and R ⁵ is a hydrogen atom or a linear or branched C _1-16 An alkyl group, a halogen atom, an oxo group, or a linear or branched C _1-16 alkyl group substituted with a linear or branched C _1-6 alkyl group, or C ₃ optionally substituted with a halogen atom ₆ cycloalkyl is there.

In the general formulas (I) to (IV), particularly preferably, L ² is a single bond or a divalent amino group represented by —NH—, and L ³ is a single bond or the following formula (O-1), (O-2), (M-2) or (N-1), and R ¹ , R ² and R ³ are each independently a linear or branched C _1-4 alkyl group, R ⁴ is an optionally substituted phenyl group or thienyl group, R ⁵ is a hydrogen atom, a linear or branched C _1-16 alkyl group, or a halogen atom , straight-chain or branched _{C 1-16} alkyl group _or a _{C 3-6} cycloalkyl group. In the present specification, the chemical structure represented by the formula (O-1) is also referred to as “C (Me) ₂ CH ₂ ”, and the chemical structure represented by the formula (O-2) is “CH ₂ C Me) ₂ ", and the chemical structure represented by formula (M-2) is also called" CH ₂ -1, 1-cyclopropylene ", and the chemical structure represented by formula (N-1) is" 1, 1 also referred to as a 1-cyclo-butylene -CH ₂ ".

In the general formulas (I) to (IV), as another embodiment, particularly preferably, L ² is a divalent amino group represented by —NH—, and L ³ is a group represented by the above formula (O-1), R ¹ , R ² and R ³ are each independently a linear or branched C _1-4 alkyl group, which is a group represented by (O-2), (M-2) or (N-1) R ⁴ is an optionally substituted phenyl group or a thienyl group, and R ⁵ is a hydrogen atom, a linear or branched C _1-16 alkyl group, a linear or branched group substituted with a halogen atom It is a _C1-16 alkyl group or a _C3-6 cycloalkyl group.

Among the compounds (I) or pharmacologically acceptable salts thereof according to this embodiment, R ⁵ is substituted with an oxo group as represented by the general formula (V), and the oxo group and R ⁵ are A compound in which an oxygen atom to be bonded forms an ester bond, or an alkylene group in which R ⁵ is substituted by a substituent containing an oxygen atom as represented by general formula (VI), wherein the oxygen atom and R ⁵ The compound in which an acetal group containing an oxygen atom to which is attached may be a compound that acts as a prodrug. The compound (V) or the compound (VI) tends to be more excellent in oral absorbability and skin permeability, and can be metabolized to give a compound (I) (wherein R ⁵ is a hydrogen atom).

In the general formula (V) and the general formula (VI), R, R ¹ , R ² , R ³ , R ⁴ , L ² and L ³ are defined in the same manner as the general formula (I). R ⁶ represents a hydrogen atom, an optionally substituted linear or branched C _1-15 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _1-6 alkoxy group R ⁶ represents a C _6-10 aryl group which may be substituted or a heterocyclic group which may be substituted, and R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-4 alkyl group. R ⁷ represents a linear or branched C _1-15 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, Or a heterocyclic group which may be substituted. A linear or branched C _1-15 alkyl group, a C _3-6 cycloalkyl group, a C _6-10 aryl group, and a heterocyclic group as R ⁶ or R ⁷ and a substituent that substitutes them are represented by the general formula It is defined in the same manner as the groups in (I) to (IV).

R ⁶ may be a linear or branched C _1-15 alkyl group which may be substituted, or a C _6-10 aryl group which may be substituted. R ⁷ may be a linear or branched C _1-16 alkyl group which may be substituted.

As L ² and L ³ in the general formula (V) and the general formula (VI), preferably, L ² is a divalent amino group represented by —NH— and L ³ is substituted It is a good linear or branched _C1-6 alkylene group.

In the general formula (V), preferably, two R's are a group bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, L ² is a single bond or R ³ is a divalent amino group represented by —NH—, L ³ is a single bond, or a linear or branched C _1-6 alkylene group which may be substituted, and R ¹ , R ² and R ³ is each independently a linear or branched C _1-4 alkyl group which may be substituted, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, or substituted R ⁶ is a C _6-10 aryl group which may be substituted or a heterocyclic group which may be substituted, and R ⁶ is a linear or branched C _1-15 alkyl group which may be substituted.

In the general formula (V), in another embodiment, preferably, two R's are a group bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, and L ² is A divalent amino group represented by NH-, L ³ is a linear or branched C _1-6 alkylene group which may be substituted, and R ¹ , R ² and R ³ are each independently And R ⁴ is a linear or branched C _1-4 alkyl group which may be substituted, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, C _6- which may be substituted. ₁₀ aryl group or a heterocyclic group which may be substituted, R ⁶ is a linear or branched C _1-15 alkyl group which may be substituted.

In general formula (V), preferably, two R's are a group bonded to each other to form a 1,3-propylene group, and L ² is represented by a single bond or -NH- L ³ is a divalent amino group, L ³ is a single bond, or a linear or branched C _1-6 alkylene group which may be substituted, and R ¹ , R ² and R ³ are each independently R ⁴ is a linear or branched C _1-4 alkyl group which may be substituted, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, C _6-10 which may be substituted An aryl group or a heterocyclic group which may be substituted, and R ⁶ is a linear or branched C _1-15 alkyl group which may be substituted.

In the general formula (V), as another embodiment, preferably, two R's are a group bonded to each other to form a 1,3-propylene group, and L ² is a group represented by —NH— Amino group, L ³ is a linear or branched C _1-6 alkylene group which may be substituted, and R ¹ , R ² and R ³ may be each independently substituted. R ⁴ is a linear or branched C _1-4 alkyl group, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or R ⁶ is a heterocyclic group which may be substituted, and R ⁶ is a linear or branched C _1-15 alkyl group which may be substituted.

In the general formula (VI), preferably, two R's are a group bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, L ² is a single bond or R ³ is a divalent amino group represented by —NH—, L ³ is a single bond, or a linear or branched C _1-6 alkylene group which may be substituted, and R ¹ , R ² and R ³ is each independently a linear or branched C _1-4 alkyl group which may be substituted, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, or substituted R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-4 alkyl group, and R ⁷ is a C _6-10 aryl group which may be substituted or a heterocyclic group which may be substituted. , Linear or branched C _{1 which} may have a substituent _-15 alkyl group or _C3-6 cycloalkyl group which may be substituted.

In the general formula (VI), in another embodiment, preferably, two R's are a group which is bonded to each other to form a 1,2-ethylene group or a 1,3-propylene group, and L ² is A divalent amino group represented by NH-, L ³ is a linear or branched C _1-6 alkylene group which may be substituted, and R ¹ , R ² and R ³ are each independently And R ⁴ is a linear or branched C _1-4 alkyl group which may be substituted, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, C _6- which may be substituted. ₁₀ aryl group or a heterocyclic group which may be substituted, R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-4 alkyl group, and R ⁷ has a substituent A linear or branched C _1-15 alkyl group which may be Or it is a _C3-6 cycloalkyl group which may be substituted.

In general formula (VI), preferably, two R's are a group bonded to each other to form a 1,3-propylene group, and L ² is represented by a single bond or -NH- L ³ is a divalent amino group, L ³ is a single bond, or a linear or branched C _1-6 alkylene group which may be substituted, and R ¹ , R ² and R ³ are each independently R ⁴ is a linear or branched C _1-4 alkyl group which may be substituted, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, C _6-10 which may be substituted R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-4 alkyl group, and R ⁷ is a substituted or unsubstituted heterocyclic group. A linear or branched C _1-15 alkyl group, or It is a _C3-6 cycloalkyl group which may be substituted.

In the general formula (VI), as another embodiment, preferably, two R's are a group bonded to each other to form a 1,3-propylene group, and L ² is a group represented by —NH— Amino group, L ³ is a linear or branched C _1-6 alkylene group which may be substituted, and R ¹ , R ² and R ³ may be each independently substituted. R ⁴ is a linear or branched C _1-4 alkyl group, and R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-4 alkyl group, and R ⁷ is a linear or branched group which may have a substituent. C _1-15 alkyl group or substituted It is a good _C3-6 cycloalkyl group.

Specifically, the compound according to the present embodiment or a pharmacologically acceptable salt thereof is a compound selected from the compound group shown below or a pharmacologically acceptable salt thereof.
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
(S) -2-[(2-methoxypropan-2-yl) oxy] -1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxylate,
(S) -2-hydroxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
2-Methoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate,
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(R) -N- (4-hydroxy-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (5-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -N- (2-methoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- [2- (Difluoromethoxy) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c [Pyrazole-5 (1H) -carboxamide,
(S) -N- (2-Ethoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(R) -N- (3-methoxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4.5.6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 Sodium phenylacetate,
N- [1- (2-fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(S) -N- [1- (3-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
(S) -N- [1- (4-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- [2-hydroxy-1- (pyridin-2-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
N- [2-hydroxy-1- (pyridin-3-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -N- (1-Cyclohexyl-2-hydroxyethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -N- (1-hydroxy-3-methylbutan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c [Pyrazole-5 (1H) -carboxamide,
(S) -N- (1-hydroxypropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl acetate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl propionate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl butanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pentanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl octanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl dodecanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl palmitate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl isobutanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pivalate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl 3-methylbutanoate,
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl benzoate,
(S) -4- (2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide } -2-Phenylethoxy) sodium 4-oxobutanoate,
(S)-(2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenylethoxy) methyl pivalate,
(S) -2-Acetoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate,
(S) -benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
(S) -Methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate,
N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide,
(S) -N- [1- (2-chlorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -N- [2-hydroxy-1- (o-tolyl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(S) -N- (1-hydroxy-3-phenylpropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
N- [5- (3-methoxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
N- [5- (4-methoxy-2-phenylbutanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide,
(S) -N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclopropanecarboxamide,
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclopropanecarboxamide,
(R) -N- {5- [2- (difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -1- (ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] Pyrazol-3-yl] cyclobutanecarboxamide,
(R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [5- (2-isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- [6,6-dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2- (4-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2- (3-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(R) -N- {5- [2- (2-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole- 3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl } -1- (Trimethylsilyl) cyclobutanecarboxamide,
(-)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
(+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide,
N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide,
(R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 ,, 4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- (3-ethyl-3-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (3-fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [1- (2-fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- (5-hydroxy-2,5-dimethylhexan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
(-)-N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
(+)-N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide,
N- [1- (2-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazole-5 (1H) -carboxamide,
N- (1-hydroxy-2,2,4-trimethylpentan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4- c] pyrazole-5 (1H) -carboxamide,
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide,
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c [Pyrazole-5 (1H) -carboxamide,
(-)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
(+)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide,
(R) -N- [5- (2-butoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide, and N- (3-methoxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide

  The compound or pharmacologically acceptable salt thereof according to this embodiment may be a single optically active substance or a mixture of a plurality of optically active substances.

  When a geometrical isomer or rotamer exists in the compound according to this embodiment, the isomer is also included in the scope of the present invention, and when proton tautomerism exists, their tautomerism. The body is also encompassed by the present invention.

  The “pharmacologically acceptable salt” according to the present embodiment is not particularly limited as long as it is a pharmaceutically acceptable salt, and hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salts with inorganic acids; acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, tartaric acid, adipic acid, lactic acid, salts with organic carboxylic acids such as trifluoroacetic acid; methanesulfonic acid, trifluoromethanesulfonic acid, benzene Salts with organic sulfonic acids such as sulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; salts with alkali metals such as lithium, sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonia, morpholine , Glucosamine, ethylenediamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, diethanolamine, Quaternary ammonium salts with Perazine like.

  The compound according to the present embodiment or a pharmacologically acceptable salt thereof can form a hydrate or a solvate, and each of them or a mixture thereof is included in the present invention.

The compounds according to this embodiment may also contain unnatural proportions of atomic isotopes at one or more of the constituent atoms. The atomic isotopes such as deuterium ⁽² H), tritium ⁽³ H), ^{carbon--14 (14} C), fluorine ^{-18 (18} F), sulfur ^{-35 (35} S), or, iodine-125 ( ^125I ) and the like. These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variants of the compounds according to this embodiment, whether radioactive or not, are encompassed by the present invention.

  Next, the method for producing compound (I) or a pharmacologically acceptable salt thereof will be described. Compound (I) or a pharmacologically acceptable salt thereof is not limited to the compound produced by the following production method or a pharmacologically acceptable salt thereof.

  In the production methods described below, partial structures (eg, hydroxy group, amino group, carbonyl group, carboxyl group, amido group, or thiol group) which inhibit a desired reaction or undergo side reactions in a compound If present, the desired product can be obtained by introducing protecting groups into those partial structures to carry out the desired reaction, and then removing the protecting groups.

  Methods for introducing and removing protecting groups are methods commonly used in synthetic organic chemistry (for example, Protective Groups in Organic Synthesis 4th edition, TW Greene, PG M Wuts, John Wiley & Sons Inc. (2006) and the like.

  Each specific manufacturing method of this invention compound is demonstrated in detail by the below-mentioned Example.

  Compound (I) can be produced, for example, using compound (A) as a starting material by the following production methods 1 to 4. In addition, the manufacturing method of a compound (A) is mentioned later.

<Production Method 1 of Compound (I)>
Production method 1 is a method for producing compound (I) through steps 1 to 3 using compound (A) as a starting material. Production method 1 is a preferred production method when L ² is an oxygen atom or a divalent amino group represented by —NH—. In the production method 1, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L ² and L ³ are defined in the same manner as in formula (I). P ¹ represents an amino protecting group and X represents a leaving group. The P ¹ group only has to be capable of substituting the acidic proton of pyrazole in the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton. Thus, the P ¹ group may be substituted at position 1 or at position 2 of the 4,6-dihydropyrrolo [3,4-c] pyrazole backbone. For convenience, the compound (A) will be described using a chemical formula substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton.

The P ¹ group is not particularly limited as long as it is a substituent known to those skilled in the art as a protective group for amino groups. As P ¹ group, for example, an optionally substituted C _7-11 aralkyl group such as benzyl group, p-methoxyphenylmethyl group, o-nitrophenylmethyl group and the like; acetyl group, trifluoroacetyl group, benzoyl group and the like An optionally substituted acyl group; methoxycarbonyl group, ethoxycarbonyl group, Boc group (tert-butoxycarbonyl group), Cbz group (benzyloxycarbonyl group), Fmoc group (fluorenylmethyloxycarbonyl group), Teoc An optionally substituted C _1-6 alkoxycarbonyl group such as a group (trimethylsilylethyloxycarbonyl group); an alkenyloxycarbonyl group such as an Alloc group (allyloxycarbonyl group); an alkylsulfonyl group such as a methanesulfonyl group; p- C _6- such as toluene sulfonyl group _{And 10} arylsulfonyl groups.

  The X group is not particularly limited as long as it is a substituent known to those skilled in the art as a leaving group. Examples of X include a halogen atom; an imidazolyl group; an aminooxy group such as succinyl-N-oxy group and a benzotriazolyl-N-oxy group; and an acyloxy group such as a pivaloyloxy group and a benzoyloxy group. In addition, X may be a hydroxyl group.

(Step 1)
Step 1 is a step of reacting compound (A) with an acylating agent to obtain compound (B).

  As the acylating agent, for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N, N'-disuccinimidyl carbonate, carbonate ester and the like can be used.

  The amount of the acylating agent to be used is preferably 0.4 to 3.0 mol, more preferably 0.7 to 1.5 mol, per 1 mol of compound (A).

  In step 1, the reaction may be performed in a solvent or may be performed without a solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), N, N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

  Step 1 can further add a base to accelerate the reaction. As a base, for example, triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP) can be mentioned.

  The amount of the base to be added is preferably 1 to 10 mol, more preferably 3 to 6 mol, per 1 mol of compound (A).

  The reaction temperature of step 1 can be appropriately set by those skilled in the art. The reaction temperature is usually -100 to -20.degree. C., preferably -80 to -60.degree.

(Step 2)
Step 2 is a step of reacting compound (B) with compound (C) to obtain compound (D).

In step 2, the L ² group is an oxygen atom or a divalent amino group represented by —NH—. That is, the compound (C) is an alcohol or an amine.

  The amount of compound (C) to be used is preferably 1 to 20 mol, more preferably 2 to 5 mol, per 1 mol of compound (B). The compound (C) and the compound (B) may be dissolved in an organic solvent and added to the reaction solution.

  In step 2, the reaction may be carried out in a solvent or without solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. As the organic solvent, dichloromethane, 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) It can be mentioned.

  Step 2 can further add a base to accelerate the reaction. As a base, for example, triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP); and inorganic bases such as potassium carbonate and sodium carbonate.

  The amount of the base to be added is preferably 1 to 20 mol, more preferably 2 to 5 mol, per 1 mol of compound (A).

  The reaction temperature of step 2 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 120 ° C., preferably 25 to 100 ° C.

(Step 3)
Step 3 is a step of removing compound P ¹ of compound (D) to produce compound (I).

The reaction conditions of step 3 can be appropriately selected by those skilled in the art depending on the type of P ¹ group used. For example, when the P ¹ group is an aralkyl group, it may be carried out by hydrogenolysis, or may be carried out using a protic acid or a Lewis acid. When the P ¹ group is a Boc group, it can be treated by treatment with a protonic acid or Lewis acid, and when the P ¹ group is a Cbz group, it is done by hydrogenolysis or treatment with a base In the case where the P ¹ group is a Teoc group, a reagent that generates fluoride ions such as tetrabutylammonium fluoride can be used. When the P ¹ group is an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group, in the presence of an organic amine such as triethylamine or diisopropylethylamine (DIPEA), or an inorganic base such as potassium carbonate or sodium carbonate You may carry out by heating.

  Compound (I) obtained by Step 3 can be converted into its pharmacologically acceptable salt by methods well known to those skilled in the art.

<Production Method 2 of Compound (I)>
Production method 2 is a method of obtaining compound (D) through steps 4 and 5 using compound (C) as a starting material, and then converting to compound (I) according to step 3 of the above production method 1 . Production method 2 is a preferred production method when L ² is an oxygen atom or a divalent amino group represented by —NH—. In the production method 2, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L ² , L ³ , P ¹ and X are defined in the same manner as the production method 1 above.

(Step 4)
Step 4 is a step of reacting compound (C) with an acylating agent to obtain compound (E).

In step 4, the L ² group is an oxygen atom or a divalent amino group represented by —NH—. That is, the compound (C) is an alcohol or an amine.

  As the acylating agent, for example, phosgene, diphosgene, triphosgene, carbonyldiimidazole (CDI), N, N'-disuccinimidyl carbonate, carbonate ester and the like can be used.

  The amount of the acylating agent to be used is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (C).

  In step 4, the reaction may be carried out in a solvent or without solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. Organic solvents include acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO).

  Step 4 can further add a base to accelerate the reaction. As a base, for example, triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP) can be mentioned.

  The amount of the base to be added is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (C).

  The reaction temperature of step 4 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.

(Step 5)
Step 5 is a step of reacting compound (E) with compound (A) to obtain compound (D).

  The amount of compound (E) to be used is preferably 1 to 5 mol, more preferably 1 to 2 mol, per 1 mol of compound (A). The compound (E) and the compound (A) may be dissolved in an organic solvent and added to the reaction solution.

  In step 5, the reaction may be carried out in a solvent or without solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. Organic solvents include dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO).

  Step 5 can further add a base to accelerate the reaction. As a base, for example, triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP) can be mentioned.

  The amount of the base to be added is preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of compound (A).

  The reaction temperature of step 5 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.

<Production Method 3 of Compound (I)>
Production method 3 is a method of reacting compound (A) with compound (F) to obtain compound (D), and then converting into compound (I) according to step 3 of the above production method 1. Production method 3 is a preferred production method when L ² is a single bond. In the production method 3, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L ² , L ³ and P ¹ are defined in the same manner as the production method 1 above.

(Step 6)
Step 6 is a step of condensing compound (A) and compound (F) to obtain compound (D). In the above condensation reaction, the compound (F) is converted to an acid halide, a carboxylic acid anhydride, an acid azide, or an active ester using a reagent used for an amide bond forming reaction, and then reacted with the compound (A). In addition, the reagent used for the said amide bond formation reaction will not be restrict | limited in particular, if it is a reagent known to a person skilled in the art as a reagent used for amide bond formation reaction.

  The amount of compound (F) to be used is preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of compound (A). The compound (F) may be dissolved in an organic solvent and added to the reaction solution.

  In step 6, the reaction may be carried out in a solvent or without solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. Examples of the organic solvent include dichloromethane, 1,2-dichloroethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

  Step 6 can further add a base to accelerate the reaction. As a base, for example, triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP) can be mentioned.

  The amount of the base to be added is preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of compound (A).

  The reaction temperature of step 6 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100 ° C., preferably 20 to 40 ° C.

<Production Method 4 of Compound (I)>
Production method 4 is a method of converting compound (D) into compound (I) according to step 3 of the above production method 1 after obtaining compound (D) through step 7 and step 8 using compound (H) as a starting material is there. In Production method 4, R, R ¹ , R ² , R ³ , R ⁴ , L ² and L ³ are defined in the same manner as in the general formula (I). The P ¹ group represents a protective group of amino group, and P ² represents a protective group of hydroxyl group. The P ¹ group is defined in the same manner as the production method 1 above.

The P ² group is not particularly limited as long as it is a substituent known to those skilled in the art as a hydroxyl protecting group. As P ² group, for example, an optionally substituted C _7-11 aralkyl group such as benzyl group, p-methoxyphenylmethyl group, o-nitrophenylmethyl group and the like; acetyl group, trifluoroacetyl group, benzoyl group and the like And optionally substituted acyl groups; and substituted silyl groups such as trimethylsilyl group, tert-butyldimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldiphenylsilyl group and the like.

(Step 7)
Step 7 is a step of deprotecting compound (H) to obtain compound (J). The removal reaction of P ² group can also be carried out by methods known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th Edition, TW Greene, PG M Wuts, John Wiley & Sons Inc (2006) etc.).

(Step 8)
Step 8 is a step of reacting compound (J) with an acid halide, an acid anhydride, or an alkyl halide to obtain compound (D).

  The amount of the acid halide, acid anhydride or alkyl halide to be used is preferably 1 to 10 mol, more preferably 1 to 2 mol, per 1 mol of compound (J).

  In step 8, the reaction may be carried out in a solvent or without solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. Examples of the organic solvent include dichloromethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

  In step 8, more base can be added to accelerate the reaction. As a base, for example, triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP) can be mentioned.

  The amount of the base to be added is preferably 1 to 20 mol, more preferably 1 to 5 mol, per 1 mol of compound (J).

  The reaction temperature of step 8 can be appropriately set by those skilled in the art. The reaction temperature is usually -20 to 120 ° C, preferably 15 to 100 ° C.

<Method for producing compound (A)>
Compound (A) can be produced, for example, using compound (A1) as a starting material by the following method. The compound (A1) can be produced, for example, by referring to WO2007 / 72153 or through the following Steps 11 to 15.

The compound (A1) is 3-amino-6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole, and the nitrogen atom on the pyrazole skeleton is P ^{1 and} the nitrogen atom at position 5 May be substituted by P ³ group. The P ¹ group only has to be capable of substituting the acidic proton of pyrazole in the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton. Thus, the P ¹ group may be substituted at position 1 or at position 2 of the 4,6-dihydropyrrolo [3,4-c] pyrazole backbone. For convenience, the compound (A1) and the compound (A2) will be described using a chemical formula substituted at the 1-position of the 4,6-dihydropyrrolo [3,4-c] pyrazole skeleton.

In the compound (A1), P ¹ is as defined in the compound (A). The P ³ group is not particularly limited as long as it is a substituent known to those skilled in the art as a protective group for amino group. As P ³ group, for example, an optionally substituted C _7-11 aralkyl group such as benzyl group, p-methoxyphenylmethyl group, o-nitrophenylmethyl group and the like; an acetyl group, a trifluoroacetyl group and the like Optionally substituted C _6-10 arylcarbonyl group such as C _1-6 alkylcarbonyl group, benzoyl group; methoxycarbonyl group, ethoxycarbonyl group, Boc group (tert-butoxycarbonyl group), Cbz group An optionally substituted C1-6 alkoxycarbonyl group such as (benzyloxycarbonyl group), Fmoc group (fluorenylmethyloxycarbonyl group), Teoc group (trimethylsilylethyloxycarbonyl group); Alloc group (allyloxycarbonyl group And the like) alkenyloxycarbonyl groups such as And alkylsulfonyl groups such as sulfonyl group; and optionally substituted C _6-10 arylsulfonyl group such as p-toluenesulfonyl group.

In formulas (A2) and (A3), R, R ¹ , R ² and R ³ are as defined in compound (I). The X group is not particularly limited as long as it is a substituent known to those skilled in the art as a leaving group. Examples of X include a halogen atom; an imidazolyl group; an aminooxy group such as succinyl-N-oxy group and a benzotriazolyl-N-oxy group; and an acyloxy group such as a pivaloyloxy group and a benzoyloxy group. In addition, X may be a hydroxyl group.
When the compound (A2) is a carboxylic acid (ie, X is a hydroxyl group), it may be converted to an acid anhydride by a method well known to those skilled in the art and then reacted with the compound (A1). The compound (A1) may be reacted with a reagent known as a condensing agent used in

(Step 9)
Step 9 is a step of reacting compound (A1) with compound (A2) to obtain compound (A3).

  The amount of compound (A2) to be used is preferably 1 to 10 mol, more preferably 1 to 3 mol, per 1 mol of compound (A1).

  In step 9, the reaction may be carried out in a solvent or without solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. Organic solvents include dichloromethane, diethyl ether, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO).

  In step 9, further base can be added to accelerate the reaction. As a base, for example, triethylamine, diisopropylethylamine (DIPEA), 1,5-diazabicyclo [4.3.0] nonene (DBN), 1,8-diazabicyclo [5.4.0] undecene (DBU), pyridine, Organic amines such as 4-dimethylaminopyridine (DMAP) can be mentioned.

  The amount of the base to be added is preferably 1 to 20 mol, more preferably 1 to 5 mol, per 1 mol of compound (A1).

  The reaction temperature of step 9 can be set as appropriate by those skilled in the art. The reaction temperature is usually -40 to 100 ° C, preferably -20 to 20 ° C.

(Step 10)
Step 10 is a step of subjecting compound (A3) to deprotection to obtain compound (A). The removal reaction of P ³ group can also be carried out by methods known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th Edition, TW Greene, PG M Wuts, John Wiley & Sons Inc). (2006) etc.).

<Method for producing compound (A1)>

Equation (A6), in (A7) and (A8), ^{P 3} is the same as defined in compound (A1).

(Step 11)
Step 11 is a step of reacting compound (A4) with acrylonitrile to obtain compound (A5).

  The amount of acrylonitrile to be used is preferably 1 to 10 mol, more preferably 1 to 3 mol, per 1 mol of compound (A4).

  The step 11 is not limited as long as it is a solvent that does not affect the reaction, and is preferably an aqueous solvent.

  In step 11, further base can be added to accelerate the reaction. Examples of the base include inorganic bases such as potassium hydroxide. The amount of the base to be added is preferably 0.8 to 2 mol, per 1 mol of compound (A1).

  The reaction temperature of step 11 can be appropriately set by those skilled in the art. The reaction temperature is usually 0 to 100 ° C., preferably 50 to 90 ° C.

(Step 12)
Step 12 is a step of protecting the amino group of compound (A5) with a P ³ group to obtain compound (A6). The protection reaction of an amino group with a P ³ group can be carried out by methods known to those skilled in the art (for example, Protective Groups in Organic Synthesis 4th Edition, TW Greene, PG M Wuts, John Wiley). & Sons Inc. (2006) etc.).

(Step 13)
Step 13 is a step of subjecting compound (A6) to a cyclization reaction to obtain compound (A7).

  In step 13, the reaction may be carried out in a solvent or without solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. Examples of the organic solvent include diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, N, N-dimethylformamide (DMF) toluene and the like.

  Step 13 can further add a base to accelerate the reaction. Examples of the base include sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, n-butyllithium, tert-butoxy potassium and the like. The amount of the base to be added is preferably 1 to 3 mol, per 1 mol of compound (A6).

  The reaction temperature of step 13 can be appropriately set by those skilled in the art. The reaction temperature is usually 20 to 150 ° C., preferably 50 to 100 ° C.

(Step 14)
Step 14 is a step of reacting compound (A7) with hydrazine to obtain compound (A8).
In step 14, the reaction may be carried out in a solvent or without solvent. When a solvent is used, there is no limitation as long as it does not affect the reaction, and preferably an organic solvent. As the organic solvent, ethanol, n-propanol, n-butanol and the like can be mentioned.
Step 14 can add more acid to accelerate the reaction. Examples of the acid include acetic acid, hydrochloric acid, sulfuric acid and the like. The amount of the acid to be added is preferably 1 to 10 mol, per 1 mol of compound (A7).
The reaction temperature of step 14 can be set as appropriate by those skilled in the art. The reaction temperature is usually 20 to 150 ° C., preferably 50 to 120 ° C.

(Step 15)
Step 15 is a step of protecting the amino group of compound (A7) with a P ¹ group to obtain compound (A1). The protection reaction of an amino group with a P ¹ group can be carried out by methods known to those skilled in the art (eg, Protective Groups in Organic Synthesis 4th Edition, TW Greene, PG M Wuts, John Wiley & Sons Inc. (2006) etc.).

<2. Other psoriasis treatment>
The “other psoriasis therapeutic agent” in the pharmaceutical composition according to the present embodiment is not limited as long as it is a drug used for treating psoriasis, and, for example, vitamin derivatives, steroids, immunosuppressants, immunomodulators, non-steroids Anti-inflammatory drugs (NSAIDs), cyclooxygenase inhibitors, PDE4 inhibitors, TNF inhibitors, antihistamines, molecules involved in signal transduction (eg NF-−, NF-κB, IKK-1, IKK-2, AP) -1) inhibitors, interleukin inhibitors, interleukin receptor antagonists, interleukin drugs, MAPK inhibitors, tyrosine kinase inhibitors, cytokine production inhibitors, JAK inhibitors, T cell inhibitors, B cell inhibitors Antimetabolites, gold preparations, costimulatory molecule related protein preparations, dihydroorotic acid dehydrogenase (DHODH) inhibitors, etc. Ru.

  Specifically, “other psoriasis therapeutic agents” in the pharmaceutical composition according to the present embodiment are, for example, vitamin D3 derivatives, vitamin D2 derivatives, vitamin E, retinoid preparations, diflorazone acetate, clobetasol propionate, mometasone furoate, Butamethasone butyrate, fluocinonide, betamethasone dipropionate, diflupredonate, diflupredonato, amcinonide, diflucortorone valerate, lidocaine, hydrocortisone butyrate propionate, deprodon propionate, dexamethasone propionate, harcinonide, dexamethasone valerate, betamethasone valerate, sulfate Gentamycin, fradiomycin sulfate, beclomethasone propionate, fluocinolone acetonide, fradiomycin sulfate, prednisolone valerate acetate, methyl prednisolone Triamcinolone acetonide, flumetasone pivalate, alclomethasone propionate, clobetasone butyrate, hydrocortisone butyrate, dexamethasone butyrate, dexamethasone, glycyrrhetinic acid, pyridoxine, prednisolone, chloramphenicol sulfate fradiomycin hydrochloride, hydrocortisone acetate, diphenhydramine hydrochloride, rotamimitone hydrochloride, oxytetracycline hydrochloride, phosphate acid Betamethasone sodium, salazopyrine, colchicine, sulfasalazine, acetylsalicylic acid, diflunisal, ethensamide, mefenamic acid, diclofenac, sulindac, indomethacin, felbinac, etodolac, tolmetin sodium, naptomene, loxoprofen, ibuprofen, flurbiprofen, ketoprofen, naproxen Fenobrofen, oxa Rosin, zaltoprofen, ketorolac, piroxicam, meloxicam, lornoxicam celecoxib, valdecoxib, parecoxib sodium, lumiracoxib sodium, luricacoxib, etoricoxib, tiaramide hydrochloride, tinoridine hydrochloride, epirizole, emorfazone, acetaminophen, oxycodone, tramadol hydrochloride, acetanilide, phenacetin , Phenylbutazone, antipyrine, aminopyrine, sulpyrine, isopropyl antipyrine, sulfinpyrazone, ketorolac, ketorolac tromethamine, SC-560, N- (5-amino-2-pyridinyl) -4- (trifluoromethyl) benzamide, Etanercept, adalimumab, infliximab, ustekinumab, secquinumab, tocilizumab, biaquinumab, rituximab, Lutrizumab pegol, chloroquine, tacrolimus, D-penicillamine, azathioprine, golimumab, cyclosporine, belimumab, inhibition of molecules involved in signal transduction (eg NF-κ, NF-κB, IKK-1, IKK-2, AP-1) Drugs (eg, dimethyl fumarate, dehydroxymethylepoxyquinomycin, DTCM-glutarimide, thalidomide, sesquiterpene lactone, resveratrol, curcumin, diindolylmethanenoscapine, parthenolide, bortezomib, ixazomib, carfilzomib, delanzomib, marizonib, MLN -4924, IMD-2560, IMD-0354, IMD-1041, BAY-11-7082, BAY-11-7085, MLN 120B, BMS-345 541, SC-5 4, PS-1145, denosumab, vorinostat, romidepsin, SN-50, T-5224), tofacitinib, fostamatinib, canakinumab, salilumab, valilatinib, pasitibita, ASP5094, ASP015K, TAK-020, ABT-494, cicumab, denosumab, ozolizumab, namilumab , Mabrilimumab, abatacept, atacicept, JTE-052, MT-1303, JTE-051, JTE-151, ibudilast, fingomolide, soluble interleukin-1 receptor antibody, anakinra, interleukin-10, interleukin 2 preparation, interleukin 12 formulations, biaquinumab, secquinumab (AIN-457), ixequizumab (LY-2439821), AMG 827, BMS-582949 TNF-.alpha. Vaccine, natalizumab, vedolizumab, efalizumab, MAPK inhibitor (e.g. SCI 0469, BIRB 796, SB 203 580, VX-702, parapimod, PH 797804, Bemurafenib, dabrafenib, trametinib, cobimetinib, CC-359, CC-930, Ventapi pimod, XG -104) Salicylic acid ointment, urea ointment, methotrexate, sodium thiomalate maleate, auranofin, penicillamine, bucilamine, lobezarito disodium, salazosulfapyridine, actarit, mizoribine, iglatimod, apremilast, roflumilast, AN2728, M5200, DRM02, RVT-051, OPA-15406, sodium cromoglycate, tranilast, repirinast, Nurexanone, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, ciclesonide, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, fexofenadine, Ketotifen fumarate, cetirizine hydrochloride, oxatomide, ebastine, epinastine hydrochloride, loratadine, tramadol, promethazine, hydroxyzine, homochlorcyclidine, cyproheptadine, mequitadine, emedastine fumarate, pseudoephedrine, bepotastine levocetizine besylate, hydrochloride Mycophenolate mofetil, daclizumab, galiximab, metformin hydrochloride, zidirizumab, aminopte Emissions, pazopanib hydrochloride, Fezakinumabu, Ruki warp Hee Brin salt, Ikusekizumabu, Guserukumabu, SLx-2119, PRX-167700, leflunomide, and the like. As another psoriasis treatment, preferably, it is tofacitinib or apremilast.

  The "other psoriasis therapeutic agent" in the pharmaceutical composition according to the present embodiment may be used alone or in combination of two or more.

<3. Pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which is administered in combination with one or more other therapeutic agents for psoriasis
Specifically, the pharmaceutical composition according to the present embodiment is
(I) A composition containing Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient, and a composition containing another psoriasis therapeutic agent as an active ingredient are administered simultaneously or at different times. Or a pharmaceutical composition characterized by
(Ii) It may be a pharmaceutical composition comprising Compound (I) or a pharmacologically acceptable salt thereof, and another therapeutic agent for psoriasis as an active ingredient.

  In the pharmaceutical composition of the above (i), a composition containing Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient, and a composition containing another therapeutic agent for psoriasis as an active ingredient Without limitation, the compositions described above can be administered simultaneously or at different times. In the pharmaceutical composition of the above (i), one of a composition containing Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient and a composition containing another therapeutic agent for psoriasis as an active ingredient is administered There is no limitation on the time from the administration to the administration of the other, but a certain period (for example, 1 week, preferably 2 or 3 days, more preferably 1 day, more preferably 1 week) during which one pharmacological effect remains Preferably the other within 2 to 6 hours, even more preferably 1 hour).

  Compound (I) or a pharmacologically acceptable salt thereof, and other psoriasis therapeutic agents, if necessary, an excipient, a lubricant, a binder, a disintegrant, a coating agent, a stabilizer, tonicity Agents, buffers, pH adjusters, solubilizers, thickeners, preservatives, antioxidants, sweeteners, coloring agents, flavors and the like can be added and used as a pharmaceutical composition. The pharmaceutical composition according to the present embodiment can be suitably prepared according to the purpose, for example, by a known method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations of Pharmacopoeia and the like.

  The content of the compound (I) or a pharmacologically acceptable salt thereof and the content of the other therapeutic agent for psoriasis in the pharmaceutical composition according to the present embodiment can be appropriately adjusted.

  The pharmaceutical composition according to the present embodiment is, for example, a preparation for oral administration such as a tablet, a capsule, a granule, a powder, an injection (for example, intravenous administration, subcutaneous administration, intramuscular administration, intraperitoneal administration), eye drops Formulations for parenteral administration such as nasal agents, nasal drops, suppositories, ointments, lotions, creams, gels, sprays, patches, inhalants, transdermal absorption preparations and combinations thereof, etc. (6) Revised Japanese Pharmacopoeia The dosage form described in the General Regulations of Preparation can be made.

  In the pharmaceutical composition according to this embodiment, compound (I) or a pharmacologically acceptable salt thereof, and other psoriasis therapeutic agent may be contained as active ingredients in different formulations, and both of them may be , May be contained as an active ingredient in a single preparation (compounding agent).

  Excipients include, for example, lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate and calcium hydrogen phosphate, and as lubricants, for example, stearic acid, magnesium stearate and talc It can be mentioned. Binders include, for example, starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone, and disintegrants include, for example, carboxymethyl cellulose, low substituted hydroxypropyl methylcellulose and calcium citrate. Coating agents include, for example, hydroxypropyl methylcellulose, macrogol and silicone resins, and stabilizers include, for example, ethyl parahydroxybenzoate and benzyl alcohol.

  Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like, and examples of the buffer include boric acid, borate, phosphoric acid, phosphate, citric acid, Citrate, acetic acid, acetate, ε-aminocaproic acid, trometamol and the like, and examples of pH adjusters include hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, Sodium hydrogen carbonate etc. are mentioned. Moreover, as a solubilizer, for example, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, Macrogol 4000, refined soybean lecithin, polyoxyethylene (160) polyoxypropylene (30) glycol etc. may be mentioned, and thickeners Examples of these include cellulose-based polymers such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and the like. Examples of the stabilizer include edetic acid, sodium edetate and the like, and examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate , Chlorobutanol and the like.

  Examples of components that may be contained in pharmaceutical compositions for transdermal administration, such as ointments, lotions, creams, gels, patches and sprays, include, for example, lauryl alcohol, myristyl alcohol, ethylene glycol salicylate, Absorption accelerators such as pyrothiodecane; fatty acid esters such as diisopropyl adipate, isopropyl myristate, cetyl lactate, myristyl lactate, isopropyl palmitate, diethyl sebacate, hexyl laurate, cetyl isooctanoate; cetyl alcohol, stearyl alcohol, oleyl alcohol, Aliphatic alcohols such as hexadecyl alcohol and behenyl alcohol; glycols such as propylene glycol, propylene diol, polyethylene glycol and dipropylene glycol; sorbitan fatty acid Surfactants such as sterol, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, etc. It can be mentioned.

  The dose of Compound (I) or a pharmacologically acceptable salt thereof, and the administration route of the other therapeutic agent for psoriasis, and the dose can be appropriately adjusted depending on the symptoms, age, dosage form and the like. For example, in the case of oral administration, each active ingredient can be generally administered at 0.01 to 2000 mg, preferably 1 to 500 mg per day, in one or several divided doses.

  In the case of an ointment, lotion, cream or gel, each active ingredient is generally 0.00001% (w / v) to 10% (w / v), preferably 0.001% (w) It can be administered once or in several divided doses adjusted to a concentration of / v) to 5% (w / v).

  Hereinafter, examples (examples 1 to 89), reference examples (reference examples 1 to 108), and test examples (test examples 1 to 6) of the compound according to the present embodiment or a pharmaceutically acceptable salt thereof will be described. Although the present invention will be described in more detail with reference to the drawings, these examples are for the purpose of better understanding the present invention and do not limit the scope of the present invention.

  In the silica gel column chromatography, DIOL silica gel refers to CHROMATOREX (trade name) DIOL MB 100-40 / 75 manufactured by Fuji Silysia Chemical.

  In the silica gel column chromatography, DNH silica gel refers to CHROMATOREX (trade name) DNH MB 100-40 / 75 manufactured by Fuji Silysia Chemical.

  When multiple mass spectrum values were observed due to the presence of isotopes, only the one with the lowest m / z was described. The mass spectrum ionization mode DUIS is a mixed mode of ESI and APCI.

¹ H-NMR is expressed as a chemical shift (δ) with tetramethylsilane as an internal standard (0 ppm) unless otherwise noted, and coupling constants (J value) are expressed in Hz. Moreover, the abbreviation of the division | segmentation pattern of each peak is as follows. s: singlet, d: doublet, t: triplet, q: quartet, br: broad.

The abbreviations described in the Examples and Reference Examples are generally used in the meaning generally used in the fields of organic chemistry and pharmacy. Each abbreviation is specifically understood by those skilled in the art as follows.
ATP: adenosine triphosphate Boc: tert-butyloxycarbonyl Cbz: benzyloxycarbonyl DIPEA: N, N-diisopropylethylamine DMF: N, N-dimethylformamide DMSO: dimethylsulfoxide DTT: dithiothreitol Et: ethyl FBS: fetal bovine Serum HEPES: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid MBP: myelin base protein n-: normal NADPH: nicotinamide adenine dinucleotide phosphate PBMC: peripheral blood mononuclear cells PBS: phosphate buffered chloride Aqueous sodium solution TBME: tert-butyl methyl ether TBS: tert-butyldimethylsilyl tert-: tertiary THF: tetrahydrofuran Tris: trishydroxyaminomethane

Example 1
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-18)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 synthesized in the same manner as in Reference Example 3. 0.23 ml (1.4 mmol) of DIPEA and 472 mg (3.44 mmol) of (S)-(+)-2-phenylglycinol were added at room temperature to a solution of 308 mg (0.698 mmol) of (4H) -carboxylate in 6 ml of THF. Thereafter, it was subjected to a microwave reactor and reacted at 80 ° C. for 1 hour. Next, 2.7 ml (67 mmol) of methanol and 2.7 ml (19 mmol) of triethylamine were added to the reaction solution, and the mixture was subjected to a microwave reaction apparatus and reacted at 80 ° C. for 0.5 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired substance is reduced in pressure. Concentrated. The obtained concentrated residue was crystallized with ethyl acetate / diethyl ether, and the obtained solid was collected by filtration. To the obtained solid was added 20 ml of water and the mixture was stirred, and then the insoluble matter was filtered and dried under reduced pressure to obtain 152 mg (yield 46%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 470 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.65 (br s, total 1 H), 9.66-9.46 (m, 1 H), 7.41-7.25 (m, 4 H), 7.22-7.15 (m, 1H), 6.18 & 6.06 (d, J = 7.7 Hz, total 1H), 4.88 (t, J = 5.9 Hz, 1H), 4.83-4.71 (m, 1H), 4.62-4.41 (m, 2H), 3.69- 3.52 (m, 2H), 2.49-2.41 (m, 2H), 2.30-2.12 (m, 2H), 1.93-1.73 (m, 2H), 1.68-1.44 (m, 6H), 0.17-0.04 (m, 9H) ).

(Example 2)
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide (compound number III-11)

Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxy synthesized in the same manner as in Reference Example 7 Under a nitrogen atmosphere, 0.90 ml (5.2 mmol) of DIPEA is added at room temperature to a solution of 433 mg (1.08 mmol) of hydrochloric acid hydrochloride in dehydrated dichloromethane and then 275 mg (0.928 mmol) of bis (trichloromethyl) carbonate is added. A solution of 2.5 ml of dehydrated dichloromethane was added dropwise at -78 ° C and stirred at the same temperature for 2.5 hours.
After completion of the reaction, 10 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the solution was stirred while warming up to room temperature. After separating the organic and aqueous layers, the aqueous layer was extracted twice with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90:10 to 80:20 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure The residue obtained was concentrated.
After adding 0.40 ml (2.2 mmol) of DIPEA and 528 mg (3.85 mmol) of (S)-(+)-2-phenylglycinol under nitrogen atmosphere to a solution of 457 mg of the concentrated residue obtained above at room temperature under a nitrogen atmosphere The mixture was stirred for 3.75 hours while heating to reflux. Subsequently, after adding triethylamine 0.90 ml (6.5 mmol) and methanol 0.90 ml (22 mmol) to a reaction liquid, it stirred for 1 hour, making it heat-reflux.
After completion of the reaction, water was added to the reaction solution, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 97: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue is crystallized with ethyl acetate / diisopropyl ether / n-hexane, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 388 mg of the title compound (yield 79% [2 steps]) were obtained as a white solid.
Mass spectrum (CI, m / z): 456 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.02 & 11.54 (br s, total 1 H), 9.44 & 9.25 (br s, total 1 H), 7.40-7.33 (m, 2 H), 7.33-7.24 (m , 2H), 7.23-7.16 (m, 1H), 5.88-5.69 (m, 1H), 4.86-4.79 (m, 1H), 4.61 (t, J = 5.6 Hz, 1H), 4.55-4.37 (m, 2H) ), 3.71-3.64 (m, 2H), 1.63 (s, 3H), 1.57 (s, 3H), 1.08-1.01 (m, 2H), 0.83-0.60 (m, 2H), 0.07 (s, 9H).

(Example 3)
(S) -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamide] -4,6-dihydropyrrolo [3,4- c] pyrazol-5 (1H) -carboxamide (compound No. II-13)

5-tert-butyl 1-ethyl 6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamido] pyrrolo [3,4-c] pyrazole-1, synthesized in the same manner as in Reference Example 9. Under a nitrogen atmosphere, 0.25 ml (2.2 mmol) of 2,6-lutidine and 0.39 ml of trimethylsilyl trifluoromethanesulfonate were added to a solution of 337 mg (0.714 mmol) of 5 (4H, 6H) -dicarboxylate in 3 ml of dehydrated dichloromethane. 2.2 mmol) was sequentially added at 0 ° C., and stirred at the same temperature for 1.5 hours.
After completion of the reaction, the reaction solution was diluted with dichloromethane and then washed with saturated aqueous sodium hydrogen carbonate solution. After separating the organic and aqueous layers, the aqueous layer was extracted twice with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. After 25 ml of toluene was added to the obtained concentrated residue and the operation of concentration under reduced pressure was repeated three times, followed by drying under reduced pressure to obtain a concentrated residue.
After adding 0.38 ml (2.2 mmol) of DIPEA at room temperature to a solution of 292 mg of the concentrated residue thus obtained in 5 ml of dehydrated dichloromethane at room temperature under a nitrogen atmosphere, 149 mg (0.502 mmol) of bis (trichloromethyl) carbonate is added at -78.degree. The mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, 7 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was stirred while warming up to room temperature. After separating the organic and aqueous layers, the aqueous layer was extracted once with dichloromethane. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 85:15 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure The residue obtained was concentrated.
After adding 0.27 ml (1.6 mmol) of DIPEA and 255 mg (1.86 mmol) of (S)-(+)-2-phenylglycinol under nitrogen atmosphere to a solution of 262 mg of the obtained concentrated residue in 3 ml of dehydrated THF at room temperature The mixture was stirred for 2.5 hours while heating to reflux. Next, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution, and the mixture was stirred for 5.5 hours while heating under reflux.
After completion of the reaction, water was added to the reaction solution, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 0.10 ml of acetic acid is added to the obtained concentrated residue, and the resultant is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 97: 3 (V / V)) to obtain the desired product. The fractions containing were concentrated under reduced pressure. The obtained concentrated residue is crystallized with ethyl acetate / n-hexane, and the obtained solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give the title compound 206 mg (yield 63%) [Step 3] was obtained as a pale yellow solid.
Mass spectrum (CI, m / z): 458 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.25 & 11.64 (br s, total 1 H), 9.42-9.11 (m, 1 H), 7.38-7.25 (m, 4 H), 7.23-7.15 (m, 1H), 6.21-6.05 (m, 1H), 4.87 (t, J = 5.9 Hz, 1H), 4.81-4.73 (m, 1H), 4.57-4.41 (m, 2H), 3.70-3.54 (m, 2H) , 1.66-1.47 (m, 6 H), 1.25 (s, 6 H), 0.04 (s, 9 H).

(Example 4)
(S) -3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-20)

Ethyl 5- (chlorocarbonyl) -3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] synthesized in the same manner as in Reference Example 13. A solution of 454 mg (0.997 mmol) of pyrazole-2 (4H) -carboxylate in 10 ml of dehydrated THF under an argon atmosphere, 700 mg (5.10 mmol) of (S)-(+)-2-phenylglycinol, 0.35 ml (2) of DIPEA .0 mmol) was added at room temperature and then stirred at 60.degree. C. for 4 hours. Then, 6 ml of methanol and 2 ml of triethylamine were added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained concentrated residue, and the mixture was extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired substance is reduced in pressure. Concentrated. The concentrated residue was crystallized with dichloromethane / diisopropyl ether, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 404 mg (yield 84%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 484 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.66 (br s, total 1 H), 9.64-9.47 (m, 1 H), 7.40-7.14 (m, 5 H), 6.26-6.01 (m, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.83-4.71 (m, 1H), 4.60-4.43 (m, 2H), 3.66-3.54 (m, 2H), 2.48-2.42 (m, 2H) , 2.33-2.14 (m, 2 H), 1. 93-1.72 (m, 2 H), 1. 67-1. 45 (m, 6 H), 0.92 (t, J = 7.9 Hz, 3 H), 0.60 (q, J = 7.9 Hz, 2 H) ), 0.08 (s, 6 H).

(Example 5)
(S) -3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -N- (2-hydroxy-1-phenylethyl) -6,6-dimethyl-4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide (compound number II-14)

Ethyl 3- [2- (ethyldimethylsilyl) -2-methylpropanamido] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] pyrazole-1 synthesized in the same manner as in Reference Example 16 To a solution of 2.44 g (6.41 mmol) of (4H) -carboxylate in 30 ml of dehydrated dichloromethane under a nitrogen atmosphere, 5.6 ml (32 mmol) of DIPEA, 1.33 g (4.48 mmol) of bis (trichloromethyl) carbonate, 10 ml of dehydrated dichloromethane The solution was added sequentially at -78 ° C and stirred at the same temperature for 1 hour.
After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred and heated up to room temperature. After separation, the aqueous layer was extracted with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 70:30 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. , 2.51 g of concentrated residue was obtained.
Under argon atmosphere, 700 mg (5.10 mmol) of (S) -2-amino-2-phenylethanol and 0.35 ml (2.0 mmol) of DIPEA are added to a solution of 474 mg of the obtained concentrated residue under dry atmosphere at room temperature, The mixture was subjected to a microwave reaction and reacted at 100 ° C. for 2 hours. After leaving to cool, 6 ml of methanol and 2 ml of triethylamine were added, and the mixture was subjected to a microwave reaction and reacted at 80 ° C. for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained concentrated residue, and the mixture was extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired substance is reduced in pressure. Concentrated. The concentrated residue was crystallized with dichloromethane / diisopropyl ether, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 321 mg of the title compound (yield 56% [2 steps]) as a white solid.
Mass spectrum (DUIS, m / z): 472 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.26 & 11.67 (br s, total 1 H), 9.42-9.16 (m, 1 H), 7.38-7.25 (m, 4 H), 7.25-7.14 (m, 1H), 6.20-6.04 (m, 1H), 4.88 (t, J = 5.8 Hz, 1H), 4.82-4.72 (m, 1H), 4.55-4.42 (m, 2H), 3.66-3.55 (m, 2H) , 1.64-1.48 (m, 6 H), 1. 26 (s, 6 H), 0.90 (t, J = 7.9 Hz, 3 H), 0.56 (q, J = 7.9 Hz, 2 H), 0.02 (s, 6 H).

(Example 6)
(S) -2-[(2-methoxypropan-2-yl) oxy] -1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazol-5 (1H) -carboxylate (Compound No. VI-100)

5-tert-butyl 1-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-1,5 (4H, 5) synthesized in the same manner as in Reference Example 4. Crude ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo obtained by the same reaction as Reference Example 5 from 225 mg (0.470 mmol) of 6H) -dicarboxylate (S) -2,5-dioxopyrrolidine-1 synthesized in the same manner as in Reference Example 18 with [3,4-c] pyrazole-1 (4H) -carboxylate [containing impurities] in a nitrogen atmosphere. -Yl {2-[(2-methoxypropan-2-yl) oxy] -1-phenylethyl} carbonate 187 mg (0.533 mmo A solution of l) in 3 ml of THF, 0.28 ml (1.6 mmol) of DIPEA was added at room temperature and stirred at the same temperature for 15 hours. Next, 1.0 ml (7.2 mmol) of triethylamine and 0.70 ml (17 mmol) of methanol are added to the reaction solution, and the mixture is stirred at room temperature for 4.5 hours while heating under reflux for 2 hours, and then the reaction solution (S) -2 -Amino-2-phenylethanol 247 mg (1.80 mmol) was added, and it stirred for 4.5 hours, making it heat-reflux.
After completion of the reaction, water was added to the reaction solution, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue is crystallized with ethyl acetate / n-hexane, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 22.7 mg of the title compound (yield 9). % [2 steps]) was obtained as a white solid. The filtrate was further concentrated under reduced pressure and dried under reduced pressure to obtain 178 mg of the title compound (yield: 70% [2 steps]) as a white foam.
Mass spectrum (ESI, m / z): 565 [M + 23 (Na)] ⁺ , 541 [M-1] ^- .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.35-12.19 & 11.96-11.80 (m, total 1 H), 9.85-9.44 (m, 1 H), 7.45-7.26 (m, 5 H), 5.81-5.68 (m, 1H), 4.63-4.18 (m, 2H), 3.72-3.50 (m, 2H), 3.08-2.94 (m, 3H), 2.56-2.38 (m, 2H), 2.30-2.10 (m, 2H) , 1.94-1.75 (m, 2H), 1.73-1.45 (m, 6H), 1.32-1.18 (m, 6H), 0.13-0.02 (m, 9H).

(Example 7)
(S) -2-hydroxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate (Compound No. IV-1)

(S) -2-[(2-Methoxypropan-2-yl) oxy] -1-phenylethyl synthesized in the same manner as in Example 6 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] A solution of 175 mg (0.322 mmol) of 4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate in 2.5 ml of methanol under a nitrogen atmosphere, 9.6 mg of pyridinium p-toluenesulfonate (0.038 mmol) was added at 0 ° C. and stirred at the same temperature for 70 minutes.
After completion of the reaction, 0.1 ml of triethylamine was added to the reaction solution and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 65:35 to 25:75 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue is crystallized with ethyl acetate / n-hexane, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 124 mg of the title compound (yield 82%) Was obtained as a white solid.
Mass spectrum (CI, m / z): 471 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.35-12.11 & 11.97-11.79 (m, total 1 H), 9.84-9.46 (m, 1 H), 7.46-7.20 (m, 5 H), 5.71-5.58 (m, 1H), 5.12-4.95 (m, 1H), 4.72-4.18 (m, 2H), 3.80-3.54 (m, 2H), 2.60-2.38 (m, 2H), 2.30-2.10 (m, 2H) , 1.93-1.74 (m, 2 H), 1. 74-1.4 3 (m, 6 H), 0.16-0.02 (m, 9 H).

(Example 8)
2-Methoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate ( Compound No. III-3)

Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxy synthesized in the same manner as in Reference Example 7 To a solution of 2.15 g (5.36 mmol) of hydrochloride in 72 ml of dehydrated dichloromethane at room temperature is added 3.6 ml (21 mmol) of DIPEA at room temperature and then cooling in a dry ice / acetone refrigerant, 1.17 g of bis (trichloromethyl) carbonate A solution of (3.94 mmol) in 12 ml of dehydrated dichloromethane was added dropwise over 30 minutes, and stirred at the same temperature for 6 hours. At this time, 3.6 ml (21 mmol) of DIPEA and 1 time of DIPEA (1.0 ml, 5.7 mmol) were sequentially added in the middle of the reaction.
After completion of the reaction, 46 ml of a saturated aqueous solution of sodium hydrogen carbonate was added at -78 ° C, and the temperature was raised to room temperature as a matter of course. After separation of the reaction solution, the aqueous layer was extracted twice with 50 ml of dichloromethane, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 78: 22 to 57: 43 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. 20 ml of n-hexane was added to the concentration residue, and after ice cooling, the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1.96 g of a white solid.
In 40.4 mg (0.0946 mmol) of the obtained white solid, 2-methoxy-1-phenylethanol [synthesized according to the method described in WO 2012/138648] 224 mg (1.48 mmol), potassium carbonate 26 .0 mg (0.188 mmol), 0.8 ml of 1,2-dimethoxyethane, and 80 mg of molecular sieve 4A (powder) were added at room temperature, followed by stirring at 80 ° C. for 26 hours.
After completion of the reaction, insolubles were filtered, and 10 ml of ethyl acetate, 5 ml of water and 5 ml of a saturated aqueous solution of sodium chloride were added to the filtrate, and then separated. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue thus obtained was subjected to 4 times silica gel column chromatography (silica gel (first time), elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 93: 7 (V / V): silica gel (second time), Elution solvent: ethyl acetate: methanol = 98: 2 to 95: 5 (V / V): silica gel (third time), elution solvent: 1,2-dichloroethane: methanol = 98: 2 to 95: 5 (V / V) : DNH silica gel, elution solvent: 1,2-dichloroethane: methanol = 98: 2 to 95: 5 (V / V), and preparative HPLC (column; X-Bridge (trade name) ODS, elution solvent; 0 The fraction containing the target substance was subjected to concentration under reduced pressure after being neutralized with dilute aqueous ammonia and then subjected to a 1% aqueous solution of formic acid: 0.1% formic acid: acetonitrile = 50: 50 to 5: 95 (V / V)). . The obtained concentrated residue was dissolved in acetonitrile and water, and then lyophilized to obtain 4.1 mg of the title compound (yield 8% [2 steps]) as a white foam.
Mass spectrum (DUIS, m / z): 471 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.40-11.86 (m, 1 H), 10.11-9.61 (m, 1 H), 7.49-7.22 (m, 5 H), 5.90-5.71 (m, 1 H) , 4.63-4.14 (m, 2H), 3.77-3.51 (m, 2H), 3.30-3.29 (m, 3H), 1.78-1.40 (m, 6H), 1.11-0.92 (m, 2H), 0.81-0.59 ( m, 2H), 0.11--0.04 (m, 9H).

(Example 9)
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-49)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. (R) -3-amino-3-phenylpropan-1-ol [Ark Pharm, Inc.] under argon atmosphere in a solution of 216 mg (0.489 mmol) of 2 (4H) -carboxylate in 4.5 ml of 1,4-dioxane . After adding 379 mg (2.51 mmol) and 0.17 ml (0.99 mmol) of DIPEA at room temperature, the mixture was subjected to a microwave reaction apparatus and reacted at 100 ° C. for 1 hour. After cooling, 1.0 ml of methanol and 0.5 ml of triethylamine were added, and the mixture was subjected to a microwave reaction and allowed to react at 80 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and ethyl acetate, water and a saturated aqueous sodium chloride solution were added to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 99: 1 to 96: 4 (V / V)), and the fraction containing the desired substance is reduced in pressure Concentrated. The obtained concentrated residue was crystallized with ethyl acetate / diisopropyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 173 mg (yield 73%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 484 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.19 & 11.66 (s, total 1 H), 9.61-9.47 (m, 1 H), 7.39-7.13 (m, 5 H), 6.46 & 6.38 (d, J = 8.0 Hz, total 1H), 4.92-4.83 (m, 1H), 4.66-4.33 (m, 3H), 3.46-3.34 (m, 2H), 2.50-2.41 (m, 2H), 2.26-2.13 (m, 2) 2H), 2.01-1.72 (m, 4H), 1.65-1.47 (m, 6H), 0.12-0.06 (m, 9H).

(Example 10)
(R) -N- (3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide (compound number III-17)

Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxy synthesized in the same manner as in Reference Example 7 After adding 0.72 ml (4.1 mmol) of DIPEA at room temperature to a solution of 468 mg (1.17 mmol) of hydrochloride in 10 ml of dehydrated dichloromethane at room temperature, 235 mg (0.791 mmol) of bis (trichloromethyl) carbonate is added. Add at ° C and stir at the same temperature for 3 hours.
After completion of the reaction, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred while warming up to room temperature. After separating the organic and aqueous layers, the aqueous layer was extracted twice with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 75:25 (V / V)) to give ethyl 5- (chlorocarbonyl) -6,6- Dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate by concentration under reduced pressure and drying under reduced pressure 490 mg of concentrated residue was obtained.
Under a nitrogen atmosphere, 0.14 ml (0.80 mmol) of DIPEA, (R) -3-amino-3-phenylpropan-1-ol [Ark Pharm, Inc.] was added to a solution of 113 mg of the obtained concentration residue in 2 ml of dehydrated THF. After the addition of 105 mg (0.692 mmol) at room temperature, the mixture was stirred for 2.5 hours while heating to reflux. Next, 0.10 ml (1.7 mmol) of 2-aminoethanol was added, and the mixture was stirred for 2 hours while heating to reflux.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 0.1 ml of acetic acid is added to the obtained concentrated residue, and the resultant is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 15:85 (V / V)), The fractions containing the desired product were concentrated under reduced pressure. The obtained concentrated residue was again subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 99: 1 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The resulting concentrated residue is crystallized with ethyl acetate / n-hexane, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 49 mg of the title compound (yield 39%) Two steps were obtained as a white solid.
Mass spectrum (CI, m / z): 470 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.22 & 11.84 (br s, total 1 H), 9.91-9.66 (m, 1 H), 7.37-7.26 (m, 4 H), 7.21-7.14 (m, 1H), 6.50-6.28 (m, 1H), 4.92-4.80 (m, 1H), 4.65-4.52 (m, 1H), 4.49-4.31 (m, 2H), 3.44-3.36 (m, 2H), 2.00- 1.77 (m, 2H), 1.59 (br s, 3H), 1.51 (br s, 3H), 1.06-0.93 (m, 2H), 0.81-0.61 (m, 2H), 0.03 (s, 9H).

(Example 11)
(R) -N- (4-hydroxy-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-64)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 100 mg (0.227 mmol) of 2 (4H) -carboxylate, (R) -4-amino-4-phenylbutan-1-ol hydrochloride [NetChem, Inc. Under argon atmosphere, 0.24 ml (1.4 mmol) of DIPEA was added at room temperature and stirred at 100 ° C. for 3 hours. Then, 1 ml of triethylamine and 1 ml of ethanol were added to the reaction solution, and the mixture was heated and stirred at 80 ° C. for 5 hours.
After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50-0: 100 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, Drying under reduced pressure gave 91.3 mg (yield 81%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 498 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.18 & 11.73 (s, total 1 H), 9.66-9.40 (m, 1 H), 7.38-7.33 (m, 2 H), 7.33-7.26 (m, 2 H) ), 7.21-7.13 (m, 1H), 6.43-6.16 (m, 1H), 4.75-4.66 (m, 1H), 4.47 (br s, 2H), 4.38 (t, J = 5.2 Hz, 1H), 3.45 -3.35 (m, 2H), 2.49-2.42 (m, 2H), 2.25-2.14 (m, 2H), 1.88-1.64 (m, 4H), 1.60 (br s, 3H), 1.55-1.28 (m, 5H) ), 0.09 (s, 9H).

(Example 12)
(R) -N- (5-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-67)

A solution of 9.50 ml (9.50 mmol) of 1 M lithium aluminum hydride / THF solution in 40 ml of dehydrated THF was stirred under an argon atmosphere and (R) -ethyl 5-[(tert-butoxycarbonyl) amino] -5-phenylpentane. Noato [Tetrahedron Lett. , 1998, 39, 5951-5954. A solution of 2.02 g (6.28 mmol) in 20 ml of dehydrated THF was dropped at 0 ° C., and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, 50 ml of THF was added, 0.4 ml of water and 1.6 ml (1.6 mmol) of 1N aqueous solution of sodium hydroxide were added, and the mixture was stirred at the same temperature for 30 minutes. The precipitated solid was filtered using a celite filter, and the solid was washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Under argon atmosphere, 2 ml of trifluoroacetic acid was added at room temperature to a solution of 1.68 g of the obtained concentrated residue 1.68 g in dichloromethane, and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain 1.35 g of concentrated residue.
After adding 0.60 ml (3.4 mmol) of DIPEA while stirring under an argon atmosphere to a solution of 905 mg of the resulting concentrated residue in 3 ml of dehydrated THF, ethyl 5- (chlorocarbonyl) -6 synthesized in the same manner as in Reference Example 3 6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 205 mg (0.465 mmol) is added at room temperature, 60 Stir for 4 hours at ° C. Next, 0.5 ml of triethylamine and 1 ml of methanol were added to the reaction solution, and the mixture was heated and stirred at 60 ° C. for 3 hours, and then stirred at room temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The concentrated residue thus obtained was subjected to silica gel chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired substance was concentrated under reduced pressure and dried under reduced pressure . The resulting concentrated residue is further subjected to silica gel chromatography (DNH silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 93: 7 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure did. The resulting concentrated residue is subjected to silica gel chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30-0: 100 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, Drying under reduced pressure gave 131 mg (yield 55%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 512 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.18 & 11.64 (br s, total 1 H), 9.58-9.47 (m, 1 H), 7.38-7.33 (m, 2 H), 7.32-7.25 (m, 2H), 7.21-7.14 (m, 1H), 6.38-6.15 (m, 1H), 4.75-4.65 (m, 1H), 4.52-4.38 (m, 2H), 4.33 (t, J = 5.2 Hz, 1H) , 3.39-3.33 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.14 (m, 2H), 1.88-1.72 (m, 3H), 1.72-1.30 (m, 10H), 1.27-1.14 ( m, 1 H), 0.13-0.06 (m, 9 H).

(Example 13)
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazol-5 (1H) -carboxamide (compound No. IV-34)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 0.16 ml (0.92 mmol) of DIPEA and (S) -1-amino-2-methyl-1-phenylpropane-2 in a solution of 200 mg (0.454 mmol) of 2 (4H) -carboxylate in 3 ml of dehydrated THF under an argon atmosphere -All [purchased from IS Chemical Technology] 385 mg (2.33 mmol) was added at room temperature and stirred at 60 ° C for 4 hours. Then, 1 ml of methanol and 1 ml of triethylamine were added at room temperature and stirred at the same temperature for 15 hours.
After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue thus obtained was subjected to silica gel chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired substance was concentrated under reduced pressure and dried under reduced pressure . The resulting concentrated residue is again subjected to silica gel chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 182 mg (yield 81%) of the title compound was obtained as a white solid.
Mass spectrum (DUIS, m / z): 498 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.22 & 11.78 (br s, total 1 H), 9.74-9.49 (m, 1 H), 7.38-7.16 (m, 5 H), 5.90-5.74 (m, 5) 1H), 4.85 (s, 1H), 4.65-4.35 (m, 3H), 2.49-2.41 (m, 2H), 2.28-2.15 (m, 2H), 1.91-1.73 (m, 2H), 1.67-1.44 ( m, 6H), 1.22 (s, 3H), 0.91 (s, 3H), 0.09 (s, 9H).

(Example 14)
(S) -N- (2-hydroxy-2-methyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide (compound number III-14)

Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxy synthesized in the same manner as in Reference Example 7 After adding 0.72 ml (4.1 mmol) of DIPEA at room temperature to a solution of 468 mg (1.17 mmol) of hydrochloride in 10 ml of dehydrated dichloromethane at room temperature, 235 mg (0.791 mmol) of bis (trichloromethyl) carbonate is added. Add at ° C and stir at the same temperature for 3 hours.
After completion of the reaction, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred while warming up to room temperature. After separating the organic and aqueous layers, the aqueous layer was extracted twice with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 75:25 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure By doing this, 490 mg of concentrated residue was obtained.
In a nitrogen atmosphere, 0.14 ml (0.80 mmol) of DIPEA, (S) -1-amino-2-methyl-1-phenylpropan-2-ol [from IS Chemical Technology] was added to a solution of 112 mg of the obtained concentration residue in 2 ml of dehydrated THF. Purchase] 109 mg (0.660 mmol) was sequentially added at room temperature, and the mixture was stirred for 3 hours while heating to reflux. Next, 0.10 ml (1.7 mmol) of 2-aminoethanol was added, and the mixture was stirred for 2.5 hours while heating to reflux.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 0.1 ml of acetic acid is added to the obtained concentrated residue, and the resultant is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 20:80 (V / V)), The fractions containing the desired product were concentrated under reduced pressure. The resulting concentrated residue is crystallized with ethyl acetate / n-hexane, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 100 mg of the title compound (yield 77% [yield Two steps] was obtained as a white solid.
Mass spectrum (CI, m / z): 484 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.24 & 11.90 (br s, total 1 H), 10.02-9.68 (m, 1 H), 7.38-7.16 (m, 5 H), 5.89-5.71 (m, 5) 1H), 4.82 (s, 1H), 4.59 (d, J = 8.4 Hz, 1H), 4.56-4.31 (m, 2H), 1.66-1.43 (m, 6H), 1.21 (s, 3H), 1.06-0.97 (m, 2H), 0.91 (s, 3H), 0.81-0.61 (m, 2H), 0.04 (s, 9H).

(Example 15)
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-85)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 152 mg (0.346 mmol) of 2 (4H) -carboxylate, 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [Synthetic Communications 1994, 24 (7), 899-906. After adding 0.18 ml (1.0 mmol) of DIPEA at room temperature to a solution of 201 mg (1.12 mmol) in 1,4-dioxane at room temperature, the resultant is subjected to a microwave reaction apparatus. It reacted at 100 ° C. for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentrated residue, and the mixture was stirred at room temperature for 15 hours.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, and the obtained concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 99: 1 to 97: 3 (V / V)). The fractions containing the desired product were concentrated under reduced pressure. The concentrated residue thus obtained is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 99: 1 to 92: 8 (V / V)) to obtain a fraction containing the desired substance. It concentrated under reduced pressure. The obtained concentrated residue was crystallized with dichloromethane / n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 55 mg (yield 31%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 512 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.95 (br s, total 1 H), 9.89-9.36 (m, 1 H), 7.36-7.17 (m, 5 H), 6.85 (d, J = 8.1 Hz, 1 H), 5. 50-5. 39 (m, 1 H), 4. 64 (d, J = 8.1 Hz, 1 H), 4. 47-4. 28 (m, 2 H), 3. 30-3.22 (m, 1 H), 3.0 3 (dd, J = 4.1, 10.4 Hz, 1H), 2.49-2.40 (m, 2H), 2.28-2.13 (m, 2H), 1. 92-1.71 (m, 2H), 1.60 (br s, 3H), 1.53 (s, 3H) , 1.06 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).

(Example 16)
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazol-5 (1H) -carboxamide (compound No. IV-70)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 132 mg (0.300 mmol) of 2 (4H) -carboxylate, 155 mg (0.865 mmol) of (R) -4-amino-2-methyl-4-phenylbutan-2-ol synthesized as described in Reference Example 21 After adding 0.15 ml (0.86 mmol) of DIPEA at room temperature under argon atmosphere to a solution of 1,4-dioxane 4 ml, the mixture was stirred at 100 ° C. for 2 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentrated residue, and the mixture was stirred at room temperature for 18 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and ethyl acetate, water, and a saturated aqueous sodium chloride solution were added to the obtained concentrated residue, and then separated. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 98: 2 to 91: 9 (V / V)), and the fraction containing the desired product is reduced in pressure Concentrated. The obtained concentration was crystallized with dichloromethane / diethyl ether / n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 104 mg (yield 68%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 512 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.73 (br s, 1 H), 9.66-9.40 (m, 1 H), 7.37-7.25 (m, 4 H), 7.19-7.13 (m, 1 H) ), 6.54 (d, J = 5.3 Hz, 1 H), 4. 95-4. 84 (m, 1 H), 4. 75-4.57 (m, 1 H), 4. 45 (br s, 2 H), 2. 47-2.42 (m, 2 H), 2. 25 -2.14 (m, 2H), 2.02-1.74 (m, 3H), 1.65 (dd, J = 3.3, 14.3 Hz, 1H), 1.58 (s, 3H), 1.53 (s, 3H), 1.16 (s, 3H) ), 1.13 (s, 3 H), 0.09 (s, 9 H).

(Example 17)
(S) -N- (2-methoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-21)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. In a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 4.5 ml of 1,4-dioxane, 0.16 ml (0.91 mmol) of DIPEA, (S) -2-methoxy-1-phenylamine [J. Chem. Soc. , Perkin Transactions 1, 2002, 20, 2237-2242. Synthesis was carried out according to the method described in [1.] After adding 213 mg (1.41 mmol) at room temperature, it was subjected to a microwave reaction apparatus and reacted at 100 ° C. for 1 hour. Then, 1 ml of methanol and 0.5 ml of triethylamine were added, and the mixture was reacted again at 80 ° C. for 1 hour in the microwave reactor.
After completion of the reaction, 8 ml of ethyl acetate, 0.4 ml of water and 8 ml of a saturated aqueous sodium chloride solution were added to the reaction mixture, and the phases were separated, and the aqueous layer was extracted with 10 ml of dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product is reduced in pressure Concentrated. Diethyl ether was added to the obtained concentrated residue, and the mixture was sonicated, and the precipitated insoluble matter was collected by filtration and dried under reduced pressure to obtain 180 mg (yield 82%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 484 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.67 (br s, total 1 H), 9.68-9.41 (m, 1 H), 7.41-7.35 (m, 2 H), 7.34-7.27 (m, 2H), 7.25-7.17 (m, 1H), 6.44-6.13 (m, 1H), 5.02-4.92 (m, 1H), 4.57-4.39 (m, 2H), 3.63 (dd, J = 7.9, 9.9 Hz, 1H), 3.50 (dd, J = 6.0, 9.9 Hz, 1H), 3.26 (s, 3H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.92-1.73 (m, 2H) , 1.60 (br s, 3 H), 1.53 (br s, 3 H), 0.09 (s, 9 H).

(Example 18)
(S) -N- [2- (Difluoromethoxy) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c ] Pyrazole-5 (1H) -carboxamide (Compound No. IV-23)

210 mg (0.697 mmol) of (S) -2- (difluoromethoxy) -1-phenylethanamine trifluoroacetate salt synthesized in the same manner as in Reference Example 23 and 0.425 ml (2.43 mmol) of dehydrated DIPEA Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo synthesized in the same manner as in Reference Example 3 in a solution of 3 ml of dioxane under an argon atmosphere. 107 mg (0.243 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate was added at room temperature, and the mixture was heated and stirred at 100 ° C. for 1 hour. Then, 1 ml of triethylamine and 1 ml of methanol were added to the reaction solution, and the mixture was heated and stirred at 80 ° C. for 1 hour.
After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50-0: 100 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, Drying under reduced pressure gave 40.5 mg (yield 32%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 520 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 (br s, 1 H), 10.12-9.41 (m, 1 H), 7.43-7.38 (m, 2 H), 7.38-7.32 (m, 2 H), 7.28-7.23 (m, 1H), 6.70 (t, J = 76.0 Hz, 1H), 6.59-6.46 (m, 1H), 5.10-5.01 (m, 1H), 4.52-4.43 (m, 2H), 4.13 (m, 1H) dd, J = 8.3, 10.4 Hz, 1 H), 4.05-3.99 (m, 1 H), 2. 48-2.42 (m, 2 H), 2. 24-2. 15 (m, 2 H), 1. 88-1. 75 (m, 2 H), 1. 60 (1. s, 3H), 1.53 (s, 3H), 0.09 (s, 9H).

(Example 19)
(S) -N- (2-Ethoxy-1-phenylethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-25)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. A solution of 136 mg (0.308 mmol) of 2 (4H) -carboxylate and 162 mg (0.979 mmol) of (S) -2-ethoxy-1-phenylethanamine synthesized as in Reference Example 24 in 4 ml of 1,4-dioxane Under argon atmosphere, 0.16 ml (0.92 mmol) of DIPEA was added at room temperature and then stirred at 100 ° C. for 2 hours. After allowing to cool, 4 ml of methanol and 1 ml of triethylamine were added to the concentrated residue obtained by concentrating the reaction solution under reduced pressure, and the mixture was subjected to a microwave reaction apparatus and reacted at 80 ° C. for 1 hour.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, ethyl acetate is added to the obtained concentrated residue, and the solution is washed successively with 10% aqueous potassium dihydrogenphosphate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 98: 2 to 91: 9 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure did. The resulting concentrated residue was crystallized with dichloromethane / diethyl ether / n-hexane, and the precipitated solid was collected by filtration. The obtained solid is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 93: 7 (V / V)), and the fraction containing the desired product is reduced in pressure Concentrated. The resulting concentrated residue is subjected again to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 67:33 (V / V)), and the fraction containing the desired product The solution was concentrated under vacuum Diethyl ether and n-hexane were added to the obtained concentrated residue, and after ultrasonication, the precipitated solid was collected by filtration and dried under reduced pressure to obtain 81 mg (yield 53%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 498 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.71 (br s, total 1 H), 9.67-9.47 (m, 1 H), 7.41-7.34 (m, 2 H), 7.34-7.27 (m, 2H), 7.25-7.17 (m, 1H), 6.38-6.11 (m, 1H), 4.99-4.91 (m, 1H), 4.56-4.38 (m, 2H), 3.65 (dd, J = 8.0, 9.9 Hz, 1H), 3.54 (dd, J = 6.0, 9.9 Hz, 1H), 3.51-3.41 (m, 2H), 2.49-2.41 (m, 2H), 2.28-2.14 (m, 2H), 1.91-1.71 (m, 2) 2H), 1.61 (br s, 3H), 1.54 (br s, 3H), 1.08 (t, J = 7.0 Hz, 3H), 0.09 (s, 9H).

Example 20
(R) -N- (3-methoxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-51)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 138 mg (0.314 mmol) of 2 (4H) -carboxylate, and 163 mg (0.987 mmol) of (R) -3-methoxy-1-phenylpropan-1-amine synthesized in the same manner as in Reference Example 1; After 0.16 ml (0.92 mmol) of DIPEA was added to a solution of 4 ml of dioxane under an argon atmosphere at room temperature, the mixture was stirred at 100 ° C. for 2 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the obtained residue, and the mixture was stirred at room temperature for 18 hours.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, ethyl acetate is added to the obtained concentrated residue, and the solution is washed successively with 10% aqueous potassium dihydrogenphosphate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 95: 5 to 88:12 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. Diethyl ether and n-hexane were added to the obtained concentrated residue, and after ultrasonication, the precipitated solid was collected by filtration and dried under reduced pressure to obtain 88 mg (yield 56%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 498 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.18 & 11.73 (br s, total 1 H), 9.54 (br s, 1 H), 7.35-7.28 (m, 4 H), 7.22-7.16 (m, 1 H) ), 6.41 (br s, 1 H), 4.91-4.79 (m, 1 H), 4.53-4.40 (m, 2 H), 3.32-3.27 (m, 2 H), 3.23 (s, 3 H), 2.50-2.42 (m, 2) 2H), 2.26-2.15 (m, 2H), 2.08-1.70 (m, 4H), 1.60 (s, 3H), 1.52 (s, 3H), 0.09 (s, 9H).

(Example 21)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4.5.6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 Sodium phenylacetate (sodium salt of compound No. IV-95)

The (S) -benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-] synthesized in the same manner as in Example 44. c) Pyrazole-5-carboxamido} -2-phenyl acetate in a solution of 98.0 mg (0.171 mmol) in 15 ml of ethanol under a nitrogen atmosphere using palladium / carbon [ASCA 2 (trade name), N. E. After adding 19.9 mg of CHEMCAT's 52% water content], the atmosphere was changed to a hydrogen atmosphere under reduced pressure and stirred at room temperature for 50 minutes.
After completion of the reaction, the reaction was replaced with argon and the reaction solution was filtered through celite. To the obtained filtrate was added 14.8 mg (0.176 mmol) of sodium hydrogen carbonate and concentrated under reduced pressure. Purified water and diethyl ether were added to the obtained concentrated residue, and the resultant was dried under reduced pressure to obtain 82 mg (yield 95%) of the title compound as a white solid.
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.41 (br s, 1 H), 9.95 (br. S, 1 H), 7.38-7.30 (m, 2 H), 7.24-7.17 (m, 2 H), 7.14-7.08 (m, 1H), 6.42 (d, J = 4.6 Hz, 1 H), 4.68 (d, J = 4.6 Hz, 1 H), 4.48 (d, J = 11.3 Hz, 1 H), 4.45 (d, J = 11.3 Hz, 1 H), 2.51-2.41 (m, 2 H), 2. 28-2. 14 (m, 2 H), 1. 90-1. 74 (m, 2 H), 1. 59 (s, 3 H), 1.55 (s, 3 H), 0.08 ( s, 9H).

(Example 22)
N- [1- (2-fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1H) -carboxamide (compound No. IV-107)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. Under argon atmosphere, 0.23 ml (1.4 mmol) of DIPEA, 2-amino-2- (2-fluorophenyl) ethanol [in a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in a solution of 5 ml of 1,4-dioxane After adding 212 mg (1.37 mmol) of Amatek Chemical at room temperature, the mixture was allowed to react at 100 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and 4 ml of methanol and 1 ml of triethylamine were added to the concentrated residue, and reacted at 65 ° C. for 4.5 hours, and further at 70 ° C. for 1.5 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained concentrated residue was dissolved in 5 ml of ethyl acetate and washed twice with 10 ml of a 5% aqueous solution of potassium hydrogen sulfate. The obtained total organic layer was washed with 10 ml of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired substance is reduced in pressure. Concentration and drying under reduced pressure gave 131 mg (yield 59%) of the title compound as a white foam.
Mass spectrum (CI, m / z): 488 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.41-11.66 (m, 1 H), 9.94-9.30 (m, 1 H), 7.51-7.42 (m, 1 H), 7.31-7.06 (m, 3 H) , 6.19 (br s, 1H), 5.15-5.04 (m, 1H), 4.98 (t, J = 6.0 Hz, 1H), 4.54 (br s, 2H), 3.64-3.54 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.87-1.76 (m, 2H), 1.60 (s, 3H), 1.51 (s, 3H), 0.10 (s, 9H).

(Example 23)
(S) -N- [1- (3-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide (compound No. IV-111)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. Under argon atmosphere, 0.23 ml (1.4 mmol) of DIPEA, (S) -2-amino-2- (3) was added to a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 5.0 ml of 1,4-dioxane. -Fluorophenyl) ethanol [purchased from Amatek Chemical] 212 mg (1.37 mmol) was added at room temperature and then reacted at 100 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the concentrated residue, and reacted at room temperature for 17 hours.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, and the obtained concentrated residue is dissolved in 5 ml of ethyl acetate, and washed twice with 10 ml of 5% aqueous potassium dihydrogenphosphate solution and once with 10 ml of saturated aqueous sodium hydrogen carbonate solution The extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired substance is reduced in pressure. Concentration and drying under reduced pressure gave 128 mg (yield 58%) of the title compound as a white foam.
Mass spectrum (CI, m / z): 488 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.35-11.70 (m, 1 H), 9. 84-9.4 1 (m, 1 H), 7. 38-7. 29 (m, 1 H), 7.2 1-7. 15 (m, 2 H) , 7.05-6.98 (m, 1 H), 6.21 (br s, 1 H), 4.92 (t, J = 5.8 Hz, 1 H), 4.83-4.74 (m, 1 H), 4.58-4.45 (m, 2 H), 3.67- 3.55 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.89-1.73 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 0.09 ( s, 9H).

(Example 24)
(S) -N- [1- (4-Fluorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide (Compound No. IV-113)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. Under argon atmosphere, 0.23 ml (1.4 mmol) of DIPEA, (S) -2-amino-2- (4) was added to a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 5.0 ml of 1,4-dioxane. -Fluorophenyl) ethanol [purchased from Amatek Chemical] 212 mg (1.37 mmol) was added at room temperature and then reacted at 100 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the concentrated residue, and reacted at room temperature for 15 hours.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, and the obtained concentrated residue is dissolved in 5 ml of ethyl acetate, and washed twice with 10 ml of 5% aqueous potassium dihydrogenphosphate solution and once with 10 ml of saturated aqueous sodium hydrogen carbonate solution The extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired substance is reduced in pressure. Concentrated. The concentrated residue thus obtained is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 98: 2 (V / V)) to give a fraction containing the desired substance. Concentration under reduced pressure and drying under reduced pressure gave 139 mg (yield 63%) of the title compound as a pale yellow foam.
Mass spectrum (CI, m / z): 488 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.71 (br s, total 1 H), 9.75-9.43 (m, 1 H), 7.42-7.33 (m, 2 H), 7.15-7.06 (m, 2H), 6.28-6.02 (m, 1H), 4.89 (t, J = 5.8 Hz, 1H), 4.81-4.72 (m, 1H), 4.51 (br s, 2H), 3.66-3.53 (m, 2H), 2.49-2.42 (m, 2H), 2.26-2.15 (m, 2H), 1.90-1.74 (m, 2H), 1.60 (br s, 3H), 1.53 (br s, 3H), 0.09 (s, 9H).

(Example 25)
N- [2-hydroxy-1- (pyridin-2-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-115)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 152 mg (0.344 mmol) of 2 (4H) -carboxylate, 2-amino-2- (pyridin-2-yl) ethanol 2 hydrochloride [purchased from J & W PHARMLAB] 223 mg (1.06 mmol) of 1, 4-dioxane After adding 0.60 ml (3.4 mmol) of DIPEA to the solution at room temperature under an argon atmosphere, the solution was subjected to a microwave reaction and allowed to react at 100 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the concentrated residue, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 93: 7 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure did. The obtained residue is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 100: 0 to 78:22 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, reduced pressure Drying gave 78 mg (48% yield) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 469 [M−1] ⁻ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.22 & 11.78 (br s, total 1 H), 9.79-9.45 (m, 1 H), 8.54-8.49 (m, 1 H), 7.74 (dt, J = 1.7, 7.7 Hz, 1H), 7.42-7.36 (m, 1H), 7.28-7.21 (m, 1H), 6.19-6.00 (m, 1H), 4.92-4.82 (m, 2H), 4.62-4.43 (m, 2H), 3.76-3.65 (m, 2H), 2.49-2.42 (m, 2H), 2.27-2.15 (m, 2H), 1.92-1.72 (m, 2H), 1.68-1.50 (m, 6H), 0.10 (0.10) s, 9H).

(Example 26)
N- [2-hydroxy-1- (pyridin-3-yl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-119)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 150 mg (0.341 mmol) of 2 (4H) -carboxylate, 2-amino-2- (pyridin-3-yl) ethanol dihydrochloride [purchased from J & W PHARMLAB] 218 mg (1.03 mmol) of 1,4-dioxane To the solution was added 0.60 ml (3.4 mmol) of DIPEA at room temperature under an argon atmosphere, and then stirred at 100 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the concentrated residue, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. To the obtained concentrated residue, 4 ml of methanol and 1 ml of triethylamine were added, and the mixture was subjected to a microwave reaction and allowed to react at 80 ° C. for 1 hour.
After completion of the reaction, the reaction mixture is concentrated under reduced pressure, and the concentrated residue thus obtained is subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 95: 5 to 88:12 (V / V)) The fractions containing the desired product were concentrated under reduced pressure. The obtained residue was again subjected to silica gel column chromatography (DNH silica gel, elution solvent; ethyl acetate: methanol = 96: 4 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained residue is subjected again to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 99: 1 to 73:27 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, Drying under reduced pressure gave 27 mg (yield 17%) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 471 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.77 (br s, total 1 H), 9.75-9.47 (m, 1 H), 8.54 (d, J = 2.0 Hz, 1 H), 8.41 (dd , J = 2.0, 4.7 Hz, 1 H), 7. 75 (ddd, J = 2.0, 2.0, 7.6 Hz, 1 H), 7.32 (dd, J = 4.7, 7.6 Hz, 1 H), 6.39-6.13 (m, 1 H), 4.97 (t, J = 5.8 Hz, 1H), 4.84-4.76 (m, 1H), 4.61-4.42 (m, 2H), 3.71-3.59 (m, 2H), 2.49-2.42 (m, 2H), 2.27- 2.14 (m, 2H), 1.89-1.72 (m, 2H), 1.60 (br s, 3H), 1.52 (br s, 3H), 0.09 (s, 9H).

(Example 27)
(S) -N- (1-Cyclohexyl-2-hydroxyethyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-105)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. Into a solution of 326 mg (0.739 mmol) of 2 (4H) -carboxylate in 4 ml of dehydrated THF, 0.33 ml (1.9 mmol) of DIPEA, (S) -2-amino-2-cyclohexylethanol [Bioorg. Med. Chem. Lett. , 2009, 19, 926-929. After adding 304 mg (2.12 mmol) according to the method described in above at room temperature, the mixture was stirred for 1.5 hours while heating to reflux. Subsequently, after adding triethylamine 0.90 ml (6.5 mmol) and methanol 0.90 ml (22 mmol) to a reaction liquid, it stirred for 1.5 hours, making it heat-reflux.
After completion of the reaction, water was added to the reaction solution, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Acetic acid (85 μl) is added to the concentrated residue obtained, and the residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 97: 3 (V / V)), The solution was concentrated under reduced pressure. The resulting concentrated residue is crystallized with dichloromethane / n-hexane, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 295 mg (yield 84%) of the title compound. Obtained as a white solid.
Mass spectrum (CI, m / z): 476 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.71 (br s, total 1 H), 9.70-9.44 (m, 1 H), 5.46-5.15 (m, 1 H), 4.54 (t, J = 5.0 Hz, 1H), 4.49-4.21 (m, 2H), 3.53-3.40 (m, 3H), 2.48-2.40 (m, 2H), 2.27-2.10 (m, 2H), 1.88-1.45 (m, 14H) , 1.28-1.03 (m, 3 H), 1.03-0.83 (m, 2 H), 0.08 (s, 9 H).

(Example 28)
(S) -N- (1-hydroxy-3-methylbutan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c ] Pyrazole-5 (1H) -carboxamide (Compound No. IV-103)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. (S) -2-amino-3-methylbutan-1-ol 235 mg (2.27 mmol) in a nitrogen atmosphere to a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 4.5 ml of 1,4-dioxane After adding 0.16 ml (0.91 mmol) of DIPEA at room temperature, the mixture was stirred at 100 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and ethyl acetate, water and saturated aqueous sodium chloride solution were added to the concentrated residue to separate the layers. The aqueous layer was extracted with ethyl acetate, and the obtained total organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 99: 1 to 96: 4 (V / V)), and the fraction containing the desired substance is reduced in pressure Concentrated. Acetone was added to the obtained concentrated residue and then sonicated, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 129 mg (yield 65%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 436 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.67 (br s, total 1 H), 9.60-9.48 (m, 1 H), 5.45-5.20 (m, 1 H), 4.62-4.24 (m, 3H), 3.52-3.39 (m, 3H), 2.49-2.41 (m, 2H), 2.24-2.13 (m, 2H), 1.91-1.73 (m, 3H), 1.60 (br s, 6H), 0.92-0.82 (m, 6 H), 0.08 (s, 9 H).

(Example 29)
(S) -N- (1-hydroxypropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole- 5 (1H) -carboxamide (compound No. IV-101)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. In a solution of 200 mg (0.454 mmol) of 2 (4H) -carboxylate in 4.5 ml of 1,4-dioxane, 170 mg (2.26 mmol) of (S) -2-aminopropan-1-ol, 0.16 ml (0. After 91 mmol) was added at room temperature, it was subjected to a microwave reaction and allowed to react at 100 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and ethyl acetate, water and saturated aqueous sodium chloride solution were added to the concentrated residue to separate the layers. The aqueous layer was extracted with ethyl acetate, and the obtained total organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 99: 1 to 95: 5 (V / V)), and the fraction containing the desired product is reduced in pressure Concentrated. Ethyl acetate was added to the obtained concentrated residue, and the mixture was sonicated, and the precipitated solid was collected by filtration and dried under reduced pressure to give 145 mg (yield 78%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 408 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.18 & 11.64 (br s, total 1 H), 9.52 (s, 1 H), 5.70-5.32 (m, 1 H), 4.65 (t, J = 5.6 Hz) , 1H), 4.44-4.28 (m, 2H), 3.77-3.64 (m, 1H), 3.41-3.34 (m, 1H), 3.30-3.23 (m, 1H), 2.49-2.40 (m, 2H), 2.24 -2.13 (m, 2H), 1.88-1.72 (m, 2H), 1.60 (s, 6H), 1.05 (d, J = 6.7 Hz, 3H), 0.08 (s, 9H).

(Example 30)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl acetate (Compound No. V-86)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 883 mg (4.09 mmol) of (S) -2-amino-2-phenylethyl acetate hydrochloride synthesized in the same manner as in Reference Example 27 in a solution of 360 mg (0.816 mmol) of 2 (4H) -carboxylate in 10 ml of THF; .0 ml (12 mmol) was added at room temperature, subjected to microwave reaction, and reacted at 100 ° C for 2 hours. Then, after adding 1.1 ml (27 mmol) of methanol, it was subjected to a microwave reaction apparatus and reacted at 80 ° C. for 1 hour. After 2.0 ml (49 mmol) of methanol and 1.0 ml (7.2 mmol) of triethylamine were added, the mixture was subjected to microwave reaction and reacted at 80 ° C. for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and 15 ml of ethyl acetate and 15 ml of saturated aqueous sodium chloride solution were added to the concentrated residue thus obtained, and the layers were separated. The aqueous layer was extracted with 15 ml of dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product is reduced in pressure Concentrated. A small amount of ethyl acetate and diethyl ether was added to the obtained concentrated residue, and the mixture was sonicated, cooled with ice water, and filtered. The obtained solid was again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 100: 0 to 99: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. A small amount of ethyl acetate and diethyl ether was added to the obtained concentrated residue, and the mixture was sonicated, cooled in ice water, and filtered to obtain a white solid A. The filtrate is concentrated under reduced pressure, and the resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; ethyl acetate: methanol = 100: 0 to 99: 1 (V / V)), and the fractions containing the desired product are reduced in pressure. Concentrated. A small amount of ethyl acetate and diethyl ether was added to the obtained concentrated residue, and the mixture was sonicated, cooled in ice water, and filtered to obtain a white solid B. White solid A and B was dissolved in ethyl acetate, diethyl ether was added, and the precipitated solid was filtered and dried under reduced pressure to obtain 142 mg (yield 34%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 512 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.71 (br. S, total 1 H), 9.76-9.33 (m, 1 H), 7.43-7.37 (m, 2 H), 7.37-7.31 (m , 2H), 7.28-7.22 (m, 1H), 6.65-6.38 (m, 1H), 5.12-5.03 (m, 1H), 4.49 (br s, 2H), 4.30-4.19 (m, 2H), 2.49- 2.41 (m, 2H), 2.25-2.14 (m, 2H), 1.98 (s, 3H), 1.89-1.74 (m, 2H), 1.61 (br s, 3H), 1.53 (br s, 3H), 0.09 ( s, 9H).

(Example 31)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl propionate (Compound No. V-87)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. Propionic anhydride under an argon atmosphere with 200 mg (0.369 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate and 3 ml of a solution of 0.10 ml (0.74 mmol) of triethylamine in dehydrated dichloromethane After sequentially adding 0.071 ml (0.55 mmol) and 9.7 mg (0.079 mmol) of 4-dimethylaminopyridine at room temperature, they were reacted at room temperature for 5 hours. Then, 1 ml of methanol and 0.5 ml of triethylamine were added and allowed to react at room temperature for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 10 ml of ethyl acetate, 0.5 ml of water and 10 ml of a saturated aqueous sodium chloride solution were added to the concentrated residue thus obtained to separate the layers. The aqueous layer was extracted twice with 10 ml of dichloromethane, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product is reduced in pressure Concentrated. Diethyl ether was added to the obtained concentrated residue, and after ultrasonication, the insoluble matter was filtered and dried under reduced pressure to obtain 138 mg (yield 71%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 526 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.66 (br s, total 1 H), 9.70-9.39 (m, 1 H), 7.45-7.30 (m, 4 H), 7.28-7.21 (m, 1H), 6.64-6.39 (m, 1H), 5.16-5.03 (m, 1H), 4.57-4.39 (m, 2H), 4.32-4.19 (m, 2H), 2.49-2.41 (m, 2H), 2.27 (m, 2H) q, J = 7.5 Hz, 2 H), 2. 24-2. 14 (m, 2 H), 1. 91-1.7 2 (m, 2 H), 1. 67-1. 47 (m, 6 H), 0.99 (t, J = 7.5 Hz, 3 H), 0.09 (s, 9H).

(Example 32)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl butanoate (compound No. V-88)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. 6-Dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate and (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3 250 mg (0.461 mmol) of a mixture of-[1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate, 0.10 ml (0.74 mmol) of triethylamine 0.09 ml of butyric anhydride under argon atmosphere in a solution of 4.5 ml of 6 mmol), were successively added 4-dimethylaminopyridine 9.0mg of (0.074 mmol) at room temperature and 1.5 hours at 100 ° C.. Then, 1.5 ml (37 mmol) of methanol and 0.75 ml (5.4 mmol) of triethylamine were added, and the mixture was subjected to a microwave reaction and allowed to react at 80 ° C. for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 8 ml of ethyl acetate, 0.4 ml of water and 8 ml of a saturated aqueous sodium chloride solution were added to the concentrated residue thus obtained to separate the layers. The aqueous layer was extracted twice with 10 ml of dichloromethane, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product is reduced in pressure After concentration, the obtained concentrated residue is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 51:49 (V / V)) to obtain the target substance The fractions containing were concentrated under reduced pressure. Water was added to the concentrated residue, and the mixture was sonicated, and then the insolubles were filtered and dried under reduced pressure to obtain 80 mg (yield 32%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 540 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.65 (br s, total 1 H), 9.69-9.40 (m, 1 H), 7.45-7.37 (m, 2 H), 7.37-7.29 (m, 2H), 7.28-7.21 (m, 1H), 6.64-6.39 (m, 1H), 5.15-5.04 (m, 1H), 4.57-4.38 (m, 2H), 4.31-4.20 (m, 2H), 2.49- 2.41 (m, 2H), 2.28-2.14 (m, 4H), 1.92-1.73 (m, 2H), 1.64-1.44 (m, 8H), 0.83 (t, J = 7.4 Hz, 3H), 0.09 (s, 9H).

(Example 33)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pentanoate (Compound No. V-90)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. A solution of 200 mg (0.369 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate and 3 ml of a solution of 0.10 ml (0.74 mmol) of triethylamine in 3 ml of 1,4-dioxane under an argon atmosphere After adding 0.09 ml (0.5 mmol) of valeric anhydride and 9.0 mg (0.074 mmol) of 4-dimethylaminopyridine at room temperature, they were reacted at 100 ° C. for 1 hour. Then, 1 ml of methanol and 0.5 ml of triethylamine were added, and the mixture was subjected to a microwave reaction and allowed to react at 80 ° C. for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 10 ml of ethyl acetate and 10 ml of 10% potassium dihydrogenphosphate were added to the concentrated residue thus obtained to separate the layers. The aqueous layer is extracted twice with 10 ml of dichloromethane, and the obtained total organic layer is washed successively with 10 ml of water, 10 ml of saturated aqueous sodium hydrogen carbonate solution and 10 ml of saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure went. The concentrated residue thus obtained is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 51:49 (V / V)) to obtain a fraction containing the desired product. It concentrated under reduced pressure. Purified water was added to the obtained concentrated residue, and the mixture was sonicated, and then the insoluble matter was filtered and dried under reduced pressure to obtain 39 mg (yield 19%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 554 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.63 (br s, total 1 H), 9.54 (s, 1 H), 7.44-7.37 (m, 2 H), 7.36-7.30 (m, 2 H) , 7.28-7.21 (m, 1H), 6.66-6.39 (m, 1H), 5.14-5.04 (m, 1H), 4.59-4.40 (m, 2H), 4.25 (d, J = 7.5 Hz, 2H), 2.49 -2.41 (m, 2H), 2.29-2.14 (m, 4H), 1.92-1.73 (m, 2H), 1.61 (br s, 3H), 1.56-1.41 (m, 5H), 1.29-1.18 (m, 2H) ), 0.80 (t, J = 7.3 Hz, 3 H), 0.09 (s, 9 H).

(Example 34)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl octanoate (Compound No. V-93)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. 6-Dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate and (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3 -[1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate mixed with 183 mg (0.329 mmol) of a mixture of 3-diethylchloromethane in a nitrogen atmosphere 0.10 ml (0.72 mmol) of triethylamine, 0.15 ml of n-octanoic anhydride .51Mmol), were successively added 4-dimethylaminopyridine 10.6mg of (0.087 mmol) at room temperature and stirred for 2 hours at the same temperature. Next, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution, and the mixture was stirred at room temperature for 20.5 hours. To the reaction mixture were added 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol, and the mixture was stirred at 50 ° C. for 2 hours, then heated to 60 ° C. and stirred for 4 hours.
After completion of the reaction, water was added to the reaction solution, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 100: 0 to 97: 3 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. N-hexane is added to the obtained concentrated residue, and after ultrasonication, the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 115 mg (yield 58%) of the title compound as white Obtained as a solid.
Mass spectrum (CI, m / z): 596 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.16 & 11.77 (br s, total 1 H), 9.55 (br s, 1 H), 7.47-7.37 (m, 2 H), 7.37-7.29 (m, 2 H) ), 7.29-7.20 (m, 1H), 6.64-6.43 (m, 1H), 5.16-5.02 (m, 1H), 4.49 (s, 2H), 4.34-4.18 (m, 2H), 2.49-2.41 (m) , 2H), 2.28-2.14 (m, 4H), 1.89-1.73 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H), 1.50-1.43 (m, 2H), 1.24-1.13 (m) , 8H), 0.83-0.75 (m, 3H), 0.09 (s, 9H).

(Example 35)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl dodecanoate (compound No. V-94)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. Dehydration of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 202 mg (0.373 mmol), triethylamine 0.11 ml (0.79 mmol), 10 mg (0.082 mmol) 4-dimethylaminopyridine To a solution of 2 ml of dichloromethane was added 224 mg (0.585 mmol) of dodecanoic anhydride at room temperature under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour. Then, 1 ml of triethylamine and 1 ml of methanol were added to the reaction solution, and the mixture was stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 139 mg (yield 57%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 652 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.18 & 11.66 (br s, total 1 H), 9.83-9.28 (m, 1 H), 7.42-7.37 (m, 2 H), 7.37-7.30 (m, 2H), 7.28-7.21 (m, 1H), 6.67-6.35 (m, 1H), 5.14-5.03 (m, 1H), 4.56-4.42 (m, 2H), 4.30-4.20 (m, 2H), 2.49- 2.42 (m, 2H), 2.28-2.13 (m, 4H), 1.89-1.73 (m, 2H), 1.60 (br s, 3H), 1.57-1.43 (m, 5H), 1.30-1.14 (m, 16H) , 0.85 (t, J = 6.9 Hz, 3 H), 0.09 (s, 9 H).

(Example 36)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl palmitate (Compound No. V-95)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. 220 mg (0.406 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate, 0.115 ml (0.825 mmol) of triethylamine, 300 mg (0.606 mmol) of palmitic anhydride, 3 ml of dichloromethane To the solution was added 10 mg (0.082 mmol) of 4-dimethylaminopyridine at room temperature under an argon atmosphere, and the mixture was stirred at the same temperature for 1.5 hours. Then, 1.0 ml of methanol and 0.5 ml of triethylamine were added to the reaction solution, and the mixture was stirred at room temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 50:50 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 195 mg (yield 68%) of the title compound was obtained as a white solid.
Mass spectrum (DUIS, m / z): 708 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.18 & 11.64 (br s, total 1 H), 9.64-9.50 (m, 1 H), 7.43-7.38 (m, 2 H), 7.36-7.30 (m, 2H), 7.27-7.21 (m, 1H), 6.63-6.39 (m, 1H), 5.13-5.04 (m, 1H), 4.55-4.42 (m, 2H), 4.30-4.20 (m, 2H), 2.48- 2.40 (m, 2H), 2.29-2.14 (m, 4H), 1.89-1.74 (m, 2H), 1.60 (br s, 3H), 1.57-1.43 (m, 5H), 1.29-1.14 (m, 24H) , 0.89-0.81 (m, 3 H), 0.09 (s, 9 H).

(Example 37)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl isobutanoate (compound No. V-89)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. A solution of 247 mg (0.456 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate in 3 ml of dehydrated dichloromethane was treated with 0.15 ml (1.1 mmol) of triethylamine under a nitrogen atmosphere, After sequentially adding 0.060 ml (0.57 mmol) of yl chloride at room temperature, the mixture was stirred at the same temperature for 100 minutes. Next, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution, and the mixture was stirred at room temperature for 4.5 hours.
After completion of the reaction, water was added to the reaction solution, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 99: 1 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue is crystallized with ethyl acetate / n-hexane, and the obtained solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 202 mg of the title compound (yield 82%) ) As a white solid.
Mass spectrum (CI, m / z): 540 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.61 (br s, total 1 H), 9.53 (s, 1 H), 7.47-7.38 (m, 2 H), 7.38-7.29 (m, 2 H) , 7.29-7.20 (m, 1H), 6.71-6.34 (m, 1H), 5.20-5.03 (m, 1H), 4.57-4.38 (m, 2H), 4.33-4.15 (m, 2H), 2.48-2.42 ( m, 3H), 2.27-2.13 (m, 2H), 1.92-1.73 (m, 2H), 1.65-1.47 (m, 6H), 1.08-0.99 (m, 6H), 0.14-0.05 (m, 9H).

(Example 38)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl pivalate (Compound No. V-91)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. A solution of 210 mg (0.387 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate, 0.11 ml (0.79 mmol) of triethylamine in a solution of 3 ml of dehydrated dichloromethane under an argon atmosphere, pivalic anhydride 0.12 ml (0.59 mmol) and 10.5 mg (0.086 mmol) of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 4.5 hours. Next, 0.5 ml of triethylamine and 1 ml of methanol were added to the reaction solution, and reacted at room temperature for 14 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure . Diisopropyl ether was added to the obtained concentrated residue, and the mixture was sonicated, and then the insoluble matter was collected by filtration and dried under reduced pressure to obtain 144 mg (yield 67%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 554 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.66 (br s, total 1 H), 9.55 (s, 1 H), 7.45-7.38 (m, 2 H), 7.37-7.31 (m, 2 H) , 7.28-7.22 (m, 1H), 6.68-6.40 (m, 1H), 5.20-5.09 (m, 1H), 4.48 (br s, 2H), 4.29-4.19 (m, 2H), 2.49-2.41 (m) , 2H), 2.26-2.14 (m, 2H), 1.90-1.74 (m, 2H), 1.59 (s, 3H), 1.55 (s, 3H), 1.08 (s, 9H), 0.09 (s, 9H).

(Example 39)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl 3-methylbutanoate (compound No. V-92)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. 6-Dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate and (S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3 201 mg (0.371 mmol) of a mixture of-[1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate, 0.10 ml (0.74 mmol) of triethylamine In 0.13 ml of isovaleric anhydride under an argon atmosphere. 6 mmol), after addition of 4-dimethylaminopyridine 10.6mg of (0.087 mmol) at room temperature and reacted for 3 hours at the same temperature. Next, 1.0 ml of methanol and 0.5 ml of triethylamine are added and reacted at room temperature for 15.5 hours, and then the reaction solution is concentrated under reduced pressure, and 1.0 ml of methanol and 0.5 ml of triethylamine are added again to the obtained concentrated residue The reaction was performed at 40 ° C. for 6 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 8 ml of ethyl acetate, 0.4 ml of water and 8 ml of a saturated aqueous sodium chloride solution were added to the concentrated residue thus obtained to separate the layers. The aqueous layer was extracted twice with 10 ml of dichloromethane, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product is reduced in pressure Concentrated. Diethyl ether was added to the obtained concentrated residue, and the mixture was sonicated and concentrated under reduced pressure. Water was added to the obtained concentrated residue, the mixture was sonicated, and after standing overnight, the insolubles were filtered and dried under reduced pressure to obtain 97 mg (yield 47%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 554 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.50-11.49 (m, 1 H), 9.55 (s, 1 H), 7.44-7.38 (m, 2 H), 7.37-7.30 (m, 2 H), 7.29 -7.22 (m, 1H), 6.84-6.25 (m, 1H), 5.13-5.06 (m, 1H), 4.55-4.41 (m, 2H), 4.31-4.21 (m, 2H), 2.49-2.42 (m, 1H) 2H), 2.26-2.11 (m, 4H), 2.01-1.87 (m, 1H), 1.87-1.74 (m, 2H), 1.59 (s, 3H), 1.53 (s, 3H), 0.87-0.82 (m, 6H), 0.09 (s, 9H).

(Example 40)
(S) -2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide} -2 -Phenylethyl benzoate (compound number V-96)

(S) -Ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 30. A solution of 132 mg (0.244 mmol) of 6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate, 2.58 ml (0.49 mmol) of triethylamine in a solution of 2.5 ml of dehydrated dichloromethane under argon atmosphere 0.042 ml (0.36 mmol) of benzoyl was added at room temperature and stirred at the same temperature for 1 hour. Next, 0.5 ml of triethylamine and 0.5 ml of methanol were added to the reaction solution, and the mixture was stirred at room temperature for 20 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 50:50 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 94 mg (yield 67%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 574 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.19 & 11.71 (br s, total 1 H), 9.55 (br. S., 1 H), 7.95-7.91 (m, 2 H), 7.66-7.60 (m , 1H), 7.52-7.46 (m, 4H), 7.39 -7.33 (m, 2H), 7.30-7.24 (m, 1H), 6.73-6.59 (m, 1H), 5.35-5.26 (m, 1H), 4.57 -4.44 (m, 4H), 2.48-2.42 (m, 2H), 2.23-2.15 (m, 2H), 1.87-1.73 (m, 2H), 1.57 (s, 3H), 1.55 (s, 3H), 0.08 (s, 9H).

(Example 41)
(S) -4- (2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide } -2-Phenylethoxy) -4-oxobutanoic acid sodium (sodium salt of compound No. V-97)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. (S) -2-Amino-2-phenylethyl benzyl succinato trif furoate synthesized in the same manner as in Reference Example 32 into a solution of 201 mg (0.456 mmol) of 2 (4H) -carboxylate in 7.0 ml of 1,4-dioxane Acetate 628 mg (including impurities) and 1.0 ml (5.7 mmol) of DIPEA were added, and the mixture was subjected to a microwave reaction and reacted at 100 ° C. for 1 hour. Then, 1 ml of methanol and 1 ml of triethylamine were added, and the mixture was subjected to a microwave reaction and reacted at 80 ° C. for 3 hours.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, ethyl acetate is added to the obtained concentrated residue, and the mixture is washed successively with 10% aqueous potassium dihydrogenphosphate solution, water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and then anhydrous sulfuric acid After drying over magnesium and filtration, the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 70:30 (V / V)) to obtain (S) -benzyl (2) -{6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamido} -2-phenylethyl) succinate The fraction containing was concentrated under reduced pressure to obtain a concentrated residue.
After adding 25.4 mg of palladium / carbon (ASCA2 (trade name), NE CHEMCAT, 52% water content) to a solution of 171 mg of the obtained concentrated residue in ethanol under a nitrogen atmosphere, a hydrogen atmosphere under reduced pressure And stirred at room temperature for 2 hours.
After completion of the reaction, the reaction was replaced with argon and the reaction solution was filtered through celite. To the filtrate was added 0.26 ml (0.26 mmol) of 1 N aqueous sodium hydroxide solution, and concentrated under reduced pressure. Diethyl ether was added to the obtained residue, followed by ultrasonication, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 147 mg of the title compound (yield 54% [2 steps]) as a white solid.
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 13.32 (br. S, 1 H), 10.75 (br. S, 1 H), 7.44 to 7.38 (m, 2 H), 7.36 to 7.29 (m, 2 H) , 7.28-7.19 (m, 1 H), 6.47 (d, J = 7.3 Hz, 1 H), 5.11-5.02 (m, 1 H), 4.57-4.41 (m, 2 H), 4.28 (dd, J = 5.6, 10.8 Hz) , 1H), 4.17 (dd, J = 8.0, 10.8 Hz, 1H), 2.49-2.42 (m, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.25-2.16 (m, 2H), 2.11 ( t, J = 7.2 Hz, 2 H), 1.87-1.71 (m, 2 H), 1.58 (s, 3 H), 1.51 (s, 3 H), 0.08 (s, 9 H).

(Example 42)
(S)-(2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenylethoxy) methyl pivalate (Compound No. VI-125)

0.15 ml (0.86 mmol) of DIPEA in a nitrogen atmosphere in a solution of 272 mg (1.08 mmol) of (S)-(2-amino-2-phenylethoxy) methyl pivalate synthesized in the same manner as in Reference Example 34 in a nitrogen atmosphere Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. After adding 162 mg (0.368 mmol) of 2 (4H) -carboxylate sequentially at room temperature, the mixture was stirred for 130 minutes while heating to reflux. Next, 1.0 ml of triethylamine and 0.8 ml of methanol were added to the reaction solution, and the mixture was stirred for 70 minutes while heating under reflux.
After completion of the reaction, water was added to the reaction solution, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DNH silica gel, elution solvent; dichloromethane: methanol = 100: 0 to 98: 2 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue is crystallized with ethyl acetate / n-hexane, and the precipitated solid is collected by filtration, washed with n-hexane, and dried under reduced pressure to give the title compound 176 mg (yield 82%) Was obtained as a white solid.
Mass spectrum (CI, m / z): 584 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.64 (br s, total 1 H), 9.59-9.49 (m, 1 H), 7.41-7.35 (m, 2 H), 7.35-7.27 (m, 2H), 7. 25-7. 19 (m, 1 H), 6.42 & 6. 28 (d, J = 8.0 Hz, total 1 H), 5. 29 (d, J = 6.2 Hz, 1 H), 5.22 (d, J = 6.2 Hz, 1 H) , 5.02-4.94 (m, 1H), 4.57-4.37 (m, 2H), 3.91-3.83 (m, 1H), 3.79 (dd, J = 6.0, 10.0 Hz, 1H), 2.49-2.40 (m, 2H) , 2.28-2.13 (m, 2H), 1.92-1.73 (m, 2H), 1.67-1.45 (m, 6H), 1.13 (s, 9H), 0.14-0.06 (m, 9H).

(Example 43)
(S) -2-Acetoxy-1-phenylethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H)- Carboxylate (Compound No. V-75)

5-tert-Butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, synthesized in the same manner as in Reference Example 2 Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [synthesized in the same manner as in Reference Example 47 using 506 mg (1.06 mmol) of 6H) -dicarboxylate A solution of 412 mg of 3,4-c] pyrazole-2 (4H) -carboxylate (containing impurities) in 4 ml of dehydrated THF was synthesized in the same manner as in Reference Example 35 under the same nitrogen atmosphere as 0.70 ml (4.0 mmol) of DIPEA (Reference Example 35) S) -2-({[(2,5-dioxopyrrolidin-1-yl) oxy] carbonyl} oxy) -2-) Were successively added Eniruechiru acetate 1.30g of (3.84 mmol) at room temperature and stirred for 1.5 hours while heating under reflux. Next, 2.0 ml (14 mmol) of triethylamine and 1.5 ml (37 mmol) of methanol were added to the reaction solution, and the mixture was stirred for 3.5 hours while heating under reflux.
After completion of the reaction, water was added to the reaction solution, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentration residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure Thus, 225 mg of concentrated residue was obtained.
About 50 mg of the obtained concentrated residue is subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile: 1 mM aqueous solution of potassium dibasic hydrogen phosphate = 50: 50 (V / V)) The fractions containing the desired product were concentrated under reduced pressure to remove acetonitrile. The concentrated residue was extracted twice with ethyl acetate, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is crystallized with ethyl acetate / diisopropyl ether / n-hexane, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 11.6 mg of the title compound ( A 2% yield [two steps] was obtained as a white solid.
Mass spectrum (CI, m / z): 513 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.35-12.21 & 11.97-11.83 (m, total 1 H), 9.87-9.45 (m, 1 H), 7.47-7.24 (m, 5 H), 5.99-5.85 (m, 1H), 4.65-4.17 (m, 4H), 2.48-2.36 (m, 2H), 2.28-2.10 (m, 2H), 2.05-1.95 (m, 3H), 1.92-1.72 (m, 2H) , 1.71-1.43 (m, 6H), 0.16-0.02 (m, 9H).

(Example 44)
(S) -benzyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate (Compound No. IV-97)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. (S) -Benzyl 2-amino-2-phenylacetate synthesized in the same manner as in Reference Example 37 in a solution of 195 mg (0.442 mmol) of 2 (4H) -carboxylate in 7 ml of 1,4-dioxane under an argon atmosphere After adding 565 mg (containing impurities) of trifluoroacetic acid salt and 0.50 ml (2.9 mmol) of DIPEA at room temperature, the mixture was subjected to a microwave reaction apparatus and stirred at 100 ° C. for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, 4 ml of methanol and 1 ml of triethylamine were added to the obtained concentrated residue, and the mixture was subjected to a microwave reaction apparatus and reacted at 80 ° C. for 1 hour.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, ethyl acetate is added to the obtained concentrated residue, and the organic layer is washed with a 10% aqueous solution of potassium dihydrogenphosphate, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride successively. After drying over magnesium sulfate and filtration, the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 55:45 (V / V)) to make the title compound the main component Fraction and by-product [(S) -methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -1,4,5,6-tetrahydropyrrolo [3,4-c] The fractions containing pyrazole-5-carboxamido} -2-phenyl acetate] as a main component were each concentrated under reduced pressure. The concentrated residue of the fraction mainly composed of the title compound is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 55:45 (V / V)) The fractions containing the desired product were concentrated under reduced pressure to give 99 mg (yield 39%) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 574 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.70 (br s, total 1 H), 9.63-9.44 (m, 1 H), 7.51-7.41 (m, 2 H), 7.38-7.23 (m, 8H), 6.81-6.47 (m, 1H), 5.42 (d, J = 7.2 Hz, 1 H), 5.17 (d, J = 12.7 Hz, 1 H), 5.11 (d, J = 12.7 Hz, 1 H), 4.61- 4.39 (m, 2H), 2.49-2.38 (m, 2H), 2.25-2.12 (m, 2H), 1.91-1.72 (m, 2H), 1.68-1.52 (m, 6H), 0.07 (s, 9H).

(Example 45)
(S) -Methyl 2- {6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-5-carboxamide}- 2-phenyl acetate (Compound No. IV-99)

The concentrated residue of the fraction mainly composed of the title compound recovered during the first silica gel column chromatography purification in the working step of Example 44 is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent: 1,2-dichloroethane: acetic acid The product was subjected to ethyl = 100: 0 to 55:45 (V / V), and the fractions containing the desired product were concentrated under reduced pressure to obtain 29 mg (yield 13%) of the title compound as a white foam.
Mass spectrum (DUIS, m / z): 498 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.71 (br s, total 1 H), 9.63-9.46 (m, 1 H), 7.48-7.41 (m, 2 H), 7.40-7.28 (m, 3H), 6.73-6.56 (m, 1H), 5.36 (d, J = 7.2 Hz, 1H), 4.61-4.38 (m, 2H), 3.62 (s, 3H), 2.49-2.38 (m, 2H), 2.27 -2.10 (m, 2H), 1.92-1.71 (m, 2H), 1.67-1.51 (m, 6H), 0.08 (s, 9H).

(Example 46)
N- (2,2-difluoro-3-hydroxy-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-89)

A solution of 249 mg (1.33 mmol) of 3-amino-2,2-difluoro-3-phenylpropan-1-ol synthesized in the same manner as in Reference Example 40 in 2 ml of dehydrated 1,4-dioxane was treated with DIPEA 0.2. 30 ml (1.7 mmol) of ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3 synthesized in the same manner as in Reference Example 3 After sequentially adding 178 mg (0.403 mmol) of 4, 4-c] pyrazole-2 (4H) -carboxylate at room temperature, the mixture was stirred at 80 ° C. for 7 hours. Next, 0.10 ml (1.7 mmol) of 2-aminoethanol was added to the reaction solution which was allowed to cool to room temperature, and the mixture was stirred at room temperature for 1.5 hours as it was.
After completion of the reaction, the reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and stirred, and then extracted three times with dichloromethane. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 30:70 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 155 mg of the title compound (yield 74 %) As a white solid.
Mass spectrum (CI, m / z): 520 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.43-11.84 (m, 1 H), 10.02-9.36 (m, 1 H), 7.56-7.50 (m, 2 H), 7.40-7.27 (m, 3 H) , 6.61 (br s, 1H), 5.71 (br s, 1H), 5.49-5.34 (m, 1H), 4.70-4.56 (m, 1H), 4.47 (br d, J = 12.0 Hz, 1H), 3.73- 3.45 (m, 2 H), 2.57-2.42 (m, 2 H), 2. 26-2. 15 (m, 2 H), 1. 90-1. 74 (m, 2 H), 1.61 (s, 3 H), 1.51 (s, 3 H), 0.09 ( s, 9H).

(Example 47)
(S) -N- [1- (2-chlorophenyl) -2-hydroxyethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazol-5 (1H) -carboxamide (compound No. IV-286)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 2 (4H) -carboxylate 0.105 g (0.238 mmol), (S) -2-amino-2- (2-chlorophenyl) ethanol [Amatek Chemical Co. , Ltd. Under a nitrogen atmosphere, 0.200 ml (1.15 mmol) of DIPEA was added at room temperature to a solution of 0.124 g (0.723 mmol) of dehydrated 1,4-dioxane at room temperature, and then stirred at 100 ° C. for 1 hour . After allowing to cool, 0.50 ml (12 mmol) of methanol and 0.070 ml (1.2 mmol) of 2-aminoethanol were added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, ethyl acetate is added to the residue, and the mixture is washed successively with 10% aqueous potassium dihydrogenphosphate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and the organic layer is dried over anhydrous magnesium sulfate After filtration, the filtrate was concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 84: 16-33: 67 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, The residue is dissolved in a small amount of dichloromethane, n-hexane is added, the mixture is sonicated, and the precipitated solid is collected by filtration and dried under reduced pressure to give 0.0958 g (yield 80%) of the title compound as a white solid. The
Mass spectrum (DUIS, m / z): 504 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.75 (br s, total 1 H), 9.71-9.52 (m, 1 H), 7.51 (dd, J = 1.6, 7.7 Hz, 1 H), 7.38 (dd, J = 1.2, 7.8 Hz, 1 H), 7.33-7.20 (m, 2 H), 6.36-6.14 (m, 1 H), 5.21-5.12 (m, 1 H), 5.04 (t, J = 6.0 Hz, 1 H) ), 4.66-4.45 (m, 2H), 3.64-3.48 (m, 2H), 2.57-2.41 (m, 2H), 2.28-2.13 (m, 2H), 1.91-1.72 (m, 2H), 1.66-1.42 (m, 6H), 0.10 (s, 9H).

(Example 48)
(S) -N- [2-hydroxy-1- (o-tolyl) ethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazol-5 (1H) -carboxamide (compound No. IV-306)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 0.104 g (0.235 mmol) of 2 (4H) -carboxylate, (S) -2-amino-2- (o-tolyl) ethanol hydrochloride [Acesys Pharmatech Ltd. Under a nitrogen atmosphere, 0.400 ml (2.30 mmol) of DIPEA is added at room temperature to a solution of 0.131 g (0.696 mmol) of dehydrated 1,4-dioxane at room temperature, and then heated and stirred at 100 ° C. for 1 hour did. After allowing to cool, 0.50 ml (12 mmol) of methanol and 0.070 ml (1.2 mmol) of 2-aminoethanol were added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, ethyl acetate is added, and the mixture is washed successively with 10% aqueous potassium dihydrogenphosphate solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, and the organic layer is dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 84: 16-33: 67 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, The residue is dissolved in a small amount of dichloromethane, n-hexane is added, the mixture is sonicated, and the precipitated solid is collected by filtration and dried under reduced pressure to obtain 0.0738 g (yield 65%) of the title compound as a white solid. The
Mass spectrum (CI, m / z): 484 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.66 (br s, total 1 H), 9.63-9.50 (m, 1 H), 7.40 (d, J = 7.4 Hz, 1 H), 7.18-7.03 (m, 3H), 6.28-6.05 (m, 1H), 5.04-4.95 (m, 1H), 4.89 (t, J = 6.0 Hz, 1H), 4.58-4.41 (m, 2H), 3.61-3.43 (m , 2H), 2.56-2.41 (m, 2H), 2.36 (s, 3H), 2.27-2.11 (m, 2H), 1.93-1.70 (m, 2H), 1.69-1.41 (m, 6H), 0.10 (s) , 9H).

(Example 49)
(S) -N- (1-hydroxy-3-phenylpropan-2-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4- c] pyrazol-5 (1H) -carboxamide (compound No. IV-227)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. Under argon atmosphere, 0.115 ml (0.673 mmol) of DIPEA, (S) -2-amino-3-phenylpropane-1 in a solution of 101 mg (0.229 mmol) of 2 (4H) -carboxylate in a solution of 3 ml of 1,4-dioxane After sequentially adding 102 mg (0.675 mmol) of ol, the mixture was stirred at 100 ° C. for 1 hour. Then, the reaction solution was concentrated under reduced pressure, 2 ml of methanol and 0.5 ml of triethylamine were sequentially added at room temperature, and the mixture was stirred at 80 ° C. for 1 hour in a microwave reactor.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was dissolved in 5 ml of ethyl acetate and washed twice with 5% aqueous potassium dihydrogen phosphate solution, and then the organic layer was washed with 5 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 100: 0 to 86:14 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure, Then, drying under reduced pressure at 50 ° C. gave 88.5 mg (yield 80%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 484 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.19 & 11.71 (br s, total 1 H), 9.54 (br s, 1 H), 7.28-7.18 (m, 4 H), 7.18-7.12 (m, 1 H) ), 5.72-5.45 (m, 1H), 4.77 (t, J = 5.5 Hz, 1H), 4.46-4.17 (m, 2H), 3.90-3.77 (m, 1H), 3.44-3.28 (m, 2H), 2.87-2.70 (m, 2H), 2.54-2.40 (m, 2H), 2.25-2.13 (m, 2H), 1. 92-1.70 (m, 2H), 1.58 (br s, 3H), 1.50 (br s, 3H ), 0.09 (s, 9H).

(Example 50)
N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-125)

Under a nitrogen atmosphere, 3- (benzyloxy) -2-phenylpropanoic acid [Tetrahedron Lett. , 2002 (43), 969 1-9693. 0.13 ml (1.0 mmol) of DIPEA, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbe in a solution of 139 mg (0.540 mmol) in 3 ml of dehydrated DMF After sequentially adding 233 mg (0.544 mmol) of sodium hexafluorophosphate [COMU (trade name)] at 0 ° C., the mixture was stirred at the same temperature for 15 minutes. Subsequently, ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-1 (4H)-synthesized in the same manner as in Reference Example 5 After adding 158 mg (0.418 mmol) of carboxylates at 0 ° C., the mixture was stirred at room temperature for 3.5 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was stirred, and then extracted three times with ethyl acetate. The obtained whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a concentrated residue.
Under nitrogen atmosphere, 0.25 ml (1.8 mmol) of triethylamine and 0.10 ml (1.7 mmol) of 2-aminoethanol were sequentially added to a THF 4 ml solution of the obtained concentrated residue at room temperature, and then 1. Stir for 5 hours.
After completion of the reaction, the reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and stirred, and then extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 50:50 (V / V)), then concentrated under reduced pressure and dried under reduced pressure. , Concentrated residue was obtained.
Under a nitrogen atmosphere, 25.4 mg of 20% palladium hydroxide / carbon [50 wt% water content] is added at room temperature to a solution of 2 ml of ethanol obtained in the concentration residue, and then it is replaced with a hydrogen atmosphere under reduced pressure. Stir for 5 hours. The inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure, then 68.3 mg of 20% palladium hydroxide / carbon [50 wt% water content] was added at room temperature, and then replaced again with a hydrogen atmosphere under reduced pressure. Stir for 5 hours.
After completion of the reaction, the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, and then the removed solid was washed with ethanol, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 104 mg of the title compound (yield 55 % [2 steps]) was obtained as a white solid.
Mass spectrum (EI, m / z): 454 [M] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.45-11.70 (m, 1 H), 9.58 (br s, 1 H), 7.35-7.20 (m, 5 H), 4.81-4.64 (m, 2 H), 4.23 (d, J = 12.0 Hz, 1 H), 3.98-3.89 (m, 1 H), 3.84 (dd, J = 5.4, 8.2 Hz, 1 H), 3.52-3.44 (m, 1 H), 2.58-2.37 (m, 1) 2H), 2.24-2.12 (m, 2H), 1.87-1.73 (m, 2H), 1.69 (s, 3H), 1.58 (s, 3H), 0.05 (s, 9H).

(Example 51)
(S) -N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-126)

The (S) -N- {5- [3- (benzyloxy) -2-phenylpropanoyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [synthesized in the same manner as Reference Example 48] 20% palladium hydroxide / carbon [50 wt% water content] under nitrogen atmosphere to a solution of 139 mg (0.256 mmol) of 3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide under nitrogen atmosphere 58. After 4 mg was added at room temperature, it was replaced with a hydrogen atmosphere under reduced pressure and stirred at room temperature for 3 hours.
After completion of the reaction, the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, and then the removed solid was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 85: 15 to 35:65 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 55 mg of the title compound (yield 47 %) As a white solid.
Mass spectrum (CI, m / z): 455 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.24 & 11.85 (br s, total 1 H), 9.73-9.44 (m, 1 H), 7.35-7.20 (m, 5 H), 4.81-4.63 (m, 5) 2H), 4.33-4.11 (m, 1H), 3.98-3.89 (m, 1H), 3.88-3.80 (m, 1H), 3.52-3.44 (m, 1H), 2.60-2.36 (m, 2H), 2.26- 2.10 (m, 2H), 1.89-1.64 (m, 5H), 1.58 (br s, 3H), 0.05 (s, 9H).

(Example 52)
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-331)

0.24 ml (2.8 mmol) of oxalyl chloride and 0.025 ml (0.32 mmol) of DMF were added to a solution of 263 mg (1.58 mmol) of (R) -2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane under an argon atmosphere. After sequential addition at <RTIgt; C, </ RTI> it was stirred at that temperature for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was prepared in the same manner as Reference Example 47 in a solution of 3 ml of anhydrous concentrated dichloromethane in a solution of dehydrated dichloromethane in an argon atmosphere. Add dropwise to a solution of 300 mg (0.793 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate, 0.55 ml (3.2 mmol) of DIPEA in 5 ml of dehydrated dichloromethane at 0 ° C. and stir at room temperature for 15 hours did. Next, 0.37 ml (4.0 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 3 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained total organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 35:65 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. Ethyl acetate is added to the obtained concentrated residue to dissolve it, n-hexane is added and the precipitated solid is collected by filtration and dried under reduced pressure to give 224 mg of the title compound (yield 62%) as a white solid Obtained.
Mass spectrum (CI, m / z): 455 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.26 & 11.86 (br s, total 1 H), 9.71-9.47 (m, 1 H), 7.44-7.27 (m, 5 H), 4.96 (s, 1 H) , 4.74-4.52 (m, 1 H), 4.39-4.21 (m, 1 H), 3.31 (s, 3 H), 2.48-2.36 (m, 2 H), 2.26-2.07 (m, 2 H), 1. 92-1.53 (m, 2) 8H), 0.05 (s, 9H).

(Example 53)
(S) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-332)

0.24 ml (2.8 mmol) of oxalyl chloride and 0.025 ml (0.32 mmol) of DMF were added to a solution of 263 mg (1.58 mmol) of (S) -2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane under an argon atmosphere. After sequential addition at <RTIgt; C, </ RTI> it was stirred at that temperature for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was prepared in the same manner as Reference Example 47 in a solution of 3 ml of anhydrous concentrated dichloromethane in a solution of dehydrated dichloromethane in an argon atmosphere. Add dropwise to a solution of 300 mg (0.793 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate, 0.55 ml (3.2 mmol) of DIPEA in 5 ml of dehydrated dichloromethane at 0 ° C. and stir at room temperature for 15 hours did. Next, 0.37 ml (4.0 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 3 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained total organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 35:65 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. Ethyl acetate is added to the obtained concentrated residue for dissolution, and then n-hexane is added, the precipitated solid is collected by filtration and dried under reduced pressure to give 206 mg (yield 57%) of the title compound as a white solid. Obtained.
Mass spectrum (CI, m / z): 455 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.26 & 11.86 (br s, total 1 H), 9.71-9.45 (m, 1 H), 7.46-7.26 (m, 5 H), 4.96 (s, 1 H) , 4.73-4.53 (m, 1H), 4.30 (br d, J = 12.3 Hz, 1H), 3.31 (s, 3H), 2.47-2.36 (m, 2H), 2.24-2.11 (m, 2H), 1.89- 1.53 (m, 8 H), 0.05 (s, 9 H).

(Example 54)
N- [5- (3-methoxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-127)

0.14 ml (1.6 mmol) of oxalyl chloride, 0.0060 ml of dehydrated DMF, in a solution of 212 mg (1.18 mmol) of 3-methoxy-2-phenylpropanoic acid synthesized in the same manner as in Reference Example 50 under a nitrogen atmosphere and 6 ml of dehydrated dichloromethane After sequentially adding 0.077 mmol) at 0 ° C., the mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a concentrated residue.
Under a nitrogen atmosphere, a solution of the concentrated residue thus obtained in 1 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47. Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [ After being added at 0 ° C. to a solution of 156 mg (0.413 mmol) of 3,4-c] pyrazole-2 (4H) -carboxylate, 0.36 ml (2.1 mmol) of DIPEA at 0 ° C., 1.5 at the temperature as it is Stir for hours. Next, 0.23 ml (2.1 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, the reaction solution diluted with dichloromethane was washed with a 5% aqueous potassium hydrogen sulfate solution, and then separated. The aqueous layer was extracted twice with dichloromethane, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was again subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The concentrated residue thus obtained is subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: acetonitrile: 1 mM aqueous solution of dipotassium hydrogen phosphate = 40: 60 (V / V)) to obtain the desired product. The fractions containing were concentrated under reduced pressure to distill off acetonitrile. The concentrated residue obtained was extracted three times with ethyl acetate, and the obtained total organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 101 mg of the title compound (yield 52 %) As a white solid.
Mass spectrum (CI, m / z): 469 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.50-11.61 (m, 1 H), 9.57 (br s, 1 H), 7.36-7.22 (m, 5 H), 4.70 (d, J = 12.3 Hz, 1H), 4.22 (d, J = 12.3 Hz, 1H), 3.99-3.92 (m, 1H), 3.90-3.83 (m, 1H), 3.40 (dd, J = 5.7, 8.8 Hz, 1H), 3.23 (s) , 3H), 2.57-2.37 (m, 2H), 2.22-2.12 (m, 2H), 1.86-1.74 (m, 2H), 1.68 (s, 3H), 1.57 (s, 3H), 0.05 (s, 9H) ).

(Example 55)
N- [5- (4-methoxy-2-phenylbutanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- ( Trimethylsilyl) cyclobutanecarboxamide (compound No. IV-376)

0.14 ml (1.6 mmol) of oxalyl chloride under an argon atmosphere in a solution of 154 mg (0.793 mmol) of 4-methoxy-2-phenylbutanoic acid synthesized in the same manner as in Reference Example 52 under an argon atmosphere, 0.0092 ml of DMF After sequentially adding 0.12 mmol) at 0 ° C., the mixture was stirred at the same temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was prepared in the same manner as Reference Example 47 in a solution of 3 ml of anhydrous concentrated dichloromethane in a solution of dehydrated dichloromethane in an argon atmosphere. After dropwise addition of 150 mg (0.396 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate, 0.28 ml (1.6 mmol) of DIPEA in 3 ml of dehydrated dichloromethane at 0 ° C., the mixture is stirred at room temperature for 3 hours did. Next, 0.185 ml (1.98 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 14 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained total organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 40:60 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The concentrated residue obtained is subjected to preparative HPLC (column: XSelect (trade name) HSSC18, elution solvent; acetonitrile: 1 mM aqueous potassium dihydrogen phosphate solution = 50: 50 (V / V)) to contain the desired product. The fraction was concentrated under reduced pressure to remove acetonitrile. The obtained concentrated residue was extracted with ethyl acetate, and the obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Ethyl acetate is added to the obtained concentrated residue for dissolution, and then n-hexane is added, and the precipitated solid is collected by filtration and dried under reduced pressure to give 78 mg (yield 41%) of the title compound as a white solid. Obtained.
Mass spectrum (CI, m / z): 483 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.24 & 11.95 (br s, total 1 H), 9.78-9.46 (m, 1 H), 7.39-7.18 (m, 5 H), 4.79-4.57 (m, 5) 1H), 4.24 (br d, J = 12.2 Hz, 1 H), 3.92-3.75 (m, 1 H), 3.29-3.21 (m, 2 H), 3.20 (s, 3 H), 2.59-2.37 (m, 2 H), 2.25-2.11 (m, 3H), 1.88-1.62 (m, 6H), 1.57 (br s, 3H), 0.05 (s, 9H).

(Example 56)
(S) -N- [5- (3-hydroxy-2-phenylpropanoyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclopropanecarboxamide (compound No. III-31)

The (S) -N- {5- [3- (benzyloxy) -2-phenylpropanoyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [synthesized in the same manner as Reference Example 53] A solution of 45.8 mg (0.0864 mmol) of 3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclopropanecarboxamide in 1 ml of ethanol under an atmosphere of nitrogen containing 20% palladium hydroxide / carbon [50 wt% water content After adding 13.6 mg at room temperature, it was replaced with a hydrogen atmosphere under reduced pressure and stirred at room temperature for 2.5 hours.
After completion of the reaction, the inside of the reaction vessel was replaced with a nitrogen atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, and then the removed solid was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was again subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 99: 1 to 95: 5 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The resulting concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 19 mg of the title compound (yield 50 %) As a white solid.
Mass spectrum (CI, m / z): 441 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.25 & 11.96 (br s, total 1 H), 9.98-9.65 (m, 1 H), 7.37-7.19 (m, 5 H), 4.80-4.58 (m, 5) 2H), 4.33-4.10 (m, 1H), 3.98-3.88 (m, 1H), 3.88-3.80 (m, 1H), 3.52-3.43 (m, 1H), 1.68 (br s, 3H), 1.57 (br) s, 3H), 1.05-0.91 (m, 2H), 0.80-0.56 (m, 2H), 0.01 (s, 9H).

(Example 57)
(R) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (Trimethylsilyl) cyclopropanecarboxamide (Compound No. III-56)

0.15 ml (1.92 mmol) of oxalyl chloride and 0.017 ml (0.22 mmol) of DMF were added to a solution of 182 mg (1.10 mmol) of (R) -2-methoxy-2-phenylacetic acid in 5 ml of dehydrated dichloromethane under an argon atmosphere. After sequential addition at <RTIgt; C, </ RTI> it was stirred at that temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydro was prepared in the same manner as in Reference Example 38 under argon atmosphere, and a solution of the obtained concentrated residue in 3 ml of dehydrated dichloromethane was prepared. After dropwise addition of 200 mg (0.549 mmol) of pyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate, 5 ml of dehydrated dichloromethane solution of 0.38 ml (2.2 mmol) of DIPEA at 0 ° C. Stir for 5 hours. Next, 0.26 ml (2.7 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 1 hour.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained total organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue is again subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 97: 3 to 90:10 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, Drying under reduced pressure gave 191 mg (yield 79%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 441 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.38-11.88 (m, 1 H), 9.97-9.65 (m, 1 H), 7.45-7.27 (m, 5 H), 4.96 (s, 1 H), 4.71 -4.49 (m, 1H), 4.29 (br d, J = 12.8 Hz, 1H), 3.31 (s, 3H), 1.68 (br s, 3H), 1.59 (s, 3H), 1.05-0.91 (m, 2H) ), 0.78-0.58 (m, 2 H), 0.01 (s, 9 H).

(Example 58)
(R) -N- {5- [2- (difluoromethoxy) -2-phenylacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3- Yl} -1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-336)

C. at 60 DEG C. in a solution of 1.01 g (4.17 mmol) of (R) -benzyl 2-hydroxy-2-phenylacetate and 158 mg (0.83 mmol) of copper (I) iodide in 15 ml of acetonitrile under an argon atmosphere; A solution of 2.2 ml (17 mmol) of 2-difluoro-2- (fluorosulfonyl) acetic acid in 20 ml of acetonitrile was added in portions of 2 ml every 5 minutes, and stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction solution allowed to cool to room temperature was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 70:30 (V / V)), and then the fraction containing the desired substance is concentrated under reduced pressure Gave 0.67 g of concentrated residue as a colorless oil.
After adding palladium / carbon 70 mg (ASCA2 (trade name), N.E. CHEMCAT company make, 54% water content) under argon atmosphere to a methanol solution of 0.67 g of the obtained concentrated residue, add hydrogen under reduced pressure And stirred at room temperature for 2 hours.
After completion of the reaction, the reaction solution was replaced with nitrogen atmosphere, the reaction solution was filtered through celite, the solid component was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain 0.42 g of concentrated residue as a pale yellow solid.
Under argon atmosphere, 0.072 ml (0.82 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of dehydrated DMF are sequentially added to 3 ml of a solution of 115 mg of the concentrated residue obtained at room temperature at room temperature, and then the temperature is as it is Stir for 15 minutes.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a concentrated residue.
Under a argon atmosphere, a solution of the concentrated residue thus obtained in 1 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47. Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [ After adding at room temperature to a solution of 103 mg (0.273 mmol) of 3,4-c] pyrazole-2 (4H) -carboxylate and 0.24 ml (1.4 mmol) of DIPEA in dehydrated dichloromethane at room temperature, the temperature is maintained for 3.5 hours It stirred. Next, 0.15 ml (1.4 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at room temperature, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50-0: 100 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue was dissolved in ethyl acetate and n-hexane was added. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 48.1 mg (yield 36%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 491 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.30 & 11.86 (br s, total 1 H), 9.67-9.51 (m, 1 H), 7.48-7.37 (m, 5 H), 6.83 (t, J = 76.0 Hz, 1H), 5.78 (s, 1H), 4.83-4.61 (m, 1H), 4.24-4.07 (m, 1H), 2.56-2.35 (m, 2H), 2.24-2.10 (m, 2H), 1.91 -1.50 (m, 8 H), 0.04 (s, 9 H).

(Example 59)
(R) -N- [5- (2-Ethoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-344)

0.090 ml (1.0 mmol) of oxalyl chloride in a solution of 128 mg (0.710 mmol) of (R) -2-ethoxy-2-phenylacetic acid obtained in the same manner as in Reference Example 55 in 3 ml of dehydrated dichloromethane under an argon atmosphere, After sequentially adding 0.010 ml (0.13 mmol) of dehydrated DMF at 0 ° C., the mixture was stirred at the same temperature for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a concentrated residue.
Under a argon atmosphere, a solution of the concentrated residue thus obtained in 1 ml of dehydrated dichloromethane was synthesized in the same manner as in Reference Example 47. Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [ After adding at 0 ° C to a solution of 112 mg (0.295 mmol) of 3,4-c] pyrazole-2 (4H) -carboxylate and 0.30 ml (1.7 mmol) of DIPEA at 0 ° C., the solution is stirred for 30 minutes as it is did. Next, 0.11 ml (1.01 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous potassium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50-0: 100 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in ethyl acetate, n-hexane was added, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 69.7 mg (yield 50%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 469 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.26 & 11.85 (br s, total 1 H), 9.67-9.48 (m, 1 H), 7.43-7.27 (m, 5 H), 5.04 (s, 1 H) , 4.73-4.47 (m, 1H), 4.44-4.24 (m, 1H), 3.62-3.40 (m, 2H), 2.58-2.36 (m, 2H), 2.25-2.10 (m, 2H), 1.90-1.53 ( m, 8 H), 1. 14 (t, J = 7.0 Hz, 3 H), 0.05 (s, 9 H).

(Example 60)
(R) -1- (ethyldimethylsilyl) -N- [5- (2-methoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c ] Pyrazol-3-yl] cyclobutanecarboxamide (Compound No. IV-334)

Under nitrogen atmosphere, 0.080 ml (0.93 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF were added to a solution of 107 mg (0.646 mmol) of (R) -2-methoxy-2-phenylacetic acid in 2 ml of dehydrated dichloromethane After sequentially added at 0 ° C., the mixture was stirred at the same temperature for 3 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5,6-dihydro, which was synthesized in the same manner as in Reference Example 12, was obtained a solution of the concentrated residue thus obtained in 1 ml of anhydrous dichloromethane under a nitrogen atmosphere. After adding to a solution of 1 117 mg (0.299 mmol) of pyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate, 0.21 ml (1.2 mmol) of DIPEA in 1 ml of dehydrated dichloromethane at 0 ° C., Stir for .5 hours. Next, 0.16 ml (1.5 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution diluted with dichloromethane was washed with a 5% aqueous potassium hydrogen sulfate solution, and then separated. The aqueous layer was extracted twice with dichloromethane, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentration residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 115 mg of the title compound (yield 82 %) As a white solid.
Mass spectrum (CI, m / z): 469 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.26 & 11.84 (s, total 1 H), 9.67-9.48 (m, 1 H), 7.42-7.27 (m, 5 H), 4.95 (s, 1 H), 4.71-4.52 (m, 1H), 4.35-4.23 (m, 1H), 3.30 (s, 3H), 2.56-2.37 (m, 2H), 2.26-2.11 (m, 2H), 1.90-1.52 (m, 8H) ), 0.88 (t, J = 7.8 Hz, 3 H), 0.53 (q, J = 7.8 Hz, 2 H), 0.09-0.01 (m, 6 H).

(Example 61)
(R) -N- [5- (2-Cyclopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-364)

To a solution of 140 mg (0.728 mmol) of (R) -2-cyclopropoxy-2-phenylacetic acid synthesized in the same manner as in Reference Example 57 in 2 ml of dehydrated dichloromethane was added 0.006 ml (0.08 mmol) of DMF while stirring under an argon atmosphere. ), Oxalyl chloride 0.083 ml (0.95 mmol) was added at 0 ° C. and stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, synthesized by the same method as in Reference Example 47, was used to prepare a solution of the concentrated residue thus obtained in 3 ml of dehydrated dichloromethane. To a solution of 150 mg (0.396 mmol) of 4-c] pyrazole-2 (4H) -carboxylate and 0.350 ml (2.00 mmol) of DIPEA in 2 ml of dehydrated dichloromethane was added dropwise at 0 ° C. with stirring under an argon atmosphere, at room temperature. Stir for 2 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under argon atmosphere, 0.130 ml (1.19 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of 2 ml of dehydrated dichloromethane obtained at room temperature at room temperature and then stirred at room temperature for 16 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in ethyl acetate, then added to n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 80 mg (yield 42%) of the title compound as a white solid .
Mass spectrum (CI, m / z): 481 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.37-11.83 (m, 1 H), 9.59 (br s, 1 H), 7.42-7.28 (m, 5 H), 5.10 (s, 1 H), 4.73- 4.54 (m, 1 H), 4. 35 (d, J = 12.4 Hz, 1 H), 3. 40 (tt, J = 3.0, 6.1 Hz, 1 H), 2.59-2.37 (m, 2 H), 2.24-2.12 (m, 2 H) , 1.90-1.74 (m, 2H), 1.70 (s, 3H), 1.61 (s, 3H), 0.69-0.53 (m, 2H), 0.51-0.39 (m, 2H), 0.05 (s, 9H).

(Example 62)
(R) -N- [5- (2-isopropoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl] -1- (trimethylsilyl) cyclobutanecarboxamide (compound number IV-360)

0.10 ml (1.2 mmol) of oxalyl chloride in a solution of 165 mg (0.849 mmol) of (R) -2-isopropoxy-2-phenylacetic acid synthesized in the same manner as in Reference Example 58 under argon atmosphere in 2 ml of dehydrated dichloromethane After sequentially adding 0.0050 ml (0.065 mmol) of dehydrated DMF at 0 ° C., the mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was prepared in the same manner as in Reference Example 47, and a solution of the concentrated residue thus obtained in 1 ml of dehydrated dichloromethane was synthesized under an argon atmosphere. After adding to a solution of 128 mg (0.338 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate, 0.30 ml (1.7 mmol) of DIPEA in 1 ml of dehydrated dichloromethane at 0 ° C., Stir for 5 hours.
After completion of the reaction, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution and stirred. After separation, the aqueous layer was extracted twice with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 60:40 (V / V)), then concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue I got
Under argon atmosphere, 0.15 ml (1.4 mmol) of N, N-dimethylethane-1,2-diamine was added to a THF 2 ml solution of the obtained concentrated residue at room temperature, and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentration residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 135 mg of the title compound (yield 83 %) As a white solid.
Mass spectrum (CI, m / z): 483 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.40 to 11.82 (m, 1 H), 9.75-9.42 (m, 1 H), 7.40-7.27 (m, 5 H), 5.11 (s, 1 H), 4.65 -4.38 (m, 2H), 3.68 (spt, J = 6.0 Hz, 1H), 2.47-2.35 (m, 2H), 2.23-2.09 (m, 2H), 1.87-1.71 (m, 2H), 1.67 (s) , 3H), 1.61 (s, 3H), 1.16 (d, J = 6.0 Hz, 3 H), 1. 13 (d, J = 6.0 Hz, 3 H), 0.04 (s, 9 H).

(Example 63)
(R) -N- {6,6-dimethyl-5- [2-phenyl-2- (trifluoromethoxy) acetyl] -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-340)

To a solution of 160 mg of (R) -2-phenyl-2- (trifluoromethoxy) acetic acid (containing impurities) synthesized in the same manner as in Reference Example 60 in 2 ml of dehydrated dichloromethane under stirring in an argon atmosphere, 0.083 ml of oxalyl chloride (0.95 mmol), 0.006 ml (0.08 mmol) of DMF were added at 0 ° C., and stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, synthesized by the same method as in Reference Example 47, was used to prepare a solution of the concentrated residue thus obtained in 3 ml of dehydrated dichloromethane. To a solution of 150 mg (0.396 mmol) of 4-c] pyrazole-2 (4H) -carboxylate and 0.350 ml (2.00 mmol) of DIPEA in 2 ml of dehydrated dichloromethane was added dropwise at 0 ° C. with stirring under an argon atmosphere, at room temperature. Stir for 2 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.130 ml (1.19 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of 2 ml of dehydrated dichloromethane obtained above at room temperature, and then stirred at room temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue is dissolved in ethyl acetate, then added to n-hexane, and the precipitated solid is collected by filtration and dried under reduced pressure to give 97.6 mg (yield 48%) of the title compound as a white solid. Obtained.
Mass spectrum (CI, m / z): 509 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.39-11.84 (m, 1 H), 9.58 (br s, 1 H), 7.54-7.41 (m, 5 H), 6.06 (s, 1 H), 4.78 ( br d, J = 11.9 Hz, 1H), 4.08 (br d, J = 11.9 Hz, 1H), 2.58-2.35 (m, 2H), 2.23-2.10 (m, 2H), 1.88-1.73 (m, 2H) , 1.70 (s, 3 H), 1. 60 (s, 3 H), 0.04 (s, 9 H).

(Example 64)
(R) -N- [6,6-dimethyl-5- (2-phenyl-2-propoxyacetyl) -1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-352)

0.10 ml (1.2 mmol) of oxalyl chloride in a solution of 146 mg (0.753 mmol) of (R) -2-phenyl-2-propoxyacetic acid synthesized in the same manner as in Example 62 under argon atmosphere and 2 ml of dehydrated dichloromethane; After sequentially adding 0.0050 ml (0.065 mmol) of DMF at 0 ° C., the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was prepared in the same manner as in Reference Example 47, and a solution of the concentrated residue thus obtained in 1 ml of dehydrated dichloromethane was synthesized under an argon atmosphere. After adding at 0 ° C. a solution of 144 mg (0.380 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate, 0.33 ml (1.9 mmol) of DIPEA at 0 ° C., the temperature is Stir for 5 hours.
After completion of the reaction, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution and stirred. After separation, the aqueous layer was extracted twice with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 60:40 (V / V)), then concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue I got
Under argon atmosphere, 0.17 ml (1.6 mmol) of N, N-dimethylethane-1,2-diamine was added to a THF 2 ml solution of the obtained concentrated residue at room temperature, and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 85:15 to 60:40 (V / V)), and the fractions containing the desired substance are concentrated under reduced pressure did. The resulting concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 144 mg of the title compound (yield 80 %) As a white solid.
Mass spectrum (CI, m / z): 483 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.42-11.75 (m, 1 H), 9.56 (br s, 1 H), 7.43-7.27 (m, 5 H), 5.03 (s, 1 H), 4.71- 4.47 (m, 1H), 4.39 (br d, J = 12.5 Hz, 1H), 3.51-3.43 (m, 1H), 3.41-3.24 (m, 1H), 2.60-2.36 (m, 2H), 2.25-2.10 (m, 2 H), 1. 88-1.7 2 (m, 2 H), 1. 68 (s, 3 H), 1. 65-1. 48 (m, 5 H), 0.87 (t, J = 7.4 Hz, 3 H), 0.04 (s, 9 H).

(Example 65)
N- {5- [2- (4-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-394)

To a suspension of 229 mg (containing impurities) of 2- (4-fluorophenyl) -2-methoxyacetic acid (containing impurities) synthesized in the same manner as in Reference Example 64 in 2 ml of dehydrated dichloromethane was added 0.150 ml of oxalyl chloride while stirring under an argon atmosphere ( 1.71 mmol) and 0.011 ml (0.14 mmol) of DMF were added at 0 ° C., and stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, synthesized by the same method as in Reference Example 47, was used to prepare a solution of the concentrated residue thus obtained in 3 ml of dehydrated dichloromethane. A solution of 265 mg (0.700 mmol) of 4-c] pyrazole-2 (4H) -carboxylate, 0.620 ml (3.55 mmol) of DIPEA in 2 ml of dehydrated dichloromethane is added dropwise at 0 ° C. with stirring under an argon atmosphere, at room temperature. Stir for 1 hour.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under argon atmosphere, 0.230 ml (2.11 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of 2 ml of dehydrated dichloromethane obtained at room temperature at room temperature, and then stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in dichloromethane, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was stirred and partitioned. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was dissolved in ethyl acetate, then added to n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 174 mg (yield 53%) of the title compound as a white solid .
Mass spectrum (CI, m / z): 473 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.27 & 11.91 (br s, total 1 H), 9.58 (br s, 1 H), 7.47-7.36 (m, 2 H), 7.26-7.14 (m, 2 H) ), 4.99 (s, 1 H), 4. 76-4.5 3 (m, 1 H), 4.32 (br d, J = 12.4 Hz, 1 H), 3. 29 (s, 3 H), 2.58-2.36 (m, 2 H), 2. 25-2.10 (m, 2H), 1.88-1.72 (m, 2H), 1.69 (br s, 3H), 1.60 (s, 3H), 0.05 (s, 9H).

(Example 66)
N- {5- [2- (3-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-389)

To a suspension of 146 mg (containing impurities) of 2- (3-fluorophenyl) -2-methoxyacetic acid (containing impurities) synthesized in the same manner as in Reference Example 67 in 2 ml of dehydrated dichloromethane was added 0.080 ml of oxalyl chloride while stirring under an argon atmosphere ( 0.91 mmol) and 0.010 ml (0.13 mmol) of DMF were added at 0 ° C. and stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, synthesized by the same method as in Reference Example 47, was used to prepare a solution of the concentrated residue thus obtained in 3 ml of dehydrated dichloromethane. A solution of 200 mg (0.528 mmol) of 4-c] pyrazole-2 (4H) -carboxylate, 0.462 ml (2.65 mmol) of DIPEA in 2 ml of dehydrated dichloromethane was added dropwise at room temperature with stirring under an argon atmosphere. Stir for hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.173 ml (1.59 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of 2 ml of anhydrous dichloromethane obtained in the concentration residue at room temperature, and then stirred at room temperature for 16 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in methanol, then added to water, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 187 mg (yield 75%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 473 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.40-11.81 (m, 1 H), 9.60 (br s, 1 H), 7.48-7.38 (m, 1 H), 7.24-7.13 (m, 3 H), 5.03 (s, 1H), 4.75-4.54 (m, 1H), 4.39 (br d, J = 12.7 Hz, 1H), 3.32 (s, 3H), 2.59-2.36 (m, 2H), 2.24-2.10 (m , 2H), 1.88-1.72 (m, 2H), 1.69 (s, 3H), 1.60 (s, 3H), 0.05 (s, 9H).

(Example 67)
(R) -N- {5- [2- (2-fluorophenyl) -2-methoxyacetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole- 3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-385)

A solution of 200 mg (1.09 mmol) of (R) -2- (2-fluorophenyl) -2-methoxyacetic acid synthesized in the same manner as in Reference Example 69 in a 2 ml suspension of dehydrated dichloromethane was stirred under an argon atmosphere and chloride was added. 0.111 ml (1.27 mmol) of oxalyl and 0.010 ml (0.13 mmol) of DMF were added at 0 ° C. and stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, synthesized by the same method as in Reference Example 47, was used to prepare a solution of the concentrated residue thus obtained in 3 ml of dehydrated dichloromethane. To a solution of 200 mg (0.528 mmol) of 4-c] pyrazole-2 (4H) -carboxylate and 0.500 ml (2.86 mmol) of DIPEA in 2 ml of dehydrated dichloromethane was added dropwise at room temperature with stirring under an argon atmosphere. Stir for hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.173 ml (1.59 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of 2 ml of anhydrous dichloromethane obtained in the concentration residue at room temperature and then stirred at room temperature for 3 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in methanol, then added to water, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 164 mg (yield 66%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 473 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.42-11.83 (m, 1 H), 9.60 (br s, 1 H), 7.46-7.34 (m, 2 H), 7.27-7.18 (m, 2 H), 5.22 (s, 1H), 4.75 (d, J = 12.3 Hz, 1 H), 4.20 (d, J = 12.3 Hz, 1 H), 3.32 (s, 3 H), 2.58-2.37 (m, 2 H), 2.25-2.11 (m, 2 H), 1. 88-1. 73 (m, 2 H), 1. 70 (s, 3 H), 1. 60 (s, 3 H), 0.05 (s, 9 H).

(Example 68)
N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl } -1- (Trimethylsilyl) cyclobutanecarboxamide (Compound No. IV-399)

A suspension of 60 mg (containing impurities) of 2-methoxy-2- (thiophen-2-yl) acetic acid synthesized in the same manner as in Reference Example 72 in 2 ml of dehydrated dichloromethane was added with 0. 0. oxalyl chloride while stirring under an argon atmosphere. 036 ml (0.41 mmol), DMF 0.005 ml (0.07 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, synthesized by the same method as in Reference Example 47, was used to prepare a solution of the concentrated residue thus obtained in 3 ml of dehydrated dichloromethane. A solution of 120 mg (0.317 mmol) of 4-c] pyrazole-2 (4H) -carboxylate, 0.166 ml (0.950 mmol) of DIPEA in 2 ml of dehydrated dichloromethane is added dropwise at 0 ° C. with stirring under an argon atmosphere, at room temperature. Stir for 2 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure. Gave a concentrated residue.
Under an argon atmosphere, 0.104 ml (0.954 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of the concentrated residue obtained in 2 ml of dehydrated dichloromethane at room temperature, and the mixture was stirred at room temperature for 16 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in methanol and then added to water, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 62 mg (yield 42%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 461 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.41-11.86 (m, 1 H), 9.82-9.47 (m, 1 H), 7.57 (dd, J = 1.3, 5.0 Hz, 1 H), 7.13-7.06 (m, 1 H), 7.01 (dd, J = 3.5, 5.0 Hz, 1 H), 5.26 (s, 1 H), 4.84-4.64 (m, 1 H), 4.41 (br d, J = 12.4 Hz, 1 H), 3.28 (s, 3 H), 2.58-2. 37 (m, 2 H), 2. 26-2. 10 (m, 2 H), 1. 89-1. 73 (m, 2 H), 1. 70 (s, 3 H), 1.62 (s, 3 H), 0.06 (s , 9H).

(Example 69)
(-)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-401)

N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3, synthesized as in Example 68. 4-c] pyrazol-3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide 0.041 g (0.089 mmol) was subjected to optical resolution preparative chromatography (column; CHIRALPAK (trade name) ID, elution solvent; n-hexane: The fraction was subjected to ethanol = 85: 15 (V / V) and the fraction containing the previously eluted optical active substance was concentrated under reduced pressure to obtain 17 mg (yield 41%) of the title compound as a white solid.
Specific rotation: [α] _D ²⁰ = −51 ° (c = 0.20, methanol).
Mass spectrum (CI, m / z): 461 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.23 (br s, 1 H), 9.67 (br s, 1 H), 7.57 (dd, J = 1.2, 5.0 Hz, 1 H), 7.13-7.06 (m , 1H), 7.01 (dd, J = 3.5, 5.0 Hz, 1 H), 5.26 (s, 1 H), 4.74 (br d, J = 12.5 Hz, 1 H), 4.41 (d, J = 12.5 Hz, 1 H), 3.28 (s, 3 H), 2.58-2. 37 (m, 2 H), 2. 24-2. 11 (m, 2 H), 1. 89-1. 74 (m, 2 H), 1. 70 (s, 3 H), 1.62 (s, 3 H), 0.06 ( s, 9H).
HPLC analysis:
Column; CHIRALPAK (trade name) ID 4.6 x 250 mm
Eluent; n-hexane / ethanol = 85/15 (V / V)
Flow rate: 1.0 ml / min
Temperature; 40 ° C
Detection wavelength: 254 nm
Retention time; 7.6 minutes Optical purity:> 99% ee

(Example 70)
(+)-N- {5- [2-methoxy-2- (thiophen-2-yl) acetyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole -3-yl} -1- (trimethylsilyl) cyclobutanecarboxamide (compound number IV-400)

In the optical resolution preparative chromatography operation of Example 69, the fraction containing the optically active substance eluted later was concentrated under reduced pressure to give 14 mg (yield 34%) of the title compound as a white solid.
Specific rotation: [α] _D ²⁰ = + 66 ° (c = 0.20, methanol).
Mass spectrum (CI, m / z): 461 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.23 (br s, 1 H), 9.66 (br s, 1 H), 7.57 (dd, J = 1.2, 5.0 Hz, 1 H), 7.14-7.06 (m , 1H), 7.01 (dd, J = 3.5, 5.0 Hz, 1 H), 5.26 (s, 1 H), 4.74 (br d, J = 12.4 Hz, 1 H), 4.41 (d, J = 12.4 Hz, 1 H), 3.28 (s, 3 H), 2.58-2. 37 (m, 2 H), 2. 26-2. 10 (m, 2 H), 1. 89-1. 74 (m, 2 H), 1. 70 (s, 3 H), 1.62 (s, 3 H), 0.06 ( s, 9H).
HPLC analysis:
Column; CHIRALPAK (trade name) ID 4.6 x 250 mm
Eluent; n-hexane / ethanol = 85/15 (V / V)
Flow rate: 1.0 ml / min
Temperature; 40 ° C
Detection wavelength: 254 nm
Retention time; 9.7 minutes Optical purity:> 99% ee

(Example 71)
N-{[1- (hydroxymethyl) cyclobutyl] (phenyl) methyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4-c] pyrazole -5 (1 H)-carboxamide (compound number IV-179)

2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2 synthesized in the same manner as in Reference Example 73 under an argon atmosphere. , 5 (4H, 6H) -dicarboxylates 131 mg (0.243 mmol) and ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo In a solution of a mixture of 79 mg (0.18 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate in 3 ml of dehydrated 1,4-dioxane, 0.34 ml (2.0 mmol) of DIPEA was prepared in the same manner as in Reference Example 74. Mg of {1- [amino (phenyl) methyl] cyclobutyl} methanol synthesized by Were successively added .23Mmol) was stirred at room temperature for 1.5 hours at 90 ° C.. The reaction solution was allowed to cool to room temperature, 0.21 ml (1.9 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature, and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 30:70 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in ethyl acetate, n-hexane was added, and the precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 187 mg of a white solid. The resulting solid is subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent; acetonitrile: 1 mM aqueous potassium dihydrogen phosphate solution = 50: 50 (V / V)) to contain the desired product. The fraction was concentrated under reduced pressure to remove acetonitrile. The solid precipitated in the concentration process was collected by filtration, washed with water and dried under reduced pressure to obtain 156 mg (yield 70%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 524 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.34-11.78 (m, 1 H), 9.87-9.34 (m, 1 H), 7.35-7.27 (m, 4 H), 7.24-7.16 (m, 1 H) , 6.75 (d, J = 7.9 Hz, 1H), 5.49 (br s, 1H), 4.95 (d, J = 7.9 Hz, 1H), 4.47-4.20 (m, 2H), 3.49-3.41 (m, 1H) , 3.26-3.18 (m, 1H), 2.57-2.39 (m, 2H), 2.26-2.14 (m, 2H), 2.11-1.99 (m, 2H), 1.98-1.74 (m, 5H), 1.61 (s, 3H), 1.53 (s, 3H), 1.26-1.13 (m, 1H), 0.08 (s, 9H).

(Example 72)
(R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 ,, 4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-200)

Under argon atmosphere, a solution of 128 mg (containing impurities) of (R) -1- (2-amino-2-phenylethyl) cyclopropanol synthesized in the same manner as in Reference Example 76 in 2 ml of dehydrated 1,4-dioxane was added with DIPEA0. 26 ml (1.5 mmol) of ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3 synthesized in the same manner as in Reference Example 3 After sequentially adding 154 mg (0.349 mmol) of 4, 4-c] pyrazole-2 (4H) -carboxylate at room temperature, the mixture was stirred at 90 ° C. for 2 hours. After the reaction solution was allowed to cool to room temperature, 0.16 ml (1.5 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature, and the mixture was stirred at that temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and extracted twice with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 40:60 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue is suspended in an ethyl acetate / n-hexane mixed solvent and stirred, and then the insoluble matter is collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 139 mg of the title compound (yield 79%) was obtained as a white solid.
Mass spectrum (CI, m / z): 510 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.23 & 11.80 (br s, total 1 H), 9.75-9.47 (m, 1 H), 7.43-7.37 (m, 2 H), 7.34-7.27 (m, 2H), 7.23-7.17 (m, 1H), 6.51-6.33 (m, 1H), 5.54-5.37 (m, 1H), 5.14-5.05 (m, 1H), 4.66-4.29 (m, 2H), 2.61- 2.39 (m, 2H), 2.26-2.06 (m, 3H), 1.90-1.50 (m, 9H), 0.55-0.37 (m, 3H), 0.18-0.04 (m, 10H).

(Example 73)
(R) -N- (3-ethyl-3-hydroxy-1-phenylpentyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4- c] pyrazol-5 (1H) -carboxamide (compound No. IV-215)

In a solution of 118 mg (0.568 mmol) of (R) -1-amino-3-ethyl-1-phenylpentan-3-ol synthesized in the same manner as in Reference Example 78 under argon atmosphere in 2 ml of dehydrated 1,4-dioxane, 0.2 ml (1.1 mmol) of DIPEA, ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo synthesized as described in Reference Example 3 After 128 mg (0.290 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate were sequentially added at room temperature, the mixture was stirred at 90 ° C. for 2 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 75: 25 to 40:60 (V / V)), then concentrated under reduced pressure and dried under reduced pressure. I got
Under an argon atmosphere, 0.13 ml (1.2 mmol) of N, N-dimethylethane-1,2-diamine was added to a THF 2 ml solution of the obtained concentrated residue at room temperature, and then stirred at room temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue is suspended in a mixed solvent of ethyl acetate / n-hexane, stirred at room temperature, insolubles are collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 123 mg of the title compound (yield 79%) was obtained as a white solid.
Mass spectrum (CI, m / z): 540 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.35-11.68 (m, 1 H), 9.56 (br s, 1 H), 7.37-7.24 (m, 4 H), 7.19-7.13 (m, 1 H), 6.56 (d, J = 5.8 Hz, 1H), 4.91-4.81 (m, 1H), 4.54-4.31 (m, 3H), 2.58-2.41 (m, 2H), 2.26-2.13 (m, 2H), 1.95- 1.73 (m, 3H), 1.63-1.55 (m, 4H), 1.53 (s, 3H), 1.49-1.33 (m, 4H), 0.82 (t, J = 7.4 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3 H), 0.09 (s, 9 H).

(Example 74)
(R) -N- [1- (4-Fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-272)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. (R) -4-amino-4- (4-fluoro) synthesized in the same manner as in Reference Example 82 under argon flow to a solution of 599 mg (1.36 mmol) of 2 (4H) -carboxylate in 3 ml of 1,4-dioxane After successively adding 134 mg (containing impurities) of phenyl) -2-methylbutan-2-ol and 0.602 ml (3.40 mmol) of DIPEA at room temperature, the mixture was stirred at 100 ° C. for 1 hour. Then, 0.318 ml (3.40 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature and stirred at the same temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; ethyl acetate: methanol = 100: 0 to 90:10 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The resulting concentrated residue is subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent; acetonitrile: 1 mM aqueous potassium dihydrogen phosphate solution = 30: 70 to 50:50 (V / V)) The fractions containing the desired product were concentrated under reduced pressure to remove acetonitrile and extracted with ethyl acetate. The resulting organic layer is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to give 48 mg of the title compound (yield 8% [2 steps]) as a white solid. Obtained.
Mass spectrum (CI, m / z): 530 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.77 (br s, total 1 H), 9.74-9.41 (m, 1 H), 7.40-7.32 (m, 2 H), 7.14-7.05 (m, 2H), 6.66-6.44 (m, 1H), 4.94-4.84 (m, 1H), 4.75-4.60 (m, 1H), 4.52-4.31 (m, 2H), 2.59-2.39 (m, 2H), 2.27- 2.11 (m, 2 H), 2.04-1. 73 (m, 3 H), 1. 70-1. 45 (m, 7 H), 1. 15 (s, 3 H), 1. 13 (s, 3 H), 0.09 (s, 9 H).

(Example 75)
(R) -N- [1- (3-fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide (compound No. IV-254)

The (R) -ethyl 5-{[1- (3-fluorophenyl) -3-hydroxy-3-methylbutyl] carbamoyl} -6,6-dimethyl-3- [1- (1-) synthesized in the same manner as in Reference Example 87. Trimethylsilyl) cyclobutanecarboxamido] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate A solution of 149 mg (0.248 mmol) in 3 ml of dichloromethane was stirred under argon flow with N, N- 0.108 ml (0.992 mmol) of dimethylethane-1,2-diamine was added in one portion at room temperature and stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 17:83 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane and dried under reduced pressure at 50 ° C. to give 101 mg (yield 77%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 530 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.77 (br s, total 1 H), 9.71-9.47 (m, 1 H), 7.37-7.26 (m, 1 H), 7.22-7.11 (m, 2H), 7.02-6.92 (m, 1H), 6.65-6.51 (m, 1H), 4.95-4.87 (m, 1H), 4.76-4.60 (m, 1H), 4.55-4.35 (m, 2H), 2.57- 2.40 (m, 2H), 2.27-2.12 (m, 2H), 2.03-1.74 (m, 3H), 1.66 (dd, J = 3.1, 14.2 Hz, 1H), 1.59 (br s, 3H), 1.54 (br s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.09 (s, 9H).

(Example 76)
(R) -N- [1- (2-fluorophenyl) -3-hydroxy-3-methylbutyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [ 3,4-c] pyrazole-5 (1H) -carboxamide (compound No. IV-236)

The (R) -ethyl 5-{[1- (2-fluorophenyl) -3-hydroxy-3-methylbutyl] carbamoyl} -6,6-dimethyl-3- [1- (1-) synthesized in the same manner as in Reference Example 92. Trimethylsilyl) cyclobutanecarboxamido] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 150 mg (0.249 mmol) of a solution of 150 ml (0.249 mmol) in dichloromethane was treated under argon flow with stirring N, N- 0.109 ml (1.00 mmol) of dimethylethane-1,2-diamine was added at once at room temperature and stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 17:83 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane, and dried at 50 ° C. under reduced pressure to give 112 mg (yield 85%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 530 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.20 & 11.76 (br s, total 1 H), 9.72-9.46 (m, 1 H), 7.54-7.43 (m, 1 H), 7.26-7.17 (m, 1H), 7.17-7.04 (m, 2H), 6.62-6.47 (m, 1H), 5.23-5.14 (m, 1H), 4.78-4.62 (m, 1H), 4.55-4.35 (m, 2H), 2.58- 2.40 (m, 2H), 2.27-2.12 (m, 2H), 2.02-1.73 (m, 3H), 1.67-1.45 (m, 7H), 1.18 (s, 3H), 1.15 (s, 3H), 0.09 ( s, 9H).

(Example 77)
(R) -N- (5-hydroxy-2,5-dimethylhexan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide (compound number IV-221)

The (R) -ethyl 5-[(5-hydroxy-2,5-dimethylhexan-3-yl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) was synthesized in the same manner as in Reference Example 96. Cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate A solution of 99 mg (0.18 mmol) in 3 ml of dichloromethane was stirred under argon flow with N, N-dimethyl ethane. -1, 2-diamine 0.078 ml (0.72 mmol) was added at once at room temperature and stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 16:84 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane and dried under reduced pressure at 50 ° C. to give 72 mg (yield 84%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 478 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.19 & 11.81 (br s, total 1 H), 9.71-9.44 (m, 1 H), 5.63 (br s, 1 H), 4.47-4.25 (m, 3 H) ), 3.71-3.60 (m, 1H), 2.57-2.39 (m, 2H), 2.27-2.11 (m, 2H), 1.90-1.66 (m, 3H), 1.65-1.52 (m, 7H), 1.49-1.42 (m, 1 H), 1.10 (s, 3 H), 1.09 (s, 3 H), 0.82 (d, J = 6.8 Hz, 6 H), 0.08 (s, 9 H).

(Example 78)
N- [1- (4-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazol-5 (1H) -carboxamide (compound No. IV-276)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 2) To a solution of 0.745 g (1.69 mmol) of 2 (4H) -carboxylate in 8 ml of 1,4-dioxane while stirring under argon, 1.47 ml (8.44 mmol) of DIPEA, synthesized in the same manner as in Reference Example 3 Then, 1.00 g (5.07 mmol) of -amino-3- (4-fluorophenyl) -2,2-dimethylpropan-1-ol was sequentially added at room temperature, and the mixture was stirred at 90 ° C for 1.5 hours. Then, after the reaction solution was allowed to cool to room temperature, 0.738 ml (6.78 mmol) of N, N-dimethylethane-1,2-diamine was added dropwise at room temperature and stirred at room temperature for 4 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentration residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 19:81 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The concentrated residue was dissolved in 60 ml of ethyl acetate and washed three times with 10 ml of 5% aqueous potassium hydrogen sulfate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane and dried under reduced pressure at 50 ° C. to give 509 mg (yield 57%) of the title compound as a white solid.
Mass spectrum (ESI, m / z): 530 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.80 (br s, total 1 H), 9.68-9.44 (m, 1 H), 7.39-7.32 (m, 2 H), 7.17-7.09 (m, 2H), 6.91-6.78 (m, 1H), 5.46 (br s, 1H), 4.65 (d, J = 7.9 Hz, 1H), 4.45-4.28 (m, 2H), 3.23 (dd, J = 4.2, 10.6) Hz, 1H), 3.08-2.99 (m, 1H), 2.60-2.39 (m, 2H), 2.27-2.14 (m, 2H), 1.91-1.73 (m, 2H), 1.65-1.49 (m, 6H), 1.05 (s, 3H), 0.64 (s, 3H), 0.09 (s, 9H).

(Example 79)
N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazol-5 (1H) -carboxamide (compound No. IV-258)

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. 3-amino-3 synthesized in the same manner as in Reference Example 100, into a solution of 162 mg (0.367 mmol) of 2 (4H) -carboxylate in 4 ml of 1,4-dioxane under an argon atmosphere, 0.32 ml (1.9 mmol) of DIPEA After adding 227 mg (1.15 mmol) of-(3-fluorophenyl) -2,2-dimethylpropan-1-ol at room temperature, the reaction was performed at 100 ° C. for 2.5 hours. After allowing to cool, 0.12 ml (1.1 mmol) of N, N-dimethyl-1,2-diamine was added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, 20 ml of ethyl acetate is added to the residue, 10 ml of 5% aqueous potassium hydrogen sulfate solution, 10 ml of saturated aqueous sodium hydrogencarbonate solution and 10 ml of saturated aqueous sodium chloride solution are sequentially washed, and the organic layer is anhydrous magnesium sulfate The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 81: 19 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue was dissolved in a small amount of dichloromethane, n-hexane was added, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 159 mg (yield 82%) of the title compound as a white solid .
Mass spectrum (CI, m / z): 530 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.22 & 11.89 (br s, total 1 H), 9.79-9.40 (m, 1 H), 7.39-7.29 (m, 1 H), 7.22-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (d, J = 8.0 Hz, 1 H), 5.56-5.41 (m, 1 H), 4.67 (d, J = 8.0 Hz, 1 H), 4.49-4.27 (m , 2H), 3.25 (dd, J = 4.0, 10.6 Hz, 1H), 3.05 (dd, J = 4.0, 10.6 Hz, 1H), 2.56-2.40 (m, 2H), 2.29-2.13 (m, 2H), 1.92-1.72 (m, 2H), 1.60 (br s, 3H), 1.52 (br s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).

(Example 80)
(-)-N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-260)

N- [1- (3-Fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] synthesized as in Example 79 0.129 g (0.244 mmol) of 4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide was subjected to optical resolution preparative chromatography (column; CHIRALPAK (trade name) ID, elution solvent; By subjecting to n-hexane: ethanol: methanol = 95: 5: 1 (V / V), and concentrating the fraction containing the previously eluted optically active substance under reduced pressure, 47 mg of the title compound (yield 36%) Was obtained as a white solid.
Specific rotation: [α] _D ²⁰ = −53 ° (c = 0.23, methanol).
Mass spectrum (CI, m / z): 530 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.88 (br s, total 1 H), 9.78-9.41 (m, 1 H), 7.38-7.30 (m, 1 H), 7.21-7.13 (m, 1 2H), 7.08-7.01 (m, 1H), 6.86 (br d, J = 8.3 Hz, 1H), 5.56-5.40 (m, 1H), 4.67 (d, J = 8.3 Hz, 1H), 4.47-4.30 ( m, 2H), 3.25 (brdd, J = 3.9, 10.5 Hz, 1H), 3.05 (br dd, J = 3.9, 10.5 Hz, 1H), 2.60-2.40 (m, 2H), 2.26-2.13 (m, 2H) ), 1.90-1.73 (m, 2H), 1.60 (br s, 3H), 1.52 (s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).
HPLC analysis:
Column; CHIRALPAK (trade name) ID 4.6 x 250 mm
Eluent; n-hexane / ethanol / methanol = 95/5/1 (V / V)
Flow rate: 1.0 ml / min
Temperature; 40 ° C
Detection wavelength: 254 nm
Retention time; 8.8 minutes Optical purity:> 99% ee

(Example 81)
(+)-N- [1- (3-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6- Dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxamide (Compound No. IV-259)

In the optical resolution preparative chromatography operation of Example 80, the fraction containing the optically active substance eluted later was concentrated under reduced pressure to obtain 45 mg (yield 35%) of the title compound as a white solid.
Specific rotation: [α] _D ²⁰ = + 59 ° (c = 0.22, methanol).
Mass spectrum (CI, m / z): 530 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.94 (br s, total 1 H), 9.78-9.41 (m, 1 H), 7.38-7.30 (m, 1 H), 7.21-7.13 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (br d, J = 8.1 Hz, 1 H), 5.56-5.39 (m, 1 H), 4.67 (d, J = 8.1 Hz, 1 H), 4.47-4.30 ( m, 2H), 3.25 (brdd, J = 3.8, 10.5 Hz, 1H), 3.05 (br dd, J = 3.8, 10.5 Hz, 1H), 2.59-2.40 (m, 2H), 2.27-2.13 (m, 2H) ), 1.90-1.73 (m, 2H), 1.60 (br s, 3H), 1.52 (s, 3H), 1.05 (s, 3H), 0.67 (s, 3H), 0.09 (s, 9H).
HPLC analysis:
Column; CHIRALPAK (trade name) ID 4.6 x 250 mm
Elution solvent; n-hexane / ethanol / methanol = 95/5/1 (V / V)
Flow rate: 1.0 ml / min
Temperature; 40 ° C
Detection wavelength: 254 nm
Retention time; 11.6 minutes Optical purity:> 98% ee

(Example 82)
N- [1- (2-fluorophenyl) -3-hydroxy-2,2-dimethylpropyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3 , 4-c] pyrazol-5 (1H) -carboxamide (compound number IV-240)

Argon atmosphere in a solution of 225 mg (1.14 mmol) of 3-amino-3- (2-fluorophenyl) -2,2-dimethylpropan-1-ol synthesized in the same manner as in Reference Example 101 in 4 ml of 1,4-dioxane Below, 0.32 ml (1.9 mmol) of DIPEA, ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] synthesized in the same manner as in Reference Example 3-5, 6- After adding dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 166 mg (0.376 mmol) at room temperature, it was reacted at 100 ° C. for 2.5 hours. After allowing to cool, 0.12 ml (1.1 mmol) of N, N-dimethylethane-1,2-diamine was added, and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, 20 ml of ethyl acetate is added to the residue, 10 ml of 5% aqueous potassium hydrogen sulfate solution, 10 ml of saturated aqueous sodium hydrogencarbonate solution and 10 ml of saturated aqueous sodium chloride solution are sequentially washed, and the organic layer is anhydrous magnesium sulfate The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 81: 19 to 30:70 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The obtained concentrated residue was dissolved in a small amount of dichloromethane, n-hexane was added, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 154 mg (yield 77%) of the title compound as a white solid .
Mass spectrum (CI, m / z): 530 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.22 & 11.87 (br s, total 1 H), 9.75-9.42 (m, 1 H), 7.53-7.44 (m, 1 H), 7.32-7.24 (m, 1H), 7.23-7.17 (m, 1H), 7.17-7.08 (m, 1H), 6.96-6.85 (m, 1H), 5.53 (br s, 1H), 5.03 (d, J = 7.9 Hz, 1H), 4.46-4.26 (m, 2H), 3.40-3.28 (m, 1H), 3.08 (dd, J = 4.0, 10.5 Hz, 1H), 2.56-2.39 (m, 2H), 2.27-2.12 (m, 2H), 1.92-1.72 (m, 2H), 1.65-1.47 (m, 6H), 1.10 (s, 3H), 0.69-0.60 (m, 3H), 0.09 (s, 9H).

(Example 83)
N- (1-hydroxy-2,2,4-trimethylpentan-3-yl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -4,6-dihydropyrrolo [3,4- c] pyrazol-5 (1H) -carboxamide (compound No. IV-225)

2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2 synthesized in the same manner as in Reference Example 73 under an argon atmosphere. , 5 (4H, 6H) -dicarboxylate: 133 mg (0.246 mmol) and ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo A solution of 80 mg (0.18 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate in 3 ml of a solution of dehydrated 1,4-dioxane in 0.37 ml (2.1 mmol) of DIPEA was prepared in the same manner as in Reference Example 103. Of 3-amino-2,2,4-trimethylpentan-1-ol synthesized by Were successively added 30 mmol) was stirred at room temperature for 2.5 hours at 90 ° C.. After the reaction solution was allowed to cool to room temperature, 0.23 ml (2.1 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature, and the mixture was stirred at that temperature for 14 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 30:70 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 107 mg of the title compound (yield 52 %) As a white solid.
Mass spectrum (CI, m / z): 478 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.42-11.70 (m, 1 H), 9.86-9.33 (m, 1 H), 5.48 (br d, J = 9.2 Hz, 1 H), 5.13-4.93 ( m, 1H), 4.48-4.22 (m, 2H), 3.55-3.48 (m, 1H), 3.45 (dd, J = 3.9, 10.7 Hz, 1H), 3.04 (dd, J = 5.4, 10.7 Hz, 1H) , 2.58-2.38 (m, 2H), 2.26-2.12 (m, 2H), 2.05-1.92 (m, 1H), 1.88-1.73 (m, 2H), 1.61 (br s, 3H), 1.59 (br s, 3H), 0.93 (s, 3H), 0.89 (d, J = 6.7 Hz, 6H), 0.79 (s, 3H), 0.07 (s, 9H).

(Example 84)
(R) -N- (3-hydroxy-3-methyl-1-phenylbutyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4 -C] pyrazole-5 (1H) -carboxamide (compound No. III-22)

Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (synthesized as in Reference Example 38 under an argon atmosphere) To a solution of 1.53 g (4.19 mmol) of 4H) -carboxylate in 20 ml of dry dichloromethane was added 2.60 ml (14.9 mmol) of DIPEA at room temperature. Next, 5 ml of a solution of 700 mg (2.36 mmol) of bis (trichloromethyl) carbonate in 5 ml of dehydrated dichloromethane was added dropwise at -78 ° C, and the temperature was raised for 0.5 hours as it is, and further heated to room temperature and stirred for 2 hours did.
After completion of the reaction, to the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and dichloromethane at -78 ° C, and the mixture was stirred for 1.5 hours while warming up to room temperature. The reaction mixture was separated, and the aqueous layer was extracted twice with ethyl acetate. The whole organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 75:25 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure to obtain a white solid. I got 1.75g.
A solution of 97.1 mg (0.542 mmol) of (R) -4-amino-2-methyl-4-phenylbutan-2-ol synthesized in the same manner as in Reference Example 21 in an argon atmosphere in 2 ml of dehydrated 1,4-dioxane After sequentially adding 0.18 ml (1.0 mmol) of DIPEA and a portion of 130 mg of the solid obtained by the above operation at room temperature, the mixture was stirred at 90 ° C. for 1.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), then concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue I got
Under an argon atmosphere, 0.12 ml (1.1 mmol) of N, N-dimethylethane-1,2-diamine was added to a THF 2 ml solution of the obtained concentrated residue at room temperature, and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 50: 50 to 25:75 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 96 mg of the title compound (yield 62 % [2 steps]) was obtained as a white solid.
Mass spectrum (CI, m / z): 498 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.35-11.77 (m, 1 H), 9.95-9.67 (m, 1 H), 7.36-7.23 (m, 4 H), 7.19-7.11 (m, 1 H) , 6.58-6.44 (m, 1H), 4.94-4.84 (m, 1H), 4.64 (br s, 1H), 4.40 (br s, 2H), 2.00-1.88 (m, 1H), 1.65 (dd, J = 3.2, 14.2 Hz, 1H), 1.57 (brs, 3H), 1.52 (br s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 0.97 (br s, 2H), 0.98 (brs, 2H) ), 0.03 (s, 9 H).

(Example 85)
N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -4,6-dihydropyrrolo [3,4-c ] Pyrazole-5 (1H) -carboxamide (Compound No. III-25)

Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (synthesized as in Reference Example 38 under an argon atmosphere) To a solution of 1.53 g (4.19 mmol) of 4H) -carboxylate in 20 ml of dry dichloromethane was added 2.60 ml (14.9 mmol) of DIPEA at room temperature. Next, 5 ml of a solution of 700 mg (2.36 mmol) of bis (trichloromethyl) carbonate in 5 ml of dehydrated dichloromethane was added dropwise at -78 ° C, and the temperature was raised for 0.5 hours as it is, and further heated to room temperature and stirred for 2 hours did.
After completion of the reaction, to the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and dichloromethane at -78 ° C, and the mixture was stirred for 1.5 hours while warming up to room temperature. The reaction mixture was separated, and the aqueous layer was extracted twice with ethyl acetate. The whole organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 75:25 (V / V)), and then concentrated under reduced pressure and dried under reduced pressure to obtain a white solid. I got 1.75g.
Under an argon atmosphere, 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [Synthetic Communications 1994, 24 (7), 899-906. Synthesis in accordance with the method described in [1.] To a solution of 109 mg (0.608 mmol) in 2 ml of dehydrated 1,4-dioxane, 0.20 ml (1.1 mmol) of DIPEA, 142 mg of a portion of the solid obtained by the above procedure at room temperature After addition, it was stirred at 90 ° C. for 2.5 hours. The reaction solution was allowed to cool to room temperature, 0.13 ml (1.2 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature, and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 40:60 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue is dissolved in ethyl acetate, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 112 mg of the title compound (yield 66 % [2 steps]) was obtained as a white solid.
Mass spectrum (CI, m / z): 498 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.40-11.84 (m, 1 H), 10.11-9.58 (m, 1 H), 7.37-7.26 (m, 4 H), 7.25-7.18 (m, 1 H) , 6.85 (br d, J = 8.2 Hz, 1 H), 5.53-5.39 (m, 1 H), 4.63 (d, J = 8.2 Hz, 1 H), 4.45-4.25 (m, 2 H), 3.29-3.22 (m, 1H), 3.07-2.98 (m, 1H), 1.58 (s, 3H), 1.51 (s, 3H), 1.06 (s, 3H), 1.03-0.94 (m, 2H), 0.76-0.58 (m, 5H) , 0.03 (s, 9H).

(Example 86)
(-)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide (compound No. IV-142)

2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2 synthesized in the same manner as in Reference Example 73 under an argon atmosphere. , 5 (4H, 6H) -dicarboxylate: 545 mg (1.16 mmol) and ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo In a solution of 329 mg (0.853 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate in 7 ml of dehydrated 1,4-dioxane, 1.80 ml (10.3 mmol) of DIPEA, 3-amino-2, 2-Dimethyl-3-phenylpropan-1-ol [Synthetic Communi cations 1994, 24 (7), 899-906. Synthesis according to the method described in 1. After adding 1.16 g (6.47 mmol) sequentially at room temperature, the mixture was stirred at 90 ° C. for 2 hours. After the reaction solution was allowed to cool to room temperature, 0.90 ml (8.3 mmol) of N, N-dimethylethane-1,2-diamine was added at room temperature, and the mixture was stirred at that temperature for 2.5 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred, and then extracted three times with ethyl acetate. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 40:60 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The resulting concentrated residue is again subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: ethyl acetate = 100: 0 to 85:15 (V / V)), and the fractions containing the desired product Was concentrated under reduced pressure. The obtained concentrated residue is dissolved in a mixed solvent of ethyl acetate / ethanol, n-hexane is added, the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to obtain white solid 802 mg I got
A portion of 0.50 g of the obtained solid is subjected to optical resolution preparative chromatography (column: CHIRALPAK (trade name) ID, elution solvent; n-hexane: ethanol = 90: 10 (V / V)), The fraction containing the optically active substance eluting to. Was concentrated under reduced pressure. The obtained concentrated residue was dissolved in an acetonitrile / water mixed solvent, and then lyophilized to obtain 225 mg (yield 35%) of the title compound as a white solid.
Specific rotation: [α] _D ²⁰ = −66 ° (c = 0.50, methanol).
Mass spectrum (CI, m / z): 512 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.35-11.77 (m, 1 H), 9.86-9.35 (m, 1 H), 7.36-7.27 (m, 4 H), 7.25-7.17 (m, 1 H) , 6.86 (br d, J = 8.2 Hz, 1 H), 5. 45 (br s, 1 H), 4. 64 (d, J = 8.2 Hz, 1 H), 4.46-4.30 (m, 2 H), 3. 45-3.23 (m, 1 H) ), 3.06-2.99 (m, 1 H), 2.58-2. 40 (m, 2 H), 2. 26-2. 14 (m, 2 H), 1. 90-1. 73 (m, 2 H), 1. 60 (s, 3 H), 1.52 (s, 3 H) ), 1.06 (s, 3 H), 0.64 (s, 3 H), 0.09 (s, 9 H).
SFC (supercritical fluid chromatography) analysis:
Column; CHIRALPAK (trade name) ID 2.1 x 150 mm (particle diameter 3 um)
Eluent; CO ₂ / Methanol = 90/10 (V / V)
Flow rate: 0.85 ml / min
Temperature; 40 ° C
Detection wavelength: 240 nm
Retention time; 5.3 minutes Optical purity:> 99% ee

(Example 87)
(+)-N- (3-hydroxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3, 4-c] pyrazole-5 (1H) -carboxamide (compound No. IV-141)

In the optical resolution preparative chromatography operation of Example 86, the fraction containing the optically active substance eluted later was concentrated under reduced pressure. The obtained concentrated residue was dissolved in an acetonitrile / water mixed solvent, and then lyophilized to obtain 223 mg (yield 35%) of the title compound as a white solid.
Specific rotation: [α] _D ²⁰ = + 60 ° (c = 0.50, methanol).
Mass spectrum (CI, m / z): 512 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.42-11.76 (m, 1 H), 9.57 (br s, 1 H), 7.35-7.27 (m, 4 H), 7.25-7.18 (m, 1 H), 6.86 (br d, J = 8.2 Hz, 1 H), 5. 45 (br s, 1 H), 4. 64 (d, J = 8.2 Hz, 1 H), 4.44-4.30 (m, 2 H), 3.44-3.23 (m, 1 H) , 3.06-2.98 (m, 1H), 2.59-2.40 (m, 2H), 2.26-2.14 (m, 2H), 1.89-1.74 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H) , 1.06 (s, 3 H), 0.64 (s, 3 H), 0.09 (s, 9 H).
SFC (supercritical fluid chromatography) analysis:
Column; CHIRALPAK (trade name) ID 2.1 x 150 mm (particle diameter 3 um)
Eluent; CO ₂ / Methanol = 90/10 (V / V)
Flow rate: 0.85 ml / min
Temperature; 40 ° C
Detection wavelength: 240 nm
Retention time; 6.5 minutes Optical purity:> 99% ee

(Example 88)
(R) -N- [5- (2-butoxy-2-phenylacetyl) -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazol-3-yl]- 1- (trimethylsilyl) cyclobutanecarboxamide (compound No. IV-356)

300 mg of lithium hydroxide monohydrate was prepared in a solution of 1.65 g (5.53 mmol) of (R) -benzyl 2-butoxy-2-phenylacetate synthesized in the same manner as in Reference Example 104 in 8 ml of methanol / 8 ml of water. 7.15 mmol) was added at room temperature and then allowed to react at room temperature for 3 hours with stirring.
After completion of the reaction, diethyl ether was added to the reaction solution to separate it. The aqueous layer was adjusted to pH 2 by addition of 2N hydrochloric acid, and extracted three times with ethyl acetate. The obtained total organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 1.34 g of concentrated residue.
0.002 ml (0.08 mmol) of DMF and 0.083 ml (0.95 mmol) of oxalyl chloride are added at 0 ° C. to a solution of 150 mg of a portion of the obtained concentration residue in 2 ml of dehydrated dichloromethane while stirring under an argon atmosphere, Stir at room temperature for 1.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3, synthesized by the same method as in Reference Example 47, was used to prepare a solution of the concentrated residue thus obtained in 3 ml of dehydrated dichloromethane. Add dropwise to 2 ml of a dehydrated dichloromethane solution of 150 mg (0.396 mmol) of 4-c] pyrazole-2 (4H) -carboxylate and 0.350 ml (2.00 mmol) of DIPEA at 0 ° C. with stirring under an argon atmosphere, at room temperature Stir for 3 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)) and then concentrated under reduced pressure to obtain a concentrated residue. I got
Under argon atmosphere, 0.130 ml (1.19 mmol) of N, N-dimethylethane-1,2-diamine was added to a solution of 2 ml of dehydrated dichloromethane obtained at room temperature at room temperature and then stirred at room temperature for 16 hours.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 100: 0 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The concentrated residue thus obtained is subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent; acetonitrile: 1 mM aqueous potassium dihydrogen phosphate solution = 50: 50 (V / V)) to obtain the desired product. Ethyl acetate and water were added to the fraction containing, and the organic layer and the aqueous layer were separated. The obtained organic layer was concentrated under reduced pressure. The obtained concentrated residue was dissolved in ethyl acetate, then added to n-hexane, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 77 mg (yield 39%) of the title compound as a white solid .
Mass spectrum (CI, m / z): 497 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.34-11.89 (m, 1 H), 9.56 (br s, 1 H), 7.45-7.25 (m, 5 H), 5.02 (s, 1 H), 4.68- 4.49 (m, 1H), 4.40 (br d, J = 12.7 Hz, 1H), 3.57-3.39 (m, 2H), 2.59-2.35 (m, 2H), 2.24-2.09 (m, 2H), 1.87-1.73 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.56-1.45 (m, 2H), 1.40-1.28 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H), 0.05 (s, 9H).

(Example 89)
N- (3-methoxy-2,2-dimethyl-1-phenylpropyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -4,6-dihydropyrrolo [3,4-c] Pyrazole-5 (1H) -carboxamide (Compound No. IV-145)

Ethyl 5-[(3-methoxy-2,2-dimethyl-1-phenylpropyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] synthesized in the same manner as in Reference Example 108 A solution of 131 mg (0.219 mmol) of 5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate in 3 ml of dichloromethane was stirred under argon flow with N, N-dimethylethane-1,2 -0.095 ml (0.87 mol) of diamine was added in one portion at room temperature and stirred at room temperature for 1 hour.
After completion of the reaction, 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 70: 30 to 13:87 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure did. The obtained concentrated residue was dissolved in a small amount of ethyl acetate, and n-hexane was added to precipitate a solid. The solid was collected by filtration, washed with n-hexane and dried under reduced pressure at 50 ° C. to give 62 mg (yield 54%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 526 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.21 & 11.76 (br s, total 1 H), 9.58 (br s, 1 H), 7.38-7.18 (m, 5 H), 6.75-6.52 (m, 1 H) ), 4.59 (d, J = 7.7 Hz, 1 H), 4.52-4.30 (m, 2 H), 3. 38 (s, 3 H), 3. 13 (d, J = 9.3 Hz, 1 H), 2. 92 (d, J = 9.3 Hz) , 1H), 2.58-2.40 (m, 2H), 2.29-2.12 (m, 2H), 1.91-1.74 (m, 2H), 1.59 (br s, 3H), 1.50 (s, 3H), 1.12 (s, 2) 3H), 0.68 (s, 3H), 0.09 (s, 9H).

(Reference Example 1)
1- (trimethylsilyl) cyclobutanecarboxylic acid

After adding 214 ml (428 mmol) of a 2 M lithium diisopropylamide / THF solution to 200 ml of dehydrated THF under an argon atmosphere, 10.1 ml (107 mmol) of cyclobutanecarboxylic acid is added dropwise while stirring under ice water cooling. Stir while stirring for 4 hours. Next, add 20 ml (116 mmol) of hexamethyl phosphate triamide, add 51 ml (490 mmol) of chlorotrimethylsilane dropwise under stirring while keeping the internal temperature below -60 ° C under dry ice / acetone refrigerant cooling, and then at -78 ° C. Stir for 16.5 hours.
After completion of the reaction, 67 ml of methanol was added to the reaction liquid, and the temperature was raised to 0 ° C., and then 134 ml of cold water was added. The pH was adjusted to 2.1 with 2N hydrochloric acid, 268 ml of diethyl ether was added and the phases were separated, and the organic layer was washed with 268 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the obtained concentrated residue, 50 ml of 2N aqueous sodium hydroxide solution and 267 ml of n-hexane were added to separate the layers. Then, 1N hydrochloric acid was added to the aqueous layer to adjust to pH 2.7, and 267 ml of ethyl acetate was added to the solution to separate it. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the resulting concentrated residue was added n-hexane and cooled in an ice water bath. The resulting solid was filtered, washed with cooled n-hexane and dried under reduced pressure to give 6.24 g (yield 34%) of the title compound as a white solid. The filtrate is further concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)) to contain the desired product. The fraction was concentrated under reduced pressure and dried under reduced pressure to obtain 4.33 g (yield 23%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 173 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 11.64 (br s, 1 H), 2.45-2.34 (m, 2 H), 2.17-2.06 (m, 2 H), 1. 91-1. 70 (m, 2 H), 0.06 (s, 9H).

(Reference Example 2)
5-tert-Butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate

To a solution of 13.9 g (80.4 mmol) of 1- (trimethylsilyl) cyclobutanecarboxylic acid synthesized in the same manner as in Reference Example 1 in 105 ml of dehydrated dichloromethane under an argon atmosphere 6.96 ml (81.2 mmol) oxalyl chloride, 0.32 ml DMF (4.14 mmol) was sequentially added dropwise at -25 ° C to -10 ° C, and then heated to 0 ° C and stirred for 2 hours. The reaction mixture was purified by using 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012] , 55 (10), 4728-4749. Synthesis according to the method described in [1] under argon atmosphere at 0 ° C was added dropwise to a solution of 8.74 g (26.9 mmol) and 23.5 ml of DIPEA (135 mmol) in 122 mL of dehydrated dichloromethane, and stirred at the same temperature for 16 hours .
After completion of the reaction, 486 ml of 5% aqueous potassium hydrogen sulfate solution was added to the reaction liquid to separate the layers, and the aqueous layer was extracted twice with 200 ml of dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 86: 14-53: 47 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 8.30 g (yield 64%) of the title compound was obtained as a white foam.
Mass spectrum (CI, m / z): 479 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.98 & 9.72 & 9.71 (s, total 1 H), 4.50-4.37 (m, 4 H), 2.53-2.43 (m, 2 H), 2.32-2.07 (m , 2H), 2.02-1.72 (m, 2H), 1.65-1.55 (m, 6H), 1.51-1.42 (m, 9H), 1.38-1.31 (m, 3H), 0.10 & 0.06 & 0.01 (s, total 9H) ).

(Reference Example 3)
Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

5-tert-Butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, synthesized in the same manner as in Reference Example 2 6H) -Dicarboxylate In a solution of 8.30 g (17.3 mmol) in 81 ml of dehydrated dichloromethane, under argon, 6.0 ml (52 mmol) of 2,6-lutidine and 9.2 ml (51 mmol) of trimethylsilyl trifluoromethanesulfonate were added. The reaction solution was dropwise added at ° C and stirred at the same temperature for 2 hours.
After completion of the reaction, 64 ml of a saturated aqueous solution of sodium hydrogen carbonate and 64 ml of dichloromethane were added to the reaction solution, and then separated. The aqueous layer was extracted twice with 72 ml of dichloromethane, and the obtained total organic layer was washed successively with 72 ml of saturated aqueous sodium hydrogen carbonate solution and 72 ml of saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. . To the obtained concentrated residue, 5 ml of toluene is added and the operation of concentration under reduced pressure is repeated five times to obtain crude ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4 -C] pyrazole-2 (4H) -carboxylate was obtained.
The obtained crude ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 6.70 g dehydrated After adding 8.8 ml (51 mmol) of DIPEA at room temperature to a solution of 235 ml of dichloromethane under an argon atmosphere, a solution of 38 ml of dehydrated dichloromethane in 3.79 g (12.8 mmol) of bis (trichloromethyl) carbonate was added dropwise at -78 ° C. Stir at temperature for 3 hours. At this time, 1.0 ml (5.7 mmol) of DIPEA was added at each time point of 1 hour, 2 hours and 2.6 hours after the start of the reaction.
After completion of the reaction, 150 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred while warming up to room temperature. After separation, the aqueous layer was extracted twice with 130 ml of dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 78: 22 to 57: 43 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. To the resulting concentrated residue was added n-hexane and sonicated. After cooling in a refrigerator, the precipitated solid was filtered and dried under reduced pressure to obtain 3.51 g of the title compound (yield 46% [2 steps]) as a white solid.
Mass spectrum (CI, m / z): 441 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.83-9.65 (m, 1 H), 4.84 (s, 2 H), 4.49-4.37 (m, 2 H), 2.54-2.43 (m, 2 H), 2.31 -2.21 (m, 2H), 1.95-1.83 (m, 2H), 1.71-1.58 (m, 6H), 1.35 (t, J = 7.1 Hz, 3H), 0.13-0.08 (m, 9H).

(Reference Example 4)
5-tert-Butyl 1-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) -dicarboxylate

A solution of 24.52 g (142 mmol) of 1- (trimethylsilyl) cyclobutanecarboxylic acid synthesized in the same manner as in Reference Example 1 in 180 ml of dehydrated dichloromethane under an argon atmosphere, 0.55 ml (7.1 mmol) of DMF, 12.2 ml (142 mmol) of oxalyl chloride ) Was added dropwise at 0 ° C. and stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure (water bath temperature: 30 ° C.) to obtain a concentrated residue.
Under argon atmosphere, 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) under argon atmosphere of the concentrated residue thus obtained was subjected to 120 ml of dehydrated dichloromethane solution. ) -Dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4749. Synthesis according to the method described in the above was added dropwise to a solution of 15.39 g (47.4 mmol) and 40.6 ml (238 mmol) of DIPEA in 180 ml of dehydrated dichloromethane at 0 ° C. and stirred at the same temperature for 20 hours.
After completion of the reaction, the reaction solution was poured into 800 ml of 5% aqueous potassium hydrogen sulfate solution, and the mixture was stirred and then separated. The aqueous layer was extracted twice with 250 ml of dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 91: 9 to 70:30 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 14.6 g (yield 64%) of the title compound was obtained as a white foam.
Mass spectrum (EI, m / z): 478 [M] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 10.32-10.20 (m, 1 H), 4.46-4.32 (m, 4 H), 2.48-2.39 (m, 2 H), 2.24-2.14 (m, 2 H) , 1.84-1.68 (m, 8 H), 1.52-1.40 (m, 9 H), 1.32 (t, J = 7.1 Hz, 3 H), 0.07 (s, 9 H).

(Reference Example 5)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate

5-tert-butyl 1-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-1,5 (4H, 5) synthesized in the same manner as in Reference Example 4. In 100 mL of a solution of 10.02 g (20.9 mmol) of 6H) -dicarboxylate in 100 mL of dehydrated dichloromethane, 7.26 mL (62.7 mmol) of 2,6-lutidine under an argon atmosphere, 11.3 mL (62. 2) of trimethylsilyl trifluoromethanesulfonate. 7 mmol) was added dropwise at 0 ° C. and stirred at the same temperature for 1.5 hours.
After completion of the reaction, 60 ml of saturated aqueous sodium hydrogen carbonate solution and 60 ml of dichloromethane were added to the reaction solution. After separation, the aqueous layer was extracted twice with 60 ml of dichloromethane. The obtained total organic layer was washed successively with 60 ml of saturated aqueous sodium hydrogen carbonate solution and 60 ml of saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Toluene was added to the obtained concentrated residue, and the operation of concentration under reduced pressure was repeated three times to obtain 7.43 g (yield 94%) of the title compound as a pale yellow solid.
Mass spectrum (EI, m / z): 378 [M] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 10.03 (s, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 3. 85 (s, 2 H), 2.48-2.38 (m, 2 H), 2.23-2.12 (m, 2H), 1.85-1.72 (m, 2H), 1.41 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H), 0.06 (s, 9H).

(Reference Example 6)
5-tert-Butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate

1- (trimethylsilyl) cyclopropanecarboxylic acid [J. Org. Chem. , 1982, 47 (5), 893-895. Under a nitrogen atmosphere, 0.70 ml (8.2 mmol) of oxalyl chloride and 0.020 ml (0.26 mmol) of DMF were added to a solution of 1.05 g (6.63 mmol) of dry dichloromethane according to the method described in Add at ° C and stir at the same temperature for 3 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure (water bath temperature: 25 ° C.) to obtain a concentrated residue.
To a solution of the obtained concentrated residue in 15 ml of dehydrated dichloromethane under a nitrogen atmosphere, 1.80 ml (10.3 mmol) of DIPEA, 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c Pyrazole-2,5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4737. Synthesis according to the method described in [1] 839 mg (2.59 mmol) was added at 0 ° C. and stirred at the same temperature for 20.5 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 75:25 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 1.19 g (containing impurities) of the title compound was obtained as a pale yellow foam.
Mass spectrum (CI, m / z): 465 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 10.09 & 9. 92 (s, total 1 H), 4. 70-4. 46 (m, 4 H), 1.7 2 (s, 3 H), 1. 65 (s, 3 H), 1.5 4-1. 44 ( m, 12H), 1.15-1.07 (m, 2H), 0.84-0.78 (m, 2H), 0.17-0.07 (m, 9H).

(Reference Example 7)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate hydrochloride

5-tert-butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H) synthesized in the same manner as in Reference Example 6. To a solution of 1.19 g of (6H) -dicarboxylate (containing impurities) in 20 ml of ethyl acetate under a nitrogen atmosphere, 4.0 ml (16 mmol) of 4N hydrogen chloride / ethyl acetate is added at room temperature, and at the same temperature 6.5 Stir for hours. Thereafter, 2.0 ml (8.0 mmol) of 4 N hydrogen chloride / ethyl acetate was added, and the mixture was further stirred at room temperature for 14.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained concentrated residue was suspended in diisopropyl ether and stirred at room temperature. The insoluble matter was collected by filtration, and the obtained solid was washed with diisopropyl ether and then dried under reduced pressure to obtain 0.91 g of the title compound (yield: 88% [2 steps]) as a white solid.
Mass spectrum (CI, m / z): 365 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.99 (br s, 2 H), 9.91 (s, 1 H), 4.51-4.39 (m, 4 H), 1.63 (s, 6 H), 1.35 (t, J = 7.2 Hz, 3 H), 1.08 (dd, J = 4.2, 6.0 Hz, 2 H), 0.87 (dd, J = 4.2, 6.0 Hz, 2 H), 0.08 (s, 9 H).

(Reference Example 8)
2-Methyl-2- (trimethylsilyl) propanoic acid

Under argon atmosphere, 200 ml (400 mmol) of 2 M lithium diisopropylamide / THF solution was added to 100 ml of dehydrated THF, and then 4.7 ml (51 mmol) of isobutanoic acid was dropped at 0 ° C., followed by stirring at room temperature for 4 hours. After 10 ml (58 mmol) of hexamethylphosphate triamide was added, 29 ml (230 mmol) of chlorotrimethylsilane was added dropwise at -78 ° C, and the mixture was stirred for 24 hours while gradually warming to room temperature.
After completion of the reaction, 25 ml of methanol and 50 ml of water were added to the reaction solution. The solution was then acidified by the addition of 2N hydrochloric acid and extracted with diethyl ether. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue obtained was dissolved in 2N aqueous sodium hydroxide solution and washed with ethyl acetate. After separation, the aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue was suspended in n-hexane, sonicated, and the insoluble matter was collected by filtration. The filtrate is concentrated under reduced pressure, and the obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 99: 1 (V / V)) to give a fraction containing the desired product. The fraction and the solid collected by filtration as described above were combined, concentrated under reduced pressure, and dried under reduced pressure to obtain 2.66 g (yield 32%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 161 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 1.22 (s, 6 H), 0.08 (s, 9 H).

(Reference Example 9)
5-tert-Butyl 1-ethyl 6,6-dimethyl-3- [2-methyl-2- (trimethylsilyl) propanamido] pyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) -dicarboxy Rat

0.85 ml (9.9 mmol) of oxalyl chloride in a solution of 1.30 g (8.11 mmol) of 2-methyl-2- (trimethylsilyl) propanoic acid synthesized in the same manner as in Reference Example 8 in 25 ml of dehydrated dichloromethane Then, 0.040 ml (0.52 mmol) of DMF was sequentially added at 0 ° C., and the mixture was stirred at the same temperature for 3.5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure (water bath temperature: 25 ° C.) to obtain a concentrated residue.
2.15 ml (13.2 mmol) of DIPEA and 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] in a nitrogen atmosphere in a solution of 15 ml of the concentration residue thus obtained in a solution of dehydrated dichloromethane [Pyrazole-1,5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4737. Synthesis according to the method described in 1.] 1.08 g (3.33 mmol) was sequentially added at 0 ° C., and the mixture was stirred at the same temperature for 17.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and stirred, and then extracted three times with dichloromethane. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 93: 7 to 80:20 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 1.28 g (yield 82%) of the title compound was obtained as a pale yellow foam.
Mass spectrum (CI, m / z): 467 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.87-7.74 (m, 1 H), 4.60-4.47 (m, 4 H), 1.84 & 1.78 (s, total 6 H), 1.55-1.48 (m, 9 H), 1.47 (t, J = 7.2 Hz, 3 H), 1.31-1.25 (m, 6 H), 0.10-0.04 (m, 9 H).

(Reference Example 10)
1- (ethyldimethylsilyl) cyclobutanecarboxylic acid

After adding 214 ml (428 mmol) of a 2 M lithium diisopropylamide / THF solution to 200 ml of dehydrated THF under an argon atmosphere, 10.7 ml (112 mmol) of cyclobutanecarboxylic acid is added dropwise under ice water cooling and stirring is conducted while warming up to room temperature. did. Then 20 ml (120 mmol) of hexamethyl phosphate triamide were added. After cooling with a dry ice / ethanol refrigerant, 67.6 ml (485 mmol) of chloro (ethyl) dimethylsilane was added dropwise at -75 ° C to -69 ° C and stirred overnight at a temperature of -60 ° C or lower.
After completion of the reaction, 67 ml of methanol and then 134 ml of cold water were added dropwise to the reaction solution, and the temperature was then raised to room temperature. The mixture was acidified (pH 2.0) by adding 240 ml of 2N hydrochloric acid, and 200 ml of diethyl ether was added, followed by separation. The obtained organic layer was washed with 250 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 41 ml of 2N sodium hydroxide aqueous solution was added to the obtained concentration residue, and it washed with 250 ml of n-hexane. To the aqueous layer was added 82 ml of 1N hydrochloric acid to acidify again (pH 2.0). The solution was extracted with 250 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 11.7 g (yield 59%) of the title compound was obtained as a white solid.
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 11.71 (br s, 1 H), 2.44-2.33 (m, 2 H), 2.19-2.08 (m, 2 H), 1.91-1.73 (m, 2 H), 0.92 (t, J = 7.9 Hz, 3 H), 0.55 (q, J = 7.9 Hz, 2 H), 0.05 (s, 6 H).

(Reference Example 11)
5-tert-butyl 2-ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate

5.3 ml (62 mmol) of oxalyl chloride in an argon atmosphere and a solution of 11.7 g (62.8 mmol) of 1- (ethyldimethylsilyl) cyclobutanecarboxylic acid synthesized in the same manner as in Reference Example 10 under argon atmosphere, 0.24 ml of DMF (3.1 mmol) was sequentially added under ice water cooling, and stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
Under a nitrogen atmosphere, a solution of 5 ml of the obtained concentrated residue in 5 ml of dehydrated dichloromethane was treated with 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H ) -Dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4749. To a solution of 6.73 g (20.7 mmol) and 18 ml (100 mmol) of DIPEA in 94 ml of dehydrated dichloromethane was added dropwise under ice-water cooling, and the mixture was stirred at the same temperature for 16 hours.
After completion of the reaction, 350 ml of a 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture to separate the layers, and the aqueous layer was extracted twice with 150 ml of dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 86: 14-53: 47 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure to give the title compound 7.51 g (yield 74%) was obtained as a pale yellow oil.
Mass spectrum (DUIS, m / z): 493 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.82-9.69 (m, 1 H), 4.51-4.36 (m, 4 H), 2.49-2.42 (m, 2 H), 2.32-2.23 (m, 2 H) , 1.95-1.84 (m, 2H), 1.62-1.55 (m, 6H), 1.49-1.42 (m, 9H), 1.38-1.31 (m, 3H), 0.91 (t, J = 7.9 Hz, 3H), 0.57 (q, J = 7.9 Hz, 2H), 0.09 (s, 6H).

(Reference Example 12)
Ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

5-tert-butyl 2-ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamido] -6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (5 A solution of 7.27 g (14.8 mmol) of 4H, 6 H) -dicarboxylate in 70 ml of dehydrated dichloromethane under an argon atmosphere, 5.1 ml (44 mmol) of 2,6-lutidine, 7.8 ml (43 mmol) of trimethylsilyl trifluoromethanesulfonate The reaction solution was dropwise added under ice-cooling and stirred at the same temperature for 2 hours.
After completion of the reaction, 57 ml of a saturated aqueous solution of sodium hydrogen carbonate and 57 ml of dichloromethane were added to the reaction mixture, and then separated. The aqueous layer was extracted twice with 60 ml of dichloromethane, and the obtained total organic layer was washed successively with 60 ml of saturated aqueous sodium hydrogen carbonate solution and 60 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the obtained concentrated residue, toluene was added and the operation of concentration under reduced pressure was performed 5 times to obtain 5.92 g (containing impurities) of the title compound as a yellow oil.
Mass spectrum (DUIS, m / z): 393 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.68 (s, 1 H), 4.39 (q, J = 7.0 Hz, 2 H), 3.92 (s, 2 H), 2.48-2.40 (m, 2 H), 2.29-2.22 (m, 2H), 1.93-1.82 (m, 2H), 1.33 (t, J = 7.0 Hz, 3 H), 1.29 (s, 6 H), 0.91 (t, J = 8.1 Hz, 3 H), 0.56 (q, J = 8.1 Hz, 2 H), 0.08 (s, 6 H).

(Reference Example 13)
Ethyl 5- (chlorocarbonyl) -3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

5-tert-butyl 2-ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamido] -6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (5 Ethyl 3- [1- (ethyldimethylsilyl) cyclobutanecarboxamide] -6,6-dimethyl-5 synthesized in the same manner as in Reference Example 12 using 7.27 g (14.8 mmol) of 4H, 6H) -dicarboxylate Under argon atmosphere, 7.3 ml (43 mmol) of DIPEA was added at room temperature to a solution of 5.92 g of 6,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate (containing impurities) in 200 ml of dehydrated dichloromethane The reaction mixture was then washed with 3.24 g (10.9 mmol) of bis (trichloromethyl) carbonate to give dehydrated dichlorometa. 33ml solution was added dropwise at -60 ° C. or less, and stirred for 2 hours at the same temperature.
After completion of the reaction, 130 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the temperature was raised to room temperature while stirring. After separation, the aqueous layer was extracted twice with 100 ml of dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 78: 22 to 57: 43 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. To the concentration residue, n-hexane was added, and the mixture was concentrated again under reduced pressure to obtain 5.13 g of the title compound (yield 76% [2 steps]) as a white solid.
Mass spectrum (CI, m / z): 455 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.85-9.76 (m, 1 H), 4.88-4.81 & 4.53-4.48 (m, total 2 H), 4.44 (q, J = 7.1 Hz, 2 H), 2.55-2.44 (m, 2H), 2.35-2.24 (m, 2H), 1.96-1.85 (m, 2H), 1.69-1.61 (m, 6H), 1.34 (t, J = 7.1 Hz, 3H), 0.92 ( t, J = 7.9 Hz, 3 H), 0.58 (q, J = 7.9 Hz, 2 H), 0.13-0.07 (m, 6 H).

(Reference Example 14)
2- (ethyldimethylsilyl) -2-methylpropanoic acid

Under an argon atmosphere, 100 ml (200 mmol) of 2 M lithium diisopropylamide / THF solution was added to 100 ml of dehydrated THF, 4.7 ml (51 mmol) of isobutanoic acid was added dropwise at 0 ° C., and the mixture was warmed to room temperature and stirred for 4 hours. Then, 10 ml (58 mmol) of hexamethylphosphate triamide was added, and 32 ml (230 mmol) of chloro (ethyl) dimethylsilane was dropped at -78 ° C. After completion of the dropwise addition, the solution was stirred for 1 day while raising the temperature to room temperature.
After completion of the reaction, 25 ml of methanol and then 50 ml of water were added while cooling with ice water. Thereafter, the mixture was acidified with 2N hydrochloric acid and extracted with diethyl ether. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. To the concentrated residue was added 2N aqueous sodium hydroxide solution and it was washed with ethyl acetate. The aqueous layer was then acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: 1,2-dichloroethane: methanol = 100: 0 to 99: 1 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 2.24 g (yield 25%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 175 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 11.57 (br s, 1 H), 1.23 (s, 6 H), 0.95 (t, J = 8.0 Hz, 3 H), 0.62 (q, J = 8.0 Hz, 2 H ), 0.06 (s, 6 H).

(Reference Example 15)
5-tert-butyl 1-ethyl 3- [2- (ethyldimethylsilyl) -2-methylpropanamido] -6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H, 6H)- Dicarboxylate

To 40 ml of a solution of 4.7 g (27 mmol) of 2- (ethyldimethylsilyl) -2-methylpropanoic acid synthesized in the same manner as in Reference Example 14 in 40 ml of dehydrated dichloromethane was added 2.3 ml (27 mmol) of oxalyl chloride under an argon atmosphere. It was added dropwise at C and stirred for 10 minutes at the same temperature. Then, 0.10 ml (1.3 mmol) of DMF was added at 0 ° C. and stirred at the same temperature for 4 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature to obtain a concentrated residue.
A solution of the concentrated residue thus obtained in 20 ml of dehydrated dichloromethane was treated with 5-tert-butyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H, 4) under argon atmosphere. 6H) -Dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4737. To a solution of 2.9 g (8.9 mmol) in 10 ml of dehydrated dichloromethane was added dropwise at 0 ° C., then 7.9 ml (45 mmol) of DIPEA was added and stirred at 0 ° C. for 24 hours.
After completion of the reaction, water was added to the reaction solution, and extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 98: 2 to 80:20 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure to 3.18 g (yield 74%) of the title compound was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 481 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.88-7.73 (m, 1 H), 4.62-4.46 (m, 4 H), 1.87-1.75 (m, 6 H), 1.55-1. 41 (m, 12 H), 1.31 -1.26 (m, 6H), 0.99-0.88 (m, 3H), 0.66-0.53 (m, 2H), 0.09-0.02 (m, 6H).

(Reference Example 16)
Ethyl 3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -6,6-dimethyl-5,6-dihydropyrrolo [3,4-c] pyrazole-1 (4H) -carboxylate

5-tert-butyl 1-ethyl 3- [2- (ethyldimethylsilyl) -2-methylpropanamide] -6,6-dimethylpyrrolo [3,4-c] pyrazole-synthesized in the same manner as in Reference Example 15 3. 30 ml of a solution of 3.18 g (6.62 mmol) of 1,5 (4 H, 6 H) -dicarboxylate in 30 ml of dehydrated dichloromethane under an argon atmosphere, 2.3 ml (20 mmol) of 2,6-lutidine, trimethylsilyl trifluoromethanesulfonate; 6 ml (20 mmol) were sequentially added dropwise at 0 ° C., and stirred at the same temperature for 1 hour.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. After toluene was added to the residue, concentration under reduced pressure gave 2.44 g (yield 97%) of the title compound as a pale yellow solid.
Mass spectrum (CI, m / z): 381 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.77 (s, 1 H), 4.50 (q, J = 7.2 Hz, 2 H), 4. 15 (s, 2 H), 1.55 (s, 6 H), 1.46 (t, J = 7.2 Hz, 3 H), 1.32-1.25 (m, 6 H), 0.93 (t, J = 8.0 Hz, 3 H), 0.60 (q, J = 8.0 Hz, 2 H), 0.05 (s, 6 H).

(Reference Example 17)
(S) -2-[(2-methoxypropan-2-yl) oxy] -1-phenylethanol

(S) -2-[(tert-butyldimethylsilyl) oxy] -2-phenylethanol [Angew. Chem. Int. Ed. , 2012, 51 (31), 7825-782. Under a nitrogen atmosphere, 0.33 ml (3.5 mmol) of 2-methoxy-1-propene was added to a solution of 664 mg (2.63 mmol) of dichloromethane in 15 ml of dichloromethane, pyridinium p-toluenesulfonate 68. 3 mg (0.272 mmol) were added at 0 ° C. and stirred for 2 hours at the same temperature.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and stirred, and then extracted twice with dichloromethane. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 98: 2 to 97: 3 (V / V)) to obtain (S) -3,3,8,8, The fraction containing 9,9-hexamethyl-6-phenyl-2,4,7-trioxa-8-siladecane was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Under nitrogen atmosphere, 428 mg (1.64 mmol) of tetrabutylammonium fluoride was added at 0 ° C. to a solution of 347 mg of the obtained concentration residue in 10 ml of THF, and stirred at the same temperature for 3.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and stirred, and then extracted twice with a mixed solvent of ethyl acetate / n-hexane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 85:15 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 160 mg (yield 29% [2 steps]) of the title compound was obtained as a colorless oil.
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.43-7.27 (m, 5 H), 4. 89-4. 83 (m, 1 H), 3.59 (dd, J = 3.2, 9.8 Hz, 1 H), 3.45 (dd, J = 9.0, 9.8 Hz, 1 H), 3.19 (s, 3 H), 2.82 (d, J = 2.4 Hz, 1 H), 1.38 (s, 3 H), 1. 37 (s, 3 H).

(Reference Example 18)
(S) -2,5-dioxopyrrolidin-1-yl {2-[(2-methoxypropan-2-yl) oxy] -1-phenylethyl} carbonate

A solution of 157 mg (0.747 mmol) of (S) -2-[(2-methoxypropan-2-yl) oxy] -1-phenylethanol synthesized in the same manner as in Reference Example 17 in 4 ml of dehydrated acetonitrile under a nitrogen atmosphere 0.16 ml (1.2 mmol) of triethylamine and 233 mg (0.908 mmol) of N, N'-disuccinimidyl carbonate were added at room temperature and stirred at the same temperature for 6 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting concentrated residue was dissolved in ethyl acetate and it was washed with water. After separation, the aqueous layer was extracted twice with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 65:35 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 190 mg (yield 72%) of the title compound was obtained as a colorless oil.
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.42-7.33 (m, 5 H), 5. 86 (dd, J = 3.4, 8.8 Hz, 1 H), 3.83 (dd, J = 8.8, 11.0 Hz, 1 H), 3.64 (dd, J = 3.4, 11.0 Hz, 1 H), 3.20 (s, 3 H), 2.81 (s, 4 H), 1.38 (s, 3 H), 1. 34 (s, 3 H).

(Reference Example 19)
(R) -Methyl 3-amino-3-phenylpropanoate hydrochloride

(R) -3-amino-3-phenylpropanoic acid [Shanhai HC Biotech CO. , LTD. Purchased from a mixture of 2.01 g (12.2 mmol) of dehydrated methanol in 100 ml of dehydrated methanol at room temperature with dropwise addition of 1.32 ml (18.2 mmol) of thionyl chloride while stirring under a nitrogen atmosphere, followed by stirring at the same temperature for 24 hours. Thereafter, the temperature was raised to 65 ° C. and stirring was performed for 9.5 hours.
After allowing to cool, the reaction solution is concentrated under reduced pressure, diethyl ether is added to the obtained concentrated residue, and sonicated, and the precipitated solid is collected by filtration and dried under reduced pressure to give the title compound 2.55 g (yield 97%) ) As a white solid.
Mass spectrum (DUIS, m / z): 180 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 8.67 (br s, 3 H), 7.57-7.50 (m, 2 H), 7. 45-7. 36 (m, 3 H), 4.58 (dd, J = 6.0, 8.6 Hz, 1 H), 3. 35 (br s, 3 H), 3. 20 (dd, J = 6.0, 16.3 Hz, 1 H), 3.00 (dd, J = 8.6, 16.3 Hz, 1 H).

(Reference Example 20)
(R) -Methyl 3-phenyl-3- (2,2,2-trifluoroacetamido) propanoate

A solution of 2.55 g (11.8 mmol) of (R) -methyl 3-amino-3-phenylpropanoate hydrochloride synthesized in the same manner as in Reference Example 19 in 50 ml of dichloromethane was stirred at 0 ° C. under an argon atmosphere. After dropwise addition of 10.5 ml (60.3 mmol) of DIPEA and 1.75 ml (12.4 mmol) of trifluoroacetic anhydride, the mixture was stirred at the same temperature for 2 hours and further stirred overnight at room temperature.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 91: 9 to 70:30 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, 2.75 g (yield 85%) of the title compound was obtained as a white solid.
Mass spectrum (DUIS, m / z): 276 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.80-7.64 (m, 1 H), 7.39-7.25 (m, 5 H), 5.46-5.39 (m, 1 H), 3.65 (s, 3 H), 3.00 (dd) , J = 5.5, 16.2 Hz, 1 H), 2.93 (dd, J = 5.5, 16.2 Hz, 1 H).

(Reference Example 21)
(R) -4-amino-2-methyl-4-phenylbutan-2-ol

Under argon atmosphere, a solution of 506 mg (1.84 mmol) of (R) -methyl 3-phenyl-3- (2,2,2-trifluoroacetamide) propanoate synthesized in the same manner as in Reference Example 20 in 5 ml of dehydrated THF was prepared. While stirring, 6.60 ml (9.24 mmol) of a 1.4 M methylmagnesium bromide / THF solution was added dropwise at room temperature and stirred at room temperature for 3.5 hours.
After completion of the reaction, 10 ml of a saturated aqueous solution of ammonium chloride was added dropwise to the reaction solution under ice-cooling, and the mixture was returned to room temperature and stirred for a while. The reaction mixture was adjusted to pH 10 by adding dichloromethane and water and further dilute aqueous sodium hydroxide solution, and then separated. The aqueous layer was extracted with dichloromethane, and the obtained total organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)) to obtain (R) -2,2,2 The fraction containing trifluoro-N- (3-hydroxy-3-methyl-1-phenylbutyl) acetamide was concentrated under reduced pressure to obtain a concentrated residue.
After adding 64.6 mg (1.71 mmol) of sodium borohydride in several portions at room temperature to a solution of 427 mg of the obtained concentrated residue 427 mg in ethanol, the mixture was stirred at room temperature for 14 hours. Furthermore, 77.0 mg (2.04 mmol) of sodium borohydride was added in several portions, and the mixture was stirred at room temperature for 2 hours and then at 75 ° C. for 2 hours.
After completion of the reaction, the reaction solution was ice-cooled, 10 ml of a saturated aqueous ammonium chloride solution was added dropwise, and the mixture was stirred at room temperature. Dichloromethane and water were added, diluted aqueous sodium hydroxide solution was added to adjust the pH of the aqueous layer to 10, and then liquid separation was performed. The aqueous layer was extracted with dichloromethane, and the obtained total organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated residue is subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure This gave 160 mg (yield 49%) of the title compound as a colorless oil.
Mass spectrum (DUIS, m / z): 180 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.37-7.26 (m, 4 H), 7.21-7.15 (m, 1 H), 4.05 (dd, J = 2.8, 10.7 Hz, 1 H), 1.66 (dd , J = 10.7, 14.0 Hz, 1 H), 1.52 (dd, J = 2.8, 14.0 Hz, 1 H), 1.22 (s, 3 H), 1. 10 (s, 3 H).

(Reference Example 22)
(S) -tert-butyl [2- (difluoromethoxy) -1-phenylethyl] carbamate

(S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chemy Ltd. Under argon atmosphere, 165 mg (0.866 mmol) of copper (I) iodide was added at room temperature to a solution of 1.00 g (4.21 mmol) of dehydrated acetonitrile at room temperature and stirred at the same temperature for 30 minutes. Then, 10 ml of a solution of 0.87 ml (8.4 mmol) of 2- (fluorosulfonyl) difluoroacetic acid in 10 ml of dehydrated acetonitrile was added in portions of 1 ml at 45 ° C. over 40 minutes, and stirred at the same temperature for 1 hour.
After completion of the reaction, the reaction solution allowed to cool to room temperature was concentrated under reduced pressure. Water and ethyl acetate were added to the obtained concentrated residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 50:50 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The resulting concentrated residue is again subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate 95: 5 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure. , 213 mg (yield 18%) of the title compound were obtained as a yellow solid.
Mass spectrum (CI, m / z): 288 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.55 (d, J = 8.7 Hz, 1 H), 7.37-7.24 (m, 5 H), 6.67 (t, J = 75.9 Hz, 1 H), 4.83- 4.73 (m, 1 H), 3.95-3.86 (m, 2 H), 1.42-1.23 (m, 9 H).

(Reference Example 23)
(S) -2- (Difluoromethoxy) -1-phenylethanamine trifluoroacetate salt

A solution of 210 mg (0.731 mmol) of (S) -tert-butyl [2- (difluoromethoxy) -1-phenylethyl] carbamate synthesized in the same manner as in Reference Example 22 in 4 ml of dehydrated dichloromethane was subjected to trifluoroacetic acid under an argon atmosphere. 1 ml was added at room temperature and stirred at the same temperature for 2 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain 210 mg (yield 95%) of the title compound as a yellow oil.
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 8.59 (br s, 3 H), 7.54-7.40 (m, 5 H), 6.76 (t, J = 74.8 Hz, 1 H), 4.70-4.59 (m, 1H), 4.19-4.11 (m, 2H).

(Reference Example 24)
(S) -2-Ethoxy-1-phenylethanamine

(S) -2-amino-2-phenylethanol 1.40 g (10.2 mmol), 1,4,7,10,13-pentaoxacyclopentadecane 3.0 ml (15 mmol) in a solution of 10 ml of dehydrated THF under an argon atmosphere While stirring, 481 mg (11.0 mmol) of 55% sodium hydride was added in portions at room temperature and stirred at the same temperature until bubbling ceased. Subsequently, 0.82 ml (10 mmol) of ethyl iodides were dripped at room temperature, and it stirred at the same temperature for 24 hours.
After completion of the reaction, water and diethyl ether were added to the reaction solution to separate it. The aqueous layer was extracted with diethyl ether, and the whole organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure The reaction gave 1.17 g (yield 69%) of the title compound as a pale yellow oil.
Mass spectrum (CI, m / z): 166 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.39-7.33 (m, 2 H), 7.33-7.25 (m, 2 H), 7.25-7.19 (m, 1 H), 4.01 (dd, J = 4.9, 8.0 Hz, 1 H), 3.53-3. 35 (m, 3 H), 3. 28 (dd, J = 8.0, 9.3 Hz, 1 H), 1.82 (br s, 2 H), 1.09 (t, J = 7.0 Hz, 3 H).

(Reference Example 25)
(R) -3-methoxy-1-phenylpropan-1-amine

(R) -3-amino-3-phenylpropan-1-ol [Ark Pharm, Inc. Purchased from 1.53 g (10.1 mmol), 1,4,7,10,13-pentaoxacyclopentadecane 3.0 ml (15 mmol) in a solution of 10 ml of dehydrated THF under argon atmosphere with stirring 55% hydrogen Sodium 473 mg (10.9 mmol) was added in portions at room temperature and stirred at the same temperature until bubbling ceased. Next, 0.62 ml (10 mmol) of methyl iodide was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 17 hours.
After completion of the reaction, water and diethyl ether were added to the reaction solution to separate it. The aqueous layer was extracted with diethyl ether, and the whole organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (DNH silica gel, elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure As a result, 1.49 g (yield 89%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 166 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.35-7.26 (m, 4 H), 7.24-7.15 (m, 1 H), 3. 85 (dd, J = 6.4, 7.4 Hz, 1 H), 3.38-3.20 (m, 2H), 3.19 (s, 3H), 1.93-1.63 (m, 4H).

(Reference Example 26)
(S) -2-[(tert-butoxycarbonyl) amino] -2-phenylethyl acetate

(S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chemy Ltd. Purchased from a total of 10 g (42 mmol) of triethylamine 7.1 ml (51 mmol) in 100 ml of dehydrated dichloromethane under argon atmosphere, 4.80 ml (50.8 mmol) of acetic anhydride is added dropwise at 0 ° C. did.
After completion of the reaction, 100 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and then separated. The aqueous layer was extracted twice with dichloromethane (100 ml), and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 93: 7 to 72:28 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 10.5 g (yield 89%) of the title compound was obtained as a white solid.
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.53 (d, J = 8.9 Hz, 1 H), 7.38-7.31 (m, 4 H), 7.30-7.22 (m, 1 H), 4.87-4.74 (m , 1H), 4.15 (dd, J = 4.8, 11.0 Hz, 1 H), 4.02 (dd, J = 8.8, 11.0 Hz, 1 H), 1.98 (s, 3 H), 1.43-1.20 (m, 9 H).

(Reference Example 27)
(S) -2-Amino-2-phenylethyl acetate hydrochloride

A solution of 10.5 g (37.6 mmol) of (S) -2-[(tert-butoxycarbonyl) amino] -2-phenylethyl acetate synthesized in the same manner as in Reference Example 26 in 110 ml of dehydrated dichloromethane was subjected to 4N under an argon atmosphere. Hydrogen chloride / 1, 4-dioxane solution 47 ml (188 mmol) was added at room temperature, and it stirred as it is for 14 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. Diethyl ether was added to the obtained concentrated residue, and after sonication, filtration and drying under reduced pressure gave 6.78 g (yield 84%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 180 [M (Free body) + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 8.80 (br s, 3 H), 7.59-7.52 (m, 2 H), 7.49-7.38 (m, 3 H), 4.58 (dd, J = 6.1, 6.1 Hz, 1 H), 4. 39-4. 29 (m, 2 H), 2.06 (s, 3 H).

(Reference Example 28)
(S) -tert-butyl [2- (benzyloxy) -1-phenylethyl] carbamate

(S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chemy Ltd. Under argon atmosphere, 2.58 g (64.5 mmol) of 60% sodium hydride was added at 0 ° C. to a solution of 10.01 g (42.2 mmol) in dehydrated DMF and stirred at the same temperature for 20 minutes. Then, 5.50 ml (46.3 mmol) of benzyl bromide was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour.
After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed three times with water and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 80:20 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 9.94 g (yield 72%) of the title compound was obtained as a white solid.
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.44 (d, J = 8.7 Hz, 1 H), 7.37-7.21 (m, 10 H), 4.84-4.73 (m, 1 H), 4.49 (s, 2 H) ), 3.61-3.46 (m, 2H), 1.46-1.15 (m, 9H).

(Reference Example 29)
(S) -Ethyl 5-{[2- (benzyloxy) -1-phenylethyl] carbamoyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -5,6-dihydropyrrolo [3 , 4-c] Pyrazole-2 (4H) -carboxylate

A solution of 9.94 g (30.4 mmol) of (S) -tert-butyl [2- (benzyloxy) -1-phenylethyl] carbamate synthesized in the same manner as in Reference Example 28 in 120 ml of dichloromethane was prepared under an argon atmosphere. 30 ml of fluoroacetic acid was added at room temperature and stirred at the same temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure and dried under reduced pressure to obtain 10.25 g of concentrated residue.
A solution of 3.02 g of a part of the obtained concentrated residue, 3.10 ml (17.8 mmol) of DIPEA in 50 ml of dehydrated 1,4-dioxane under the argon atmosphere was synthesized in the same manner as in Reference Example 3. Chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 1.95 g (4. 42 mmol) was added at room temperature and stirred at 60 ° C. for 8 hours.
After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 50:50 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure Thus, 1.86 g (yield 67%) of the title compound was obtained as a white foam.
Mass spectrum (DUIS, m / z): 632 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.80 (s, 1 H), 7.43 to 7.18 (m, 10 H), 6.56 (d, J = 8.2 Hz, 1 H), 5.11-5.03 (m, 1 H) ), 4.66 (d, J = 13.8 Hz, 1 H), 4.60 (d, J = 13.8 Hz, 1 H), 4.52 (s, 2 H), 4.42 (q, J = 7.1 Hz, 2 H), 3.74 (dd, J) = 8.0, 10.0 Hz, 1 H), 3.63 (dd, J = 6.0, 10.0 Hz, 1 H), 2.58-2.52 (m, 2 H), 2.31-2.22 (m, 2 H), 1.95-1.84 (m, 2 H), 1.62 (s, 3 H), 1.55 (s, 3 H), 1. 34 (t, J = 7.1 Hz, 3 H), 0.12 (s, 9 H).

(Reference Example 30)
(S) -ethyl 5-[(2-hydroxy-1-phenylethyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -5,6-dihydropyrrolo [3,4-c] ] Pyrazole-2 (4H) -Carboxylate

The (S) -ethyl 5-{[2- (benzyloxy) -1-phenylethyl] carbamoyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] synthesized in the same manner as in Reference Example 29 20% palladium hydroxide / carbon under an argon atmosphere to a solution of 1.86 g (2.94 mmol) of 5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate in 30 ml of 2-propanol After 0.19 g (50 wt% water content) was added at room temperature, it was replaced with a hydrogen atmosphere under reduced pressure and stirred at room temperature for 1.5 hours. After substituting for argon atmosphere, the reaction solution was filtered through celite. The solid on celite was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. 2. 20% palladium hydroxide / carbon 0.19g (50wt% water content) is added at room temperature to a solution of 30 ml of 2-propanol obtained in the concentration residue under argon atmosphere, and it is replaced with a hydrogen atmosphere under reduced pressure. Stir for 5 hours.
After completion of the reaction, the reaction solution was filtered through celite after substitution into an argon atmosphere. The solid on celite was washed with ethyl acetate and the filtrate was concentrated in vacuo. The resulting concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 60:40 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure Thus, 1.34 g (yield 84%) of the title compound was obtained as a white foam.
Mass spectrum (DUIS, m / z): 542 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.81 (s, 1 H), 7.38-7.26 (m, 4 H), 7.23-7.17 (m, 1 H), 6.36 (d, J = 7.5 Hz, 1 H ), 4.87 (t, J = 6.0 Hz, 1 H), 4.82-4.75 (m, 1 H), 4.66 (s, 2 H), 4.42 (q, J = 7.2 Hz, 2 H), 3.67-3.55 (m, 2 H) , 2.60-2.52 (m, 2H), 2.31-2.21 (m, 2H), 1.96-1.85 (m, 2H), 1.62 (s, 3H), 1.54 (s, 3H), 1.34 (t, J = 7.2 Hz , 3H), 0.13 (s, 9H).

(Reference Example 31)
(S) -benzyl {2-[(tert-butoxycarbonyl) amino] -2-phenylethyl} succinate

(S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chemy Ltd. Under a nitrogen atmosphere, 26.2 mg (0.214 mmol) of 4-dimethylaminopyridine is added at room temperature to a solution of 496 mg (2.09 mmol) and 227 mg (2.26 mmmol) of succinic anhydride in 3 mL of the solution at room temperature. Stir for hours. Then, 0.270 ml (2.27 mmol) of benzyl bromide was added at room temperature and stirred at room temperature for 15 hours.
After completion of the reaction, toluene is added to the reaction solution, and the reaction solution is washed twice with water and once with a saturated aqueous sodium chloride solution, and the obtained organic layer is dried over anhydrous magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 86: 14 to 65:35 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. 872 mg (yield 98%) of the title compound were obtained as a white solid.
Mass spectrum (CI, m / z): 428 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.39-7.25 (m, 10 H), 5.21-5.08 (m, 3 H), 5.04-4.90 (m, 1 H), 4.39-4.21 (m, 2 H), 2.70 -2.59 (m, 4H), 1.42 (br s, 9H).

(Example 32)
(S) -2-Amino-2-phenylethyl benzyl succinate trifluoroacetate

A solution of 608 mg (1.42 mmol) of (S) -benzyl {2-[(tert-butoxycarbonyl) amino] -2-phenylethyl} succinate synthesized in the same manner as in Reference Example 31 in 10 ml of dichloromethane was stirred under a nitrogen atmosphere. 2.0 ml (26 mmol) of fluoroacetic acid was added at room temperature and stirred at room temperature for 1 hour.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure, toluene was added to the obtained concentrated residue, and the operation of concentration under reduced pressure was repeated several times to obtain 813 mg of the title compound (containing impurities).
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 8.57 (br s, 3 H), 7.53-7.30 (m, 10 H), 5.09 (s, 2 H), 4.67-4.55 (m, 1 H), 4.38- 4.27 (m, 2H), 2.66 (s, 4H).

(Reference Example 33)
(S)-{2-[(tert-butoxycarbonyl) amino] -2-phenylethoxy} methyl pivalate

(S) -tert-butyl (2-hydroxy-1-phenylethyl) carbamate [Novo Chemy Ltd. Under a nitrogen atmosphere, 0.762 g (19.1 mmol) of 60 wt% sodium hydride was added at 0 ° C. to a solution of 4.09 g (17.2 mmol) in dry THF, and the mixture was stirred at the same temperature for 1 hour. Then, 2.65 ml (18.3 mmol) of chloromethyl pivalate was added at 0 ° C., and the mixture was further warmed to room temperature for 25 minutes at the same temperature and stirred for 2.5 hours.
After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction solution and stirred, and then extracted twice with a mixed solvent of ethyl acetate and n-hexane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 75:25 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 3.32 g (yield 55%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 352 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.36-7.23 (m, 5 H), 5. 27 (d, J = 6.3 Hz, 1 H), 5.33-5.21 (m, 1 H), 5. 19 (d, J = 6.3) Hz, 1H), 4.80 (br s, 1H), 3.91 (dd, J = 4.4, 9.6 Hz, 1H), 3.87-3.77 (m, 1H), 1.41 (br s, 9H), 1.18 (s, 9H) .

(Reference Example 34)
(S)-(2-Amino-2-phenylethoxy) methyl pivalate

A nitrogen atmosphere was applied to a solution of 3.32 g (9.45 mmol) of (S)-{2-[(tert-butoxycarbonyl) amino] -2-phenylethoxy} methyl pivalate synthesized in the same manner as in Reference Example 33 in 50 ml of dehydrated dichloromethane Below, 6.0 ml (78 mmol) of trifluoroacetic acid was added at 0 ° C., and the mixture was stirred at the same temperature for 2 hours, then warmed to room temperature and stirred for 70 minutes.
After completion of the reaction, the reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution to be neutralized, and extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DNH silica gel, elution solvent; n-hexane: ethyl acetate = 95: 5 to 80:20 (V / V)), and the fractions containing the desired substance are concentrated under reduced pressure Drying under reduced pressure gave 1.83 g (yield 77%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 252 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.40-7.24 (m, 5 H), 5. 36 (d, J = 6.1 Hz, 1 H), 5.26 (d, J = 6.1 Hz, 1 H), 4.21 (dd, J = 3.8, 8.8 Hz, 1 H), 3.78 (dd, J = 3.8, 9.6 Hz, 1 H), 3.59 (dd, J = 8.8, 9.6 Hz, 1 H), 1.21 (s, 9 H).

(Reference Example 35)
(S) -2-({[(2,5-dioxopyrrolidin-1-yl) oxy] carbonyl} oxy) -2-phenylethyl acetate

(S) -2-hydroxy-2-phenylethyl acetate [J. Org. Chem. , 2013, 78 (22), 11618-11622. Synthesis in accordance with the method described in 1. to a solution of 0.84 g (4.7 mmol) in 30 ml of dehydrated acetonitrile under a nitrogen atmosphere, 0.90 ml (6.4 mmol) of triethylamine, N, N′-disuccinimidyl carbonate 1. 33 g (5.19 mmol) were sequentially added at room temperature and stirred at the same temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting concentrated residue was dissolved in ethyl acetate and it was washed with water. After separating the organic layer and the aqueous layer, the aqueous layer was extracted once with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 1.28 g (yield 85%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 322 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.45-7.34 (m, 5 H), 5. 95 (dd, J = 5.2, 7.2 Hz, 1 H), 4.39 (d, J = 5.2 Hz, 1 H), 4.38 ( d, J = 7.2 Hz, 1 H), 2.83 (s, 4 H), 2. 12 (s, 3 H).

(Reference Example 36)
(S) -Benzyl 2-[(tert-butoxycarbonyl) amino] -2-phenyl acetate

To a solution of 2.50 g (9.95 mmol) of (S) -2-[(tert-butoxycarbonyl) amino] -2-phenylacetic acid in 30 ml of DMF, 1.47 g (10.6 mmol) of potassium carbonate while stirring under a nitrogen atmosphere Was added portionwise at room temperature, then 1.20 ml (10.1 mmol) of benzyl bromide was added dropwise at room temperature, and the mixture was stirred at the same temperature for 7 hours and then left at room temperature for 3 days.
After completion of the reaction, toluene was added to the reaction solution, and washed twice with water. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 79:21 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. Thus, 3.24 g (yield 95%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 342 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.37-7.27 (m, 8 H), 7.23-7.15 (m, 2 H), 5.61-5.50 (m, 1 H), 5.40-5.33 (m, 1 H), 5.23 -5.08 (m, 2H), 1.49-1.29 (m, 9H).

(Reference Example 37)
(S) -benzyl 2-amino-2-phenyl acetate trifluoroacetate

In 10 ml of a solution of 462 mg (1.35 mmol) of (S) -benzyl 2-[(tert-butoxycarbonyl) amino] -2-phenylacetate synthesized in the same manner as in Reference Example 36 in 2.0 ml of trifluoroacetic acid 26 mmol) was added at room temperature and stirred at room temperature for 24 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. Dichloromethane was added to the obtained concentrated residue, and the operation of concentration under reduced pressure was repeated several times to obtain 572 mg (containing impurities) of the title compound.
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 8.93 (br s, 3 H), 7.54-7.44 (m, 5 H), 7.38-7.31 (m, 3 H), 7.27-7.21 (m, 2 H), 5.40 (br s, 1 H), 5. 27 (d, J = 12.5 Hz, 1 H), 5.21 (d, J = 12.5 Hz, 1 H).

(Reference Example 38)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

1- (trimethylsilyl) cyclopropanecarboxylic acid [J. Org. Chem. , 1982 (47) 5, 893-895. Into a solution of 9.70 g (61.3 mmol) of dry dichloromethane in 120 ml of dehydrated dichloromethane, 6.60 ml (76.9 mmol) of oxalyl chloride and 0.25 ml (3.2 mmol) of dry DMF were added under a nitrogen atmosphere. After sequential addition at <RTIgt; C, </ RTI> it was stirred at the temperature for 2.5 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain a concentrated residue.
Under nitrogen atmosphere, 30 ml of a solution of 30 ml of dehydrated dichloromethane obtained in the concentration residue was used as a solution of dehydrated ether in 19.0 ml (109 mmol) of DIPEA, 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2 , 5 (4H, 6H) -dicarboxylate [Journal of Medicinal Chemistry 2012, 55 (10), 4728-4737. Synthesis according to the method described in [1.] To a solution of 9.94 g (30.6 mmol) in 170 ml of dehydrated dichloromethane was added at 0 ° C. and then stirred at the same temperature for 24 hours.
After completion of the reaction, the reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and stirred, and then extracted once with dichloromethane and twice with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 70:30 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. The concentrated residue of the impurity-containing fraction is again subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 75:25 (V / V)) to obtain the purified product previously obtained. The residue was concentrated under reduced pressure and dried under reduced pressure to obtain 10.63 g of a concentrated residue.
After adding 60.0 ml (240 mmol) of 4N hydrogen chloride / ethyl acetate at room temperature under nitrogen atmosphere to a solution of 100 ml of the obtained concentrated residue in ethyl acetate, the mixture was stirred at the same temperature for 5 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. The concentrated residue obtained was suspended in diisopropyl ether and the suspension was stirred at room temperature. The insolubles were collected by filtration, and the obtained solid was washed with diisopropyl ether. The obtained solid was dissolved in water, saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added, and the mixture was stirred at room temperature for 5 minutes. After separation, the aqueous layer was extracted twice with dichloromethane. The whole organic layer is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried under reduced pressure to obtain 8.27 g of the title compound (yield 73% [2 steps]) as a slightly orange solid. The
Mass spectrum (DUIS, m / z): 365 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 10.02 (s, 1 H), 4.53 (q, J = 7.2 Hz, 2 H), 4.16 (s, 2 H), 1.50-1.43 (m, 9 H), 1.14- 1.08 (m, 2H), 0.84-0.77 (m, 2H), 0.12 (s, 9H).

(Reference Example 39)
N- (2,2-Difluoro-3-hydroxy-1-phenylpropyl) -2-methylpropane-2-sulfinamide

Under argon atmosphere, 3.29 g (50.3 mmol) of active zinc powder was added to 32 ml of degassed dehydrated THF at room temperature and then heated to 40.degree. Then, 8.60 ml (66.1 mmol) of ethyl bromodifluoroacetate was added in portions to the reaction solution at 40 ° C., and the mixture was stirred at 40 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and N-benzylidene-2-methylpropane-2-sulfinamide [Org. Lett. , 2005, 7, 5495-3549. After adding a solution of 3.47 g (16.6 mmol) in dry THF at room temperature at room temperature, the mixture was stirred at room temperature for 23 hours.
After completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The resulting suspension was filtered using a celite filter, and then the removed solid was washed with ethyl acetate, and the filtrate was separated. The aqueous layer was extracted twice with ethyl acetate, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 85: 15 to 65:35 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 4.08 g of concentrated residue was obtained.
After adding 136 mg (6.23 mmol) of lithium borohydride to a solution of 1.01 g of a portion of the obtained concentration residue in 20 ml of dehydrated THF at room temperature under a nitrogen atmosphere, the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added dropwise to the reaction solution until the bubbling ceased, and then an excess amount of a saturated aqueous ammonium chloride solution was further added, followed by stirring at room temperature for 10 minutes. It was then extracted three times with ethyl acetate. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), then concentrated under reduced pressure and dried under reduced pressure to give the title compound. 573 mg (yield 48% [two steps]) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 292 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.42-7.33 (m, 5 H), 4. 97-4. 85 (m, 1 H), 4. 37 (d, J = 6.8 Hz, 1 H), 4.03-3.74 (m, 3 H) ), 1.25 (s, 9 H).

(Reference Example 40)
3-amino-2,2-difluoro-3-phenylpropan-1-ol

N- (2,2-Difluoro-3-hydroxy-1-phenylpropyl) -2-methylpropane-2-sulfinamide 568 mg (1.95 mmol) of ethanol synthesized in the same manner as Reference Example 39 under a nitrogen atmosphere in 5 ml of ethanol After adding 2.0 ml (8.0 mmol) of 4 N hydrogen chloride / 1,4-dioxane to the solution at room temperature, the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and then extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 254 mg (yield 70%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 188 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.46-7.32 (m, 5 H), 4.44 (dd, J = 9.8, 13.1 Hz, 1 H), 3.88 (ddd, J = 8.6, 12.4, 17.8 Hz, 1 H ), 3.79-3.67 (m, 1 H).

(Reference Example 41)
Methyl 2-{[(benzyloxy) carbonyl] (2-cyanoethyl) amino} -2-methylpropanoate

Methyl 2-[(2-cyanoethyl) amino] -2-methylpropanoate [J. Med. Chem. , 1968, 11 (3), 616-618. To a solution of 5.00 g (29.4 mmol) in toluene in 23 ml of toluene, 15.5 ml (90.7 mol) of DIPEA, 30-35% benzyl chloroformate in toluene, with stirring under an argon atmosphere [Tokyo Purchased from Kasei Kogyo Co., Ltd.] 32.0 ml was sequentially added at room temperature and stirred at the same temperature for 1.5 hours. Then, after stirring at 50 ° C. for 1.5 hours, the mixture is allowed to cool to room temperature, 4.80 ml (44.1 mmol) of N, N-dimethylethane-1,2-diamine is added at room temperature, and the temperature is kept for 2.5 hours. It stirred.
After completion of the reaction, the reaction solution was poured into 2N hydrochloric acid and stirred. The aqueous layer and the organic layer were separated, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 84: 16 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure to give the title 8.32 g (yield 93%) of compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 305 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.43-7.28 (m, 5 H), 5.07 (s, 2 H), 3.64 (t, J = 6.7 Hz, 2 H), 3.50 (br s, 3 H) , 2.76 (t, J = 6.7 Hz, 2 H), 1. 45 (s, 6 H).

(Reference Example 42)
Benzyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate

Methyl 2-{[(benzyloxy) carbonyl] (2-) synthesized in the same manner as in Reference Example 41 while heating 52 ml (52 mmol) of a 1 mol / L potassium tert-butoxide THF solution at 60 ° C. and stirring under an argon stream. A solution of 12.1 g (39.7 mmol) of cyanoethyl) amino} -2-methylpropanoate in 30 ml of dehydrated THF was added dropwise, and the mixture was stirred for 1 hour while heating to reflux.
After completion of the reaction, 90 ml of water was added to the reaction solution which was allowed to cool to room temperature, and 2N hydrochloric acid was further added to adjust to pH <2. The mixture was extracted twice with 100 ml of ethyl acetate, and all the organic layers were combined and sequentially washed with 100 ml of water and 100 ml of a saturated aqueous sodium chloride solution. After drying over magnesium sulfate, filtration and concentration under reduced pressure were carried out to remove half of the solvent. To the resulting solution was added 12 g of activated carbon, and the mixture was stirred at room temperature for 30 minutes, filtered, and concentrated under reduced pressure. The concentrated residue obtained was diluted with 10 ml of diisopropyl ether, 50 ml of n-hexane was added thereto, and the precipitated solid was crushed and then stirred at room temperature for 30 minutes. The solid component was collected by filtration and vacuum dried at 50 ° C. to give 8.27 g (yield 76%) of the title compound as a pale yellow solid.
Mass spectrum (DUIS, m / z): 273 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.32 (br s, 1 H), 7.46-7.25 (m, 5 H), 5.18-5.02 (m, 2 H), 4.24-4.02 (m, 2 H), 1.51-1.35 (m, 6H).

(Reference Example 43)
Benzyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate

In 5 ml of a solution of 200 mg (0.734 mmol) of benzyl 4-cyano-3-hydroxy-2,2-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxylate synthesized in the same manner as in Reference Example 42, While stirring under a stream of argon, 0.336 ml (5.87 mmol) of acetic acid was added at room temperature and stirred at room temperature for 5 minutes. Then, 0.178 ml (3.66 mmol) of hydrazine monohydrate was added dropwise at room temperature with stirring, and the mixture was stirred for 12 hours while heating under reflux.
After completion of the reaction, 15 ml of water was added to the reaction solution which was allowed to cool to room temperature, and then an aqueous sodium hydrogen carbonate solution was added to adjust to pH 8. The mixed solution was extracted three times with ethyl acetate, and the whole organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 50: 50-0: 100 (V / V) → 1,2-dichloroethane: methanol = 80: 20 (V / V)) The residue containing the desired product was concentrated under reduced pressure to give 141 mg (yield 67%) of the title compound as a pale yellow foam.
Mass spectrum (CI, m / z): 287 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 11.20 (br s, 1 H), 7.45-7.28 (m, 5 H), 5.18-5.05 (m, 2 H), 5.05-4.77 (m, 2 H), 4.28-4.14 (m, 2H), 1.58-1.46 (m, 6H).

(Reference Example 44)
5-benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate

Dehydration of benzyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo [3,4-c] pyrazole-5 (1H) -carboxylate 400 mg (1.40 mmol) synthesized in the same manner as in Reference Example 43 To a solution of THF 4 ml, 0.594 ml (3.49 mmol) of DIPEA was added at room temperature with stirring under argon flow, and stirred at room temperature for 3 minutes. Then, 0.133 ml (1.40 mmol) of ethyl chloroformate was added dropwise at 0 ° C. with stirring, and stirred at 0 ° C. for 30 minutes.
After completion of the reaction, water was added to the reaction solution, and the mixture solution was extracted twice with ethyl acetate. The whole organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 71: 29 to 30:70 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure to give the title compound Using 200 mg (yield 40%) of a white foam, the isomer of the title compound (5-benzyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H) (6H) -dicarboxylate) 190 mg (yield 38%) were each obtained as a white foam.
Title compound (5-benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate)
Mass spectrum (CI, m / z): 359 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.45-7.29 (m, 5 H), 6.63-6.49 (m, 2 H), 5.19-5.04 (m, 2 H), 4.41-4.30 (m, 2 H) , 4.28-4.15 (m, 2H), 1.62-1.49 (m, 6H), 1.36-1.28 (m, 3H).
Isomers of the title compound (5-benzyl 1-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-1,5 (4H, 6H) -dicarboxylate)
Mass spectrum (CI, m / z): 359 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.45-7.29 (m, 5 H), 5.78-5.65 (m, 2 H), 5.19-5.05 (m, 2 H), 4.36-4.17 (m, 4 H) , 1.79-1.66 (m, 6H), 1.33-1.25 (m, 3H).

(Reference Example 45)
5-benzyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate

0.530 ml (6.17 mmol) of oxalyl chloride and 0.020 mL (0 ml) of DMF in a solution of 885 mg (5.14 mmol) of 1- (trimethylsilyl) cyclobutanecarboxylic acid synthesized in the same manner as in Reference Example 1 under argon atmosphere and 20 ml of dehydrated dichloromethane 26 mmol) was sequentially added at 0 ° C., and stirred at that temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure.
A solution of the concentrated residue in 10 ml of anhydrous dichloromethane obtained under the argon atmosphere was prepared in the same manner as in Reference Example 44 in 2.25 ml (12.9 mmol) of DIPEA, 5-benzyl 2-ethyl 3-amino-6,6-dimethylpyrrolo. The solution was added dropwise to a solution of 920 mg (2.57 mmol) of [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate in 10 ml of dehydrated dichloromethane at 0 ° C., and then stirred at room temperature for 24 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the solution was extracted twice with dichloromethane. All organic layers were combined, washed successively with 5% aqueous potassium hydrogen sulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure to give the title compound 991 mg (75% yield) was obtained as a pale yellow foam.
Mass spectrum (DUIS, m / z): 513 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.78-9.70 (m, 1 H), 7.45-7.29 (m, 5 H), 5.20-5.08 (m, 2 H), 4.63-4.50 (m, 2 H) , 4.47-4.37 (m, 2H), 2.58-2.41 (m, 2H), 2.31-2.18 (m, 2H), 1.95-1.80 (m, 2H), 1.67-1.51 (m, 6H), 1.39-1.29 ( m, 3H), 0.12-0.06 (m, 9H).

(Reference Example 46)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

5-benzyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) synthesized in the same manner as in Reference Example 45 10% palladium on carbon [N. E. CHEMCAT, PE type, 50% water content] 75 mg and 1 ml of acetic acid were sequentially added at room temperature. After replacing with hydrogen atmosphere, the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution was diluted with ethyl acetate, added with celite, and filtered. To the filtrate was added an aqueous sodium hydrogen carbonate solution and the mixture was stirred for neutralization. It was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (elution solvent; 1,2-dichloroethane: methanol = 100: 0 to 86:14 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure to give the title compound 101 mg (91% yield) were obtained as a white foam.
Mass spectrum (DUIS, m / z): 379 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 9.86 (s, 1 H), 4.52 (q, J = 7.1 Hz, 2 H), 4.22 (s, 2 H), 2.65-2.52 (m, 2 H), 2.38- 2.26 (m, 2H), 2.03-1.88 (m, 2H), 1.50-1.43 (m, 9H), 0.15 (s, 9H).

(Reference Example 47)
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

5-tert-Butyl 2-ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, synthesized in the same manner as in Reference Example 2 A solution of 57.1 g (119 mmol) of 6H) -dicarboxylate in 500 ml of dichloromethane, under nitrogen atmosphere, 28.0 ml (242 mmol) of 2,6-dimethylpyridine, 43.0 ml (238 mmol) of trimethylsilyl trifluoromethanesulfonate at 0 ° C. The solution was added dropwise successively and reacted at 0 ° C. for 2 hours while stirring.
After completion of the reaction, the reaction solution was poured into 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, stirred at room temperature and then separated. The aqueous layer was extracted twice with 500 ml of ethyl acetate, and the obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Toluene is added to the obtained concentrated residue, and the operation of concentration under reduced pressure is performed three times, and the obtained brown oil is kept refrigerated overnight, then 50 ml of diethyl ether and 100 ml of n-hexane are added, and 0. Stir for 5 hours. The precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 17.0 g (yield 38%) of the title compound as a white solid.
Mass spectrum (DUIS, m / z): 379 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 9.86 (s, 1 H), 4.52 (q, J = 7.1 Hz, 2 H), 4.23 (s, 2 H), 2.64-2.52 (m, 2 H), 2.38- 2.27 (m, 2H), 2.03-1.89 (m, 2H), 1.53-1.42 (m, 9H), 0.14 (s, 9H).

(Reference Example 48)
(S) -N- {5- [3- (benzyloxy) -2-phenylpropanoyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclobutanecarboxamide

Under nitrogen atmosphere, (S) -3- (benzyloxy) -2-phenylpropanoic acid [Tetrahedron Lett. , 2002 (43), 969 1-9693. 0.10 ml (1.2 mmol) of oxalyl chloride and 0.010 ml (0.13 mmol) of dehydrated DMF are sequentially added to a solution of 168 mg (0.657 mmol) in 3 ml of dehydrated dichloromethane at 0 ° C. The mixture was stirred at the same temperature for 3.5 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo was synthesized in the same manner as in Reference Example 47, and a solution of the concentrated residue thus obtained in 1 ml of dehydrated dichloromethane was synthesized under a nitrogen atmosphere. After addition of 127 mg (0.335 mmol) of [3,4-c] pyrazole-2 (4H) -carboxylate, 0.23 ml (1.3 mmol) of DIPEA in 3 ml of a solution of dehydrated dichloromethane at 0 ° C., 1 hour at the same temperature It stirred. Next, 1.0 ml (7.2 mmol) of triethylamine and 1.0 ml (25 mmol) of methanol were added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 19 hours.
After completion of the reaction, the reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and stirred, and then extracted three times with dichloromethane. The obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentration residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure Drying under reduced pressure gave 142 mg (yield 78%) of the title compound as a pale yellow foam.
Mass spectrum (CI, m / z): 545 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.43-7.37 (m, 2 H), 7. 35-7. 16 (m, 10 H), 4. 89 (d, J = 12.0 Hz, 1 H), 4.59 (d, J = 12.0) Hz, 1H), 4.50-4.39 (m, 2H), 4.19-4.12 (m, 1H), 4.05 (dd, J = 5.3, 8.6 Hz, 1 H), 3.61 (dd, J = 5.3, 8.8 Hz, 1 H) , 2.62-2.49 (m, 2H), 2.33-2.23 (m, 2H), 2.00-1.89 (m, 2H), 1.86 (s, 3H), 1. 73 (s, 3H), 0.14 (s, 9H).

(Reference Example 49)
3- (3-Methoxy-2-phenylpropanoyl) oxazolidin-2-one

Under a nitrogen atmosphere, 3- (2-phenylacetyl) oxazolidin-2-one [Tetrahedron, 1998 (54) 2697-2708. Synthesis according to the method described in [1.] 0.33 ml (3.0 mmol) of titanium tetrachloride was added at 0 ° C. to a solution of 506 mg (2.46 mmol) of dehydrated dichloromethane at 0 ° C., followed by stirring for 5 minutes at the same temperature. Then, 0.52 ml (3.0 mmol) of DIPEA was added at 0 ° C., and stirred at the same temperature for 1 hour. Next, 0.37 ml (4.9 mmol) of chloromethyl methyl ether was added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 2 hours.
After completion of the reaction, water was added to the reaction mixture at 0 ° C. and stirred, and then extracted three times with dichloromethane. The obtained total organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 75: 25 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 522 mg (yield 85%) of the title compound was obtained as an orange oil.
Mass spectrum (CI, m / z): 250 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.44-7.38 (m, 2 H), 7. 35-7. 27 (m, 3 H), 5. 38 (dd, J = 4.6, 10.2 Hz, 1 H), 4.44-4.27 (m , 2H), 4.18-4.07 (m, 2H), 3.95 (ddd, J = 6.8, 9.2, 11.0 Hz, 1 H), 3.50 (dd, J = 4.6, 9.2 Hz, 1 H), 3.37 (s, 3 H).

(Reference Example 50)
3-methoxy-2-phenylpropanoic acid

A solution of 517 mg (2.07 mmol) of 3- (3-methoxy-2-phenylpropanoyl) oxazolidin-2-one synthesized in the same manner as Reference Example 49 in a nitrogen atmosphere and a solution of 12 ml of THF in 4 ml of water After sequentially adding 1.0 ml (9.7 mmol) of [30%] at room temperature and 111 mg (4.63 mmol) of lithium hydroxide at 0 ° C., the mixture was stirred at that temperature for 2.5 hours. Next, 10 ml of 10% aqueous sodium thiosulfate solution and 10 ml of saturated aqueous sodium hydrogen carbonate solution were added little by little at 0 ° C., and the mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to distil out THF. The concentrated residue was washed twice with dichloromethane, adjusted to pH 2 by addition of 6N hydrochloric acid, and then this solution was extracted three times with ethyl acetate. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 80: 20 to 65:35 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 331 mg (yield 89%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 181 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.38-7.27 (m, 5 H), 4.01-3.95 (m, 1 H), 3.91 (dd, J = 4.8, 9.2 Hz, 1 H), 3.63 (dd, J = 4.8, 8.7 Hz, 1 H), 3. 39 (s, 3 H).

(Reference Example 51)
Benzyl 4-methoxy-2-phenylbutanoate

After adding 139 mg (3.19 mmol) of 55% sodium hydride at 0 ° C. under argon atmosphere to a solution of 0.45 ml (2.2 mmol) of benzyl phenyl acetate in 6 ml of dehydrated DMF, the mixture was stirred at the same temperature for 30 minutes. Next, 0.35 ml (3.7 mmol) of 2-bromoethyl methyl ether was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. 528 mg (yield 84%) of the title compound were obtained as a colorless oil.
Mass spectrum (ESI, m / z): 285 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.34-7.21 (m, ¹⁰ H), 5.15 (d, J = 12.5 Hz, 1 H), 5.05 (d, J = 12.5 Hz, 1 H), 3.83 (t, J = 7.7 Hz, 1 H), 3.38-3.30 (m, 1 H), 3.29-3.20 (m, 4 H), 2.45-2.34 (m, 1 H), 2.06-1.95 (m, 1 H).

(Example 52)
4-methoxy-2-phenylbutanoic acid

A solution of 528 mg (1.86 mmol) of benzyl 4-methoxy-2-phenylbutanoate synthesized in the same manner as in Reference Example 5 in 7 ml of ethanol was treated with 10% Pd-C (54.33% water, N.B.) under an argon atmosphere. E. CHEMCAT company PE-type 130 mg was added at room temperature, and it replaced with hydrogen atmosphere, and stirred at room temperature for 2 hours.
After completion of the reaction, the reaction solution was filtered through celite and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 60: 40 to 40:60 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure As a result, 304 mg (yield 84%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 195 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.37 (br s, 1 H), 7.38-7.20 (m, 5 H), 3.61 (t, J = 7.7 Hz, 1 H), 3.29-3.16 (m, 5H), 2.26-2.14 (m, 1 H), 1. 88-1. 77 (m, 1 H).

(Reference Example 53)
(S) -N- {5- [3- (benzyloxy) -2-phenylpropanoyl] -6,6-dimethyl-1,4,5,6-tetrahydropyrrolo [3,4-c] pyrazole-3 -Yl} -1- (trimethylsilyl) cyclopropanecarboxamide

Under nitrogen atmosphere, (S) -3- (benzyloxy) -2-phenylpropanoic acid [Tetrahedron Lett. , 2002 (43), 969 1-9693. To a solution of 51.9 mg (0.202 mmol) in 2 ml of dehydrated dichloromethane, sequentially add 0.040 ml (0.47 mmol) of oxalyl chloride and 0.0050 ml (0.065 mmol) of dehydrated DMF at 0 ° C. After stirring, the mixture was stirred at the same temperature for 2.5 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a concentrated residue.
Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclopropanecarboxamide] -5,6-dihydro was prepared in the same manner as in Reference Example 38. A solution of the concentrated residue thus obtained in 1 ml of anhydrous dichloromethane was prepared under a nitrogen atmosphere. After being added at 0 ° C. to a solution of 47.0 mg (0.129 mmol) of pyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate, 0.10 ml (0.57 mmol) of DIPEA at 0 ° C., the temperature as it is The mixture was stirred for 2 hours. Next, 0.10 ml (0.92 mmol) of N, N-dimethylethane-1,2-diamine was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, the reaction solution diluted with dichloromethane was washed with a 5% aqueous potassium hydrogen sulfate solution, and then separated. The aqueous layer was extracted twice with dichloromethane, and the obtained total organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentration residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 80: 20 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure Drying under reduced pressure gave 48 mg (yield 70%) of the title compound as a pale yellow foam.
Mass spectrum (DUIS, m / z): 531 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.55 (s, 1 H), 7.41-7.37 (m, 2 H), 7.34-7.20 (m, 9 H), 4.84 (d, J = 12.0 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.42 (d, J = 12.0 Hz, 1 H), 4.16 (t, J = 8.8 Hz, 1 H), 4.02 (4 dd, J = 5.4, 8.8 Hz, 1 H), 3.61 (dd, J = 5.4, 8.8 Hz, 1 H), 1. 85 (s, 3 H), 1.72 (s, 3 H), 1.09-1.04 (m, 2 H), 0.81 -0.76 (m, 2 H), 0.10 (s, 9 H).

(Reference Example 54)
(R) -benzyl 2-ethoxy-2-phenyl acetate

Under an argon atmosphere, 1.93 g (8.33 mmol) of silver oxide was added at room temperature to a solution of 1.01 g (4.17 mol) of (R) -benzyl 2-hydroxy-2-phenyl acetate in 20 ml (0.25 mol) of iodoethane The mixture was stirred at 60 ° C. for 18 hours.
After completion of the reaction, the reaction solution is filtered through Celite, and the solid component is washed with ethyl acetate, and the filtrate is concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 80:20 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure. 1.03 g (yield 91%) of the title compound was obtained as a colorless oil.
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.49-7.43 (m, 2 H), 7.38-7.27 (m, 6 H), 7.24-7.18 (m, 2 H), 5.19 (d, J = 12.4 Hz, 1 H , 5.11 (d, J = 12.4 Hz, 1 H), 4.92 (s, 1 H), 3.65-3.46 (m, 2 H), 1.27 (t, J = 7.0 Hz, 3 H).

(Example 55)
(R) -2-ethoxy-2-phenylacetic acid

A solution of 1.03 g (3.81 mmol) of (R) -benzyl 2-ethoxy-2-phenylacetate synthesized in the same manner as in Reference Example 54 in 20 ml of methanol was subjected to palladium / carbon 0.11 (ASCA2 (ASCA2 After adding brand name) and NE CHEMCAT company make, 54% water-containing), it substituted to hydrogen atmosphere under pressure reduction, and stirred at room temperature for 2 hours.
After completion of the reaction, the reaction solution was filtered through Celite, the solid component was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain 0.63 g (yield 92%) of the title compound as a pale yellow oil.
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.80 (br s, 1 H), 7.44 to 7.28 (m, 5 H), 4.84 (s, 1 H), 3.60 to 3.50 (m, 1 H), 3.47- 3.20 (m, 1 H), 1. 15 (t, J = 7.0 Hz, 3 H).

(Reference Example 56)
(R) -benzyl 2-cyclopropoxy-2-phenyl acetate

To a solution of 7.50 ml (7.50 mmol) of 1 M diethylzinc n-hexane solution in 4 ml of dehydrated dichloromethane was added dropwise at 0 ° C. a solution of 0.750 ml (9.31 mmol) of diiodomethane in 1 ml of dehydrated dichloromethane while stirring under argon. The mixture was stirred at the same temperature for 30 minutes. Then, 500 mg (1.86 mmol) of (R) -benzyl 2-phenyl-2- (vinyloxy) acetate [J. Am. Chem. Soc. , 2006, 128, 2587-2593. A solution of 1 ml of dehydrated dichloromethane] was added dropwise at 0 ° C. with stirring, and stirred at room temperature for 6 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 80:20 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure to The title compound (416 mg, yield 79%) was obtained as a colorless oil.
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.47-7.41 (m, 2 H), 7.38-7.28 (m, 6 H), 7.25-7.20 (m, 2 H), 5.20 (d, J = 12.5 Hz, 1 H ), 5.12 (d, J = 12.5 Hz, 1 H), 5.01 (s, 1 H), 3.43 (tt, J = 3.0, 6.1 Hz, 1 H), 0.76-0.65 (m, 2 H), 0.53-0.43 (m, 2H).

(Reference Example 57)
(R) -2-Cyclopropoxy-2-phenylacetic acid

93 mg of lithium hydroxide monohydrate was dissolved in a solution of 416 mg (1.47 mmol) of (R) -benzyl 2-cyclopropoxy-2-phenylacetate synthesized in the same manner as in Reference Example 56 in 2 ml of methanol and 2 ml of water. .2 mmol) were added at room temperature and then allowed to react at room temperature for 2 hours with stirring.
After completion of the reaction, diethyl ether was added to the reaction solution to separate it. The aqueous layer was adjusted to pH 2 by addition of 2N hydrochloric acid, and extracted three times with ethyl acetate. The obtained total organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 274 mg (yield 97%) of the title compound as a colorless oil.
Mass spectrum (DUIS, m / z): 191 [M−1] ⁻ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.48-7.32 (m, 5 H), 4.99 (s, 1 H), 3.43 (tt, J = 2.9, 6.0 Hz, 1 H), 0.76-0.64 (m, 2 H) ), 0.61-0.43 (m, 2H).

(Reference Example 58)
(R) -2-isopropoxy-2-phenylacetic acid

Silver (I) oxide 2.79 g in a suspension of 1.46 g (6.03 mmol) of (R) -benzyl 2-hydroxy-2-phenyl acetate in 14.0 ml (140 mmol) of 2-iodopropane under an argon atmosphere After adding (12.0 mmol) at room temperature, it was reacted with heating under reflux for 14.5 hours with stirring.
After completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. After the filtrate was washed with ethyl acetate, all filtrates were concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 90:10 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 675 mg of concentrated residue was obtained.
Under argon atmosphere, 176 mg (4.19 mmol) of lithium hydroxide monohydrate was added at room temperature to a solution of 10 ml of methanol / 2.0 ml of water of the obtained concentrated residue, and then reacted at room temperature for 4 hours with stirring .
After completion of the reaction, water and diethyl ether were added to the reaction solution and the mixture was stirred and then separated. The aqueous layer was adjusted to pH 2 by addition of 2N hydrochloric acid, and extracted three times with ethyl acetate. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 85:15 to 70:30 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure As a result, 467 mg of concentrated residue was obtained. The resulting concentrated residue is subjected to preparative HPLC (column: X-Bridge (trade name) ODS, elution solvent: 1 vol% formic acid / acetonitrile: 1 vol% formic acid aqueous solution = 20: 80 to 70:30 (V / V)) The fractions containing the desired product were concentrated under reduced pressure to distill off acetonitrile. The concentrated residue thus obtained is extracted three times with ethyl acetate, and then the whole organic layer is washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and dried under reduced pressure to give the title compound 346 mg (yield 30% [2 steps]) were obtained as a white solid.
Mass spectrum (CI, m / z): 195 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.42 (br s, 1 H), 7.43-7.27 (m, 5 H), 4.95 (s, 1 H), 3.62 (spt, J = 6.1 Hz, 1 H) , 1.15 (d, J = 6.1 Hz, 3 H), 1.09 (d, J = 6.1 Hz, 3 H).

(Reference Example 59)
(R) -ethyl 2-phenyl-2- (trifluoromethoxy) acetate

(R) -Ethyl 2-hydroxy-2-phenylacetate 25.0 g (139 mmol) in 10 ml of a chloroform solution containing 40% 1-trifluoromethyl-3,3-dimethyl-1 while stirring under an argon atmosphere , 2-benzoiodoxol [Togni Reagent II (trade name), diatomaceous earth mixture, purchased from Tokyo Chemical Industry Co., Ltd.] 3.75 g (4.75 mmol), bis (trifluoromethylsulfonyl) imido zinc (II) 0 .900 g (1.44 mmol) were added at room temperature and stirred at room temperature for 88 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure, 421 mg (containing impurities) of the title compound were obtained as a yellow oil.
Mass spectrum (CI, m / z): 249 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.53-7.36 (m, 5 H), 5.52 (s, 1 H), 4.32-4.16 (m, 2 H), 1.25 (t, J = 7.1 Hz, 3 H).

(Reference Example 60)
(R) -2-phenyl-2- (trifluoromethoxy) acetic acid

93 mg of lithium hydroxide monohydrate were prepared in a solution of 421 mg of (R) -ethyl 2-phenyl-2- (trifluoromethoxy) acetate (containing impurities) synthesized in the same manner as in Reference Example 59 in 3 ml of methanol / 3 ml of water. After adding 2.2 mmol) at room temperature, it was reacted at room temperature for 4 hours while stirring.
After completion of the reaction, diethyl ether was added to the reaction solution to separate it. The aqueous layer was adjusted to pH 2 by addition of 2N hydrochloric acid, and extracted three times with ethyl acetate. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 390 mg (containing impurities) of the title compound as a pale yellow oil.
Mass spectrum (DUIS, m / z): 219 [M−1] ⁻ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.52 to 7.37 (m, 5 H), 5.57 (s, 1 H).

(Reference Example 61)
(R) -benzyl 2-phenyl-2-propoxy acetate

3.03 g of silver (I) oxide in a suspension of 1.58 g (6.52 mmol) of (R) -benzyl 2-hydroxy-2-phenyl acetate in 14.5 ml (149 mmol) of 1-iodopropane under an argon atmosphere After adding (13.1 mmol) at room temperature, it was allowed to react at 80 ° C. for 14 hours while stirring.
After completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. After the filtrate was washed with ethyl acetate, all filtrates were concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 97: 3 to 90:10 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 1.23 g (yield 66%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 285 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.43-7.27 (m, 8 H), 7.26-7.20 (m, 2 H), 5.13 (s, 2 H), 5.06 (s, 1 H), 3.46 (td , J = 6.6, 9.0 Hz, 1 H), 3.40-3.28 (m, 1 H), 1.60-1.49 (m, 2 H), 0.85 (t, J = 7.4 Hz, 3 H).

(Reference Example 62)
(R) -2-phenyl-2-propoxyacetic acid

A solution of 1.23 g (4.33 mmol) of (R) -benzyl 2-phenyl-2-propoxyacetate synthesized in the same manner as in Reference Example 61 in an argon atmosphere in 15 ml of ethanol was treated with 10% palladium / carbon [PE type Trade name), N. E. After adding 274 mg of CHEMCAT, 54% water-containing) at room temperature, the atmosphere was replaced with a hydrogen atmosphere under reduced pressure, and reaction was carried out for 1.5 hours at room temperature while stirring.
After completion of the reaction, the inside of the reaction vessel was replaced with an argon atmosphere under reduced pressure. The reaction solution was filtered using a celite filter, the removed solid was washed with ethanol, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 892 mg (containing impurities) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 195 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 12.78 (br s, 1 H), 7.42-7.29 (m, 5 H), 4.83 (s, 1 H), 3.47 (td, J = 6.6, 9.0 Hz, 1H), 3.40-3.25 (m, 1 H), 1.61-1.49 (m, 2 H), 0.87 (t, J = 7.4 Hz, 3 H).

(Reference Example 63)
Methyl 2- (4-fluorophenyl) -2-methoxyacetate

To a solution of 800 mg (4.70 mmol) of 4-fluoromandelic acid in 20 ml of dehydrated DMF, 450 mg (10.3 mmol) of 55% sodium hydride was added in portions at 0 ° C. while stirring under an argon atmosphere, and stirred at the same temperature for 1 hour did. Subsequently, 0.732 ml (11.8 mmol) of iodomethane was dropped at 0 ° C., and the mixture was stirred at room temperature for 2 hours. After 0.732 ml (11.8 mmol) of iodomethane was further added dropwise at 0 ° C., the mixture was stirred at room temperature for 2 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, The title compound 247 mg (yield 27%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 199 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.46-7.38 (m, 2 H), 7.11-7.02 (m, 2 H), 4. 76 (s, 1 H), 3.73 (s, 3 H), 3. 40 (s, 3 H) ).

(Reference Example 64)
2- (4-Fluorophenyl) -2-methoxyacetic acid

To a solution of 247 mg (1.25 mmol) of methyl 2- (4-fluorophenyl) -2-methoxyacetate synthesized in the same manner as in Reference Example 63 in 5 ml of THF was added 2.0 ml of a 1 N aqueous solution of sodium hydroxide while stirring. 0 mmol) was added at room temperature and stirred at the same temperature for 16 hours.
After completion of the reaction, the reaction mixture was adjusted to pH 2 by adding 1N hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 260 mg (containing impurities) of the title compound as a brown oil.
Mass spectrum (CI, m / z): 185 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.49-7.36 (m, 2 H), 7.13- 7.03 (m, 2 H), 4.77 (s, 1 H), 3.43 (s, 3 H).

(Reference Example 65)
Ethyl 2- (3-fluorophenyl) -2-hydroxy acetate

To a suspension of 1.00 g (7.15 mmol) of 3-fluorophenylboronic acid in 30 ml of a suspension of dehydrated toluene under stirring in an argon atmosphere, a solution of 50% ethyl oxoacetate in toluene [purchased from Apollo scientific Limited] 2.20 g (10. 8 mmol) and 107 mg (0.359 mmol) of 2- (di-tert-butylphosphino) biphenyl were added at room temperature, and the atmosphere was replaced with a nitrogen atmosphere under reduced pressure. Then, 92.0 mg (0.100 mmol) of tris (dibenzylideneacetone) dipalladium (0) was added at room temperature with stirring, and allowed to react at 80 ° C. for 9 hours.
The reaction solution was filtered using a celite filter, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure, 263 mg (yield 19%) of the title compound were obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 199 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.38-7.29 (m, 1 H), 7.25-7.20 (m, 1 H), 7.19-7.13 (m, 1 H), 7.06-6.98 (m, 1 H), 5.15 (d, J = 5.4 Hz, 1 H), 4.34-4.14 (m, 2 H), 3.50 (d, J = 5.4 Hz, 1 H), 1.25 (t, J = 7.2 Hz, 3 H).

(Reference Example 66)
Ethyl 2- (3-fluorophenyl) -2-methoxyacetate

In an argon atmosphere, a solution of 263 mg (1.33 mmol) of ethyl 2- (3-fluorophenyl) -2-hydroxyacetate synthesized in the same manner as in Reference Example 65 in 8.0 ml (130 mmol) of iodomethane was mixed with 615 mg of silver oxide 2.65 mmol) was added at room temperature and allowed to react for 3 hours with stirring at the same temperature.
After completion of the reaction, the reaction solution was filtered using a celite filter, and the filtrate was concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. The title compound (155 mg, yield 55%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 213 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.37-7.29 (m, 1 H), 7.25-7.15 (m, 2 H), 7.07-7.00 (m, 1 H), 4.75 (s, 1 H), 4.28-4.12 (m, 2H), 3.43 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H).

(Reference Example 67)
2- (3-Fluorophenyl) -2-methoxyacetic acid

A solution of 155 mg (0.730 mmol) of ethyl 2- (3-fluorophenyl) -2-methoxyacetate synthesized in the same manner as in Reference Example 66 in 5 ml of THF was stirred with 1.0 ml of a 1 N aqueous solution of sodium hydroxide (1. 0 mmol) was added at room temperature and stirred at the same temperature for 20 hours.
After completion of the reaction, the reaction mixture was adjusted to pH 2 by adding 1N hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 144 mg of the title compound (containing impurities) as a colorless oil.
Mass spectrum (CI, m / z): 185 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.41-7.32 (m, 1 H), 7.25-7.20 (m, 1 H), 7.19-7.13 (m, 1 H), 7.10-7.03 (m, 1 H), 4.79 (s, 1 H), 3. 46 (s, 3 H).

(Reference Example 68)
(R) -Methyl 2- (2-fluorophenyl) -2-methoxyacetate

(R) -2- (2-fluorophenyl) -2-hydroxyacetic acid [purchased from Combi-Blocks] 55% hydrogenation while stirring under argon atmosphere to a solution of 1.00 g (5.88 mmol) in 20 ml of dehydrated DMF 310 mg (7.10 mmol) of sodium were added in portions at 0 ° C. and stirred at the same temperature for 1 hour. Then, after 0.842 ml (13.5 mmol) of iodomethane was dropped at 0 ° C., the mixture was stirred at room temperature for 4 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 70:30 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure, The title compound 858 mg (yield 74%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 199 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.50-7.42 (m, 1 H), 7.38-7.30 (m, 1 H), 7.21-7.14 (m, 1 H), 7.13-7.05 (m, 1 H), 5.14 (s, 1 H), 3.43 (s, 3 H).

(Reference Example 69)
(R) -2- (2-fluorophenyl) -2-methoxyacetic acid

5. A solution of 858 mg (4.33 mmol) of (R) -methyl 2- (2-fluorophenyl) -2-methoxyacetate synthesized in the same manner as in Reference Example 68 in 10 ml of THF was added with 1N aqueous solution of sodium hydroxide while stirring. 2 ml (5.2 mmol) were added at room temperature and stirred at 50 ° C. for 3 hours.
After completion of the reaction, the reaction solution was allowed to cool to room temperature, 1N hydrochloric acid was added to the reaction mixture to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 390 mg (yield 49%) of the title compound as a brown oil.
Mass spectrum (CI, m / z): 185 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.46-7.32 (m, 2 H), 7.22-7.05 (m, 2 H), 5.11 (s, 1 H), 3.43 (s, 3 H).

(Reference example 70)
Ethyl 2-hydroxy-2- (thiophen-2-yl) acetate

A 30% suspension of thiophene-2-boronic acid in 1.00 g (7.82 mmol) in 30 ml of dehydrated toluene was stirred under an argon atmosphere with a 50% solution of ethyl oxoacetate in toluene [purchased from Apollo scientific limited] 2.40 g (11. 8 mmol) and 117 mg (0.392 mmol) of 2- (di-tert-butylphosphino) biphenyl were added at room temperature, and the atmosphere was replaced with nitrogen under reduced pressure. Then, 101 mg (0.110 mmol) of tris (dibenzylideneacetone) dipalladium (0) was added at room temperature with stirring, and reacted at 80 ° C. for 9 hours.
The reaction solution was filtered using a celite filter, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure, 86 mg (yield 6%) of the title compound were obtained as a yellow oil.
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.29 (dd, J = 1.2, 5.1 Hz, 1 H), 7.13-7.09 (m, 1 H), 7.00 (dd, J = 3.6, 5.1 Hz, 1 H), 5.43-5.37 (m, 1 H), 4.37-4.22 (m, 2 H), 3.48 (d, J = 6.4 Hz, 1 H), 1.30 (t, J = 7.2 Hz, 3 H).

(Reference example 71)
Ethyl 2-methoxy-2- (thiophen-2-yl) acetate

214 mg (silver oxide) of a solution of 86 mg (0.46 mmol) of ethyl 2-hydroxy-2- (thiophen-2-yl) acetate synthesized in the same manner as in Reference Example 70 in 4.0 ml (64 mmol) of iodomethane under an argon atmosphere 0.923 mmol) was added at room temperature and allowed to react for 3 hours while stirring at the same temperature.
After completion of the reaction, the reaction solution was filtered using a celite filter, and the filtrate was concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. 68.5 mg (yield 74%) of the title compound was obtained as a colorless oil.
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.33 (dd, J = 1.2, 5.1 Hz, 1 H), 7.16-7.10 (m, 1 H), 7.00 (dd, J = 3.5, 5.1 Hz, 1 H), 5.02 (s, 1 H), 4.33-4.17 (m, 2 H), 3. 44 (s, 3 H), 1. 28 (t, J = 7.2 Hz, 3 H).

(Reference example 72)
2-methoxy-2- (thiophen-2-yl) acetic acid

A solution of 68 mg (0.34 mmol) of ethyl 2-methoxy-2- (thiophen-2-yl) acetate synthesized in the same manner as in Reference Example 71 in 3 ml of THF was stirred with 0.5 ml of a 1 N aqueous solution of sodium hydroxide (0. 1). 5 mmol) was added at room temperature and stirred at the same temperature for 16 hours.
After completion of the reaction, the reaction mixture was adjusted to pH 2 by adding 1N hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried under reduced pressure to obtain 60 mg of the title compound (containing impurities) as a pale yellow oil.
Mass spectrum (DUIS, m / z): 171 [M−1] ⁻ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.36 (dd, J = 1.2, 5.1 Hz, 1 H), 7.19-7.14 (m, 1 H), 7.02 (dd, J = 3.5, 5.1 Hz, 1 H), 5.07 (s, 1 H), 3. 48 (s, 3 H).

(Reference Example 73)
2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarbo quirate, and Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate blend

Ethyl 6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamido] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) synthesized in the same manner as in Reference Example 47 under an argon atmosphere. 12.9 ml (74.1 mmol) of DIPEA was added at room temperature to a solution of 8.03 g (21.2 mmol) of carboxylate in 100 ml of dry dichloromethane. Next, a solution of 4.40 g (14.8 mmol) of bis (trichloromethyl) carbonate in 10 ml of dehydrated dichloromethane was added dropwise at -78 ° C, and the mixture was stirred at the same temperature for 1.5 hours.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the reaction solution, and the mixture was stirred for 1 hour while warming up to room temperature. The reaction mixture was separated, and the aqueous layer was extracted twice with ethyl acetate. The whole organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 85: 15 → 75: 25 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure. To the obtained concentrated residue, n-hexane was added, and the mixture was stirred at room temperature for 10 minutes and then allowed to stand in a freezer for 15 minutes. The solid obtained was separated by filtration, and the removed solid was washed with n-hexane, and the filtrate obtained was concentrated under reduced pressure and dried under reduced pressure to give 2-ethyl 5- (trichloromethyl) 6,6-dimethyl-3. -[1- (Trimethylsilyl) cyclobutanecarboxamido] pyrrolo [3,4-c] pyrazole-2,5 (4H, 6H) -dicarboxylate, 2.90 g (yield 25%) and ethyl 5- (chlorocarbonyl)- 6,6-Dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate 1.75 g (yield 19%) The mixture was obtained as a white foam.
Mass spectrum (ESI, m / z): 539 [M + 1] ⁺ , 441 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 9.99-9.84 (m, total 1H), 4.97 (s, 0.85 H), 4.84-4.79 (m, total 1.15 H), 4.59-4.51 (m, total 2 H) ), 2.64-2.53 (m, total 2H), 2.39-2.28 (m, total 2H), 2.03-1.92 (m, total 2H), 1.82-1.75 (m, total 6H), 1.51-1.44 (m, total 3H) ), 0.19-0.13 (m, total 9H).

(Example 74)
{1- [Amino (phenyl) methyl] cyclobutyl} methanol

Under an argon atmosphere, 2.36 ml (23.2 mmol) of benzaldehyde and 235 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate were sequentially added to a solution of 2.07 g (23.2 mmol) of ethyl carbamate in 20 ml of toluene at room temperature. After addition, it was stirred at room temperature for 5 minutes. Then, after adding 1.80 ml (23.2 mmol) of cyclobutanecarbaldehyde at room temperature, the mixture was stirred at 60 ° C. for 4 hours.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and then stirred at room temperature. After separation, the aqueous layer was extracted once with toluene. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 2.20 g of concentrated residue was obtained.
Under an argon atmosphere, 199 mg (5.26 mmol) of sodium borohydride is added in portions to an ethanol 10 ml solution of the obtained concentrated residue at 0 ° C., and the mixture is stirred at 0 ° C. for 0.5 hours and further at room temperature for 2.5 hours did. Next, 990 mg (17.7 mmol) of potassium hydroxide and 5.0 ml of water were added to the reaction mixture at room temperature, and the mixture was stirred for 2.5 hours while heating under reflux.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to distil off ethanol. The concentrated residue was added with 2N hydrochloric acid and then washed with diethyl ether. The aqueous layer obtained by separation was added with 2N aqueous sodium hydroxide solution to adjust to pH> 10, and then extracted three times with dichloromethane. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is dissolved in 1,2-dichloroethane, n-hexane is added, and the precipitated solid is collected by filtration, washed with n-hexane and dried under reduced pressure to give 859 mg of the title compound ( A 19% yield [two steps] was obtained as a white solid.
Mass spectrum (CI, m / z): 192 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.36-7.25 (m, 4 H), 7.24-7.16 (m, 1 H), 3. 97 (s, 1 H), 3.41 (d, J = 10.7 Hz, 1 H ), 3.25 (d, J = 10.7 Hz, 1 H), 2.06-1.92 (m, 2 H), 1. 79-1.63 (m, 2 H), 1.61-1.50 (m, 1 H), 1. 47-1.37 (m, 1 H).

(Reference Example 75)
(R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -2,2,2-trifluoroacetamide

In 10 ml of a solution of 1.01 g (3.67 mmol) of (R) -methyl 3-phenyl-3- (2,2,2-trifluoroacetamide) propanoate synthesized in the same manner as in Reference Example 20 in an argon atmosphere and in 10 ml of dehydrated THF 0.22 ml (0.75 mmol) of tetraisopropyl orthotitanate is added at 0 ° C., and 11.0 ml (11.0 mmol) of 1 M ethylmagnesium bromide / THF solution is added dropwise over 1 hour at 0 ° C. The mixture was stirred at the same temperature for 3 hours and then warmed to room temperature and stirred for 1.5 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution and stirred, and then the insoluble matter was separated by filtration using a celite filter. The filtered solid was washed with ethyl acetate, and the filtrate was separated. The aqueous layer was extracted once with ethyl acetate, and then the whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 75:25 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 489 mg (yield 49%) of the title compound was obtained as a slightly yellow solid.
Mass spectrum (CI, m / z): 274 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.67 (br s, 1 H), 7.37-7.30 (m, 4 H), 7.30-7.21 (m, 1 H), 5.33-5.05 (m, 2 H), 2.01 (dd, J = 5.2, 14.2 Hz, 1 H), 1. 93 (dd, J = 9.2, 14.2 Hz, 1 H), 0.57-0.46 (m, 2 H), 0.45-0.37 (m, 1 H), 0.11-0.04 ( m, 1H).

(Reference Example 76)
(R) -1- (2-amino-2-phenylethyl) cyclopropanol

  (R) -N- [2- (1-hydroxycyclopropyl) -1-phenylethyl] -2,2,2-trifluoroacetamide 412 mg (1. 1) synthesized in the same manner as in Reference Example 75 under an argon atmosphere. After adding 174 mg (4.60 mmol) of sodium borohydride at room temperature to a solution of 51 mmol) in ethanol, the mixture was stirred at room temperature for 14.5 hours.

After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature. Water was added to dissolve insolubles, and the mixture was extracted twice with dichloromethane. The whole organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 75: 25 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure By drying under reduced pressure, 259 mg (containing impurities) of the title compound was obtained as a slightly yellow solid.
Mass spectrum (CI, m / z): 178 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.38-7.24 (m, 4 H), 7.21-7.14 (m, 1 H), 4.15 (dd, J = 4.0, 9.4 Hz, 1 H), 1.82 (ddd , J = 1.3, 9.4, 13.9 Hz, 1 H), 1.51-1.44 (m, 1 H), 0.58-0.51 (m, 1 H), 0.49-0.42 (m, 1 H), 0.41-0.34 (m, 1 H), 0.21 -0.14 (m, 1 H).

(Reference Example 77)
(R) -N- (3-ethyl-3-hydroxy-1-phenylpentyl) -2,2,2-trifluoroacetamide

A solution of 700 mg (2.54 mmol) of (R) -methyl 3-phenyl-3- (2,2,2-trifluoroacetamide) propanoate synthesized in the same manner as in Reference Example 20 in 10 ml of dehydrated THF was mixed with 1 M under an argon atmosphere. After dropwise addition of 7.63 ml (7.63 mmol) of ethyl magnesium bromide-THF solution at 0 ° C., the mixture was stirred at room temperature for 6 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 90:10 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 714 mg (containing impurities) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 304 [M + 1] ⁺ .

(Reference Example 78)
(R) -1-amino-3-ethyl-1-phenylpentan-3-ol

1 ml of water / 5 ml of water containing (R) -N- (3-ethyl-3-hydroxy-1-phenylpentyl) -2,2,2-trifluoroacetamide (containing an impurity) synthesized in Reference Example 77 To the solution was added 651 mg (4.71 mmol) of potassium carbonate at room temperature under an argon atmosphere, and then stirred at the same temperature for 20 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 75: 25 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 120 mg (yield 23% [two steps]) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 208 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.38-7.25 (m, 4 H), 7.22-7.15 (m, 1 H), 4.01 (dd, J = 2.6, 10.9 Hz, 1 H), 1.66-1.41 (m, 4H), 1.38-1.25 (m, 2H), 0.86-0.71 (m, 6H).

(Reference Example 79)
(E) -Methyl 3- (4-fluorophenyl) acrylate

After adding 6.47 g (19.4 mmol) of methyl 2- (triphenylphosphoranylidene) acetate at room temperature to a solution of 2.0 g (16 mmol) of 4-fluorobenzaldehyde in 20 ml of dehydrated THF at room temperature, Stir for 20 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the obtained concentration residue, 20 ml of TBME was added and filtered, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 90:10 (v / v)), and the fraction containing the desired product is concentrated under reduced pressure and dried under reduced pressure As a result, 2.74 g (yield 94%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 181 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.66 (d, J = 16.0 Hz, 1 H), 7.55-7.47 (m, 2 H), 7.13-7.03 (m, 2 H), 6.41-6.33 (m, 1 H) ), 3.81 (s, 3 H).

(Reference Example 80)
(R) -Methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (4-fluorophenyl) propanoate

(S) -N-benzyl-1-phenylethanamine solution in 2.79 ml (13.3 mmol) of THF solution in 30 ml of dehydrated THF under an argon atmosphere 7.80 ml (12.5 mmol) of a 1.6 M n-butyllithium n-hexane solution The reaction mixture was added dropwise at -78.degree. C. and stirred for 30 minutes at the same temperature. Subsequently, a THF 5 ml solution of 1.5 g (8.3 mmol) of (E) -methyl 3- (4-fluorophenyl) acrylate synthesized in the same manner as in Reference Example 79 was added at -78 ° C. Stir for hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. 1.53 g (yield 47%) of the title compound was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 392 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.43-7.16 (m, 12 H), 7.08-6.96 (m, 2 H), 4.42 (dd, J = 5.4, 9.7 Hz, 1 H), 3.97 (q, J = 6.9 Hz, 1 H), 3.72 (d, J = 14.7 Hz, 1 H), 3. 65 (d, J = 14.7 Hz, 1 H), 3. 47 (s, 3 H), 2. 65 (dd, J = 5.4, 14.9 Hz, 1 H ), 2.52 (dd, J = 9.7, 14.9 Hz, 1 H), 1.27-1.21 (m, 3 H).

(Example 81)
(R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (4-fluorophenyl) -2-methylbutan-2-ol

Dehydration of 1.35 g (3.45 mmol) of (R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (4-fluorophenyl) propanoate synthesized in the same manner as Reference Example 80] To the THF 20 ml solution was added dropwise 10.4 ml (10.4 mmol) of 1 M methylmagnesium bromide-THF solution at 0 ° C. under argon flow, and the mixture was stirred at room temperature for 20 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5 to 85:15 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 850 mg (yield 63%) of the title compound was obtained as a colorless oil.
Mass spectrum (ESI, m / z): 392 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.48-7.09 (m, ¹⁴ H), 4.21 (s, 1 H), 4.09-3.98 (m, 1 H), 2.92-3.85 (m, 1 H), 3.74 (d, J = 15.1 Hz, 1 H), 3.63 (d, J = 15.1 Hz, 1 H), 2. 10 (dd, J = 9.2, 13.9 Hz, 1 H), 2.02-1.93 (m, 1 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.82 (s, 3 H), 0.69 (s, 3 H).

(Reference Example 82)
(R) -4-amino-4- (4-fluorophenyl) -2-methylbutan-2-ol

(R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (4-fluorophenyl) -2-methylbutan-2-ol 850 mg (2. To a solution of 17 mmol) in 10 ml of methanol was added 425 mg of 20% palladium hydroxide / carbon (50% water-containing) at room temperature under argon flow, and after replacing with a hydrogen atmosphere, the mixture was stirred at room temperature for 7 hours.
After completion of the reaction, the reaction solution was diluted with ethyl acetate and filtered through celite. The filtrate is concentrated under reduced pressure, and the obtained concentrated residue is subjected to silica gel column chromatography (DIOL, elution solvent; n-hexane: ethyl acetate = 75: 25 to 50:50 (V / V)) to contain the desired product. The fractions were concentrated under reduced pressure to give 248 mg of the title compound (containing impurities) as a colorless oil.
Mass spectrum (CI, m / z): 198 [M + 1] ⁺ .

(Reference Example 83)
(E) -Methyl 3- (3-fluorophenyl) acrylate

After adding 5.25 g (15.7 mmol) of methyl 2- (triphenylphosphoranylidene) acetate at room temperature to a solution of 1.27 ml (12.1 mmol) of 3-fluorobenzaldehyde in 25 ml of dehydrated THF at room temperature, Stir at temperature for 16 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. 20 ml of TBME was added to the obtained concentration residue, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 90:10 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. Thus, 1.75 g (yield 80%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 181 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.65 (d, J = 16.1 Hz, 1 H), 7.40-7.33 (m, 1 H), 7.32-7.27 (m, 1 H), 7.25-7.19 (m, 1 H) ), 7.12-7.05 (m, 1 H), 6. 44 (d, J = 16.1 Hz, 1 H), 3.82 (s, 3 H).

(Reference Example 84)
(R) -Methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (3-fluorophenyl) propanoate

(S) -N-benzyl-1-phenylethanamine solution in 3.25 ml (15.5 mmol) of THF solution in 30 ml of dehydrated THF under an argon atmosphere, 9.11 ml of a 1.6 M n-butyllithium n-hexane solution (14.6 mmol) The reaction mixture was added dropwise at -78.degree. C. and stirred for 1 hour at the same temperature. Then, a THF (5 ml) solution of 1.75 g (9.71 mmol) of (E) -methyl 3- (3-fluorophenyl) acrylate synthesized in the same manner as in Reference Example 83 was added at -78 ° C. Stir for hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. Thus, 2.22 g (yield 58%) of the title compound was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 392 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.45-7.09 (m, 13 H), 7.00-6.91 (m, 1 H), 4.44 (dd, J = 5.4, 9.4 Hz, 1 H), 3.98 (q, J = 6.9 Hz, 1 H), 3.73 (d, J = 14.6 Hz, 1 H), 3. 66 (d, J = 14.6 Hz, 1 H), 3. 49 (s, 3 H), 2. 63 (dd, J = 5.4, 15.2 Hz, 1 H ), 2.54 (dd, J = 9.4, 15.2 Hz, 1 H), 1.25 (d, J = 6.9 Hz, 3 H).

(Reference Example 85)
(R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (3-fluorophenyl) -2-methylbutan-2-ol

Dehydration of 2.22 g (5.67 mmol) of (R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (3-fluorophenyl) propanoate synthesized as in Reference Example 84 After dropwise addition of 17.0 ml (17.0 mmol) of a 1 M methylmagnesium bromide-THF solution at 0 ° C. under argon atmosphere to a THF 20 ml solution, the mixture was stirred at room temperature for 17 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5-85: 15 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. The title compound (1.95 g, yield 88%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 392 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.42-7.22 (m, 11 H), 7.20-7.15 (m, 1 H), 7.13-7.07 (m, 1 H), 7.06- 6.99 (m, 1 H), 5.45 (s, 1H), 4.32-4.20 (m, 2H), 4.17-4.05 (m, 1H), 3.61 (d, J = 13.2 Hz, 1H), 2.39 (dd, J = 10.6, 14.7 Hz, 1H), 1.40 (dd, J = 3.4, 14.7 Hz, 1 H), 1. 12 (s, 3 H), 1.03 (d, J = 7.0 Hz, 3 H), 0.62 (s, 3 H).

(Reference Example 86)
(R) -4-amino-4- (3-fluorophenyl) -2-methylbutan-2-ol

1.1 g of (R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (3-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 85 Under argon flow, 200 mg of 20% palladium hydroxide / carbon (50% hydrous) was added to a solution of 2.8 mmol) in methanol at room temperature, and the atmosphere was replaced with a hydrogen atmosphere and stirred at room temperature for 6 hours. Next, after substituting for an argon atmosphere, 0.354 g (5.61 mmol) of ammonium formate was added at room temperature, and the mixture was stirred at 60 ° C. for 2 hours.
After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL, elution solvent; n-hexane: ethyl acetate = 75: 25 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure As a result, 276 mg (yield 50%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 198 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.37-7.28 (m, 1 H), 7.25-7.14 (m, 2 H), 7.03-6.95 (m, 1 H), 4.08 (dd, J = 3.0, 10.5 Hz, 1 H), 1.63 (dd, J = 10.5, 13.9 Hz, 1 H), 1.52 (dd, J = 3.0, 13.9 Hz, 1 H), 1.22 (s, 3 H), 1.09 (s, 3 H).

(Reference Example 87)
(R) -ethyl 5-{[1- (3-fluorophenyl) -3-hydroxy-3-methylbutyl] carbamoyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6 -Dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

Argon was added to a solution of 70 mg (0.35 mmol) of (R) -4-amino-4- (3-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 86 in 5 ml of 1,4-dioxane Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as in Reference Example 3 with 0.31 ml (1.8 mol) of DIPEA while stirring under an air stream. 172 mg (0.390 mmol) of 6,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate were sequentially added at room temperature and stirred at 90 ° C. for 2 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution which was allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 70: 30 to 27:73 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. The title compound 149 mg (yield 70%) was obtained as a white foam.
Mass spectrum (CI, m / z): 602 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.78 (s, 1 H), 7.36-7.26 (m, 1 H), 7.19-7.12 (m, 2 H), 7.01-6.93 (m, 1 H), 6.71 (d, J = 6.2 Hz, 1 H), 4. 96-4. 88 (m, 1 H), 4. 67-4. 60 (m, 2 H), 4.5 4 (d, J = 13.6 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2H), 2.59-2.42 (m, 2H), 2.29-2.21 (m, 2H), 2.02-1.84 (m, 3H), 1.66 (dd, J = 3.2, 14.2 Hz, 1H), 1.59 (s, 3H) , 1.54 (s, 3 H), 1.33 (t, J = 7.1 Hz, 3 H), 1. 14 (s, 3 H), 1. 13 (s, 3 H), 0.11 (s, 9 H).

(Reference example 88)
(E) -Methyl 3- (2-fluorophenyl) acrylate

After adding 5.25 g (15.7 mmol) of methyl 2- (triphenylphosphoranylidene) acetate at room temperature to a solution of 1.26 ml (12.1 mmol) of 2-fluorobenzaldehyde in 25 ml of dehydrated THF at room temperature, Stir at temperature for 17 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure. 20 ml of TBME was added to the obtained concentration residue, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 90:10 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. There was obtained 1.58 g (yield 73%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 181 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.83 (d, J = 16.3 Hz, 1 H), 7.57-7.50 (m, 1 H), 7.40-7.33 (m, 1 H), 7.20-7.07 (m, 2 H) ), 6.55 (d, J = 16.3 Hz, 1 H), 3.82 (s, 3 H).

(Reference Example 89)
(R) -Methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (2-fluorophenyl) propanoate

(S) -N-Benzyl-1-phenylethanamine To a solution of 2.94 ml (14.1 mmol) of THF in 30 ml of dehydrated THF under a stream of argon, 8.22 ml (13.2 mmol) of a 1.6 M n-butyllithium n-hexane solution The reaction mixture was added dropwise at -78.degree. C. and stirred for 1 hour at the same temperature. Then, a THF 5 ml solution of 1.58 g (8.77 mmol) of (E) -methyl 3- (2-fluorophenyl) acrylate synthesized in the same manner as in Reference Example 88 was dropped at -78 ° C. Stir for hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 95: 5 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. Thus, 1.27 g (yield 37%) of the title compound was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 392 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.45-7.03 (m, ¹⁴ H), 4. 75 (dd, J = 6.8, 8.9 Hz, 1 H), 4.05 (q, J = 6.9 Hz, 1 H), 3.81 ( d, J = 14.6 Hz, 1 H), 3. 65 (d, J = 14.6 Hz, 1 H), 3. 44 (s, 3 H), 2. 79 (dd, J = 6.8, 14.9 Hz, 1 H), 2. 65 (dd, J = 8.9) , 14.9 Hz, 1 H), 1.20 (d, J = 6.9 Hz, 3 H).

(Reference Example 90)
(R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (2-fluorophenyl) -2-methylbutan-2-ol

Dehydration of 1.27 g (3.24 mmol) of (R) -methyl 3- {benzyl [(S) -1-phenylethyl] amino} -3- (2-fluorophenyl) propanoate synthesized in the same manner as in Reference Example 89 After dropwise addition of 9.73 ml (9.73 mmol) of 1 M methylmagnesium bromide-THF solution at 0 ° C. to a solution of THF 15 ml under argon flow, the mixture was stirred at room temperature for 17 hours.
After completion of the reaction, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 95: 5-85: 15 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. Thus, 1.10 g (yield 87%) of the title compound was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 392 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ: 7.51 to 7.08 (m, ¹⁴ H), 5.58 (s, 1 H), 4.72 (dd, J = 3.1, 11.3 Hz, 1 H), 4.31 (d, J = 12.9) Hz, 1H), 4.16-4.05 (m, 1H), 3.55 (d, J = 12.9 Hz, 1H), 2.47 (dd, J = 11.3, 14.6 Hz, 1H), 1.32 (dd, J = 3.1, 14.6 Hz) , 1H), 1.11 (s, 3H), 1.06 (d, J = 7.0 Hz, 3H), 0.53 (s, 3H).

(Reference Example 91)
(R) -4-amino-4- (2-fluorophenyl) -2-methylbutan-2-ol

1.1 g of (R) -4- {benzyl [(S) -1-phenylethyl] amino} -4- (2-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 90 Under argon flow, 200 mg of 20% palladium hydroxide / carbon (50% hydrous) was added to a solution of 2.8 mmol) in methanol at room temperature, and after replacing with a hydrogen atmosphere, the mixture was stirred at room temperature for 6 hours. Then, after replacing with argon atmosphere, 354 mg (5.61 mmol) of ammonium formate was added at room temperature, and stirred at 60 ° C. for 2 hours.
After completion of the reaction, the reaction mixture was diluted with ethyl acetate and filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (DIOL, elution solvent; n-hexane: ethyl acetate = 75: 25 to 50:50 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. Drying under reduced pressure gave 265 mg (yield 48%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 198 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.61-7.55 (m, 1 H), 7.28-7.21 (m, 1 H), 7.20-7.14 (m, 1 H), 7.13-7.06 (m, 1 H) , 4.39 (dd, J = 2.7, 10.4 Hz, 1 H), 1.64 (dd, J = 10.4, 13.8 Hz, 1 H), 1.52 (dd, J = 2.7, 13.8 Hz, 1 H), 1.22 (s, 3 H), 1.09 (s, 3H).

(Reference Example 92)
(R) -ethyl 5-{[1- (2-fluorophenyl) -3-hydroxy-3-methylbutyl] carbamoyl} -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6 -Dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

Argon was added to a solution of 70 mg (0.35 mmol) of (R) -4-amino-4- (2-fluorophenyl) -2-methylbutan-2-ol synthesized in the same manner as in Reference Example 91 in 5 ml of 1,4-dioxane Ethyl 3- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5 synthesized in the same manner as Reference Example 3 with 0.309 ml (1.77 mol) of DIPEA while stirring under air flow. Then, 235 mg (0.533 mmol) of 6,6-dihydropyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate was sequentially added at room temperature and stirred at 90 ° C. for 2 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution which was allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 65: 35 to 29:71 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 150 mg (yield 70%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 602 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.79 (s, 1 H), 7.54-7.46 (m, 1 H), 7.27-7.07 (m, 3 H), 6.70 (d, J = 5.8 Hz, 1 H ), 5.24-5.16 (m, 1H), 4.71-4.54 (m, 3H), 4.42 (q, J = 7.2 Hz, 2H), 2.58-2.44 (m, 2H), 2.32-2.22 (m, 2H), 2.02-1.87 (m, 3H), 1.67-1.57 (m, 4H), 1.53 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.19-1.14 (m, 6H), 0.13 (s, 9H).

(Reference Example 93)
(R) -Methyl 3-[(tert-butoxycarbonyl) amino] -4-methylpentanoate

A solution of 600 mg (2.59 mmol) of (R) -3-[(tert-butoxycarbonyl) amino] -4-methylpentanoic acid in 6 ml of dichloromethane was added 63 mg (0.52 mmol) of 4-dimethylaminopyridine while stirring under a stream of argon. 0.53 ml (13 mmol) of methanol were sequentially added at room temperature.
Then, 746 mg (3.89 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added in one portion at 0 ° C. with stirring, and stirred at room temperature for 2 hours.
After completion of the reaction, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 80:20 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure. The title compound (630 mg, yield 99%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 246 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 6.72 & 6.37 (br d, J = 9.2 Hz, total 1 H), 3.71-3.61 (m, 1 H), 3.60-3.52 (m, 3 H), 2.44 (dd, J = 4.6, 15.0 Hz, 1 H), 2. 30 (dd, J = 9.4, 15.0 Hz, 1 H), 1.71-1.58 (m, 1 H), 1. 36 (s, 9 H), 0.86-0.73 (m, 6 H ).

(Reference Example 94)
(R) -tert-butyl (5-hydroxy-2,5-dimethylhexan-3-yl) carbamate

A solution of 630 mg (2.57 mmol) of (R) -methyl 3-[(tert-butoxycarbonyl) amino] -4-methylpentanoate, which was synthesized in the same manner as in Reference Example 93, in 6 ml of dehydrated THF was added while stirring under a stream of argon. 7.7 ml (7.7 mol) of 1 M methylmagnesium bromide-THF solution was added dropwise at 0 ° C. and stirred at room temperature for 4 hours.
After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Obtained residue The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 91: 9 to 70:30 (V / V)) to obtain a fraction containing the desired product. Concentration under reduced pressure gave 133 mg (yield 21%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 246 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 6.53 & 6.14 (br d, J = 8.9 Hz, total 1 H), 4.09 (s, 1 H), 3.47-3.39 (m, 1 H), 1.63-1.50 (m, 1 H), 1.42-1.33 (m, 11 H), 1.06 (s, 3 H), 1.05 (s, 3 H), 0.80-0.74 (m, 6 H).

(Reference Example 95)
(R) -4-amino-2,5-dimethyl-hexan-2-ol hydrochloride

Example 1 In a solution of 133 mg (0.542 mmol) of (R) -tert-butyl (5-hydroxy-2,5-dimethylhexan-3-yl) carbamate synthesized in the same manner as in Reference Example 94 in 2 ml of 1,4-dioxane While stirring under a stream, 0.678 ml (2.71 mol) of 4 N hydrogen chloride / 1,4-dioxane was added in one portion at room temperature, and the mixture was stirred at room temperature for 3 hours. Then, 0.678 ml (2.71 mol) of 4 N hydrogen chloride / 1,4-dioxane was added at once with stirring at room temperature and stirred at room temperature for 15 hours.
After completion of the reaction, the reaction solution was concentrated. 5 ml of n-hexane was added there, and it stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with n-hexane and dried under reduced pressure to obtain 58 mg (yield 59%) of the title compound as a white solid.
Mass spectrum (CI, m / z): 146 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 8.25-4.63 (m, 3 H), 3.16-3.04 (m, 1 H), 1.96-1.82 (m, 1 H), 1.58 (dd, J = 2.0, 15.0 Hz, 1 H), 1. 49 (dd, J = 9.8, 15.0 Hz, 1 H), 1.21 (s, 3 H), 1.17 (s, 3 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H).

(Reference Example 96)
(R) -ethyl 5-[(5-hydroxy-2,5-dimethylhexan-3-yl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydro Pyrrolo [3,4-c] pyrazole-2 (4H) -carboxylate

Ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3,4-c] pyrazole synthesized in the same manner as in Reference Example 3. A solution of 260 mg (0.590 mmol) of 2 (4H) -carboxylate in 4 ml of 1,4-dioxane was synthesized in the same manner as in Reference Example 95 while stirring under argon flow with 0.342 ml (1.96 mol) of DIPEA (R) 57 mg (0.31 mmol) of -4-amino-2,5-dimethylhexan-2-ol hydrochloride were sequentially added at room temperature, and the mixture was stirred at 90 ° C. for 1.5 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution which was allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 70: 30 to 30:70 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 99 mg (yield 57%) of the title compound was obtained as a white foam.
Mass spectrum (CI, m / z): 550 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.78 (s, 1 H), 5. 83 (d, J = 7.7 Hz, 1 H), 4.55 (d, J = 13.6 Hz, 1 H), 4.47 (d, J = 13.6 Hz, 1 H), 4.42 (q, J = 7.1 Hz, 2 H), 4.30 (s, 1 H), 3.73-3.62 (m, 1 H), 2.58-2.43 (m, 2 H), 2.31-2.21 (m , 2H), 1.96-1.82 (m, 2H), 1.75-1.57 (m, 8H), 1.50-1.42 (m, 1H), 1.34 (t, J = 7.1 Hz, 3H), 1.10 (s, 3H), 1.08 (s, 3 H), 0.89-0.78 (m, 6 H), 0.15-0.08 (m, 9 H).

(Reference Example 97)
Ethyl [1- (4-fluorophenyl) -2,2-dimethyl-3-oxopropyl] carbamate

A solution of 2.63 g (29.5 mmol) of ethyl carbamate in 25 ml of toluene was stirred under argon flow with 3.1 ml (29 mmol) of 4-fluorobenzaldehyde and 0.281 g (1.48 mmol) of p-toluenesulfonic acid monohydrate. ) Was added sequentially at room temperature and stirred for 5 minutes at room temperature. Then, 2.68 ml (29.5 mmol) of isobutyraldehyde was added dropwise at room temperature with stirring, and stirred at 60 ° C. for 3 hours.
After completion of the reaction, the reaction solution was poured into saturated aqueous sodium hydrogen carbonate solution and then stirred at room temperature for 5 minutes. The organic layer and the aqueous layer were separated, and the separated aqueous layer was extracted once with toluene. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 69:31 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure The reaction gave 3.85 g (yield 49%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 268 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.59 (s, 1 H), 7.95 (d, J = 10.1 Hz, 1 H), 7.43-7.33 (m, 2 H), 7.21-7.12 (m, 2 H) ), 5.04 (d, J = 10.1 Hz, 1 H), 4.01-3.93 (m, 2 H), 1.15 (t, J = 7.1 Hz, 3 H), 0.94 (s, 3 H), 0.87 (s, 3 H).

(Reference Example 98)
3-amino-3- (4-fluorophenyl) -2,2-dimethylpropan-1-ol

A solution of 3.84 g (14.4 mmol) of ethyl [1- (4-fluorophenyl) -2,2-dimethyl-3-oxopropyl] carbamate synthesized in the same manner as in Reference Example 97 in 20 ml of ethanol was stirred under a stream of argon. While adding 0.326 g (8.62 mmol) of sodium borohydride in portions at 0 ° C., the mixture was stirred at room temperature for 1 hour. Subsequently, after adding potassium hydroxide 1.61g (28.7 mmol) and water (10 ml) with stirring at room temperature, it stirred under heat-refluxing for 2 hours.
After completion of the reaction, the reaction solution allowed to cool was concentrated under reduced pressure to distil off ethanol. The concentrated residue was adjusted to pH 2 by adding 2N hydrochloric acid, and washed with diethyl ether. The aqueous layer was made basic (pH 9) by adding 1N aqueous sodium hydroxide solution, and then extracted three times with dichloromethane. The obtained total organic layer was washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried under reduced pressure to obtain 1.93 g (yield 68%) of the title compound as a white solid. .
Mass spectrum (CI, m / z): 198 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.38-7.29 (m, 2 H), 7.15-7.03 (m, 2 H), 3.81 (s, 1 H), 3.25 (d, J = 10.5 Hz, 1 H ), 3.13 (d, J = 10.5 Hz, 1 H), 0.74 (s, 3 H), 0.65 (s, 3 H).

(Reference Example 99)
Ethyl [1- (3-Fluorophenyl) -2,2-dimethyl-3-oxopropyl] carbamate

Under argon atmosphere, 3.10 ml (29.5 mmol) of 3-fluorobenzaldehyde and 288 mg (1.51 mmol) of p-toluenesulfonic acid monohydrate were added to a solution of 2.63 g (29.5 mmol) of ethyl carbamate in 25 ml of toluene. After sequentially added at room temperature, the mixture was stirred at room temperature for 5 minutes. Then, 2.70 ml (29.7 mmol) of isobutyraldehyde was added at room temperature, and the solution was stirred under heating reflux for 3 hours with a Dean-Stark apparatus attached. Subsequently, 2.70 ml (29.7 mmol) of isobutyraldehyde was further added, and the mixture was further stirred for 3 hours while heating under reflux.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and then stirred at room temperature. After separation, the aqueous layer was extracted once with toluene. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 4.61 g (yield 59%) of the title compound was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 268 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.59 (s, 1 H), 7. 95 (br d, J = 10.2 Hz, 1 H), 7. 36 (dt, J = 6.2, 7.9 Hz, 1 H), 7.27 -7.06 (m, 3H), 5.07 (d, J = 10.2 Hz, 1H), 4.06-3.89 (m, 2H), 1.18-1.12 (m, 3H), 0.94 (s, 3H), 0.88 (s, 3H) ).

(Reference Example 100)
3-amino-3- (3-fluorophenyl) -2,2-dimethylpropan-1-ol

In 12 ml of a solution of 4.75 g (17.8 mmol) of ethyl [1- (3-fluorophenyl) -2,2-dimethyl-3-oxopropyl] carbamate synthesized in the same manner as in Reference Example 99 under an argon atmosphere, After adding 352 mg (9.30 mmol) of sodium borohydride in portions at 0 ° C. while stirring, the mixture was stirred at room temperature for 4 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 75 ml of dichloromethane was added to the residue. The solution was poured into 50 ml of saturated aqueous ammonium chloride solution, stirred at room temperature until bubbling ceased, and then separated. The aqueous layer was extracted with 25 ml of dichloromethane, and the whole organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 78: 22 to 57:43 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure.
12 ml of ethanol and 2.45 g (37.1 mmol) of 85% potassium hydroxide were added to the obtained residue (3.91 g), and the mixture was heated under reflux for 4 hours.
After cooling, the reaction solution was concentrated under reduced pressure, 50 ml of water and 50 ml of dichloromethane were added, and the mixture was stirred at room temperature. After separation, the aqueous layer was extracted twice with 50 ml of dichloromethane. The whole organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.58 g (yield 74%) of the title compound as a slightly yellow viscous liquid.
Mass spectrum (CI, m / z): 198 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.36-7.25 (m, 1 H), 7.19-7.08 (m, 2 H), 7.06-6.97 (m, 1 H), 5.00 (br s, 1 H), 3.81 (s, 1 H), 3. 25 (d, J = 10.5 Hz, 1 H), 3. 14 (d, J = 10.5 Hz, 1 H), 1.99 (br s, 2 H), 0.77 (s, 3 H), 0.66 (s, 3H).

(Reference Example 101)
3-amino-3- (2-fluorophenyl) -2,2-dimethylpropan-1-ol

In an argon atmosphere, 3.05 ml (29.2 mmol) of 2-fluorobenzaldehyde and 286 mg (1.51 mmol) of p-toluenesulfonic acid monohydrate were added to a solution of 2.62 g (29.4 mmol) of ethyl carbamate in 25 ml of toluene. After sequentially added at room temperature, it was allowed to react at room temperature for 5 minutes. Then, 2.70 ml (29.7 mmol) of isobutyraldehyde was added at 60 ° C., and then the reaction was carried out at the same temperature for 5.5 hours.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and stirred at room temperature for 5 minutes. After separation, the aqueous layer was extracted once with toluene. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure Concentration residue was obtained.
After adding 478 mg (12.6 mmol) of sodium borohydride in portions at 0 ° C. while stirring under an argon atmosphere to a solution of 6.23 g of the obtained residue 6.23 g in ethanol, the mixture was stirred at room temperature for 4 hours.
After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 75 ml of dichloromethane was added to the residue. The solution was poured into 50 ml of saturated aqueous ammonium chloride solution, stirred at room temperature until bubbling ceased, and then separated. The aqueous layer was extracted with 25 ml of dichloromethane, and the whole organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; n-hexane: ethyl acetate = 77: 23-56: 44 (V / V)), and the fraction containing the desired product was concentrated under reduced pressure.
15 ml of ethanol and 3.08 g (46.7 mmol) of 85% potassium hydroxide were added to 5.03 g of the obtained residue, and the mixture was heated under reflux for 5 hours.
After allowing to cool, the solution was concentrated under reduced pressure, 50 ml of water and 100 ml of dichloromethane were added, and the mixture was stirred at room temperature, then separated, and the aqueous layer was extracted twice with 50 ml of dichloromethane. Diethyl ether is added until the turbidity of the obtained total organic layer disappears, then it is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain 3.60 g (yield 63%) of the title compound Obtained as a viscous liquid.
Mass spectrum (CI, m / z): 198 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.55-7.49 (m, 1 H), 7.30-7.21 (m, 1 H), 7.20-7.13 (m, 1 H), 7.12-7.03 (m, 1 H) , 5.03 (br s, 1 H), 4.15 (s, 1 H), 3. 35 (d, J = 10.5 Hz, 1 H), 3.21 (d, J = 10.5 Hz, 1 H), 2.01 (br s, 2 H), 0.73 ( s, 3H), 0.71-0.66 (m, 3H).

(Reference Example 102)
Ethyl (2,2,4-trimethyl-1-oxopentan-3-yl) carbamate

Under an argon atmosphere, to a solution of 2.06 g (23.1 mmol) of ethyl carbamate in 20 ml of toluene, 6.00 ml (66.1 mmol) of isobutyraldehyde, 224 mg (1.18 mmol) of p-toluenesulfonic acid monohydrate at room temperature After sequentially added, the mixture was stirred at room temperature for 5 minutes and at 60 ° C. for 4 hours.
After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and then stirred at room temperature. After separation, the aqueous layer was extracted once with toluene. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 90: 10 to 60:40 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 1.55 g (yield 31%) of the title compound was obtained as a pale yellow oil.
Mass spectrum (CI, m / z): 216 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.55 (s, 1 H), 7.11 (br d, J = 10.4 Hz, 1 H), 4.01 (q, J = 7.1 Hz, 2 H), 3.67 (dd , J = 6.2, 10.4 Hz, 1 H), 1. 80-1. 66 (m, 1 H), 1. 17 (t, J = 7.1 Hz, 3 H), 0.98 (s, 3 H), 0.90 (s, 3 H), 0.80 (d, J = 6.8 Hz, 3 H), 0.75 (d, J = 6.8 Hz, 3 H).

(Reference Example 103)
3-amino-2,2,4-trimethylpentan-1-ol

Boron hydride was added to 10 ml of a solution of 1.55 g (7.20 mmol) of ethyl (2,2,4-trimethyl-1-oxopentan-3-yl) carbamate synthesized in the same manner as in Reference Example 102 under an argon atmosphere. After 176 mg (4.66 mmol) of sodium was added in portions at 0 ° C., the mixture was stirred at 0 ° C. for 1 hour and further at room temperature for 13.5 hours. Next, 853 mg (15.2 mmol) of potassium hydroxide and 5.0 ml of water were added to the reaction solution at room temperature, and the mixture was stirred for 3 hours under heating to reflux.
After completion of the reaction, the reaction solution was concentrated under reduced pressure to distil off ethanol. The concentrated residue was added with 2N hydrochloric acid and then washed with diethyl ether. The aqueous layer obtained by separation was added with 1N aqueous sodium hydroxide solution to adjust to pH> 10, and then extracted three times with dichloromethane. The obtained total organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue was subjected to silica gel column chromatography (DIOL silica gel, elution solvent; 1,2-dichloroethane: n-hexane = 30: 70 to 100: 0 → 1,2-dichloroethane: methanol = 95: 5 (V / V) ), And the fraction containing the desired product was concentrated under reduced pressure and dried under reduced pressure to obtain 577 mg (yield 55%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 146 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 3.23 (d, J = 10.4 Hz, 1 H), 3.15 (d, J = 10.4 Hz, 1 H), 2.36 (d, J = 1.8 Hz, 1 H) , 1.87 (dspt, J = 1.8, 6.8 Hz, 1 H), 0.88 (d, J = 6.8 Hz, 3 H), 0.81-0.76 (m, 9 H).

(Reference Example 104)
(R) -benzyl 2-butoxy-2-phenyl acetate

In an argon atmosphere, a suspension of 2.34 g (9.66 mmol) of (R) -benzyl 2-hydroxy-2-phenyl acetate in 25.0 ml (219 mmol) of 1-iodobutane was treated with 4.55 g of silver oxide (I). 19.6 mmol) was added at room temperature and then reacted at 80 ° C. for 10.5 hours while stirring.
After completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered using a celite filter. After the filtrate was washed with ethyl acetate, all filtrates were concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 97: 3 to 93: 7 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure and dried under reduced pressure As a result, 1.65 g (yield 57%) of the title compound was obtained as a colorless oil.
Mass spectrum (CI, m / z): 299 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.45-7.17 (m, 10 H), 5.18-5.09 (m, 2 H), 5.05 (s, 1 H), 3.50 (td, J = 6.4, 9.2 Hz , 1H), 3.40 (td, J = 6.4, 9.2 Hz, 1H), 1.58-1.46 (m, 2H), 1.38 -1.26 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).

(Reference Example 105)
tert-Butyl (3-hydroxy-2,2-dimethyl-1-phenylpropyl) carbamate

Under an argon stream, 3-amino-2,2-dimethyl-3-phenylpropan-1-ol [Synthetic Communications, 1994, 24 (7), 899-906. To a solution of 1.00 g (5.58 mmol) in 5 ml of dichloromethane, 2.34 ml (16.8 mmol) of triethylamine and 2.56 ml (11.1 mmol) of di-tert-butyl dicarbonate were added. The reaction solution was sequentially added at room temperature and stirred at room temperature for 2 hours.
After completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 91: 9 to 70:30 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. Thus, 1.45 g (yield 93%) of the title compound was obtained as a white solid.
Mass spectrum (CI, m / z): 280 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.37-7.18 (m, 6 H), 4.97-4.75 (m, 1 H), 4.62-4.32 (m, 1 H), 3.22-3.08 (m, 1 H) , 3.05-2.90 (m, 1 H), 1. 40-1. 29 (m, 9 H), 0.83-0.73 (m, 6 H).

(Reference Example 106)
tert-Butyl (3-methoxy-2,2-dimethyl-1-phenylpropyl) carbamate

In 6 ml of dichloromethane solution of 600 mg (2.15 mmol) of tert-butyl (3-hydroxy-2,2-dimethyl-1-phenylpropyl) carbamate synthesized in the same manner as in Reference Example 105, potassium hydroxide while stirring under a stream of argon 370 mg (6.59 mmol) were added in one portion at 0 ° C. and stirred at 0 ° C. for 15 minutes. Then, 0.407 ml (4.29 mmol) of dimethyl sulfate was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 8 hours.
After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting concentrated residue is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 100: 0 to 87:13 (V / V)), and the fraction containing the desired product is concentrated under reduced pressure. The title compound 114 mg (yield 18%) was obtained as a colorless oil.
Mass spectrum (CI, m / z): 294 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.35-7.16 & 6.95-6.82 (m, total 6 H), 4.67-4.37 (m, 1 H), 3.28-3.19 (m, 3 H), 3.08-2.91 (m, 1 H), 2. 88-2. 76 (m, 1 H), 1.4 3-1. 13 (m, 9 H), 0.90-0.82 (m, 3 H), 0.81-0.70 (m, 3 H).

(Reference Example 107)
3-methoxy-2,2-dimethyl-1-phenylpropan-1-amine

A solution of 114 mg (0.389 mmol) of tert-butyl (3-methoxy-2,2-dimethyl-1-phenylpropyl) carbamate synthesized in the same manner as in Reference Example 106 in 2 ml of 1,4-dioxane was stirred under a stream of argon. While adding 0.486 ml (1.94 mmol) of 4 N hydrogen chloride / 1,4-dioxane in one portion at room temperature, the mixture was stirred at room temperature for 20 hours.
After completion of the reaction, the reaction solution was concentrated. Water was added to dissolve the residue, saturated aqueous sodium hydrogen carbonate solution was added to adjust to pH 8, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 71 mg (yield 95%) of the title compound as a colorless oil.
Mass spectrum (CI, m / z): 194 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 7.34-7.16 (m, 5 H), 3. 78 (s, 1 H), 3.23 (s, 3 H), 3. 13 (d, J = 8.8 Hz, 1 H), 2.92 (d, J = 8.8 Hz, 1 H), 1.82 (br s, 2 H), 0.83 (s, 3 H), 0.70 (s, 3 H).

(Reference Example 108)
Ethyl 5-[(3-methoxy-2,2-dimethyl-1-phenylpropyl) carbamoyl] -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [3 ,, 4-c] pyrazole-2 (4H) -carboxylate

A solution of 70 mg (0.36 mmol) of 3-methoxy-2,2-dimethyl-1-phenylpropan-1-amine synthesized in the same manner as in Reference Example 107 in 5 ml of 1,4-dioxane was stirred under argon flow and DIPEA0 was obtained. .315 ml (1.81 mol) of ethyl 5- (chlorocarbonyl) -6,6-dimethyl-3- [1- (trimethylsilyl) cyclobutanecarboxamide] -5,6-dihydropyrrolo [synthesized in the same manner as in Reference Example 3]. 176 mg (0.399 mmol) of 3,4-c] pyrazole-2 (4H) -carboxylate were sequentially added at room temperature, and stirred at 90 ° C. for 2 hours.
After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction solution which was allowed to cool to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue thus obtained is subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 61: 39-40: 60 (V / V)), and the fraction containing the desired substance is concentrated under reduced pressure. The title compound (131 mg, yield 61%) was obtained as a white foam.
Mass spectrum (CI, m / z): 598 [M + 1] ⁺ .
¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ: 9.75 (s, 1 H), 7. 38-7. 20 (m, 5 H), 6. 78 (d, J = 8.3 Hz, 1 H), 4. 64-4.50 (m, 3 H) ), 4.42 (q, J = 7.1 Hz, 2H), 3.40 (s, 3H), 3.15 (d, J = 9.2 Hz, 1H), 2.93 (d, J = 9.2 Hz, 1H), 2.57-2.45 (m , 2H), 2.32-2.23 (m, 2H), 1.97-1.82 (m, 2H), 1.61 (s, 3H), 1.52 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H), 1.13 ( s, 3H), 0.68 (s, 3H), 0.13 (s, 9H).

[Test Example 1]
CDK7 Enzyme Inhibition Test Preparation of buffer solution: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer (HEPES buffer) (pH 7.4), dithiothreitol (DTT), Triton X-100, It was performed by mixing magnesium chloride (MgCl ₂ ). The 500 μM [γ- ³³ P] ATP solution was used by diluting a 10 mM ATP solution and a commercially available [γ- ³³ P] ATP solution (Perkin Elmer Code No. NEG-302H) with a buffer solution. The CDK7 solution was used by diluting commercially available CDK7 (Carna biosciences Catalog No. 04-108) with a buffer solution. The substrate solution was used by diluting Myelin Basic Protein (MBP) with buffer. The reaction solution was prepared by mixing a buffer solution, 500 μM [γ- ³³ P] ATP solution, CDK 7 solution, and substrate solution at 4 ° C. to prepare a reaction solution.
For CDK7 enzyme reaction, add 5 μL of the test compound solution prepared in 10% dimethyl sulfoxide (DMSO) / 90% distilled water for injection at 4 ° C, 45 μL of the reaction solution to a 1.5 mL microtube, The reaction was carried out at 30 ° C. for 20 minutes in an incubator. After the reaction, while cooling to 4 ° C., an aqueous 10% trichloroacetic acid (TCA) solution was added to each microtube to mix and stop the reaction. After standing at 4 ° C. for 10 minutes, it was centrifuged by a centrifuge and the supernatant was discarded. Next, 2% TCA aqueous solution was added, mixed, centrifuged by a centrifuge, and the supernatant was discarded. This washing operation was performed twice. After washing, the precipitate was dissolved in 1N aqueous sodium hydroxide (NaOH) solution, and the amount of energy (radioactivity) of the reaction product was measured by a liquid scintillation counter.
The calculation of the inhibitory activity of the test compound for CDK7 was carried out using EXSUS (version 8.0.0 or version 8.0.1, as the test compound concentration (IC ₅₀ value) that inhibits 50% of the amount of ³³ P binding to MBP. It carried out using CAC Exciare company).
The Ki value was calculated according to the following formula. S represents the ATP concentration contained in the reaction solution, and Km represents the Michaelis-Menten constant.
Ki = IC ₅₀ / (1 + S / Km)

  The compounds of the present invention exhibit excellent CDK7 inhibitory activity in this test, and for example, compound Nos. II-13, II-14, III-11, III-14, III-17, III-22, III-25, III-31 , IV-1, IV-18, IV-20, IV-21, IV-25, IV-34, IV-49, IV-64, IV-67, IV-70, IV-89, IV-95. Salts, IV-101, IV-103, IV-105, IV-107, IV-111, IV-113, IV-115, IV-119, IV-125, IV-126, IV-127, IV-142, IV-200, IV-221, IV-225, IV-227, IV-254, IV-260, IV-272, IV-286, IV-306, IV-331, IV-332, IV 334, IV-336, IV-344, IV-352, IV-360, IV-364, IV-385, IV-389, IV-394, IV-399, and IV-400 have Ki values of 50 nM or less there were.

[Test Example 2]
CDK2 Enzyme Inhibition Test The buffer was prepared by mixing HEPES buffer (pH 7.4), DTT, Triton X-100, and MgCl ₂ . The 500 μM [γ- ³³ P] ATP solution was used by diluting a 10 mM ATP solution and a commercially available [γ- ³³ P] ATP solution (Perkin Elmer Code No. NEG-302H) with a buffer solution. The CDK2 solution was used by diluting commercially available CDK2 (Invitrogen Catalog No. PV3267) with a buffer solution. The substrate solution was used by diluting MBP with buffer. The reaction solution was prepared by mixing a buffer solution, 500 μM [γ- ³³ P] ATP solution, CDK 2 solution, and substrate solution at 4 ° C. to prepare a reaction solution.
For CDK2 enzyme reaction, add 5 μL of the test compound solution prepared in 10% DMSO / 90% distilled water for injection at 4 ° C, 45 μL of the reaction solution in a 1.5 mL microtube, and use the microtube in a water bath incubator The reaction was carried out at 30 ° C. for 20 minutes. After the reaction, while cooling to 4 ° C., 10% TCA aqueous solution was added to each microtube to mix and stop the reaction. After standing at 4 ° C. for 10 minutes, it was centrifuged by a centrifuge and the supernatant was discarded. Next, 2% TCA aqueous solution was added and mixed, and then centrifuged with a centrifuge to discard the supernatant. This washing operation was performed twice. After washing, the precipitate was dissolved in 1N aqueous NaOH solution, and the radioactivity was measured by a liquid scintillation counter.
The inhibitory activity of the test compound against CDK2 was calculated as EXSUS (version 8.0.0 or version 8.0.1, as the test compound concentration (IC ₅₀ value) that inhibits 50% of the amount of ³³ P binding to MBP. It carried out using CAC Exciare company).
The Ki value was calculated according to the following formula. S represents the ATP concentration contained in the reaction solution, and Km represents the Michaelis-Menten constant.
Ki = IC ₅₀ / (1 + S / Km)

  Compounds of the present invention in this test, such as compound Nos. II-13, II-14, III-11, III-22, III-25, IV-1, IV-18, IV-20, IV-21, IV-34 , IV-49, IV-64, IV-67, IV-70, IV-95 sodium salt, IV-101, IV-103, IV-105, IV-125, IV-125, IV-179, IV- 200, IV-225, IV-236, IV-240, IV-254, IV-272, IV-276, IV-340, IV-352, and IV-360 The Ki value of CDK2 inhibitory activity is 1000 nM or more There was a high selectivity of CDK7 inhibitory activity to CDK2 inhibitory activity.

[Test Example 3]
PAK4 enzyme inhibition test Preparation of buffer solution, Tris-hydroxyaminomethane buffer (Tris buffer) (pH 7.5), DTT, Triton X-100, MgCl ₂ , ethylene glycol bis (β-aminoethyl ether) -N, N , N ′, N′-tetraacetic acid (EGTA), β-glycerol phosphate, and sodium orthovanadate (V) were mixed. The 40 μM [γ- ³³ P] ATP solution was used by diluting a 10 mM ATP solution and a commercially available [γ- ³³ P] ATP solution (Perkin Elmer Code No. NEG-302H) with a buffer solution. The PAK4 solution was used by diluting commercially available PAK4 (Invitrogen Catalog No. PV4212) with a buffer solution. The substrate solution was used by diluting MBP with buffer. The reaction solution was prepared by mixing a buffer solution, 40 μM [γ- ³³ P] ATP solution, PAK 4 solution, and substrate solution at 4 ° C. to form a reaction solution.
For the PAK4 enzyme reaction, add 5 μL of the test compound solution prepared in 10% DMSO / 90% distilled water for injection at 4 ° C and 45 μL of the reaction solution in a 1.5 mL microtube, and use the microtube in a water bath incubator The reaction was carried out at 30 ° C. for 20 minutes. After the reaction, while cooling to 4 ° C., 10% TCA aqueous solution was added to each microtube to mix and stop the reaction. After standing for 10 minutes at 4 ° C., centrifuge with a centrifuge and discard the supernatant. Next, 2% TCA aqueous solution was added and mixed, and then centrifuged with a centrifuge to discard the supernatant. This washing operation was performed twice. After washing, the precipitate was dissolved in 1N aqueous NaOH solution, and the radioactivity was measured by a liquid scintillation counter.
The inhibitory activity of the test compound against PAK4 was calculated using EXSUS (version 8.0.0 or version 8.0.1,) as the test compound concentration (IC ₅₀ value) that inhibits 50% of the amount of ³³ P binding to MBP. It carried out using CAC Exciare company).
The Ki value was calculated according to the following formula. S represents the ATP concentration contained in the reaction solution, and Km represents the Michaelis-Menten constant.
Ki = IC ₅₀ / (1 + S / Km)

  Compounds of the present invention in this test, such as compound Nos. II-13, II-14, III-11, III-22, III-25, IV-1, IV-18, IV-20, IV-21, IV-34 , IV-49, IV-64, IV-67, IV-70, IV-95 sodium salt, IV-101, IV-103, IV-105, IV-125, IV-125, IV-142, IV- 179, IV-200, IV-225, IV-236, IV-254, IV-258, IV-276, IV-340, IV-360, IV-364, IV-385, IV-389, and IV- The Ki value of 399 PAK4 inhibitory activity was 500 nM or more, and CDK7 inhibitory activity had high selectivity to PAK4 inhibitory activity.

[Test Example 4]
Human PBMC Various Stimulant Cocktail-Induced Inhibition of IL-17 Production Inhibition PBMCs were separated and collected from blood collected under heparin from healthy adults using Ficoll-Paque (17-1440-02 manufactured by GE Healthcare). The collected PBMCs were further cultured in a flask for a certain period of time, and then non-adherent cells in the supernatant were collected and used as T-cell suspensions. T cell activation Plate Anti-Human CD3 96-well plate (Corning REF. 354725), test compound dissolved in DMSO, and final concentration 2 μg / mL CD28 antibody (BioLegend Cat. No. 302914), final concentration 10 μg / mL human IFN-γ antibody (BD Biosciences Cat. No. 554698), final concentration 10 μg / mL human IL-4 antibody (BD Biosciences Cat. No. 554481), final concentration 20 ng / mL human IL-6 BioLegend Cat. No. 570802), final concentration 10 ng / mL human IL-23 (BioLegend Cat. No. 574102), final concentration 10 ng / mL human IL-1 β (PEPROTECH Cat. No. 200-01B), final concentration 10 ng / mL human TGF-β (BioLegend Cat. No. 580702) 10% FBS (GIBCO company REF. 10082), 1% penicillin / Streptomycin / Anhotelin B (GIBCO's REF. 15240-096), 1% non essential amino acid (GIBCO's REF. 11140-050), 1% pyruvic acid (GIBCO's REF. 11140) containing RPMI 1640 medium 100 μL each of (REF. 11875 manufactured by GIBCO) was added. Then, 100 μL of T-cell suspension adjusted to 2 × 10 ⁵ cells / mL was added to each well (DMSO final concentration 0.1%). Only DMSO was added to the wells to which no test compound was added. After 5 days of incubation in a carbon dioxide incubator, culture supernatants were harvested and stored at -20 ° C until IL-17 content determination.
A sandwich ELISA kit (Quantikine Human IL-17, manufactured by R & D Systems) was used to measure the content of IL-17 in the culture supernatant. The IL-17 content of each sample was calculated from the standard curve of Standard IL-17 attached to the kit. The amount of IL-17 production by each stimulus cocktail in the case of addition of only DMSO was made 100%, and the IL-17 production suppression rate at each concentration of the test compound was calculated. From the concentration of the test compound added and the IL-17 production suppression rate of the test compound, the concentration (IC ₅₀ value) of the test compound necessary to inhibit IL-17 production by 50% is set to EXSUS (version 8.0.0 or Calculated using version 8.0.1 (manufactured by CAC Exciare).

The compounds of the present invention exhibit excellent IL-17 production inhibitory activity in this test, and for example, compound Nos. IV-70, IV-85, IV-142, IV-179, IV-200, IV-254, IV-258. IV-272, IV-276, IV-331, IV-334, IV-336, IV-340, IV-352, IV-360, IV-364, IV-385, IV-389, and , And an IC ₅₀ value of IV-399 was 50 nM or less.

[Test Example 5]
Human Keratinocyte Growth Inhibition Test The measurement of human keratinocyte growth inhibition was carried out by modifying the method of Schafer et al. (British Journal of Pharmacology, 159, 842 (2011)).
Human keratinocytes (NHEK-Neo Pooled, Lonza Cat. No. 00192906) were cultured with KGM-GoldBulletKit (Lonza Cat. No. 00192060), and 2.0 × 10 ³ cells / well were added to a 96-well plate. Sowed. The cells were cultured overnight in a carbon dioxide incubator, and a test compound (final concentration of DMSO: 0.1%) dissolved in DMSO was added and allowed to stand in the carbon dioxide incubator. After culturing for 2 days, the absorbance was measured using Cell Counting Kit-8 (Dojin Chemical Research Institute, Inc. 343-07623).
Calculate the cell growth inhibition rate of each concentration from the test compound concentration and the absorbance of Cell Counting Kit-8, and use the concentration (IC ₅₀ value) of the test compound required to inhibit 50% of cell growth as EXSUS (version 8.0) .0 or version 8.0.1 (manufactured by CAC Exciare).
The compounds of the present invention exhibit excellent human keratinocyte proliferation inhibitory activity in this test, and for example, compound No. III-14, III-17, III-56, IV-21, IV-23, IV-25, IV-34, IV The IC ₅₀ values of -49, IV-51, IV-70, IV-85, IV-111, IV-113, IV-331, IV-334, IV- 344 and IV-344 were 500 nM or less .

[Test Example 6]
Ear Thickening Inhibition Test Using Mouse Imiquimod-Induced Psoriasis Model The imiquimod-induced psoriasis model test was conducted by modifying the method of Leslie van der Fits et al. (J. Immunol. 182, 5836 (2009)).
As experimental animals, female BALB / c strain mice (supplied by Japan Charles River) were used. The thickness of the right auricle of the mouse was measured with a thickness gauge (Model SMD-565J, manufactured by Techlock) on the day of the test start. The test compound administration solution (0.01% methanol solution at the time of application, 0.5% methylcellulose suspension) is applied or orally administered, and 60 minutes after that, Beselna cream 5% (containing 5% imiquimod, Mochida) Pharmaceutical Co., Ltd.) was applied to the inside of 5 mg right auricle. The test compound administration solution application or oral administration and imiquimod application were carried out for 4 days, and the thickness of the right auricle was measured again on the 5th day. Assuming that the increase in thickness of the right auricle in the solvent administration group on day 5 was 100%, the inhibition rate (%) of the increase in each administration dose of the test compound was calculated.

  In this test, the compound of the present invention exhibits excellent ear thickening inhibitory activity, for example, compound numbers III-56, IV-70, IV-85, IV-142, IV-145, by application of a 0.01% methanol solution. IV-179, IV-200, IV-254, IV-258, IV-272, IV-276, IV-331, IV-334, IV-336, IV-340, IV-344, IV-352, IV- 356, IV-360, IV-364, IV-385, IV- 389, and IV- 399 showed 50% or more suppression rate.

[Test Example 7]
Ear thickening suppression test (combination test) using mouse imikimod induced psoriasis model
The imiquimod-induced psoriasis model test was conducted by modifying the method of Leslie van der Fits et al. (J. Immunol. 182, 5836 (2009)).
As experimental animals, female BALB / c strain mice (supplied by Japan Charles River) were used. On the day of the test start, the thickness of the right auricle of the mouse was measured with a thickness gauge (manufactured by Techklock).
For a single drug administration group, another psoriasis treatment (0.5% methylcellulose suspension; 10 mg / kg) or a solvent (0.5% methylcellulose) is orally administered, and one hour later, the other psoriasis Vaseline containing 1% propylene glycol (PG below) for the therapeutic agent administration group, and test compound solution (Vaseline containing 0.0001% of the test compound and 1% PG) for the solvent administration group, respectively After 6 hours, a predetermined amount of Becelna cream 5% (containing imiquimod 5%, Mochida Pharmaceutical Co., Ltd.) was applied to the inside of the right auricle.
For the combined administration group, another psoriasis treatment (0.5% methylcellulose suspension) is orally administered, and one hour later, the test compound solution (Vaseline containing 0.0001% of the test compound and 1% PG) After 6 hours, 5% of Vecella cream (containing 5% of imiquimod, manufactured by Mochida Pharmaceutical Co., Ltd.) was applied to the inside of 4 mg of the right auricle.
The application of the test compound and / or the oral administration of other therapeutic agents for psoriasis, the oral administration of a solvent, and the application of imiquimod were carried out for 4 days, and the thickness of the right auricle was measured again on the 5th. The increase in thickness of the auricle in the solvent administration group on day 5 was taken as 100%, and the inhibition rate (%) of the increase in each administration dose of the test compound and / or other psoriasis therapeutic agents was calculated.

  As shown in Tables 21 and 22 below, the compound of the present invention (for example, IV-331) exhibited a synergistic ear thickening inhibitory action when used in combination with tofacitinib or apremilast.

[Test Example 8]
Metabolic test using human liver microsome fraction 50 μL of reaction composition solution (NADPH production system solution A (Corning Inc. REF. 451220)) prepared by suspending 2 mg protein equivalent of human liver microsome (Cat. No. H610 manufactured by Xenotech), NADPH production 10 μL of a solution B (Corning REF. 451200), 40 μL 250 mM UDP-glucuronic acid, 200 μL UGT Reaction Mix solution B (Corning REF. 451320), 590 μL distilled water, DMSO (Wako Pure Chemical Industries, Ltd.) 10 μL (final DMSO concentration 1.0%) of the test compound (prodrug represented by formula (V) or (VI)) dissolved in Code No. 043-07216) was added, and incubated at 37 ° C. for 5 minutes.
Test compound (prodrug represented by the general formula (V) or (VI) by high performance liquid chromatography (Model LC-20A series manufactured by Shimadzu Corporation) and peak area of the formed pharmacologically active alcohol The measured UV wavelength (245 nm) was calculated.
HPLC conditions; column: Phenomenex Kinetex C 18 (Phenomenex Part No. 00D-4462-AN), 2.1 mm × 100 mm, 2.6 μm, column temperature 40 ° C., eluent; solution A: 0.1% formic acid (Wako pure Yaku Kogyo Co., Ltd. Code No. 063-04192),
Solution B: acetonitrile (Wako Pure Chemical Industries, Ltd. Code No. 019-08631) / Methanol (Wako Pure Chemical Industries Co., Ltd. Code No. 138-06473) / formic acid = 500/500/1, gradient condition: 0 → 3 minutes : Liquid A 90%, 3 → 11 minutes: Liquid A 20% → 5%, 11 → 15 minutes: Liquid A 5%, analysis time 20 minutes)

  In this test, for example, for compound No. V-86, only a peak of compound No. IV-18 which is an alcohol formed was detected after 5 minutes of incubation.

  In this test, the prodrug of the present invention was rapidly converted to the pharmacologically active form.

  From the results of Test Examples 1 to 6 and 8, it is found that the novel substituted dihydropyrrolopyrazole compound having a specific structure represented by the general formula (I) or the pharmacologically acceptable salt thereof is itself excellent CDK7 It functions as a prodrug of a compound having an inhibitory activity and a high selectivity, or an excellent CDK7 inhibitory activity and a high selectivity. A pharmaceutical composition comprising a pharmaceutically acceptable salt, which is characterized in that it is administered in combination with another therapeutic agent for psoriasis can be said to be useful as a therapeutic agent and / or a preventive agent for psoriasis.

Claims (19)

General Formula (I):

[In the formula,
Two R's each independently represent a C _1-3 alkyl group, or represent a group bonded to each other to form a C _2-5 alkylene group;
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis. General formula (II):

[In the formula,
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis. L ² and ^{L 3,} a single bond, claim 2 pharmaceutical composition according. L ² is a divalent group represented by -NH-, L ³ indicates a straight chain may be substituted or branched C _1-6 alkylene group, a pharmaceutical composition according to claim 2, wherein . General formula (III):

[In the formula,
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis. L ² and ^{L 3} is a single bond, claim 5 pharmaceutical composition according. L ² is a divalent group represented by -NH-, L ³ indicates a straight chain may be substituted or branched C _1-6 alkylene group, 5. A pharmaceutical composition according . Formula (IV):

[In the formula,
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁵ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an _optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _6-10 aryl group Or a heterocyclic group which may be substituted]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis. The pharmaceutical composition according to claim 8, wherein L ² and L ³ represent a single bond. L ² is a divalent group represented by -NH-, L ³ indicates the optionally substituted straight or branched C _1-6 alkylene group, a pharmaceutical composition according to claim 8 . Formula (V) or (VI):

[In the formula,
Two R's each independently represent a C _1-3 alkyl group, or represent a group bonded to each other to form a C _2-5 alkylene group;
L ² represents a single bond, an oxygen atom, or a divalent amino group represented by —NH—;
L ³ represents a single bond or a linear or branched C _1-6 alkylene group which may be substituted,
R ¹ , R ² and R ³ each independently represent a linear or branched C _1-4 alkyl group which may be substituted,
R ⁴ is a linear or branched C _1-6 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁶ represents a hydrogen atom, an optionally substituted linear or branched C _1-16 alkyl group, an optionally substituted C _3-6 cycloalkyl group, an optionally substituted C _1-6 alkoxy group A C _6-10 aryl group which may be substituted, or a heterocyclic group which may be substituted,
R ⁷ represents a linear or branched C _1-16 alkyl group which may be substituted, a C _3-6 cycloalkyl group which may be substituted, a C _6-10 aryl group which may be substituted, or Represents an optionally substituted heterocyclic group,
R ⁸ and R ⁹ each independently represent a hydrogen atom or a C _1-4 alkyl group]
A pharmaceutical composition comprising a compound represented by: or a pharmacologically acceptable salt thereof,
A pharmaceutical composition, which is administered in combination with another therapeutic agent for psoriasis. L ² is a divalent group represented by -NH-, L ³ indicates a straight chain may be substituted or branched C _1-6 alkylene group, pharmaceutical composition according to claim 11 wherein .   A composition containing the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient, and a composition containing another therapeutic agent for psoriasis as an active ingredient simultaneously or A pharmaceutical composition characterized in that it is administered at different times.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof, and another psoriasis therapeutic agent as an active ingredient.   Said other psoriasis treatment is related to vitamin derivatives, steroids, immunosuppressants, immunomodulators, non-steroidal anti-inflammatory agents, cyclooxygenase inhibitors, PDE4 inhibitors, TNF inhibitors, antihistamines, signal transduction Molecular inhibitor, interleukin inhibitor, interleukin receptor antagonist, interleukin drug, MAPK inhibitor, tyrosine kinase inhibitor, cytokine production inhibitor, JAK inhibitor, T cell inhibitor, B cell inhibitor, metabolism The pharmaceutical composition according to any one of claims 1 to 14, which is selected from the group consisting of an antagonist, a gold preparation, a costimulatory molecule related protein preparation, and a dihydroorotic acid dehydrogenase (DHODH) inhibitor.   Said other psoriasis treatment agents are vitamin D3 derivatives, vitamin D2 derivatives, vitamin E, retinoid preparations, diflorazone acetate, clobetasol propionate, mometasone furoate, betamethasone butyrate propionate, fluocinonide, betamethasone dipropionate, diflupredonate, Amcinonide, diflucortorone valerate, lidocaine, hydrocortisone butyrate, deprodon propionate, dexamethasone propionate, harcinonide, dexamethasone valerate, betamethasone valerate, gentamicin sulfate, fradiomycin sulfate, beclomethasone propionate, fluocinolone acetonide, Fludomycin sulfate, prednisolone valerate acetate, methyl prednisolone, triamcinolone acetonide, flumetasone pivalate, Alpromethasone lopionate, clobetasone butyrate, hydrocortisone butyrate, dexamethasone butyrate, glycyrrhetinic acid, pyridoxine, prednisolone, chloramphenicol sulfate fradiomycin acetate, hydrocortisone acetate, diphenhydramine hydrochloride, crotamiton, oxytetracycline hydrochloride, betamethasone sodium phosphate, salazopyrine, colchicine, sulfafa Salazine, acetylsalicylic acid, diflunisal, etendamide, mefenamic acid, diclofenac, sulindac, indomethacin, felbinac, etodolac, tolmetin sodium, naptomene, loxoprofen, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenobrofen, oxabrodine, zaltoprofen, Ketorolac, piroxicam Meloxicam, lornoxicam celecoxib, valdecoxib, parecoxib sodium, lumiracoxib, etoricoxib, tiaramide hydrochloride, tinoridine hydrochloride, epilizole, emorfazone, acetaminophen, oxycodone, tramadol hydrochloride, acetanilide, phenacetin, phenylbutazone, antipyrine, aminopyrine Sulpyrin, isopropyl antipyrine, sulfinpyrazone, ketorolac, ketorolac tromethamine, SC-560, N- (5-amino-2-pyridinyl) -4- (trifluoromethyl) benzamide, etanercept, adalimumab, infliximab, estequinumab, Sequinumab, Tocilizumab, Briaquinumab, Rituximab, Certolizumab Pegol, Chloroquine, Tacrolimus, D- Nicylamine, azathioprine, golimumab, cyclosporin, belimumab, dimethyl fumarate, dehydroxymethyl epoxyquinomycin, DTCM-glutarimide, thalidomide, sesquiterpene lactone, resveratrol, curcumin, diindolylmethannoscapine, parthenolide, bortezomib, ixazomib carfilzomib , Delanzomib, marizonib, MLN-4924, IMD-2560, IMD- 0354, IMD-1041, BAY-11-7082, BAY-11-7085, MLN 120B, BMS-345541, SC-514, PS-1145, denosumab, vorinostat , Romidepsin, SN-50, T-5224, tofacitinib, fostamatinib, canakinumab, salilumab, balishitini , ASP 5094, ASP 015 K, TAK-020, ABT-494, Cicumab, Denosumab, Ozolalizumab, Namilumab, Mabrillimumab, Abatacept, Atacicept, JTE-052, MT-1303, JTE-051, JTE-151, Ibudilast, Fingomolid, Soluble Interleukin -1 receptor antibody, anakinra, interleukin-10, interleukin 2 preparation, interleukin 12 preparation, biaquinumab, secquinumab (AIN-457), ixequizumab (LY-2439821), AMG 827, BMS-582949, TNF-α vaccine, Natalizumab, Vedolizumab, Efarizumab, SCI 0469, BIRB 796, SB 203 580, VX-702, Parapimod, PH 797804, Bem Fenib, dabrafenib, trametinib, cobimetinib, CC-359, CC-930, bentapapimod, XG-104, salicylic acid ointment, urea ointment, methotrexate, gold thiomalate sodium, auranofin, penicillamine, bucilamine, lobenzarit disodium, salazosulfa Pyridine, Actarit, Mizoribine, Igratimod, Apremilast, Roflumilast, AN2728, M5200, DRM02, RVT-051, OPA-15406, Sodium Cromoglycate, Tranilast, Repirinast, Anlexanone, Ibudilast, Ketotifen, Terfenadine, Mequitazine Azezertine, Lukast hydrate, seratrodust, ciclesonide, chlorpheniramine maleate, ant Madin tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, fexofenadine, ketotifen fumarate, cetirizine hydrochloride, oxatomide, ebastine, epinastine hydrochloride, loratadine, tramadol, promethazine, hydroxyzine, homochlorcyclidine, cyproheptadine, mequitazine , Ememastine fumarate pseudoephedrine, bepotastine levocetirizine besilate, olopatadine hydrochloride, mycophenolate mofetil, daclizumab, galiximab, galiximab, metformin hydrochloride, vidilizumab, aminopterin, pazopanib hydrochloride, fezakinumab, luxolitinib phosphate, icusezumab , Guxercumab, SLx-2119, PRX-167700, and leflunomide, which is selected from the group consisting of A pharmaceutical composition according to any one of the preceding claims.   The pharmaceutical composition according to any one of claims 1 to 14, wherein the other psoriasis therapeutic agent is tofacitinib.   The pharmaceutical composition according to any one of claims 1 to 14, wherein the other psoriasis therapeutic agent is apremilast.   The pharmaceutical composition according to any one of claims 1 to 18 for treating or preventing psoriasis.