JP2024515985A - Derivatives of six-membered aromatic heterourea rings and uses thereof - Google Patents
Derivatives of six-membered aromatic heterourea rings and uses thereof Download PDFInfo
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
式（Ｉ）で表される６員芳香族ヘテロ尿素環の誘導体、及び糖尿病性腎症又は高血圧性腎症を治療するための医薬の製造におけるその使用を開示する。【化１】TIFF2024515985000111.tif57168Disclosed are derivatives of 6-membered aromatic heterourea rings represented by formula (I) and their use in the manufacture of medicaments for treating diabetic or hypertensive nephropathy.
Description
本出願は下記の優先権を主張する。
ＣＮ２０２１１０４６２００９．４、出願日は：２０２１年０４月２７日であり、
ＣＮ２０２２１０３０７７９９．３、出願日は：２０２２年０３月２５日である。
This application claims priority to the following:
CN202110462009.4, filing date: April 27, 2021;
CN202210307799.3, filing date: March 25, 2022.
［技術分野］
本発明は、一類の６員芳香族ヘテロ尿素環の誘導体及びその使用を開示し、具体的には、式（Ｉ）で表される化合物及びその薬学的に許容される塩を開示する。
[Technical field]
The present invention discloses a class of 6-membered aromatic heterourea derivatives and uses thereof, specifically, the compounds represented by formula (I) and pharma- ceutically acceptable salts thereof.
［背景技術］
可溶性グアニル酸シクラーゼ（ｓＧＣ）は、哺乳動物細胞のサイトゾルに広く存在し、αサブユニット及びβサブユニットで構成されるヘテロ二量体であり、αサブユニット及びβサブユニットにはそれぞれ２つのアイソフォーム、α１、α２及びβ１、β２が含まれる。α１β１二量体は主に心血管組織に分布し、発現レベルは組織の血管新生の程度と正の相関があるのに対して、α２β１二量体は主に脳及び神経系で発現される。この２つは組織分布と細胞局在に大きな違いがあるが、ｓＧＣ酵素機能の維持においては同様の役割を果たしている。
[Background Art]
Soluble guanylate cyclase (sGC) is widely present in the cytosol of mammalian cells and is a heterodimer composed of α and β subunits, which each have two isoforms, α1, α2 and β1, β2. The α1β1 dimer is mainly distributed in cardiovascular tissues and its expression level is positively correlated with the degree of tissue angiogenesis, whereas the α2β1 dimer is mainly expressed in the brain and nervous system. Although the two have significant differences in tissue distribution and cellular localization, they play similar roles in maintaining sGC enzyme function.
可溶性グアニル酸シクラーゼは、ＮＯ－ｓＧＣ－ｃＧＭＰシグナル経路における重要なシグナル伝達酵素であり、ｓＧＣは体内で活性化された後、グアノシン三リン酸（ＧＴＰ）から環状グアノシン一リン酸（ｃＧＭＰ）への変換を触媒する。ｃＧＭＰは重要なセカンドメッセンジャー分子であり、ホスホジエステラーゼ（ＰＤＥ）、環状ヌクレオチド依存性イオンチャネル（ＣＮＧ）、プロテインキナーゼＧ（ＰＫＧ）などの様々な下流エフェクター分子を活性化させることにより、一連の下流カスケード反応を引き起して、血管や平滑筋の弛緩の促進、血小板凝集、血管リモデリング、細胞のアポトーシス及び炎症の抑制、神経伝達への関与など、胃腸系、血液循環系及び神経系において重要な生理学的機能を果たしている。病態生理学的条件下では、ＮＯ／ｃＧＭＰシステムが阻害される可能性があり、高血圧、血小板活性化、細胞増殖の増加、内皮機能不全、動脈硬化、狭心症、心不全、心筋梗塞、血栓症、脳卒中、性機能障害などの症状を引き起こす可能性がある。過去２年間の研究により、ｓＧＣによって媒介されるシグナル伝達経路の異常が慢性腎臓病、全身性硬化症などの線維性疾患の発生と密接に関連していることが示された。 Soluble guanylate cyclase is an important signaling enzyme in the NO-sGC-cGMP signaling pathway, and after sGC is activated in the body, it catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is an important second messenger molecule that activates various downstream effector molecules, such as phosphodiesterase (PDE), cyclic nucleotide-gated ion channel (CNG), and protein kinase G (PKG), thereby triggering a series of downstream cascade reactions to play important physiological functions in the gastrointestinal system, blood circulation system, and nervous system, such as promoting relaxation of blood vessels and smooth muscles, platelet aggregation, vascular remodeling, suppressing cell apoptosis and inflammation, and participating in neurotransmission. Under pathophysiological conditions, the NO/cGMP system may be inhibited, which may lead to symptoms such as hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke, and sexual dysfunction. Research over the past two years has demonstrated that abnormalities in the signaling pathway mediated by sGC are closely related to the development of fibrotic diseases such as chronic kidney disease and systemic sclerosis.
可溶性グアニル酸シクラーゼに対する従来の刺激治療では、有機硝酸塩などのＮＯに基づいて効果を発揮する化合物のみが使用されている。これは生体内変換によって形成され、ヘムの中心鉄原子を攻撃することで可溶性グアニル酸シクラーゼを活性化する。副作用に加えて、耐性の発現もこの種の治療法の決定的な欠点の１つである。 Conventional stimulation treatments of soluble guanylate cyclase only use compounds that exert their effect based on NO, such as organic nitrates, which are formed by biotransformation and activate soluble guanylate cyclase by attacking the central iron atom of heme. In addition to side effects, the development of resistance is also one of the crucial drawbacks of this type of treatment.
２０１３年１０月、ＦＤＡは、肺動脈性肺高血圧症の治療に使用されるピラゾロピリジン化合物としてリオシグアト（Ｒｉｏｃｉｇｕａｔ）と称される新しいグアニル酸シクラーゼ刺激剤を承認したが（ＷＯ２００３０９５４５１Ａ１）、人体内での半減期がより短く、クリアランスが高いため、１日３回の投与が必要である。 In October 2013, the FDA approved a new guanylate cyclase stimulator called riociguat (WO2003095451A1) for the treatment of pulmonary arterial hypertension, but it has a shorter half-life in the human body and high clearance, which requires three times daily dosing.
現在の市場及び臨床現場におけるそのような可溶性グアニル酸シクラーゼ刺激剤に対する満たされていないニーズを考慮して、本発明は、可溶性グアニル酸シクラーゼの刺激剤として使用することができ、グアニル酸シクラーゼに対して有効な体外刺激活性を示し、優れた薬物動態特性を有する、新しい種類の化合物を提供する。 In view of the current unmet need for such soluble guanylate cyclase stimulators in the market and in clinical practice, the present invention provides a new class of compounds that can be used as stimulators of soluble guanylate cyclase, exhibit effective in vitro stimulatory activity against guanylate cyclase, and have excellent pharmacokinetic properties.
［発明の概要］
一つの方面において、本発明は、式（Ｉ）で表される化合物又はその薬学的に許容される塩を提供する。
Summary of the Invention
In one aspect, the present invention provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.
ただし、Ｒ１は、Ｈ、Ｆ又はＣｌであり、
Ｒ２は、Ｃ１－６アルキル、－ＣＨ２－フェニル、－ＣＨ２－ピリジル又は－ＣＨ２－ピリミジニルであり、ここで、前記Ｃ１－６アルキル、－ＣＨ２－フェニル、－ＣＨ２－ピリジル又は－ＣＨ２－ピリミジニルは、それぞれ独立して任意選択で１、２、３、４又は５つのＲａにより置換され、
各Ｒａは、独立してＨ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２、－Ｃ（＝Ｏ）ＯＨ、Ｃ１－３アルコキシ又は任意選択で１、２又は３つの独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２及び－ＯＣＨ３から選択される置換基により置換されたＣ１－３アルキルであり、
Ｒ３及びＲ４は、それぞれ独立してＨ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ又は－ＮＨ２であり、
Ｒ５は、－Ｌ－Ｒｂであり、
Ｌは、単結合、－ＮＲｃＣ（＝Ｏ）Ｏ－又は－ＮＲｃＣ（＝Ｏ）－であり、
Ｒｂは、Ｃ１－６アルキル、
where R 1 is H, F or Cl;
R 2 is C 1-6 alkyl, —CH 2 -phenyl, —CH 2 -pyridyl or —CH 2 -pyrimidinyl, wherein said C 1-6 alkyl, —CH 2 -phenyl, —CH 2 -pyridyl or —CH 2 -pyrimidinyl is each independently optionally substituted by 1, 2, 3, 4 or 5 R a ;
each R a is independently H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -C(=O)OH, C 1-3 alkoxy or C 1-3 alkyl optionally substituted with 1 , 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH 2 and -OCH 3 ;
R3 and R4 are each independently H, F, Cl, Br, I, -OH, -CN, or -NH2 ;
R5 is -L- Rb ;
L is a single bond, -NR c C(=O)O- or -NR c C(=O)-;
R b is C 1-6 alkyl,
各Ｒは、独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２、Ｃ１－３アルコキシ又は任意選択で１、２又は３つの独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２及び－ＯＣＨ３から選択される置換基により置換されたＣ１－３アルキルであり、
或いは、Ｒ３及びＲ５は、それらと連結された炭素原子と連結され、構造単位
each R is independently F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , C1-3alkoxy or C1-3alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH2 and -OCH3 ;
Alternatively, R 3 and R 5 are linked to the carbon atom to which they are linked to form a structural unit
Ｒ６、Ｒ７及びＲ８は、それぞれ独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２又は任意選択で１、２又は３つの独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２及び－ＯＣＨ３から選択される置換基により置換されたＣ１－３アルキ
ルである。
R 6 , R 7 and R 8 are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 or C 1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH 2 and -OCH 3 .
本発明の一部の実施形態において、上記Ｌは、単結合、－ＮＨ－Ｃ（＝Ｏ）Ｏ－、－ＮＨ－Ｃ（＝Ｏ）－、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－又は－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）－であり、他の変量は本発明で定義された通りである。 In some embodiments of the invention, L is a single bond, -NH-C(=O)O-, -NH-C(=O)-, -N(CH 3 )-C(=O)O- or -N(CH 3 )-C(=O)-, and all other variables are as defined herein.
本発明の一部の実施形態において、上記化合物又はその薬学的に許容される塩において、その化合物は、式（Ｉ－１）～（Ｉ－４）で表される構造を有する。 In some embodiments of the present invention, the compound or a pharma- ceutically acceptable salt thereof has a structure represented by formulas (I-1) to (I-4).
ただし、Ｒ１、Ｒ２、Ｒ４及びＲｂは、本発明で定義された通りである。
本発明の一部の実施形態において、上記各Ｒは、独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２、－ＣＨ３、－ＣＨ２ＣＨ３、－ＯＣＨ３、－ＯＣＨ２ＣＨ３、－ＣＦ３、－ＣＨ２ＣＦ３、－ＣＨ２ＣＨ２ＣＦ３、－ＣＨ２ＯＨ又は－ＣＨ２ＣＨ２ＯＨであり、他の変量は本発明で定義された通りである。
wherein R 1 , R 2 , R 4 and R b are as defined in the present invention.
In some embodiments of the invention, each R is independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 OH or -CH 2 CH 2 OH, with the other variables being as defined herein.
本発明の一部の実施形態において、上記Ｒｂは、Ｃ１－４アルキル、 In some embodiments of the present invention, R b is C 1-4 alkyl,
本発明の一部の実施形態において、上記Ｒｂは、－ＣＨ３、－ＣＨ２ＣＨ３、－ＣＨ２ＣＨ２ＣＨ３、－ＣＨ（ＣＨ３）２、－ＣＨ２ＣＨ２ＣＨ２ＣＨ３、－ＣＨ（ＣＨ３）ＣＨ２ＣＨ３、－ＣＨ２ＣＨ（ＣＨ３）２、－Ｃ（ＣＨ３）３、 In some embodiments of the invention, R b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 ,
本発明の一部の実施形態において、上記Ｒｂは、－ＣＨ３、－ＣＨ２ＣＨ３、－ＣＨ２ＣＨ２ＣＨ３、－ＣＨ（ＣＨ３）２、－ＣＨ２ＣＨ２ＣＨ２ＣＨ３、－ＣＨ（ＣＨ３）ＣＨ２ＣＨ３、－ＣＨ２ＣＨ（ＣＨ３）２、－Ｃ（ＣＨ３）３、 In some embodiments of the invention, R b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 ,
本発明の一部の実施形態において、上記Ｒ５は、－ＮＨ－Ｃ（＝Ｏ）Ｏ－Ｃ１－４アルキル、－ＮＨＣ（＝Ｏ）－Ｃ１－４アルキル、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－Ｃ１－４
アルキル、－ＮＨ－Ｃ（＝Ｏ）－（Ｃ３－６シクロアルキル）、－Ｎ（ＣＨ３）Ｃ（＝Ｏ）－（Ｃ３－６シクロアルキル）、－ＮＨ－Ｃ（＝Ｏ）－フェニル、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）－フェニル又は５～６員ヘテロシクロアルキルであり、ここで、前記ＮＨ－Ｃ（＝Ｏ）Ｏ－Ｃ１－４アルキル、－ＮＨＣ（＝Ｏ）－Ｃ１－４アルキル、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－Ｃ１－４アルキル、－ＮＨ－Ｃ（＝Ｏ）－（Ｃ３－６シクロアルキル）、－Ｎ（ＣＨ３）Ｃ（＝Ｏ）－（Ｃ３－６シクロアルキル）、－ＮＨ－Ｃ（＝Ｏ）－フェニル、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）－フェニル及び５～６員ヘテロシクロアルキルは、それぞれ独立して任意選択で１、２又は３つのＲにより置換され、Ｒ及び他の変量は本発明で定義された通りである。
In some embodiments of the present invention, R 5 is -NH-C(=O)O-C 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, -N(CH 3 )-C(=O)O-C 1-4
and 5-6 membered heterocycloalkyl, wherein said NH-C(=O)O-C 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, -N(CH 3 )-C(=O)O-C 1-4 alkyl, -NH-C(=O)-(C 3-6 cycloalkyl ), -N(CH 3 )-C(=O)-(C 3-6 cycloalkyl), -NH - C(=O )-phenyl, -N(CH 3 ) -C(=O)-phenyl and 5-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R, and R and the other variables are as defined herein.
本発明の一部の実施形態において、上記Ｒ５は、－ＮＨ－Ｃ（＝Ｏ）Ｏ－ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ２ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）Ｏ－ＣＨ（ＣＨ３）２、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ２ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ２ＣＨ２ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ（ＣＨ３）２、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ３、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ３、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ２ＣＨ３、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ（ＣＨ３）２、 In some embodiments of the invention, R 5 is -NH-C(=O)O-CH 3 , -NH-C(=O)O-CH 2 CH 3 , -NH-C(=O)O-CH 2 CH 2 CH 3 , -NH-C(=O)O-CH(CH 3 ) 2 , -NH-C(=O)-CH 3 , -NH-C(=O)-CH 2 CH 3 , -NH-C(=O)-CH 2 CH 2 CH 3 , -NH-C(=O)-CH(CH 3 ) 2 , -N(CH 3 )-C(=O)O-CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH( CH3 ) 2 ,
本発明の一部の実施形態において、上記Ｒ５は、－ＮＨ－Ｃ（＝Ｏ）Ｏ－ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ２ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）Ｏ－ＣＨ（ＣＨ３）２、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ２ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ２ＣＨ２ＣＨ３、－ＮＨ－Ｃ（＝Ｏ）－ＣＨ（ＣＨ３）２、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ３、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ３、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ２ＣＨ３、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ（ＣＨ３）２、 In some embodiments of the invention, R 5 is -NH-C(=O)O-CH 3 , -NH-C(=O)O-CH 2 CH 3 , -NH-C(=O)O-CH 2 CH 2 CH 3 , -NH-C(=O)O-CH(CH 3 ) 2 , -NH-C(=O)-CH 3 , -NH-C(=O)-CH 2 CH 3 , -NH-C(=O)-CH 2 CH 2 CH 3 , -NH-C(=O)-CH(CH 3 ) 2 , -N(CH 3 )-C(=O)O-CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH( CH3 ) 2 ,
本発明の一部の実施形態において、上記化合物又はその薬学的に許容される塩において、その化合物は、式（Ｉ－５）～（Ｉ－１３）で表される構造を有する。 In some embodiments of the present invention, the compound or a pharma- ceutically acceptable salt thereof has a structure represented by formulas (I-5) to (I-13).
ただし、ｐは、０、１又は２であり、Ｒ４は、Ｈ又は－ＮＨ２であり、Ｒ２及びＲは、本発明で定義された通りである。
本発明の一部の実施形態において、上記化合物又はその薬学的に許容される塩において、その化合物は、式（Ｉ－１４）～（Ｉ－１５）で表される構造を有する。
wherein p is 0, 1 or 2, R 4 is H or —NH 2 , and R 2 and R are as defined herein.
In some embodiments of the present invention, in the above compound or a pharma- ceutically acceptable salt thereof, the compound has a structure represented by formula (I-14) to (I-15).
ただし、Ｒ１、Ｒ２、Ｒ４、Ｒ６、Ｒ７及びＲ８は、本発明で定義された通りである。
本発明の一部の実施形態において、上記化合物又はその薬学的に許容される塩において、その化合物は、式（Ｉ－１６）～（Ｉ－１９）で表される構造を有する。
wherein R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are as defined in the present invention.
In some embodiments of the present invention, in the above compound or a pharma- ceutically acceptable salt thereof, the compound has a structure represented by formulae (I-16) to (I-19).
ただし、Ｒ２、Ｒ６、Ｒ７及びＲ８は、本発明で定義された通りである。
本発明の一部の実施形態において、上記構造単位
wherein R 2 , R 6 , R 7 and R 8 are as defined in the present invention.
In some embodiments of the present invention, the structural unit
本発明の一部の実施形態において、上記構造単位 In some embodiments of the present invention, the structural unit
本発明の一部の実施形態において、上記Ｒ６、Ｒ７及びＲ８は、それぞれ独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２、－ＣＨ３、－ＣＨ２ＣＨ３、－ＣＦ３、－ＣＨ２ＣＦ３又は－ＣＨ２ＣＨ２ＯＨであり、他の変量は本発明で定義された通りである。 In some embodiments of the invention, R 6 , R 7 and R 8 are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -CH 3 , -CH 2 CH 3 , -CF 3 , -CH 2 CF 3 or -CH 2 CH 2 OH, and other variables are as defined herein.
本発明の一部の実施形態において、上記化合物又はその薬学的に許容される塩において、その化合物は、式（Ｉ－２０）～（Ｉ－２５）で表される構造を有する。 In some embodiments of the present invention, the compound or a pharma- ceutically acceptable salt thereof has a structure represented by formulas (I-20) to (I-25).
ただし、Ｒ２は本発明で定義された通りである。
本発明の一部の実施形態において、上記各Ｒａは、独立してＨ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２、－Ｃ（＝Ｏ）ＯＨ、－ＣＨ３、－ＣＨ２ＣＨ３、－ＣＨ２ＣＨ２ＣＨ３、－ＣＨ（ＣＨ３）２、－ＯＣＨ３、－ＯＣＨ２ＣＨ３、－ＣＦ３、－ＣＨ２ＣＦ３、－ＣＦ２ＣＦ３、－ＣＨ２ＣＨ２ＣＦ３、－ＣＨ２ＯＨ又は－ＣＨ２ＣＨ２ＯＨであり、他の変量は本発明で定義された通りである。
wherein R2 is as defined herein.
In some embodiments of the invention, each R a is independently H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -C(═O)OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 OH or -CH 2 CH 2 OH, with the other variables being as defined herein.
本発明の一部の実施形態において、上記各Ｒａは、独立してＨ、Ｆ、Ｃｌ、又は－ＮＨ２であり、他の変量は本発明で定義された通りである。
本発明の一部の実施形態において、上記Ｒ２は、Ｃ１－６アルキル、－ＣＨ２－フェニル、－ＣＨ２－ピリジル、－ＣＨ２－ピリミジニル又は－ＣＨ２－ピラジニルであり、ここで、前記Ｃ１－６アルキル、フェニル、ピリジル、ピリミジニル及びピラジニルは、任意選択で１、２、３、４又は５つのＲａにより置換され、Ｒａ及び他の変量は本発明で定義された通りである。
In some embodiments of the invention, each R a above is independently H, F, Cl, or --NH2 , and all other variables are as defined herein.
In some embodiments of the invention, R 2 is C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 -pyrimidinyl or -CH 2 -pyrazinyl, wherein said C 1-6 alkyl, phenyl, pyridyl, pyrimidinyl and pyrazinyl are optionally substituted by 1, 2, 3, 4 or 5 R a , and R a and other variables are as defined herein.
本発明の一部の実施形態において、上記Ｒ２は、 In some embodiments of the present invention, R2 is
本発明の一部の実施形態において、上記Ｒ２は、 In some embodiments of the present invention, R2 is
本発明の一部の実施形態において、上記Ｒ３及びＲ４は、それぞれ独立してＨ又は－ＮＨ２であり、他の変量は本発明で定義された通りである。
本発明の一部の実施形態において、上記化合物は、式（Ｉ－１５－ａ）、（Ｉ－１５－ｂ）、（Ｉ－１５－ｃ）又は（Ｉ－１５－ｄ）で表される構造を有する。
In some embodiments of the present invention, R 3 and R 4 are each independently H or -NH 2 , and other variables are as defined herein.
In some embodiments of the invention, the compound has a structure represented by formula (I-15-a), (I-15-b), (I-15-c) or (I-15-d).
ただし、Ｒ１、Ｒ４、Ｒ７、Ｒ８及びＲａは、本発明で定義された通りである。
本発明一部の実施形態は、更に上記の変量の任意の組み合わせにより形成される。
本発明の一部の実施形態において、上記化合物又はその薬学的に許容される塩は、下記から選択される。
wherein R 1 , R 4 , R 7 , R 8 and R a are as defined in the present invention.
Some embodiments of the present invention are further formed by any combination of the above variables.
In some embodiments of the invention, the compound, or a pharma- ceutically acceptable salt thereof, is selected from the following:
本発明は、更に糖尿病性腎症又は高血圧性腎症を治療するための医薬の製造における、上記化合物又はその薬学的に許容される塩の使用を提供する。
本発明は、更に対象に有効量の上記技術的解決策のいずれかで限定された化合物又はその薬学的に許容される塩を提供することを含む、必要とする対象における糖尿病性腎症又は高血圧性腎症の治療方法を提供する。
The present invention further provides the use of the above compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating diabetic or hypertensive nephropathy.
The present invention further provides a method for treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, comprising providing to the subject an effective amount of a compound defined in any of the above technical solutions or a pharma- ceutically acceptable salt thereof.
［技術効果］
本発明は、一類の可溶性グアニル酸シクラーゼ刺激剤に関し、関連化合物はグアニル酸シクラーゼに対して有意な体外刺激活性を有し、優れた薬物動態特性を有し、５つのＣＹＰアイソザイムに対していずれも弱い阻害効果を示す。
[Technical Effects]
The present invention relates to a class of soluble guanylate cyclase stimulators, the related compounds of which have significant in vitro stimulating activity against guanylate cyclase, excellent pharmacokinetic properties, and weak inhibitory effects against all five CYP isoenzymes.
［定義及び説明］
別途に説明しない限り、本明細書で用いられる下記の用語及び連語は以下の意味を含む。１つの特定の用語又は連語は、特別に定義されない場合、不確定又は不明瞭ではなく、一般的な定義として理解されるべきである。本明細書で商品名が出た場合、相応の商品又はその活性成分を指す。
[Definitions and Explanations]
Unless otherwise stated, the following terms and phrases used herein have the following meanings: A particular term or phrase, unless specifically defined, should be understood to be generally defined, not indefinite or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.
本明細書で用いられる「薬学的許容される」は、それらの化合物、材料、組成物及び／又は剤形に対するもので、これらは信頼できる医学判断の範囲内にあり、ヒト及び動物の組織との接触に適し、毒性、刺激性、アレルギー反応又はほかの問題又は合併症があまりなく、合理的な利益／リスク比に合う。 As used herein, "pharmacologically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit/risk ratio.
用語「薬学的に許容される塩」とは、本発明の化合物の塩を指し、本発明で発見された特定の置換基を有する化合物と比較的に無毒の酸又は塩基とで製造される。本発明の化合物に比較的に酸性の官能基が含まれる場合、単独の溶液又は適切な不活性溶媒において十分な量の塩基でこれらの化合物と接触することで塩基付加塩を得ることができる。薬学的許容される塩基付加塩は、ナトリウム、カリウム、カルシウム、アンモニウム、有機アミン又はマグネシウム塩あるいは類似の塩を含む。本発明で化合物に比較的塩基性の官能基が含まれる場合、単独の溶液又は、適切な不活性溶媒において十分な量の酸でこれらの化合物と接触することで酸付加塩を得ることができる。薬学的に許容される酸付加塩の実例は、無機酸塩及び有機酸塩、更にアミノ酸（例えばアルギニンなど）の塩、及びグルクロン酸のような有機酸の塩を含み、上記無機酸は、例えば塩酸、臭化水素酸、硝酸、炭酸、炭酸水素イオン、リン酸、リン酸一水素イオン、リン酸二水素イオン、硫酸、硫酸水素イオン、ヨウ化水素酸、亜リン酸などを含み、上記有機酸は、例えば酢酸、プロピオン酸、イソ酪酸、マレイン酸、マロン酸、安息香酸、コハク酸、スベリン酸、フマル酸、乳酸、マンデル酸、フタル酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、クエン酸、酒石酸及びメタンスルホン酸などの類似の酸を含む。本発明の一部の特定的の化合物は、塩基性及び酸性の官能基を含有するため、任意の塩基付加塩又は酸付加塩に転換することができる。 The term "pharmaceutical acceptable salts" refers to salts of the compounds of the present invention, which are prepared with relatively non-toxic acids or bases with certain substituents found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds with a sufficient amount of base in a solution alone or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting these compounds with a sufficient amount of acid in a solution alone or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and similar acids. Some specific compounds of the present invention contain basic and acidic functional groups and can therefore be converted into any base or acid addition salt.
本発明の薬学的許容される塩は、酸基又は塩基性基を含む母体化合物から通常の化学的方法で合成することができる。通常の場合、このような塩の製造方法は、水又は有機溶媒或いは両者の混合物において、遊離酸又は塩基の形態のこれらの化合物を化学量論量の適切な塩基又は酸と反応させて製造する。 The pharma- ceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds that contain acidic or basic groups. Typically, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.
本発明の化合物は、特定の幾何又は立体異性体の形態が存在してもよい。本発明は、全てのこのような化合物を想定し、シス及びトランス異性体、（－）－及び（＋）－エナンチオマー、（Ｒ）－及び（Ｓ）－エナンチオマー、ジアステレオマー、（Ｄ）－異性体、（Ｌ）－異性体、及びそのラセミ混合物並びに他の混合物、例えばエナンチオマー又はジアステレオマーを多く含有する混合物を含み、全てのこれらの混合物は本発明の範囲内に
含まれる。アルキル等の置換基に他の不斉炭素原子が存在してもよい。全てのこれらの異性体及びこれらの混合物はいずれも本発明の範囲内に含まれる。
The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures, such as mixtures enriched in an enantiomer or diastereomer, and all such mixtures are included within the scope of the invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are both included within the scope of the invention.
別途に説明しない限り、用語「エナンチオマー」又は「光学異性体」とは互いに鏡像の関係にある立体異性体である。
別途に説明しない限り、用語「シス－トランス異性体」又は「幾何異性体」とは二重結合又は環構成炭素原子の単結合が自由に回転できないことによるものである。
Unless otherwise stated, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other.
Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.
別途に説明しない限り、用語「ジアステレオマー」とは分子が二つ又は複数のキラル中心を有し、かつ分子同士は非鏡像の関係である立体異性体である。
別途に説明しない限り、「（＋）」は右旋性を意味し、「（－）」は左旋性を意味し、「（±）」はラセミ体を意味する。
Unless otherwise explained, the term "diastereomer" is a stereoisomer in which the molecules have two or more centers of chirality and the molecules are not mirror-images of each other.
Unless otherwise stated, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.
別途に説明しない限り、楔形実線結合（ Unless otherwise stated, solid wedge connections (
本発明の化合物は、特定の形態で存在することができる。特に明記しない限り、「互変異性体」又は「互変異性体の形態」という用語は、異なる官能基の異性体が室温で動的平衡状態にあり、かつ急速に相互変換可能であることを意味する。互変異性体が可能であれば（例えば、溶液の中等）、互変異性体の化学的平衡を達成することができる。例えば、プロトン互変異性体（ｐｒｏｔｏｎ ｔａｕｔｏｍｅｒ）（プロトトロピー互変異性体（ｐｒｏｔｏｔｒｏｐｉｃ ｔａｕｔｏｍｅｒ）とも呼ばれる）は、プロトンの移動を介する相互変換、例えばケト－エノール異性化やイミン－エナミン異性化を含む。原子価互変異性体（ｖａｌｅｎｃｅ ｔａｕｔｏｍｅｒ）は、一部の結合電子の再結合による相互変換を含む。ここで、ケト－エノール互変異性化の具体的な実例は、ペンタン－２，４－ジオンと４－ヒドロキシペント－３－エン－２－オンの二つの互変異性体の間の相互変換である。 The compounds of the present invention can exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that isomers of different functional groups are in dynamic equilibrium at room temperature and can be rapidly interconverted. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via recombination of some of the bond electrons. Here, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
別途に説明しない限り、「１つの異性体が豊富な」、「異性体が豊富な」、「１つのエナンチオマーが豊富な」又は「エナンチオマーが豊富な」という用語は、その中の１つの異性体又はエナンチオマーの含有量が１００％未満であり、且つこの異性体又はエナンチオマーの含有量が６０％以上、又は７０％以上、又は８０％以上、又は９０％以上、又は９５％以上、又は９６％以上、又は９７％以上、又は９８％以上、又は９９％以上、又は９９．５％以上、又は９９．６％以上、又は９９．７％以上、又は９９．８％以上、又は９９．９％以上であることを指す。 Unless otherwise stated, the terms "enriched in one isomer," "enriched in one enantiomer," or "enantiomer-enriched" refer to a mixture that contains less than 100% of one isomer or enantiomer and that contains 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.
別途に説明しない限り、「異性体過剰率」又は「エナンチオマー過剰率」という用語は、２つの異性体又は２つのエナンチオマーの相対百分率の間の差を指す。例えば、１つの異性体又はエナンチオマーの含有量が９０％であり、もう１つの異性体又はエナンチオマーの含有量が１０％である場合、異性体又はエナンチオマー過剰率（ｅｅ値）は８０％である。 Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer at 10%, the isomeric or enantiomeric excess (ee value) is 80%.
光学活性な（Ｒ）－及び（Ｓ）－異性体、ならびにＤ及びＬ異性体は、キラル合成又はキラル試薬又は他の通常の技術によって製造することができる。本発明のある化合物の一つのエナンチオマーを得るには、不斉合成又はキラル補助剤を有する誘導作用によって製造することができ、ここで、得られたジアステレオマー混合物を分離し、かつ補助基を切断して純粋な所望のエナンチオマーを提供する。或いは、分子に塩基性官能基（例えばアミノ）又は酸性官能基（例えばカルボキシル）が含まれる場合、適切な光学活性な酸又は塩基とジアステレオマーの塩を形成し、次に当分野で公知の通常の方法によってジアステレオマーの分割を実行した後、回収して純粋なエナンチオマーを得る。また、エナンチオマーとジアステレオマーの分離は、通常、クロマトグラフィーを使用し、前記クロマトグラフィーはキラル固定相を使用し、かつ任意選択で化学的誘導体化法（例えば、アミンからカルバメートを生成する）を組み合わせて実行される。 Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. One enantiomer of a compound of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the salt of the diastereomeric form with an appropriate optically active acid or base is formed, and then the separation of the diastereomers is carried out by conventional methods known in the art, followed by recovery to obtain the pure enantiomers. Separation of enantiomers and diastereomers is also typically carried out using chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization methods (e.g., forming carbamates from amines).
本発明の化合物は、化合物を構成する１つ又は複数の原子に不自然な割合の原子同位体を含有してもよい。例えば、化合物はトリチウム（３Ｈ）、ヨウ素－１２５（１２５Ｉ）、Ｃ－１４（１４Ｃ）などの放射性同位元素で標識することができる。又は例えば、重水素で水素を置換して重水素化薬物を形成させることができ、重水素と炭素で形成された結合は、通常の水素と炭素で形成された結合よりも強く、非重水素化薬物と比較して、重水素化薬物は、毒性副作用を低減し、薬物の安定性を高め、有効性を増強し、薬物の生物学的半減期を延長するなどの利点がある。本発明の化合物の同位体からなる変換は、放射性であるか否かにかかわらず、本発明の範囲内に含まれる。 The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms that constitute the compounds. For example, the compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), C-14 ( 14 C), etc. Or, for example, deuterium may be substituted for hydrogen to form a deuterated drug, in which the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, enhanced efficacy, and extended biological half-life of the drug. Isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
用語「任意」また「任意に」は後記の事項又は状況によって可能であるが必ずしも現れるわけではなく、且つ当該記述はそれに記載される事項又は状況が生じる場合とその事項又は状況が生じない場合を含むことを意味する。 The terms "optionally" and "optionally" mean that the following event or circumstance is possible but not necessarily occurring, and that the description includes instances where the described event or circumstance occurs and instances where the event or circumstance does not occur.
用語「置換された」は特定の原子における任意の一つ又は複数の水素原子が置換基で置換されたことで、特定の原子価状態が正常でかつ置換後の化合物が安定していれば、置換基は重水素及び水素の変形体を含んでもよい。置換基がケトン基（即ち＝Ｏ）である場合、２つの水素原子が置換されたことを意味する。ケトン基置換は、芳香族基で生じない。用語「任意に置換される」は、置換されてもよく、置換されなくてもよく、別途に定義しない限り、置換基の種類と数は化学的に現できれば任意である。 The term "substituted" means that any one or more hydrogen atoms at a particular atom have been replaced with a substituent, which may include variants of deuterium and hydrogen, provided that the particular valence state is correct and the compound is stable after substitution. When the substituent is a ketone group (i.e. =O), it means that two hydrogen atoms have been replaced. Ketone group substitution does not occur in aromatic groups. The term "optionally substituted" means that the group may or may not be substituted, and unless otherwise defined, the type and number of substituents are any that can be chemically expressed.
変量（例えばＲ）のいずれかが化合物の組成又は構造に１回以上現れた場合、その定義はいずれの場合においても独立である。そのため、例えば、１つの基が０～２個のＲで置換された場合、上記基は任意選択で２個以下のＲで置換され、且ついずれの場合においてもＲは独立した選択肢を有する。また、置換基及び／又はその変形体の組み合わせは、このような組み合わせが安定した化合物になる場合のみ許容される。 When any variable (e.g., R) occurs more than one time in a composition or structure of a compound, its definition is independent at each occurrence. So, for example, if a group is substituted with 0-2 R, then said group is optionally substituted with up to 2 R, and each occurrence of R has an independent choice. Also, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
1つ連結基の数が０の場合、例えば、－（ＣＲＲ）０－は、当該連結基が単結合であることを意味する。
そのうち一つの変量が単結合の場合、それで連結される２つの基が直接連結されていることを指し、例えばＡ－Ｌ－ＺにおけるＬが単結合を表す場合、この構造は実際にＡ－Ｚになる。
When the number of linking groups is 0, for example, --(CRR) 0 -- means that the linking group is a single bond.
When one of the variables is a single bond, it indicates that the two groups connected by it are directly linked; for example, when L in ALZ represents a single bond, the structure actually becomes AZ.
1つ置換基が空である場合、当該置換基が存在しないことを意味し、例えば、Ａ－ＸのＸが空である場合、当該構造は実際にＡであることを意味する。列挙された置換基がどの原子を介して置換された基に結合しているかを示していない場合、このような置換基はその任意の原子を介して結合することができ、例えば、置換基としてのピリジニルは、ピリジン環の任意の炭素原子を介して置換された基に結合してもよい。 If one substituent is empty, it means that the substituent is not present, for example, if X in A-X is empty, it means that the structure is actually A. If there is no indication of which atom a listed substituent is bonded to the substituted group through, such substituent may be bonded through any atom thereof, for example, pyridinyl as a substituent may be bonded to the substituted group through any carbon atom of the pyridine ring.
挙げられた連結基の連結方向を明示していない場合、その連結方向は任意であり、例えば、 When the linking direction of the listed linking groups is not specified, the linking direction is arbitrary, for example,
特に明記しない限り、ある基が１つ又は複数の結合可能な部位を有する場合、当該基の任意の一つ又は複数の部位は、化学結合によって他の基に結合することができる。当該化学結合の結合方式が非局在であり、且つ結合可能な部位にＨ原子が存在する場合、化学結合を結合する時、当該部位のＨ原子の個数は、結合された化学結合の個数に応じて相応の価数の基に減少する。前記部位が他の基と結合する化学結合は、直線実線結合（ Unless otherwise specified, if a group has one or more bondable sites, any one or more of the sites of the group can be bonded to other groups by chemical bonds. If the bonding method of the chemical bond is delocalized and there is an H atom at the bondable site, when the chemical bond is bonded, the number of H atoms at the site is reduced to a group of the corresponding valence according to the number of bonded chemical bonds. The chemical bond by which the site is bonded to another group is represented by a straight solid bond (
別途に説明しない限り、環内の原子の数は一般に環員の数として定義され、例えば、「５～７員環」とは、その周囲に５～７個の原子配置された「環」を指す。
別途に説明しない限り、「３～１２員環」は、３～１２個の環原子からなるシクロアルキル、ヘテロシクロアルキル、シクロアルケニル又はヘテロシクロアルケニルを指す。前記環は、単環を含み、更にスピロ環、縮合環及び架橋環などの二環系又は多環系も含む。別途に説明しない限り、前記環は、任意選択でＯ、Ｓ及びＮから独立して選択される１、２又は３個のヘテロ原子を含む。前記３～１２員環は、３～１０員、３～９員、３～８員、３～７員、３～６員、３～５員、４～１０員、４～９員、４～８員、４～７員、４～６員、４～５員、５～１０員、５～９員、５～８員、５～７員、５～６員、６～１０員、６～９員、６～８員及び６～７員環などを含む。用語「５～７員ヘテロシクロアルキル」は、ピペリジニルなどを含むが、フェニルは含まない。用語「環」はまた、少なくとも１つの環を含む環系を含み、ここで、それぞれの「環」はいずれも独立して上記の定義に適合する。
Unless otherwise stated, the number of atoms in a ring is generally defined as the number of ring members, e.g., a "5- to 7-membered ring" refers to a "ring" having from 5 to 7 atoms arranged around it.
Unless otherwise stated, a "3- to 12-membered ring" refers to a cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl consisting of 3 to 12 ring atoms. The ring includes monocyclic rings, as well as bicyclic or polycyclic ring systems such as spiro, fused, and bridged rings. Unless otherwise stated, the ring optionally includes 1, 2, or 3 heteroatoms independently selected from O, S, and N. The 3- to 12-membered ring includes 3-10 membered, 3-9 membered, 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 4-10 membered, 4-9 membered, 4-8 membered, 4-7 membered, 4-6 membered, 4-5 membered, 5-10 membered, 5-9 membered, 5-8 membered, 5-7 membered, 5-6 membered, 6-10 membered, 6-9 membered, 6-8 membered, and 6-7 membered rings, and the like. The term "5- to 7-membered heterocycloalkyl" includes piperidinyl and the like, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, where each "ring" independently meets the above definition.
別途に定義しない限り、Ｃｎ－ｎ＋ｍ又はＣｎ－Ｃｎ＋ｍはｎ～ｎ＋ｍ個の炭素の任意の１つの具体的な様態を含み、例えば、Ｃ１－１２はＣ１、Ｃ２、Ｃ３、Ｃ４、Ｃ５、Ｃ６、Ｃ７、Ｃ８、Ｃ９、Ｃ１０、Ｃ１１、及びＣ１２を含み、ｎ～ｎ＋ｍのうちの任意の１つの範囲も含み、例えば、Ｃ１－１２はＣ１－３、Ｃ１－６、Ｃ１－９、Ｃ３－６、Ｃ３－９、Ｃ３－１２、Ｃ６－９、Ｃ６－１２、及びＣ９－１２等を含む。同様に、ｎ員～ｎ＋ｍ員は環における原子数がｎ～ｎ＋ｍ個であることを表し、例えば、３～１２員環は３員環、４員環、５員環、６員環、７員環、８員環、９員環、１０員環、１１員環、及び１２員環を含み、ｎ～ｎ＋ｍのうちの任意の１つの範囲も含み、例えば、３～１２員環は３～６員環、３～９員環、５～６員環、５～７員環、６～７員環、６～８員環、及び６～１０員環等を含む。 Unless otherwise defined, C n-n+m or C n -C n+m includes any one specific embodiment of n through n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also includes any one range from n through n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12, C 6-9 , C 6-12 , and C 9-12 , etc. Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m. For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of the ranges of n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.
別途に定義しない限り、用語「Ｃ１－６アルキル」は直鎖又は分枝鎖の１～６個の炭素原子で構成された飽和炭化水素基を表す。前記Ｃ１－６アルキルにはＣ１－５、Ｃ１－４、Ｃ１－３、Ｃ１－２、Ｃ２－６、Ｃ２－４、Ｃ６とＣ５アルキルなどが含まれ、それは１価（例えばメチル）、２価（例えばメチレン）及び多価（例えばメチン）であってもよい。Ｃ１－６アルキルの実例は、メチル（Ｍｅ）、エチル（Ｅｔ）、プロピル（ｎ－プロピル及びイソプロピルを含む）、ブチル（ｎ－ブチル、イソブチル、ｓ－ブチル、ｔ－ブチルを含む）、ペンチル（ｎ－ペンチル、イソペンチル、ネオペンチルを含む）、ヘキシルなどなどを含むが、これらに限定されない。 Unless otherwise defined, the term "C 1-6 alkyl" refers to a saturated hydrocarbon group composed of 1 to 6 carbon atoms in a straight or branched chain. The C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). Illustrative examples of C 1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, t-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), hexyl, and the like.
別途に定義しない限り、用語「Ｃ１－４アルキル」は直鎖又は分枝鎖の１～４個の炭素
原子で構成された飽和炭化水素基を表す。前記Ｃ１－４アルキルにはＣ１－２、Ｃ１－３とＣ２－３アルキルなどが含まれ、それは１価（例えばメチル）、２価（例えばメチレン）及び多価（例えばメチン）であってもよい。Ｃ１－４アルキルの実例は、メチル（Ｍｅ）、エチル（Ｅｔ）、プロピル（ｎ－プロピル及びイソプロピルを含む）、ブチル（ｎ－ブチル、イソブチル、ｓ－ブチル、ｔ－ブチルを含む）などを含むが、これらに限定されない。
Unless otherwise defined, the term "C 1-4 alkyl" refers to a saturated hydrocarbon group composed of 1 to 4 carbon atoms in a straight or branched chain. Said C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). Illustrative examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.
別途に定義しない限り、用語「Ｃ１－３アルキル」は直鎖又は分枝鎖の１～３個の炭素原子で構成された飽和炭化水素基を表す。前記Ｃ１－３アルキルにはＣ１－２とＣ２－３アルキルなどが含まれ、それは１価（例えばメチル）、２価（例えばメチレン）及び多価（例えばメチン）であってもよい。Ｃ１－３アルキルの実例には、メチル（Ｍｅ）、エチル（Ｅｔ）、プロピル（ｎ－プロピル及びイソプロピルを含む）などが含まれるが、これらに限定されない。 Unless otherwise defined, the term "C 1-3 alkyl" refers to a saturated hydrocarbon group composed of 1 to 3 carbon atoms in a straight or branched chain. Said C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). Illustrative examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
別途に定義しない限り、用語「Ｃ１－３アルコキシ」は1つの酸素原子を介して分子の残り部分に連結した１～３個の炭素原子を含むアルキル基を表す。前記Ｃ１－３アルコキシには、Ｃ１－２、Ｃ２－３、Ｃ３及びＣ２アルコキシなどが含まれる。Ｃ１－３アルコキシの実例には、メトキシ、エトキシ、プロポキシ（ｎ―プロポキシ又はイソプロポキシを含む）などが含まれるが、これらに限定されない。 Unless otherwise defined, the term "C 1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule via an oxygen atom. Said C 1-3 alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, etc. Illustrative examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), etc.
「脱離基」という用語は、別の官能基又は原子で置換反応（例えば、求核置換反応）によって置換されてもよい官能基又は原子を指す。例えば、代表的な脱離基は、トリフルオロメタンスルホネート；塩素、臭素、ヨウ素；メシレート、トシレート、ｐ－ブロモベンゼンスルホネート、ｐ－トルエンスルホネートなどのスルホン酸；アセトキシ、トリフルオロアセトキシなどのアシルオキシなどを含む。 The term "leaving group" refers to a functional group or atom that may be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonic acids such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate; acyloxy such as acetoxy, trifluoroacetoxy, and the like.
「保護基」という用語は、「アミノ保護基」、「ヒドロキシ保護基」又は「メルカプト保護基」を含むが、これらに限定されない。「アミノ保護基」という用語は、アミノの窒素上の副反応を防止するのに適した保護基を指す。代表的なアミノ酸保護基は、ホルミル；アルカノイル（例えばアセチル、トリクロロアセチル又はトリフルオロアセチル）などのアシル；ｔｅｒｔ－ブトキシカルボニル（Ｂｏｃ）などのアルコキシカルボニル；ベンジルオキシカルボニル（Ｃｂｚ）及び９－フルオレニルメトキシカルボニル（Ｆｍｏｃ）などのアリールメトキシカルボニル；ベンジル（Ｂｎ）、トリチル（Ｔｒ）、１，１－ビス－（４’－メトキシフェニル）メチルなどのアリールメチル；トリメチルシリル（ＴＭＳ）及びｔｅｒｔ－ブチルジメチルシリル（ＴＢＳ）などのシリルなどを含むが、これらに限定されない。「ヒドロキシル保護基」という用語は、ヒドロキシル上の副反応を防止するのに適した保護基を指す。代表的なヒドロキシル保護基は、メチル、エチル及びｔｅｒｔ－ブチルなどのアルキル、アルカノイル（例えば、アセチル）などのアシル、ベンジル（Ｂｎ）、ｐ－メトキシベンジル（ＰＭＢ）、９－フルオレニルメチル（Ｆｍ）及びジフェニルメチル（ベンズヒドリル、ＤＰＭ）などのアリールメチル、トリメチルシリル（ＴＭＳ）及びｔｅｒｔ－ブチルジメチルシリル（ＴＢＳ）などのシリルなどを含むが、これらに限定されない。 The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions on the amino nitrogen. Representative amino acid protecting groups include, but are not limited to, formyl; acyl such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS). The term "hydroxyl protecting group" refers to a protecting group suitable for preventing side reactions on hydroxyl. Representative hydroxyl protecting groups include, but are not limited to, alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS).
本発明の化合物は、以下に列挙する特定の実施形態、それらを他の化学合成法と組み合わせることによって形成される実施形態、及び当業者に周知の等価置換形態を含む、当業者に周知の様々な合成方法によって製造することができ、好ましい実施形態には、本発明の実施例が含まれるが、これらに限定されない。 The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitution forms known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.
本発明の化合物の構造は、当業者に周知の従来の方法によって確認することができ、本発明が化合物の絶対配置に関する場合、この絶対配置は、当業者の従来の技術的手段によ
って確認することができる。例えば、単結晶Ｘ線回折（ＳＸＲＤ）の場合、培養した単結晶をＢｒｕｋｅｒ Ｄ８ ｖｅｎｔｕｒｅ回折計によって回折強度データを収集し、光源はＣｕＫα放射線であり、走査方法：φ／ω走査、更に直接法（Ｓｈｅｌｘｓ９７）で結晶構造解析して、絶対配置を確認できる。
The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art, and when the present invention relates to the absolute configuration of the compound, this absolute configuration can be confirmed by conventional technical means of those skilled in the art.For example, in the case of single crystal X-ray diffraction (SXRD), the diffraction intensity data of the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ/ω scanning, and the crystal structure is analyzed by direct method (Shelxs97) to confirm the absolute configuration.
本発明に使用されたすべての溶媒は市販品から得ることができる。
本発明は下記の略語を使用する。ＤＭＦはＮ，Ｎ－ジメチルホルムアミドを表し；Ｋ２ＣＯ３は炭酸カリウムを表し；ＭｅＩはヨードメタンを表し；ＥｔＯＡｃは酢酸エチルを表し；ＥＡは酢酸エチルを表し；ＴＨＦはテトラヒドロフランを表し；ＮａＨＭＤＳはヘキサメチルジシラザンナトリウムを表し；ＭｅＯＨはメタノールを表し；ＤＣＭはジクロロメタンを表し；ＤＭＳＯはジメチルスルホキシドを表し；ＰＥは石油エーテルを表し；ＥｔＯＨはエタノールを表し；ＡＣＮはアセトニトリルを表し；ＴＦＡはトリフルオロ酢酸を表し；ＦＡはギ酸を表し；ＮＨ３・Ｈ２Ｏはアンモニア水を表し；ＴＥＡはトリエチルアミンを表し；ＤＩＰＥＡはＮ，Ｎ－ジイソプロピルエチルアミンを表し；Ｂｏｃ２Ｏは二炭酸ジ－ｔｅｒｔ－ブチルを表し；Ｂｏｃはｔｅｒｔ－ブトキシカルボニルを表し、アミノの保護基であり；ＥＤＣＩは１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩を表し；ＣＤＩはＮ，Ｎ’－カルボニルジイミダゾールを表し；ＤＤＱは２，３－ジクロロ－５，６－ジシアノ－ｐ－ベンゾキノンを表し；ＬＣＭＳは液体クロマトグラフィー－質量クロマトグラフィーを表し；ＨＰＬＣは高速液体クロマトグラフィーを表し；ＴＬＣは薄層クロマトグラフィーを表し；ＭＥＣは最小有効濃度を表し；ＬｎＣａｐは前立腺癌細胞を表し；ｓＧＣは可溶性グアニル酸シクラーゼを表し；ｃＧＭＰは環状グアノシン一リン酸を表す。
All solvents used in this invention can be obtained commercially.
The present invention uses the following abbreviations: DMF stands for N,N-dimethylformamide; K 2 CO 3 stands for potassium carbonate; MeI stands for iodomethane; EtOAc stands for ethyl acetate; EA stands for ethyl acetate; THF stands for tetrahydrofuran; NaHMDS stands for sodium hexamethyldisilazane; MeOH stands for methanol; DCM stands for dichloromethane; DMSO stands for dimethylsulfoxide; PE stands for petroleum ether; EtOH stands for ethanol; ACN stands for acetonitrile; TFA stands for trifluoroacetic acid; FA stands for formic acid; NH 3.H 2 O stands for aqueous ammonia; TEA stands for triethylamine; DIPEA stands for N,N-diisopropylethylamine; Boc 2 O stands for di-tert-butyl dicarbonate; Boc stands for tert-butoxycarbonyl, an amino protecting group; EDCI stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; CDI stands for N,N'-carbonyldiimidazole; DDQ stands for 2,3-dichloro-5,6-dicyano-p-benzoquinone; LCMS stands for liquid chromatography-mass chromatography; HPLC stands for high performance liquid chromatography; TLC stands for thin layer chromatography; MEC stands for minimum effective concentration; LnCap stands for prostate cancer cells; sGC stands for soluble guanylate cyclase; cGMP stands for cyclic guanosine monophosphate.
化合物は、当分野の通常の命名原則に従って、又はＣｈｅｍＤｒａｗ（登録商標）ソフトウェアを使用して命名され、市販の化合物はサプライヤーのカタログで命名される。 Compounds are named according to conventional naming principles in the art or using ChemDraw® software; commercially available compounds are named in the supplier's catalogue.
以下、実施例によって本発明を具体的に説明するが、本発明の不利な制限を意味するものではない。本発明は本明細書で詳細に説明されており、その特定の実施形態も開示されており、当業者にとって、本発明の精神および範囲から逸脱することなく、本発明の特定の実施形態において様々な変更及び修正を行うことができることは明らかである。 The present invention will be described in detail below with reference to examples, but this is not intended to impose any adverse restrictions on the present invention. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is clear to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
実施例１
合成スキーム：
Example 1
Synthesis scheme:
ステップＡ：１－１（２ｇ、１２．６１ｍｍｏｌ、１ｅｑ）のトルエン（２０ｍＬ）溶液に２－フルオロベンジルアミン（１．８９ｇ、１５．１４ｍｍｏｌ、１．７２ｍＬ、１．２ｅｑ）及び炭酸セシウム（６．１７ｇ、１８．９２ｍｍｏｌ、１．５ｅｑ）を加えた。窒素ガスで置換し、窒素ガスの保護下で、８０℃で１２時間撹拌した。反応溶液に水（２０ｍＬ）を加え、ＥｔＯＡｃ（３０ｍＬ）で抽出し、有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝５０：１～２０：１）により精製し、得られた粗生成物を石油エーテル（１０ｍＬ）で撹拌し、濾過して乾燥させた後化合物１－ａを得た。 Step A: 2-fluorobenzylamine (1.89 g, 15.14 mmol, 1.72 mL, 1.2 eq) and cesium carbonate (6.17 g, 18.92 mmol, 1.5 eq) were added to a solution of 1-1 (2 g, 12.61 mmol, 1 eq) in toluene (20 mL). The mixture was replaced with nitrogen gas and stirred at 80°C for 12 hours under nitrogen gas protection. Water (20 mL) was added to the reaction solution, extracted with EtOAc (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EtOAc = 50: 1 to 20: 1), and the resulting crude product was stirred with petroleum ether (10 mL), filtered and dried to obtain compound 1-a.
ステップＢ：１－ａ（２．５ｇ、７．７０ｍｍｏｌ、１ｅｑ）のＥｔＯＨ（２０ｍＬ）及び水（５ｍＬ）の混合物に還元鉄粉末（３．４４ｇ、６１．５６ｍｍｏｌ、８ｅｑ）及びＮＨ４Ｃｌ（４．９４ｇ、９２．３５ｍｍｏｌ、３．２３ｍＬ、１２ｅｑ）を加えた。窒素ガスで置換し、７０℃で３時間撹拌し、反応溶液に水（２０ｍＬ）及びＥｔＯＡｃ（５０ｍＬ）を加え、濾過した後分離し、有機相を飽和食塩水（１０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をシリカゲルカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１０：１～５：１）により精製して化合物１－ｂを得た。 Step B: Reduced iron powder (3.44 g, 61.56 mmol, 8 eq) and NH 4 Cl (4.94 g, 92.35 mmol, 3.23 mL, 12 eq) were added to a mixture of 1-a (2.5 g, 7.70 mmol, 1 eq) in EtOH (20 mL) and water (5 mL). The mixture was purged with nitrogen gas and stirred at 70° C. for 3 hours. Water (20 mL) and EtOAc (50 mL) were added to the reaction solution, which was then filtered and separated. The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to obtain compound 1-b.
ステップＣ：１－ｂ（１．１ｇ、３．９３ｍｍｏｌ、１ｅｑ）のＴＨＦ（５０．００ｍＬ）溶液にＣＤＩ（９５５．６９ｍｇ、５．８９ｍｍｏｌ、１．５ｅｑ）をゆっくりと加えた。添加完了後、混合物を７０℃で１２時間撹拌した。反応溶液を濃縮し、残留物をシリカゲルカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝４：１～２：１）により精製して化合物１－ｃを得た。 Step C: CDI (955.69 mg, 5.89 mmol, 1.5 eq) was slowly added to a solution of 1-b (1.1 g, 3.93 mmol, 1 eq) in THF (50.00 mL). After the addition was complete, the mixture was stirred at 70 °C for 12 h. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE: EtOAc = 4: 1 to 2: 1) to obtain compound 1-c.
ステップＤ：３０℃で、１－２（５．０ｇ、２８．８９ｍｍｏｌ、１ｅｑ）のオキシ塩化リン（４９．５０ｇ、３２２．８３ｍｍｏｌ、３０．００ｍＬ、１１．１８ｅｑ）溶液に２，６－ルチジン（１３．８０ｇ、１２８．７９ｍｍｏｌ、１５．００ｍＬ、４．４６
ｅｑ）をゆっくりと滴下し、滴下完了後、窒素ガスで３回置換し、反応溶液を８０℃で１２時間撹拌した。反応溶液を３０℃に冷却させ、次に、減圧濃縮して過剰の溶媒を除去し、最後に０～５℃で反応溶液を氷水（１００ｍＬ）にゆっくりと加え、次に、ＰＥ／ＥＡ（１００ｍＬ、１／１）で抽出し、有機相を無水硫酸ナトリウムで乾燥させ、濾過して濃縮し、残留物をシリカゲルカラムクロマトグラフィー（ＰＥ／ＥＡ＝１／０～２０／１）により精製して化合物１－ｆを得た。
Step D: A solution of 1-2 (5.0 g, 28.89 mmol, 1 eq) in phosphorus oxychloride (49.50 g, 322.83 mmol, 30.00 mL, 11.18 eq) at 30 °C was added 2,6-lutidine (13.80 g, 128.79 mmol, 15.00 mL, 4.46
eq) was slowly added dropwise, and after completion of the addition, the atmosphere was replaced with nitrogen gas three times, and the reaction solution was stirred at 80° C. for 12 hours. The reaction solution was cooled to 30° C., then concentrated under reduced pressure to remove excess solvent, and finally the reaction solution was slowly added to ice water (100 mL) at 0-5° C., then extracted with PE/EA (100 mL, 1/1), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE/EA=1/0-20/1) to obtain compound 1-f.
ステップＥ：－２０℃で、化合物１－ｆ（３．３ｇ、１４．４５ｍｍｏｌ、１ｅｑ）のエタノール（２０ｍＬ）溶液にＮＨ３のエタノール溶液（２０ｍＬ）を加え、反応溶液を－２０℃で５０分間撹拌し、反応溶液を濾過し、ケーキを収集し、次に、水（１０ｍＬ）及びエタノール（１０ｍＬ）で洗浄して、化合物１－ｇを得た。 Step E: At −20° C., a solution of NH3 in ethanol (20 mL) was added to a solution of compound 1-f (3.3 g, 14.45 mmol, 1 eq) in ethanol (20 mL), the reaction solution was stirred at −20° C. for 50 min, the reaction solution was filtered, the cake was collected, and then washed with water (10 mL) and ethanol (10 mL) to obtain compound 1-g.
ステップＦ：１－ｃ（２００ｍｇ、８００．８７μｍｏｌ、１ｅｑ）のＤＭＦ（１．００ｍＬ）溶液に１－ｇ（４０３．７６ｍｇ、８００．８７μｍｏｌ、１．０ｅｑ）、炭酸セシウム（５２１．８８ｍｇ、１．６０ｍｍｏｌ、２ｅｑ）、ヨウ化第一銅（１５．２５ｍｇ、８０．０９μｍｏｌ、０．１０ｅｑ）及び１，１０－フェナントロリン（２８．８６ｍｇ、１６０．１７μｍｏｌ、０．２ｅｑ）を加えた。窒素ガスで置換し、９０℃で３時間撹拌し、反応溶液に水（２０ｍＬ）を加え、ＥｔＯＡｃ（５０ｍＬ×２）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮して化合物１－ｄを得た。 Step F: 1-g (403.76 mg, 800.87 μmol, 1.0 eq), cesium carbonate (521.88 mg, 1.60 mmol, 2 eq), cuprous iodide (15.25 mg, 80.09 μmol, 0.10 eq) and 1,10-phenanthroline (28.86 mg, 160.17 μmol, 0.2 eq) were added to a solution of 1-c (200 mg, 800.87 μmol, 1 eq) in DMF (1.00 mL). The mixture was replaced with nitrogen gas and stirred at 90°C for 3 hours. Water (20 mL) was added to the reaction solution, which was then extracted with EtOAc (50 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 1-d.
ステップＧ：１－ｄ（３００ｍｇ、７５６．９４μｍｏｌ、１ｅｑ）のＭｅＯＨ（９ｍＬ）及び水（３ｍＬ）の混合物に還元鉄粉末（８４５．４２ｍｇ、１５．１４ｍｍｏｌ、２０ｅｑ）及びＮＨ４Ｃｌ（８０９．７９ｍｇ、１５．１４ｍｍｏｌ、２０ｅｑ）を加えた。窒素ガスで置換し、７０℃で２時間撹拌し、反応溶液に水（１０ｍＬ）を加え、ＥｔＯＡｃ（２５ｍＬ×２）で抽出し、合わせた有機相を飽和食塩水（１０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物を薄層クロマトグラフィー（ＤＣＭ：ＭｅＯＨ＝１０：１）により精製して化合物１－ｅを得た。 Step G: Reduced iron powder (845.42 mg, 15.14 mmol, 20 eq) and NH 4 Cl (809.79 mg, 15.14 mmol, 20 eq) were added to a mixture of 1-d (300 mg, 756.94 μmol, 1 eq) in MeOH (9 mL) and water (3 mL). The mixture was purged with nitrogen gas and stirred at 70° C. for 2 hours. Water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (25 mL×2). The combined organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 1-e.
ステップＨ：０℃で、１－ｅ（１２０ｍｇ、２９３．８２μｍｏｌ、１ｅｑ）のピリジン（１．５ｍＬ）溶液にクロロギ酸メチル（４１．６５ｍｇ、４４０．７２μｍｏｌ、３４．１４μＬ、１．５ｅｑ）を加え、０℃で３０分間撹拌し、反応溶液に水（１０ｍＬ）を加え、ＥｔＯＡｃ（５０ｍＬ）で抽出し、有機相を飽和食塩水（１０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物にＥｔＯＡｃ（１０ｍＬ）を加えて撹拌し、濾過して乾燥させた後化合物１を得た。１Ｈ ＮＭＲ （４００ＭＨｚ，
ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．０８ － ８．０１ （ｍ， ２Ｈ）， ７．９５ （ｂｒ ｓ， １Ｈ）， ７．３５ （ｍ， １Ｈ）， ７．２８ － ７．１９
（ｍ， ２Ｈ）， ７．１８ － ７．０８ （ｍ， ２Ｈ）， ６．３３ （ｂｒ ｓ， ４Ｈ）， ５．１５ （ｓ， ２Ｈ）， ３．６２ （ｓ， ３Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４２５．３ ［Ｍ＋１］＋。
Step H: At 0° C., methyl chloroformate (41.65 mg, 440.72 μmol, 34.14 μL, 1.5 eq) was added to a pyridine (1.5 mL) solution of 1-e (120 mg, 293.82 μmol, 1 eq), and the mixture was stirred at 0° C. for 30 minutes. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (50 mL). The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. EtOAc (10 mL) was added to the residue, and the mixture was stirred. After filtering and drying, compound 1 was obtained. 1 H NMR (400 MHz,
DMSO- d6 ): δ ppm 8.08 - 8.01 (m, 2H), 7.95 (br s, 1H), 7.35 (m, 1H), 7.28 - 7.19
(m, 2H), 7.18 - 7.08 (m, 2H), 6.33 (br s, 4H), 5.15 (s, 2H), 3.62 (s, 3H); LCMS (ESI) m/z: 425.3 [M+1] + .
実施例２
合成スキーム：
Example 2
Synthesis scheme:
０℃で、化合物１（５０ｍｇ、１１５．０４μｍｏｌ、１ｅｑ）のＤＭＦ（１ｍＬ）溶液にＮａＨ（６．９０ｍｇ、１７２．５５μｍｏｌ、６０％の純度、１．５ｅｑ）を加え、０℃で１０分間撹拌し、次に、ヨードメタン（２４．４９ｍｇ、１７２．５５μｍｏｌ、１０．７４μＬ、１．５ｅｑ）を加え、得られた混合物を０℃で３０分間撹拌し、反応溶液に水（５ｍＬ）を加え、ＥｔＯＡｃ（１０ｍＬ×２）で抽出し、合わせた有機相を飽和食塩水（５ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物を薄層クロマトグラフィー（ＥｔＯＡｃ）により精製して化合物２を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．０９ － ８．０２ （ｍ， ２Ｈ）， ７．３９ － ７．３０ （ｍ， １Ｈ）， ７．２７ － ７．１９
（ｍ， ２Ｈ）， ７．１８ － ７．０８ （ｍ， ２Ｈ）， ６．５５ （ｂｒ ｓ， ４Ｈ）， ５．１５ （ｓ， ２Ｈ）， ３．６６ （ｓ， １Ｈ）， ３．５５
（ｓ， ２Ｈ）， ３．００ （ｓ， ３Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４３９．３ ［Ｍ＋１］＋。
At 0° C., NaH (6.90 mg, 172.55 μmol, 60% purity, 1.5 eq) was added to a solution of compound 1 (50 mg, 115.04 μmol, 1 eq) in DMF (1 mL), and the mixture was stirred at 0° C. for 10 minutes. Then, iodomethane (24.49 mg, 172.55 μmol, 10.74 μL, 1.5 eq) was added, and the resulting mixture was stirred at 0° C. for 30 minutes. Water (5 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL×2). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (EtOAc) to obtain compound 2. 1H NMR (400MHz, DMSO- d6 ): δ ppm 8.09 - 8.02 (m, 2H), 7.39 - 7.30 (m, 1H), 7.27 - 7.19
(m, 2H), 7.18 - 7.08 (m, 2H), 6.55 (br s, 4H), 5.15 (s, 2H), 3.66 (s, 1H), 3.55
(s, 2H), 3.00 (s, 3H); LCMS (ESI) m/z: 439.3 [M+1] <+ >.
実施例３
合成スキーム：
Example 3
Synthesis scheme:
ステップＡ：窒素ガスの保護下で、化合物３－１（２ｇ、１１．３３ｍｍｏｌ、１ｅｑ
）のトルエン（２０．００ｍＬ）溶液に炭酸セシウム（５．５４ｇ、１６．９９ｍｍｏｌ、１．５ｅｑ）及び２－フルオロベンジルアミン（１．７０ｇ、１３．６０ｍｍｏｌ、１．５５ｍＬ、１．２ｅｑ）を加えた。混合物を８０℃に昇温させて１２時間撹拌した。冷却させた後、水（４０ｍＬ）を加え、ＥｔＯＡｃ（４０ｍＬ）で抽出し、有機相を塩水（４０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝５０：１～５：１）により分離して化合物３－ａを得た。
Step A: Under the protection of nitrogen gas, compound 3-1 (2 g, 11.33 mmol, 1 eq.) was added.
To a solution of 3-(2-fluorobenzylamine) in toluene (20.00 mL) were added cesium carbonate (5.54 g, 16.99 mmol, 1.5 eq) and 2-fluorobenzylamine (1.70 g, 13.60 mmol, 1.55 mL, 1.2 eq). The mixture was heated to 80° C. and stirred for 12 h. After cooling, water (40 mL) was added and extracted with EtOAc (40 mL). The organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (PE:EtOAc=50:1-5:1) to obtain compound 3-a.
ステップＢ：３－ａ（１．５０ｇ、５．６６ｍｍｏｌ、１ｅｑ）のＴＨＦ（２０ｍＬ）及び水（１０ｍＬ）の混合物に還元鉄粉末（１．２６ｇ、２２．６２ｍｍｏｌ、４ｅｑ）及びＮＨ４Ｃｌ（１．５１ｇ、５３．４９ｍｍｏｌ、５ｅｑ）を加えた。窒素ガスで置換し、６０℃で６時間撹拌し、反応溶液を濾過し、ケーキをＥｔＯＡｃ（４０ｍＬ）で洗浄し、濾液に更に飽和食塩水（５０ｍＬ）を加え、ＥｔＯＡｃ（４０ｍＬ）で抽出し、有機相を飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１０：１～４：１）により精製して化合物３－ｂを得た。 Step B: Reduced iron powder (1.26 g, 22.62 mmol, 4 eq) and NH 4 Cl (1.51 g, 53.49 mmol, 5 eq) were added to a mixture of 3-a (1.50 g, 5.66 mmol, 1 eq) in THF (20 mL) and water (10 mL). The mixture was purged with nitrogen gas and stirred at 60° C. for 6 hours. The reaction solution was filtered, the cake was washed with EtOAc (40 mL), and saturated saline (50 mL) was added to the filtrate. The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 10: 1 to 4: 1) to obtain compound 3-b.
ステップＣ：３－ｂ（１．００ｇ、４．２５ｍｍｏｌ、１ｅｑ）のＴＨＦ（２０．００ｍＬ）溶液にＣＤＩ（１．０３ｇ、６．３８ｍｍｏｌ、１．５ｅｑ）をゆっくりと加えた。添加完了後、混合物を７０℃で１２時間撹拌した。反応溶液を濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝５：１～２：１）により精製して化合物３－ｃを得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＣＤＣｌ３）： δ ｐｐｍ ９．９９ （ｂｒ ｓ， １Ｈ）， ７．９６ （ｔ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ７．３３ － ７．２９ （ｍ， １Ｈ）， ７．２８ － ７．２４ （ｍ， １Ｈ）， ７．１６ （ｄｄ， Ｊ＝２．５， ８．０ Ｈｚ， １Ｈ）， ７．１２ － ７．０５ （ｍ， ２Ｈ）， ５．２７ （ｓ， ２Ｈ）。 Step C: To a solution of 3-b (1.00 g, 4.25 mmol, 1 eq) in THF (20.00 mL) was slowly added CDI (1.03 g, 6.38 mmol, 1.5 eq). After the addition was complete, the mixture was stirred at 70° C. for 12 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE:EtOAc=5:1 to 2:1) to give compound 3-c. 1H NMR (400 MHz, CDCl3 ): δ ppm 9.99 (br s, 1H), 7.96 (t, J=2.1 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.28 - 7.24 (m, 1H), 7.16 (dd, J=2.5, 8.0 Hz, 1H), 7.12 - 7.05 (m, 2H), 5.27 (s, 2H).
ステップＤ：３－ｃ（１１３ｍｇ、４３２．５７μｍｏｌ、１ｅｑ）のＤＭＦ（４．００ｍＬ）溶液に１－ｇ（２６１．７０ｍｇ、５１９．０９μｍｏｌ、１．０ｅｑ）、炭酸セシウム（２８１．８８ｍｇ、８６５．１５μｍｏｌ、２ｅｑ）、ヨウ化第一銅（８．２４ｍｇ、４３．２６μｍｏｌ、０．１０ｅｑ）及び１，１０－フェナントロリン（１５．５９ｍｇ、８６．５１μｍｏｌ、０．２ｅｑ）を加えた。窒素ガスで置換し、１００℃で３時間撹拌し、反応溶液を冷却させた後、反応溶液に飽和食塩水（２０ｍＬ）を加え、ＥｔＯＡｃ（２０ｍＬ）で抽出し、有機相を飽和食塩水（２０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝５：１～２：１）により化合物３－ｄを得た。 Step D: To a solution of 3-c (113 mg, 432.57 μmol, 1 eq) in DMF (4.00 mL) was added 1-g (261.70 mg, 519.09 μmol, 1.0 eq), cesium carbonate (281.88 mg, 865.15 μmol, 2 eq), cuprous iodide (8.24 mg, 43.26 μmol, 0.10 eq) and 1,10-phenanthroline (15.59 mg, 86.51 μmol, 0.2 eq). The atmosphere was replaced with nitrogen gas, and the reaction solution was stirred at 100°C for 3 hours. After cooling, saturated saline (20 mL) was added to the reaction solution, which was then extracted with EtOAc (20 mL). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 3-d was obtained from the residue by column chromatography (PE: EtOAc = 5: 1 to 2: 1).
ステップＥ：３－ｄ（１２０ｍｇ、２８９．６３μｍｏｌ、１ｅｑ）のＭｅＯＨ（６ｍＬ）及び水（２ｍＬ）の混合物に還元鉄粉末（６４．７０ｍｇ、１．１６ｍｍｏｌ、４ｅｑ）及びＮＨ４Ｃｌ（７７．４６ｍｇ、１．４５ｍｍｏｌ、５ｅｑ）を加えた。窒素ガスで置換し、７０℃で３時間撹拌し、反応溶液を濾過し、ケーキをメタノール（１０ｍＬ）及びジクロロメタン（１０ｍＬ）で洗浄し、濾液に飽和食塩水（１０ｍＬ）を加え、ＤＣＭ（１０ｍＬ）で抽出し、有機相を飽和食塩水（１０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物を薄層クロマトグラフィー（ＤＣＭ：ＭｅＯＨ＝１０：１）により精製して化合物３－ｅを得た。 Step E: Reduced iron powder (64.70 mg, 1.16 mmol, 4 eq) and NH 4 Cl (77.46 mg, 1.45 mmol, 5 eq) were added to a mixture of 3-d (120 mg, 289.63 μmol, 1 eq) in MeOH (6 mL) and water (2 mL). The mixture was purged with nitrogen gas and stirred at 70° C. for 3 hours. The reaction solution was filtered, the cake was washed with methanol (10 mL) and dichloromethane (10 mL), saturated saline (10 mL) was added to the filtrate, and the mixture was extracted with DCM (10 mL). The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 3-e.
ステップＦ：０℃で、３－ｅ（４２ｍｇ、９１．０６μｍｏｌ、１ｅｑ）のピリジン（１．５ｍＬ）溶液にクロロギ酸メチル（１２．９１ｍｇ、１３６．６０μｍｏｌ、１０．５８μＬ、１．５ｅｑ）を加え、０℃で１時間撹拌し、反応溶液を氷水（２０ｍＬ）に注ぎ、飽和食塩水（１０ｍＬ）を加え、ＥｔＯＡｃ（２０ｍＬ）で抽出し、有機相を飽和食
塩水（１０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物３を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．１８
（ｄｄ， Ｊ＝２．５， ９．４ Ｈｚ， １Ｈ）， ８．０７ （ｓ， １Ｈ）， ７．９６ （ｂｒ ｓ， １Ｈ）， ７．４１ － ７．３１ （ｍ， １Ｈ）， ７．３０ － ７．１１ （ｍ， ３Ｈ）， ６．３７ （ｂｒ ｓ， ４Ｈ）， ５．１４
（ｓ， ２Ｈ）， ３．６２ （ｓ， ３Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４４３．１ ［Ｍ＋１］＋。
Step F: At 0° C., methyl chloroformate (12.91 mg, 136.60 μmol, 10.58 μL, 1.5 eq) was added to a solution of 3-e (42 mg, 91.06 μmol, 1 eq) in pyridine (1.5 mL), and the mixture was stirred at 0° C. for 1 hour. The reaction solution was poured into ice water (20 mL), saturated saline (10 mL) was added, and the mixture was extracted with EtOAc (20 mL). The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 3. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 8.18
(dd, J=2.5, 9.4 Hz, 1H), 8.07 (s, 1H), 7.96 (br s, 1H), 7.41 - 7.31 (m, 1H), 7.30 - 7.11 (m, 3H), 6.37 (br s, 4H), 5.14
(s, 2H), 3.62 (s, 3H); LCMS (ESI) m/z: 443.1 [M+1] <+> .
実施例４
合成スキーム：
Example 4
Synthesis scheme:
ステップＡ：窒素ガスの保護下で、３－１（２ｇ、１１．３３ｍｍｏｌ、１ｅｑ）のトルエン（２０．００ｍＬ）溶液に炭酸セシウム（５．５４ｇ、１６．９９ｍｍｏｌ、１．５ｅｑ）及び２－トリフルオロメチルベンジルアミン（２．３８ｇ、１３．６０ｍｍｏｌ、１．５５ｍＬ、１．２ｅｑ）を加えた。混合物を８０℃に昇温させて１２時間撹拌した。冷却させた後、水（４０ｍＬ）を加え、ＥｔＯＡｃ（４０ｍＬ）で抽出し、有機相を塩水（４０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝５０：１～５：１）により分離して化合物４－ａを得た。 Step A: Under the protection of nitrogen gas, cesium carbonate (5.54 g, 16.99 mmol, 1.5 eq) and 2-trifluoromethylbenzylamine (2.38 g, 13.60 mmol, 1.55 mL, 1.2 eq) were added to a solution of 3-1 (2 g, 11.33 mmol, 1 eq) in toluene (20.00 mL). The mixture was heated to 80°C and stirred for 12 hours. After cooling, water (40 mL) was added and extracted with EtOAc (40 mL). The organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EtOAc = 50: 1 to 5: 1) to obtain compound 4-a.
ステップＢ：４－ａ（１．７０ｇ、５．３９ｍｍｏｌ、１ｅｑ）のＴＨＦ（２０ｍＬ）及び水（１０ｍＬ）の混合物に還元鉄粉末（１．２０ｇ、２１．５７ｍｍｏｌ、４ｅｑ）及びＮＨ４Ｃｌ（１．４４ｇ、２６．９７ｍｍｏｌ、５ｅｑ）を加えた。窒素ガスで置換し、６０℃で３時間撹拌し、反応溶液を濾過し、ケーキをＥｔＯＡｃ（４０ｍＬ）で洗浄し、濾液に更に飽和食塩水（６０ｍＬ）を加え、ＥｔＯＡｃ（５０ｍＬ）で抽出し、有機相を飽和食塩水（６０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１０：１～４：１）により精製して化合物４－ｂを得た。 Step B: Reduced iron powder (1.20 g, 21.57 mmol, 4 eq) and NH 4 Cl (1.44 g, 26.97 mmol, 5 eq) were added to a mixture of 4-a (1.70 g, 5.39 mmol, 1 eq) in THF (20 mL) and water (10 mL). The mixture was purged with nitrogen gas and stirred at 60° C. for 3 hours. The reaction solution was filtered, the cake was washed with EtOAc (40 mL), and saturated saline (60 mL) was added to the filtrate. The mixture was extracted with EtOAc (50 mL). The organic phase was washed with saturated saline (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 10: 1 to 4: 1) to obtain compound 4-b.
ステップＣ：４－ｂ（１．２１ｇ、４．２５ｍｍｏｌ、１ｅｑ）のＴＨＦ（２０．００ｍＬ）溶液にＣＤＩ（１．０３ｇ、６．３８ｍｍｏｌ、１．５ｅｑ）をゆっくりと加えた
。添加完了後、混合物を７０℃で１２時間撹拌した。反応溶液を濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝４：１～２：１）により精製して化合物４－ｃを得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ １１．６０ （ｂｒ ｓ， １Ｈ）， ７．９１ （ｔ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．８０ （ｄ， Ｊ＝７．７ Ｈｚ， １Ｈ）， ７．６３ － ７．５３ （ｍ， １Ｈ）， ７．５３ － ７．４０ （ｍ， ２Ｈ）， ７．０２ （ｄ， Ｊ＝７．７ Ｈｚ， １Ｈ）， ５．１９ （ｓ， ２Ｈ）。
Step C: To a solution of 4-b (1.21 g, 4.25 mmol, 1 eq) in THF (20.00 mL) was added CDI (1.03 g, 6.38 mmol, 1.5 eq) slowly. After the addition was complete, the mixture was stirred at 70° C. for 12 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE:EtOAc=4:1 to 2:1) to give compound 4-c. 1H NMR (400 MHz, DMSO- d6 ): δ ppm 11.60 (br s, 1H), 7.91 (t, J=2.0 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.63 - 7.53 (m, 1H), 7.53 - 7.40 (m, 2H), 7.02 (d, J=7.7 Hz, 1H), 5.19 (s, 2H).
ステップＤ：４－ｃ（１４０ｍｇ、４４９．８２μｍｏｌ、１ｅｑ）のＤＭＦ（１．００ｍＬ）溶液に１－ｇ（２２６．７８ｍｇ、４４９．８２μｍｏｌ、１．０ｅｑ）、炭酸セシウム（２９３．１２ｍｇ、８９９．６４μｍｏｌ、２ｅｑ）、ヨウ化第一銅（８．５７ｍｇ、４４．９８μｍｏｌ、０．１０ｅｑ）及び１，１０－フェナントロリン（１６．２１ｍｇ、８９．９６μｍｏｌ、０．２ｅｑ）を加えた。窒素ガスで置換し、１００℃で３時間撹拌し、反応溶液を冷却させた後濾過し、ケーキをＭｅＯＨ（１０ｍＬ）及びＥｔＯＡｃ（１０ｍＬ）で洗浄し、更に濾液に飽和食塩水（２０ｍＬ）を加え、ＥｔＯＡｃ（３０ｍＬ）で抽出し、有機相を飽和食塩水（２０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮して化合物４－ｄを得た。 Step D: To a solution of 4-c (140 mg, 449.82 μmol, 1 eq) in DMF (1.00 mL) was added 1-g (226.78 mg, 449.82 μmol, 1.0 eq), cesium carbonate (293.12 mg, 899.64 μmol, 2 eq), cuprous iodide (8.57 mg, 44.98 μmol, 0.10 eq) and 1,10-phenanthroline (16.21 mg, 89.96 μmol, 0.2 eq). The atmosphere was replaced with nitrogen gas, and the mixture was stirred at 100°C for 3 hours. The reaction solution was cooled and then filtered. The cake was washed with MeOH (10 mL) and EtOAc (10 mL). Saturated saline (20 mL) was added to the filtrate, which was then extracted with EtOAc (30 mL). The organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 4-d.
ステップＥ：４－ｄ（１５０ｍｇ、３２３．０４μｍｏｌ、１ｅｑ）のＭｅＯＨ（９ｍＬ）及び水（３ｍＬ）の混合物に還元鉄粉末（３６０．８４ｍｇ、６．４６ｍｍｏｌ、２０ｅｑ）及びＮＨ４Ｃｌ（３４５．５９ｍｇ、６．４６ｍｍｏｌ、２０ｅｑ）を加えた。窒素ガスで置換し、７０℃で３時間撹拌し、反応溶液を濾過し、ケーキをメタノール（１０ｍＬ）及びＥｔＯＡｃ（１０ｍＬ）で洗浄し、濾液を濃縮した後薄層クロマトグラフィー（ＤＣＭ：ＭｅＯＨ＝１０：１）により精製して化合物４－ｅを得た。 Step E: Reduced iron powder (360.84 mg, 6.46 mmol, 20 eq) and NH 4 Cl (345.59 mg, 6.46 mmol, 20 eq) were added to a mixture of 4-d (150 mg, 323.04 μmol, 1 eq) in MeOH (9 mL) and water (3 mL). The mixture was purged with nitrogen gas and stirred at 70° C. for 3 hours. The reaction solution was filtered, the cake was washed with methanol (10 mL) and EtOAc (10 mL), and the filtrate was concentrated and then purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 4-e.
ステップＦ：０℃で、４－ｅ（３９．５５ｍｇ、９１．０６μｍｏｌ、１ｅｑ）のピリジン（１．０ｍＬ）溶液にクロロギ酸メチル（１２．９１ｍｇ、１３６．６０μｍｏｌ、１０．５８μＬ、１．５ｅｑ）を加え、０℃で１時間撹拌し、反応溶液を氷水（１０ｍＬ）に注ぎ、飽和食塩水（１０ｍＬ）を加え、ＥｔＯＡｃ（５ｍＬ×３）で抽出し、有機相を飽和食塩水（１０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物４を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．１８ （ｄｄ， Ｊ＝２．５， ９．４ Ｈｚ， １Ｈ）， ８．０７ （ｓ， １Ｈ）， ７．９６ （ｂｒ ｓ， １Ｈ）， ７．４１ － ７．３１ （ｍ， １Ｈ）， ７．３０ － ７．１１ （ｍ， ３Ｈ）， ６．３７ （ｂｒ ｓ， ４Ｈ）， ５．１４ （ｓ， ２Ｈ）， ３．６２ （ｂｒ ｓ， ３Ｈ）；ＬＣＭＳ （ＥＳＩ）
ｍ／ｚ： ４９３．１ ［Ｍ＋１］＋。
Step F: At 0° C., methyl chloroformate (12.91 mg, 136.60 μmol, 10.58 μL, 1.5 eq) was added to a solution of 4-e (39.55 mg, 91.06 μmol, 1 eq) in pyridine (1.0 mL), and the mixture was stirred at 0° C. for 1 hour. The reaction solution was poured into ice water (10 mL), saturated saline (10 mL) was added, and the mixture was extracted with EtOAc (5 mL×3). The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 4. 1H NMR (400MHz, DMSO- d6 ): δ ppm 8.18 (dd, J=2.5, 9.4 Hz, 1H), 8.07 (s, 1H), 7.96 (br s, 1H), 7.41 - 7.31 (m, 1H), 7.30 - 7.11 (m, 3H), 6.37 (br s, 4H), 5.14 (s, 2H), 3.62 (br s, 3H); LCMS (ESI)
m/z: 493.1 [M+1] + .
実施例５
合成スキーム：
Example 5
Synthesis scheme:
ステップＡ：－２０℃で、１－ｆ（１．３ｇ、５．６９ｍｍｏｌ、１ｅｑ）のＤＣＭ（１００．００ｍＬ）溶液にｐ－メトキシベンジルアミン（１．５６ｇ、１１．３８ｍｍｏｌ、１．４７ｍＬ、２ｅｑ）のＤＣＭ（１００．００ｍＬ）溶液をゆっくりと加え、混合物を－２０℃で１時間撹拌し、水（５０．００ｍＬ）を加えて洗浄し、有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をＥｔＯＡｃ（１５ｍＬ）で撹拌し、濾過して乾燥させた後化合物５－ｂを得た。 Step A: At -20°C, a solution of p-methoxybenzylamine (1.56 g, 11.38 mmol, 1.47 mL, 2 eq) in DCM (100.00 mL) was slowly added to a solution of 1-f (1.3 g, 5.69 mmol, 1 eq) in DCM (100.00 mL), the mixture was stirred at -20°C for 1 hour, washed with water (50.00 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was stirred with EtOAc (15 mL), filtered and dried to give compound 5-b.
ステップＢ：ＣｏＣｌ２・６Ｈ２Ｏ（１．７１ｇ、７．１９ｍｍｏｌ、０．１ｅｑ）のＴＨＦ（２００．００ｍＬ）及び水（１００．００ｍＬ）溶液に５－２（１０ｇ、７１．８９ｍｍｏｌ、８．００ｍＬ、１ｅｑ）を加え、次に、ＮａＢＨ４（１３．６０ｇ、３５９．４５ｍｍｏｌ、５ｅｑ）をバッチで加え、反応溶液を３０℃で１２時間撹拌し、反応溶液にＮＨ３・Ｈ２Ｏ（２５％、２０ｍＬ）をゆっくりと加え、更に水（１００ｍＬ）を加え、ＥｔＯＡｃ（１００ｍＬ×２）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１０：１～３：１）により分離して化合物５－ｃを得た。 Step B: To a solution of CoCl 2 ·6H 2 O (1.71 g, 7.19 mmol, 0.1 eq) in THF (200.00 mL) and water (100.00 mL), 5-2 (10 g, 71.89 mmol, 8.00 mL, 1 eq) was added, and then NaBH 4 (13.60 g, 359.45 mmol, 5 eq) was added in batches. The reaction solution was stirred at 30 ° C. for 12 hours, NH 3 ·H 2 O (25%, 20 mL) was slowly added to the reaction solution, and water (100 mL) was further added. Extraction was performed with EtOAc (100 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EtOAc = 10: 1 to 3: 1) to obtain compound 5-c.
ステップＣ：５－ｃ（３．６５ｇ、２５．４９ｍｍｏｌ、２．９９ｍＬ、１．５ｅｑ）のトルエン（３０．００ｍＬ）溶液に炭酸セシウム（８．３１ｇ、２５．４９ｍｍｏｌ、１．５ｅｑ）及び３－１（３．０ｇ、１６．９９ｍｍｏｌ、１ｅｑ）を加えた。混合物を８０℃に昇温させて１２時間撹拌し、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１００：１～１０：１）により分離して化合物５－ｄを得た。 Step C: To a solution of 5-c (3.65 g, 25.49 mmol, 2.99 mL, 1.5 eq) in toluene (30.00 mL) was added cesium carbonate (8.31 g, 25.49 mmol, 1.5 eq) and 3-1 (3.0 g, 16.99 mmol, 1 eq). The mixture was heated to 80°C and stirred for 12 hours, filtered and concentrated, and the residue was separated by column chromatography (PE: EtOAc = 100: 1 to 10: 1) to obtain compound 5-d.
ステップＤ：５－ｄ（２．０ｇ、７．０６ｍｍｏｌ、１ｅｑ）のＥｔＯＨ（１００ｍＬ）及び水（５０ｍＬ）の混合物に還元鉄粉末（１．９７ｇ、３５．３０ｍｍｏｌ、５ｅｑ）及びＮＨ４Ｃｌ（１．８９ｇ、３５．３０ｍｍｏｌ、１．２３ｍＬ、５ｅｑ）を加え、７０℃で１時間撹拌し、ＥｔＯＡｃ（１００ｍＬ×３）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１０：１～３：１）により精製して化合物５－ｅを得た。 Step D: To a mixture of 5-d (2.0 g, 7.06 mmol, 1 eq) in EtOH (100 mL) and water (50 mL), reduced iron powder (1.97 g, 35.30 mmol, 5 eq) and NH 4 Cl (1.89 g, 35.30 mmol, 1.23 mL, 5 eq) were added, stirred at 70° C. for 1 h, extracted with EtOAc (100 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EtOAc=10:1-3:1) to give compound 5-e.
ステップＥ：５－ｅ（１．０ｇ、３．９５ｍｍｏｌ、１ｅｑ）のＴＨＦ（１００．００ｍＬ）溶液にＣＤＩ（９６０．５１ｍｇ、５．９２ｍｍｏｌ、１．５ｅｑ）をゆっくりと加えた。添加完了後、混合物を７０℃で２時間撹拌した。反応溶液を濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝２０：１～３：１）により精製して化合物５－ｆを得た。 Step E: CDI (960.51 mg, 5.92 mmol, 1.5 eq) was slowly added to a solution of 5-e (1.0 g, 3.95 mmol, 1 eq) in THF (100.00 mL). After the addition was complete, the mixture was stirred at 70 °C for 2 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE: EtOAc = 20: 1 to 3: 1) to obtain compound 5-f.
ステップＦ：５－ｆ（４５０ｍｇ、１．６１ｍｍｏｌ、１ｅｑ）のＤＭＦ（１０．００ｍＬ）溶液に５－ｂ（１．０４ｇ、２．４２ｍｍｏｌ、１．５ｅｑ）、炭酸セシウム（６３０．１３ｍｇ、１．９３ｍｍｏｌ、１．２ｅｑ）、ヨウ化第一銅（３０．６９ｍｇ、１６１．１６μｍｏｌ、０．１ｅｑ）及び８－ヒドロキシキノリン（２３．３９ｍｇ、１６１．１６μｍｏｌ、２７．８５μＬ、０．１ｅｑ）を加え、窒素ガスで置換し、１００℃で３時間撹拌し、反応溶液に水（５０ｍＬ）を加え、ＥｔＯＡｃ（５０ｍＬ×２）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１０：１～３：１）により精製して化合物５－ｇを得た。 Step F: 5-b (1.04 g, 2.42 mmol, 1.5 eq), cesium carbonate (630.13 mg, 1.93 mmol, 1.2 eq), cuprous iodide (30.69 mg, 161.16 μmol, 0.1 eq) and 8-hydroxyquinoline (23.39 mg, 161.16 μmol, 27.85 μL, 0.1 eq) were added to a solution of 5-f (450 mg, 1.61 mmol, 1 eq) in DMF (10.00 mL), purged with nitrogen gas, stirred at 100°C for 3 hours, added water (50 mL) to the reaction solution, extracted with EtOAc (50 mL x 2), dried the combined organic phase over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE: EtOAc = 10: 1 to 3: 1) to obtain compound 5-g.
ステップＧ：５－ｇ（９００ｍｇ、１．３４ｍｍｏｌ、１ｅｑ）のＤＣＭ（５０．００ｍＬ）及び水（５．００ｍＬ）溶液にＤＤＱ（１．５２ｇ、６．６９ｍｍｏｌ、５ｅｑ）を加え、３０℃で１２時間撹拌し、反応溶液に飽和炭酸水素ナトリウム水溶液（２０ｍＬ）を加え、ＤＣＭ（５０ｍＬ×２）で抽出し、合わせた有機相を水（５０ｍＬ×２）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をＥｔＯＡｃ（１０ｍＬ）と撹拌し、濾過して乾燥させた後化合物５－ｈを得た。 Step G: DDQ (1.52 g, 6.69 mmol, 5 eq) was added to a solution of 5-g (900 mg, 1.34 mmol, 1 eq) in DCM (50.00 mL) and water (5.00 mL), and the mixture was stirred at 30°C for 12 hours. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (50 mL x 2). The combined organic phase was washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was stirred with EtOAc (10 mL), filtered, and dried to obtain compound 5-h.
ステップＨ：５－ｈ（５０ｍｇ、８５．５９μｍｏｌ、１ｅｑ）のＭｅＯＨ（３ｍＬ）及び水（１ｍＬ）の混合物に還元鉄粉末（９５．５９ｍｇ、１．７１ｍｍｏｌ、２０ｅｑ）及びＮＨ４Ｃｌ（９１．５６ｍｇ、１．７１ｍｍｏｌ、２０ｅｑ）を加え、７０℃で１時間撹拌し、冷却させた後反応溶液を濾過し、濾液に水（２０ｍＬ）を加え、ＤＣＭ（２５ｍＬ×２）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮して化合物５－ｉを得た。 Step H: Reduced iron powder (95.59 mg, 1.71 mmol, 20 eq) and NH 4 Cl (91.56 mg, 1.71 mmol, 20 eq) were added to a mixture of 5-h (50 mg, 85.59 μmol, 1 eq) in MeOH (3 mL) and water (1 mL), and the mixture was stirred at 70° C. for 1 hour. After cooling, the reaction solution was filtered, water (20 mL) was added to the filtrate, and the mixture was extracted with DCM (25 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-i.
ステップＩ：０℃で、５－ｉ（２０ｍｇ、４９．７１μｍｏｌ、１ｅｑ）のピリジン（１．０ｍＬ）溶液にクロロギ酸メチル（７．０５ｍｇ、７４．５７μｍｏｌ、５．７８μＬ、１．５ｅｑ）を加え、０℃で３０分間撹拌し、反応溶液に水（１０ｍＬ）を加え、ＥｔＯＡｃ（１０ｍＬ×２）で抽出し、有機相を飽和食塩水（１０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物５を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．２０ （ｄｄ， Ｊ＝２．６， ９．４
Ｈｚ， １Ｈ）， ８．０７ （ｔ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ７．９８ （ｂｒ ｓ， １Ｈ）， ７．４４ － ７．３０ （ｍ， １Ｈ）， ７．２２ － ７．０８ （ｍ， ２Ｈ）， ６．３７ （ｂｒ ｓ， ４Ｈ）， ５．１７ （ｓ， ２Ｈ）， ３．６２ （ｓ， ３Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４６１．１ ［Ｍ＋１］＋。
Step I: At 0° C., methyl chloroformate (7.05 mg, 74.57 μmol, 5.78 μL, 1.5 eq) was added to a solution of 5-i (20 mg, 49.71 μmol, 1 eq) in pyridine (1.0 mL), and the mixture was stirred at 0° C. for 30 minutes. Water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL×2). The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 5. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 8.20 (dd, J=2.6, 9.4
Hz, 1H), 8.07 (t, J=2.1 Hz, 1H), 7.98 (br s, 1H), 7.44-7.30 (m, 1H), 7.22-7.08 (m, 2H), 6.37 (br s, 4H), 5.17 (s, 2H), 3.62 (s, 3H); LCMS (ESI) m/z: 461.1 [M+1] + .
実施例６
合成スキーム：
Example 6
Synthesis scheme:
０℃で、化合物５（１５ｍｇ、３２．５８μｍｏｌ、１ｅｑ）のＤＭＦ（１．００ｍＬ）溶液にＮａＨ（１．９５ｍｇ、４８．８７μｍｏｌ、６０％の純度、１．５ｅｑ）を加え、０℃で３０分間撹拌した後ヨードメタン（６．９４ｍｇ、４８．８７μｍｏｌ、３．０４μＬ、１．５ｅｑ）を加え、０℃で３０分間撹拌を続け、反応溶液を水（３０ｍＬ）にゆっくりと注ぎ、次に、ＥｔＯＡｃ（３０ｍＬ×２）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物６を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．４７ （ｂｒ ｓ， １Ｈ）， ８．２２ （ｂｒ ｄｄ， Ｊ＝２．６， ９．４ Ｈｚ， １Ｈ）， ７．４５ － ７．３０ （ｍ， １Ｈ）， ７．２２ － ７．０６ （ｍ， ２Ｈ）， ６．６４ － ６．４９ （ｍ， ４Ｈ）， ５．１７ （ｓ， ２Ｈ）， ３．６６ －３．５５ （ｓ， ３Ｈ）， ３．００ （ｓ， ３Ｈ）。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４７５．１ ［Ｍ＋１］＋。 At 0° C., NaH (1.95 mg, 48.87 μmol, 60% purity, 1.5 eq) was added to a solution of compound 5 (15 mg, 32.58 μmol, 1 eq) in DMF (1.00 mL), and the mixture was stirred at 0° C. for 30 minutes, followed by the addition of iodomethane (6.94 mg, 48.87 μmol, 3.04 μL, 1.5 eq), and stirring was continued at 0° C. for 30 minutes. The reaction solution was slowly poured into water (30 mL), and then extracted with EtOAc (30 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 6. 1H NMR (400 MHz, DMSO- d6 ): δ ppm 8.47 (br s, 1H), 8.22 (br dd, J=2.6, 9.4 Hz, 1H), 7.45-7.30 (m, 1H), 7.22-7.06 (m, 2H), 6.64-6.49 (m, 4H), 5.17 (s, 2H), 3.66-3.55 (s, 3H), 3.00 (s, 3H). LCMS (ESI) m/z: 475.1 [M+1] <+> .
実施例７
合成スキーム：
Example 7
Synthesis scheme:
ステップＡ：窒素ガスの保護下で、３－１（２ｇ、１１．３３ｍｍｏｌ、１ｅｑ）のトルエン（２０．００ｍＬ）溶液にＤＩＰＥＡ（２．２０ｇ、１６．９９ｍｍｏｌ、２．９６ｍＬ、１．５ｅｑ）及び２－クロロベンジルアミン（１．６０ｇ、１１．３３ｍｍｏｌ、１．３７ｍＬ、１ｅｑ）を加えた。混合物を８０℃に昇温させて１７時間撹拌した。冷却させた後、水（２０ｍＬ）を加え、ＥｔＯＡｃ（２０ｍＬ×３）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１００：１～５０：１）により分離して化合物７－ａを得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ｐｐｍ ４．９４ （ｄ， Ｊ＝６．０２ Ｈｚ， ２ Ｈ） ７．１７ － ７．３４ （ｍ， ２ Ｈ） ７．３７ － ７．４７ （ｍ， ２ Ｈ） ８．２２ （ｄｄ， Ｊ＝７．９１， ２．８９
Ｈｚ， １ Ｈ） ８．４０ （ｄ， Ｊ＝２．８９ Ｈｚ， １ Ｈ） ８．４７ － ８．６７ （ｍ， １ Ｈ）。
Step A: Under the protection of nitrogen gas, DIPEA (2.20 g, 16.99 mmol, 2.96 mL, 1.5 eq) and 2-chlorobenzylamine (1.60 g, 11.33 mmol, 1.37 mL, 1 eq) were added to a solution of 3-1 (2 g, 11.33 mmol, 1 eq) in toluene (20.00 mL). The mixture was heated to 80° C. and stirred for 17 hours. After cooling, water (20 mL) was added and extracted with EtOAc (20 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (PE: EtOAc = 100: 1 to 50: 1) to obtain compound 7-a. 1H NMR (400 MHz, CDCl3 ) δ ppm 4.94 (d, J=6.02 Hz, 2H) 7.17 - 7.34 (m, 2H) 7.37 - 7.47 (m, 2H) 8.22 (dd, J=7.91, 2.89
Hz, 1 H) 8.40 (d, J=2.89 Hz, 1 H) 8.47 - 8.67 (m, 1 H).
ステップＢ：７－ａ（３．１３ｇ、８．０１ｍｍｏｌ、１ｅｑ）のＴＨＦ（４５ｍＬ）及び水（１５ｍＬ）の混合物に還元鉄粉末（２．２４ｇ、４０．０３ｍｍｏｌ、５ｅｑ）及びＮＨ４Ｃｌ（１．７１ｇ、３２．０２ｍｍｏｌ、１．１２ｍＬ、４ｅｑ）を加えた。窒素ガスで置換し、８０℃で１７時間撹拌し、反応溶液を濾過し、濾液に更に水（８０ｍＬ）を加え、ＥｔＯＡｃ（８０ｍＬ×３）で抽出し、合わせた有機相を飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１００：１～５：１）により精製して化合物７－ｂを得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ７．４４ － ７．３８ （ｍ， １Ｈ）， ７．３５ － ７．３０ （ｍ， １Ｈ），
７．２８ － ７．２４ （ｍ， ２Ｈ）， ７．２２ （ｄ， Ｊ＝２．６ Ｈｚ，
１Ｈ）， ６．６４ （ｄｄ， Ｊ＝２．８， １０．４ Ｈｚ， １Ｈ）， ６．０９ （ｔ， Ｊ＝５．６ Ｈｚ， １Ｈ）， ５．２２ （ｓ， ２Ｈ）， ４．５８ （ｄ， Ｊ＝５．６ Ｈｚ， ２Ｈ）。
Step B: Reduced iron powder (2.24 g, 40.03 mmol, 5 eq) and NH 4 Cl (1.71 g, 32.02 mmol, 1.12 mL, 4 eq) were added to a mixture of 7-a (3.13 g, 8.01 mmol, 1 eq) in THF (45 mL) and water (15 mL). The mixture was purged with nitrogen gas and stirred at 80° C. for 17 hours. The reaction solution was filtered, and water (80 mL) was added to the filtrate. The mixture was extracted with EtOAc (80 mL×3). The combined organic phase was washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (PE: EtOAc = 100: 1 to 5: 1) to obtain compound 7-b. 1H NMR (400 MHz, DMSO- d6 ): δ ppm 7.44 - 7.38 (m, 1H), 7.35 - 7.30 (m, 1H),
7.28 - 7.24 (m, 2H), 7.22 (d, J=2.6 Hz,
1H), 6.64 (dd, J=2.8, 10.4 Hz, 1H), 6.09 (t, J=5.6 Hz, 1H), 5.22 (s, 2H), 4.58 (d, J=5.6 Hz, 2H).
ステップＣ：７－ｂ（１．１６ｇ、３．７５ｍｍｏｌ、１ｅｑ）のＴＨＦ（３０．００ｍＬ）溶液にＣＤＩ（９１１．３７ｍｇ、５．６２ｍｍｏｌ、１．５ｅｑ）をゆっくりと加えた。添加完了後、混合物を７５℃で４時間撹拌した。反応溶液を濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝２０：１～４：１）により精製して化合物
７－ｃを得た。
Step C: To a solution of 7-b (1.16 g, 3.75 mmol, 1 eq) in THF (30.00 mL) was slowly added CDI (911.37 mg, 5.62 mmol, 1.5 eq). After the addition was complete, the mixture was stirred at 75° C. for 4 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE:EtOAc=20:1 to 4:1) to give compound 7-c.
ステップＤ：７－ｃ（０．３ｇ、１．０８ｍｍｏｌ、１ｅｑ）のＤＭＦ（５．００ｍＬ）溶液に１－ｇ（２４５．７６ｍｇ、１．３０ｍｍｏｌ、１．２ｅｑ）、炭酸セシウム（７０４．０１ｍｇ、２．１６ｍｍｏｌ、２．０ｅｑ）、ヨウ化第一銅（２０．５８ｍｇ、１０８．０４μｍｏｌ、０．１ｅｑ）及び１，１０－フェナントロリン（３８．９４ｍｇ、２１６．０８μｍｏｌ、０．２ｅｑ）を加えた。窒素ガスで置換し、９０℃で３時間撹拌し、反応溶液を冷却させた後濾過し、濾液に水（１０ｍＬ）を加え、ＤＣＭ：ＭｅＯＨ＝５：１（１０ｍＬ×４）で抽出し、合わせた有機相を飽和食塩水（１０ｍＬ×３）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮して化合物７－ｄを得た。 Step D: 1-g (245.76 mg, 1.30 mmol, 1.2 eq), cesium carbonate (704.01 mg, 2.16 mmol, 2.0 eq), cuprous iodide (20.58 mg, 108.04 μmol, 0.1 eq) and 1,10-phenanthroline (38.94 mg, 216.08 μmol, 0.2 eq) were added to a solution of 7-c (0.3 g, 1.08 mmol, 1 eq) in DMF (5.00 mL). The mixture was replaced with nitrogen gas and stirred at 90°C for 3 hours. The reaction solution was cooled and then filtered. Water (10 mL) was added to the filtrate, and the mixture was extracted with DCM:MeOH = 5:1 (10 mL x 4). The combined organic phase was washed with saturated saline (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 7-d.
ステップＥ：７－ｄ（２７６．００ｍｇ、６４０．７０μｍｏｌ、１ｅｑ）のＭｅＯＨ（８ｍＬ）及び水（２ｍＬ）の混合物に還元鉄粉末（７１５．６０ｍｇ、１２．８１ｍｍｏｌ、２０ｅｑ）及びＮＨ４Ｃｌ（６８５．４４ｍｇ、１２．８１ｍｍｏｌ、４４８．００μＬ、２０ｅｑ）を加え、７５℃で１．５時間撹拌し、冷却させた後反応溶液を濾過し、濾液を濃縮した後水（１０ｍＬ）を加え、ＤＣＭ：ＭｅＯＨ＝１０：１（１０ｍｌ×３）で抽出し、合わせた有機相を飽和食塩水（１０ｍＬ×２）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮した後残留物を薄層クロマトグラフィー（ＤＣＭ：ＭｅＯＨ＝１０：１）により精製して化合物７－ｅを得た。 Step E: Reduced iron powder (715.60 mg, 12.81 mmol, 20 eq) and NH 4 Cl (685.44 mg, 12.81 mmol, 448.00 μL, 20 eq) were added to a mixture of 7-d (276.00 mg, 640.70 μmol, 1 eq) in MeOH (8 mL) and water (2 mL), and the mixture was stirred at 75° C. for 1.5 hours. After cooling, the reaction solution was filtered, the filtrate was concentrated, and then water (10 mL) was added. The mixture was extracted with DCM:MeOH=10:1 (10 ml×3). The combined organic phase was washed with saturated saline (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 7-e.
ステップＦ：０℃で、７－ｅ（２０ｍｇ、４９．９０μｍｏｌ、１ｅｑ）のピリジン（１．０ｍＬ）溶液にクロロギ酸メチル（４．７２ｍｇ、４９．９５μｍｏｌ、３．８７μＬ、１．００ｅｑ）を加え、０℃で３０分間撹拌し、反応溶液を水（１ｍＬ）に注ぎ、ＥｔＯＡｃ（２ｍＬ×３）で抽出し、無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物７を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ８．２３ （ｄｄ， Ｊ＝９．４７， ２．５７ Ｈｚ， １ Ｈ）， ７．９８ － ８．１４ （ｍ， １ Ｈ）， ７．９６ （ｂｒ ｓ， １ Ｈ）， ７．５１ （ｄｄ， Ｊ＝７．８４， １．３２ Ｈｚ， １ Ｈ）， ７．１９ － ７．４３ （ｍ，
２ Ｈ）， ７．０８ （ｄ， Ｊ＝６．４０ Ｈｚ， １ Ｈ）， ６．３７ （ｂｒ ｓ， ４ Ｈ）， ５．１５ （ｓ， ２ Ｈ）， ３．６２ （ｂｒ ｓ， ３ Ｈ） ；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４５９．０ ［Ｍ＋１］＋。
Step F: At 0° C., methyl chloroformate (4.72 mg, 49.95 μmol, 3.87 μL, 1.00 eq) was added to a solution of 7-e (20 mg, 49.90 μmol, 1 eq) in pyridine (1.0 mL), stirred at 0° C. for 30 minutes, poured into water (1 mL), extracted with EtOAc (2 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 7. 1H NMR (400 MHz, DMSO- d6 ) δ ppm 8.23 (dd, J=9.47, 2.57 Hz, 1H), 7.98-8.14 (m, 1H), 7.96 (br s, 1H), 7.51 (dd, J=7.84, 1.32 Hz, 1H), 7.19-7.43 (m,
2H), 7.08 (d, J=6.40 Hz, 1H), 6.37 (br s, 4H), 5.15 (s, 2H), 3.62 (br s, 3H); LCMS (ESI) m/z: 459.0 [M+1] <+ >.
実施例８
合成スキーム：
Example 8
Synthesis scheme:
ステップＡ：３－ｅ（４０ｍｇ、１０４．０６μｍｏｌ、１ｅｑ）のＤＭＦ（１ｍＬ）溶液に順次にトリフルオロメタンスルホン酸トリフルオロエチル（４８．３１ｍｇ、２０８．１５μｍｏｌ、２．０ｅｑ）及びＤＩＰＥＡ（４０．３５ｍｇ、３１２．２２μｍｏｌ、５４．３８μＬ、３．０ｅｑ）を加えた。混合物を８０℃で１２時間撹拌した。冷却させた後水（２０ｍＬ）を加え、ＥＡ（１０ｍＬ×２）で抽出し、合わせた有機相を飽和食塩水（１０ｍＬ）で洗浄し、有機相を無水硫酸ナトリウムで乾燥させ、濾過して濃縮し、残余物をカラムクロマトグラフィー（ジクロロメタン：メタノール＝１５：１）により精製して化合物８－ａを得た。 Step A: To a solution of 3-e (40 mg, 104.06 μmol, 1 eq) in DMF (1 mL), trifluoroethyl trifluoromethanesulfonate (48.31 mg, 208.15 μmol, 2.0 eq) and DIPEA (40.35 mg, 312.22 μmol, 54.38 μL, 3.0 eq) were added in sequence. The mixture was stirred at 80°C for 12 hours. After cooling, water (20 mL) was added, extracted with EA (10 mL x 2), the combined organic phase was washed with saturated saline (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 15:1) to obtain compound 8-a.
ステップＢ：８－ａ（１５ｍｇ、３２．１６μｍｏｌ、１ｅｑ）のＤＭＦ（１ｍＬ）溶液にＣＤＩ（１０．４３ｍｇ、６４．３３μｍｏｌ、２．０ｅｑ）を加え、混合物を９０℃で６時間撹拌した。反応溶液に飽和食塩水（１０ｍＬ）を加え、ＥＡ（８ｍＬ×２）で抽出し、塩水（１０ｍＬ）で有機相を洗浄し、無水Ｎａ２ＳＯ４で乾燥させ、濾過して濃縮し、残余物を得た。残余物を分取ＨＰＬＣ［移動相：水（１０ｍＭのＮＨ４ＨＣＯ３）－ＡＣＮ］により精製して化合物８を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．１９ （ｄｄ， Ｊ＝２．４， ９．３ Ｈｚ， １Ｈ）， ８．１０ （ｄ， Ｊ＝１．９ Ｈｚ， １Ｈ）， ７．４０ － ７．２６ （ｍ， １Ｈ）， ７．２６ － ７．１９ （ｍ， １Ｈ）， ７．２６ － ７．１９ （ｍ， １Ｈ）， ７．１８ － ７．１２ （ｍ， １Ｈ）， ７．４３ － ７．１２ （ｍ， １Ｈ）， ７．１２ － ７．０４ （ｍ， １Ｈ）， ７．０９ （ｂｒ
ｓ， １Ｈ）， ５．１６ （ｓ， ２Ｈ）， ４．９１ （ｑ， Ｊ＝９．０ Ｈｚ， ２Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４９３．１ ［Ｍ＋１］＋。
Step B: To a solution of 8-a (15 mg, 32.16 μmol, 1 eq) in DMF (1 mL) was added CDI (10.43 mg, 64.33 μmol, 2.0 eq), and the mixture was stirred at 90° C. for 6 h. Saturated brine (10 mL) was added to the reaction solution, which was extracted with EA (8 mL×2), and the organic phase was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the residue. The residue was purified by preparative HPLC [mobile phase: water (10 mM NH 4 HCO 3 )-ACN] to give compound 8. 1H NMR (400MHz, DMSO- d6 ): δ ppm 8.19 (dd, J=2.4, 9.3 Hz, 1H), 8.10 (d, J=1.9 Hz, 1H), 7.40 - 7.26 (m, 1H), 7.26 - 7.19 (m, 1H), 7.26 - 7.19 (m, 1H), 7.18 - 7.12 (m, 1H), 7.43 - 7.12 (m, 1H), 7.12 - 7.04 (m, 1H), 7.09 (br
s, 1H), 5.16 (s, 2H), 4.91 (q, J=9.0 Hz, 2H); LCMS (ESI) m/z: 493.1 [M+1] <+> .
実施例９
合成スキーム：
Example 9
Synthesis scheme:
ステップＡ：アンモニア水（３．６４ｇ、１０３．８６ｍｍｏｌ、４．００ｍＬ、４．０３ｅｑ）及びジイソプロピルエチルアミン（５．００ｇ、３８．６６ｍｍｏｌ、６．７３ｍＬ、１．５ｅｑ）をジクロロメタン（８０ｍＬ）に溶解させて溶液１を得、９－１（５ｇ、２５．７８ｍｍｏｌ、１ｅｑ）をジクロロメタン（１５ｍＬ）溶液に溶解させて溶液２を得、０℃の条件下で、溶液１を溶液２にゆっくりと滴下し、０℃で１時間撹拌し、反応溶液を濾過して化合物９－ａを得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．５７ （ｂｒ ｓ， １ Ｈ） ９．０１ （ｓ， １ Ｈ） ９．１９ （ｂｒ ｓ， １ Ｈ）。 Step A: Ammonia water (3.64 g, 103.86 mmol, 4.00 mL, 4.03 eq) and diisopropylethylamine (5.00 g, 38.66 mmol, 6.73 mL, 1.5 eq) were dissolved in dichloromethane (80 mL) to obtain solution 1, 9-1 (5 g, 25.78 mmol, 1 eq) was dissolved in dichloromethane (15 mL) to obtain solution 2, and solution 1 was slowly added dropwise to solution 2 under the condition of 0° C., and the mixture was stirred at 0° C. for 1 hour, and the reaction solution was filtered to obtain compound 9-a. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 8.57 (br s, 1 H) 9.01 (s, 1 H) 9.19 (br s, 1 H).
ステップＢ：９－ａ（０．２ｇ、１．１５ｍｍｏｌ、１．２ｅｑ）、化合物３－ｃ（２
４９．４４ｍｇ、９５４．８６μｍｏｌ、１ｅｑ）及び無水炭酸カリウム（２６３．９４ｍｇ、１．９１ｍｍｏｌ、２ｅｑ）をＤＭＦ（５ｍＬ）に溶解させ、窒素ガスで３回置換し、２５℃で２時間撹拌した。反応溶液を４０ｍＬの水に滴下し、１５分間撹拌し、次に、濾過して化合物９－ｂを得た。
Step B: 9-a (0.2 g, 1.15 mmol, 1.2 eq), compound 3-c (2
Compound 9-b (49.44 mg, 954.86 μmol, 1 eq) and anhydrous potassium carbonate (263.94 mg, 1.91 mmol, 2 eq) were dissolved in DMF (5 mL), purged with nitrogen gas three times, and stirred for 2 hours at 25° C. The reaction solution was added dropwise to 40 mL of water, stirred for 15 minutes, and then filtered to obtain compound 9-b.
ステップＣ：化合物９－ｂ（４００ｍｇ、８７９．５２μｍｏｌ、１ｅｑ）をＭｅＯＨ（９ｍＬ）及びＨ２Ｏ（３ｍＬ）に溶解させ、当該溶液にＦｅ（９８２．３３ｍｇ、１７．５９ｍｍｏｌ、２０ｅｑ）及びＮＨ４Ｃｌ（９４０．９３ｍｇ、１７．５９ｍｍｏｌ、６１４．９９μＬ、２０ｅｑ）を加え、７５℃で１時間撹拌した。反応溶液を２５℃に冷却させ、珪藻土で濾過し、濾液を濃縮した後、薄層クロマトグラフィー（ＤＣＭ：ＭｅＯＨ＝１０：１）により精製して化合物９－ｃを得た。 Step C: Compound 9-b (400 mg, 879.52 μmol, 1 eq) was dissolved in MeOH (9 mL) and H 2 O (3 mL), and Fe (982.33 mg, 17.59 mmol, 20 eq) and NH 4 Cl (940.93 mg, 17.59 mmol, 614.99 μL, 20 eq) were added to the solution and stirred at 75° C. for 1 hour. The reaction solution was cooled to 25° C. and filtered through diatomaceous earth. The filtrate was concentrated and then purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 9-c.
ステップＤ：化合物９－ｃ（４５ｍｇ、１２１．８４μｍｏｌ、１ｅｑ）をピリジン（２ｍＬ）に溶解させ、０℃でクロロギ酸メチル（１７．２７ｍｇ、１８２．７６μｍｏｌ、１４．１６μＬ、１．５ｅｑ）を滴下し、当該温度で３０分間撹拌し、反応溶液を２ｍＬの水に滴下し、ＥＡ（３ｍＬ×３）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過し、濾液を減圧濃縮した。残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物９を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ３．６８ （ｓ， ３ Ｈ） ５．１５ （ｓ，
２ Ｈ） ７．０９ － ７．４３ （ｍ， ６ Ｈ） ８．０９ （ｄ， Ｊ＝１．８８ Ｈｚ， １ Ｈ） ８．１６ （ｄｄ， Ｊ＝９．３５， ２．４５ Ｈｚ， １
Ｈ） ８．２８ （ｂｒ ｓ， １ Ｈ） ８．８５ （ｂｒ ｓ， １ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４２８．０ ［Ｍ＋１］＋。
実施例１０
合成スキーム：
Step D: Compound 9-c (45 mg, 121.84 μmol, 1 eq) was dissolved in pyridine (2 mL), and methyl chloroformate (17.27 mg, 182.76 μmol, 14.16 μL, 1.5 eq) was added dropwise at 0° C. and stirred at the temperature for 30 minutes. The reaction solution was added dropwise to 2 mL of water, extracted with EA (3 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 9. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.68 (s, 3 H) 5.15 (s,
2H) 7.09 - 7.43 (m, 6H) 8.09 (d, J = 1.88 Hz, 1H) 8.16 (dd, J = 9.35, 2.45 Hz, 1
1H) 8.28 (br s, 1H) 8.85 (br s, 1H); LCMS (ESI) m/z: 428.0 [M+1] <+> .
Example 10
Synthesis scheme:
ステップＡ：０℃及び窒素ガスの保護下で、化合物３－ｅ（２０３ｍｇ、５１２．３３μｍｏｌ、１ｅｑ）のピリジン（２．０ｍＬ）溶液に化合物１０－１（２１９．７４ｍｇ、１．５４ｍｍｏｌ、１５８．０９μＬ、３ｅｑ）を一回で加え、混合物を０℃で１時間撹拌して反応させ、得られた反応溶液を水（２０ｍＬ）に一滴ずつ加え、次に、酢酸エチル（１０ｍＬ×３）で抽出した。合わせた有機相を飽和食塩水（２０ｍＬ）で洗浄し、無水Ｎａ２ＳＯ４で乾燥させ、濾過し、濾液を減圧濃縮した後、残留物を薄層クロマトグラフィー（ＳｉＯ２、ＤＣＭ／ＭｅＯＨ＝１５／１）により精製して化合物１０－ａの粗生成物を得、当該粗生成物を更に精製せずに次のステップの反応に直接に使用した。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４９１．０ ［Ｍ＋１］＋。 Step A: At 0° C. and under the protection of nitrogen gas, compound 10-1 (219.74 mg, 1.54 mmol, 158.09 μL, 3 eq) was added in one portion to a solution of compound 3-e (203 mg, 512.33 μmol, 1 eq) in pyridine (2.0 mL), and the mixture was stirred and reacted at 0° C. for 1 hour. The resulting reaction solution was added dropwise to water (20 mL), and then extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (SiO 2 , DCM/MeOH=15/1) to obtain the crude product of compound 10-a, which was directly used in the next step reaction without further purification. LCMS (ESI) m/z: 491.0 [M+1] + .
ステップＢ：０℃及び窒素ガスの保護下で、化合物１０－ａ（６５ｍｇ、１３２．４２μｍｏｌ、１ｅｑ）のＴＨＦ（４．０ｍＬ）溶液にＮａＨＭＤＳ（１Ｍ、２６４．８５μＬ、２ｅｑ）を一回で加え、混合物を０℃で１時間反応させた。次に、氷浴（１０ｍＬ）に一滴ずつ加えた後、酢酸エチル（１０ｍＬ×３）で抽出し、合わせた有機相を飽和食塩水（２０ｍＬ）で洗浄し、無水Ｎａ２ＳＯ４で乾燥させ、吸引濾過し、濾液を減圧濃縮した後の残留物を分取ＨＰＬＣ［移動相：水（０．０４％のＮＨ３・Ｈ２Ｏ＋１０ｍＭのＮＨ４ＨＣＯ３）－ＡＣＮ］により精製して化合物１０を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ １１．７７ （ｂｒ ｓ， １Ｈ）， ８．１７ － ８．０５ （ｍ， ２Ｈ）， ７．４０ － ７．２６ （ｍ， ２Ｈ）， ７．２６ － ７．１２ （ｍ， ２Ｈ）， ６．９５ （ｂｒ ｓ， ２Ｈ）， ５．３５ （ｔ， Ｊ＝４．９ Ｈｚ， １Ｈ）， ５．１５ （ｓ， ２Ｈ）， ３．９７
（ｔ， Ｊ＝４．８ Ｈｚ， ２Ｈ）， ３．６８ － ３．５６ （ｍ， ２Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４５５．２ ［Ｍ＋１］＋。
Step B: At 0° C. and under the protection of nitrogen gas, NaHMDS (1M, 264.85 μL, 2 eq) was added in one portion to a solution of compound 10-a (65 mg, 132.42 μmol, 1 eq) in THF (4.0 mL), and the mixture was reacted at 0° C. for 1 hour. Then, it was added dropwise to an ice bath (10 mL), and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated saline (20 mL), dried over anhydrous Na 2 SO 4 , and filtered under suction. The residue after the filtrate was concentrated under reduced pressure was purified by preparative HPLC [mobile phase: water (0.04% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 )-ACN] to obtain compound 10. 1H NMR (400MHz, DMSO- d6 ): δ ppm 11.77 (br s, 1H), 8.17 - 8.05 (m, 2H), 7.40 - 7.26 (m, 2H), 7.26 - 7.12 (m, 2H), 6.95 (br s, 2H), 5.35 (t, J = 4.9 Hz, 1H), 5.15 (s, 2H), 3.97
(t, J=4.8 Hz, 2H), 3.68-3.56 (m, 2H); LCMS (ESI) m/z: 455.2 [M+1] + .
実施例１１
合成スキーム：
Example 11
Synthesis scheme:
化合物９－ｃ（２００ｍｇ、３４９．２８μｍｏｌ、１ｅｑ）をピリジン（２ｍＬ）に溶解させ、０℃で１１－１（５５．８２ｍｇ、５２３．９２μｍｏｌ、１．５ｅｑ）を滴下し、当該温度で３０分間撹拌した。反応完了後、反応溶液を２ｍＬの水に滴下し、ＥＡ（４ｍＬ×３）で抽出し、有機相を減圧濃縮した。残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物１１を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ １．１３ （ｄ， Ｊ＝６．７８ Ｈｚ， ６ Ｈ） ２．６７ （ｑｕｉｎ， Ｊ＝６．７８ Ｈｚ， １ Ｈ） ５．１５
（ｓ， ２ Ｈ） ７．１０ － ７．１８ （ｍ， １ Ｈ） ７．１７ － ７．３９ （ｍ， ５ Ｈ） ８．０９ （ｓ， １ Ｈ） ８．１６ （ｄｄ， Ｊ＝９．２９， ２．３８ Ｈｚ， １ Ｈ） ８．３７ （ｓ， １ Ｈ） ９．３３ （ｓ，
１ Ｈ）。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４４０．１ ［Ｍ＋１］＋。
Compound 9-c (200 mg, 349.28 μmol, 1 eq) was dissolved in pyridine (2 mL), and 11-1 (55.82 mg, 523.92 μmol, 1.5 eq) was added dropwise at 0° C., and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was added dropwise to 2 mL of water, extracted with EA (4 mL×3), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 11. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.13 (d, J=6.78 Hz, 6 H) 2.67 (quin, J=6.78 Hz, 1 H) 5.15
(s, 2H) 7.10 - 7.18 (m, 1H) 7.17 - 7.39 (m, 5H) 8.09 (s, 1H) 8.16 (dd, J=9.29, 2.38 Hz, 1H) 8.37 (s, 1H) 9.33 (s,
1H). LCMS (ESI) m/z: 440.1 [M+1] <+> .
実施例１２
合成スキーム：
Example 12
Synthesis scheme:
化合物９－ｃ（２００ｍｇ、３４９．２８μｍｏｌ、１ｅｑ）をピリジン（２ｍＬ）に溶解させ、０℃で１２－１（７６．８１ｍｇ、５２３．９２μｍｏｌ、６９．８３μＬ、１．５ｅｑ）を滴下し、当該温度で３０分間撹拌した。反応溶液を２ｍＬの水に滴下し、ＥＡ（４ｍＬ×３）で抽出し、有機相を無水硫酸ナトリウムで乾燥させ、濾過し、濾液を減圧濃縮し、残留物を分取ＨＰＬＣ［移動相：水（１０ｍＭのＮＨ４ＨＣＯ３）－ＡＣＮ］により精製して化合物１２を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ １．１５ － １．５６ （ｍ， ３ Ｈ） １．４０ （ｑ， Ｊ＝１２．０５ Ｈｚ， ２ Ｈ） １．６６ （ｂｒ ｄ， Ｊ＝１１．６７ Ｈｚ，
１ Ｈ） １．７６ （ｂｒ ｄ， Ｊ＝１２．６７ Ｈｚ， ２ Ｈ） １．８８ （ｂｒ ｄ， Ｊ＝１１．１７ Ｈｚ， ２ Ｈ） ２．３１ － ２．４３ （ｍ， １ Ｈ） ５．１４ （ｓ， ２ Ｈ） ７．０６ － ７．４３ （ｍ， ６ Ｈ） ８．０９ （ｔ， Ｊ＝２．０７ Ｈｚ， １ Ｈ） ８．１５ （ｄｄ， Ｊ＝９．２２， ２．４５ Ｈｚ， １ Ｈ） ８．３６ （ｓ， １ Ｈ） ９．１５ （ｂｒ ｓ， １ Ｈ）。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４８０．０ ［Ｍ＋１］＋。
Compound 9-c (200 mg, 349.28 μmol, 1 eq) was dissolved in pyridine (2 mL), and 12-1 (76.81 mg, 523.92 μmol, 69.83 μL, 1.5 eq) was added dropwise at 0° C., followed by stirring at the same temperature for 30 minutes. The reaction solution was added dropwise to 2 mL of water, extracted with EA (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (10 mM NH 4 HCO 3 )-ACN] to obtain compound 12. 1H NMR (400 MHz, DMSO- d6 ): δ ppm 1.15 - 1.56 (m, 3H) 1.40 (q, J = 12.05 Hz, 2H) 1.66 (br d, J = 11.67 Hz,
1H) 1.76 (br d, J = 12.67 Hz, 2H) 1.88 (br d, J = 11.17 Hz, 2H) 2.31 - 2.43 (m, 1H) 5.14 (s, 2H) 7.06 - 7.43 (m, 6H) 8.09 (t, J = 2.07 Hz, 1H) 8.15 (dd, J = 9.22, 2.45 Hz, 1H) 8.36 (s, 1H) 9.15 (br s, 1H). LCMS (ESI) m/z: 480.0 [M+1] <+> .
実施例１３
合成スキーム：
Example 13
Synthesis scheme:
化合物９－ｃ（０．０３６ｇ、９４．０６μｍｏｌ、１ｅｑ）をＤＭＦ（１ｍＬ）に溶解させ、ＤＩＥＡ（４８．６３ｍｇ、３７６．２５μｍｏｌ、６５．５４μＬ、４ｅｑ）及び１３－１（２４．００ｍｇ、１０３．４７μｍｏｌ、１２．９７μＬ、１．１ｅｑ）
を加え、得られた混合物を１３０℃で２時間撹拌した。反応溶液を分取ＨＰＬＣ［移動相：水（０．０５％のアンモニア水）－ＡＣＮ］により精製して化合物１３を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．１９ － ８．０６
（ｍ， ２Ｈ）， ７．９９ （ｓ， １Ｈ）， ７．３９ － ７．３２ （ｍ， １Ｈ）， ７．３１ － ７．１９ （ｍ， ２Ｈ）， ７．１８ － ７．１２ （ｍ， １Ｈ）， ５．１５ （ｓ， ２Ｈ）， ３．８３ － ３．７１ （ｍ， ４Ｈ）， ２．９５ － ２．８０ （ｍ， ４Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４４０．２ ［Ｍ＋１］＋。
Compound 9-c (0.036 g, 94.06 μmol, 1 eq) was dissolved in DMF (1 mL) and mixed with DIEA (48.63 mg, 376.25 μmol, 65.54 μL, 4 eq) and 13-1 (24.00 mg, 103.47 μmol, 12.97 μL, 1.1 eq).
was added, and the resulting mixture was stirred at 130° C. for 2 hours. The reaction solution was purified by preparative HPLC [mobile phase: water (0.05% aqueous ammonia)-ACN] to obtain compound 13. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 8.19 - 8.06
(m, 2H), 7.99 (s, 1H), 7.39-7.32 (m, 1H), 7.31-7.19 (m, 2H), 7.18-7.12 (m, 1H), 5.15 (s, 2H), 3.83-3.71 (m, 4H), 2.95-2.80 (m, 4H); LCMS (ESI) m/z: 440.2 [M+1] + .
実施例１４
合成スキーム：
Example 14
Synthesis scheme:
２５℃で、１４－１（０．１５９ｇ、１．０３ｍｍｏｌ、１ｅｑ）をＤＣＭ（１ｍＬ）に溶解させ、塩化オキサリル（１１７．８８ｍｇ、９２８．７０μｍｏｌ、８１．２９μＬ、０．９ｅｑ）及びＤＭＦ（７．５４ｍｇ、１０３．１９μｍｏｌ、７．９４μＬ、０．１ｅｑ）を加え、ガスが放出されなくなるまで撹拌し、当該反応溶液を化合物９－ｃ（１１９．０９ｍｇ、２０６．３８μｍｏｌ、０．２ｅｑ）のＤＣＭ（１ｍＬ）及びピリジン（１ｍＬ）の溶液に滴下し、２５℃で２時間撹拌した。反応溶液に２ｍＬの水を加え、ＤＣＭ（４ｍＬ×３）で抽出し、有機相を無水硫酸ナトリウムで乾燥させ、濾過し、濾液を濃縮した。残留物を分取ＨＰＬＣ［移動相：水（０．０４％のＮＨ３Ｈ２Ｏ）－ＡＣＮ］により精製して化合物１４を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ １．３１ － １．３８ （ｍ， ２ Ｈ） １．６８ （ｂｒ ｓ， ２ Ｈ） ５．１５ （ｓ， ２ Ｈ） ７．１１ － ７．１８ （ｍ， ２ Ｈ）７．１７ － ７．４０ （ｍ， ４ Ｈ） ８．０５ － ８．１２ （ｍ， ２ Ｈ） ８．２２ （ｄｄ， Ｊ＝９．３５， ２．５７ Ｈｚ， １ Ｈ） ９．１０ （ｂｒ ｓ， １ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ５０６．０ ［Ｍ＋１］＋。 At 25° C., 14-1 (0.159 g, 1.03 mmol, 1 eq) was dissolved in DCM (1 mL), oxalyl chloride (117.88 mg, 928.70 μmol, 81.29 μL, 0.9 eq) and DMF (7.54 mg, 103.19 μmol, 7.94 μL, 0.1 eq) were added, and the mixture was stirred until gas was no longer released. The reaction solution was added dropwise to a solution of compound 9-c (119.09 mg, 206.38 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL), and the mixture was stirred for 2 hours at 25° C. 2 mL of water was added to the reaction solution, which was then extracted with DCM (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.04% NH 3 H 2 O)-ACN] to give compound 14. 1H NMR (400 MHz, DMSO- d6 ) δ ppm 1.31 - 1.38 (m, 2H) 1.68 (br s, 2H) 5.15 (s, 2H) 7.11 - 7.18 (m, 2H) 7.17 - 7.40 (m, 4H) 8.05 - 8.12 (m, 2H) 8.22 (dd, J=9.35, 2.57 Hz, 1H) 9.10 (br s, 1H); LCMS (ESI) m/z: 506.0 [M+1] + .
実施例１５
合成スキーム：
Example 15
Synthesis scheme:
ステップＡ：ピリジニウムトリブロミド（ｐｙｒｉｄｉｎｉｕｍ ｔｒｉｂｒｏｍｉｄｅ）（１２．５０ｇ、７．８１ｍｍｏｌ、４ｅｑ）を化合物１５－１（１．５０ｇ、９．７７ｍｍｏｌ、１ｅｑ）のｔｅｒｔ－ブタノール（５４ｍＬ）溶液に加え、２５℃で６時間撹拌した。反応溶液を濾過し、ＥＡ（２０ｍＬ）でケーキを洗浄し、濾液に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。有機相を収集し、飽和食塩水（５０ｍＬ×２）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、残留物をカラムクロマトグラフィー（ＳｉＯ２、ＰＥ：ＥＡ＝５：１～３：１）により精製・分離して化合物１５－ａを得た。 Step A: Pyridinium tribromide (12.50 g, 7.81 mmol, 4 eq) was added to a solution of compound 15-1 (1.50 g, 9.77 mmol, 1 eq) in tert-butanol (54 mL), and the mixture was stirred at 25° C. for 6 hours. The reaction solution was filtered, the cake was washed with EA (20 mL), water (30 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was collected, washed with saturated saline (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified and separated by column chromatography (SiO 2 , PE:EA=5:1-3:1) to obtain compound 15-a.
ステップＢ：化合物１５－ａ（１．５ｇ、４．５８ｍｍｏｌ、１ｅｑ）及び塩化アンモニウム（１．２３ｇ、２２．９１ｍｍｏｌ、５ｅｑ）をテトラヒドロフラン（１６ｍＬ）及び水（８ｍＬ）に溶解させ、次に、上記混合溶液に亜鉛粉末（１．５０ｇ、２２．９１ｍｍｏｌ、５ｅｑ）を加え、当該反応系を２５℃で１時間撹拌した。反応溶液を濾過し、濾液を酢酸エチル（２０ｍＬ×２）で抽出し、有機相を収集し、飽和食塩水（２０ｍＬ×２）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過して濃縮し、残留物をカラムクロマトグラフィー（ＳｉＯ２、ＰＥ：ＥＡ＝５：１～１：１）により分離・精製して化合物１５－ｂを得た。 Step B: Compound 15-a (1.5 g, 4.58 mmol, 1 eq) and ammonium chloride (1.23 g, 22.91 mmol, 5 eq) were dissolved in tetrahydrofuran (16 mL) and water (8 mL), then zinc powder (1.50 g, 22.91 mmol, 5 eq) was added to the above mixture, and the reaction system was stirred at 25° C. for 1 hour. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (20 mL×2), and the organic phase was collected, washed with saturated saline (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by column chromatography (SiO 2 , PE:EA=5:1-1:1) to obtain compound 15-b.
ステップＣ：化合物１５－ｂ（１５０ｍｇ、０．８８５ｍｍｏｌ、１ｅｑ）を無水ＤＭＦ（１５ｍＬ）に溶解させ、窒素ガスで置換し、０℃でＮａＨ（３５．３８ｍｇ、０．８８５ｍｍｏｌ、６０％の純度、１ｅｑ）を当該反応溶液に加え、２５℃で３０分間撹拌した。次に、２－（トリメチルシリル）エトキシメチルクロリド（１４７．５ｍｇ、０．８８５ｍｍｏｌ、１５６．６μＬ、１ｅｑ）を一滴ずつ滴下し、２５℃で１時間撹拌した。０℃に冷却させ、窒素ガスの保護下でＮａＨ（７０．７６ｍｇ、１．７７ｍｍｏｌ、６０％の純度、２ｅｑ）を上記反応系に加え、３０分間撹拌した後、ヨードメタン（２６３．６７ｍｇ、１．８６ｍｍｏｌ、１１５．６５μＬ、２．１ｅｑ）を一滴ずつ加え、反応系を２５℃で１時間撹拌した。反応溶液をＨ２Ｏ（４５ｍＬ）に注ぎ、酢酸エチル（４０ｍＬ×２）で抽出した。合わせた有機相を飽和食塩水（４０ｍＬ×２）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濾液を減圧濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥＡ＝５：１）により分離・精製して化合物１５－ｃを得た。 Step C: Compound 15-b (150 mg, 0.885 mmol, 1 eq) was dissolved in anhydrous DMF (15 mL), and the mixture was replaced with nitrogen gas. NaH (35.38 mg, 0.885 mmol, 60% purity, 1 eq) was added to the reaction solution at 0° C., and the mixture was stirred at 25° C. for 30 minutes. Then, 2-(trimethylsilyl)ethoxymethyl chloride (147.5 mg, 0.885 mmol, 156.6 μL, 1 eq) was added dropwise, and the mixture was stirred at 25° C. for 1 hour. The mixture was cooled to 0° C., and NaH (70.76 mg, 1.77 mmol, 60% purity, 2 eq) was added to the reaction system under the protection of nitrogen gas, and the mixture was stirred for 30 minutes. After that, iodomethane (263.67 mg, 1.86 mmol, 115.65 μL, 2.1 eq) was added dropwise, and the reaction system was stirred at 25° C. for 1 hour. The reaction solution was poured into H 2 O (45 mL) and extracted with ethyl acetate (40 mL×2). The combined organic phase was washed with saturated saline (40 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=5:1) to obtain compound 15-c.
ステップＤ：化合物１５－ｃ（７０ｍｇ、２１３．４９μｍｏｌ、１ｅｑ）及び化合物３－ｃ（６６．９２ｍｇ、２５６．１９μｍｏｌ、１．２ｅｑ）のＤＭＦ（５．０ｍＬ）溶液に炭酸セシウム（１３９．１２ｍｇ、４２６．９８μｍｏｌ、２．０ｅｑ）を加え、窒素ガスで置換した。窒素ガスの雰囲気下で、当該反応系を１００℃で１５時間撹拌した。反応系にＨ２Ｏ（２０ｍＬ）を加え、酢酸エチル（２０ｍＬ×２）で抽出した。合わせた有機相を飽和食塩水（２０ｍＬ×２）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥＡ＝５：１）により分離・精製して化合物１５－ｄを得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３）：
δ ｐｐｍ ８．４３ （ｓ， １Ｈ）， ８．１５ （ｄｄ， Ｊ＝８．８５， ２．５７ Ｈｚ， １ Ｈ）， ８．０４ （ｄｄ， Ｊ＝２．４５， １．５７ Ｈｚ，
１ Ｈ）， ７．３８－７．４２ （ｍ， １Ｈ）， ７．２３－７．２５ （ｍ， １Ｈ）， ７．０４－７．０９ （ｍ， ２Ｈ）， ５．３１ （ｓ， ２Ｈ）， ５．２８ （ｓ， ２Ｈ）， ３．７０ （ｔ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， １．５２
（ｓ， ６Ｈ）， ０．９９ （ｔ， Ｊ＝８．０ Ｈｚ， ２Ｈ）， ０．０２ （ｓ， ９Ｈ）。
Step D: Cesium carbonate (139.12 mg, 426.98 μmol, 2.0 eq) was added to a solution of compound 15-c (70 mg, 213.49 μmol, 1 eq) and compound 3-c (66.92 mg, 256.19 μmol, 1.2 eq) in DMF (5.0 mL), and the mixture was replaced with nitrogen gas. Under a nitrogen gas atmosphere, the reaction system was stirred at 100° C. for 15 hours. H 2 O (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated saline (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=5:1) to obtain compound 15-d. 1 H NMR (400 MHz, CDCl 3 ):
δ ppm 8.43 (s, 1H), 8.15 (dd, J=8.85, 2.57 Hz, 1H), 8.04 (dd, J=2.45, 1.57 Hz,
1H), 7.38-7.42 (m, 1H), 7.23-7.25 (m, 1H), 7.04-7.09 (m, 2H), 5.31 (s, 2H), 5.28 (s, 2H), 3.70 (t, J=8.4 Hz, 2H), 1.52
(s, 6H), 0.99 (t, J=8.0 Hz, 2H), 0.02 (s, 9H).
ステップＥ：トリフルオロ酢酸（１５４ｍｇ、１．３５ｍｍｏｌ、１８．６６ｅｑ）を化合物１５－ｄ（４０ｍｇ、７２．３８μｍｏｌ、１ｅｑ）の無水ジクロロメタン（５．０ｍＬ）溶液に加え、２５℃で４８時間撹拌した。反応溶液を減圧濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．０４％のＮＨ３・Ｈ２Ｏ）－ＡＣＮ］により精製して化合物１５を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＣＤＣｌ３）： δ ｐｐｍ ８．３５
（ｓ， １Ｈ）， ８．１７ （ｄ， Ｊ＝２．８ Ｈｚ， １Ｈ）， ８．１５ （ｄ， Ｊ＝２．８ Ｈｚ， １Ｈ）， ８．０５－８．０４ （ｍ， １Ｈ）， ７．２７ － ７．２４ （ｍ， １Ｈ）， ７．０７ － ７．０３ （ｍ， ２Ｈ）， ５．２９ （ｓ， ２Ｈ）， １．５１ （ｓ， ６ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４２３．２ ［Ｍ＋１］＋。
Step E: Trifluoroacetic acid (154 mg, 1.35 mmol, 18.66 eq) was added to a solution of compound 15-d (40 mg, 72.38 μmol, 1 eq) in anhydrous dichloromethane (5.0 mL) and stirred at 25° C. for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (0.04% NH 3 ·H 2 O)-ACN] to obtain compound 15. 1 H NMR (400 MHz, CDCl 3 ): δ ppm 8.35
(s, 1H), 8.17 (d, J=2.8 Hz, 1H), 8.15 (d, J=2.8 Hz, 1H), 8.05-8.04 (m, 1H), 7.27-7.24 (m, 1H), 7.07-7.03 (m, 2H), 5.29 (s, 2H), 1.51 (s, 6H); LCMS (ESI) m/z: 423.2 [M+1] + .
実施例１６
合成スキーム：
Example 16
Synthesis scheme:
２５℃で、ｐ－フルオロ安息香酸（２４５．４５ｍｇ、１．７５ｍｍｏｌ、１ｅｑ）をＤＣＭ（１ｍＬ）に溶解させ、ＤＭＦ（７．５４ｍｇ、１０３．１９μｍｏｌ、７．９４μＬ、０．１ｅｑ）及び塩化オキサリル（２００．１２ｍｇ、１．５８ｍｍｏｌ、１３８
．０１μＬ、０．９ｅｑ）を加え、ガスが放出されなくなるまで撹拌し、当該反応溶液を化合物９－ｃ（０．２ｇ、３５０．３７μｍｏｌ、０．２ｅｑ）のＤＣＭ（１ｍＬ）及びピリジン（１ｍＬ）溶液に滴下し、２５℃で２時間撹拌した。反応溶液に２ｍＬの水を加え、ＤＣＭ（４ｍＬ×３）で抽出し、有機相を無水硫酸ナトリウムで乾燥させ、濾過し、濾液を濃縮した。残留物を分取ＨＰＬＣ［移動相：水（０．０４％のＮＨ３・Ｈ２Ｏ）－ＡＣＮ］により精製して化合物１６を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ ５．１６ （ｓ， ２ Ｈ） ７．１２ － ７．１８ （ｍ， １ Ｈ） ７．１９ － ７．２６ （ｍ， １ Ｈ） ７．２７ － ７．４３ （ｍ， ６ Ｈ） ８．０４ － ８．１８ （ｍ， ３ Ｈ） ８．１８ － ８．３４ （ｍ， ２ Ｈ） ９．８２ （ｓ， １ Ｈ）。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ：
４９２．２ ［Ｍ＋１］＋。
At 25° C., p-fluorobenzoic acid (245.45 mg, 1.75 mmol, 1 eq) was dissolved in DCM (1 mL) and mixed with DMF (7.54 mg, 103.19 μmol, 7.94 μL, 0.1 eq) and oxalyl chloride (200.12 mg, 1.58 mmol, 138
0.01 μL, 0.9 eq) was added and stirred until gas was no longer released, and the reaction solution was added dropwise to a solution of compound 9-c (0.2 g, 350.37 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL) and stirred at 25° C. for 2 hours. 2 mL of water was added to the reaction solution, extracted with DCM (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.04% NH 3 H 2 O)-ACN] to obtain compound 16. 1H NMR (400 MHz, DMSO- d6 ) δ ppm 5.16 (s, 2H) 7.12 - 7.18 (m, 1H) 7.19 - 7.26 (m, 1H) 7.27 - 7.43 (m, 6H) 8.04 - 8.18 (m, 3H) 8.18 - 8.34 (m, 2H) 9.82 (s, 1H). LCMS (ESI) m/z:
492.2 [M+1] + .
実施例１７
合成スキーム：
Example 17
Synthesis scheme:
ステップＡ：０℃で、１７－１（３ｇ、２５．８４ｍｍｏｌ、１ｅｑ）のＤＭＦ（３０ｍＬ）溶液にＮａＨ（２．０７ｇ、５１．６７ｍｍｏｌ、６０％の純度、２ｅｑ）を注意深くゆっくりと加え、０℃で０．５時間撹拌し、更に溶液にヨードメタン（４．４０ｇ、３１．００ｍｍｏｌ、１．９３ｍＬ、１．２ｅｑ）を加え、室温にゆっくりと戻せ、０．５時間撹拌し、４５℃で３時間撹拌し、室温に冷却させた後、飽和塩化アンモニウム溶液（６０ｍＬ）を加えて反応をクエンチングさせ、水（１０ｍＬ）を加えて希釈し、ＤＣＭ（３０ｍＬ×３）で抽出し、合わせた有機相を水（３０ｍＬ×３）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過した後１０℃以下で濃縮して化合物１７－ａを得た。１ＨＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ３．６５ （ｓ， ３Ｈ）， ３．３０ （ｓ， ３Ｈ）， １．３１－１．２７ （ｄｄ，Ｊ＝４．８Ｈｚ， ８．４ Ｈｚ， ２Ｈ）， １．１７－１．１４ （ｄｄ， Ｊ＝４ Ｈｚ， ７．２ Ｈｚ， ２Ｈ）。 Step A: At 0° C., NaH (2.07 g, 51.67 mmol, 60% purity, 2 eq) was carefully and slowly added to a solution of 17-1 (3 g, 25.84 mmol, 1 eq) in DMF (30 mL), and the mixture was stirred at 0° C. for 0.5 hours. Further, iodomethane (4.40 g, 31.00 mmol, 1.93 mL, 1.2 eq) was added to the solution, and the mixture was slowly warmed to room temperature and stirred for 0.5 hours. The mixture was then stirred at 45° C. for 3 hours. After cooling to room temperature, the reaction was quenched by adding saturated ammonium chloride solution (60 mL), diluted with water (10 mL), and extracted with DCM (30 mL×3). The combined organic phase was washed with water (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated at 10° C. or less to obtain compound 17-a. 1H NMR (400 MHz, DMSO- d6 ): δ 3.65 (s, 3H), 3.30 (s, 3H), 1.31-1.27 (dd, J=4.8 Hz, 8.4 Hz, 2H), 1.17-1.14 (dd, J=4 Hz, 7.2 Hz, 2H).
ステップＢ：１７－ａ（０．５６ｇ、４．３０ｍｍｏｌ、１ｅｑ）のＭｅＯＨ（５ｍＬ）溶液にＫＯＨ（４８３．１９ｍｇ、８．６１ｍｍｏｌ、２ｅｑ）の水（２．５ｍＬ）溶液をゆっくりと加えた。添加完了後、混合物を２０℃で１５時間撹拌した。反応溶液を４０℃未満で濃縮し、濃縮溶液を石油エーテル（１５ｍＬ）で洗浄し、次に、水相を氷水（１５ｍＬ）に注ぎ、溶液を３Ｍの塩酸水溶液でｐＨを５～６に調節し、ＤＣＭ（１２ｍＬ）で抽出し、有機相を無水硫酸ナトリウムで乾燥させて濾過し、濃縮して化合物１７－ｂ
を得た。１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）： δ １２．５５ （ｓ， １Ｈ）， ３．２９ （ｓ，３Ｈ）， １．１４－１．１２ （ｄｄ，Ｊ＝６Ｈｚ，８．８ Ｈｚ， ２Ｈ），１．０７－１．０４（ｄｄ，Ｊ＝３．２Ｈｚ， ６．４ Ｈｚ， ２Ｈ）。
Step B: To a solution of 17-a (0.56 g, 4.30 mmol, 1 eq) in MeOH (5 mL) was slowly added a solution of KOH (483.19 mg, 8.61 mmol, 2 eq) in water (2.5 mL). After the addition was complete, the mixture was stirred at 20° C. for 15 h. The reaction solution was concentrated below 40° C., the concentrated solution was washed with petroleum ether (15 mL), and then the aqueous phase was poured into ice water (15 mL), the solution was adjusted to pH 5-6 with 3M aqueous hydrochloric acid, extracted with DCM (12 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 17-b.
1 H NMR (400 MHz, DMSO-d 6 ): δ 12.55 (s, 1H), 3.29 (s, 3H), 1.14-1.12 (dd, J=6 Hz, 8.8 Hz, 2H), 1.07-1.04 (dd, J=3.2 Hz, 6.4 Hz, 2H).
ステップＣ：０℃で、１７－ｂ（３５０ｍｇ、３．０１ｍｍｏｌ、１ｅｑ）のＤＣＭ（２．００ｍＬ）及びＤＭＦ（２２．０３ｍｇ、３０１．４３μｍｏｌ、２３．１９μＬ、０．１ｅｑ）溶液に塩化オキサリル（３４４．３３ｍｇ、２．７１ｍｍｏｌ、２３７．４７μＬ、０．９ｅｑ）を加え、窒素ガスで置換し、０℃で０．５時間撹拌し、溶液に９－ｃ（２６１．９４ｍｇ、６０２．８５μｍｏｌ、０．２ｅｑ）のＤＣＭ（３ｍＬ）溶液を一滴ずつ加え、更にピリジン（４７６．８５ｍｇ、６．０３ｍｍｏｌ、４８６．５９μＬ、２ｅｑ）を加え、混合溶液を２０℃で５時間撹拌し、反応溶液を水（２０ｍＬ）でクエンチングさせ、ＥｔＯＡｃ（１５ｍＬ×３）で抽出し、有機相を飽和食塩水（１５ｍＬ×３）で洗浄し、合わせた有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１０：１～０．１：１）により精製して得られた粗生成物を更に分取ＨＰＬＣ［移動相：水（０．０５％のアンモニア水）－ＡＣＮ］により精製して化合物１７を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＣＤ３ＯＤ）： δ ｐｐｍ １．２３－１．２５（ｄｄ， Ｊ＝２．８Ｈｚ， ７．２ Ｈｚ， ２Ｈ）， １．３２－１．３５ （ｄｄ， Ｊ＝４Ｈｚ， ６．８ Ｈｚ， ２Ｈ）， ２．０３ （ｓ， １Ｈ）， ３．５０（ｓ， ３Ｈ）， ５．２８（ｓ， ２Ｈ）， ７．０９－７．１４（ｔ，Ｊ＝６Ｈｚ， ２Ｈ）， ７．２９－７．３６（ｄｄ， Ｊ＝７．２Ｈｚ， １４．８Ｈｚ， ２Ｈ）， ８．０１（ｓ， １Ｈ）， ８．１９（ｓ， １Ｈ）， ８．３５－８．３７（ｄ，Ｊ＝２．４Ｈｚ， １Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４６８．０ ［Ｍ＋１］＋。 Step C: At 0° C., oxalyl chloride (344.33 mg, 2.71 mmol, 237.47 μL, 0.9 eq) was added to a solution of 17-b (350 mg, 3.01 mmol, 1 eq) in DCM (2.00 mL) and DMF (22.03 mg, 301.43 μmol, 23.19 μL, 0.1 eq), purged with nitrogen gas, and stirred at 0° C. for 0.5 hours. To the solution was added a solution of 9-c (261.94 mg, 602.85 μmol, 0.2 eq) in DCM (3 mL) dropwise, and further pyridine (476.85 mg, 6.03 mmol) , 486.59 μL, 2 eq) was added, and the mixture was stirred at 20° C. for 5 hours. The reaction solution was quenched with water (20 mL), extracted with EtOAc (15 mL×3), the organic phase was washed with saturated saline (15 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated. The residue was purified by column chromatography (PE: EtOAc = 10: 1 to 0.1: 1), and the obtained crude product was further purified by preparative HPLC [mobile phase: water (0.05% aqueous ammonia) -ACN] to obtain compound 17. 1H NMR (400MHz, CD3OD ): δ ppm 1.23-1.25 (dd, J=2.8Hz, 7.2Hz, 2H), 1.32-1.35 (dd, J=4Hz, 6.8Hz, 2H), 2.03 (s, 1H), 3.50 (s, 3H), 5.28 (s, 2H), 7.09-7.14 (t, J=6Hz, 2H), 7.29-7.36 (dd, J=7.2Hz, 14.8Hz, 2H), 8.01 (s, 1H), 8.19 (s, 1H), 8.35-8.37 (d, J=2.4Hz, 1H); LCMS (ESI) m/z: 468.0 [M+1] <+> .
実施例１８
合成スキーム：
Example 18
Synthesis scheme:
３－ｅ（１００ｍｇ、２６０．１８μｍｏｌ、１ｅｑ）を溶解させたピリジン（４ｍＬ）溶液にＥＤＣＩ（３９９．０２ｍｇ、２．０８ｍｍｏｌ、８ｅｑ）及び１４－１（８０．１８ｍｇ、５２０．３７μｍｏｌ、２ｅｑ）を加え、反応混合物を３０℃で２時間撹拌した。反応溶液を水（５０ｍＬ）で希釈した後、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を無水硫酸ナトリウムで乾燥させた後減圧濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物１８を得た。１Ｈ ＮＭＲ
（４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．６０ （ｂｒ ｓ， １Ｈ
）， ８．２２ （ｄｄ， Ｊ＝２．３， ９．４ Ｈｚ， １Ｈ）， ８．０８ （ｓ， １Ｈ）， ７．３９ － ７．３１ （ｍ， １Ｈ）， ７．３１ － ７．１９ （ｍ， ２Ｈ）， ７．１８ － ７．１２ （ｍ， １Ｈ）， ６．２６ （ｂｒ ｓ， ４Ｈ）， ５．１４ （ｓ， ２Ｈ）， １．７４ （ｂｒ ｓ， ２Ｈ）， １．３２ － １．１５ （ｍ， ２Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ５２１．２ ［Ｍ＋１］＋。
EDCI (399.02 mg, 2.08 mmol, 8 eq) and 14-1 (80.18 mg, 520.37 μmol, 2 eq) were added to a pyridine (4 mL) solution of 3-e (100 mg, 260.18 μmol, 1 eq), and the reaction mixture was stirred at 30° C. for 2 hours. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 18. 1 H NMR
(400MHz, DMSO- d6 ): δ ppm 8.60 (br s, 1H
), 8.22 (dd, J=2.3, 9.4 Hz, 1H), 8.08 (s, 1H), 7.39-7.31 (m, 1H), 7.31-7.19 (m, 2H), 7.18-7.12 (m, 1H), 6.26 (br s, 4H), 5.14 (s, 2H), 1.74 (br s, 2H), 1.32-1.15 (m, 2H); LCMS (ESI) m/z: 521.2 [M+1] + .
実施例１９
合成スキーム：
Example 19
Synthesis scheme:
１－ｅ（１００ｍｇ、２７２．９６μｍｏｌ、１ｅｑ）を溶解させたピリジン（３ｍＬ）溶液にＥＤＣＩ（４１８．６２ｍｇ、２．１８ｍｍｏｌ、８ｅｑ）及び１４－１（８４．１２ｍｇ、５４５．９２μｍｏｌ、２ｅｑ）を加え、反応混合物を３０℃で２時間撹拌した。反応溶液を水（５０ｍＬ）で希釈した後、酢酸エチル（５０ｍＬ×３）で抽出し、有機相を無水硫酸ナトリウムで乾燥させた後減圧濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物１９を得た。１Ｈ ＮＭＲ
（４００ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ８．５８ （ｂｒ ｓ， １Ｈ）， ８．１４ － ８．０１ （ｍ， ２Ｈ）， ７．３８ － ７．３２ （ｍ， １Ｈ）， ７．２９ － ７．２０ （ｍ， ２Ｈ）， ７．１８ － ７．１１ （ｍ， ２Ｈ）， ６．２２ （ｂｒ ｓ， ４Ｈ）， ５．１６ （ｓ， ２Ｈ）， １．７７ － １．６９ （ｍ， ２Ｈ）， １．３１ － １．２０ （ｍ， ２Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ５０３．２ ［Ｍ＋１］＋。
EDCI (418.62 mg, 2.18 mmol, 8 eq) and 14-1 (84.12 mg, 545.92 μmol, 2 eq) were added to a pyridine (3 mL) solution of 1-e (100 mg, 272.96 μmol, 1 eq), and the reaction mixture was stirred at 30° C. for 2 hours. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 19. 1 H NMR
(400 MHz, DMSO- d6 ): δ ppm 8.58 (br s, 1H), 8.14 - 8.01 (m, 2H), 7.38 - 7.32 (m, 1H), 7.29 - 7.20 (m, 2H), 7.18 - 7.11 (m, 2H), 6.22 (br s, 4H), 5.16 (s, 2H), 1.77 - 1.69 (m, 2H), 1.31 - 1.20 (m, 2H); LCMS (ESI) m/z: 503.2 [M+1] + .
実施例２０
合成スキーム：
Example 20
Synthesis scheme:
０℃で、化合物９（１６９ｍｇ、３９５．４５μｍｏｌ、１ｅｑ）をＴＨＦ（２ｍＬ）に溶解させ、次に、得られた溶液にＮａＨ（２０．５６ｍｇ、５１４．０８μｍｏｌ、６０％の純度、１．３ｅｑ）を加え、９０分間撹拌し、次に、２，２，２－トリフルオロエチルトリフルオロメタンスルホネート（１１０．１４ｍｇ、４７４．５４μｍｏｌ、１．２ｅｑ）を加え、２０℃に昇温させ、３６時間撹拌した。反応溶液に２ｍＬの水を加え、１Ｍの塩酸水溶液でそのｐＨを６～７に調節し、次に、ＥＡ（４ｍＬ×３）で抽出し、有機相を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．０４％のＮＨ３Ｈ２Ｏ＋１０ｍＭのＮＨ４ＨＣＯ３）－ＡＣＮ］により精製して化合物２０を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ ４．８５ （ｑ， Ｊ＝９．０３ Ｈｚ， ２ Ｈ） ５．１８ （ｓ， ２ Ｈ） ７．１４ － ７．１９ （ｍ， １ Ｈ） ７．２１ － ７．２７ （ｍ， １ Ｈ） ７．３０ － ７．４０ （ｍ， ２ Ｈ） ７．９９ （ｄｄ， Ｊ＝９．１０， ２．４５ Ｈｚ， １ Ｈ） ８．１２ （ｔ， Ｊ＝２．１３ Ｈｚ， １ Ｈ） ８．５２ （ｓ， １ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４７８．２ ［Ｍ＋１］＋。 Compound 9 (169 mg, 395.45 μmol, 1 eq) was dissolved in THF (2 mL) at 0° C., then NaH (20.56 mg, 514.08 μmol, 60% purity, 1.3 eq) was added to the resulting solution and stirred for 90 minutes, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (110.14 mg, 474.54 μmol, 1.2 eq) was added, the temperature was raised to 20° C., and the mixture was stirred for 36 hours. 2 mL of water was added to the reaction solution, and its pH was adjusted to 6-7 with 1 M aqueous hydrochloric acid, then extracted with EA (4 mL x 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.04% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-ACN] to obtain compound 20. 1H NMR (400 MHz, DMSO- d6 ): δ ppm 4.85 (q, J=9.03 Hz, 2H), 5.18 (s, 2H), 7.14-7.19 (m, 1H), 7.21-7.27 (m, 1H), 7.30-7.40 (m, 2H), 7.99 (dd, J=9.10, 2.45 Hz, 1H), 8.12 (t, J=2.13 Hz, 1H), 8.52 (s, 1H); LCMS (ESI) m/z: 478.2 [M+1] + .
実施例２１
合成スキーム：
Example 21
Synthesis scheme:
２５℃で、２１－１（２０３ｍｇ、２．０３ｍｍｏｌ、１ｅｑ）をＤＣＭ（１ｍＬ）に溶解させ、塩化オキサリル（２３１．６３ｍｇ、１．８２ｍｍｏｌ、１５９．７４μＬ、
０．９ｅｑ）及びＤＭＦ（１４．８２ｍｇ、２０２．７７μｍｏｌ、１５．６０μＬ、０．１ｅｑ）を加え、ガスが放出されなくなるまで撹拌し、当該反応溶液を化合物９－ｃ（１７６．２０ｍｇ、４０５．５３μｍｏｌ、０．２ｅｑ）のＤＣＭ（１ｍＬ）及びピリジン（１ｍＬ）の溶液に滴下し、２５℃で２時間撹拌した。反応溶液に２ｍＬの水を加え、ＤＣＭ（４ｍＬ×３）で抽出し、有機相を無水硫酸ナトリウムで乾燥させ、濾過し、濾液を濃縮した。残留物を分取ＨＰＬＣ（水（０．０４％のＮＨ３・Ｈ２Ｏ＋１０ｍＭのＮＨ４ＨＣＯ３）－ＡＣＮ］；アセトニトリル：３５％～６２％、１０分）により精製して化合物２１を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ
０．５３ － ０．７５ （ｍ， ２ Ｈ） １．１４ （ｂｒ ｄ， Ｊ＝２．３８
Ｈｚ， ２ Ｈ） １．４４ （ｓ， ３ Ｈ） ５．１６ （ｓ， ２ Ｈ） ７．１２ － ７．２８ （ｍ， ４ Ｈ） ７．２７ － ７．４０ （ｍ， ２ Ｈ） ８．０７ （ｓ， １ Ｈ） ８．１１ （ｓ， １ Ｈ） ８．２１ （ｄｄ， Ｊ＝９．２９， ２．３８ Ｈｚ， １ Ｈ） ８．８５ （ｂｒ ｓ， １ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４５２．２ ［Ｍ＋１］＋。
At 25° C., 21-1 (203 mg, 2.03 mmol, 1 eq) was dissolved in DCM (1 mL) and oxalyl chloride (231.63 mg, 1.82 mmol, 159.74 μL,
0.9 eq) and DMF (14.82 mg, 202.77 μmol, 15.60 μL, 0.1 eq) were added and stirred until gas was no longer released, and the reaction solution was added dropwise to a solution of compound 9-c (176.20 mg, 405.53 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL) and stirred at 25° C. for 2 hours. 2 mL of water was added to the reaction solution, extracted with DCM (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (water (0.04% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 )-ACN]; acetonitrile: 35% to 62%, 10 min) to give compound 21. 1H NMR (400 MHz, DMSO- d6 ): δ ppm
0.53 - 0.75 (m, 2H) 1.14 (br d, J = 2.38
Hz, 2H) 1.44 (s, 3H) 5.16 (s, 2H) 7.12-7.28 (m, 4H) 7.27-7.40 (m, 2H) 8.07 (s, 1H) 8.11 (s, 1H) 8.21 (dd, J=9.29, 2.38 Hz, 1H) 8.85 (br s, 1H); LCMS (ESI) m/z: 452.2 [M+1] + .
実施例２２
合成スキーム：
Example 22
Synthesis scheme:
化合物３－ｅ（０．１ｇ、２６０．１８μｍｏｌ、１ｅｑ）をピリジン（２ｍＬ）に溶解させ、０℃でクロロギ酸エチル（４２．３５ｍｇ、３９０．２８μｍｏｌ、３７．１５μＬ、１．５ｅｑ）を滴下し、当該温度下で３０分間撹拌した。反応完了後、反応溶液を４ｍＬの水に滴下し、酢酸エチル（５ｍＬ×３）で抽出し、有機相を飽和食塩水（５ｍＬ×２）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濾液を減圧濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物２２を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ １．０２ － １．３３ （ｍ， ３ Ｈ） ４．０６ （ｂｒ ｄ， Ｊ＝６．７８ Ｈｚ，
２ Ｈ） ５．１３ （ｓ， ２ Ｈ） ６．３３ （ｂｒ ｓ， ４ Ｈ） ７．１０ － ７．１７ （ｍ， １ Ｈ） ７．１８ － ７．２９ （ｍ， ２ Ｈ） ７．３０ － ７．３９ （ｍ， １ Ｈ） ７．９２ （ｂｒ ｓ， １ Ｈ） ８．０６ （ｓ， １ Ｈ） ８．１８ （ｂｒ ｄ， Ｊ＝９．０３ Ｈｚ， １ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４５７．０ ［Ｍ＋１］＋。
Compound 3-e (0.1 g, 260.18 μmol, 1 eq) was dissolved in pyridine (2 mL), and ethyl chloroformate (42.35 mg, 390.28 μmol, 37.15 μL, 1.5 eq) was added dropwise at 0° C., followed by stirring at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was added dropwise to 4 mL of water, extracted with ethyl acetate (5 mL×3), the organic phase was washed with saturated saline (5 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 22. 1H NMR (400 MHz, DMSO- d6 ): δ ppm 1.02-1.33 (m, 3H) 4.06 (br d, J=6.78 Hz,
2H) 5.13 (s, 2H) 6.33 (br s, 4H) 7.10-7.17 (m, 1H) 7.18-7.29 (m, 2H) 7.30-7.39 (m, 1H) 7.92 (br s, 1H) 8.06 (s, 1H) 8.18 (br d, J=9.03 Hz, 1H); LCMS (ESI) m/z: 457.0 [M+1] + .
実施例２３
合成スキーム：
Example 23
Synthesis scheme:
化合物３－ｅ（１００ｍｇ、２６０．１８μｍｏｌ、１ｅｑ）及び２３－１（５７．８１ｍｇ、５２０．３７μｍｏｌ、２ｅｑ）をピリジン（４ｍＬ）に溶解させ、その中にＥＤＣＩ（３９９．０２ｍｇ、２．０８ｍｍｏｌ、８ｅｑ）を加え、当該反応溶液を３０℃で２時間反応させた。反応溶液をＨ２Ｏ（４ｍＬ）に滴下し、次に、ＥＡ（５ｍＬ×３）で抽出し、有機相を飽和食塩水（５ｍＬ×２）で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濾液を減圧濃縮した。残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物２３を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６）： δ ｐｐｍ １．５０ － １．６４ （ｍ， ２ Ｈ） １．６４ － １．８７ （ｍ， ２ Ｈ） ５．１４ （ｓ， ２ Ｈ） ６．４７ （ｂｒ
ｓ， ４ Ｈ） ７．１０ － ７．１９ （ｍ， １ Ｈ） ７．１８ － ７．３０ （ｍ， ２ Ｈ） ７．３５ （ｑ， Ｊ＝６．４８ Ｈｚ， １ Ｈ） ８．０７
（ｓ， １ Ｈ） ８．２２ （ｄｄ， Ｊ＝９．３５， ２．２０ Ｈｚ， １ Ｈ） ８．６０ （ｂｒ ｓ， １ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４７８．０
［Ｍ＋１］＋。
Compound 3-e (100 mg, 260.18 μmol, 1 eq) and 23-1 (57.81 mg, 520.37 μmol, 2 eq) were dissolved in pyridine (4 mL), EDCI (399.02 mg, 2.08 mmol, 8 eq) was added thereto, and the reaction solution was reacted at 30° C. for 2 hours. The reaction solution was added dropwise to H 2 O (4 mL), and then extracted with EA (5 mL×3), the organic phase was washed with saturated saline (5 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 23. 1H NMR (400 MHz, DMSO- d6 ): δ ppm 1.50 - 1.64 (m, 2H) 1.64 - 1.87 (m, 2H) 5.14 (s, 2H) 6.47 (br
s, 4H) 7.10 - 7.19 (m, 1H) 7.18 - 7.30 (m, 2H) 7.35 (q, J=6.48 Hz, 1H) 8.07
(s, 1H) 8.22 (dd, J=9.35, 2.20 Hz, 1H) 8.60 (br s, 1H); LCMS (ESI) m/z: 478.0
[M+1] + .
実施例２４
合成スキーム：
Example 24
Synthesis scheme:
３－ｅ（１００ｍｇ、２６０．１８μｍｏｌ、１ｅｑ）を溶解させたピリジン（５ｍＬ）溶液にＥＤＣＩ（３９９．０２ｍｇ、２．０８ｍｍｏｌ、８ｅｑ）及び１７－ｂ（９０．６３ｍｇ、７８０．５５μｍｏｌ、３ｅｑ）を加えた。反応溶液を２０℃で１時間撹拌した。反応溶液を水（５０ｍＬ）で希釈し、ＥｔＯＡｃ（５０ｍＬ×２）で抽出した。有
機相を無水Ｎａ２ＳＯ４で乾燥させ、濾過し、濃縮して粗生成物化合物を得、分取ＨＰＬＣ［移動相：水（１０ｍＭの炭酸水素アンモニウム）－アセトニトリル］により分離した後、更に薄層クロマトグラフィー（ＳｉＯ２、ＤＣＭ：ＭｅＯＨ＝１０：１）により精製して化合物２４を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＭｅＯＨ－ｄ４） δ＝８．２８ － ８．２２ （ｍ， １Ｈ）， ７．９８ － ７．９３ （ｍ， １Ｈ）， ７．３０ （ｔ， Ｊ＝７．５ Ｈｚ， １Ｈ）， ７．２７ － ７．２０ （ｍ， １Ｈ）， ７．０７ － ７．００ （ｍ， ２Ｈ）， ５．２４ （ｓ， ２Ｈ）， ３．４６ （ｓ， ３Ｈ）， １．４１ － １．３１ （ｍ， ２Ｈ）， １．２６ － １．１６ （ｍ， ２Ｈ）。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４８３．４ ［Ｍ＋１］＋。
EDCI (399.02 mg, 2.08 mmol, 8 eq) and 17-b (90.63 mg, 780.55 μmol, 3 eq) were added to a solution of 3-e (100 mg, 260.18 μmol, 1 eq) in pyridine (5 mL). The reaction solution was stirred at 20° C. for 1 h. The reaction solution was diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give the crude product compound, which was separated by preparative HPLC [mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile] and then further purified by thin layer chromatography (SiO 2 , DCM:MeOH=10:1) to give compound 24. 1H NMR (400MHz, MeOH- d4 ) δ=8.28-8.22 (m, 1H), 7.98-7.93 (m, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.27-7.20 (m, 1H), 7.07-7.00 (m, 2H), 5.24 (s, 2H), 3.46 (s, 3H), 1.41-1.31 (m, 2H), 1.26-1.16 (m, 2H). LCMS (ESI) m/z: 483.4 [M+1] <+> .
実施例２５
合成スキーム：
Example 25
Synthesis scheme:
３－ｅ（１５０ｍｇ、３９０．２８μｍｏｌ、１ｅｑ）を溶解させたピリジン（５ｍＬ）溶液にＥＤＣＩ（５９８．５３ｍｇ、３．１２ｍｍｏｌ、８ｅｑ）及び１－メチルシクロプロパン－１－カルボン酸（１１７．２２ｍｇ、１．１７ｍｍｏｌ、３ｅｑ）を加え、反応混合物を２０℃で１時間撹拌した。反応溶液を水（５０ｍＬ）で希釈した後、酢酸エチル（５０ｍＬ×２）で抽出し、有機相を無水硫酸ナトリウムで乾燥させた後減圧濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物２５を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６） δ＝８．２９
（ｓ， １Ｈ）， ８．２０ （ｄｄ， Ｊ＝２．４， ９．３ Ｈｚ， １Ｈ）， ８．０８ （ｄ， Ｊ＝１．７ Ｈｚ， １Ｈ）， ７．３５ （ｑ， Ｊ＝７．３ Ｈｚ， １Ｈ）， ７．３１ － ７．１９ （ｍ， ２Ｈ）， ７．１８ － ７．１２
（ｍ， １Ｈ）， ６．２１ （ｂｒ ｓ， ４Ｈ）， ５．１４ （ｓ， ２Ｈ），
１．４３ （ｓ， ３Ｈ）， １．１１ （ｂｒ ｄ， Ｊ＝２．４ Ｈｚ， ２Ｈ）， ０．６３ － ０．４６ （ｍ， ２Ｈ）。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４６７．４ ［Ｍ＋１］＋。
EDCI (598.53 mg, 3.12 mmol, 8 eq) and 1-methylcyclopropane-1-carboxylic acid (117.22 mg, 1.17 mmol, 3 eq) were added to a pyridine (5 mL) solution of 3-e (150 mg, 390.28 μmol, 1 eq), and the reaction mixture was stirred at 20° C. for 1 hour. The reaction solution was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 25. 1 H NMR (400 MHz, DMSO-d 6 ) δ=8.29
(s, 1H), 8.20 (dd, J=2.4, 9.3 Hz, 1H), 8.08 (d, J=1.7 Hz, 1H), 7.35 (q, J=7.3 Hz, 1H), 7.31 - 7.19 (m, 2H), 7.18 - 7.12
(m, 1H), 6.21 (br s, 4H), 5.14 (s, 2H),
1.43 (s, 3H), 1.11 (br d, J=2.4 Hz, 2H), 0.63-0.46 (m, 2H). LCMS (ESI) m/z: 467.4 [M+1] <+> .
実施例２６
合成スキーム：
Example 26
Synthesis scheme:
ステップＡ：マロノニトリル（１４．９３ｇ、２２５．９８ｍｍｏｌ、１４．２２ｍＬ、１ｅｑ）をＴＨＦ（１００ｍＬ）に溶解させ、次に、カリウムｔｅｒｔ－ブトキシド（２７．８９ｇ、２４８．５８ｍｍｏｌ、１．１ｅｑ）を加え、反応溶液を５０℃で０．５時間撹拌し、次に、化合物２６－１（４５ｇ、２４８．５８ｍｍｏｌ、３２．１４ｍＬ、１．１ｅｑ）を加え、反応溶液を５０℃で１１．５時間撹拌を続け、反応完了後１００ｍＬの水を加えてクエンチングさせ、次に、ＥｔＯＡｃ（１００ｍＬ×２）で抽出し、有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濾液を濃縮し、残留物をカラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ＝１０／１～５／１）により精製して化合物２６－ａを得た。 Step A: Malononitrile (14.93 g, 225.98 mmol, 14.22 mL, 1 eq) was dissolved in THF (100 mL), then potassium tert-butoxide (27.89 g, 248.58 mmol, 1.1 eq) was added, and the reaction solution was stirred at 50°C for 0.5 hours, then compound 26-1 (45 g, 248.58 mmol, 32.14 mL, 1.1 eq) was added, and the reaction solution was continued to be stirred at 50°C for 11.5 hours, and after the reaction was completed, 100 mL of water was added to quench, and then extracted with EtOAc (100 mL x 2), the organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated after filtration, and the residue was purified by column chromatography (PE/EtOAc = 10/1 to 5/1) to obtain compound 26-a.
ステップＢ：化合物２６－ａ（２０ｇ、１２０．３５ｍｍｏｌ、１ｅｑ）、Ｓ－メチルチオ尿素（２７．０４ｇ、１４４．４２ｍｍｏｌ、１．２ｅｑ、ＨＳＯ４）及びトリエチルアミン（２４．３６ｇ、２４０．７１ｍｍｏｌ、３３．５０ｍＬ、２ｅｑ）をＤＭＦ（６０ｍＬ）に溶解させ、窒素ガスで３回置換した後、１００℃で１２時間撹拌し、反応完了後、反応溶液を濾過し、濾液を濃縮し、残留物をカラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ＝１０／１～１／１）により精製して化合物２６－ｂを得た。 Step B: Compound 26-a (20 g, 120.35 mmol, 1 eq), S-methylthiourea (27.04 g, 144.42 mmol, 1.2 eq, HSO 4 ) and triethylamine (24.36 g, 240.71 mmol, 33.50 mL, 2 eq) were dissolved in DMF (60 mL), purged with nitrogen gas three times, and then stirred at 100° C. for 12 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 10/1 to 1/1) to obtain compound 26-b.
ステップＣ：化合物２６－ｂ（３．８ｇ、１６．９４ｍｍｏｌ、１ｅｑ）をＤＣＭ（５０ｍＬ）に溶解させ、次に、ｍ－クロロペルオキシ安息香酸（６．８８ｇ、３３．８９ｍｍｏｌ、８５％の純度、２ｅｑ）を加えた。反応溶液を２０℃で１２時間撹拌した。反応完了後、濾過し、ケーキを収集し、ジクロロメタン（１００ｍＬ）で撹拌し、濾過し、乾燥させて化合物２６－ｃを得た。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ２５７．２ ［Ｍ＋１］＋。 Step C: Compound 26-b (3.8 g, 16.94 mmol, 1 eq) was dissolved in DCM (50 mL) and then m-chloroperoxybenzoic acid (6.88 g, 33.89 mmol, 85% purity, 2 eq) was added. The reaction solution was stirred at 20° C. for 12 h. After completion of the reaction, it was filtered, the cake was collected, stirred with dichloromethane (100 mL), filtered and dried to give compound 26-c. LCMS (ESI) m/z: 257.2 [M+1] + .
ステップＤ：２０℃で、３－ｃ（５．７４ｇ、２１．９８ｍｍｏｌ、１．１ｅｑ）のＤＭＦ（３０ｍＬ）溶液に炭酸カリウム（８．２８ｇ、５９．９３ｍｍｏｌ、３ｅｑ）及び２６－ｃ（５．１２ｇ、１９．９８ｍｍｏｌ、１．０ｅｑ）を加え、反応溶液を１２０℃に昇温させて２時間温度させながら反応させた。反応完了後、反応溶液を室温に冷却させ、濾過し、メタノール（２０ｍＬ）及びＤＭＦ（２０ｍＬ）でケーキを洗浄し、濾液を合わせ、減圧濃縮してメタノールを除去し、残留液を分取ＨＰＬＣ［移動相：水（０．１％のＦＡ）－ＡＣＮ］により精製して化合物２６を得た。１Ｈ ＮＭＲ （４００ＭＨｚ，
ＤＭＳＯ－ｄ６） δ＝１１．１５ （ｓ， １Ｈ）， ８．２７ （ｄｄ， Ｊ＝２．５， ９．４ Ｈｚ， １Ｈ）， ８．１０ （ｔ， Ｊ＝２．０ Ｈｚ， １Ｈ），
７．３９ － ７．３２ （ｍ， １Ｈ）， ７．２９ （ｔ， Ｊ＝７．６ Ｈｚ，
１Ｈ）， ７．２５ － ７．２０ （ｍ， １Ｈ）， ７．１８ － ７．１２ （ｍ， １Ｈ）， ７．０３ （ｂｒ ｓ， ２Ｈ）， ５．１５ （ｓ， ２Ｈ）， １．３５ （ｓ， ６Ｈ）。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４２８．４ ［Ｍ＋１］＋。
Step D: At 20° C., potassium carbonate (8.28 g, 59.93 mmol, 3 eq) and 26-c (5.12 g, 19.98 mmol, 1.0 eq) were added to a solution of 3-c (5.74 g, 21.98 mmol, 1.1 eq) in DMF (30 mL), and the reaction solution was heated to 120° C. and reacted for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the cake was washed with methanol (20 mL) and DMF (20 mL). The filtrate was combined and concentrated under reduced pressure to remove methanol, and the remaining liquid was purified by preparative HPLC [mobile phase: water (0.1% FA)-ACN] to obtain compound 26. 1 H NMR (400 MHz,
DMSO- d6 ) δ = 11.15 (s, 1H), 8.27 (dd, J = 2.5, 9.4 Hz, 1H), 8.10 (t, J = 2.0 Hz, 1H),
7.39 - 7.32 (m, 1H), 7.29 (t, J=7.6 Hz,
1H), 7.25 - 7.20 (m, 1H), 7.18 - 7.12 (m, 1H), 7.03 (br s, 2H), 5.15 (s, 2H), 1.35 (s, 6H). LCMS (ESI) m/z: 428.4 [M+1] <+> .
実施例２７
合成スキーム：
Example 27
Synthesis scheme:
５－ｆ（２００ｍｇ、６７０．４５μｍｏｌ、１ｅｑ）のＤＭＦ（２ｍＬ）溶液に２６－ｃ（２７３ｍｇ、８５８．５８μｍｏｌ、１．２８ｅｑ）及び炭酸カリウム（２００ｍｇ、１．４５ｍｍｏｌ、２．１６ｅｑ）を加えた。窒素ガスで置換し、１２０℃で１２時間撹拌した。反応溶液を濾過し、ケーキを２ｍＬのＤＭＦで洗浄し、濾液を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物２７を得た。１Ｈ
ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ ｄ６） δ ｐｐｍ １．３４ （ｓ， ６ Ｈ） ５．１８ （ｓ， ２ Ｈ） ６．９４ － ７．２２ （ｍ， ４ Ｈ） ７．３７ （ｑ， Ｊ＝８．２３ Ｈｚ， １ Ｈ） ８．１０ （ｔ， Ｊ＝２．１４
Ｈｚ， １ Ｈ） ８．２７ （ｄｄ， Ｊ＝９．４８， ２．６３ Ｈｚ， １ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４５６．１ ［Ｍ＋１］＋。
To a solution of 5-f (200 mg, 670.45 μmol, 1 eq) in DMF (2 mL), 26-c (273 mg, 858.58 μmol, 1.28 eq) and potassium carbonate (200 mg, 1.45 mmol, 2.16 eq) were added. The mixture was purged with nitrogen gas and stirred at 120° C. for 12 hours. The reaction solution was filtered, the cake was washed with 2 mL of DMF, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 27. 1 H
NMR (400 MHz, DMSO- d6 ) δ ppm 1.34 (s, 6H) 5.18 (s, 2H) 6.94 - 7.22 (m, 4H) 7.37 (q, J = 8.23 Hz, 1H) 8.10 (t, J = 2.14
Hz, 1H) 8.27 (dd, J=9.48, 2.63 Hz, 1H); LCMS (ESI) m/z: 456.1 [M+1] <+> .
実施例２８
合成スキーム：
Example 28
Synthesis scheme:
ステップＡ：２８－１（３．５ｇ、３１．７９ｍｍｏｌ、１ｅｑ）のジクロロメタン（１００．００ｍＬ）及びトルエン（１０ｍＬ）の混合物にジフェニルホスホリルアジド（１７．４９ｇ、６３．５７ｍｍｏｌ、１３．７８ｍＬ、２ｅｑ）及び１．８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（９．６８ｇ、６３．５７ｍｍｏｌ、９．５８ｍＬ、２ｅｑ）を加えた。反応溶液を２０℃で２時間撹拌した。反応完了後、反応溶液を減圧濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝５：１～１：１）により精製して化合物２８－ａを得た。 Step A: To a mixture of 28-1 (3.5 g, 31.79 mmol, 1 eq) in dichloromethane (100.00 mL) and toluene (10 mL), diphenylphosphoryl azide (17.49 g, 63.57 mmol, 13.78 mL, 2 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.68 g, 63.57 mmol, 9.58 mL, 2 eq) were added. The reaction solution was stirred at 20°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 5: 1 to 1: 1) to obtain compound 28-a.
ステップＢ：窒素ガスの保護下で、２８－ａ（３．０ｇ、２２．２０ｍｍｏｌ、１ｅｑ）のメタノール（１０ｍＬ）溶液に湿式Ｐｄ／Ｃ（１．０ｇ、１０％の純度）を加え、反応溶液を水素ガスで３回置換した後、１５ｐｓｉの圧力で、２０℃で２時間撹拌し、反応完了後、反応溶液を濾過し、次に、濾液を濃縮して化合物２８－ｂを得た。 Step B: Under the protection of nitrogen gas, wet Pd/C (1.0 g, 10% purity) was added to a solution of 28-a (3.0 g, 22.20 mmol, 1 eq) in methanol (10 mL), and the reaction solution was replaced with hydrogen gas three times, then stirred at 15 psi pressure and 20°C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was then concentrated to obtain compound 28-b.
ステップＣ：３－１（２．５ｇ、１４．１６ｍｍｏｌ、１ｅｑ）及び２８－ｂ（１．８５ｇ、１６．９９ｍｍｏｌ、１．２ｅｑ）をトルエン（１００ｍＬ）に溶解させ、混合物を８０℃に昇温させて１２時間撹拌した。冷却させた後、反応溶液を減圧濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１：１）により精製して化合物２８－ｃを得た。 Step C: 3-1 (2.5 g, 14.16 mmol, 1 eq) and 28-b (1.85 g, 16.99 mmol, 1.2 eq) were dissolved in toluene (100 mL), and the mixture was heated to 80°C and stirred for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EtOAc = 1:1) to obtain compound 28-c.
ステップＤ：窒素ガスの保護下で、２８－ｃ（２．４ｇ、９．６３ｍｍｏｌ、１ｅｑ）のメタノール（１０ｍＬ）にＰｄ／Ｃ（１．０ｇ、９．６３ｍｍｏｌ、１０％の純度）を加えた。反応溶液を水素ガス３回置換した後、１５ｐｓｉの圧力で、３０℃で２時間撹拌し、反応完了後、反応溶液を濾過し、濾液を濃縮して化合物２８－ｄを得た。 Step D: Under the protection of nitrogen gas, Pd/C (1.0 g, 9.63 mmol, 10% purity) was added to 28-c (2.4 g, 9.63 mmol, 1 eq) in methanol (10 mL). The reaction solution was purged with hydrogen gas three times, and then stirred at 15 psi pressure and 30°C for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain compound 28-d.
ステップＥ：２８－ｄ（２．１ｇ、９．５８ｍｍｏｌ、１ｅｑ）のＴＨＦ（１００ｍＬ）溶液にＣＤＩ（３．１１ｇ、１９．１６ｍｍｏｌ、２ｅｑ）を加えた。混合物を７０℃で１２時間撹拌した。反応溶液を濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１：１～０：１）により化合物２８－ｅを得た。 Step E: CDI (3.11 g, 19.16 mmol, 2 eq) was added to a solution of 28-d (2.1 g, 9.58 mmol, 1 eq) in THF (100 mL). The mixture was stirred at 70 °C for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (PE: EtOAc = 1: 1 to 0: 1) to obtain compound 28-e.
ステップＦ：２８－ｅ（２００ｍｇ、８１５．６２μｍｏｌ、１ｅｑ）のＤＭＦ（３ｍＬ）溶液に２６－ｃ（５１９ｍｇ、１．６３ｍｍｏｌ、２ｅｑ）及び炭酸カリウム（３３８ｍｇ、２．４５ｍｍｏｌ、３ｅｑ）を加えた。窒素ガスで置換し、１２０℃で１２時間撹拌した。反応溶液を濾過し、ケーキを２ｍＬのＤＭＦで洗浄し、濾液を分取ＨＰＬＣ［
移動相：水（０．２２５％のＦＡ）－ＡＣＮ］により精製して化合物２８を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ ｄ６） δ ｐｐｍ １．３４ （ｓ， ６
Ｈ） ５．１６ （ｓ， ２ Ｈ） ７．０１ （ｂｒ ｓ， ２ Ｈ） ８．０６ － ８．１７ （ｍ， １ Ｈ） ８．２９ （ｄｄ， Ｊ＝９．４８， ２．６３ Ｈｚ， １ Ｈ） ８．８４ （ｓ， ２ Ｈ） ９．１２ （ｓ， １ Ｈ）；ＬＣＭＳ
（ＥＳＩ） ｍ／ｚ： ４２２．１ ［Ｍ＋１］＋。
Step F: 26-c (519 mg, 1.63 mmol, 2 eq) and potassium carbonate (338 mg, 2.45 mmol, 3 eq) were added to a solution of 28-e (200 mg, 815.62 μmol, 1 eq) in DMF (3 mL). The mixture was purged with nitrogen gas and stirred at 120° C. for 12 hours. The reaction solution was filtered, the cake was washed with 2 mL of DMF, and the filtrate was analyzed by preparative HPLC [
The residue was purified by elution with a 1H NMR (400 MHz, DMSO- d6 ) δ ppm 1.34 (s, 6
1H) 5.16 (s, 2H) 7.01 (br s, 2H) 8.06 - 8.17 (m, 1H) 8.29 (dd, J=9.48, 2.63 Hz, 1H) 8.84 (s, 2H) 9.12 (s, 1H); LCMS
(ESI) m/z: 422.1 [M+1] <+> .
実施例２９
合成スキーム：
Example 29
Synthesis scheme:
ステップＡ：窒素ガスの保護下で、３－１（７２０ｍｇ、４．０８ｍｍｏｌ、１ｅｑ）のトルエン（２０．００ｍＬ）溶液にジイソプロピルエチルアミン（２．１１ｇ、１６．３１ｍｍｏｌ、２．８４ｍＬ、４ｅｑ）及び３－フルオロ－２－ピリジルメチルアミン塩酸塩（８９３ｍｇ、４．４９ｍｍｏｌ、１．１ｅｑ）を加えた。混合物を７０℃に昇温させ１２時間撹拌した。冷却させた後、水（１００ｍＬ）を加え、ＥｔＯＡｃ（２００ｍＬ）で抽出し、有機相を無水硫酸ナトリウムで乾燥させ、濾過した後濃縮し、残留物をカラムクロマトグラフィー（石油エーテル：酢酸エチル＝２０：１～５：１）により分離・精製して化合物２９－ａを得た。 Step A: Under the protection of nitrogen gas, diisopropylethylamine (2.11 g, 16.31 mmol, 2.84 mL, 4 eq) and 3-fluoro-2-pyridylmethylamine hydrochloride (893 mg, 4.49 mmol, 1.1 eq) were added to a solution of 3-1 (720 mg, 4.08 mmol, 1 eq) in toluene (20.00 mL). The mixture was heated to 70°C and stirred for 12 hours. After cooling, water (100 mL) was added and extracted with EtOAc (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 5: 1) to obtain compound 29-a.
ステップＢ：２９－ａ（６５０ｍｇ、２．４４ｍｍｏｌ、１ｅｑ）のテトラヒドロフラン（１５ｍＬ）及び水（５ｍＬ）に還元亜鉛粉末（６３８ｍｇ、９．７７ｍｍｏｌ、４ｅｑ）及び塩化アンモニウム（６５３ｍｇ、１２．２１ｍｍｏｌ、５ｅｑ）を加えた。反応溶液を７０℃で１２時間撹拌し、反応溶液を濾過した後濃縮し、残留物をカラムクロマトグラフィー（石油エーテル：酢酸エチル＝４：１～２：１）により分離・精製して化合物２９－ｂを得た。 Step B: Reduced zinc powder (638 mg, 9.77 mmol, 4 eq) and ammonium chloride (653 mg, 12.21 mmol, 5 eq) were added to 29-a (650 mg, 2.44 mmol, 1 eq) in tetrahydrofuran (15 mL) and water (5 mL). The reaction solution was stirred at 70°C for 12 hours, filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1 to 2:1) to obtain compound 29-b.
ステップＣ：２９－ｂ（４３０ｍｇ、１．８２ｍｍｏｌ、１ｅｑ）のＴＨＦ（２０．００ｍＬ）溶液にＣＤＩ（４４２ｍｇ、２．７３ｍｍｏｌ、１．５ｅｑ）を加えた。窒素ガスで３回置換し、混合物を７０℃で１２．５時間撹拌した。反応溶液を濃縮し、残留物を直接にカラムクロマトグラフィー（石油エーテル：酢酸エチル＝４：１～１：１）により化合物２９－ｃを得た。 Step C: CDI (442 mg, 2.73 mmol, 1.5 eq) was added to a solution of 29-b (430 mg, 1.82 mmol, 1 eq) in THF (20.00 mL). The atmosphere was purged with nitrogen gas three times, and the mixture was stirred at 70°C for 12.5 hours. The reaction solution was concentrated, and the residue was directly subjected to column chromatography (petroleum ether:ethyl acetate = 4:1 to 1:1) to obtain compound 29-c.
ステップＤ：２９－ｃ（２００ｍｇ、７６２．７３μｍｏｌ、１ｅｑ）のＤＭＦ（３ｍＬ）溶液に炭酸カリウム（３１６ｍｇ、２．２９ｍｍｏｌ、３ｅｑ）及び２６－ｃ（４８５ｍｇ、１．５３ｍｍｏｌ、２ｅｑ）を加え、次に、１２０℃で１２時間反応させた。反応溶液を濾過し、ケーキをＤＭＦ（２ｍＬ）で洗浄し、濾液を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－アセトニトリル］により精製して化合物２９を得た。１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ １．２２ － １．４８ （ｍ， ６ Ｈ） ５．３０ （ｓ， ２ Ｈ） ７．０２ （ｂｒ ｓ， ２ Ｈ） ７．２６ － ７．５２ （ｍ， １ Ｈ） ７．７６ （ｄｄｄ， Ｊ＝１０．０６，
８．５３， １．１０ Ｈｚ， １ Ｈ） ７．９４ － ８．１３ （ｍ， １ Ｈ） ８．１５ － ８．３６ （ｍ， ２ Ｈ） １１．１２ （ｂｒ ｓ， １ Ｈ）。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４３９．１ ［Ｍ＋１］＋。
Step D: Potassium carbonate (316 mg, 2.29 mmol, 3 eq) and 26-c (485 mg, 1.53 mmol, 2 eq) were added to a solution of 29-c (200 mg, 762.73 μmol, 1 eq) in DMF (3 mL), and then reacted at 120° C. for 12 h. The reaction solution was filtered, the cake was washed with DMF (2 mL), and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to obtain compound 29. 1H NMR (400 MHz, DMSO- d6 ) δ ppm 1.22 - 1.48 (m, 6H) 5.30 (s, 2H) 7.02 (br s, 2H) 7.26 - 7.52 (m, 1H) 7.76 (ddd, J = 10.06,
8.53, 1.10 Hz, 1H) 7.94 - 8.13 (m, 1H) 8.15 - 8.36 (m, 2H) 11.12 (br s, 1H). LCMS (ESI) m/z: 439.1 [M+1] <+> .
実施例３０
合成スキーム：
Example 30
Synthesis scheme:
ステップＡ：３－ｃ（２５０ｍｇ、９５７．０２μｍｏｌ、１ｅｑ）を溶解させたＤＭＦ（２．００ｍＬ）溶液に２－クロロ－４－アミノ－５－ブロモピリミジン（１９９．４９ｍｇ、９５７．０２μｍｏｌ、１ｅｑ）及び炭酸カリウム（２６４．５３ｍｇ、１．９１ｍｍｏｌ、２ｅｑ）を加えた。反応系を１２０℃で１２時間撹拌し、反応溶液を冷却させた後、水（５０ｍＬ）で希釈し、酢酸エチル（５０ｍＬ×２）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させた後減圧濃縮し、残留物を薄層クロマトグラフィー（ＳｉＯ２、ＰＥ：ＥｔＯＡｃ＝２：１）により精製して化合物３０－ａを得た。 Step A: 2-chloro-4-amino-5-bromopyrimidine (199.49 mg, 957.02 μmol, 1 eq) and potassium carbonate (264.53 mg, 1.91 mmol, 2 eq) were added to a solution of 3-c (250 mg, 957.02 μmol, 1 eq) in DMF (2.00 mL). The reaction was stirred at 120° C. for 12 hours, cooled, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer chromatography (SiO 2 , PE:EtOAc=2:1) to give compound 30-a.
ステップＢ：３０－ａ（２００ｍｇ、４６１．６７μｍｏｌ、１ｅｑ）、シクロプロピルボロン酸（１１８．９７ｍｇ、１．３９ｍｍｏｌ、３ｅｑ）、炭酸カリウム（１９１．４２ｍｇ、１．３９ｍｍｏｌ、３ｅｑ）及びビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（１６２．０２ｍｇ、２３０．８４μｍｏｌ、０．５ｅｑ）を１，４－ジオキサン（５ｍＬ）に溶解させ、窒素ガスで３回置換した後、１００℃で２時間撹拌した。反応溶液を水（２０ｍＬ）で希釈し、酢酸エチル（５０ｍＬ×２）で抽出し、合わせた有機相を無水硫酸ナトリウムで乾燥させた後減圧濃縮し、残留物を分取ＨＰＬＣ［移動相：水（０．１％のＴＦＡ）－ＡＣＮ］により精製して化合物３０を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６） δ＝８．５５ （ｂｒ ｄ， Ｊ＝９．３ Ｈｚ， １Ｈ）， ８．２２ （ｄ， Ｊ＝１．７ Ｈｚ， １Ｈ）， ７．８５ （ｓ， １Ｈ）， ７．４１ － ７．３３ （ｍ， ２Ｈ）， ７．２４ （ｍ， １Ｈ）， ７．２０ － ７．１１ （ｍ， １Ｈ）， ５．１９ （ｓ， ２Ｈ）， １．６７（ｍ， １ Ｈ）， ０．９６ （ｄｄ， Ｊ＝１．９， ８．３ Ｈｚ， ２Ｈ），
０．６３ （ｄｄ， Ｊ＝１．７， ５．３ Ｈｚ， ２Ｈ）。ＬＣＭＳ （ＥＳＩ）
ｍ／ｚ： ３９５．３ ［Ｍ＋１］＋。
Step B: 30-a (200 mg, 461.67 μmol, 1 eq), cyclopropylboronic acid (118.97 mg, 1.39 mmol, 3 eq), potassium carbonate (191.42 mg, 1.39 mmol, 3 eq) and bis(triphenylphosphine)palladium(II) dichloride (162.02 mg, 230.84 μmol, 0.5 eq) were dissolved in 1,4-dioxane (5 mL), purged with nitrogen gas three times, and then stirred at 100° C. for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.1% TFA)-ACN] to obtain compound 30. 1H NMR (400MHz, DMSO- d6 ) δ=8.55 (br d, J=9.3 Hz, 1H), 8.22 (d, J=1.7 Hz, 1H), 7.85 (s, 1H), 7.41-7.33 (m, 2H), 7.24 (m, 1H), 7.20-7.11 (m, 1H), 5.19 (s, 2H), 1.67 (m, 1H), 0.96 (dd, J=1.9, 8.3 Hz, 2H),
0.63 (dd, J=1.7, 5.3 Hz, 2H). LCMS (ESI)
m/z: 395.3 [M+1] + .
実施例３１
合成スキーム：
Example 31
Synthesis scheme:
ステップＡ：３－１（２ｇ、１１．３３ｍｍｏｌ、１ｅｑ）のトルエン（２０ｍＬ）溶液にｍ－フルオロベンジルアミン（１．５６ｇ、１２．４６ｍｍｏｌ、１．４２ｍＬ、１．１ｅｑ）及びＮ，Ｎ－ジイソプロピルエチルアミン（４．３９ｇ、３３．９９ｍｍｏｌ、５．９２ｍＬ、３ｅｑ）を加えた。添加完了後、混合物を１００℃で２時間撹拌した。反応溶液を濃縮し、残留物をカラムクロマトグラフィー（ＰＥ：ＥｔＯＡｃ＝１００：１～３０：１）により精製して化合物３１－ａを得た。 Step A: To a solution of 3-1 (2 g, 11.33 mmol, 1 eq) in toluene (20 mL) was added m-fluorobenzylamine (1.56 g, 12.46 mmol, 1.42 mL, 1.1 eq) and N,N-diisopropylethylamine (4.39 g, 33.99 mmol, 5.92 mL, 3 eq). After the addition was complete, the mixture was stirred at 100°C for 2 h. The reaction solution was concentrated and the residue was purified by column chromatography (PE: EtOAc = 100: 1 to 30: 1) to obtain compound 31-a.
ステップＢ：窒素ガスの保護下で、３１－ａ（１．６２ｇ、６．５２ｍｍｏｌ、１ｅｑ）のメタノール（３０ｍＬ）溶液に湿式パラジウム炭素（３００ｍｇ）を加え、添加完了後、真空にして水素ガスで３回置換し、反応溶液を水素ガス（１５ｐｓｉ）の雰囲気下で、４５℃で１２時間撹拌した。反応溶液を珪藻土で濾過し、ケーキをメタノール（１０ｍＬ×３）で洗浄し、濾液を濃縮して化合物３１－ｂを得た。 Step B: Under nitrogen gas protection, wet palladium on carbon (300 mg) was added to a solution of 31-a (1.62 g, 6.52 mmol, 1 eq) in methanol (30 mL). After the addition was complete, the mixture was evacuated and replaced with hydrogen gas three times, and the reaction solution was stirred under an atmosphere of hydrogen gas (15 psi) at 45°C for 12 hours. The reaction solution was filtered through diatomaceous earth, the cake was washed with methanol (10 mL x 3), and the filtrate was concentrated to obtain compound 31-b.
ステップＣ：化合物３１－ｂ（２ｇ、８．５０ｍｍｏｌ、１ｅｑ）のテトラヒドロフラン（２０ｍＬ）溶液にＣＤＩ（２．７６ｇ、１７．００ｍｍｏｌ、２ｅｑ）を加え、反応溶液を７０℃に昇温させて２時間撹拌した。反応溶液を濃縮して残留物を得、残留物をカラムクロマトグラフィー（ＰＥ／ＥＡ＝５／１－１／１）により精製して化合物３１－ｃを得た。ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ２６２．５ ［Ｍ＋１］＋。 Step C: To a solution of compound 31-b (2 g, 8.50 mmol, 1 eq) in tetrahydrofuran (20 mL) was added CDI (2.76 g, 17.00 mmol, 2 eq), and the reaction solution was heated to 70° C. and stirred for 2 hours. The reaction solution was concentrated to obtain a residue, which was purified by column chromatography (PE/EA=5/1-1/1) to obtain compound 31-c. LCMS (ESI) m/z: 262.5 [M+1] + .
ステップＦ：窒素ガスの保護下で、３１－ｃ（２６０ｍｇ、９９５．３０μｍｏｌ、１ｅｑ）のＤＭＦ（３ｍＬ）溶液に２６－ｃ（５１０ｍｇ、１．９９ｍｍｏｌ、２ｅｑ）及び炭酸カリウム（４１３ｍｇ、２．９９ｍｍｏｌ、３ｅｑ）を加えた。反応溶液を１２０℃で１２時間撹拌した。反応溶液を濾過し、濾液を分取ＨＰＬＣ［移動相：水（０．２２５％のＦＡ）－アセトニトリル］により精製して化合物３１を得た。１Ｈ ＮＭＲ （４
００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ ｐｐｍ １．３５ （ｓ， ６ Ｈ） ５．１０ （ｓ， ２ Ｈ） ７．００ （ｂｒ ｓ， ２ Ｈ） ７．０７ － ７．１４ （ｍ， １ Ｈ） ７．１５ － ７．２３ （ｍ， ２ Ｈ） ７．３８ （ｔｄ， Ｊ＝８．０１， ６．２４ Ｈｚ， １ Ｈ） ８．１０ （ｔ， Ｊ＝２．０８ Ｈｚ， １ Ｈ） ８．２６ （ｄｄ， Ｊ＝９．３５， ２．５１ Ｈｚ， １ Ｈ） １１．１２ （ｂｒ ｓ， １ Ｈ）；ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４３８．１ ［Ｍ＋１］＋。
Step F: Under the protection of nitrogen gas, 26-c (510 mg, 1.99 mmol, 2 eq) and potassium carbonate (413 mg, 2.99 mmol, 3 eq) were added to a solution of 31-c (260 mg, 995.30 μmol, 1 eq) in DMF (3 mL). The reaction solution was stirred at 120° C. for 12 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to obtain compound 31. 1 H NMR (4
00 MHz, DMSO- d6 ) δ ppm 1.35 (s, 6H) 5.10 (s, 2H) 7.00 (br s, 2H) 7.07-7.14 (m, 1H) 7.15-7.23 (m, 2H) 7.38 (td, J=8.01, 6.24 Hz, 1H) 8.10 (t, J=2.08 Hz, 1H) 8.26 (dd, J=9.35, 2.51 Hz, 1H) 11.12 (br s, 1H); LCMS (ESI) m/z: 438.1 [M+1] + .
実施例３２
合成スキーム：
Example 32
Synthesis scheme:
ステップＡ：窒素ガスの保護下で、３－１（１．４ｇ、７．９３ｍｍｏｌ、１ｅｑ）のトルエン（４０ｍＬ）溶液に２，４－ジメトキシベンジルアミン（１．３３ｇ、７．９３ｍｍｏｌ、１．１９ｍＬ、１ｅｑ）及びトリエチルアミン（１．６０ｇ、１５．８６ｍｍｏｌ、２．２１ｍＬ、２ｅｑ）を加え、反応溶液を１００℃で４時間撹拌した。反応溶液を冷却させた後水（４０ｍＬ）で洗浄し、分離させ、有機相を減圧濃縮した後メタノールを加えて１時間撹拌し、濾過し、ケーキを真空で乾燥させて化合物３２－ａを得た。 Step A: Under the protection of nitrogen gas, 2,4-dimethoxybenzylamine (1.33 g, 7.93 mmol, 1.19 mL, 1 eq) and triethylamine (1.60 g, 15.86 mmol, 2.21 mL, 2 eq) were added to a solution of 3-1 (1.4 g, 7.93 mmol, 1 eq) in toluene (40 mL), and the reaction solution was stirred at 100°C for 4 hours. After cooling the reaction solution, it was washed with water (40 mL) and separated. The organic phase was concentrated under reduced pressure, and then methanol was added and stirred for 1 hour. It was filtered, and the cake was dried in vacuum to obtain compound 32-a.
ステップＢ：３２－ａ（２ｇ、６．５１ｍｍｏｌ、１ｅｑ）のテトラヒドロフラン（６０ｍＬ）及び水（２０ｍＬ）の溶液に亜鉛粉末（２．１３ｇ、３２．５４ｍｍｏｌ、５ｅ
ｑ）及び塩化アンモニウム（１．７４ｇ、３２．５４ｍｍｏｌ、５ｅｑ）を加え、反応溶液を６０℃で１時間撹拌した。反応溶液を水（５０ｍＬ）で希釈し、酢酸エチル（５０ｍＬ）で抽出し、有機相を減圧濃縮した後カラムクロマトグラフィー（石油エーテル：酢酸エチル＝３：１～１：１）により分離して化合物３２－ｂを得た。
Step B: To a solution of 32-a (2 g, 6.51 mmol, 1 eq) in tetrahydrofuran (60 mL) and water (20 mL) was added zinc powder (2.13 g, 32.54 mmol, 5eq).
q) and ammonium chloride (1.74 g, 32.54 mmol, 5 eq) were added, and the reaction solution was stirred at 60° C. for 1 hour. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL), and the organic phase was concentrated under reduced pressure and then separated by column chromatography (petroleum ether:ethyl acetate=3:1 to 1:1) to obtain compound 32-b.
ステップＣ：窒素ガスの保護下で、３２－ｂ（１．６ｇ、５．７７ｍｍｏｌ、１ｅｑ）のテトラヒドロフラン（３０ｍＬ）溶液にＣＤＩ（１．８７ｇ、１１．５４ｍｍｏｌ、２ｅｑ）を加えた。反応溶液を６０℃で１６時間撹拌した後水（２ｍＬ）を加えてクエンチングさせ、反応溶液を減圧濃縮し、残留物にメタノール（２０ｍＬ）を加えて２時間撹拌し、濾過し、ケーキを真空で乾燥させ化合物３２－ｃを得た。 Step C: Under nitrogen gas protection, CDI (1.87 g, 11.54 mmol, 2 eq) was added to a solution of 32-b (1.6 g, 5.77 mmol, 1 eq) in tetrahydrofuran (30 mL). The reaction solution was stirred at 60°C for 16 hours, then quenched by adding water (2 mL), concentrated under reduced pressure, methanol (20 mL) was added to the residue, stirred for 2 hours, filtered, and the cake was dried in vacuum to obtain compound 32-c.
ステップＤ：窒素ガスの保護下で、３２－ｃ（１．１ｇ、３．６３ｍｍｏｌ、１ｅｑ）のＤＭＦ（１０ｍＬ）溶液に２６－ｃ（１．７３ｇ、５．４４ｍｍｏｌ、１．５ｅｑ）及び炭酸カリウム（１．５０ｇ、１０．８８ｍｍｏｌ、３ｅｑ）を加え、反応溶液を１２０℃で４時間撹拌し、反応溶液に水（４０ｍＬ）を加えて希釈し、濾過し、ケーキを真空で乾燥させて化合物３２－ｄを得た。 Step D: Under nitrogen gas protection, 26-c (1.73 g, 5.44 mmol, 1.5 eq) and potassium carbonate (1.50 g, 10.88 mmol, 3 eq) were added to a solution of 32-c (1.1 g, 3.63 mmol, 1 eq) in DMF (10 mL), and the reaction solution was stirred at 120°C for 4 hours. The reaction solution was diluted with water (40 mL), filtered, and the cake was dried in vacuum to obtain compound 32-d.
ステップＥ：３２－ｄ（１．６ｇ、３．３４ｍｍｏｌ、１ｅｑ）のＤＭＦ（４ｍＬ）溶液に炭酸カリウム（９２２．４１ｍｇ、６．６７ｍｍｏｌ、２ｅｑ）及びｐ－メトキシベンジルクロリド（７３１．６６ｍｇ、４．６７ｍｍｏｌ、６３６．２３μＬ、１．４ｅｑ）を加え、窒素ガスの保護下で５０℃で２時間撹拌し、反応溶液に水（２５ｍＬ）を加えて希釈し、濾過し、ケーキを真空で乾燥させた後化合物３２－ｅを得た。 Step E: To a solution of 32-d (1.6 g, 3.34 mmol, 1 eq) in DMF (4 mL), potassium carbonate (922.41 mg, 6.67 mmol, 2 eq) and p-methoxybenzyl chloride (731.66 mg, 4.67 mmol, 636.23 μL, 1.4 eq) were added, and the mixture was stirred at 50°C for 2 hours under nitrogen gas protection. The reaction solution was diluted with water (25 mL), filtered, and the cake was dried in vacuum to obtain compound 32-e.
ステップＦ：３２－ｅ（１．８ｇ、３．００ｍｍｏｌ、１ｅｑ）のＴＦＡ（２７．７２ｇ、２４３．１１ｍｍｏｌ、１８．００ｍＬ、８０．９８ｅｑ）溶液を３０℃で３時間撹拌し、反応溶液を濃縮し、残留物をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝１／１～０／１）により分離して化合物３２－ｆを得た。 Step F: A solution of 32-e (1.8 g, 3.00 mmol, 1 eq) in TFA (27.72 g, 243.11 mmol, 18.00 mL, 80.98 eq) was stirred at 30°C for 3 hours, the reaction solution was concentrated, and the residue was separated by column chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to obtain compound 32-f.
ステップＧ：３２－ｆ（０．６ｇ、１．３４ｍｍｏｌ、１ｅｑ）のＤＭＦ（５ｍＬ）溶液に１，１，１，２，２－ペンタフルオロ－４－ヨードブタン（１．４６ｇ、５．３４ｍｍｏｌ、４ｅｑ）及び炭酸カリウム（９２２．５５ｍｇ、６．６８ｍｍｏｌ、５ｅｑ）を加えた。反応溶液を窒素ガスの保護下で、５０℃で１時間反応させた。反応溶液に希塩酸（３０ｍＬ、１ｍｏｌ／Ｌ）を加えて中和させ、次に、酢酸エチルで抽出し、硫酸ナトリウムで乾燥させた後濃縮し、残留物をカラムクロマトグラフィー（石油エーテル／酢酸エチル＝１／１～０／１）により分離して化合物３２－ｇを得た。 Step G: 1,1,1,2,2-pentafluoro-4-iodobutane (1.46 g, 5.34 mmol, 4 eq) and potassium carbonate (922.55 mg, 6.68 mmol, 5 eq) were added to a solution of 32-f (0.6 g, 1.34 mmol, 1 eq) in DMF (5 mL). The reaction solution was reacted at 50°C for 1 hour under nitrogen gas protection. The reaction solution was neutralized by adding dilute hydrochloric acid (30 mL, 1 mol/L), then extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The residue was separated by column chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to obtain compound 32-g.
ステップＨ：窒素ガスの保護下で、３２－ｇ（０．２ｇ、３３５．８５μｍｏｌ、１ｅｑ）のＴＦＡ（２ｍＬ）溶液にトリフルオロメタンスルホン酸（３．４０ｇ、２２．６６ｍｍｏｌ、２ｍＬ、６７．４５ｅｑ）を加えた。反応溶液を５０℃で１６時間撹拌した。反応溶液を水酸化ナトリウム（８０ｍＬ、１ｍｏｌ／Ｌ）の水溶液に注いで中和させ、酢酸エチル（６０ｍＬ）で抽出し、有機相を減圧濃縮した後、分取ＨＰＬＣ［水（０．０７５％のＴＦＡ）－アセトニトリル］により精製して化合物３２を得た。１Ｈ ＮＭＲ （４００ＭＨｚ， ＤＭＳＯ－ｄ６） δ＝１１．１４ （ｓ， １Ｈ）， ８．２６ （ｄｄ， Ｊ＝２．６， ９．４ Ｈｚ， １Ｈ）， ８．１５ （ｔ， Ｊ＝２．１ Ｈｚ， １Ｈ）， ７．０１ （ｂｒ ｓ， ２Ｈ）， ４．２２ （ｔ， Ｊ＝６．９ Ｈｚ， ２Ｈ）， ２．９０ － ２．７２ （ｍ， ２Ｈ）， １．３５ （ｓ， ６Ｈ）． ＬＣＭＳ （ＥＳＩ） ｍ／ｚ： ４７６．２ ［Ｍ＋１］＋。 Step H: Under the protection of nitrogen gas, trifluoromethanesulfonic acid (3.40 g, 22.66 mmol, 2 mL, 67.45 eq) was added to a solution of 32-g (0.2 g, 335.85 μmol, 1 eq) in TFA (2 mL). The reaction solution was stirred at 50° C. for 16 hours. The reaction solution was poured into an aqueous solution of sodium hydroxide (80 mL, 1 mol/L) to neutralize it, extracted with ethyl acetate (60 mL), and the organic phase was concentrated under reduced pressure, and then purified by preparative HPLC [water (0.075% TFA)-acetonitrile] to obtain compound 32. 1H NMR (400MHz, DMSO- d6 ) δ=11.14 (s, 1H), 8.26 (dd, J=2.6, 9.4 Hz, 1H), 8.15 (t, J=2.1 Hz, 1H), 7.01 (br s, 2H), 4.22 (t, J=6.9 Hz, 2H), 2.90-2.72 (m, 2H), 1.35 (s, 6H). LCMS (ESI) m/z: 476.2 [M+1] <+> .
生物学的試験
実験例１：体外活性試験
ｌｎＣａｐ細胞に基づくｃＧＭＰ発現試験
１．実験ステップ
１）溶液の製造
・１０％のＢＳＡ（ウシ血清アルブミン）
１０ｇのＢＳＡを１００ｍＬの再蒸留水（ｄｄＨ２Ｏ）に溶解させて、１０％のＢＳＡを得た。
・５ｍＭのＤＥＴＡ（ジエチレントリアミン）－ＮＯ
１０ｍｇのＤＥＴＡ－ＮＯを秤量し、１２．２ｍＬの再蒸留水（ｄｄＨ２Ｏ）に溶解させて、５ｍＭのＤＥＴＡ－ＮＯを得、小分けして－２０℃の冷蔵庫で凍結保存した。
Biological Test Experimental Example 1: In Vitro Activity Test cGMP Expression Test Based on lnCap Cells 1. Experimental Steps 1) Preparation of Solution 10% BSA (bovine serum albumin)
10 g of BSA was dissolved in 100 mL of double distilled water (ddH 2 O) to obtain 10% BSA.
5 mM DETA (diethylenetriamine)-NO
10 mg of DETA-NO was weighed out and dissolved in 12.2 mL of double distilled water (ddH 2 O) to obtain 5 mM DETA-NO, which was then aliquoted and stored frozen in a -20°C refrigerator.
・洗浄緩衝液（Ｗａｓｈｉｎｇ Ｂｕｆｆｅｒ、５０ｍＬ） Washing Buffer (50mL)
・分析緩衝液（Ａｓｓａｙ Ｂｕｆｆｅｒ、５０ｍＬ） ・Assay Buffer (50mL)
・検出緩衝液（Ｄｅｔｅｃｔｉｏｎ Ｂｕｆｆｅｒ）
ａ）５０μＬのｃＧＭＰ－Ｄ２（Ｄ２標識環状グアノシン一リン酸）を１ｍＬの溶解緩衝液（ｌｙｓｉｓ ｂｕｆｆｅｒ）に加え、均一に混合した。
Detection Buffer
a) 50 μL of cGMP-D2 (D2-labeled cyclic guanosine monophosphate) was added to 1 mL of lysis buffer and mixed uniformly.
ｂ）５０μＬのａｎｔｉ－ｃＧＭＰ ｃｒｙｐｔａｔｅ（Ｅｕ３＋クリプテート標識抗環状グアノシン一リン酸抗体）を１ｍＬの溶解緩衝液（ｌｙｓｉｓ ｂｕｆｆｅｒ）に加え、均一に混合した。 b) 50 μL of anti-cGMP cryptate (Eu 3+ cryptate-labeled anti-cyclic guanosine monophosphate antibody) was added to 1 mL of lysis buffer and mixed uniformly.
２）化合物の希釈
（１）化合物をＤＭＳＯで５ｍＭに希釈した。１０μＬの化合物をＥｃｈｏシャローウェルプレートに移した。
2) Compound dilution (1) Compounds were diluted to 5 mM in DMSO. 10 μL of compound was transferred to an Echo shallow well plate.
（２）Ｅｃｈｏを使用して化合物の勾配希釈を実行し、各化合物を１０の濃度勾配に希釈し、それぞれ５０ｎＬを３８４マイクロウェルプレートに加えた。
３）ＬＮＣａｐ細胞の準備
（１）ＬＮＣａｐ培地：ＲＰＭＩ１６４０＋１０％のウシ胎児血清＋１％の二重抗体
（２）細胞の継代に使用されたリン酸緩衝液、トリプシン、培地を３７℃のウォーターバスで予熱した。
(2) A gradient dilution of the compounds was performed using Echo, where each compound was diluted into a concentration gradient of 10 and 50 nL of each was added to a 384 microwell plate.
3) Preparation of LNCap cells (1) LNCap medium: RPMI1640 + 10% fetal bovine serum + 1% double antibody (2) Phosphate buffer, trypsin, and medium used for cell passage were preheated in a 37°C water bath.
（３）３７℃、５％のＣＯ２インキュベーターから細胞（継代１４代）を取り出し、ピペットを使用して培養フラスコ内の古い培地を除去した。
（４）５ｍＬのリン酸緩衝液を吸引して培養フラスコに加えて細胞を洗浄し、液体を除去した。
(3) Cells (passage 14) were removed from the 37° C., 5% CO 2 incubator, and the old medium in the culture flask was removed using a pipette.
(4) 5 mL of phosphate buffer was aspirated and added to the culture flask to wash the cells, and the liquid was removed.
（５）３ｍＬのトリプシンを吸引して培養フラスコに加え、振とうしてから液体を除去し、培養フラスコをインキュベーターに入れた。
（６）約２分後培養フラスコを取り出し、細胞が分離されたことを確認した後、培養フラスコに９ｍＬの培地を加え、数回ピペッティングを繰り返し、細胞懸濁液を５０ｍＬの遠沈チューブに移した。
(5) 3 mL of trypsin was aspirated and added to the culture flask, shaken, the liquid was removed, and the culture flask was placed in the incubator.
(6) After about 2 minutes, the culture flask was removed, and after confirming that the cells had been separated, 9 mL of medium was added to the culture flask, and the cell suspension was transferred to a 50 mL centrifuge tube after repeated pipetting several times.
（７）０．７ｍＬの細胞懸濁液をピペットで計数カップに移し、ＶｉＣｅｌｌ ＸＲで計数した。残りの細胞については、１０００ｒｐｍで５分間遠心分離して、上清を除去した。 (7) 0.7 mL of the cell suspension was pipetted into a counting cup and counted using a ViCell XR. The remaining cells were centrifuged at 1000 rpm for 5 minutes and the supernatant was removed.
（８）１０ｍＬの洗浄緩衝液（ｗａｓｈｉｎｇ ｂｕｆｆｅｒ）を加えて細胞を洗浄し、１０００ｒｐｍで５分間遠心分離して、上清を除去した。
（９）分析緩衝液（ａｓｓａｙ ｂｕｆｆｅｒ）を加え、細胞濃度を１．２５×１０６／ｍＬに調節した。８μＬ／ウェルでマイクロプレートに加えた。
(8) The cells were washed by adding 10 mL of washing buffer, centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed.
(9) An assay buffer was added to adjust the cell concentration to 1.25×10 6 /mL, and 8 μL/well of the solution was added to the microplate.
４）ＤＥＴＡ－ＮＯの製造及び添加
（１）１０μＬ ５ｍＭのＤＥＴＡ－ＮＯをそれぞれ１２４０μＬ及び１６５７μＬの分析緩衝液（ａｓｓａｙ ｂｕｆｆｅｒ）に加えて、４０μＭ及び３０μＭのＤＥＴＡ－ＮＯを得た。
4) Preparation and Addition of DETA-NO (1) 10 μL 5 mM DETA-NO was added to 1240 μL and 1657 μL of assay buffer, respectively, to obtain 40 μM and 30 μM DETA-NO.
（２）Ｂｒａｖｏを使用して、２μＬ／ウェルのＤＥＴＡ－ＮＯを３８４マイクロウェルプレートに移した。
（３）１５００ｒｐｍで５分間遠心分離した。マイクロプレートを３７℃で３０分間培養した。
(2) Using a Bravo, 2 μL/well of DETA-NO was transferred to a 384 microwell plate.
(3) Centrifuge at 1500 rpm for 5 minutes. The microplate was incubated at 37° C. for 30 minutes.
５）ｃＧＭＰ標準曲線の作成
（１）１ｍＭのｃＧＭＰストック溶液を試験緩衝液（ａｓｓａｙ ｂｕｆｆｅｒ）で１０μＭに希釈した。次に、１１の濃度勾配で４倍に勾配希釈した。
5) Preparation of cGMP standard curve (1) 1 mM cGMP stock solution was diluted to 10 μM with assay buffer, then diluted 4-fold with 11 concentration gradients.
（２）希釈したｃＧＭＰを１０μＬ／ウェルでマイクロウェルプレートに加えた。
６）検出試薬を加え、プレートを読み取った
（１）Ｂｒａｖｏを使用して、５μＬ／ウェルのｃＧＭＰ－Ｄ２を３８４マイクロウェルプレートに移した。１５００ｒｐｍで１分間遠心分離した。
(2) The diluted cGMP was added to the microwell plate at 10 μL/well.
6) Detection reagent was added and the plate was read (1) Using the Bravo, 5 μL/well of cGMP-D2 was transferred to a 384 microwell plate. Centrifuge at 1500 rpm for 1 minute.
（２）Ｂｒａｖｏを使用して、５μＬ／ウェルのａｎｔｉ－ｃＧＭＰ ｃｒｙｐｔａｔｅを３８４マイクロウェルプレートに移した。１５００ｒｐｍで１分間遠心分離した。
（３）室温で１時間培養した。
(2) Using a Bravo, 5 μL/well of the anti-cGMP cryptate was transferred to a 384-microwell plate, followed by centrifugation at 1500 rpm for 1 minute.
(3) The mixture was incubated at room temperature for 1 hour.
（４）ｅｎｖｉｓａｇｅで６５／６１５を読み取った。
７）データ分析
（１）ｃＧＭＰ標準曲線：Ｇｒａｐｈｐａｄ ｐｒｉｓｍを使用して、ｃＧＭＰ濃度と６６５／６１５の比率に基づいて標準曲線を作成した。
(4) 65/615 was read on envisage.
7) Data Analysis (1) cGMP standard curve: A standard curve was prepared based on cGMP concentration and the 665/615 ratio using Graphpad prism.
（２）ＨＴＲＦ（均一時間分解蛍光技術）比率（６６５／６１５）をｃＧＭＰ濃度に変換した：Ｇｒａｐｈｐａｄ ｐｒｉｓｍにおいて、ＨＴＲＦ比率（６６５／６１５）をｃＧＭＰ標準曲線の比列にコピーし、「Ｌｏｇ ｉｎｈｉｂｉｔｏｒ ｖｓ ｒｅｓｐｏｎｓｅ－ｖａｒｉａｂｌｅ ｓｌｏｐｅ」を実行して分析し、「ｉｎｔｅｒｐｏｌａｔｅ」を選択し、ＨＴＲＦ比率（６６５／６１５）をｃＧＭＰ濃度に変換した。 (2) The HTRF (homogeneous time-resolved fluorescence technique) ratio (665/615) was converted to cGMP concentration: In Graphpad Prism, the HTRF ratio (665/615) was copied to the ratio column of the cGMP standard curve, analyzed by running "Log inhibitor vs response-variable slope," and selected "interpolate" to convert the HTRF ratio (665/615) to cGMP concentration.
（３）化合物活性化曲線：変換したｃＧＭＰ濃度と化合物濃度をＧｒａｐｈｐａｄ ｐｒｉｓｍの「Ｌｏｇ ａｇｏｎｉｓｔ ｖｓ ｒｅｓｐｏｎｓｅ－ｖａｒｉａｂｌｅ ｓｌｏｐｅ」分析方法を使用して曲線を作成した。 (3) Compound activation curve: A curve was created using the "Log agonist vs response-variable slope" analysis method in Graphpad Prism for the converted cGMP concentration and compound concentration.
実験結果により、本発明の化合物がｓＧＣに対して良好な刺激活性を有することを示し
た。
実験例２：ラット体内における薬物動態評価
実験目的：
ラット体内における本発明の化合物の薬物動態パラメータを検出するためである。
The experimental results show that the compounds of the present invention have good stimulating activity on sGC.
Experimental Example 2: Evaluation of pharmacokinetics in rats Experimental objective:
The purpose is to detect the pharmacokinetic parameters of the compound of the present invention in the rat body.
実験スキーム：
１）実験動物：７～９週齢のオスＳＤラット６匹を選択し、各群に３匹ずつ、無作為に２つの群に分けた。
Experimental scheme:
1) Experimental animals: Six male SD rats aged 7-9 weeks were selected and randomly divided into two groups, with three rats in each group.
２）薬物の製造：適量の薬物を秤量し、１０％のＤＭＳＯ＋５０％のＰＥＧ４００＋４０％のＨ２Ｏの混合溶媒に溶解させて、０．２ｍｇ／ｍＬに製造した；適量の薬物を秤量し、１０％のＥｔＯＨ＋４０％のＰＥＧ４００＋５０％のＨ２Ｏの混合溶媒に溶解させて、０．３ｍｇ／ｍＬに製造した。 2) Preparation of drugs: An appropriate amount of drug was weighed and dissolved in a mixed solvent of 10% DMSO + 50% PEG400 + 40% H2O to prepare a concentration of 0.2 mg/mL; an appropriate amount of drug was weighed and dissolved in a mixed solvent of 10% EtOH + 40% PEG400 + 50% H2O to prepare a concentration of 0.3 mg/mL.
実験的操作：
群１の動物には、単回尾静脈注射により、１．０ｍｇ／ｋｇの投与量、０．２ｍｇ／ｍＬの濃度の薬物を投与し、群２の動物には、胃内投与により、３ｍｇ／ｋｇの投与量、０．３ｍｇ／ｍＬの濃度の化合物を投与した。投与後の０．０８３３時間（尾静脈注射群のみ）、０．２５時間、０．５時間、１時間、２時間、４時間、８時間及び２４時間後に動物から血漿試料を採取した。
データ分析：
ＬＣ－ＭＳ／ＭＳ方法を使用して血漿試料における薬物濃度を測定し、試験薬物の薬物動態パラメータを得、表２に示した。
Experimental procedure:
Animals in group 1 were administered the drug at a dose of 1.0 mg/kg and a concentration of 0.2 mg/mL by a single tail vein injection, and animals in group 2 were administered the compound at a dose of 3 mg/kg and a concentration of 0.3 mg/mL by intragastric administration. Plasma samples were taken from the animals at 0.0833 hours (tail vein injection group only), 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration.
Data Analysis:
Drug concentrations in plasma samples were measured using an LC-MS/MS method, and the pharmacokinetic parameters of the test drugs were obtained and shown in Table 2.
結論：本発明の化合物はラットの体内において、良好な薬物動態特性を示した。
実験例３：ヒト肝ミクロソームＣＹＰ阻害実験
研究プロジェクトの目的は、ＣＹＰアイソザイムの５－ｉｎ－１プローブ基質を使用して、ヒト肝臓ミクロソームシトクロムＰ４５０アイソザイム（ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ２Ｃ１９、ＣＹＰ２Ｄ６、ＣＹＰ３Ａ４）に対する試験物質の阻害効果を評価することである。
Conclusion: The compounds of the present invention exhibited good pharmacokinetic properties in rats.
Experimental Example 3: Human liver microsomal CYP inhibition experiment The purpose of the research project is to evaluate the inhibitory effect of test substances on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) using 5-in-1 probe substrates for CYP isoenzymes.
混合ヒト肝ミクロソーム（ＨＬＭ）は、Ｃｏｒｎｉｎｇ Ｉｎｃ．（Ｓｔｅｕｂｅｎ、Ｎｅｗ Ｙｏｒｋ、ＵＳＡ）又はその他のサプライヤーから購入し、いずれも使用するまで－７０℃未満の条件で保存した。 Mixed human liver microsomes (HLM) were purchased from Corning Inc. (Steuben, New York, USA) or other suppliers and were stored at <-70°C until use.
一連の濃度に希釈した試験物質の作業溶液を、ヒト肝臓ミクロソーム、プローブ基質及
び循環系の補助因子を含むインキュベーションシステムに添加し、溶媒を含むが試験物質を含まない対照は、酵素活性対照（１００％）として機能した。試料中のプローブ基質によって生成された代謝産物の濃度は、液体クロマトグラフィー－タンデム質量分析法（ＬＣ－ＭＳ／ＭＳ）を使用して測定した。試験物質の濃度に対する活性の平均百分率の非線形回帰分析は、ＳｉｇｍａＰｌｏｔ（Ｖ．１１）を使用して実施した。ＩＣ５０値は、３パラメーター又は４パラメーターの逆対数方程式を使用して計算した。試験結果は表３に示された通りである。
A working solution of the test substance diluted to a series of concentrations was added to an incubation system containing human liver microsomes, probe substrates and circulatory cofactors, and a control containing solvent but no test substance served as an enzyme activity control (100%). The concentrations of metabolites generated by the probe substrate in the samples were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Nonlinear regression analysis of the mean percentage of activity versus the concentration of the test substance was performed using SigmaPlot (V.11). IC50 values were calculated using a three-parameter or four-parameter antilogarithmic equation. The test results are shown in Table 3.
結論：本発明の化合物は、５つのＣＹＰアイソザイムに対していずれも弱い阻害効果を示した。 Conclusion: The compounds of the present invention showed weak inhibitory effects against all five CYP isoenzymes.
Claims (24)
Ｒ２は、Ｃ１－６アルキル、－ＣＨ２－フェニル、－ＣＨ２－ピリジル又は－ＣＨ２－ピリミジニルであり、ここで、前記Ｃ１－６アルキル、－ＣＨ２－フェニル、－ＣＨ２－ピリジル又は－ＣＨ２－ピリミジニルは、それぞれ独立して任意選択で１、２、３、４又は５つのＲａにより置換され、
各Ｒａは、独立してＨ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２、－Ｃ（＝Ｏ）ＯＨ、Ｃ１－３アルコキシ又は任意選択で１、２又は３つの独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２及び－ＯＣＨ３から選択される置換基により置換されたＣ１－３アルキルであり、
Ｒ３及びＲ４は、それぞれ独立してＨ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ又は－ＮＨ２であり、
Ｒ５は、－Ｌ－Ｒｂであり、
Ｌは、単結合、－ＮＲｃＣ（＝Ｏ）Ｏ－又は－ＮＲｃＣ（＝Ｏ）－であり、
Ｒｂは、Ｃ１－６アルキル、
Ｒｃは、Ｈ、－ＣＨ３又は－ＣＨ２ＣＨ３であり、
各Ｒは、独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２、Ｃ１－３アルコキシ又は任意選択で１、２又は３つの独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２及び－ＯＣＨ３から選択される置換基により置換されたＣ１－３アルキルであり、
或いは、Ｒ３及びＲ５は、それらと連結された炭素原子と連結されて、構造単位
Ｒ６、Ｒ７及びＲ８は、それぞれ独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２、－ＮＯ２又は任意選択で１、２又は３つの独立してＦ、Ｃｌ、Ｂｒ、Ｉ、－ＯＨ、－ＣＮ、－ＮＨ２及び－ＯＣＨ３から選択される置換基により置換されたＣ１－３アルキルである。） A compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.
R 2 is C 1-6 alkyl, —CH 2 -phenyl, —CH 2 -pyridyl or —CH 2 -pyrimidinyl, wherein said C 1-6 alkyl, —CH 2 -phenyl, —CH 2 -pyridyl or —CH 2 -pyrimidinyl is each independently optionally substituted by 1, 2, 3, 4 or 5 R a ;
each R a is independently H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -C(═O)OH, C 1-3 alkoxy or C 1-3 alkyl optionally substituted with 1 , 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH 2 and -OCH 3 ;
R3 and R4 are each independently H, F, Cl, Br, I, -OH, -CN, or -NH2 ;
R5 is -L- Rb ;
L is a single bond, -NR c C(=O)O- or -NR c C(=O)-;
R b is C 1-6 alkyl,
R c is H, -CH3 or -CH2CH3 ;
each R is independently F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , C1-3alkoxy or C1-3alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH2 and -OCH3 ;
Alternatively, R 3 and R 5 may be joined with the carbon atom to which they are attached to form a structural unit
R 6 , R 7 and R 8 are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 or C 1-3 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH 2 and -OCH 3 .
Ｃ（＝Ｏ）Ｏ－ＣＨ２ＣＨ２ＣＨ３、－Ｎ（ＣＨ３）－Ｃ（＝Ｏ）Ｏ－ＣＨ（ＣＨ３）２、
C(=O)O - CH2CH2CH3 , -N( CH3 )-C( = O)O-CH( CH3 ) 2 ,
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