WO2022131146A1 - Nitrogen-containing heterocyclic compound - Google Patents

Nitrogen-containing heterocyclic compound Download PDF

Info

Publication number
WO2022131146A1
WO2022131146A1 PCT/JP2021/045451 JP2021045451W WO2022131146A1 WO 2022131146 A1 WO2022131146 A1 WO 2022131146A1 JP 2021045451 W JP2021045451 W JP 2021045451W WO 2022131146 A1 WO2022131146 A1 WO 2022131146A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
mmol
indicates
formula
kusc
Prior art date
Application number
PCT/JP2021/045451
Other languages
French (fr)
Japanese (ja)
Inventor
秀昭 掛谷
麻利奈 酒井
裕 古谷
Original Assignee
国立大学法人京都大学
国立研究開発法人理化学研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人京都大学, 国立研究開発法人理化学研究所 filed Critical 国立大学法人京都大学
Publication of WO2022131146A1 publication Critical patent/WO2022131146A1/en

Links

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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Provided is a compound having the effect of inhibiting HIF-1. In concrete terms, the present invention provides a specific nitrogen-containing heterocyclic compound.

Description

含窒素複素環式化合物Nitrogen-containing heterocyclic compound
　本開示は、特定の含窒素複素環式化合物及びその用途等に関する。なお、本明細書に記載される全ての文献の内容は参照により本明細書に組み込まれる。 The present disclosure relates to specific nitrogen-containing heterocyclic compounds and their uses. The contents of all documents described in this specification are incorporated herein by reference.
　がんは、日本において、生涯で２人に１人が罹患すると言われるほど一般的な病気であり、その治療法として、外科的切除、化学療法、放射線治療が挙げられる。近年、分子標的薬の出現により、その治療法の開発が進められているが、その種類は、全ての治療標的分子を網羅するほど多くはないというのが現状である。そのため、新規作用機構を有する抗がん剤の開発が望まれている。 Cancer is a common disease in Japan that affects one in two people in a lifetime, and its treatment methods include surgical resection, chemotherapy, and radiation therapy. In recent years, with the advent of molecular-targeted drugs, the development of therapeutic methods has been promoted, but the current situation is that the types are not large enough to cover all therapeutic target molecules. Therefore, the development of an anticancer drug having a novel mechanism of action is desired.
　低酸素誘導因子－１（ＨＩＦ－１）は、抗がん剤の創薬標的分子として注目を集める分子の１つであり、がんの悪性化に関与することが知られている。現在のところ、ＨＩＦ－１を阻害する抗がん剤の開発は、未達成であり、優れた阻害剤の開発が望まれている。（非特許文献１）。 Hypoxia-inducible factor-1 (HIF-1) is one of the molecules attracting attention as a drug discovery target molecule for anticancer agents, and is known to be involved in the malignant transformation of cancer. At present, the development of an anticancer agent that inhibits HIF-1 has not been achieved, and the development of an excellent inhibitor is desired. (Non-Patent Document 1).
　本発明者らは、ＨＩＦ－１を阻害する作用を有する化合物を探索した。 The present inventors searched for a compound having an action of inhibiting HIF-1.
　本発明者らは、特定の骨格を有する含窒素複素環式化合物がＨＩＦ－１を阻害する作用を有する可能性を見いだし、さらに改良を重ねた。 The present inventors have found the possibility that a nitrogen-containing heterocyclic compound having a specific skeleton has an action of inhibiting HIF-1, and further improved it.
　また、Ｂ型肝炎ウイルス（ＨＢＶ）持続感染者は日本では人口の約１％（約１００万人）、世界では人口の約７％（約４億人）と推定されており、慢性肝炎、肝硬変、肝細胞がん、肝不全に進展する感染者に対する効果的な治療薬が希求されている。 In addition, hepatitis B virus (HBV) persistent infection is estimated to be about 1% (about 1 million people) of the population in Japan and about 7% (about 400 million people) of the world, and chronic hepatitis and liver cirrhosis. , Hepatitis, an effective therapeutic agent for infected persons who progress to liver failure is sought.
　Ｂ型肝炎ウイルス由来のタンパク質であるＨｅｐａｔｉｔｉｓ　Ｂ　ｖｉｒｕｓ Ｘ ｐｒｏｔｅｉｎ（ＨＢｘ）は、ＨＩＦ－１と相互作用されることが知られており、肝がんにおける組織繊維化にＨＩＦ－１が関与するという報告があることから、ＨＩＦ－１阻害活性と抗ＨＢＶ活性には、相関がある可能性が考えられる。（非特許文献２）
　そこで、本発明者らは、ＨＩＦ－１を阻害する作用を有する可能性のある特定の骨格を有する含窒素複素環式化合物が、抗ＨＢＶ活性をも奏する可能性についても検討した。  Hepatitis B virus X protein (HBx), a protein derived from hepatitis B virus, is known to interact with HIF-1, and it has been reported that HIF-1 is involved in tissue fibrosis in liver cancer. Therefore, it is possible that there is a correlation between HIF-1 inhibitory activity and anti-HBV activity. (Non-Patent Document 2)
Therefore, the present inventors also investigated the possibility that a nitrogen-containing heterocyclic compound having a specific skeleton having an action of inhibiting HIF-1 also exerts anti-HBV activity.
　本開示は例えば以下の項に記載の主題を包含する。
項１．
式（１）：
Figure JPOXMLDOC01-appb-C000021
 〔式（１）中、
Ｘは基Ｘ－１：
Figure JPOXMLDOC01-appb-C000022
 （当該式中、
Ｘ１は炭素原子又は窒素原子を示し、
ＲＸ１、ＲＸ２、及びＲＸ３は、それぞれ独立して、水素原子、ハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示す）
を示し、
Ｙは基Ｙ－１：
Figure JPOXMLDOC01-appb-C000023
 （当該式中、
Ｙ１は炭素原子又は窒素原子を示し、
ＲＹ１ａ、ＲＹ１ｂ、及びＲＹ１ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉ（当該式中、－Ｙ１ｉ－は－ＣＯ－、－ＳＯ２－、若しくは－ＣＨ２－を示し、－Ｙ１ｉｉはＣ１～Ｃ４アルキル基、フェニル基、若しくはベンジル基を示す）で表される基を示す）
又は基Ｙ－２：
Figure JPOXMLDOC01-appb-C000024
 （当該式中、
Ｙ２は炭素原子又は窒素原子を示し、
ＲＹ２ａ、ＲＹ２ｂ、及びＲＹ２ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ２ｉ－Ｙ２ｉｉ（当該式中、－Ｙ２ｉ－は－ＣＯ－、－ＳＯ２－、若しくは－ＣＨ２－を示し、－Ｙ２ｉｉはＣ１～Ｃ４アルキル基又はフェニル基若しくはベンジル基を示す）で表される基を示す）
を示し、
Ｚはメチレン基又は基Ｚ－１：
Figure JPOXMLDOC01-appb-C000025
 （当該式中、Ａｒはベンゼン環、フラン環、若しくはピラゾール環を示す）
を示し、
ｍは０、１、又は２を示し、
ｎは１、２、又は３を示す。〕
で表される化合物。
項２．
Ｘが基Ｘ－１を示し、
ＲＸ１、ＲＸ２、及びＲＸ３のいずれか１つが水素原子を示し、残りの２つが同じハロゲン原子を示すか、あるいは、
ＲＸ１がハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示し、ＲＸ２及びＲＸ３が水素原子を示す、
項１に記載の化合物。
項３．
Ｙが基Ｙ－１又はＹ－２基を示し、
Ｙが基Ｙ－１を示すとき、
ＲＹ１ａが水素原子、ＲＹ１ｂがＣ１～Ｃ４アルキル基、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すか、
ＲＹ１ａがＣ１～Ｃ４アルキル基、ＲＹ１ｂが水素原子、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すか、あるいは
ＲＹ１ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ１ａ及びＲＹ１ｃが水素原子を示し、
ＹがＹ－２基を示すとき、
ＲＹ２ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ａ及びＲＹ２ｃが水素原子を示すか、あるいは、
ＲＹ２ａがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ｂ及びＲＹ２ｃが水素原子を示す、
項１又は２に記載の化合物
項４．
Ｚがメチレン基又は基Ｚ－１を示し、
Ｚが基Ｚ－１を示すとき、
Ａｒがベンゼン環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000026
 のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示し、
Ａｒがフラン環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000027
 のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示し、
Ａｒがピラゾール環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000028
 のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示す、
項１～３のいずれかに記載の化合物。
項５．
Ｘが基Ｘ－１を示し、
ＲＸ１、ＲＸ２、及びＲＸ３のいずれか１つが水素原子を示し、残りの２つが同じハロゲン原子を示すか、あるいは、
ＲＸ１がハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示し、ＲＸ２及びＲＸ３が水素原子を示し、
Ｙが基Ｙ－１又はＹ－２基を示し、
Ｙが基Ｙ－１を示すとき、
ＲＹ１ａが水素原子、ＲＹ１ｂがＣ１～Ｃ４アルキル基、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すか、
ＲＹ１ａがＣ１～Ｃ４アルキル基、ＲＹ１ｂが水素原子、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すか、あるいは
ＲＹ１ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ１ａ及びＲＹ１ｃが水素原子を示し、
ＹがＹ－２基を示すとき、
ＲＹ２ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ａ及びＲＹ２ｃが水素原子を示すか、あるいは、
ＲＹ２ａがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ｂ及びＲＹ２ｃが水素原子を示し、
Ｚがメチレン基又は基Ｚ－１を示し、
Ｚが基Ｚ－１を示すとき、
Ａｒがベンゼン環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000029
 のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示し、
Ａｒがフラン環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000030
 のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示し、
Ａｒがピラゾール環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000031
 のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示す、
項１に記載の化合物。
項６．
以下の表に記載のいずれかの構造式で表される化合物。
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-I000033
Figure JPOXMLDOC01-appb-I000034
Figure JPOXMLDOC01-appb-I000035
Figure JPOXMLDOC01-appb-I000036
Figure JPOXMLDOC01-appb-I000037
Figure JPOXMLDOC01-appb-I000038
Figure JPOXMLDOC01-appb-I000039
Figure JPOXMLDOC01-appb-I000040
項７．
項１～６のいずれかに記載の化合物の塩。
項８．
項１～６のいずれかに記載の化合物又はその塩を含有する抗がん剤。
項９．
項１～６のいずれかに記載の化合物又はその塩を含有する抗Ｂ型肝炎ウイルス剤。  The present disclosure includes, for example, the subjects described in the following sections.
Item 1.
Equation (1):
Figure JPOXMLDOC01-appb-C000021
 [In equation (1),
X is the base X-1:
Figure JPOXMLDOC01-appb-C000022
 (In the formula,
X 1 represents a carbon atom or a nitrogen atom,
RX1 , RX2 , and RX3 independently indicate a hydrogen atom, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group).
Show,
Y is the base Y-1:
Figure JPOXMLDOC01-appb-C000023
 (In the formula,
Y 1 represents a carbon atom or a nitrogen atom.
RY1a , RY1b , and RY1c are independently hydrogen atom, halogen atom, C1-C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or formula:-. NH-Y 1i -Y 1ii (in the formula, -Y 1i- indicates -CO-, -SO 2- , or -CH 2- , and -Y 1i is a C1-C4 alkyl group, phenyl group, or benzyl group. Indicates a group represented by))
Or group Y-2:
Figure JPOXMLDOC01-appb-C000024
 (In the formula,
Y 2 indicates a carbon atom or a nitrogen atom.
RY2a , RY2b , and RY2c are independently hydrogen atom, halogen atom, C1-C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or formula:-. NH-Y 2i -Y 2ii (in the formula, -Y 2i- indicates -CO-, -SO 2- , or -CH 2- , and -Y 2ii is a C1-C4 alkyl group or a phenyl group or a benzyl group. Indicates a group represented by))
Show,
Z is a methylene group or a group Z-1:
Figure JPOXMLDOC01-appb-C000025
 (In the formula, Ar indicates a benzene ring, a furan ring, or a pyrazole ring)
Show,
m indicates 0, 1, or 2,
n indicates 1, 2, or 3. ]
The compound represented by.
Item 2.
X indicates the base X-1,
Either one of RX1 , RX2 , and RX3 represents a hydrogen atom and the other two represent the same halogen atom, or
RX1 represents a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group, and RX2 and RX3 represent a hydrogen atom.
Item 1. The compound according to Item 1.
Item 3.
Y indicates a group Y-1 or a group Y-2,
When Y indicates the base Y-1,
Whether RY1a is a hydrogen atom, RY1b is a C1-C4 alkyl group, RY1c is a nitro group or a group represented by the formula: -NH- Y1i - Y1iii .
RY1a is a C1-C4 alkyl group, RY1b is a hydrogen atom, RY1c is a nitro group or a group represented by the formula: -NH- Y1i - Y1ii , or RY1b is a halogen atom, C1 to C4. An alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , where RY1a and RY1c indicate hydrogen atoms. ,
When Y indicates Y-2 groups
RY2b represents a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , R Y2a and RY2c indicate hydrogen atoms, or
RY2a represents a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , R Y2b and RY2c represent hydrogen atoms,
Item 4. The compound according to Item 1 or 2.
Z indicates a methylene group or a group Z-1.
When Z indicates the base Z-1,
When Ar represents a benzene ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000026
 (However, the asterisk side is the Y side in equation (1)).
When Ar represents a furan ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000027
 (However, the asterisk side is the Y side in equation (1)).
When Ar represents a pyrazole ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000028
 (However, the asterisk side is the Y side in the equation (1)).
Item 2. The compound according to any one of Items 1 to 3.
Item 5.
X indicates the base X-1,
Either one of RX1 , RX2 , and RX3 represents a hydrogen atom and the other two represent the same halogen atom, or
RX1 represents a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group, and RX2 and RX3 represent a hydrogen atom.
Y indicates a group Y-1 or a group Y-2,
When Y indicates the base Y-1,
Whether RY1a is a hydrogen atom, RY1b is a C1-C4 alkyl group, RY1c is a nitro group or a group represented by the formula: -NH- Y1i - Y1iii .
RY1a is a C1-C4 alkyl group, RY1b is a hydrogen atom, RY1c is a nitro group or a group represented by the formula: -NH- Y1i - Y1ii , or RY1b is a halogen atom, C1 to C4. An alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , where RY1a and RY1c indicate hydrogen atoms. ,
When Y indicates Y-2 groups
RY2b represents a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , R Y2a and RY2c indicate hydrogen atoms, or
RY2a represents a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , R Y2b and RY2c indicate hydrogen atoms,
Z indicates a methylene group or a group Z-1.
When Z indicates the base Z-1,
When Ar represents a benzene ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000029
 (However, the asterisk side is the Y side in equation (1)).
When Ar represents a furan ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000030
 (However, the asterisk side is the Y side in equation (1)).
When Ar represents a pyrazole ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000031
 (However, the asterisk side is the Y side in the equation (1)).
Item 1. The compound according to Item 1.
Item 6.
A compound represented by any of the structural formulas described in the table below.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-I000033
Figure JPOXMLDOC01-appb-I000034
Figure JPOXMLDOC01-appb-I000035
Figure JPOXMLDOC01-appb-I000036
Figure JPOXMLDOC01-appb-I000037
Figure JPOXMLDOC01-appb-I000038
Figure JPOXMLDOC01-appb-I000039
Figure JPOXMLDOC01-appb-I000040
Item 7.
The salt of the compound according to any one of Items 1 to 6.
Item 8.
An anticancer agent containing the compound according to any one of Items 1 to 6 or a salt thereof.
Item 9.
An anti-hepatitis B virus agent containing the compound according to any one of Items 1 to 6 or a salt thereof.
　ＨＩＦ－１を阻害する作用を有する特定の含窒素複素環式化合物が提供される。これにより、当該特定の含窒素複素環式化合物を含有するＨＩＦ－１阻害剤、ひいては抗がん剤が提供される。さらには、当該特定の含窒素複素環式化合物を含有する抗ＨＢＶ剤が提供される。 A specific nitrogen-containing heterocyclic compound having an action of inhibiting HIF-1 is provided. As a result, a HIF-1 inhibitor containing the specific nitrogen-containing heterocyclic compound, and thus an anticancer agent, is provided. Further, an anti-HBV agent containing the specific nitrogen-containing heterocyclic compound is provided.
　以下、本開示に包含される各実施形態について、さらに詳細に説明する。本開示は、特定の含窒素複素環式化合物及びその用途等を好ましく包含するが、これらに限定されるわけではなく、本開示は本明細書に開示され当業者が認識できる全てを包含する。 Hereinafter, each embodiment included in the present disclosure will be described in more detail. The present disclosure preferably includes, but is not limited to, specific nitrogen-containing heterocyclic compounds and uses thereof, and the present disclosure includes all disclosed in the present specification and recognized by those skilled in the art.
　本開示に包含される特定の含窒素複素環式化合物は、式（１）：
Figure JPOXMLDOC01-appb-C000041
 〔式（１）中、
Ｘは基Ｘ－１：
Figure JPOXMLDOC01-appb-C000042
 （当該式中、
Ｘ１は炭素原子又は窒素原子を示し、
ＲＸ１、ＲＸ２、及びＲＸ３は、それぞれ独立して、水素原子、ハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示す）
を示し、
Ｙは基Ｙ－１：
Figure JPOXMLDOC01-appb-C000043
 （当該式中、
Ｙ１は炭素原子又は窒素原子を示し、
ＲＹ１ａ、ＲＹ１ｂ、及びＲＹ１ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉ（当該式中、－Ｙ１ｉ－は－ＣＯ－、－ＳＯ２－、若しくは－ＣＨ２－を示し、－Ｙ１ｉｉはＣ１～Ｃ４アルキル基又はフェニル基若しくはベンジル基を示す）で表される基を示す）
又は基Ｙ－２：
Figure JPOXMLDOC01-appb-C000044
 （当該式中、
Ｙ２は炭素原子又は窒素原子を示し、
ＲＹ２ａ、ＲＹ２ｂ、及びＲＹ２ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ２ｉ－Ｙ２ｉｉ（当該式中、－Ｙ２ｉ－は－ＣＯ－、－ＳＯ２－、若しくは－ＣＨ２－を示し、－Ｙ２ｉｉはＣ１～Ｃ４アルキル基又はフェニル基若しくはベンジル基を示す）で表される基を示す）
を示し、
Ｚはメチレン基又は基Ｚ－１：
Figure JPOXMLDOC01-appb-C000045
 （当該式中、Ａｒはベンゼン環、フラン環、若しくはピラゾール環を示す）
を示し、
ｍは０、１、又は２を示し、
ｎは１、２、又は３を示す。〕
で表される化合物である。当該化合物を「本開示の化合物」と呼ぶことがある。 Specific nitrogen-containing heterocyclic compounds included in the present disclosure include formula (1) :.
Figure JPOXMLDOC01-appb-C000041
 [In equation (1),
X is the base X-1:
Figure JPOXMLDOC01-appb-C000042
 (In the formula,
X 1 represents a carbon atom or a nitrogen atom,
RX1 , RX2 , and RX3 independently indicate a hydrogen atom, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group).
Show,
Y is the base Y-1:
Figure JPOXMLDOC01-appb-C000043
 (In the formula,
Y 1 represents a carbon atom or a nitrogen atom.
RY1a , RY1b , and RY1c are independently hydrogen atom, halogen atom, C1-C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or formula:-. NH-Y 1i -Y 1ii (in the formula, -Y 1i- indicates -CO-, -SO 2- , or -CH 2- , and -Y 1ii indicates a C1-C4 alkyl group or a phenyl group or a benzyl group. Indicates a group represented by))
Or group Y-2:
Figure JPOXMLDOC01-appb-C000044
 (In the formula,
Y 2 indicates a carbon atom or a nitrogen atom.
RY2a , RY2b , and RY2c are independently hydrogen atom, halogen atom, C1-C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or formula:-. NH-Y 2i -Y 2ii (in the formula, -Y 2i- indicates -CO-, -SO 2- , or -CH 2- , and -Y 2ii is a C1-C4 alkyl group or a phenyl group or a benzyl group. Indicates a group represented by))
Show,
Z is a methylene group or a group Z-1:
Figure JPOXMLDOC01-appb-C000045
 (In the formula, Ar indicates a benzene ring, a furan ring, or a pyrazole ring)
Show,
m indicates 0, 1, or 2,
n indicates 1, 2, or 3. ]
It is a compound represented by. The compound may be referred to as the "compound of the present disclosure".
　なお、本明細書において、Ｃ１～Ｃ４アルキル基は、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、又はｔｅｒｔ－ブチル基を示し、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、又はｎ－ブチル基が好ましい。また、本明細書において、Ｃ１～Ｃ４アルコキシ基は、（Ｃ１～Ｃ４アルキル基）－Ｏ－と表されるアルコキシ基を示し、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、又はｎ－ブトキシ基が好ましい。また、本明細書において、ハロゲン原子は、Ｆ、Ｃｌ、Ｂｒ、又はＩを示し、Ｆ又はＣｌが好ましい。 In the present specification, the C1 to C4 alkyl groups represent a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, and are methyl. A group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group is preferable. Further, in the present specification, the C1-C4 alkoxy group indicates an alkoxy group represented by (C1-C4 alkyl group) -O-, and is a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, or n. -Butoxy groups are preferred. Further, in the present specification, the halogen atom indicates F, Cl, Br, or I, and F or Cl is preferable.
　上記の通り、基Ｘ－１においては、Ｘ１は炭素原子又は窒素原子を示すところ、炭素原子を示すことが好ましい。また、ＲＸ１、ＲＸ２、及びＲＸ３は、それぞれ独立して、水素原子、ハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示すところ、ＲＸ１、ＲＸ２、及びＲＸ３の１つ又は２つが水素原子であることが好ましく、２つが水素原子であることがより好ましい。 As described above, in the group X-1, where X 1 indicates a carbon atom or a nitrogen atom, it is preferable to indicate a carbon atom. Further, RX1 , RX2 , and RX3 independently have a hydrogen atom, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group. As shown, it is preferable that one or two of RX1, RX2 , and RX3 are hydrogen atoms, and more preferably two are hydrogen atoms.
　ＲＸ１、ＲＸ２、及びＲＸ３の１つが水素原子である場合、これらのいずれか１つが水素原子を示し、のこりの２つが、それぞれ独立して、ハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示す。例えば、ＲＸ１、ＲＸ２、及びＲＸ３のいずれか１つが水素原子を示し、残りの２つが同じハロゲン原子を示すことが中でも好ましい。 When one of RX1 , RX2 , and RX3 is a hydrogen atom, any one of them represents a hydrogen atom, and the other two independently represent a halogen atom, a trifluoromethyl group, and a trifluoromethoxy. A group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group is shown. For example, it is particularly preferable that any one of RX1, RX2 , and RX3 represents a hydrogen atom and the other two represent the same halogen atom.
　ＲＸ１、ＲＸ２、及びＲＸ３の２つが水素原子である場合、これらのいずれか１つがハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示し、残りの２つが水素原子を示す。例えば、ＲＸ１がハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示し、ＲＸ２及びＲＸ３が水素原子を示すことが中でも好ましい。 When two of RX1 , RX2 , and RX3 are hydrogen atoms, any one of them is a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or It shows a hydroxyl group and the other two show hydrogen atoms. For example, it is particularly preferable that RX1 represents a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group, and RX2 and RX3 represent a hydrogen atom. ..
　好ましい基Ｘ－１としては、より具体的には例えば以下の基が挙げられる。
Figure JPOXMLDOC01-appb-C000046
 More specifically, examples of the preferred group X-1 include the following groups.
Figure JPOXMLDOC01-appb-C000046
　上記の通り、Ｙは基Ｙ－１又は基Ｙ－２を示し、基Ｙ－１を示すことが好ましい。 As described above, Y indicates a group Y-1 or a group Y-2, and it is preferable to indicate a group Y-1.
　基Ｙ－１においては、Ｙ１は炭素原子又は窒素原子を示し、窒素原子を示すことが好ましい。また、ＲＹ１ａ、ＲＹ１ｂ、及びＲＹ１ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉ（当該式中、－Ｙ１ｉ－は－ＣＯ－、－ＳＯ２－、若しくは－ＣＨ２－を示し、－Ｙ１ｉｉはＣ１～Ｃ４アルキル基又はフェニル基若しくはベンジル基を示す）で表される基を示すところ、ＲＹ１ａ、ＲＹ１ｂ、及びＲＹ１ｃの１つ、２つ、又は３つが水素原子であることが好ましく、１つ又は２つが水素原子であることがより好ましく、２つが水素原子であることがさらに好ましい。 In the group Y-1, Y 1 represents a carbon atom or a nitrogen atom, preferably a nitrogen atom. Further, RY1a , RY1b , and RY1c are independently hydrogen atom, halogen atom, C1 to C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or the formula. : -NH-Y 1i -Y 1ii (in the formula, -Y 1i- indicates -CO-, -SO 2- , or -CH 2- , and -Y 1ii is a C1-C4 alkyl group or a phenyl group or benzyl. When the group represented by) is shown, one, two, or three of RY1a , RY1b , and RY1c are preferably hydrogen atoms, and one or two are hydrogen atoms. Is more preferable, and it is even more preferable that two are hydrogen atoms.
　ＲＹ１ａ、ＲＹ１ｂ、及びＲＹ１ｃの１つが水素原子である場合、これらのいずれか１つが水素原子を示し、残りの２つが、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示す。例えば、ＲＹ１ａ又はＲＹ１ｂが水素原子である場合が好ましく、ＲＹ１ａが水素原子、ＲＹ１ｂがＣ１～Ｃ４アルキル基、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すこと、あるいは、ＲＹ１ａがＣ１～Ｃ４アルキル基、ＲＹ１ｂが水素原子、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すこと、がより好ましい。 When one of RY1a , RY1b , and RY1c is a hydrogen atom, one of these indicates a hydrogen atom, and the other two are a halogen atom, a C1-C4 alkyl group, a nitro group, and -CO-NH. -CH 2 CH 3 , -NH 3 Cl, or formula: -NH-Y 1i -indicates a group represented by Y 1ii . For example, it is preferable that RY1a or RY1b is a hydrogen atom, RY1a is a hydrogen atom, RY1b is a C1-C4 alkyl group, and RY1c is a nitro group or the formula: -NH-Y 1i -Y 1ii . Or, RY1a indicates a C1 to C4 alkyl group, RY1b indicates a hydrogen atom, RY1c indicates a nitro group, or a group represented by the formula: -NH- Y1i - Y1ii . preferable.
　ＲＹ１ａ、ＲＹ１ｂ、及びＲＹ１ｃの２つが水素原子である場合、これらのいずれか１つがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、残りの２つが水素原子を示す。例えば、ＲＹ１ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ１ａ及びＲＹ１ｃが水素原子を示すことが中でも好ましい。 When two of RY1a , RY1b , and RY1c are hydrogen atoms, any one of them is a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl. , Or formula: -NH-Y 1i -Represents a group represented by Y 1ii , and the remaining two represent hydrogen atoms. For example, RY1b indicates a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii . , RY1a and RY1c particularly preferably exhibit hydrogen atoms.
　基Ｙ－２においては、Ｙ２は炭素原子又は窒素原子を示し、窒素原子を示すことが好ましい。また、ＲＹ２ａ、ＲＹ２ｂ、及びＲＹ２ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ２ｉ－Ｙ２ｉｉ（当該式中、－Ｙ２ｉ－は－ＣＯ－、－ＳＯ２－、若しくは－ＣＨ２－を示し、－Ｙ２ｉｉはＣ１～Ｃ４アルキル基又はフェニル基若しくはベンジル基を示す）で表される基を示すところ、ＲＹ２ａ、ＲＹ２ｂ、及びＲＹ２ｃの１つ、２つ、又は３つが水素原子であることが好ましく、１つ又は２つが水素原子であることがより好ましく、２つが水素原子であることがさらに好ましい。 In the group Y-2, Y 2 represents a carbon atom or a nitrogen atom, preferably a nitrogen atom. Further, RY2a , RY2b , and RY2c are independently hydrogen atom, halogen atom, C1-C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or the formula. : -NH-Y 2i -Y 2ii (in the formula, -Y 2i- indicates -CO-, -SO 2- , or -CH 2- , and -Y 2i is a C1-C4 alkyl group or a phenyl group or benzyl. When the group represented by) is shown, one, two, or three of RY2a , RY2b , and RY2c are preferably hydrogen atoms, and one or two are hydrogen atoms. Is more preferable, and it is even more preferable that two are hydrogen atoms.
　ＲＹ２ａ、ＲＹ２ｂ、及びＲＹ２ｃの２つが水素原子である場合、これらのいずれか１つがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ２ｉ－Ｙ２ｉｉで表される基を示し、残りの２つが水素原子を示す。例えば、ＲＹ２ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ａ及びＲＹ２ｃが水素原子を示すこと、あるいは、ＲＹ２ａがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ｂ及びＲＹ２ｃが水素原子を示すことが中でも好ましい。 When two of RY2a , RY2b , and RY2c are hydrogen atoms, any one of them is a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl. , Or formula: -NH-Y 2i -Represents a group represented by Y 2ii , and the remaining two represent hydrogen atoms. For example, RY2b indicates a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii . , RY2a and RY2c indicate a hydrogen atom, or RY2a is a halogen atom, C1-C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or formula: -NH. -Y 1i -It is particularly preferable that the group represented by Y 1ii is shown, and RY2b and RY2c represent hydrogen atoms.
　好ましい基Ｙ－１及び基Ｙ－２としては、より具体的には例えば以下の基が挙げられる。
Figure JPOXMLDOC01-appb-C000047
 More specifically, the following groups can be mentioned as preferable groups Y-1 and Y-2.
Figure JPOXMLDOC01-appb-C000047
　上記の通り、Ｚはメチレン基又は基Ｚ－１を示す。 As described above, Z represents a methylene group or a group Z-1.
　基Ｚ－１においては、Ａｒはベンゼン環、フラン環、若しくはピラゾール環を示すところ、ピラゾール環を示すことが好ましい。 In the group Z-1, where Ar indicates a benzene ring, a furan ring, or a pyrazole ring, it is preferable to indicate a pyrazole ring.
　Ａｒがベンゼン環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000048
 のいずれかの基を示し、この左側又は中央の基を示すことが好ましい。なお、アスタリスク側が、式（１）におけるＹ側であること（換言すれば、アスタリスクが無い側が、式（１）におけるＸ側であること）がより好ましい。 When Ar represents a benzene ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000048
 It is preferable to indicate one of the groups, and to indicate the left side or the center group. It is more preferable that the asterisk side is the Y side in the equation (1) (in other words, the side without the asterisk is the X side in the equation (1)).
　Ａｒがフラン環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000049
 のいずれかの基を示し、この左側の基を示すことが好ましい。なお、アスタリスク側が、式（１）におけるＹ側であること（換言すれば、アスタリスクが無い側が、式（１）におけるＸ側であること）がより好ましい。 When Ar represents a furan ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000049
 It is preferable to indicate one of the groups of 1 and the group on the left side thereof. It is more preferable that the asterisk side is the Y side in the equation (1) (in other words, the side without the asterisk is the X side in the equation (1)).
　Ａｒがピラゾール環を示す場合、基Ｚ－１は、
Figure JPOXMLDOC01-appb-C000050
 のいずれかの基を示すことが好ましく、この左側の基を示すことがより好ましい。なお、アスタリスク側が、式（１）におけるＹ側であること（換言すれば、アスタリスクが無い側が、式（１）におけるＸ側であること）が特に好ましい。 When Ar represents a pyrazole ring, the group Z-1 is
Figure JPOXMLDOC01-appb-C000050
 It is preferable to indicate one of the groups, and it is more preferable to indicate the group on the left side. It is particularly preferable that the asterisk side is the Y side in the equation (1) (in other words, the side without the asterisk is the X side in the equation (1)).
　式（１）で表される化合物としては、具体的には以下の表に挙げられる化合物が好ましく例示される。なお、特に限定はされないが、当該表の一番上に示される化合物（ＩＤ：５００１）は、本開示の化合物から除かれてもよい。
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-I000052
Figure JPOXMLDOC01-appb-I000053
Figure JPOXMLDOC01-appb-I000054
Figure JPOXMLDOC01-appb-I000055
Figure JPOXMLDOC01-appb-I000056
Figure JPOXMLDOC01-appb-I000057
Figure JPOXMLDOC01-appb-I000058
Figure JPOXMLDOC01-appb-I000059
As the compound represented by the formula (1), specifically, the compounds listed in the following table are preferably exemplified. Although not particularly limited, the compound (ID: 5001) shown at the top of the table may be excluded from the compounds of the present disclosure.
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-I000052
Figure JPOXMLDOC01-appb-I000053
Figure JPOXMLDOC01-appb-I000054
Figure JPOXMLDOC01-appb-I000055
Figure JPOXMLDOC01-appb-I000056
Figure JPOXMLDOC01-appb-I000057
Figure JPOXMLDOC01-appb-I000058
Figure JPOXMLDOC01-appb-I000059
　本開示の化合物は、優れた低酸素誘導因子－１（ＨＩＦ－１）阻害効果を奏する。このため、本開示の化合物又はその塩はＨＩＦ－１阻害のために好ましく用いることができる。そして、このため、本開示の化合物又はその塩は、抗がん剤として好ましく用いることができる。本開示は、本開示の化合物又はその塩を含有するＨＩＦ－１阻害剤、及び本開示の化合物又はその塩を含有する抗がん剤を好ましく包含する。当該ＨＩＦ－１阻害剤及び抗癌剤をそれぞれ本開示のＨＩＦ－１阻害剤及び本開示の抗がん剤ということがある。 The compound of the present disclosure exhibits an excellent hypoxia-inducible factor-1 (HIF-1) inhibitory effect. Therefore, the compounds of the present disclosure or salts thereof can be preferably used for HIF-1 inhibition. Therefore, the compound of the present disclosure or a salt thereof can be preferably used as an anticancer agent. The present disclosure preferably includes HIF-1 inhibitors containing the compounds of the present disclosure or salts thereof, and anticancer agents containing the compounds of the present disclosure or salts thereof. The HIF-1 inhibitor and the anticancer agent may be referred to as the HIF-1 inhibitor of the present disclosure and the anticancer agent of the present disclosure, respectively.
　また、本開示の化合物は、抗ＨＢＶ（抗Ｂ型肝炎ウイルス）活性をも奏し得る。より詳細には、本開示の化合物は、Ｂ型肝炎ウイルスの複製に関与するプロモーターの１つであるｂａｓａｌ　ｃｏｒｅ　ｐｒｏｍｏｔｅｒ（ＢＣＰ）を阻害する活性を奏し得る。このため、本開示の化合物は、抗ＨＢＶ剤としても用い得る。このため、本開示は、本開示の化合物又はその塩を含有する抗ＨＢＶ剤をも好ましく包含する。当該抗ＨＢＶ剤を本開示の抗ＨＢＶ剤ということがある。 The compounds of the present disclosure may also exhibit anti-HBV (anti-hepatitis B virus) activity. More specifically, the compounds of the present disclosure may exhibit activity to inhibit the basic core promoter (BCP), which is one of the promoters involved in the replication of hepatitis B virus. Therefore, the compounds of the present disclosure can also be used as anti-HBV agents. For this reason, the present disclosure also preferably includes anti-HBV agents containing the compounds of the present disclosure or salts thereof. The anti-HBV agent may be referred to as an anti-HBV agent of the present disclosure.
　またさらに、本開示の化合物は、抗癌作用及び抗ＨＢＶ作用を併せ持つ化合物を好ましく包含しており、このような化合物を含有する剤は、抗がん兼抗ＨＢＶ剤として好ましく用いることができる。 Furthermore, the compound of the present disclosure preferably includes a compound having both an anticancer effect and an antiHBV effect, and an agent containing such a compound can be preferably used as an anticancer and antiHBV agent.
　なお、本開示の化合物又はその塩を含有するこれらの剤をまとめて本開示の剤ということがある。本開示の剤は、医薬組成物として好ましく用いることができる。 Note that these agents containing the compound of the present disclosure or a salt thereof may be collectively referred to as the agent of the present disclosure. The agents of the present disclosure can be preferably used as pharmaceutical compositions.
　本開示の化合物の塩としては、薬理学的に許容される塩であることが好ましい。より具体的には、例えば、塩基性基に対する塩として、塩酸、硫酸、リン酸、硝酸、臭化水素酸等の無機酸との塩、酢酸、クエン酸、安息香酸、マレイン 酸、フマル酸、酒石酸、コハク酸、タンニン酸、酪酸、ヒベンズ酸、パモ酸、エナント酸 、デカン酸、テオクル酸、サリチル酸、乳酸、シュウ酸、マンデル酸、リンゴ酸等の有機カルボン酸との塩、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等 の有機スルホン酸との塩が例示される。また、例えば、酸性基に対する塩として、アンモニウム塩、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マ グネシウム等のアルカリ土類金属との塩、アルミニウム塩、亜鉛塩、トリエチルアミン、 エタノールアミン、モルホリン、ピロリジン、ピペリジン、ピペラジン、ジシクロへキシ ルアミン等の有機アミンとの塩、アルギニン、リジン等の塩基性アミノ酸との塩が挙げられる。なお、塩としては、１種の塩を用いてもよく、２以上の塩を組み合わせて用いてもよい。 The salt of the compound of the present disclosure is preferably a pharmacologically acceptable salt. More specifically, for example, as a salt for a basic group, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, Salts with organic carboxylic acids such as tartrate acid, succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enant acid, decanoic acid, theocric acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid, methanesulfonic acid, Examples thereof include salts with organic sulfonic acids such as benzene sulfonic acid and p-toluene sulfonic acid. Further, for example, as a salt for an acidic group, a salt with an alkali metal such as ammonium salt, sodium and potassium, a salt with an alkaline earth metal such as calcium and magnesium, an aluminum salt, a zinc salt, a triethylamine, an ethanolamine and a morpholin. , Salts with organic amines such as pyrrolidine, piperidine, piperazine, dicyclohexylamine, and salts with basic amino acids such as arginine and lysine. As the salt, one kind of salt may be used, or two or more salts may be used in combination.
　また、本開示の剤においては、本開示の化合物又はその塩は、溶媒和物の形態であってもよい。例えば好ましい溶媒和物として 水和物が例示できる。また、本開示の剤においては、本開示の化合物又はその塩は、任意の結晶型であってもよい。 Further, in the agent of the present disclosure, the compound of the present disclosure or a salt thereof may be in the form of a solvate. For example, a hydrate can be exemplified as a preferable solvate. Further, in the agent of the present disclosure, the compound of the present disclosure or a salt thereof may be of any crystalline form.
　本開示の剤は、有効成分である上記化合物又はその塩を、薬理学的に許容される溶媒（例えば水、生理食塩水、緩衝液等）を用いて希釈、溶解 、または分散等し、対象に投与するための医薬形態とすることができる。当該剤は、任意の剤形で製剤化されていてよい。剤形としては、例えば、錠剤、カプセル剤、顆粒剤、細粒剤、散剤、徐放性製剤、液剤、懸濁剤、エマルジョン剤、シロップ剤、エリキシル剤等の経口剤、注射剤、坐剤等の非経口剤が挙げられる。製剤化にあたっては、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、緩衝剤、安定化剤、矯味剤、矯臭剤、着色剤、香料、希釈剤、界面活性剤等の薬理学的に許容される添加剤を使用することができる。 The agent of the present disclosure is a subject obtained by diluting, dissolving, or dispersing the above compound or a salt thereof, which is an active ingredient, with a pharmacologically acceptable solvent (for example, water, physiological saline, buffer solution, etc.). It can be in the form of a pharmaceutical for administration to. The agent may be formulated in any dosage form. Dosage forms include, for example, tablets, capsules, granules, fine granules, powders, sustained release preparations, solutions, suspensions, emulsions, syrups, elixirs and other oral preparations, injections, suppositories. Examples thereof include parenteral preparations such as. Pharmacological preparations include, for example, excipients, binders, disintegrants, lubricants, buffers, stabilizers, flavoring agents, odorants, colorants, fragrances, diluents, surfactants and the like. Allowable additives can be used.
　また、本開示の剤における有効成分である本開示の化合物又はその塩の含有割割合は、剤形や投与形態、投与対象等に応じて適宜設定することができる。例えば、本開示の化合物の重量に換算して、５０％（ｗ／ｗ）以下、１０％（ｗ／ｗ）以下、または５％（ｗ／ｗ）以下であってよい。また例えば、０．０１％（ｗ／ｗ）以上、０．１％（ｗ／ｗ ）以上、または１％（ｗ／ｗ）以上であってよい。 Further, the content ratio of the compound of the present disclosure or a salt thereof, which is the active ingredient in the agent of the present disclosure, can be appropriately set according to the dosage form, administration form, administration target, and the like. For example, it may be 50% (w / w) or less, 10% (w / w) or less, or 5% (w / w) or less in terms of the weight of the compound of the present disclosure. Further, for example, it may be 0.01% (w / w) or more, 0.1% (w / w) or more, or 1% (w / w) or more.
　本発明の抗がん剤を対象に投与することにより、対象のがんを予防又は治療することができる。対象としては、特に制限されず、ヒトの他には、例えば非ヒト哺乳動物が挙げられる。非ヒト哺乳動物として例えばペット又は家畜が挙げられ、より具体的には例えばマウス、ラット、イヌ、ネコ、サル、ウシ、ブタ、ヒツジ、ウマ等が挙げられる。対象はがんを患っている対象であることが好ましい。また、がんのみならずＨＢＶ感染症をも患っている対象に対しても好ましく用いることができる。 By administering the anticancer agent of the present invention to a subject, the target cancer can be prevented or treated. The target is not particularly limited, and examples thereof include non-human mammals in addition to humans. Examples of non-human mammals include pets or livestock, and more particularly examples include mice, rats, dogs, cats, monkeys, cows, pigs, sheep, horses and the like. The subject is preferably a subject suffering from cancer. Further, it can be preferably used for a subject suffering from not only cancer but also HBV infection.
　本発明の抗ＨＢＶ剤を対象に投与することにより、対象のＨＢＶ感染症を予防又は治療することができる。対象としては、特に制限されず、ヒトの他には、例えば非ヒト哺乳動物が挙げられる。非ヒト哺乳動物として例えばペット又は家畜が挙げられ、より具体的には例えばマウス、ラット、イヌ、ネコ、サル、ウシ、ブタ、ヒツジ、ウマ等が挙げられる。対象はＨＢＶ感染症を患っている対象であることが好ましい。また、ＨＢＶ感染症のみならずがんをも患っている対象に対しても好ましく用いることができる。 By administering the anti-HBV agent of the present invention to a subject, the HBV infection of the subject can be prevented or treated. The target is not particularly limited, and examples thereof include non-human mammals in addition to humans. Examples of non-human mammals include pets or livestock, and more particularly examples include mice, rats, dogs, cats, monkeys, cows, pigs, sheep, horses and the like. The subject is preferably a subject suffering from an HBV infection. Further, it can be preferably used for a subject suffering from cancer as well as HBV infection.
　本開示の剤の投与量は、例えば、有効成分の含有量、用法、年齢、性別、症状の程度等の諸条件に応じて適宜設定することができる。例えば、含有される有効成分（本開示の化合物又はその塩）を、本開示の化合物の量に換算して、好ましくは０．１ｍｇ／ｋｇ体重／日～５００ｍｇ／ｋｇ 体重／日、より好ましくは１ｍｇ／ｋｇ体重／日～１００ｍｇ／ｋｇ体重／日であること ができる。また、１日１回又は複数回（例えば２又は３回）に分けて投与することができる。各回の投与時の投与量は、有効成分の投与量に換算して一定であってもよく、差があってもよい。 The dose of the agent of the present disclosure can be appropriately set according to various conditions such as the content of the active ingredient, usage, age, gender, degree of symptom, and the like. For example, the active ingredient contained (the compound of the present disclosure or a salt thereof) is preferably converted into the amount of the compound of the present disclosure, preferably 0.1 mg / kg body weight / day to 500 mg / kg body weight / day, more preferably. It can be from 1 mg / kg body weight / day to 100 mg / kg body weight / day. In addition, it can be administered once a day or divided into a plurality of times (for example, 2 or 3 times). The dose at each administration may be constant or different in terms of the dose of the active ingredient.
　なお、本明細書において「含む」とは、「本質的にからなる」と、「からなる」をも包含する（The term "comprising" includes "consisting essentially of” and "consisting of."）。また、本開示は、本明細書に説明した構成要件を任意の組み合わせを全て包含する。 In addition, in this specification, "includes" also includes "consisting of" and "consisting of" (The term "comprising" includes "consisting essentially of" and "consisting of."). In addition, the present disclosure includes all combinations of the constituent elements described herein.
　また、上述した本開示の各実施形態について説明した各種特性（性質、構造、機能等）は、本開示に包含される主題を特定するにあたり、どのように組み合わせられてもよい。すなわち、本開示には、本明細書に記載される組み合わせ可能な各特性のあらゆる組み合わせからなる主題が全て包含される。  Further, the various characteristics (property, structure, function, etc.) described for each embodiment of the present disclosure described above may be combined in any way in specifying the subject matter included in the present disclosure. That is, the present disclosure includes all subjects consisting of any combination of each of the combinable properties described herein. The
　以下、例を示して本開示の実施形態をより具体的に説明するが、本開示の実施形態は下記の例に限定されるものではない。なお、以下化合物はＩＤ番号（「ＫＵＳＣ－５０００番台の番号」の記載）及び／又は各スキームにおいて記載する化合物番号（一桁又は二桁の整数）を用いて特定することがある。 Hereinafter, embodiments of the present disclosure will be described in more detail with reference to examples, but the embodiments of the present disclosure are not limited to the following examples. The following compounds may be specified by using an ID number (described in "KUSC-5000 series number") and / or a compound number (one-digit or two-digit integer) described in each scheme.
　 実施例（各化合物の合成）　 Example (synthesis of each compound)
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　・ブロモ体３，４の合成は、文献既知の方法（Brunet,E. et al. Eur. J. Org. Chem,2000,1913.）に従って、行った。１ＨＮＭＲの値は、文献値と一致した。 -Synthesis of bromo forms 3 and 4 was carried out according to a method known in the literature (Brunet, E. et al. Eur. J. Org. Chem, 2000, 1913.). 1 The 1 HNMR value was in agreement with the literature value.
　・エステル体６の合成
　４－ニトロピラゾール５（１００．２ｍｇ,０．８８６ｍｍｏｌ）のＤＭＦ溶液０．４９ｍｌにブロモ体３(２２７．１ｍｇ，０．９７４ｍｍｏｌ)，Ｋ２ＣＯ３（２４４．９ｍｇ，１．７７ｍｍｏｌ）を添加し、室温で５．３時間撹拌した。水で反応を停止させ、ＣＨＣｌ３で抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）にて精製し 、エステル体６（２２５．１ｍｇ，９６％）を得た。
　１ＨＮＭＲ　（５００ＭＨｚ,ＣＤＣｌ３）δ　ｐｐｍ：　１．４０（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．４２（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），６．３７（２Ｈ，ｓ），６．８７（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．７４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．１０（１Ｈ，ｓ），８．４５（１Ｈ，ｓ）；
ＨＲ―ＥＳＩ―ＭＳ　ｃａｌｃｄ　Ｃ１０Ｈ１１Ｎ５Ｏ４Ｎａ　［Ｍ＋Ｎａ］＋　
２８８．０７０４，ｆｏｕｎｄ，２８８．０７２５ -Synthesis of ester form 6 4-nitropyrazole 5 (100.2 mg, 0.886 mmol) in 0.49 ml of DMF solution, bromo form 3 (227.1 mg, 0.974 mmol), K2 CO 3 ( 244.9 mg, 1). .77 mmol) was added, and the mixture was stirred at room temperature for 5.3 hours. The reaction was stopped with water, extraction was performed with CHCl 3 , the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1) to obtain ester 6 (225.1 mg, 96%).
1 1 HNMR (500 MHz, CDCl 3 ) δ ppm: 1.40 (3H, t, J = 7.0 Hz), 4.42 (2H, q, J = 7.0 Hz), 6.37 (2H, s), 6.87 (1H, d, J = 3.0Hz), 7.74 (1H, d, J = 2.0Hz), 8.10 (1H, s), 8.45 (1H, s);
HR-ESI-MS calcd C 10 H 11 N 5 O 4 Na [M + Na] +
288.0704, found, 288.0725
　・カルボン酸中間体７の合成
　エステル体６（５３．０ｍｇ，０．２０ｍｍｏｌ）をＭｅＯＨ　３ｍｌと水　１ｍｌの混合溶媒に溶解し、水酸化ナトリウム（１１．２ｍｇ，０．２８ｍｍｏｌ）を添加し、１１０℃で１８時間加熱還流した。反応溶液を室温に冷却し、濃塩酸を反応溶液がｐＨ＝２程度になるまで加えて、酸性化した。水で反応溶液を希釈し、ＣＨＣｌ３で抽出した。有機層を合わせて、硫酸ナトリウムで乾燥させ、溶媒を留去した。カルボン酸中間体７（３７．８ｍｇ，６１％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．６１（２Ｈ，ｓ），６．７９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．１９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．３９（１Ｈ，ｓ），９．２３（１Ｈ，ｓ）
　ＨＲ－ＥＳＩ－ＭＳ　ｃａｌｃｄ　Ｃ８Ｈ７Ｎ５Ｏ４　［Ｍ＋Ｈ］＋，２３８．０５３２，ｆｏｕｎｄ，２３８．０５３６ -Synthesis of Carboxylic Acid Intermediate 7 Ester 6 (53.0 mg, 0.20 mmol) was dissolved in a mixed solvent of 3 ml of MeOH and 1 ml of water, sodium hydroxide (11.2 mg, 0.28 mmol) was added, and 110 The mixture was heated under reflux at ° C. for 18 hours. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added until the reaction solution had a pH of about 2 to acidify the reaction solution. The reaction solution was diluted with water and extracted with CHCl 3 . The organic layers were combined, dried over sodium sulfate, and the solvent was distilled off. Carboxylic acid intermediate 7 (37.8 mg, 61%) was obtained.
1 1 HNMR 500MHz in DMSO-d 6 6.61 (2H, s), 6.79 (1H, d, J = 2.5Hz), 8.19 (1H, d, J = 2.5Hz), 8.39 (1H, s), 9.23 (1H, s)
HR-ESI-MS calcd C 8 H 7 N 5 O 4 [M + H] + , 238.0532, found, 238.0536
　・ＫＵＳＣ－５００１の合成
　カルボン酸中間体６（２４．２ｍｇ，０．１０２ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（１．４０ｍＬ）にＤＩＰＥＡ（３６μＬ，０．２０７ｍｍｏｌ），ＨＡＴＵ（３４．８ｍｇ，０．１０２ｍｍｏｌ）を添加し、室温で３０分攪拌した。ｐ－ブロモアニリン（８．０ｍｇ，０．０４７ｍｍｏｌ）を添加し、室温で２２時間反応させた。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて、１ＭＨＣｌで洗浄し、その後、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。分取ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５００１（１８．７１ｍｇ，４７％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　６．３３（２Ｈ，ｓ），６．９６（１Ｈ，ｍ），７．４７（２Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝９Ｈｚ），７．７６（１Ｈ，ｄ，Ｊ＝２．５），８．１２（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．４３（１Ｈ，ｓ），８．５８（１Ｈ，ｂｒ）
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１１ＢｒＮ６Ｏ３Ｎａ　［Ｍ＋Ｎａ］＋，４１２．９９６９，ｆｏｕｎｄ，４１２．９９８３ -Synthesis of KUSC-5001 DIPEA (36 μL, 0.207 mmol), HATU (34.8 mg, 0.102 mmol) in CH 2 Cl 2 solution (1.40 mL) of carboxylic acid intermediate 6 (24.2 mg, 0.102 mmol). ) Was added, and the mixture was stirred at room temperature for 30 minutes. p-Bromoaniline (8.0 mg, 0.047 mmol) was added and reacted at room temperature for 22 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined and washed with 1M HCl, and then washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification is performed by preparative TLC (Hexane / AcOEt = 1: 1), and then the obtained residue is purified by HPLC (cosmosil MSII, φ20 × 250 mm, elution: CH 3 CN / H 2 O = 60: 40). , KUSC-5001 (18.71 mg, 47%) was obtained.
1 1 HNMR 500MHz in CDCl 3 6.33 (2H, s), 6.96 (1H, m), 7.47 (2H, dd, J = 8.8Hz), 7.59 (2H, d, J = 9Hz) ), 7.76 (1H, d, J = 2.5), 8.12 (1H, d, J = 2Hz), 8.43 (1H, s), 8.58 (1H, br)
HR-ESI-MS: calcd C 14 H 11 BrN 6 O 3 Na　[M + Na] + , 412.99969, found, 412.9983
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　・ＫＵＳＣ－５００２の合成
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　６．７３（２Ｈ，ｓ）６．８９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．０９（１Ｈ，ｔｄ，Ｊ＝７．５，２．０Ｈｚ），７．４２（１Ｈ，ｔｄ，Ｊ＝８．０，２．０Ｈｚ），７．６７（１Ｈ，ｄｄ，Ｊ＝８．０，１．０Ｈｚ），８．２１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．２２（１Ｈ，ｓ），８．４７（１Ｈ，ｄｄ，Ｊ＝８．０，１．０Ｈｚ），９．０４（１Ｈ，ｓ），９．３８（１Ｈ，ｂｒ）
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１１ＢｒＮ６ＮａＯ３　
　［Ｍ＋Ｎａ］＋　，４１２．９９６９，　ｆｏｕｎｄ，４１２．９９８０ -Synthesis of KUSC-5002 Synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in Deuterated-d 6 6.73 (2H, s) 6.89 (1H, d, J = 2.5Hz), 7.09 (1H, td, J = 7.5,2.0Hz), 7.42 (1H, td, J = 8.0, 2.0Hz), 7.67 (1H, dd, J = 8.0, 1.0Hz), 8.21 (1H, d, J = 2. 5Hz), 8.22 (1H, s), 8.47 (1H, dd, J = 8.0, 1.0Hz), 9.04 (1H, s), 9.38 (1H, br)
HR-ESI-MS: calcd C 14 H 11 BrN 6 NaO 3
[M + Na] + , 412.99969, found, 412.9980
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　・ＫＵＳＣ－５００３
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　６．３４（２Ｈ，ｓ），６．９６（１Ｈ，ｓ），７．２３（２Ｈ，ｍ），７．６１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝２Ｈｚ），７．９２（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．４５（１Ｈ，ｓ），８．５９（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１１ＢｒＮ６ＮａＯ３　［Ｍ＋Ｎａ］＋，４１４．９９４８，ｆｏｕｎｄ，４１４．９９５５ ・ KUSC-5003
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 6.34 (2H, s), 6.96 (1H, s), 7.23 (2H, m), 7.61 (1H, d, J = 8Hz), 7.78 ( 1H, d, J = 2Hz), 7.92 (1H, d, J = 2Hz), 8.45 (1H, s), 8.59 (1H, br)
HR-ESI-MS: calcd C 14 H 11 BrN 6 NaO 3 [M + Na] + , 414.9948, found, 414.9955
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　・ＫＵＳＣ－５００４
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　６．３４（２Ｈ，ｓ），６．９９（１Ｈ，ｓ）７．６２（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７８－８２（３Ｈ，ｍ），８．１３（１Ｈ，ｓ），８．４３（１Ｈ，ｓ），８．７０（１Ｈ，ｓ）　　
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１１Ｆ３Ｎ６ＮａＯ３　［Ｍ＋Ｎａ］＋，
４０３．０７３７，ｆｏｕｎｄ，４０３．０７５７ ・ KUSC-5004
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 6.34 (2H, s), 6.99 (1H, s) 7.62 (2H, d, J = 8.5Hz), 7.78-82 (3H, m), 8 .13 (1H, s), 8.43 (1H, s), 8.70 (1H, s)
HR-ESI-MS: calcd C 15 H 11 F 3 N 6 NaO 3 [M + Na] + ,
403.0737, found, 403.0757
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　・ＫＵＳＣ－５００５
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　６．６５（２Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．１２（２Ｈ，ｍ），７．８１（２Ｈ，ｍ），８．１５（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．２１（１Ｈ，ｓ），８．９４（１Ｈ，ｓ），９．４８（１Ｈ，ｂｒ）
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１１ＦＮ６ＮａＯ３　［Ｍ＋Ｎａ］＋，３５３．０７６９，ｆｏｕｎｄ，３５３．０７７４ ・ KUSC-5005
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in Acetone-d 6 6.65 (2H, s), 6.86 (1H, d, J = 2.0Hz), 7.12 (2H, m), 7.81 (2H, m), 8.15 (1H, d, J = 2.5Hz), 8.21 (1H, s), 8.94 (1H, s), 9.48 (1H, br)
HR-ESI-MS: calcd C 14 H 11 FN 6 NaO 3 [M + Na] + , 353.0769, found, 353.0774
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　・ＫＵＳＣ－５００６
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　６．３５（２Ｈ，ｓ），６．９８（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．３９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．４８（１Ｈ，ｔ，Ｊ＝３．０Ｈｚ），７．７９（１Ｈ，ｍ），７．９０（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．９６（１Ｈ，ｓ），８．１２（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），８．４７（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），８．７３（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１１Ｆ３Ｎ６ＮａＯ３　
［Ｍ＋Ｎａ］＋　，４０３．０７３７，ｆｏｕｎｄ，４０３．０７４０ ・ KUSC-5006
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 6.35 (2H, s), 6.98 (1H, d, J = 3.0Hz), 7.39 (1H, d, J = 2.5Hz), 7.48 (1H) , T, J = 3.0Hz), 7.79 (1H, m), 7.90 (1H, d, J = 8.0Hz), 7.96 (1H, s), 8.12 (1H, d) , J = 7.5Hz), 8.47 (1H, d, J = 3.0Hz), 8.73 (1H, br)
HR-ESI-MS: calcd C 15 H 11 F 3 N 6 NaO 3
[M + Na] + , 403.0737, found, 403.0740
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　・ＫＵＳＣ－５００７
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　６．３３（２Ｈ，ｓ），６．９７（１Ｈ，ｓ），７．３３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．１２（１Ｈ，ｓ），８．４３（１Ｈ，ｓ），８．５８（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１１ＣｌＮ６ＮａＯ３［Ｍ＋Ｎａ］＋，３６９．０４７９，ｆｏｕｎｄ，３６９．０４８３ ・ KUSC-5007
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 6.33 (2H, s), 6.97 (1H, s), 7.33 (2H, d, J = 8.5Hz), 7.64 (2H, d, J = 8) .5Hz), 7.76 (1H, d, J = 2.5Hz), 8.12 (1H, s), 8.43 (1H, s), 8.58 (1H, br)
HR-ESI-MS: calcd C 14 H 11 ClN 6 NaO 3 [M + Na] + , 369.0479, found, 369.0483
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　・ＫＵＳＣ－５００８
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　６．３３（２Ｈ，ｓ），６．９７（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．１５（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．３７（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．６８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．１２（１Ｈ，ｓ），８．４４（１Ｈ，ｓ），８．５７（１Ｈ，ｂｒ）
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１２Ｎ６ＮａＯ３［Ｍ＋Ｎａ］＋，
　３３５．０８６９，ｆｏｕｎｄ，３３５．０８６４ ・ KUSC-5008
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 6.33 (2H, s), 6.97 (1H, d, J = 2.5Hz), 7.15 (1H, t, J = 7.5Hz), 7.37 (2H) , T, J = 8.0Hz), 7.68 (2H, d, J = 8.5Hz), 7.76 (1H, d, J = 2.5Hz), 8.12 (1H, s), 8 .44 (1H, s), 8.57 (1H, br)
HR-ESI-MS: calcd C 14 H 12 N 6 NaO 3 [M + Na] + ,
335.0869, found, 335.0864
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　・ＫＵＳＣ－５０１０
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．２５（６Ｈ，ｄ，Ｊ＝７．０Ｈｚ），２．８９（１Ｈ，ｓｅｐｔｅｔ，Ｊ＝７．０Ｈｚ），６．３２（２Ｈ，ｓ），６．９６（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．２２（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７５（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．１２（１Ｈ，ｓ），８．４４（１Ｈ，ｓ），８．５４（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１７Ｈ１８Ｎ６Ｏ３Ｎａ　［Ｍ＋Ｈ］＋，
３７７．１３３３，ｆｏｕｎｄ，３７７．１３５２ ・ KUSC-5010
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 1.25 (6H, d, J = 7.0Hz), 2.89 (1H, septet, J = 7.0Hz), 6.32 (2H, s), 6.96 (1H) , D, J = 3.0Hz), 7.22 (2H, d, J = 8.5Hz), 7.58 (2H, d, J = 8.5Hz), 7.75 (1H, d, J =) 2.5Hz), 8.12 (1H, s), 8.44 (1H, s), 8.54 (1H, br)
HR-ESI-MS: calcd C 17 H 18 N 6 O 3 Na [M + H] + ,
377.1333, found, 377.1352
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　・ＫＵＳＣ－５０１１
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　３．８０（３Ｈ，ｓ），６．３２（２Ｈ，ｓ），６．９０（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），６．９５（１Ｈ，ｓ），７．５８（２Ｈ，ｄ，Ｊ＝９．５Ｈｚ），７．７４（１Ｈ，ｓ），８．１２（１Ｈ，ｓ），８．４３（１Ｈ，ｓ），８．４９（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１４Ｎ６Ｏ４Ｎａ［Ｍ＋Ｎａ］＋，
３６５．０９６９，ｆｏｕｎｄ，３６５．０９９０ ・ KUSC-5011
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 3.80 (3H, s), 6.32 (2H, s), 6.90 (2H, d, J = 8.5Hz), 6.95 (1H, s), 7. 58 (2H, d, J = 9.5Hz), 7.74 (1H, s), 8.12 (1H, s), 8.43 (1H, s), 8.49 (1H, s)
HR-ESI-MS: calcd C 15 H 14 N 6 O 4 Na [M + Na] + ,
365.0969, found, 365.0990
　・ＫＵＳＣ－５０１２
Figure JPOXMLDOC01-appb-C000070
 ・ KUSC-5012
Figure JPOXMLDOC01-appb-C000070
　・ＫＵＳＣ－５０１２
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　６．３３（２Ｈ，ｓ），６．９８（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．４２（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５３（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．７９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．９２（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．１４（１Ｈ，ｓ），８．４３（１Ｈ，ｓ），８．６（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１０Ｃｌ２Ｎ６ＮａＯ３［Ｍ＋Ｎａ］＋，４０３．００８４，ｆｏｕｎｄ，４０３．００９２ ・ KUSC-5012
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 6.33 (2H, s), 6.98 (1H, d, J = 2.5Hz), 7.42 (1H, d, J = 8.5Hz), 7.53 (1H) , D, J = 3.0Hz), 7.79 (1H, d, J = 2.5Hz), 7.92 (1H, d, J = 2.5Hz), 8.14 (1H, s), 8 .43 (1H, s), 8.6 (1H, s)
HR-ESI-MS: calcd C 14 H 10 Cl 2 N 6 NaO 3 [M + Na] + , 403.084, found, 403.0092
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　・ＫＵＳＣ－５０１３
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．６３（２Ｈ，ｓ），６．８１（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），６．８５（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），６．９２（２Ｈ，ｍ），８．１７（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．２２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．３６（１Ｈ，ｓ），９．２２（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），１０．１９（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１２Ｎ６Ｏ４Ｎａ［Ｍ＋Ｎａ］＋　
３５１．０８１３，ｆｏｕｎｄ，３５１．０８０８ ・ KUSC-5013
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in DMSO - d 6.63 (2H, s), 6.81 (1H, t, J = 7.5Hz), 6.85 (1H, d, J = 2.5Hz), 6.92 (2H, m), 8.17 (1H, d, J = 8.0Hz), 8.22 (1H, d, J = 2.0Hz), 8.36 (1H, s), 9.22 (2H) , D, J = 7.0Hz), 10.19 (1H, s)
HR-ESI-MS: calcd C 14 H 12 N 6 O 4 Na [M + Na] +
351.0833 found, 351.0808
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　・ＫＵＳＣ－５０２３
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　６．７２（２Ｈ，ｓ），６．９２（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．０１（１Ｈ，ｄｄ，Ｊ＝２．５Ｈｚ），８．２０（２Ｈ，ｄ，Ｊ＝３．０Ｈｚ），８．２７（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．４３（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），９．０７（１Ｈ，ｓ），９．３６（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：　Ｃ１３Ｈ１０ＢｒＮ７ＮａＯ３　［Ｍ＋Ｎａ］＋，
４１３．９９２１，ｆｏｕｎｄ，４１３．９９３０  ・ KUSC-5023
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in Acetone-d 66.72 (2H, s), 6.92 (1H, d, J = 2.5Hz ), 8.01 (1H, dd, J = 2.5Hz), 8.20 (2H, d, J = 3.0Hz), 8.27 (1H, d, J = 9.0Hz), 8.43 (1H, d, J = 3.0Hz), 9.07 (1H, s) , 9.36 (1H, br)
HR-ESI-MS: C 13 H 10 BrN 7 NaO 3 [M + Na] + ,
413.9921, found, 413.9930
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　・ＫＵＳＣ－５０２７
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．６３（２Ｈ，ｓ），６．８９（１Ｈ，ｓ），７．４７（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７３（１Ｈ，ｓ），７．９６（１Ｈ，ｄ，８．５Ｈｚ），８．２３（１Ｈ，ｓ），８．３７（１Ｈ，ｓ），９．２１（１Ｈ，ｓ），９．６５（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１０Ｃｌ２Ｎ６ＮａＯ３　［Ｍ＋Ｎａ］＋　４０３．００８４，ｆｏｕｎｄ，４０３．０１０６ ・ KUSC-5027
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in DMSO-d 6 6.63 (2H, s), 6.89 (1H, s), 7.47 (1H, d, J = 8.5Hz), 7.73 (1H, s), 7.96 (1H, d, 8.5Hz), 8.23 (1H, s), 8.37 (1H, s), 9.21 (1H, s), 9.65 (1H, s)
HR-ESI-MS: calcd C 14 H 10 Cl 2 N 6 NaO 3 [M + Na] + 403.084, found, 403.0106
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　・ＫＵＳＣ－５０２８
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．６１（２Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．１０（１Ｈ，ｔ，Ｊ＝３．５Ｈｚ），７．３６（１Ｈ，ｔ，Ｊ＝３．０Ｈｚ），７．６６（１Ｈ，ｑ，Ｊ＝８．５Ｈｚ），８．２０（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．３６（１Ｈ，ｓ），９．１８（１Ｈ，ｓ），９．７７（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１０Ｆ２Ｎ６ＮａＯ３　［Ｍ＋Ｎａ］＋，３６１．０６７５，ｆｏｕｎｄ，３６１．０６８３ ・ KUSC-5028
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in DMSO-d 6 6.61 (2H, s), 6.86 (1H, d, J = 2.5Hz), 7.10 (1H, t, J = 3.5Hz), 7.36 (1H, t, J = 3.0Hz), 7.66 (1H, q, J = 8.5Hz), 8.20 (1H, d, J = 2.5Hz), 8.36 (1H, s) , 9.18 (1H, s), 9.77 (1H, s)
HR-ESI-MS: calcd C 14 H 10 F 2 N 6 NaO 3 [M + Na] + , 361.0675, found, 361.0683
　・ＫＵＳＣ－５０３２
Figure JPOXMLDOC01-appb-C000075
 　エステル体４からＫＵＳＣ－５００１と同様の手法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．８５（２Ｈ，ｓ），７．１６（１Ｈ，ｓ），７．５８（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７２（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．２８（１Ｈ，ｓ），９．０２（１Ｈ，ｓ），１０．５３（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１１ＢｒＮ６Ｏ３　［Ｍ－Ｈ］－，３９１．００８６，ｆｏｕｎｄ，３９１．０００４  ・ KUSC-5032
Figure JPOXMLDOC01-appb-C000075
 Synthesis was carried out from the ester body 4 in the same manner as in KUSC-5001.
1 1 HNMR 500MHz in DMSO-d 6 6.85 (2H, s), 7.16 (1H, s), 7.58 (1H, d, J = 8.5Hz), 7.72 (1H, d, J) = 8.5Hz), 8.28 (1H, s), 9.02 (1H, s), 10.53 (1H, s)
HR-ESI-MS: calcd C 14 H 11 BrN 6 O 3 [MH] - , 391.0086, found, 391.0004
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　・ＫＵＳＣ－５００９
　ＫＵＳＣ－５００１と同様の方法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　２．８７（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），３．６５（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），６．２６（２Ｈ，ｓ），６．８５（１Ｈ，ｓ），７．１１（１Ｈ，ｓ），７．４４（１Ｈ，ｓ），７．７０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．０９（１Ｈ，ｓ），８．３６（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ　ｃａｌｃｄ，Ｃ１６Ｈ１５ＢｒＮ６ＮａＯ３［Ｍ＋Ｎａ］＋，４４１．０２８２，ｆｏｕｎｄ，４４１．０２９６　 ・ KUSC-5009
The synthesis was carried out in the same manner as KUSC-5001.
1 1 HNMR 500MHz in CDCl 3 2.87 (2H, d, J = 6.5Hz), 3.65 (2H, t, J = 6.5Hz), 6.26 (2H, s), 6.85 (1H) , S), 7.11 (1H, s), 7.44 (1H, s), 7.70 (1H, d, J = 2.0Hz), 8.09 (1H, s), 8.36 ( 1H, s)
HR-ESI-MS calcd, C 16 H 15 BrN 6 NaO 3 [M + Na] + , 441.0282, found, 441.0296
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　・ブロモ体８，９
　１Ｈ―ピラゾール―３―カルボン酸エチル　（２００ｍｇ，１．４３ｍｍｏｌ）のアセトニトリル溶液　１４．３ｍｌに１，２－ジブロモメタン（０．６１ｍｌ，７．０８ｍｍｏｌ），Ｋ２ＣＯ３（３９４．５ｍｇ，２．８５ｍｍｏｌ）を添加し、室温で３日間攪拌した。水で反応を停止し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２クロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３：１）で精製を行った。ブロモ体８（１２２．７ｍｇ，３５％），ブロモ体９（１４８．９３ｍｇ，４２％）を得た。 -Bromo form 8, 9
Acetonitrile solution of 1H-pyrazole-3-carboxylate (200 mg, 1.43 mmol) in 14.3 ml, 1,2-dibromomethane (0.61 ml, 7.08 mmol), K2 CO 3 (394.5 mg, 2 . 85 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction was stopped with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 chromatography (Hexane / AcOEt = 3: 1). Bromo 8 (122.7 mg, 35%) and Bromo 9 (148.93 mg, 42%) were obtained.
　・ブロモ体８
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４０（３Ｈ，ｔ，Ｊ＝６．５Ｈｚ），３．７６（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），４．４２（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．５８（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），６．８２（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．５１（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）
　ＨＭＱＣ，ＨＭＢＣで相関を確認した。
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ，Ｃ８Ｈ１１ＢｒＮ２ＮａＯ２　［Ｍ＋Ｎａ］＋，
２７０．９８７６，ｆｏｕｎｄ，２７０．９８２７ -Bromo form 8
1 1 HNMR 500MHz in CDCl 3 1.40 (3H, t, J = 6.5Hz), 3.76 (2H, t, J = 6.5Hz), 4.42 (2H, t, J = 7.0Hz) , 4.58 (2H, t, J = 6.5Hz), 6.82 (1H, d, J = 2.5Hz), 7.51 (1H, d, J = 2.0Hz)
Correlation was confirmed by HMQC and HMBC.
HR-ESI-MS: calcd, C 8 H 11 BrN 2 NaO 2 [M + Na] + ,
270.9876, found, 270.9827
　・ブロモ体９
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３９（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），３．７２（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．３５（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．９６（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），６．８７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．５４（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ）
　ＨＭＱＣ，ＨＭＢＣで相関を確認した。
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ，Ｃ８Ｈ１１ＢｒＮ２ＮａＯ２　［Ｍ＋Ｎａ］＋，
２７０．９８７６，ｆｏｕｎｄ，２７１．１８１７ -Bromo form 9
1 1 HNMR 500MHz in CDCl 3 1.39 (3H, t, J = 7.0Hz), 3.72 (2H, t, J = 7.0Hz), 4.35 (2H, t, J = 7.0Hz) , 4.96 (2H, t, J = 7.0Hz), 6.87 (1H, d, J = 2.0Hz), 7.54 (1H, d, J = 1.5Hz)
Correlation was confirmed by HMQC and HMBC.
HR-ESI-MS: calcd, C 8 H 11 BrN 2 NaO 2 [M + Na] + ,
270.9876, found, 271.1817
　・ＫＵＳＣ－５０１６の合成
Figure JPOXMLDOC01-appb-C000078
 -Synthesis of KUSC-5016
Figure JPOXMLDOC01-appb-C000078
　・エステル体１０
　4－ニトロ―１Ｈ－ピラゾール（１０ｍｇ，０．０８８４ｍｍｏｌ）のＤＭＦ溶液　０．４９ｍｌに、１－ブロモエチルー５－カルボン酸エチル８（２４．０ｍｇ，０．０９７１ｍｍｏｌ）、Ｋ２ＣＯ３（２４．４ｍｇ，０．１７７ｍｍｏｌ）を添加し、室温で２２．５時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２クロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝２：１）で精製を行い、エステル体１０（２２．３６ｍｇ，９１％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３６（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．３１（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．６４（１Ｈ，ｔ，Ｊ＝６．０Ｈｚ），５．０４（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），６．８４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．５０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．８０（１Ｈ，ｓ），８．０５（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ１４Ｎ５Ｏ４［Ｍ＋Ｈ］＋　，２８０．１０４０，ｆｏｕｎｄ，２８０．０９８４ ・ Ester body 10
In 0.49 ml of a DMF solution of 4-nitro-1H-pyrazole (10 mg, 0.0884 mmol), ethyl 1-bromoethyl-5-carboxylate 8 (24.0 mg, 0.0971 mmol), K2 CO 3 ( 24.4 mg, 24.4 mg, 0.177 mmol) was added, and the mixture was stirred at room temperature for 22.5 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 chromatography (Hexane / AcOEt = 2: 1) to obtain ester 10 (22.36 mg, 91%).
1 1 HNMR 500MHz in CDCl 3 1.36 (3H, t, J = 7.0Hz), 4.31 (2H, q, J = 7.0Hz), 4.64 (1H, t, J = 6.0Hz) , 5.04 (2H, t, J = 6.0Hz), 6.84 (1H, d, J = 2.0Hz), 7.50 (1H, d, J = 2.0Hz), 7.80 ( 1H, s), 8.05 (1H, s)
HR-ESI-MS: calcd C 11 H 14 N 5 O 4 [M + H] + , 280.1040, found, 280.0984
　・カルボン酸中間体１１
　エステル体１０（２２．３６ｍｇ，０．０８０１ｍｍｏｌ）のＭｅＯＨ／Ｈ２Ｏ＝３：１混合溶液　４ｍｌに、水酸化ナトリウム（９ｍｇ，０．２２５ｍｍｏｌ）を添加し、８時間加熱還流した。室温に冷却し、濃塩酸を加えてｐＨ＝２とした。水とＣＨＣｌ３で２層に分離し、ＣＨＣｌ３で抽出した。有機層を合わせて硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体１１（１７．６１ｍｇ，８８％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　４．６８（２Ｈ，ｔ，Ｊ＝５．０Ｈｚ），５．０５（２Ｈ，ｔ，Ｊ＝５．０Ｈｚ），６．８９（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．５０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．０５（１Ｈ，ｓ），８．２６（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ９Ｈ１０Ｎ５Ｏ４［Ｍ＋Ｈ］＋，２５２．０７２７，ｆｏｕｎｄ，２５２．０６９３ -Carboxylic acid intermediate 11
Sodium hydroxide (9 mg, 0.225 mmol) was added to 4 ml of a MeOH / H 2 O = 3: 1 mixed solution of ester 10 (22.36 mg, 0.0801 mmol), and the mixture was heated under reflux for 8 hours. The mixture was cooled to room temperature and concentrated hydrochloric acid was added to adjust the pH to 2. It was separated into two layers with water and CHCl 3 , and extracted with CHCl 3 . The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 11 (17.61 mg, 88%) was obtained.
1 1 HNMR 500MHz in MeOH-d 4 4.68 (2H, t, J = 5.0Hz), 5.05 (2H, t, J = 5.0Hz), 6.89 (1H, d, J = 1. 5Hz), 7.50 (1H, d, J = 2.0Hz), 8.05 (1H, s), 8.26 (1H, s)
HR-ESI-MS: calcd C 9 H 10 N 5 O 4 [M + H] + , 252.0727, found, 252.0693
　・ＫＵＳＣ－５０１６の合成
　カルボン酸中間体１１（１７．６１ｍｇ，０．０７０１ｍｍｏｌ）のＣＨ２Ｃｌ２溶液　０．９５ｍｌに、ＤＩＰＥＡ（２４μＬ，０．１３８ｍｍｏｌ）、ＨＡＴＵ（２６．７ｍｇ，０．０７０２ｍｍｏｌ）を添加し、室温で３０分間攪拌した。反応溶液にｐ－ブロモアニリン（１３．３ｍｇ，０．０７３１ｍｍｏｌ）を添加し、室温で１６．５時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２クロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製を行い、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０１６（１４．２７ｍｇ，５０％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　４．７０（２Ｈ，ｔ，Ｊ＝８．０Ｈｚ），５．０６（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），６．６７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．４５（２Ｈ，ｄｄ，Ｊ＝８．０Ｈｚ），７．５０（２Ｈ，ｄｄ，Ｊ＝８．０Ｈｚ），７．５４（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．５８（１Ｈ，ｂｒ），７．８３（１Ｈ，ｓ），８．０３（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１３ＢｒＮ６ＮａＯ３［Ｍ＋Ｎａ］＋，
　４２７．０１２５，ｆｏｕｎｄ，４２７．０１６６
Figure JPOXMLDOC01-appb-C000079
 -Synthesis of KUSC-5016 DIPEA (24 μL, 0.138 mmol), HATU (26.7 mg, 0.0702 mmol) in 0.95 ml of CH 2 Cl 2 solution of carboxylic acid intermediate 11 (17.61 mg, 0.0701 mmol). Was added, and the mixture was stirred at room temperature for 30 minutes. P-Bromoaniline (13.3 mg, 0.0731 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16.5 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by SiO 2 chromatography (CHCl 3 / MeOH = 20: 1), and then the obtained residue is obtained by HPLC (cosmosil MSII, φ20 × 250 mm, chloroform: CH 3 CN / H 2 O = 60: 40). ) To obtain KUSC-5016 (14.27 mg, 50%).
1 1 HNMR 500MHz in CDCl 3 4.70 (2H, t, J = 8.0Hz), 5.06 (2H, t, J = 7.5Hz), 6.67 (1H, d, J = 2.0Hz) , 7.45 (2H, dd, J = 8.0Hz), 7.50 (2H, dd, J = 8.0Hz), 7.54 (1H, d, J = 3.0Hz), 7.58 ( 1H, br), 7.83 (1H, s), 8.03 (1H, s)
HR-ESI-MS: calcd C 15 H 13 BrN 6 NaO 3 [M + Na] + ,
427.0125, found, 427.0166
Figure JPOXMLDOC01-appb-C000079
　・エステル体１２
　4－ニトロー１Ｈ－ピラゾール（１０．２ｍｇ，０．０８８４ｍｍｏｌ）のＤＭＦ溶液　０．４９ｍｌに、１－ブロモエチルー３－カルボン酸エチル７（２４．０ｍｇ，０．０９７１ｍｍｏｌ）、Ｋ２ＣＯ３（２４．４ｍｇ，０．１７７ｍｍｏｌ）を添加し、室温で５．６時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２クロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製を行い、エステル体１２（２０．３ｍｇ，８１％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４１（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），４．４１（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），４．６８（４Ｈ，ｍ）６．６９（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．０６（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．７５（１Ｈ，ｓ），８．１０（１Ｈ，ｓ）
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ１４Ｎ５Ｏ４［Ｍ＋Ｈ］＋　，
　２８０．１０４０，ｆｏｕｎｄ，２８０．０９８１ ・ Ester body 12
In 0.49 ml of a DMF solution of 4-nitro-1H-pyrazole (10.2 mg, 0.0884 mmol), ethyl 1-bromoethyl- 3-carboxylate 7 (24.0 mg, 0.0971 mmol), K2 CO 3 ( 24.4 mg). , 0.177 mmol) was added, and the mixture was stirred at room temperature for 5.6 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 chromatography (CHCl 3 / MeOH = 20: 1) to obtain ester 12 (20.3 mg, 81%).
1 1 HNMR 500MHz in CDCl 3 1.41 (3H, t, J = 7.5Hz), 4.41 (2H, t, J = 7.5Hz), 4.68 (4H, m) 6.69 (1H, 1H, d, J = 3.0Hz), 7.06 (1H, d, J = 3.0Hz), 7.75 (1H, s), 8.10 (1H, s)
HR-ESI-MS: calcd C 11 H 14 N 5 O 4 [M + H] + ,
280.1040, found, 280.0981
　・カルボン酸中間体１３
　エステル中間体１２（２５．６５ｍｇ，０．０９１８ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶液　２．４ｍＬに、２Ｍの水酸化ナトリウム水溶液（６９μＬ，０．１３８ｍｍｏｌ）を添加し、４５℃で２１．５時間攪拌した。室温に冷却し、塩酸を加えてｐＨ＝２～３とした。水と酢酸エチルで２層に分離し、酢酸エチルで抽出した。有機層を合わせて硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体１３（２２．８９ｍｇ，９９％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　４．６５－４．６８（４Ｈ，ｍ），６．６２（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．６１（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），８．２６（１Ｈ，ｓ），８．７０（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ９Ｈ１０Ｎ５Ｏ４［Ｍ＋Ｈ］＋，
２５２．０７２７，ｆｏｕｎｄ，２５２．０６９２ -Carboxylic acid intermediate 13
To 2.4 mL of a MeOH / water = 3: 1 mixed solution of ester intermediate 12 (25.65 mg, 0.0918 mmol), a 2 M aqueous sodium hydroxide solution (69 μL, 0.138 mmol) was added and 21. The mixture was stirred for 5 hours. The mixture was cooled to room temperature and hydrochloric acid was added to adjust the pH to 2 to 3. It was separated into two layers with water and ethyl acetate, and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 13 (22.89 mg, 99%) was obtained.
1 1 HNMR 600MHz in DMSO-d 6 4.65-4.68 (4H, m), 6.62 (1H, d, J = 2.4Hz), 7.61 (1H, d, J = 1.8Hz) , 8.26 (1H, s), 8.70 (1H, s)
HR-ESI-MS: calcd C 9 H 10 N 5 O 4 [M + H] + ,
252.0727, found, 252.0692
　・ＫＵＳＣ－５０２４
　カルボン酸中間体１３（１６．２１ｍｇ，０．０７０１ｍｍｏｌ）のＣＨ２Ｃｌ２溶液　０．５５ｍｌに、ＤＩＰＥＡ（２２．５μＬ，０．１２９ｍｍｏｌ）、ＨＡＴＵ（２４．５ｍｇ，０．０６４４ｍｍｏｌ）を添加し、室温で３０分間攪拌した。反応溶液にｐ－ブロモアニリン（１２．２ｍｇ，０．０７１０ｍｍｏｌ）を添加し、室温で１７時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて硫酸ナトリウムで乾燥し、溶媒を減圧留去した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０２４（２１．５６ｍｇ，８３％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　４．６７（４Ｈ，ｄｄ，Ｊ＝５．５Ｈｚ），６．８１（１Ｈ，ｓ），７．１６（１Ｈ，ｓ），７．４８（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．８３（１Ｈ，ｓ），８．１３（１Ｈ，ｓ），８．５７（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１３ＢｒＮ６ＮａＯ３［Ｍ＋Ｎａ］＋，４２９．０１０５，ｆｏｕｎｄ，４２９．００８７ ・ KUSC-5024
DIPEA (22.5 μL, 0.129 mmol) and HATU (24.5 mg, 0.0644 mmol) were added to 0.55 ml of a CH 2 Cl 2 solution of carboxylic acid intermediate 13 (16.21 mg, 0.0701 mmol). The mixture was stirred at room temperature for 30 minutes. P-Bromoaniline (12.2 mg, 0.0710 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 17 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 60: 40) to obtain KUSC-5024 (21.56 mg, 83%).
1 1 HNMR 500MHz in CDCl 3 4.67 (4H, dd, J = 5.5Hz), 6.81 (1H, s), 7.16 (1H, s), 7.48 (2H, d, J = 9) 0.0Hz), 7.59 (2H, d, J = 8.5Hz), 7.83 (1H, s), 8.13 (1H, s), 8.57 (1H, s)
HR-ESI-MS: calcd C 15 H 13 BrN 6 NaO 3 [M + Na] + , 429.0105, found, 429.0087
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　・ブロモ体１４，１５
　１Ｈ－ピラゾールー３－カルボン酸エチル（２００．１ｍｇ，１．４３ｍｍｏｌ）のアセトニトリル溶液（１４．３ｍｌ）に炭酸カリウム（３９４．５ｍｇ，２．８５ｍｍｏｌ），１，３－ジブロモプロパン（０．７２ｍｌ，７．０９ｍｍｏｌ）を添加し、室温で３日間攪拌した。水で反応を停止し、酢酸エチルで抽出した。有機層を合わせて飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２カラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３：１）で精製を行った。１―ブロモプロピルピラゾールー３－カルボン酸エチル１４（８２．１２ｍｇ，２２％），ブロモ体１５（４．６７ｍｇ，１％）を得た。 ・ Bromo form 14,15
Potassium carbonate (394.5 mg, 2.85 mmol), 1,3-dibromopropane (0.72 ml, 7) in an acetonitrile solution (14.3 ml) of 1H-pyrazole-3-carboxylate (200.1 mg, 1.43 mmol) .09 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction was stopped with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 column chromatography (Hexane / AcOEt = 3: 1). Ethyl 1-bromopropylpyrazole-3-carboxylate 14 (82.12 mg, 22%) and bromo compound 15 (4.67 mg, 1%) were obtained.
・ブロモ体１４
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３７（１Ｈ，ｔ，Ｊ＝７．０Ｈｚ），２．４２（２Ｈ，ｍ），３．２８（２Ｈ，ｍ），４．３４（４Ｈ，ｍ），６．７７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．４６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）
　ＨＭＱＣ，ＨＭＢＣで置換位置を確認した。
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ９Ｈ１３ＢｒＮ２Ｏ２Ｎａ［Ｍ＋Ｎａ］＋，
　２８３．００５３，ｆｏｕｎｄ，２８３．００４４ -Bromo form 14
1 1 HNMR 500MHz in CDCl 3 1.37 (1H, t, J = 7.0Hz), 2.42 (2H, m), 3.28 (2H, m), 4.34 (4H, m), 6. 77 (1H, d, J = 2.0Hz), 7.46 (1H, d, J = 2.0Hz)
The replacement position was confirmed by HMQC and HMBC.
HR-ESI-MS: calcd C 9 H 13 BrN 2 O 2 Na [M + Na] + ,
283.0053, found, 283.0044
　・エステル体１６
　４－ニトロー１Ｈ－ピラゾール（１０．３ｍｇ，０．０８８４ｍｍｏｌ）のＤＭＦ溶液０．５９ｍｌにＫ２ＣＯ３（２４．４ｍｇ，０．１７７ｍｍｏｌ）、１－ブロモプロピルピラゾールー３－カルボン酸エチル１４（２５．４ｍｇ，０．０９３ｍｍｏｌ）を添加し、室温で３．８時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出を行った。有機層を合わせて飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。エステル体１６（２０．４９ｍｇ，８５％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４２（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ）２．５２（２Ｈ，ｍ），４．１５（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．２４（２Ｈ，ｔ，Ｊ＝７．０Ｈｚ）４．４２（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），６．８２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）、７．４５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．０９（１Ｈ，ｓ），８．２２（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１２Ｈ１６Ｎ５Ｏ４［Ｍ＋Ｈ］＋，
２９４．１１９７，ｆｏｕｎｄ，２９４．１１３２ ・ Ester body 16
K 2 CO 3 (24.4 mg, 0.177 mmol) in 0.59 ml of a DMF solution of 4-nitro-1H-pyrazole (10.3 mg, 0.0884 mmol), ethyl 14 (25) 1-bromopropylpyrazole-3-carboxylate. (0.4 mg, 0.093 mmol) was added, and the mixture was stirred at room temperature for 3.8 hours. The reaction was stopped with water and extraction was performed with CHCl 3 . The organic layers were combined and washed with saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 20: 1). Ester 16 (20.49 mg, 85%) was obtained.
1 1 HNMR 500MHz in CDCl 3 1.42 (3H, t, J = 7.0Hz) 2.52 (2H, m), 4.15 (2H, t, J = 7.0Hz), 4.24 (2H, t, J = 7.0Hz) 4.42 (2H, q, J = 7.0Hz), 6.82 (1H, d, J = 2.0Hz), 7.45 (1H, d, J = 2. 0Hz), 8.09 (1H, s), 8.22 (1H, s)
HR-ESI-MS: calcd C 12 H 16 N 5 O 4 [M + H] + ,
294.1197, found, 294.1132
　・カルボン酸中間体１７
　エステル体１６（２０．４９ｍｇ，０．０７０ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒４ｍｌに水酸化ナトリウム（６．９３ｍｇ，０．１７３ｍｍｏｌ）を添加し、１７．２時間加熱還流した。濃塩酸でｐＨ＝２程度に酸性化し、ＣＨＣｌ３で抽出した。有機層を合わせて硫酸ナトリウムで乾燥した。溶媒を減圧留去した。カルボン酸中間体１７（１５．４８ｍｇ，８４％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　２．５１（２Ｈ，ｍ），４．２８（４Ｈ，ｍ）６．７９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．４０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．１３（１Ｈ，ｓ），８．６１（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１０Ｈ１１Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，
２８８．０７０４，ｆｏｕｎｄ，２８８．０７２４ -Carboxylic acid intermediate 17
Sodium hydroxide (6.93 mg, 0.173 mmol) was added to 4 ml of a MeOH / water = 3: 1 mixed solvent of ester 16 (20.49 mg, 0.070 mmol), and the mixture was heated under reflux for 17.2 hours. It was acidified to pH = 2 with concentrated hydrochloric acid and extracted with CHCl 3 . The organic layers were combined and dried over sodium sulfate. The solvent was distilled off under reduced pressure. Carboxylic acid intermediate 17 (15.48 mg, 84%) was obtained.
1 1 HNMR 500MHz in MeOH-d 4 2.51 (2H, m), 4.28 (4H, m) 6.79 (1H, d, J = 2.5Hz), 7.40 (1H, d, J = 2.0Hz), 8.13 (1H, s), 8.61 (1H, s)
HR-ESI-MS: calcd C 10 H 11 N 5 NaO 4 [M + Na] + ,
288.0704, found, 288.0724
　・ＫＵＳＣ－５０１８
　カルボン酸中間体１７（１５．８７ｍｇ，０．０５９８ｍｍｏｌ）のＣＨ２Ｃｌ２溶液０．８１ｍｌにＤＩＰＥＡ（２１μＬ，０．１２１ｍｍｏｌ）、ＨＡＴＵ（２２．８ｍｇ，０．０６００ｍｍｏｌ）を加えて、室温で３０分間攪拌した。ｐ－ブロモアニリン（１１．３ｍｇ，０．０６５７ｍｍｏｌ）を加えて、１７時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０１８（１１．８７ｍｇ，４７％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　２．５４（２Ｈ，ｍ），４．１４（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），４．２２（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），
　６．９１（１Ｈ，ｓ），７．５（３Ｈ，ｍ），７．６１（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．１２（１Ｈ，ｓ），８．６３（１Ｈ，ｓ）
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ１５ＢｒＮ６ＮａＯ３［Ｍ＋Ｎａ］＋，４４３．０２６１，ｆｏｕｎｄ，４４３．０２４８
Figure JPOXMLDOC01-appb-C000081
 ・ KUSC-5018
Add DIPEA (21 μL, 0.121 mmol) and HATU (22.8 mg, 0.0600 mmol) to 0.81 ml of CH 2 Cl 2 solution of carboxylic acid intermediate 17 (15.87 mg, 0.0598 mmol) and add 30 at room temperature. Stir for minutes. p-Bromoaniline (11.3 mg, 0.0657 mmol) was added, and the mixture was stirred for 17 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 20: 1). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 60: 40) to obtain KUSC-5018 (11.87 mg, 47%).
1 1 HNMR 500MHz in CDCl 3 2.54 (2H, m), 4.14 (2H, t, J = 6.5Hz), 4.22 (2H, t, J = 6.5Hz),
6.91 (1H, s), 7.5 (3H, m), 7.61 (2H, d, J = 9.0Hz), 8.12 (1H, s), 8.63 (1H, s)
HR-ESI-MS: calcd C 16 H 15 BrN 6 NaO 3 [M + Na] + , 443.0261, found, 443.0248
Figure JPOXMLDOC01-appb-C000081
　エステル体１８
　　１－ブロモメチルピラゾールー３－カルボン酸エチル（５０．０ｍｇ，０．２１５ｍｍｏｌ）のアセトニトリル溶液２．８ｍＬに１Ｈ－イミダゾール（３３．０ｍｇ，０．４８５ｍｍｏｌ）、Ｋ２ＣＯ３（６５．２ｍｇ，０．４７２ｍｍｏｌ）を加えて、室温で１日攪拌した。水で反応を停止し、酢酸エチルで抽出を行った。飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。エステル体１８（３６．1ｍｇ，７６％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３８（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．３９（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），６．２１（２Ｈ，ｓ），６．８３（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．０７（１Ｈ，ｓ），７．１０（１Ｈ，ｓ），７．５１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．７３（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１０Ｈ１３Ｎ４Ｏ２　［Ｍ＋Ｈ］＋，
２２１．１０３３，ｆｏｕｎｄ，２２１．１０１２［Ｍ＋Ｈ］＋ Ester body 18
1H-imidazole (33.0 mg, 0.485 mmol), K2 CO 3 (65.2 mg, 0) in 2.8 mL of an acetonitrile solution of 1-bromomethylpyrazole-3-carboxylate (50.0 mg, 0.215 mmol) .472 mmol) was added, and the mixture was stirred at room temperature for 1 day. The reaction was stopped with water and extraction was performed with ethyl acetate. It was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 20: 1). Ester 18 (36.1 mg, 76%) was obtained.
1 1 HNMR 500MHz in CDCl3 1.38 (3H, t, J = 7.0Hz), 4.39 (2H, q, J = 7.0Hz), 6.21 (2H, s), 6.83 (1H, 1H, d, J = 3.0Hz), 7.07 (1H, s), 7.10 (1H, s), 7.51 (1H, d, J = 2.5Hz), 7.73 (1H, s)
HR-ESI-MS: calcd C 10 H 13 N 4 O 2 [M + H] + ,
221.1303, found, 221.1012 [M + H] +
　カルボン酸中間体１９
　エステル中間体１８（３６．１ｍｇ，０．１６４ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒３．２ｍＬに２Ｍ水酸化ナトリウム水溶液（０．１２ｍＬ，０．２４ｍｍｏｌ）を加えて、２０．０時間加熱還流した。濃塩酸でｐＨ＝５程度に酸性化し、酢酸エチルで抽出した。有機層を合わせて硫酸ナトリウムで乾燥した。溶媒を減圧留去し、カルボン酸中間体１９（５．６ｍｇ）を得た。 Carboxylic acid intermediate 19
Add 2M aqueous sodium hydroxide solution (0.12mL, 0.24 mmol) to 3.2 mL of MeOH / water = 3: 1 mixed solvent of ester intermediate 18 (36.1 mg, 0.164 mmol) and heat for 20.0 hours. Refluxed. It was acidified to pH = about 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain carboxylic acid intermediate 19 (5.6 mg).
　ＫＵＳＣ－５０１４
　カルボン酸中間体１９（５．６ｍｇ，０．０２９１ｍｍｏｌ）のＣＨ２Ｃｌ２溶液０．３９ｍＬにＤＩＰＥＡ（１０．２μＬ，０．０５８６ｍｍｏｌ）、ＨＡＴＵ（１１．１ｍｇ，０．０２９２ｍｍｏｌ）を加えて、室温で３０分間攪拌した。ｐ－ブロモアニリン（５．０ｍｇ，０．０２９１ｍｍｏｌ）を加えて、室温で１日攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣を分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。ＫＵＳＣ－５０１４（５．０ｍｇ，９％，２ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．４２（２Ｈ，ｓ），６．８４（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），６．９４（１Ｈ，ｓ），７．４０（１Ｈ，ｓ），７．５２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７７（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９４（１Ｈ，ｓ），８．１６（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），１０．２３（１Ｈ，ｂｒ）ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１２ＢｒＮ５ＮａＯ　［Ｍ＋Ｎａ］＋，３６８．０１１８，ｆｏｕｎｄ，３６８．０１５４
Figure JPOXMLDOC01-appb-C000082
 KUSC-5014
Add DIPEA (10.2 μL, 0.0586 mmol) and HATU (11.1 mg, 0.0292 mmol) to 0.39 mL of CH 2 Cl 2 solution of carboxylic acid intermediate 19 (5.6 mg, 0.0291 mmol) at room temperature. Was stirred for 30 minutes. p-Bromoaniline (5.0 mg, 0.0291 mmol) was added, and the mixture was stirred at room temperature for 1 day. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative TLC (CHCl 3 / MeOH = 20: 1). KUSC-5014 (5.0 mg, 9%, 2 steps) was obtained.
1 1 HNMR 600MHz in DMSO-d 6 6.42 (2H, s), 6.84 (1H, d, J = 1.8Hz), 6.94 (1H, s), 7.40 (1H, s), 7.52 (2H, d, J = 9.0Hz), 7.77 (2H, d, J = 9.0Hz), 7.94 (1H, s), 8.16 (1H, d, J = 1) .8Hz), 10.23 (1H, br) HR-ESI-MS: calcd C 14 H 12 BrN 5 NaO [M + Na] + , 368.0118, found, 368.0154
Figure JPOXMLDOC01-appb-C000082
　・ＫＵＳＣ－５０１９
　エステル体２０
　　１－ブロモメチルピラゾールー３－カルボン酸エチル（１００ｍｇ，０．４２９ｍｍｏｌ）のアセトニトリル溶液５．６ｍＬに１Ｈ－ピラゾール（６６．０ｍｇ，０．９６９ｍｍｏｌ）、Ｋ２ＣＯ３（１３０．５ｍｇ，０．９４４ｍｍｏｌ）を加えて、室温で３．５日攪拌した。水で反応を停止し、酢酸エチルで抽出を行った。飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。エステル体２０（９４．８ｍｇ, quant.）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），４．３９（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），６．３０（１Ｈ，ｓ），６．３７（２Ｈ，ｓ），６．８１（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．５６（１Ｈ，ｓ），７．６７（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．７０（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１０Ｈ１３Ｎ４Ｏ２［Ｍ＋Ｈ］＋，
２２１．１０３３，ｆｏｕｎｄ，２２１．１００３ ・ KUSC-5019
Ester body 20
1H-pyrazole (66.0 mg, 0.969 mmol), K2 CO 3 (130.5 mg, 0.944 mmol) in 5.6 mL of an acetonitrile solution of 1-bromomethylpyrazole- 3 -carboxylate (100 mg, 0.429 mmol). ) Was added, and the mixture was stirred at room temperature for 3.5 days. The reaction was stopped with water and extraction was performed with ethyl acetate. It was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 20: 1). Ester 20 (94.8 mg, quant.) Was obtained.
1 1 HNMR 600MHz in CDCl 3 1.37 (3H, t, J = 7.2Hz), 4.39 (2H, q, J = 7.2Hz), 6.30 (1H, s), 6.37 (2H) , S), 6.81 (1H, d, J = 3.0Hz), 7.56 (1H, s), 7.67 (1H, d, J = 1.8Hz), 7.70 (1H, d) , J = 1.8Hz)
HR-ESI-MS: calcd C 10 H 13 N 4 O 2 [M + H] + ,
221.1303, found, 221.1003
　カルボン酸中間体２１
　エステル中間体２０（３０．０ｍｇ，０．１３６ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒２．８ｍＬに２Ｍ水酸化ナトリウム水溶液０．１０ｍＬを加えて、４８℃で１４．６時間攪拌した。濃塩酸でｐＨ＝５程度に酸性化し、酢酸エチルで抽出した。有機層を合わせて硫酸ナトリウムで乾燥した。溶媒を減圧留去し、カルボン酸中間体２１（９．７ｍｇ，３７％，２ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　６．３８（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），６．４７（２Ｈ，ｓ），６．８１（１Ｈ，ｍ），７．５９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．９３（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ８Ｈ８Ｎ４ＮａＯ２［Ｍ＋Ｎａ］＋，
２１５．０５４０，ｆｏｕｎｄ，２１５．０５２７ Carboxylic acid intermediate 21
To 2.8 mL of a MeOH / water = 3: 1 mixed solvent of ester intermediate 20 (30.0 mg, 0.136 mmol), 0.10 mL of a 2M sodium hydroxide aqueous solution was added, and the mixture was stirred at 48 ° C. for 14.6 hours. It was acidified to pH = about 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain carboxylic acid intermediate 21 (9.7 mg, 37%, 2 steps).
1 1 HNMR 500MHz in MeOH-d 4 6.38 (1H, d, J = 2.0Hz), 6.47 (2H, s), 6.81 (1H, m), 7.59 (1H, d, J) = 2.0Hz), 7.93 (1H, d, J = 2.5Hz), 7.96 (1H, d, J = 2.5Hz)
HR-ESI-MS: calcd C 8 H 8 N 4 NaO 2 [M + Na] + ,
215.0540, found, 215.0527
　ＫＵＳＣ－５０１９
　カルボン酸中間体２１（９．７２ｍｇ，０．０５０６ｍｍｏｌ）のＣＨ２Ｃｌ２溶液０．６８ｍＬにＤＩＰＥＡ（１８μＬ，０．１０３ｍｍｏｌ）、ＨＡＴＵ（１９．４３ｍｇ，０．０５０５ｍｍｏｌ）を加えて、室温で３０分間攪拌した。ｐ－ブロモアニリン（９．６０ｍｇ，０．０５５８ｍｍｏｌ）を加えて、室温で１１．３時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝５０：５０）にて精製し、ＫＵＳＣ－５０１９（７．８４ｍｇ，４５％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　６．３１（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），６．５０（２Ｈ，ｓ），６．８１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．４９－５１（３Ｈ，ｍ），７．８２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９９（１Ｈ，ｓ），８．００（１Ｈ，ｓ），９．５５（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１２ＢｒＮ５ＮａＯ［Ｍ＋Ｎａ］＋，
　３６８．０１１８，ｆｏｕｎｄ，３６８．００９３
Figure JPOXMLDOC01-appb-C000083
 KUSC-5019
Add DIPEA (18 μL, 0.103 mmol) and HATU (19.43 mg, 0.0505 mmol) to 0.68 mL of a CH 2 Cl 2 solution of carboxylic acid intermediate 21 (9.72 mg, 0.0506 mmol) and add 30 at room temperature. Stir for minutes. p-Bromoaniline (9.60 mg, 0.0558 mmol) was added, and the mixture was stirred at room temperature for 11.3 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 100: 3). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 50: 50) to obtain KUSC-5019 (7.84 mg, 45%).
1 1 HNMR 500MHz in Acetone-d 6 6.31 (1H, t, J = 2.0Hz), 6.50 (2H, s), 6.81 (1H, d, J = 2.5Hz), 7.49 -51 (3H, m), 7.82 (2H, d, J = 9.0Hz), 7.99 (1H, s), 8.00 (1H, s), 9.55 (1H, s)
HR-ESI-MS: calcd C 14 H 12 BrN 5 NaO [M + Na] + ,
368.0118, found, 368.093
Figure JPOXMLDOC01-appb-C000083
　・ＫＵＳＣ－５０２０の合成
　エステル体２２
　４－ニトロイミダゾール（２０．０ｍｇ,０．１７７ｍｍｏｌ）のＤＭＦ溶液０．１０ｍｌに１－ブロモメチルピラゾールー３－カルボン酸エチル(４５．３ｍｇ，０．１９４ｍｍｏｌ)，Ｋ２ＣＯ３（４８．９ｍｇ，０．３５４ｍｍｏｌ）を添加し、室温で７時間攪拌した。水で反応を停止させ、ＣＨＣｌ３で抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）にて精製し 、エステル体２２（６４．９３ｍｇ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　１．２７（３Ｈ，ｔ，Ｊ＝６．０Ｈｚ），４．２７（２Ｈ，ｑ，Ｊ＝６．０Ｈｚ），６．５４（２Ｈ，ｓ），６．８３（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），８．１５（１Ｈ，ｓ），８．２３（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．５９（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１０Ｈ１１Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，２８８．０７０４，ｆｏｕｎｄ，２８８．０７２６ -Synthetic ester of KUSC-5020 22
In 0.10 ml of DMF solution of 4-nitroimidazole (20.0 mg, 0.177 mmol), ethyl 1-bromomethylpyrazole-3-carboxylate (45.3 mg, 0.194 mmol), K 2 CO 3 (48.9 mg,). 0.354 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The reaction was stopped with water, extraction was performed with CHCl 3 , the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1) to obtain an ester 22 (64.93 mg).
1 1 HNMR 500MHz in DMSO-d 6 1.27 (3H, t, J = 6.0Hz), 4.27 (2H, q, J = 6.0Hz), 6.54 (2H, s), 6.83 (1H, d, J = 1.5Hz), 8.15 (1H, s), 8.23 (1H, d, J = 2.5Hz), 8.59 (1H, s)
HR-ESI-MS: calcd C 10 H 11 N 5 NaO 4 [M + Na] + , 288.0704, found, 288.0726
　カルボン酸中間体２３
　エステル体２２（３０．０ｍｇ，０．１１３ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒２．４ｍｌに２Ｍ水酸化ナトリウム水溶液０．０８５ｍＬを加えて、４８℃で１０．２時間攪拌した。濃塩酸でｐＨ＝５程度に酸性化し、酢酸エチルで抽出した。有機層を合わせて硫酸ナトリウムで乾燥した。溶媒を留去し、カルボン酸中間体２３を（２４．８８ｍｇ，９３％，２ｓｔｅｐｓ）得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．５１（２Ｈ，ｓ），６．７７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．１３（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．１９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．５６（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ８Ｈ８Ｎ５Ｏ４［Ｍ＋Ｈ］＋，
２３８．０５７２，ｆｏｕｎｄ，２３８．０５３２ Carboxylic acid intermediate 23
0.085 mL of a 2 M aqueous sodium hydroxide solution was added to 2.4 ml of a MeOH / water = 3: 1 mixed solvent of ester 22 (30.0 mg, 0.113 mmol), and the mixture was stirred at 48 ° C. for 10.2 hours. It was acidified to pH = about 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was distilled off to obtain carboxylic acid intermediate 23 (24.88 mg, 93%, 2 steps).
1 1 HNMR 500MHz in DMSO-d 6 6.51 (2H, s), 6.77 (1H, d, J = 2.0Hz), 8.13 (1H, d, J = 2.0Hz), 8.19 (1H, d, J = 2.5Hz), 8.56 (1H, d, J = 1.5Hz)
HR-ESI-MS: calcd C 8 H 8 N 5 O 4 [M + H] + ,
238.0572, found, 238.0532
・ＫＵＳＣ－５０２０
　カルボン酸中間体２３（１８．１５ｍｇ，０．０７６５ｍｍｏｌ）のＣＨ２Ｃｌ２溶液１．０ｍＬにＤＩＰＥＡ（２７μＬ，０．１５５ｍｍｏｌ）、ＨＡＴＵ（２９．３０ｍｇ，０．０７７０ｍｍｏｌ）を加えて、室温で３０分間攪拌した。ｐ－ブロモアニリン（９．６０ｍｇ，０．０５５８ｍｍｏｌ）を加えて、室温で１１．６時間攪拌した。水で反応を停止し、酢酸エチルで抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝５０：５０）にて精製し、ＫＵＳＣ－５０２０（１８．９４ｍｇ，６３％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．５４（２Ｈ，ｓ），６．８８（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．５３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７５（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．１６（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），８．２２（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），　８．５９（１Ｈ，ｓ），１０．２０（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１１ＢｒＮ６ＮａＯ３［Ｍ＋Ｎａ］＋，
　４１２．９９６９，ｆｏｕｎｄ，４１２．９９６５
Figure JPOXMLDOC01-appb-C000084
 ・ KUSC-5020
Add DIPEA (27 μL, 0.155 mmol) and HATU (29.30 mg, 0.0770 mmol) to 1.0 mL of CH 2 Cl 2 solution of Carboxylic Acid Intermediate 23 (18.15 mg, 0.0765 mmol) and add 30 at room temperature. Stir for minutes. p-Bromoaniline (9.60 mg, 0.0558 mmol) was added, and the mixture was stirred at room temperature for 11.6 hours. The reaction was stopped with water and extracted with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 100: 3). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 50: 50) to obtain KUSC-5020 (18.94 mg, 63%).
1 1 HNMR 500MHz in DMSO-d 6 6.54 (2H, s), 6.88 (1H, d, J = 2.5Hz), 7.53 (2H, d, J = 8.5Hz), 7.75 (2H, d, J = 8.5Hz), 8.16 (1H, d, J = 1.5Hz), 8.22 (1H, d, J = 2.5Hz), 8.59 (1H, s) , 10.20 (1H, s)
HR-ESI-MS: calcd C 14 H 11 BrN 6 NaO 3 [M + Na] + ,
412.9696, found, 412.9965
Figure JPOXMLDOC01-appb-C000084
　・ＫＵＳＣ－５０２１
　エステル体２４
　４－ニトロピラゾール（１００．０ｍｇ,０．８８４ｍｍｏｌ）のＤＭＦ溶液０．４９ｍｌに３－ブロモプロピオン酸メチル(０．１１ｍＬ，１．０１ｍｍｏｌ)，Ｋ２ＣＯ３（２４４．４ｍｇ，０．３５４ｍｍｏｌ）を添加し、室温で８．３時間攪拌した。水で反応を停止させ、クロロホルムで抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）にて精製し 、エステル体２４を（１７１．５ｍｇ，９７％）得た。１ＨＮＭＲは文献値と一致した。 ・ KUSC-5021
Ester body 24
Methyl 3-bromopropionate (0.11 mL, 1.01 mmol) and K2 CO 3 ( 244.4 mg, 0.354 mmol) were added to 0.49 ml of a DMF solution of 4-nitropyrazole (100.0 mg, 0.884 mmol). It was added and stirred at room temperature for 8.3 hours. The reaction was stopped with water, extraction was performed with chloroform, the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1) to obtain an ester 24 (171.5 mg, 97%). 1 1 HNMR was in agreement with the literature value.
　カルボン酸中間体２５
　エステル体２４（５０．１ｍｇ，０．２５１ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒５ｍｌに２Ｍ水酸化ナトリウム水溶液０．１９ｍＬを加えて、４８℃で１４．３時間攪拌した。濃塩酸でｐＨ＝２から３程度に酸性化し、酢酸エチルで抽出した。有機層を合わせて硫酸ナトリウムで乾燥した。溶媒を留去し、カルボン酸中間体２５を（５１．８６ｍｇ）得た。１ＨＮＭＲは文献値と一致した。 Carboxylic acid intermediate 25
0.19 mL of a 2 M aqueous sodium hydroxide solution was added to 5 ml of a MeOH / water = 3: 1 mixed solvent of ester 24 (50.1 mg, 0.251 mmol), and the mixture was stirred at 48 ° C. for 14.3 hours. It was acidified to pH = 2 to 3 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was distilled off to obtain (51.86 mg) the carboxylic acid intermediate 25. 1 1 HNMR was in agreement with the literature value.
　ＫＵＳＣ－５０２１
　カルボン酸中間体２５（１５．０ｍｇ，０．０８１０ｍｍｏｌ）のジクロロメタン溶液１．１ｍＬにＤＩＰＥＡ（２８μＬ，０．１６１ｍｍｏｌ）、ＨＡＴＵ（３０．８ｍｇ，０．０８１０ｍｍｏｌ）を加えて、室温で３０分間攪拌した。ｐ－ブロモアニリン（１５．３ｍｇ，０．０８８９ｍｍｏｌ）を加えて、室温で１８．５時間攪拌した。水で反応を停止し、酢酸エチルで抽出した。有機層を合わせて、１ＭＨＣｌ水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した。硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０２１（２０．３５ｍｇ，７４％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　４．７４（４Ｈ，ｓ），６．７５（ｄ，Ｊ＝３．０Ｈｚ），７．４８－７．４９（３Ｈ，ｍ），７．６６（２Ｈ，ｄ），８．３４（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１２Ｈ１０ＢｒＮ４Ｏ３［Ｍ―Ｈ］－，
３３８．９９８５，ｆｏｕｎｄ，３３８．９９４５ KUSC-5021
DIPEA (28 μL, 0.161 mmol) and HATU (30.8 mg, 0.0810 mmol) were added to 1.1 mL of a dichloromethane solution of carboxylic acid intermediate 25 (15.0 mg, 0.0810 mmol), and the mixture was stirred at room temperature for 30 minutes. .. p-Bromoaniline (15.3 mg, 0.0889 mmol) was added, and the mixture was stirred at room temperature for 18.5 hours. The reaction was stopped with water and extracted with ethyl acetate. The organic layers were combined and washed sequentially with a 1M HCl aqueous solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine. It was dried over sodium sulfate and the solvent was distilled off. The residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 20: 1). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 60: 40) to obtain KUSC-5021 (20.35 mg, 74%).
1 1 HNMR 500MHz in MeOH-d 4 4.74 (4H, s), 6.75 (d, J = 3.0Hz), 7.48-7.49 (3H, m), 7.66 (2H, d) ), 8.34 (1H, s)
HR-ESI-MS: calcd C 12 H 10 BrN 4 O 3 [MH] - ,
338.9985, found, 338.9945
　ＫＵＳＣ－５０２２
Figure JPOXMLDOC01-appb-C000085
 　カルボン酸中間体２５（１５．０ｍｇ，０．０８１０ｍｍｏｌ）のＣＨ２Ｃｌ２溶液１．１ｍＬにＤＩＰＥＡ（２８μＬ，０．１６１ｍｍｏｌ）、ＨＡＴＵ（３０．８ｍｇ，０．０８１０ｍｍｏｌ）を加えて、室温で３０分間攪拌した。２－アミノー５－ブロモピリジン（１５．４ｍｇ，０．０８９０ｍｍｏｌ）を加えて、室温で２４．３時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した。硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝３０：７０）にて精製し、ＫＵＳＣ－５０２２（８．６３ｍｇ，３１％）を得た。
１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　３．０４（２Ｈ，ｔ，Ｊ＝６．６Ｈｚ），４．４８（２Ｈ，ｄ，Ｊ＝６．６Ｈｚ），７．９８－８．０２（３Ｈ，ｍ），８．２６（１Ｈ，ｓ），８．４３（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），８．８８（１Ｈ，ｓ），１０．８０（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ９ＢｒＮ５Ｏ３［Ｍ－Ｈ］－，
　３３９．９９３７，ｆｏｕｎｄ，３３９．９９００
Figure JPOXMLDOC01-appb-C000086
 KUSC-5022
Figure JPOXMLDOC01-appb-C000085
 Add DIPEA (28 μL, 0.161 mmol) and HATU (30.8 mg, 0.0810 mmol) to 1.1 mL of CH 2 Cl 2 solution of Carboxylic Acid Intermediate 25 (15.0 mg, 0.0810 mmol), and add 30 at room temperature. Stir for minutes. 2-Amino-5-bromopyridine (15.4 mg, 0.0890 mmol) was added, and the mixture was stirred at room temperature for 24.3 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined and washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate and the solvent was distilled off. The residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 20: 1). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 30: 70) to obtain KUSC-5022 (8.63 mg, 31%).
1 1 HNMR 600MHz in DMSO-d 6 3.04 (2H, t, J = 6.6Hz), 4.48 (2H, d, J = 6.6Hz), 7.98-8.02 (3H, m) , 8.26 (1H, s), 8.43 (1H, d, J = 3.0Hz), 8.88 (1H, s), 10.80 (1H, br)
HR-ESI-MS: calcd C 11 H 9 BrN 5 O 3 [MH] - ,
339.9937, found, 339.9900
Figure JPOXMLDOC01-appb-C000086
　・ＫＵＳＣ－５０２６
　エステル体２２，２６
　１－ブロモメチルピラゾールー３－カルボン酸エチル（１００．０ｍｇ,０．４２９ｍｍｏｌ）のＤＭＦ溶液４．３ｍｌに４－ニトロイミダゾール(７２．８ｍｇ，０．６４４ｍｍｏｌ)，Ｃｓ２ＣＯ３（１５３．８ｍｇ，０．４７２ｍｍｏｌ）を添加し、８０℃で１９時間攪拌した。水で反応を停止させ、酢酸エチルで抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）にて精製し 、エステル体２６を３０．２ｍｇ（２７％）、エステル中間体２２（７４．８ｍｇ，６６％）得た。 ・ KUSC-5026
Ester bodies 22,26
4-Nimidazole (72.8 mg, 0.644 mmol) in 4.3 ml of DMF solution of 1-bromomethylpyrazole-3-carboxylate (100.0 mg, 0.429 mmol), Cs 2 CO 3 (153.8 mg, 0.472 mmol) was added, and the mixture was stirred at 80 ° C. for 19 hours. The reaction was stopped with water, extraction was performed with ethyl acetate, the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1), and the ester body 26 was 30.2 mg (27%) and the ester intermediate 22 (74.8 mg, 66%). Obtained.
　エステル体２６
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３８（３Ｈ，ｔ，Ｊ＝６．６Ｈｚ），４．４０（２Ｈ，ｑ，Ｊ＝６．６Ｈｚ），６．６６（２Ｈ，ｓ），６．８３（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．８４（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），８．０１（１Ｈ，ｓ），８．０４（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１０Ｈ１１Ｎ５Ｏ４Ｎａ［Ｍ＋Ｎａ］＋，
２８８．０７０４，ｆｏｕｎｄ，２８８．０６８０ Ester body 26
1 1 HNMR 600MHz in CDCl 3 1.38 (3H, t, J = 6.6Hz), 4.40 (2H, q, J = 6.6Hz), 6.66 (2H, s), 6.83 (1H) , D, J = 2.4Hz), 7.84 (1H, d, J = 3.0Hz), 8.01 (1H, s), 8.04 (1H, s)
HR-ESI-MS: calcd C 10 H 11 N 5 O 4 Na [M + Na] + ,
288.0704, found, 288.0680
　カルボン酸中間体２７
　エステル体２６（２８．５ｍｇ，０．１０７ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒２．２ｍｌに２Ｍ水酸化ナトリウム水溶液０．０８ｍＬを加えて、４５℃で１３．５時間攪拌した。濃塩酸でｐＨ＝５程度に酸性化し、酢酸エチルで抽出した。有機層を合わせて硫酸ナトリウムで乾燥した。溶媒を留去し、カルボン酸中間体２７を（１８．９４ｍｇ）得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　６．７５（２Ｈ，ｓ），６．８０（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），８．０２（１Ｈ，ｓ），８．０４（１Ｈ，ｓ），８．２３（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ８Ｈ７Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，２６０．０３９１，ｆｏｕｎｄ，２６０．０３７３ Carboxylic acid intermediate 27
0.08 mL of a 2M aqueous sodium hydroxide solution was added to 2.2 ml of a MeOH / water = 3: 1 mixed solvent of ester 26 (28.5 mg, 0.107 mmol), and the mixture was stirred at 45 ° C. for 13.5 hours. It was acidified to pH = about 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was distilled off to obtain (18.94 mg) the carboxylic acid intermediate 27.
1 1 HNMR 600MHz in MeOH-d 4 6.75 (2H, s), 6.80 (1H, d, J = 1.8Hz), 8.02 (1H, s), 8.04 (1H, s), 8.23 (1H, s)
HR-ESI-MS: calcd C 8 H 7 N 5 NaO 4 [M + Na] + , 260.03911, found, 260.0373
　ＫＵＳＣ－５０２６
　カルボン酸中間体２７（１８．４９ｍｇ，０．０７８０ｍｍｏｌ）のジクロロメタン溶液１．１ｍＬにＤＩＰＥＡ（２７μＬ，０．１５５ｍｍｏｌ）、ＨＡＴＵ（２９．６ｍｇ，０．０７７８ｍｍｏｌ）を加えて、室温で３０分間攪拌した。４－トリフルオロメチルアニリン（１１μＬ，０．０８７６ｍｍｏｌ）を加えて、室温で２０時間攪拌した。水で反応を停止し、酢酸エチルで抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝５０：５０）にて精製し、ＫＵＳＣ－５０２６（１３．３５ｍｇ，４５％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　６．８４－６．８５（３Ｈ，ｍ），７．６６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９７（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．０１（１Ｈ，ｓ），８．１０（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．２２（１Ｈ，ｓ），９．６７（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１１Ｆ３Ｎ６ＮａＯ３［Ｍ＋Ｎａ］＋，
　４０３．０７３７，ｆｏｕｎｄ，４０３．０７６０
Figure JPOXMLDOC01-appb-C000087
 KUSC-5026
DIPEA (27 μL, 0.155 mmol) and HATU (29.6 mg, 0.0778 mmol) were added to 1.1 mL of a dichloromethane solution of carboxylic acid intermediate 27 (18.49 mg, 0.0780 mmol), and the mixture was stirred at room temperature for 30 minutes. .. 4-Trifluoromethylaniline (11 μL, 0.0876 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction was stopped with water and extracted with ethyl acetate. The organic layers were combined and washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 20: 1). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 50: 50) to obtain KUSC-5026 (13.35 mg, 45%).
1 1 HNMR 500MHz in Acetone-d 6 6.84-6.85 (3H, m), 7.66 (2H, d, J = 8.5Hz), 7.97 (2H, d, J = 8.5Hz) , 8.01 (1H, s), 8.10 (1H, d, J = 2.5Hz), 8.22 (1H, s), 9.67 (1H, br)
HR-ESI-MS: calcd C 15 H 11 F 3 N 6 NaO 3 [M + Na] + ,
403.0737, found, 403.0760
Figure JPOXMLDOC01-appb-C000087
　・ＫＵＳＣ－５０３０
　エステル体２８
　４－ニトロピラゾール（５０．０ｍｇ,０．４４２ｍｍｏｌ）のＤＭＦ溶液０．９８ｍＬに４－ブロモメチル安息香酸メチル(１１１．４ｍｇ，０．４８６ｍｍｏｌ)，Ｋ２ＣＯ３（１２２．２ｍｇ，０．８８４ｍｍｏｌ）を添加し、室温で５．７時間攪拌した。水で反応を停止させ、ＣＨＣｌ３で抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３：１）にて精製し 、エステル体２８を（１０９．６ｍｇ，９５％）得た。
　１ＨＮＭＲの値は、文献値と一致した。 ・ KUSC-5030
Ester body 28
Methyl 4-bromomethylbenzoate (111.4 mg, 0.486 mmol) and K2 CO 3 (122.2 mg, 0.884 mmol) were added to 0.98 mL of a DMF solution of 4 -nitropyrazole (50.0 mg, 0.442 mmol). It was added and stirred at room temperature for 5.7 hours. The reaction was stopped with water, extraction was performed with CHCl 3 , the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO2 flash colorn chromatography (Hexane / AcOEt = 3: 1) to obtain an ester 28 (109.6 mg, 95%).
1 The 1 HNMR value was in agreement with the literature value.
　カルボン酸中間体２９
　エステル中間体２８（５０．０ｍｇ，０．１９１ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒４ｍＬに２Ｍ水酸化ナトリウム水溶液０．１４ｍＬを加えて、４５℃で１２．５時間攪拌した。濃塩酸でｐＨ＝３から４程度に酸性化し、ＣＨＣｌ３で抽出した。有機層を合わせて硫酸ナトリウムで乾燥した。溶媒を減圧留去し、カルボン酸中間体２９を（４５．４８ｍｇ，９６％）得た。
　１ＨＮＭＲの値は、文献値と一致した。 Carboxylic acid intermediate 29
To 4 mL of a MeOH / water = 3: 1 mixed solvent of ester intermediate 28 (50.0 mg, 0.191 mmol), 0.14 mL of a 2 M aqueous sodium hydroxide solution was added, and the mixture was stirred at 45 ° C. for 12.5 hours. It was acidified with concentrated hydrochloric acid to pH = 3 to about 4, and extracted with CHCl 3 . The organic layers were combined and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain carboxylic acid intermediate 29 (45.48 mg, 96%).
1 The 1 HNMR value was in agreement with the literature value.
　ＫＵＳＣ－５０３０
　カルボン酸中間体２９（１５．０ｍｇ，０．０６０７ｍｍｏｌ）のジクロロメタン溶液１．１ｍＬにＤＩＰＥＡ（２５μＬ，０．１４４ｍｍｏｌ）、ＨＡＴＵ（２３．１ｍｇ，０．０６０８ｍｍｏｌ）を加えて、室温で３０分間攪拌した。ｐ－ブロモアニリン（１１．５ｍｇ，０．０６６８ｍｍｏｌ）を加えて、室温で１５．８時間攪拌した。水で反応を停止し、酢酸エチルで抽出した。有機層を合わせて、１ＭＨＣｌ水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した。硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０３０（１２．１２ｍｇ，４９％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　５．５０（２Ｈ，ｓ），７．４６（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９２（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１７Ｈ１３ＢｒＮ４ＮａＯ３［Ｍ＋Ｎａ］＋，
４２３．００６４，ｆｏｕｎｄ，４２３．０１９２ KUSC-5030
DIPEA (25 μL, 0.144 mmol) and HATU (23.1 mg, 0.0608 mmol) were added to 1.1 mL of a dichloromethane solution of carboxylic acid intermediate 29 (15.0 mg, 0.0607 mmol), and the mixture was stirred at room temperature for 30 minutes. .. p-Bromoaniline (11.5 mg, 0.0668 mmol) was added, and the mixture was stirred at room temperature for 15.8 hours. The reaction was stopped with water and extracted with ethyl acetate. The organic layers were combined and washed sequentially with a 1M HCl aqueous solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine. It was dried over sodium sulfate and the solvent was distilled off. The residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 100: 3). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 60: 40) to obtain KUSC-5030 (12.12 mg, 49%).
1 1 HNMR 500MHz in DMSO-d 6 5.50 (2H, s), 7.46 (2H, d, J = 8.0Hz), 7.53 (2H, d, J = 9.0Hz), 7.74 (2H, d, J = 8.5Hz), 7.92 (2H, d, J = 8.0Hz)
HR-ESI-MS: calcd C 17 H 13 BrN 4 NaO 3 [M + Na] + ,
423.0064, found, 423.0192
　・ＫＵＳＣ－５０４１
Figure JPOXMLDOC01-appb-C000088
 　ＫＵＳＣ－５０３０と同様の手法にて合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　５．５９（２Ｈ，ｓ），７．５３（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．７０（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．０１（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．０６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．１７（１Ｈ，ｓ），８．８１（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１８Ｈ１４Ｆ３Ｎ４Ｏ３［Ｍ＋Ｈ］＋，
　３９１，０９７３，ｆｏｕｎｄ，３９１．１０３１
Figure JPOXMLDOC01-appb-C000089
 ・ KUSC-5041
Figure JPOXMLDOC01-appb-C000088
 The synthesis was performed by the same method as KUSC-5030.
1 1 HNMR 500MHz in Deuterated-d6 5.59 (2H, s), 7.53 (2H, d, J = 8.0Hz), 7.70 (2H, d, J = 8.5Hz), 8.01 ( 2H, d, J = 8.0Hz), 8.06 (2H, d, J = 8.5Hz), 8.17 (1H, s), 8.81 (1H, s)
HR-ESI-MS: calcd C 18 H 14 F 3 N 4 O 3 [M + H] + ,
391,0973, found, 391.1031
Figure JPOXMLDOC01-appb-C000089
　ＫＵＳＣ－５０３１
　エステル体３０
　４－ニトロ－１Ｈ－ピラゾール（５０．０ｍｇ,０．４４２ｍｍｏｌ）のＤＭＦ溶液０．９８ｍＬに１－ブロモメチル－３－安息香酸メチル(１１１．４ｍｇ，０．４８６ｍｍｏｌ)，Ｋ２ＣＯ３（１２２．２ｍｇ，０．８８４ｍｍｏｌ）を添加し、室温で３．１時間攪拌した。水で反応を停止させ、ＣＨＣｌ３で抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３：１～２：１）にて精製し 、エステル体３０を（１１６．７ｍｇ）得た。
　１ＨＮＭＲの値は、文献値と一致した。 KUSC-5031
Ester body 30
Methyl 1-bromomethyl-3-benzoate (111.4 mg, 0.486 mmol) in 0.98 mL of a DMF solution of 4-nitro-1H-pyrazol (50.0 mg, 0.442 mmol), K 2 CO 3 (122.2 mg) , 0.884 mmol) was added, and the mixture was stirred at room temperature for 3.1 hours. The reaction was stopped with water, extraction was performed with CHCl 3 , the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO 2 flash color n chromatography (Hexane / AcOEt = 3: 1 to 2: 1) to obtain an ester 30 (116.7 mg).
1 The 1 HNMR value was in agreement with the literature value.
　カルボン酸中間体３１
　エステル体３０（５０．０ｍｇ，０．１９１ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒（４ｍＬ）に２Ｍ水酸化ナトリウム水溶液０．１４ｍＬを加えて、４５℃で１２．５時間攪拌した。濃塩酸でｐＨ＝３から４程度に酸性化し、ＣＨＣｌ３で抽出した。有機層を合わせて硫酸ナトリウムで乾燥した。溶媒を減圧留去し、カルボン酸中間体３１（５１．１３ｍｇ）を得た。
　１ＨＮＭＲの値は、文献値と一致した。 Carboxylic acid intermediate 31
To a MeOH / water = 3: 1 mixed solvent (4 mL) of ester 30 (50.0 mg, 0.191 mmol) was added 0.14 mL of a 2 M sodium hydroxide aqueous solution, and the mixture was stirred at 45 ° C. for 12.5 hours. It was acidified with concentrated hydrochloric acid to pH = 3 to about 4, and extracted with CHCl 3 . The organic layers were combined and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a carboxylic acid intermediate 31 (51.13 mg).
1 The 1 HNMR value was in agreement with the literature value.
　ＫＵＳＣ－５０３１
　カルボン酸中間体３１（１５．０ｍｇ，０．０６０７ｍｍｏｌ）のＣＨ２Ｃｌ２溶液１．１ｍＬにＤＩＰＥＡ（２１μＬ，０．１２０ｍｍｏｌ）、ＨＡＴＵ（２３．１ｍｇ，０．０６０８ｍｍｏｌ）を加えて、室温で３０分間攪拌した。ｐ－ブロモアニリン（１１．５ｍｇ，０．０６６８ｍｍｏｌ）を加えて、室温で１４．９時間攪拌した。水で反応を停止し、酢酸エチルで抽出した。有機層を合わせて、１ＭＨＣｌ水溶液、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０３１（１８．７３ｍｇ，７７％，３　ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　５．５０（２Ｈ，ｓ），７．５３－５５（４Ｈ，ｍ），７．７４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９１（２Ｈ，ｓ），８．３０（１Ｈ，ｓ），９．０９（１Ｈ，ｓ），１０．４０（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１７Ｈ１４ＢｒＮ４Ｏ３［Ｍ＋Ｈ］＋，
４０２．０１５１，ｆｏｕｎｄ，４０２．０１９９ KUSC-5031
Add DIPEA (21 μL, 0.120 mmol) and HATU (23.1 mg, 0.0608 mmol) to 1.1 mL of CH 2 Cl 2 solution of carboxylic acid intermediate 31 (15.0 mg, 0.0607 mmol) and add 30 at room temperature. Stir for minutes. p-Bromoaniline (11.5 mg, 0.0668 mmol) was added, and the mixture was stirred at room temperature for 14.9 hours. The reaction was stopped with water and extracted with ethyl acetate. The organic layers were combined and washed with 1M HCl aqueous solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 100: 3). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 60: 40), and KUSC-5031 (18.73 mg, 77%, 3 steps) was added. Obtained.
1 1 HNMR 500MHz in DMSO-d 6 5.50 (2H, s), 7.53-55 (4H, m), 7.74 (2H, d, J = 8.5Hz), 7.91 (2H, s) ), 8.30 (1H, s), 9.09 (1H, s), 10.40 (1H, s)
HR-ESI-MS: calcd C 17 H 14 BrN 4 O 3 [M + H] + ,
402.0151, found, 402.0199
　・ＫＵＳＣ－５０４２
Figure JPOXMLDOC01-appb-C000090
 　ＫＵＳＣ－５０３１と同様の方法で合成を行った。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　５．５７（２Ｈ，ｓ），７．５５（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．６２（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．７０（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．００（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），８．０４－８．０５（３Ｈ，ｍ），８．１６（１Ｈ，ｓ），８．８１（１Ｈ，ｓ），９．９３（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１８Ｈ１４Ｆ３Ｎ４Ｏ３［Ｍ＋Ｈ］＋，
３９１．１０１３，ｆｏｕｎｄ，３９１．１０６４ ・ KUSC-5042
Figure JPOXMLDOC01-appb-C000090
 The synthesis was carried out in the same manner as KUSC-5031.
1 1 HNMR 600MHz in Acetone-d 6 5.57 (2H, s), 7.55 (1H, t, J = 7.2Hz), 7.62 (1H, d, J = 8.4Hz), 7.70 (2H, d, J = 8.4Hz), 8.00 (2H, d, J = 7.2Hz), 8.04-8.05 (3H, m), 8.16 (1H, s), 8 .81 (1H, s), 9.93 (1H, br)
HR-ESI-MS: calcd C 18 H 14 F 3 N 4 O 3 [M + H] + ,
391.103, found, 391.1064
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　・エステル体３２
　エステル体６（１５０ｍｇ，０．５６６ｍｍｏｌ）のＭｅＯＨ（０．７２ｍＬ）とＴＨＦ（０．７２ｍＬ）の混合溶液に（Ｂｏｃ）２Ｏ（０．１３ｍＬ，０．５６６ｍｍｏｌ）と１０％Ｐｄ／Ｃ（３９．５ｍｇ）を加えて、水素雰囲気下、１０時間反応させた。セライトでろ過し、溶媒を減圧留去した。残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。エステル体３２（１６４ｍｇ，８７％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３８（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．４７（９Ｈ，ｓ），４．３９（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），６．２７（２Ｈ，ｓ），６．３８（１Ｈ，ｓ），６．７９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．４８（１Ｈ，ｓ），７．６１（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．８４（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ２１Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，
３５８．０８１３，ｆｏｕｎｄ，３５８．１４８７ -Ester body 32
In a mixed solution of ester 6 (150 mg, 0.566 mmol) of MeOH (0.72 mL) and THF (0.72 mL), (Boc) 2 O (0.13 mL, 0.566 mmol) and 10% Pd / C (39). .5 mg) was added, and the mixture was reacted for 10 hours under a hydrogen atmosphere. The mixture was filtered through cerite and the solvent was distilled off under reduced pressure. The residue was purified with SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1). Ester 32 (164 mg, 87%) was obtained.
1 1 HNMR 500MHz in CDCl 3 1.38 (3H, t, J = 7.0Hz), 1.47 (9H, s), 4.39 (2H, q, J = 7.0Hz), 6.27 (2H) , S), 6.38 (1H, s), 6.79 (1H, d, J = 2.0Hz), 7.48 (1H, s), 7.61 (1H, d, J = 1.5Hz) ), 7.84 (1H, s)
HR-ESI-MS: calcd C 15 H 21 N 5 NaO 4 [M + Na] + ,
358.083, found, 358.1487
　・カルボン酸中間体３３
　エステル体３２（５０ｍｇ，０．１４９ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒（４ｍＬ）に２ＭＮａＯＨ溶液（０．４５ｍＬ，０．９００ｍｍｏｌ）を加えて、８０℃で１４時間加熱還流した。濃塩酸で反応を停止し、ｐＨ＝２としてＣＨＣｌ３で抽出を行った。硫酸ナトリウムで乾燥し、溶媒を留去した。Ｎ－Ｂｏｃカルボン酸中間体３３（５１．０５ｍｇ，ｑｕａｎｔ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４６（９Ｈ，ｓ），６．３８（２Ｈ，ｓ），６．５１（１Ｈ，ｂｒ），６．８４（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．５４（１Ｈ，ｓ），７．７３（１Ｈ，ｓ），７．８９（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１３Ｈ１８Ｎ５Ｏ４　［Ｍ＋Ｈ］＋，
３０８．１３５３，ｆｏｕｎｄ，３０８．１３２８　 -Carboxylic acid intermediate 33
A 2M NaOH solution (0.45 mL, 0.900 mmol) was added to a MeOH / water = 3: 1 mixed solvent (4 mL) of the ester 32 (50 mg, 0.149 mmol), and the mixture was heated under reflux at 80 ° C. for 14 hours. The reaction was stopped with concentrated hydrochloric acid, and extraction was performed with CHCl 3 at pH = 2. It was dried over sodium sulfate and the solvent was distilled off. N-Boc Carboxylic Acid Intermediate 33 (51.05 mg, quant) was obtained.
1 1 HNMR 500MHz in CDCl 3 1.46 (9H, s), 6.38 (2H, s), 6.51 (1H, br), 6.84 (1H, d, J = 1.5Hz), 7. 54 (1H, s), 7.73 (1H, s), 7.89 (1H, s)
HR-ESI-MS: calcd C 13 H 18 N 5 O 4 [M + H] + ,
308.1353, found, 308.1328
　・アミド体３４
　カルボン酸中間体３３（５１．０５ｍｇ，０．１４９ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（２．０ｍＬ）にＤＩＰＥＡ（５２μＬ，０．２９９ｍｍｏｌ），ＨＡＴＵ（５６．７ｍｇ，０．１４９ｍｍｏｌ）を加えて窒素雰囲気下室温で３０分攪拌した。ｐ－ブロモアニリン（２８．２ｍｇ，０．１６４ｍｍｏｌ）を加えて、室温で２９．９時間攪拌した。水とＣＨＣｌ３を加えて２層に分け、ＣＨＣｌ３で抽出を行った。飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。アミド体３４（６０．０２ｍｇ，８７％，２　ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　１．４３（９Ｈ，ｓ），６．４２（２Ｈ，ｓ），６．８２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．３８（１Ｈ，ｓ），７．５０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９７（１Ｈ，ｓ），８．０８（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），９．２７（１Ｈ，ｓ），１０．２８（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１９Ｈ２１ＢｒＮ６ＮａＯ３　［Ｍ＋Ｎａ］＋，４８５．０７５１，ｆｏｕｎｄ，４８５．０７２７ -Amid body 34
Add DIPEA (52 μL, 0.299 mmol) and HATU (56.7 mg, 0.149 mmol) to CH 2 Cl 2 solution (2.0 mL) of carboxylic acid intermediate 33 (51.05 mg, 0.149 mmol) to create a nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. p-Bromoaniline (28.2 mg, 0.164 mmol) was added, and the mixture was stirred at room temperature for 29.9 hours. Water and CHCl 3 were added, and the mixture was divided into two layers, and extraction was performed with CHCl 3 . It was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1). The amide compound 34 (60.02 mg, 87%, 2 steps) was obtained.
1 1 HNMR 500MHz in DMSO-d 6 1.43 (9H, s), 6.42 (2H, s), 6.82 (1H, d, J = 2.0Hz), 7.38 (1H, s), 7.50 (2H, d, J = 9.0Hz), 7.78 (2H, d, J = 8.5Hz), 7.97 (1H, s), 8.08 (1H, d, J = 2) .5Hz), 9.27 (1H, s), 10.28 (1H, s)
HR-ESI-MS: calcd C 19 H 21 BrN 6 NaO 3 [M + Na] + , 485.0751, found, 485.0727
　・ＫＵＳＣ－５０１７
　アミド体３４（２４．０８ｍｇ，０．０５２２ｍｍｏｌ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（０．５２ｍＬ）を窒素雰囲気下、室温で２．７時間攪拌した。溶媒を減圧留去し、ＫＵＳＣ－５０１７（１５．０６ｍｇ，７３％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．５５（２Ｈ，ｓ），６．８７（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．５０（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６５（１Ｈ，ｓ），７．７８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．１７（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．２９（１Ｈ，ｓ），１０．２９（２Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１３ＢｒＮ６ＮａＯ　［Ｍ＋Ｎａ］＋，３８３．０２２６，ｆｏｕｎｄ，３８３．０１７５ ・ KUSC-5017
A 4MHCl in 1,4-dioxane solution (0.52 mL) of amide 34 (24.08 mg, 0.0522 mmol) was stirred at room temperature for 2.7 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure to obtain KUSC-5017 (15.06 mg, 73%).
1 1 HNMR 500MHz in DMSO-d 6 6.55 (2H, s), 6.87 (1H, d, J = 2.5Hz), 7.50 (2H, d, J = 8.5Hz), 7.65 (1H, s), 7.78 (2H, d, J = 8.5Hz), 8.17 (1H, d, J = 2.5Hz), 8.29 (1H, s), 10.29 (2H) , Br)
HR-ESI-MS: calcd C 14 H 13 BrN 6 NaO [M + Na] + , 383.0226, found, 383.0175
　・ＫＵＳＣ－５０２５
　ＫＵＳＣ－５０１７（１５．０６ｍｇ，０．０３７９ｍｍｏｌ）のジクロロメタン溶液（０．３８ｍＬ）にトリエチルアミン（１３．２μＬ，０．０９５０ｍｍｏｌ）を加えて、３０分間反応させた。塩化アセチル（１２μＬ，０．１６９ｍｍｏｌ）を加えて、室温で１９．６時間反応させた。ＭｅＯＨで反応を停止し、水と酢酸エチルを加えて、2層に分けた。酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝４０：６０）にて精製し，ＫＵＳＣ－５０２５（１７．７１ｍｇ，７５％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　６．４２（２Ｈ，ｓ），６．８３（２Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．４８（２Ｈ，ｄ，Ｊ＝４．０Ｈｚ），７．５５（１Ｈ，ｓ），７．６８（２Ｈ，ｄ，Ｊ＝４．０Ｈｚ），７．９３（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）８．２４（１Ｈ，ｓ）
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ１５ＢｒＮ６ＮａＯ２　［Ｍ＋Ｎａ］＋，４２５．０３３３，ｆｏｕｎｄ，４２５．０３１４
Figure JPOXMLDOC01-appb-C000092
 ・ KUSC-5025
Triethylamine (13.2 μL, 0.0950 mmol) was added to a dichloromethane solution (0.38 mL) of KUSC-5017 (15.06 mg, 0.0379 mmol), and the mixture was reacted for 30 minutes. Acetyl chloride (12 μL, 0.169 mmol) was added and reacted at room temperature for 19.6 hours. The reaction was stopped with MeOH, water and ethyl acetate were added, and the mixture was divided into two layers. It was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purify by preparative TLC (CHCl 3 / MeOH = 20: 1), and then purify the obtained residue by HPLC (cosmosil MSII, φ20 × 250 mm, chloroform: CH 3 CN / H 2 O = 40: 60). Then, KUSC-5025 (17.71 mg, 75%) was obtained.
1 1 HNMR 500MHz in MeOH-d 4 6.42 (2H, s), 6.83 (2H, d, J = 1.5Hz), 7.48 (2H, d, J = 4.0Hz), 7.55 (1H, s), 7.68 (2H, d, J = 4.0Hz), 7.93 (1H, d, J = 2.0Hz) 8.24 (1H, s)
HR-ESI-MS: calcd C 16 H 15 BrN 6 NaO 2 [M + Na] + , 425.0333, found, 425.0314
Figure JPOXMLDOC01-appb-C000092
　・アミド体３７
　カルボン酸中間体３３（３１．７５ｍｇ，０．１０３ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（１．４ｍＬ）にＤＩＰＥＡ（３６μＬ，０．２０７ｍｍｏｌ），ＨＡＴＵ（３９．３ｍｇ，０．１０３ｍｍｏｌ）を加えて、窒素雰囲気下、３０分攪拌した。４－トリフルオロメチルアニリン（１４μＬ，０．１１１ｍｍｏｌ）を加えて室温で１８時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。アミド体３７（３４．７３ｍｇ，７５％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４８（９Ｈ，ｓ），６．２３（２Ｈ，ｓ），６．４５（１Ｈ，ｓ），６．９１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．４０（１Ｈ，ｓ），７．６１（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．６６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．８３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９９（１Ｈ，ｓ），８．８３（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２０Ｈ２１Ｆ３Ｎ６ＮａＯ３　［Ｍ＋Ｎａ］＋，４７３．１５２０，ｆｏｕｎｄ，４７３．１４７３ -Amid body 37
Add DIPEA (36 μL, 0.207 mmol) and HATU (39.3 mg, 0.103 mmol) to a CH 2 Cl 2 solution (1.4 mL) of carboxylic acid intermediate 33 (31.75 mg, 0.103 mmol) to add nitrogen. The mixture was stirred for 30 minutes under the atmosphere. 4-Trifluoromethylaniline (14 μL, 0.111 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was stopped with water and extraction was performed with CHCl 3 . The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off and the residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 20: 1). The amide 37 (34.73 mg, 75%) was obtained.
1 1 HNMR 500MHz in CDCl 3 1.48 (9H, s), 6.23 (2H, s), 6.45 (1H, s), 6.91 (1H, d, J = 2.5Hz), 7. 40 (1H, s), 7.61 (2H, d, J = 9.0Hz), 7.66 (1H, d, J = 2.0Hz), 7.83 (2H, d, J = 8.5Hz) ), 7.99 (1H, s), 8.83 (1H, s)
HR-ESI-MS: calcd C 20 H 21 F 3 N 6 NaO 3 [M + Na] + , 473.1520, found, 473.1473
　・ＫＵＳＣ－５０３５
　アミド体３７（１４．７１ｍｇ，０．０３２７ｍｍｏｌ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（０．３３ｍＬ）を窒素雰囲気下、室温で２．５時間攪拌した。溶媒を減圧留去し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝３０：７０，０．０１％ＴＦＡ）にて精製し、ＫＵＳＣ－５０３５（８．６０ｍｇ，６８％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　６．５３（２Ｈ，ｓ），６．８９（２Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．６６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．６８（１Ｈ，ｓ），７．９４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．１９（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１３Ｆ３Ｎ６ＮａＯ　［Ｍ＋Ｎａ］＋，３７３．０９９６，ｆｏｕｎｄ，３７３．１０１９ ・ KUSC-5035
A 4MHCl in 1,4-dioxane solution (0.33 mL) of amide 37 (14.71 mg, 0.0327 mmol) was stirred at room temperature for 2.5 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, elient: CH 3 CN / H 2 O = 30: 70, 0.01% TFA), and KUSC- 5035 (8.60 mg, 68%) was obtained.
1 1 HNMR 500MHz in MeOH-d 4 6.53 (2H, s), 6.89 (2H, d, J = 2.5Hz), 7.66 (2H, d, J = 8.5Hz), 7.68 (1H, s), 7.94 (2H, d, J = 8.5Hz), 7.99 (1H, d, J = 2.0Hz), 8.19 (1H, s)
HR-ESI-MS: calcd C 15 H 13 F 3 N 6 NaO [M + Na] + , 373.096, found, 373.1019
　・ＫＵＳＣ－５０３６
Figure JPOXMLDOC01-appb-C000093
 　ＫＵＳＣ－５０３５（４．２２ｍｇ，０．０１０９ｍｍｏｌ）のジクロロメタン溶液（０．１１ｍＬ）にトリエチルアミン（３．８μＬ，０．０２７３ｍｍｏｌ）を加えて、３０分間反応させた。塩化アセチル（１．７μＬ，０．０２３９ｍｍｏｌ）を加えて、室温で１７時間反応させた。水で反応を停止し、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０３６（２．５５ｍｇ，６０％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　２．０７（３Ｈ，ｓ），６．４４（２Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．５６（１Ｈ，ｓ），７．６５（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９４－９６（３Ｈ，ｍ），８．２５（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１７Ｈ１５Ｆ３Ｎ６ＮａＯ２　［Ｍ＋Ｎａ］＋，４１５．１１０１，ｆｏｕｎｄ，４１５．１１１３ ・ KUSC-5036
Figure JPOXMLDOC01-appb-C000093
 Triethylamine (3.8 μL, 0.0273 mmol) was added to a dichloromethane solution (0.11 mL) of KUSC-5035 (4.22 mg, 0.0109 mmol), and the mixture was reacted for 30 minutes. Acetyl chloride (1.7 μL, 0.0239 mmol) was added and the reaction was carried out at room temperature for 17 hours. The reaction was stopped with water, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification is performed by preparative TLC (CHCl 3 / MeOH = 20: 1), and then the obtained residue is purified by HPLC (cosmosil MSII, φ20 × 250 mm, chloroform: CH 3 CN / H 2 O = 60: 40). Then, KUSC-5036 (2.55 mg, 60%) was obtained.
1 1 HNMR 500MHz in MeOH-d 4 2.07 (3H, s), 6.44 (2H, s), 6.86 (1H, d, J = 2.0Hz), 7.56 (1H, s), 7.65 (2H, d, J = 8.5Hz), 7.94-96 (3H, m), 8.25 (1H, s)
HR-ESI-MS: calcd C 17 H 15 F 3 N 6 NaO 2 [M + Na] + , 415.1101, found, 415.1113
　・ＫＵＳＣ－５０３７
Figure JPOXMLDOC01-appb-C000094
 　ＫＵＳＣ－５０３６と同様の手法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１８（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），２．３４（２Ｈ，ｑ，J＝７．５Ｈｚ），６．４４（２Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．５７（１Ｈ，ｓ），７．６５（１Ｈ，ｄ，Ｊ＝３．５Ｈｚ），７．９４－９６（３Ｈ，ｍ），８．２６（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１８Ｈ１７Ｆ３Ｎ６ＮａＯ２［Ｍ＋Ｎａ］＋，
４２９．１２５８，ｆｏｕｎｄ，４２９．１２６３ ・ KUSC-5037
Figure JPOXMLDOC01-appb-C000094
 The synthesis was performed in the same manner as KUSC-5036.
1 1 HNMR 500MHz in MeOH-d 4 1.18 (3H, t, J = 7.5Hz), 2.34 (2H, q, J = 7.5Hz), 6.44 (2H, s), 6.86 (1H, d, J = 3.0Hz), 7.57 (1H, s), 7.65 (1H, d, J = 3.5Hz), 7.94-96 (3H, m), 8.26 (1H, s)
HR-ESI-MS: calcd C 18 H 17 F 3 N 6 NaO 2 [M + Na] + ,
429.1258, found, 429.1263
　・ＫＵＳＣ－５０３８
Figure JPOXMLDOC01-appb-C000095
 　ＫＵＳＣ－５０３６と同様の手法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　０．９６（３Ｈ，ｔ，Ｊ＝８．０Ｈｚ），　１．６８（２Ｈ，ｓｅｘｔｅｔ，　Ｊ＝７．５Ｈｚ），　２．２９（２Ｈ，ｔ，Ｊ＝７．５Ｈｚ），６．４３（２Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．５７（１Ｈ，ｓ），７．６４（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．２６（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１９Ｈ１９Ｆ３Ｎ６ＮａＯ２　［Ｍ＋Ｎａ］＋，４４３．１４１４，ｆｏｕｎｄ，４４３．１４３３ ・ KUSC-5038
Figure JPOXMLDOC01-appb-C000095
 The synthesis was performed by the same method as KUSC-5036.
1 1 HNMR 500MHz in MeOH-d 4 0.96 (3H, t, J = 8.0Hz), 1.68 (2H, sextet, J = 7.5Hz), 2.29 (2H, t, J = 7. 5Hz), 6.43 (2H, s), 6.86 (1H, d, J = 3.0Hz), 7.57 (1H, s), 7.64 (2H, d, J = 9.0Hz) , 7.93 (2H, d, J = 8.5Hz), 7.94 (1H, d, J = 2.5Hz), 8.26 (1H, s)
HR-ESI-MS: calcd C 19 H 19 F 3 N 6 NaO 2 [M + Na] + , 443.1414, found, 443.1433
　・ＫＵＳＣ－５０３９
Figure JPOXMLDOC01-appb-C000096
 　ＫＵＳＣ－５０３６と同様の手法で合成を行った。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　３．５６（２Ｈ，ｓ），６．４６（２Ｈ，ｓ），６．８５（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．２２－７．２４（１Ｈ，ｍ），７．２８－７．３１（４Ｈ，ｍ），７．５２（１Ｈ，ｓ），７．６９（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．０３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．０９（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），８．２３（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２３Ｈ１９Ｆ３Ｎ６Ｏ２Ｎａ［Ｍ＋Ｎａ］＋，
４９１．１４１４，ｆｏｕｎｄ，４９１．１４２３ ・ KUSC-5039
Figure JPOXMLDOC01-appb-C000096
 The synthesis was performed in the same manner as KUSC-5036.
1 1 HNMR 600MHz in DMSO-d 6 3.56 (2H, s), 6.46 (2H, s), 6.85 (1H, d, J = 2.4Hz), 7.22-7.24 (1H) , M), 7.28-7.31 (4H, m), 7.52 (1H, s), 7.69 (2H, d, J = 8.4Hz), 8.03 (2H, d, J) = 7.8Hz), 8.09 (1H, d, J = 2.4Hz), 8.23 (1H, s)
HR-ESI-MS: calcd C 23 H 19 F 3 N 6 O 2 Na [M + Na] + ,
491.1414, found, 491.1423
　・ＫＵＳＣ－５０４０
Figure JPOXMLDOC01-appb-C000097
 　ＫＵＳＣ－５０３６と同様の手法で合成を行った。
１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１７（６Ｈ，ｄ，Ｊ＝７．０Ｈｚ），２．５６（１Ｈ，ｓｅｐｔｅｔ，Ｊ＝７．０Ｈｚ），６．４４（２Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．５９（１Ｈ，ｓ），７．６５（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９４－９６（３Ｈ，ｍ），８．２５（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１９Ｈ１９Ｆ３Ｎ６ＮａＯ２［Ｍ＋Ｎａ］＋，
４４３．１４１４，ｆｏｕｎｄ，４４３．１４３４ ・ KUSC-5040
Figure JPOXMLDOC01-appb-C000097
 The synthesis was performed in the same manner as KUSC-5036.
1 1 HNMR 500MHz in MeOH-d 4 1.17 (6H, d, J = 7.0Hz), 2.56 (1H, septet, J = 7.0Hz), 6.44 (2H, s), 6.86 (1H, d, J = 2.0Hz), 7.59 (1H, s), 7.65 (2H, d, J = 8.5Hz), 7.94-96 (3H, m), 8.25 (1H, s)
HR-ESI-MS: calcd C 19 H 19 F 3 N 6 NaO 2 [M + Na] + ,
443.1414, found, 443.1.1434
　・ＫＵＳＣ－５０５０
Figure JPOXMLDOC01-appb-C000098
 　ＫＵＳＣ－５０３６と同様の手法で合成を行った。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．２９（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），３．０１（２Ｈ，ｑ，Ｊ＝７．５Ｈｚ），６．４４（２Ｈ，ｓ），６．８７（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．５０（１Ｈ，ｓ），７．６５（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９４－９６（４Ｈ，ｍ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１７Ｈ１８Ｆ３Ｎ６Ｏ３Ｓ［Ｍ＋Ｈ］＋，
　４４３．１１０８，ｆｏｕｎｄ，４４３．１１３９
Figure JPOXMLDOC01-appb-C000099
 ・ KUSC-5050
Figure JPOXMLDOC01-appb-C000098
 The synthesis was performed in the same manner as KUSC-5036.
1 1 HNMR 500MHz in MeOH-d 4 1.29 (3H, t, J = 7.5Hz), 3.01 (2H, q, J = 7.5Hz), 6.44 (2H, s), 6.87 (1H, d, J = 3.0Hz), 7.50 (1H, s), 7.65 (2H, d, J = 8.5Hz), 7.94-96 (4H, m)
HR-ESI-MS: calcd C 17 H 18 F 3 N 6 O 3 S [M + H] + ,
443.1108, found, 443.1139
Figure JPOXMLDOC01-appb-C000099
　・ＫＵＳＣ－５０４４
　・アミド体３８
　Ｎ－Ｂｏｃカルボン酸３３（３０．７８ｍｇ，０．１００ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（１．３５ｍＬ）にＤＩＰＥＡ（３５μＬ，０．２０１ｍｍｏｌ），ＨＡＴＵ（３８．１ｍｇ，０．１００ｍｍｏｌ）を加えて、窒素雰囲気下、３０分攪拌した。４－トリフルオロメトキシアニリン（１５μＬ，０．１１２ｍｍｏｌ）を加えて室温で１２時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。アミド体３８（３９．１０ｍｇ）を得た
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　６．４３（２Ｈ，ｓ），６．８３（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．３１（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．４７（１Ｈ，ｓ），７．９７－８．０１（４Ｈ，ｍ），９．６６（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２０Ｈ２１Ｆ３Ｎ６ＮａＯ４　［Ｍ＋Ｎａ］＋，４８９．１４６９，ｆｏｕｎｄ，４８９．１４４７ ・ KUSC-5044
-Amid body 38
DIPEA (35 μL, 0.201 mmol) and HATU (38.1 mg, 0.100 mmol) were added to a CH 2 Cl 2 solution (1.35 mL) of N-Boc carboxylic acid 33 (30.78 mg, 0.100 mmol). The mixture was stirred for 30 minutes under a nitrogen atmosphere. 4-Trifluoromethoxyaniline (15 μL, 0.112 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction was stopped with water and extraction was performed with CHCl 3 . The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1). Amide 38 (39.10 mg) was obtained.
1 1 HNMR 600MHz in Acetone-d 6 6.43 (2H, s), 6.83 (1H, d, J = 1.8Hz), 7.31 (2H, d, J = 8.4Hz), 7.47 (1H, s), 7.97-8.01 (4H, m), 9.66 (1H, br)
HR-ESI-MS: calcd C 20 H 21 F 3 N 6 NaO 4 [M + Na] + , 489.1469, found, 489.1474
　・アミン塩酸塩３９
　アミド体３８（３９．１０ｍｇ，０．０８３８ｍｍｏｌ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（０．８４ｍＬ）を窒素雰囲気下、室温で３時間攪拌した。溶媒を減圧留去した。アミン塩酸塩３９（３４．６４ｍｇ，８６％，２　ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．５５（２Ｈ，ｓ），６．８８（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．３４（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．６５（１Ｈ，ｓ），７．９１（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．１６（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．２７（１Ｈ，ｓ），１０．２０（２Ｈ，ｂｒ），１０．３８（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１３Ｆ３Ｎ６ＮａＯ２　［Ｍ－ＨCｌ＋Ｎａ］＋，
３８９．０９４５，ｆｏｕｎｄ，３８９．０８９９ -Amine hydrochloride 39
A 4MHCl in 1,4-dioxane solution (0.84 mL) of amide 38 (39.10 mg, 0.0838 mmol) was stirred at room temperature for 3 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure. Amine hydrochloride 39 (34.64 mg, 86%, 2 steps) was obtained.
1 1 HNMR 500MHz in DMSO-d 6 6.55 (2H, s), 6.88 (1H, d, J = 2.0Hz), 7.34 (2H, d, J = 9.0Hz), 7.65 (1H, s), 7.91 (2H, d, J = 9.0Hz), 8.16 (1H, d, J = 2.0Hz), 8.27 (1H, s), 10.20 (2H) , Br), 10.38 (1H, s)
HR-ESI-MS: calcd C 15 H 13 F 3 N 6 NaO 2 [M-HCl + Na] + ,
389.0945, found, 389.0899
　・ＫＵＳＣ－５０４４
Figure JPOXMLDOC01-appb-C000100
 　アミン塩酸塩３７（２３．０３ｍｇ，０．０５７２ｍｍｏｌ）のジクロロメタン溶液（０．５７ｍＬ）にトリエチルアミン（９．９μＬ，０．０７１２ｍｍｏｌ）を加えて、３０分間反応させた。塩化プロピオニル（５．５μＬ，０．０６３０ｍｍｏｌ）を加えて、室温で２３時間反応させた。水で反応を停止し、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝５０：５０）にて精製し、ＫＵＳＣ－５０４４（８．２５ｍｇ，３４％）を得た。　
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１８（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），２．３４（２Ｈ，ｑ，Ｊ＝７．５Ｈｚ），６．４３（２Ｈ，ｓ），６．８４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．２６（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．５７（１Ｈ，ｓ），７．８３（２Ｈ，ｄ，Ｊ＝９．５Ｈｚ），７．９３（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），８．２５（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１８Ｈ１８Ｆ３Ｎ６Ｏ３［Ｍ＋Ｈ］＋，
　４２３．１３８７，ｆｏｕｎｄ，４２３．１３９１
Figure JPOXMLDOC01-appb-C000101
 ・ KUSC-5044
Figure JPOXMLDOC01-appb-C000100
 Triethylamine (9.9 μL, 0.0712 mmol) was added to a dichloromethane solution (0.57 mL) of amine hydrochloride 37 (23.03 mg, 0.0572 mmol), and the mixture was reacted for 30 minutes. Propionyl chloride (5.5 μL, 0.0630 mmol) was added and reacted at room temperature for 23 hours. The reaction was stopped with water, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1), and then the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 50: 50). ) To obtain KUSC-5044 (8.25 mg, 34%).
1 1 HNMR 500MHz in MeOH-d 4 1.18 (3H, t, J = 7.5Hz), 2.34 (2H, q, J = 7.5Hz), 6.43 (2H, s), 6.84 (1H, d, J = 2.5Hz), 7.26 (2H, d, J = 9.0Hz), 7.57 (1H, s), 7.83 (2H, d, J = 9.5Hz) , 7.93 (1H, d, J = 3.0Hz), 8.25 (1H, s)
HR-ESI-MS: calcd C 18 H 18 F 3 N 6 O 3 [M + H] + ,
423.1387, found, 423.1391
Figure JPOXMLDOC01-appb-C000101
　・エステル体４０
Figure JPOXMLDOC01-appb-C000102
 　４－ニトロピロール（３０ｍｇ,０．２６８ｍｍｏｌ）のＤＭＦ溶液（１．５ｍｌ）に１－（ブロモメチル）ピラゾールー３－カルボン酸エチル(６８．６ｍｇ，０．２９４ｍｍｏｌ)，Ｋ２ＣＯ３（７４．０ｍｇ，０．５３５ｍｍｏｌ）を添加し、室温で２３時間攪拌した。水で反応を停止させ、ＣＨＣｌ３で抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）にて精製し 、エステル体４０を（５５．７２ｍｇ，７９％）得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３８（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），４．３９（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），６．１８（２Ｈ，ｓ），６．７１（１Ｈ，ｄｄ，Ｊ＝２．０Ｈｚ），６．８２（１Ｈ，ｔ，Ｊ＝２．５Ｈｚ），６．８５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．６４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．７４（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ１２Ｎ４ＮａＯ４　［Ｍ＋Ｎａ］＋，
２８７．０７５１，ｆｏｕｎｄ，２８７．０７７４ -Ester body 40
Figure JPOXMLDOC01-appb-C000102
 1- (bromomethyl) pyrazole-3-carboxylate ethyl (68.6 mg, 0.294 mmol), K2 CO 3 (74.0 mg,) in a DMF solution (1.5 ml) of 4-nitropyrrole (30 mg, 0.268 mmol). 0.535 mmol) was added, and the mixture was stirred at room temperature for 23 hours. The reaction was stopped with water, extraction was performed with CHCl 3 , the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 100: 3) to obtain an ester 40 (55.72 mg, 79%).
1 1 HNMR 500MHz in CDCl 3 1.38 (3H, t, J = 7.0Hz), 4.39 (2H, q, J = 7.0Hz), 6.18 (2H, s), 6.71 (1H) , Dd, J = 2.0Hz), 6.82 (1H, t, J = 2.5Hz), 6.85 (1H, d, J = 2.0Hz), 7.64 (1H, d, J =) 2.5Hz), 7.74 (1H, s)
HR-ESI-MS: calcd C 11 H 12 N 4 NaO 4 [M + Na] + ,
287.0751, found, 287.0774
　・カルボン酸中間体４１
Figure JPOXMLDOC01-appb-C000103
 エステル体４０（２０ｍｇ，０．０７５７ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒（１．６ｍＬ）に２Ｍ水酸化ナトリウム水溶液（５７μＬ，０．１１４ｍｍｏｌ）を加えて、４５℃で１３時間反応させた。濃塩酸で反応を停止し、ｐＨ＝３から４として酢酸エチルで抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体４１（１７．５８ｍｇ，９８％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　６．３９（２Ｈ，ｓ），６．７１（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），６．７５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．１５（１Ｈ，ｔ，Ｊ＝２．５Ｈｚ），８．１７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．２０（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ９Ｈ８Ｎ４ＮａＯ４［Ｍ＋Ｎａ］＋，
２５９．０４３８，ｆｏｕｎｄ，２５９．０４３７ -Carboxylic acid intermediate 41
Figure JPOXMLDOC01-appb-C000103
 A 2M aqueous sodium hydroxide solution (57 μL, 0.114 mmol) was added to a MeOH / water = 3: 1 mixed solvent (1.6 mL) of the ester 40 (20 mg, 0.0757 mmol), and the mixture was reacted at 45 ° C. for 13 hours. .. The reaction was stopped with concentrated hydrochloric acid, and extraction was performed with ethyl acetate at pH = 3 to 4. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 41 (17.58 mg, 98%) was obtained.
1 1 HNMR 600MHz in DMSO-d 6 6.39 (2H, s), 6.71 (1H, d, J = 3.0Hz), 6.75 (1H, d, J = 2.0Hz), 7.15 (1H, t, J = 2.5Hz), 8.17 (1H, d, J = 2.0Hz), 8.20 (1H, t, J = 2.0Hz)
HR-ESI-MS: calcd C 9 H 8 N 4 NaO 4 [M + Na] + ,
259.0438, found, 259.0437
　・ＫＵＳＣ－５０２９
Figure JPOXMLDOC01-appb-C000104
 　カルボン酸中間体４１（１７．８ｍｇ，０．０７４ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（１．０ｍＬ）にＤＩＰＥＡ（２６．０μＬ，０．０１５ｍｍｏｌ），ＨＡＴＵ（２８．３ｍｇ，０．０７４ｍｍｏｌ）を添加し、室温で３０分攪拌した。ｐ－ブロモアニリン（１４．１ｍｇ，０．０８２ｍｍｏｌ）を添加し、室温で１４時間反応させた。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０２９（２０．２ｍｇ，６９％）を得た。
　１ＨＮＭＲ５００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　６．４９（２Ｈ，ｓ），６．７０（１Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．１５（１Ｈ，ｓ），７．５０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．０６（１Ｈ，ｓ）, ８．１５（１Ｈ，ｓ），９．５７（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１２ＢｒＮ５Ｏ３Ｎａ［Ｍ＋Ｎａ］＋，
　４１２．００１６，ｆｏｕｎｄ，４１２．００３７
Figure JPOXMLDOC01-appb-C000105
 ・ KUSC-5029
Figure JPOXMLDOC01-appb-C000104
 DIPEA (26.0 μL, 0.015 mmol) and HATU (28.3 mg, 0.074 mmol) were added to CH 2 Cl 2 solution (1.0 mL) of carboxylic acid intermediate 41 (17.8 mg, 0.074 mmol). , Stirred at room temperature for 30 minutes. p-Bromoaniline (14.1 mg, 0.082 mmol) was added and reacted at room temperature for 14 hours. The reaction was stopped with water and extracted with CHCl3. The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1), and then the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 60 :. Purification with 40) gave KUSC-5029 (20.2 mg, 69%).
1 HNMR500MHz in Acetone-d 6 6.49 (2H, s), 6.70 (1H, s), 6.86 (1H, d, J = 2.5Hz), 7.15 (1H, s), 7 .50 (2H, d, J = 9.0Hz), 7.78 (2H, d, J = 8.5Hz), 8.06 (1H, s), 8.15 (1H, s), 9.57 (1H, s)
HR-ESI-MS: calcd C 15 H 12 BrN 5 O 3 Na [M + Na] + ,
421.016, found, 412.0037
Figure JPOXMLDOC01-appb-C000105
　・エステル体４２
　エステル体４０（３０ｍｇ，０．１１４ｍｍｏｌ）のＭｅＯＨ（０．２５ｍＬ）とＴＨＦ（０．２５ｍＬ）の混合溶液に（Ｂｏｃ）２Ｏ（２９μＬ，０．１２６ｍｍｏｌ）と５％Ｐｄ／Ｃ（１５．８ｍｇ）を加えて、水素雰囲気下、５．３時間反応させた。セライトでろ過し、溶媒を減圧留去した。残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）で精製した。エステル体４２（２７．９３ｍｇ，７４％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３９（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），１．４７（９Ｈ，ｓ），４．４０（２Ｈ，ｑ，Ｊ＝７．５Ｈｚ），５．９６（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），６．０３（２Ｈ，ｓ），６．２９（１Ｈ，ｂｒ），６．６９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），６．７９（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．０８（１Ｈ，ｂｒ），７．３９（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ２３Ｎ４Ｏ４［Ｍ＋Ｈ］＋，
３３５．１７１４，ｆｏｕｎｄ，３３５．１７１７ -Ester body 42
In a mixed solution of ester 40 (30 mg, 0.114 mmol) of MeOH (0.25 mL) and THF (0.25 mL), (Boc) 2 O (29 μL, 0.126 mmol) and 5% Pd / C (15.8 mg). ) Was added, and the mixture was reacted for 5.3 hours under a hydrogen atmosphere. The mixture was filtered through cerite and the solvent was distilled off under reduced pressure. The residue was purified with SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 100: 3). Ester 42 (27.93 mg, 74%) was obtained.
1 1 HNMR 500MHz in CDCl 3 1.39 (3H, t, J = 7.5Hz), 1.47 (9H, s), 4.40 (2H, q, J = 7.5Hz), 5.96 (1H) , D, J = 3.0Hz), 6.03 (2H, s), 6.29 (1H, br), 6.69 (1H, d, J = 2.5Hz), 6.79 (1H, d) , J = 1.5Hz), 7.08 (1H, br), 7.39 (1H, d, J = 2.5Hz)
HR-ESI-MS: calcd C 16 H 23 N 4 O 4 [M + H] + ,
335.1714, found, 335.1717
　・カルボン酸中間体４３
　エステル体４２（１２．５７ｍｇ，０．０３７６ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒（０．９６ｍＬ）に２Ｍ水酸化ナトリウム水溶液（２８μＬ，０．０５６ｍｍｏｌ）を加えて、４５℃で１５時間反応させた。１Ｍ塩酸で反応を停止し、ｐＨ＝２としてＣＨＣｌ３で抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体４３（１１．０５ｍｇ，９６％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．４７（９Ｈ，ｓ），５．９８（１Ｈ，ｓ），６．１２（２Ｈ，ｓ），６．７８（２Ｈ，ｍ），６．９９（１Ｈ，ｂｒ），７．７９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１８Ｎ４ＮａＯ４［Ｍ＋Ｎａ］＋，
３２９．１２２１，ｆｏｕｎｄ，３２９．１１９４ -Carboxylic acid intermediate 43
A 2M aqueous sodium hydroxide solution (28 μL, 0.056 mmol) was added to a MeOH / water = 3: 1 mixed solvent (0.96 mL) of the ester 42 (12.57 mg, 0.0376 mmol), and the reaction was carried out at 45 ° C. for 15 hours. I let you. The reaction was stopped with 1M hydrochloric acid, and extraction was performed with CHCl 3 at pH = 2. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 43 (11.05 mg, 96%) was obtained.
1 1 HNMR 500MHz in MeOH-d 4 1.47 (9H, s), 5.98 (1H, s), 6.12 (2H, s), 6.78 (2H, m), 6.99 (1H, br), 7.79 (1H, d, J = 2.0Hz)
HR-ESI-MS: calcd C 14 H 18 N 4 NaO 4 [M + Na] + ,
329.1221, found, 329.1194
　・アミド体４４
Figure JPOXMLDOC01-appb-C000106
 　カルボン酸中間体４３（１１．０５ｍｇ，０．０３６１ｍｍｏｌ）のジクロロメタン溶液（０．４９ｍＬ）にＤＩＰＥＡ（１２．６μＬ，０．０７２３ｍｍｏｌ），ＨＡＴＵ（１３．７ｍｇ，０．０３６０ｍｍｏｌ）を加えて、窒素雰囲気下、３０分攪拌した。４－トリフルオロメチルアニリン（５．０μＬ，０．０３９８ｍｍｏｌ）を加えて室温で１４時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣を分取ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１：１）で精製した。アミド体４４（８．８８ｍｇ，５５％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４７（９Ｈ，ｓ），５．９５（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），５．９８（２Ｈ，ｓ），６．２９（１Ｈ，ｂｒ），６．８９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），６．８９（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．１５（１Ｈ，ｂｒ），７．２５（１Ｈ，ｓ），７．４８（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．６０（２Ｈ，ｄ，Ｊ＝７．０Ｈｚ），７．８１（２Ｈ，ｄ，Ｊ＝６．５Ｈｚ），８．８０（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２１Ｈ２２Ｆ３Ｎ５ＮａＯ３［Ｍ＋Ｎａ］＋，
４７２．１５６７，ｆｏｕｎｄ，４７２．１５４０ -Amid body 44
Figure JPOXMLDOC01-appb-C000106
 Add DIPEA (12.6 μL, 0.0723 mmol) and HATU (13.7 mg, 0.0360 mmol) to a dichloromethane solution (0.49 mL) of carboxylic acid intermediate 43 (11.05 mg, 0.0361 mmol) to create a nitrogen atmosphere. Below, it was stirred for 30 minutes. 4-Trifluoromethylaniline (5.0 μL, 0.0398 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction was stopped with water and extraction was performed with CHCl 3 . The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (Hexane / AcOEt = 1: 1). The amide 44 (8.88 mg, 55%) was obtained.
1 1 HNMR 600MHz in CDCl 3 1.47 (9H, s), 5.95 (1H, d, J = 2.0Hz), 5.98 (2H, s), 6.29 (1H, br), 6. 89 (1H, d, J = 2.0Hz), 6.89 (1H, d, J = 1.5Hz), 7.15 (1H, br), 7.25 (1H, s), 7.48 ( 1H, d, J = 2.5Hz), 7.60 (2H, d, J = 7.0Hz), 7.81 (2H, d, J = 6.5Hz), 8.80 (1H, s)
HR-ESI-MS: calcd C 21 H 22 F 3 N 5 NaO 3 [M + Na] + ,
472.167, found, 472.540
　・アミン塩酸塩４５
　アミド体４４（２６．６４ｍｇ，０．０５９３ｍｍｏｌ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（０．５９ｍＬ）を窒素雰囲気下、室温で２．７時間攪拌した。溶媒を減圧留去した。アミン塩酸塩４５（１３．６４ｍｇ，６０％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　６．１８（１Ｈ，ｍ），６．３０（２Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．０９（１Ｈ，ｔ，Ｊ＝２．４Ｈｚ），７．２１（１Ｈ，ｓ），７．６３（３Ｈ，ｍ），７．９２（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．９５（１Ｈ，ｓ） -Amine hydrochloride 45
A 4MHCl in 1,4-dioxane solution (0.59 mL) of the amide 44 (26.64 mg, 0.0593 mmol) was stirred at room temperature for 2.7 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure. Amine hydrochloride 45 (13.64 mg, 60%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 6.18 (1H, m), 6.30 (2H, s), 6.86 (1H, d, J = 2.4Hz), 7.09 (1H, t, J) = 2.4Hz), 7.21 (1H, s), 7.63 (3H, m), 7.92 (2H, d, J = 8.4Hz), 7.95 (1H, s)
　・ＫＵＳＣ－５０４３
　アミン塩酸塩４５（１８．２４ｍｇ，０．０４７３ｍｍｏｌ）のジクロロメタン溶液（０．４７ｍＬ）に窒素雰囲気下トリエチルアミン（８．２μＬ，０．０５９０ｍｍｏｌ）を添加して室温で３０分間攪拌した。塩化プロピオニル（４．５４μＬ，０．０５２０ｍｍｏｌ）を添加し、室温で２４時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出後、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒減圧留去した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝５０：５０）にて精製し、ＫＵＳＣ－５０４３（３．３０ｍｇ，１７％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１４（３Ｈ，ｔ，Ｊ＝７．８Ｈｚ），２．２７（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），６．０３（１Ｈ，ｍ），６．１９（２Ｈ，ｓ），６．８３（２Ｈ，ｄ，Ｊ＝３．０Ｈｚ），６．８５（１Ｈ，ｔ，Ｊ＝３．０Ｈｚ），６．８６（１Ｈ，ｂｒ）７．３４（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．７５（１Ｈ，ｂｒ）７．８４（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）
ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１９Ｈ１８Ｆ３Ｎ５ＮａＯ２［Ｍ＋Ｎａ］＋，
　４２８．１３０５，ｆｏｕｎｄ，４２８．１２５９
Figure JPOXMLDOC01-appb-C000107
 ・ KUSC-5043
Triethylamine (8.2 μL, 0.0590 mmol) was added to a dichloromethane solution (0.47 mL) of amine hydrochloride 45 (18.24 mg, 0.0473 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. Propionyl chloride (4.54 μL, 0.0520 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction was stopped with water, extracted with CHCl 3 , the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate and distilled off under reduced pressure. Purification is performed by preparative TLC (CHCl 3 / MeOH = 20: 1), and then the obtained residue is purified by HPLC (cosmosil MSII, φ20 × 250 mm, chloroform: CH 3 CN / H 2 O = 50: 50). Then, KUSC-5043 (3.30 mg, 17%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 1.14 (3H, t, J = 7.8Hz), 2.27 (2H, q, J = 7.8Hz), 6.03 (1H, m), 6.19 (2H, s), 6.83 (2H, d, J = 3.0Hz), 6.85 (1H, t, J = 3.0Hz), 6.86 (1H, br) 7.34 (1H, 1H, d, J = 2.4Hz), 7.62 (2H, d, J = 7.8Hz), 7.75 (1H, br) 7.84 (2H, d, J = 7.8Hz), 7.92 (2H, d, J = 9.0Hz)
ESI-MS: calcd C 19 H 18 F 3 N 5 NaO 2 [M + Na] + ,
428.1305, found, 428.1259
Figure JPOXMLDOC01-appb-C000107
　・ＫＵＳＣ－５０４７
　アミド体４６
　カルボン酸中間体４３（３６．７３ｍｇ，０．１２０ｍｍｏｌ）のジクロロメタン溶液（１．６ｍＬ）にＤＩＰＥＡ（１８μＬ，０．１３４ｍｍｏｌ），ＨＡＴＵ（４５．６ｍｇ，０．１２０ｍｍｏｌ）を加えて、窒素雰囲気下、３０分攪拌した。４－トリフルオロメトキシアニリン（１８μＬ，０．１３４ｍｍｏｌ）を加えて室温で１０時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）で精製した。アミド体４６（４６．９５ｍｇ，８４％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４８（９Ｈ，ｓ），５．９５（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），５．９８（２Ｈ，ｓ），６．３２（１Ｈ，ｂｒ），６．６９（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），６．８９（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．１５（１Ｈ，ｂｒ），７．２１（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．４８（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．７３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．７２（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２１Ｈ２２Ｆ３Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，
４８８．１５１７，ｆｏｕｎｄ，４８８．１５４６ ・ KUSC-5047
Amide body 46
DIPEA (18 μL, 0.134 mmol) and HATU (45.6 mg, 0.120 mmol) were added to a dichloromethane solution (1.6 mL) of carboxylic acid intermediate 43 (36.73 mg, 0.120 mmol) under a nitrogen atmosphere. The mixture was stirred for 30 minutes. 4-Trifluoromethoxyaniline (18 μL, 0.134 mmol) was added, and the mixture was stirred at room temperature for 10 hours. The reaction was stopped with water and extraction was performed with CHCl 3 . The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 100: 3). The amide compound 46 (46.95 mg, 84%) was obtained.
1 1 HNMR 600MHz in CDCl 3 1.48 (9H, s), 5.95 (1H, d, J = 3.0Hz), 5.98 (2H, s), 6.32 (1H, br), 6. 69 (1H, d, J = 2.4Hz), 6.89 (1H, d, J = 2.4Hz), 7.15 (1H, br), 7.21 (2H, d, J = 8.4Hz) ), 7.48 (1H, d, J = 1.8Hz), 7.73 (2H, d, J = 9.0Hz), 8.72 (1H, s)
HR-ESI-MS: calcd C 21 H 22 F 3 N 5 NaO 4 [M + Na] + ,
488.1517, found, 488.1546
　・アミン塩酸塩４７
Figure JPOXMLDOC01-appb-C000108
 　アミド体４６（４０．７３ｍｇ，０．０８７５ｍｍｏｌ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（１．０ｍＬ）を窒素雰囲気下、室温で２．７時間攪拌した。溶媒を減圧留去した。アミン塩酸塩４７（３６．１３ｍｇ，１００％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　６．２０（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），６．３０（２Ｈ，ｓ），６．８６（１Ｈ，ｓ），７．０９（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．２７（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．８１（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．９４（１Ｈ，ｓ） ・ Amine hydrochloride 47
Figure JPOXMLDOC01-appb-C000108
 A 4MHCl in 1,4-dioxane solution (1.0 mL) of the amide 46 (40.73 mg, 0.0875 mmol) was stirred at room temperature for 2.7 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure. Amine hydrochloride 47 (36.13 mg, 100%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 6.20 (1H, d, J = 2.4Hz), 6.30 (2H, s), 6.86 (1H, s), 7.09 (1H, d, J) = 3.0Hz), 7.27 (2H, d, J = 8.4Hz), 7.81 (2H, d, J = 8.4Hz), 7.94 (1H, s)
　・ＫＵＳＣ－５０４７
Figure JPOXMLDOC01-appb-C000109
 　アミン塩酸塩４７（２０ｍｇ，０．０４９８ｍｍｏｌ）のジクロロメタン溶液（０．５０ｍＬ）にトリエチルアミン（８．６μＬ，０．０６１９ｍｍｏｌ）を加えて、３０分間反応させた。塩化プロピオニル（４．８μＬ，０．０５５０ｍｍｏｌ）を加えて、室温で２０時間反応させた。水で反応を停止し、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を留去した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝５０：５０）にて精製し、ＫＵＳＣ－５０４７（７．２３ｍｇ，３４％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１７（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），２．３０（２Ｈ，ｑ，Ｊ＝７．５Ｈｚ），６．０５－６．０６（１Ｈ，ｍ），６．８４（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），６．８６（１Ｈ，ｔ，Ｊ＝２．５Ｈｚ），７．２６（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．３６（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ），７．８２（２Ｈ，ｄ，Ｊ＝９．５Ｈｚ），７．８６（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１９Ｈ１８Ｆ３Ｎ５ＮａＯ３［Ｍ＋Ｎａ］＋，
　４４４．１２５４，ｆｏｕｎｄ，４４４．１２４６
Figure JPOXMLDOC01-appb-C000110
 ・ KUSC-5047
Figure JPOXMLDOC01-appb-C000109
 Triethylamine (8.6 μL, 0.0619 mmol) was added to a dichloromethane solution (0.50 mL) of amine hydrochloride 47 (20 mg, 0.0498 mmol), and the mixture was reacted for 30 minutes. Propionyl chloride (4.8 μL, 0.0550 mmol) was added and reacted at room temperature for 20 hours. The reaction was stopped with water, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate and the solvent was distilled off. Purification is performed by preparative TLC (CHCl 3 / MeOH = 20: 1), and then the obtained residue is purified by HPLC (cosmosil MSII, φ20 × 250 mm, chloroform: CH 3 CN / H 2 O = 50: 50). Then, KUSC-5047 (7.23 mg, 34%) was obtained.
1 1 HNMR 500MHz in MeOH-d 4 1.17 (3H, t, J = 7.5Hz), 2.30 (2H, q, J = 7.5Hz), 6.05-6.06 (1H, m) , 6.84 (1H, d, J = 2.5Hz), 6.86 (1H, t, J = 2.5Hz), 7.26 (2H, d, J = 8.5Hz), 7.36 ( 1H, t, J = 2.0Hz), 7.82 (2H, d, J = 9.5Hz), 7.86 (1H, d, J = 3.0Hz)
HR-ESI-MS: calcd C 19 H 18 F 3 N 5 NaO 3 [M + Na] + ,
444.1254, found, 444.1246
Figure JPOXMLDOC01-appb-C000110
　・エステル体４８
　エステル中間体２８（１００ｍｇ，０．３８３ｍｍｏｌ）のＭｅＯＨ（０．８５ｍＬ）とＴＨＦ（０．８５ｍＬ）の混合溶液に（Ｂｏｃ）２Ｏ（０．１ｍＬ，０．４３５ｍｍｏｌ）と５％Ｐｄ／Ｃ（５３．３ｍｇ）を加えて、水素雰囲気下、２３時間反応させた。セライトでろ過し、溶媒を減圧留去した。残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１：１）で精製した。エステル体４８（９６．８６ｍｇ，７６％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４８（９Ｈ，ｓ），３．９１（３Ｈ，ｓ），５．２６（２Ｈ，ｓ），７．３６（１Ｈ，ｓ），７．４０－４３（２Ｈ，ｍ），７．６７（１Ｈ，ｓ），７．９２（１Ｈ，ｓ），７．９７（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１７Ｈ２１Ｎ３ＮａＯ３［Ｍ＋Ｎａ］＋，
３５４．１４２５，ｆｏｕｎｄ，３５４．１４１２ -Ester body 48
In a mixed solution of ester intermediate 28 (100 mg, 0.383 mmol) with MeOH (0.85 mL) and THF (0.85 mL), (Boc) 2 O (0.1 mL, 0.435 mmol) and 5% Pd / C ( 53.3 mg) was added, and the mixture was reacted for 23 hours under a hydrogen atmosphere. The mixture was filtered through cerite and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 flash color n chromatography (Hexane / AcOEt = 1: 1). Ester 48 (96.86 mg, 76%) was obtained.
1 1 HNMR 500MHz in CDCl 3 1.48 (9H, s), 3.91 (3H, s), 5.26 (2H, s), 7.36 (1H, s), 7.40-43 (2H, m), 7.67 (1H, s), 7.92 (1H, s), 7.97 (1H, d, J = 2.0Hz)
HR-ESI-MS: calcd C 17 H 21 N 3 NaO 3 [M + Na] + ,
354.1425, found, 354.1412
　・カルボン酸中間体４９
　エステル体４８（５０ｍｇ，０．１５１ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒（４ｍＬ）に２ＭＮａＯＨ溶液（０．１１ｍＬ，０．２２０ｍｍｏｌ）を加えて、４５℃で１８時間反応させた。１Ｍ塩酸で反応を停止し、ｐＨ＝３として酢酸エチルで抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。Ｎ－Ｂｏｃカルボン酸中間体４９（６２．７１ｍｇ，ｑｕａｎｔ）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．４８（９Ｈ，ｓ），５．３３（２Ｈ，ｓ），７．４３－４６（３Ｈ，ｍ），７．７３（１Ｈ，ｓ），７．８９（１Ｈ，ｓ），７．９１（１Ｈ，ｓ），７．９６（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ１９Ｎ３Ｏ４Ｎａ［Ｍ＋Ｎａ］＋，
３４０．１２６８，ｆｏｕｎｄ，３４０．１２７６ -Carboxylic acid intermediate 49
A 2M NaOH solution (0.11 mL, 0.220 mmol) was added to a MeOH / water = 3: 1 mixed solvent (4 mL) of ester 48 (50 mg, 0.151 mmol), and the mixture was reacted at 45 ° C. for 18 hours. The reaction was stopped with 1M hydrochloric acid, and extraction was performed with ethyl acetate at pH = 3. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. N-Boc Carboxylic Acid Intermediate 49 (62.71 mg, quant) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 1.48 (9H, s), 5.33 (2H, s), 7.43-46 (3H, m), 7.73 (1H, s), 7.89 ( 1H, s), 7.91 (1H, s), 7.96 (1H, d, J = 7.2Hz)
HR-ESI-MS: calcd C 16 H 19 N 3 O 4 Na [M + Na] + ,
340.1268, found, 340.1276
　・アミド体５０
　カルボン酸中間体４９（２５．０ｍｇ，０．０７８８ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（１．１ｍＬ）にＤＩＰＥＡ（２７μＬ，０．１５５ｍｍｏｌ），ＨＡＴＵ（３０．０ｍｇ，０．０７８９ｍｍｏｌ）を加えて、窒素雰囲気下、３０分攪拌した。４－トリフルオロメチルアニリン（１１μＬ，０．０８７６ｍｍｏｌ）を加えて室温で２０時間攪拌した。水で反応を停止し、酢酸エチルで抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）で精製した。アミド体５０（１６．８４ｍｇ，７０％，２　ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．４６（９Ｈ，ｓ），５．３２（２Ｈ，ｓ），７．４０（２Ｈ，ｄ，Ｊ＝１０．２Ｈｚ），７．４７（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７５（１Ｈ，ｓ），７．８１（１Ｈ，ｓ），７．８４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．８９（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２３Ｈ２３Ｆ３Ｎ４Ｏ３Ｎａ［Ｍ＋Ｎａ］＋，
４８３．１６１５，ｆｏｕｎｄ，４８３．１５５９ ・ Amide body 50
Add DIPEA (27 μL, 0.155 mmol) and HATU (30.0 mg, 0.0789 mmol) to a CH 2 Cl 2 solution (1.1 mL) of carboxylic acid intermediate 49 (25.0 mg, 0.0788 mmol) and add nitrogen. The mixture was stirred for 30 minutes under the atmosphere. 4-Trifluoromethylaniline (11 μL, 0.0876 mmol) was added, and the mixture was stirred at room temperature for 20 hours. The reaction was stopped with water and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 100: 3). An amide 50 (16.84 mg, 70%, 2 steps) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 1.46 (9H, s), 5.32 (2H, s), 7.40 (2H, d, J = 10.2Hz), 7.47 (1H, t, J) = 7.8Hz), 7.62 (2H, d, J = 9.0Hz), 7.75 (1H, s), 7.81 (1H, s), 7.84 (1H, d, J = 7) .8Hz), 7.89 (2H, d, J = 9.0Hz)
HR-ESI-MS: calcd C 23 H 23 F 3 N 4 O 3 Na [M + Na] + ,
483.1615, found, 483.1559
　・アミン塩酸塩５１
　アミド体５０（１４．１２ｍｇ，０．０３０７ｍｍｏｌ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（０．６ｍＬ）を窒素雰囲気下、室温で１４時間攪拌した。溶媒を減圧留去した。アミン塩酸塩５１（１２．６８ｍｇ，１００％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　５．４８（２Ｈ，ｓ），７．５２（２Ｈ，ｄ，Ｊ＝２．８Ｈｚ），７．６５－６７（３Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．８７（１Ｈ，ｓ），７．９１（１Ｈ，ｍ），７．９３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．０８（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１８Ｈ１５Ｆ３Ｎ４ＯＮａ［Ｍ＋Ｎａ］＋，
３８３．１０９１，ｆｏｕｎｄ，３８３．１１０１ -Amine hydrochloride 51
A 4MHCl in 1,4-dioxane solution (0.6 mL) of amide 50 (14.12 mg, 0.0307 mmol) was stirred at room temperature for 14 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure. Amine hydrochloride 51 (12.68 mg, 100%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 5.48 (2H, s), 7.52 (2H, d, J = 2.8Hz), 7.65-67 (3H, d, J = 9.0Hz), 7 .87 (1H, s), 7.91 (1H, m), 7.93 (2H, d, J = 9.0Hz), 8.08 (1H, s)
HR-ESI-MS: calcd C 18 H 15 F 3 N 4 ONa [M + Na] + ,
383.1091, found, 383.1101
　・ＫＵＳＣ－５０４６
　アミン塩酸塩５１（１０ｍｇ，０．０２５２ｍｍｏｌ）のジクロロメタン溶液（０．５０ｍＬ）にトリエチルアミン（４．４μＬ，０．０３１７ｍｍｏｌ）を加えて、３０分間反応させた。塩化プロピオニル（２．４μＬ，０．０２７５ｍｍｏｌ）を加えて、室温で２０時間反応させた。水で反応を停止し、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を留去した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０４６（２．８７ｍｇ，２９％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１８（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．３４（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），５．３９（２Ｈ，ｓ），７．４５（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．５１（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．５３（１Ｈ，ｓ），７．６６（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．８５（１Ｈ，ｓ），７．８８（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），７．９２（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．０４（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２１Ｈ１９Ｆ３Ｎ４Ｏ２Ｎａ［Ｍ＋Ｎａ］＋，
　４３９．１３５８，ｆｏｕｎｄ，４３９．１３７４
Figure JPOXMLDOC01-appb-C000111
 ・ KUSC-5046
Triethylamine (4.4 μL, 0.0317 mmol) was added to a dichloromethane solution (0.50 mL) of amine hydrochloride 51 (10 mg, 0.0252 mmol), and the mixture was reacted for 30 minutes. Propionyl chloride (2.4 μL, 0.0275 mmol) was added and reacted at room temperature for 20 hours. The reaction was stopped with water, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate and the solvent was distilled off. Purification is performed by preparative TLC (CHCl 3 / MeOH = 20: 1), and then the obtained residue is purified by HPLC (cosmosil MSII, φ20 × 250 mm, chloroform: CH 3 CN / H 2 O = 60: 40). Then, KUSC-5046 (2.87 mg, 29%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 1.18 (3H, t, J = 7.2Hz), 3.34 (2H, q, J = 7.2Hz), 5.39 (2H, s), 7.45 (1H, d, J = 8.4Hz), 7.51 (1H, t, J = 7.8Hz), 7.53 (1H, s), 7.66 (2H, d, J = 9.0Hz) , 7.85 (1H, s), 7.88 (1H, d, J = 7.8Hz), 7.92 (2H, d, J = 9.0Hz), 8.04 (1H, s)
HR-ESI-MS: calcd C 21 H 19 F 3 N 4 O 2 Na [M + Na] + ,
439.1358, found, 439.1374
Figure JPOXMLDOC01-appb-C000111
　・エステル体５２
　４－ニトロ－1Ｈ－ピラゾール（１０２．８ｍｇ,０．９０９ｍｍｏｌ）のＴＨＦ溶液４．５ｍＬに１－クロロメチルフラン２－カルボン酸エチル(０．１４ｍＬ，０．９０９ｍｍｏｌ)，ｔＢｕＯＫ（１３２．６ｍｇ，１．１８ｍｍｏｌ），ＴＢＡＩ（３３．６ｍｇ，０．０９１０ｍｍｏｌ）を添加し、室温で１６時間攪拌した。飽和塩化アンモニウム水溶液で反応を停止させ、酢酸エチルで抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝２：１）にて精製し 、エステル体５２（１７４．３２ｍｇ，７２％）を得た。
　１ＨＮＭＲの値は、文献値と一致した。　 -Ester body 52
Ethyl 1-chloromethylfuran 2-carboxylate (0.14 mL, 0.909 mmol) in 4.5 mL of a THF solution of 4-nitro-1H-pyrazol (102.8 mg, 0.909 mmol), t BuOK (132.6 mg, 132.6 mg,) 1.18 mmol) and THF (33.6 mg, 0.0910 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction was stopped with saturated aqueous ammonium chloride solution, extraction was performed with ethyl acetate, the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO 2 flash color n chromatography (Hexane / AcOEt = 2: 1) to obtain an ester 52 (174.32 mg, 72%).
1 The 1 HNMR value was in agreement with the literature value.
　・エステル体５３
　エステル体５２（１００ｍｇ，０．３７７ｍｍｏｌ）のＭｅＯＨ（０．８４ｍＬ）とＴＨＦ（０．８４ｍＬ）の混合溶液に（Ｂｏｃ）２Ｏ（９５μＬ，０．４１４ｍｍｏｌ）と５％Ｐｄ／Ｃ（５２．２ｍｇ）を加えて、水素雰囲気下、１４時間反応させた。セライトでろ過し、溶媒を減圧留去した。残渣を分取ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１：１）で精製した。エステル体５３（５４．７１ｍｇ，４３％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３５（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．４７（９Ｈ，ｓ），４．３３（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），５．２６（２Ｈ，ｓ），６．３５（１Ｈ，ｓ），６．４４（１Ｈ，ｓ），７．０９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），７．３７（１Ｈ，ｓ），７．７１（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ２１Ｎ３ＮａＯ５［Ｍ＋Ｎａ］＋，
３５８．１３７４，ｆｏｕｎｄ，３５８．１４０９ -Ester body 53
In a mixed solution of ester 52 (100 mg, 0.377 mmol) of MeOH (0.84 mL) and THF (0.84 mL), (Boc) 2 O (95 μL, 0.414 mmol) and 5% Pd / C (52.2 mg). ) Was added, and the mixture was reacted for 14 hours under a hydrogen atmosphere. The mixture was filtered through cerite and the solvent was distilled off under reduced pressure. The residue was purified by preparative TLC (Hexane / AcOEt = 1: 1). Ester 53 (54.71 mg, 43%) was obtained.
1 1 HNMR 500MHz in CDCl 3 1.35 (3H, t, J = 7.0Hz), 1.47 (9H, s), 4.33 (2H, q, J = 7.0Hz), 5.26 (2H) , S), 6.35 (1H, s), 6.44 (1H, s), 7.09 (1H, d, J = 2.0Hz), 7.37 (1H, s), 7.71 ( 1H, s)
HR-ESI-MS: calcd C 16 H 21 N 3 NaO 5 [M + Na] + ,
358.1374, found, 358.1409
　・カルボン酸中間体５４
　エステル体５３（２１．３０ｍｇ，０．０６３５ｍｍｏｌ）のＭｅＯＨ／水＝３：１混合溶媒（１．６ｍＬ）に２Ｍ水酸化ナトリウム水溶液（４８μＬ，０．０９６０ｍｍｏｌ）を加えて、４５℃で１９時間反応させた。１Ｍ塩酸で反応を停止し、ｐＨ＝２としてＣＨＣｌ３で抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体５４（１９．９７ｍｇ，ｑｕａｎｔ）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．４８（９Ｈ，ｓ），５．３３（２Ｈ，ｓ），６．４８（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ），７．１５（１Ｈ，ｄ，Ｊ＝４．２Ｈｚ），７．４２（１Ｈ，ｓ），７．７５（１Ｈ，ｓ） -Carboxylic acid intermediate 54
A 2M aqueous sodium hydroxide solution (48 μL, 0.0960 mmol) was added to a MeOH / water = 3: 1 mixed solvent (1.6 mL) of ester 53 (21.30 mg, 0.0635 mmol), and the reaction was carried out at 45 ° C. for 19 hours. I let you. The reaction was stopped with 1M hydrochloric acid, and extraction was performed with CHCl3 at pH = 2. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 54 (19.97 mg, quant) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 1.48 (9H, s), 5.33 (2H, s), 6.48 (1H, d, J = 3.6Hz), 7.15 (1H, d, J) = 4.2Hz), 7.42 (1H, s), 7.75 (1H, s)
　・アミド体５５
　カルボン酸中間体５４（１９．９７ｍｇ，０．０６５０ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（０．８８ｍＬ）にＤＩＰＥＡ（２３μＬ，０．１３２ｍｍｏｌ），ＨＡＴＵ（２４．７ｍｇ，０．０６５０ｍｍｏｌ）を加えて、窒素雰囲気下、３０分攪拌した。４－トリフルオロメチルアニリン（９．０μＬ，０．０７１７ｍｍｏｌ）を加えて室温で１５時間攪拌した。水で反応を停止し、酢酸エチルで抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２カラムクロマトグラフィー（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）で精製した。アミド体５５（２０．７８ｍｇ，７１％，２　ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．４９（９Ｈ，ｓ），５．２６（２Ｈ，ｓ），６．４４（１Ｈ，ｂｒ），６．５０（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．１９（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ），７．３５（１Ｈ，ｓ），７．５９（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．８１（３Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３６（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２１Ｈ２１Ｆ３Ｎ４Ｏ４Ｎａ［Ｍ＋Ｎａ］＋，
４７３．１４０８，ｆｏｕｎｄ，４７３．１４３０　 ・ Amide 55
Add DIPEA (23 μL, 0.132 mmol) and HATU (24.7 mg, 0.0650 mmol) to a CH 2 Cl 2 solution (0.88 mL) of carboxylic acid intermediate 54 (19.97 mg, 0.0650 mmol) to add nitrogen. The mixture was stirred for 30 minutes under the atmosphere. 4-Trifluoromethylaniline (9.0 μL, 0.0717 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction was stopped with water and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 column chromatography (CHCl 3 / MeOH = 100: 3). An amide 55 (20.78 mg, 71%, 2 steps) was obtained.
1 1 HNMR 600MHz in CDCl 3 1.49 (9H, s), 5.26 (2H, s), 6.44 (1H, br), 6.50 (1H, d, J = 3.0Hz), 7. 19 (1H, d, J = 3.6Hz), 7.35 (1H, s), 7.59 (2H, d, J = 8.4Hz), 7.81 (3H, d, J = 7.8Hz) ), 8.36 (1H, br)
HR-ESI-MS: calcd C 21 H 21 F 3 N 4 O 4 Na [M + Na] + ,
473.1408, found, 473.1430
　・アミン塩酸塩５６
　アミド体５５（２０．７８ｍｇ，０．０４６１ｍｍｏｌ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（０．４６ｍＬ）を窒素雰囲気下、室温で２．５時間攪拌した。溶媒を減圧留去した。アミン塩酸塩５６（１６．９４ｍｇ，９５％）を得た。　
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　５．５２（２Ｈ，ｓ），６．６７（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．２８（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．６５（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．６９（１Ｈ，ｓ），７．９３（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．１２（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ１３ＣｌＦ３Ｎ４Ｏ２Ｎａ［Ｍ－ＨCl＋Ｎａ］＋，
３７３．０８８３，ｆｏｕｎｄ，３７３．０９０７ ・ Amine hydrochloride 56
A 4MHCl in 1,4-dioxane solution (0.46 mL) of the amide 55 (20.78 mg, 0.0461 mmol) was stirred at room temperature for 2.5 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure. Amine hydrochloride 56 (16.94 mg, 95%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 5.52 (2H, s), 6.67 (1H, d, J = 3.0Hz), 7.28 (1H, d, J = 3.0Hz), 7.65 (2H, d, J = 9.0Hz), 7.69 (1H, s), 7.93 (2H, d, J = 8.4Hz), 8.12 (1H, s)
HR-ESI-MS: calcd C 16 H 13 ClF 3 N 4 O 2 Na [M-HCl + Na] + ,
373.083, found, 373.907
　・ＫＵＳＣ－５０４９
　アミン塩酸塩５６（１６．９４ｍｇ，０．０４３８ｍｍｏｌ）のジクロロメタン溶液（０．４４ｍＬ）にトリエチルアミン（６．７μＬ，０．０４８２ｍｍｏｌ）を加えて、４５分間反応させた。塩化プロピオニル（４．８μＬ，０．０５４９ｍｍｏｌ）を加えて、室温で２１時間反応させた。水で反応を停止し、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝３０：７０）にて精製し、ＫＵＳＣ－５０４９（７．９２ｍｇ，４４％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１８（３Ｈ，ｔ，Ｊ＝８．０Ｈｚ），２．３４（２Ｈ，ｑ，Ｊ＝８．０Ｈｚ），５．４１（２Ｈ，ｓ），６．６１（１Ｈ，ｄ，Ｊ＝３．５Ｈｚ），７．２４（１Ｈ，ｄ，Ｊ＝３．５Ｈｚ），７．６５（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９２（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．０６（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１９Ｈ１７Ｆ３Ｎ４Ｏ３Ｎａ［Ｍ＋Ｎａ］＋，
　４２９．１１４５，ｆｏｕｎｄ，４２９．１１４５
Figure JPOXMLDOC01-appb-C000112
 ・ KUSC-5049
Triethylamine (6.7 μL, 0.0482 mmol) was added to a dichloromethane solution (0.44 mL) of amine hydrochloride 56 (16.94 mg, 0.0438 mmol), and the mixture was reacted for 45 minutes. Propionyl chloride (4.8 μL, 0.0549 mmol) was added and reacted at room temperature for 21 hours. The reaction was stopped with water, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purified by preparative TLC (CHCl 3 / MeOH = 20: 1). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 30: 70) to obtain KUSC-5049 (7.92 mg, 44%).
1 1 HNMR 500MHz in MeOH-d4 1.18 (3H, t, J = 8.0Hz), 2.34 (2H, q, J = 8.0Hz), 5.41 (2H, s), 6.61 ( 1H, d, J = 3.5Hz), 7.24 (1H, d, J = 3.5Hz), 7.65 (2H, d, J = 8.5Hz), 7.92 (2H, d, J) = 8.0Hz), 8.06 (1H, s)
HR-ESI-MS: calcd C 19 H 17 F 3 N 4 O 3 Na [M + Na] + ,
429.1145, found, 429.1145
Figure JPOXMLDOC01-appb-C000112
　・エステル体５８，５９
　５－メチルー３－ニトロピラゾール（１４．９ｍｇ,０．１１７ｍｍｏｌ）のＤＭＦ溶液４．５ｍＬに１－ブロモメチルー３－ピラゾールカルボン酸エチル(３０ｍｇ，０．１２９ｍｍｏｌ)，Ｋ２ＣＯ３（３３．５ｍｇ，０．２４２ｍｍｏｌ）を添加し、室温で６．２時間攪拌した。水で反応を停止させ、ＣＨＣｌ３で抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣を分取ＴＬＣで　（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝３：１）にて精製し 、エステル体５８（１９．３１ｍｇ，５９％），エステル体５９（７．８４ｍｇ，２４％）を得た。 -Ester bodies 58, 59
Ethyl 1-bromomethyl-3-pyrazole carboxylate (30 mg, 0.129 mmol) in 4.5 mL of DMF solution of 5-methyl-3-nitropyrazole (14.9 mg, 0.117 mmol), K 2 CO 3 (33.5 mg, 0) .242 mmol) was added, and the mixture was stirred at room temperature for 6.2 hours. The reaction was stopped with water, extraction was performed with CHCl 3 , the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (Hexane / AcOEt = 3: 1) to obtain ester 58 (19.31 mg, 59%) and ester 59 (7.84 mg, 24%).
　エステル体５８
Figure JPOXMLDOC01-appb-C000113
 　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３８（３Ｈ，ｔ，Ｊ＝６．６Ｈｚ），４．３８（２Ｈ，ｑ，Ｊ＝６．６Ｈｚ），６．３９（２Ｈ，ｓ），６．６６（１Ｈ，ｓ），６．８３（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．７５（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ１３Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，
３０２．０８６０，ｆｏｕｎｄ，３０２．０８７０ Ester body 58
Figure JPOXMLDOC01-appb-C000113
 1 1 HNMR 600MHz in CDCl 3 1.38 (3H, t, J = 6.6Hz), 4.38 (2H, q, J = 6.6Hz), 6.39 (2H, s), 6.66 (1H) , S), 6.83 (1H, d, J = 2.4Hz), 7.75 (1H, d, J = 3.0Hz)
HR-ESI-MS: calcd C 11 H 13 N 5 NaO 4 [M + Na] + ,
302.0860, found, 302.0870
　エステル体５９
Figure JPOXMLDOC01-appb-C000114
 　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．３０（３Ｈ，ｓ），４．３７（２Ｈ，ｑ，Ｊ＝６．６Ｈｚ），６．７６（２Ｈ，ｓ），６．８１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），６．９０（１Ｈ，ｓ），７．７１（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ１４Ｎ５Ｏ４［Ｍ＋Ｈ］＋，
２８０．１０４０，ｆｏｕｎｄ，２８０．１０１０ Ester body 59
Figure JPOXMLDOC01-appb-C000114
 1 1 HNMR 600MHz in CDCl 3 1.37 (3H, t, J = 7.2Hz), 2.30 (3H, s), 4.37 (2H, q, J = 6.6Hz), 6.76 (2H) , S), 6.81 (1H, d, J = 2.4Hz), 6.90 (1H, s), 7.71 (1H, d, J = 3.0Hz)
HR-ESI-MS: calcd C 11 H 14 N 5 O 4 [M + H] + ,
280.1040, found, 280.010
　・カルボン酸中間体６０
　エステル体５８（１９．９５ｍｇ，０．０７１４ｍｍｏｌ）のＭｅＯＨ（１．０５ｍＬ）と水（０．３５ｍＬ）の混合溶液に２Ｍ水酸化ナトリウム水溶液（５４μＬ，０．１０８ｍｍｏｌ）を加えて、４５℃で１４時間反応させた。１Ｍ塩酸で反応を停止し、ｐＨ＝２としてＣＨＣｌ３で抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体６０（１７．７３ｍｇ，９９％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　２．５８（３Ｈ，ｓ），６．５１（２Ｈ，ｓ），６．７４（１Ｈ，ｓ），６．８１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．９９（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ９Ｈ９Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，
２７４．０５４７，ｆｏｕｎｄ，２７４．０５６１ Carboxylic acid intermediate 60
A 2M aqueous sodium hydroxide solution (54 μL, 0.108 mmol) was added to a mixed solution of ester 58 (19.95 mg, 0.0714 mmol) in MeOH (1.05 mL) and water (0.35 mL), and 14 at 45 ° C. Reacted for time. The reaction was stopped with 1M hydrochloric acid, and extraction was performed with CHCl3 at pH = 2. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 60 (17.73 mg, 99%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 2.58 (3H, s), 6.51 (2H, s), 6.74 (1H, s), 6.81 (1H, d, J = 2.4Hz), 7.9 (1H, d, J = 2.4Hz)
HR-ESI-MS: calcd C 9 H 9 N 5 NaO 4 [M + Na] + ,
274.0547, found, 274.0561
　・ＫＵＳＣ－５０３４
　カルボン酸中間体６０（１７．７３ｍｇ，０．０７０６ｍｍｏｌ）のＣＨ２Ｃｌ２溶液　０．５５ｍｌに、ＤＩＰＥＡ（２４．６μＬ，０．１４１ｍｍｏｌ）、ＨＡＴＵ（２７．０ｍｇ，０．０７０５ｍｍｏｌ）を添加し、室温で３０分間攪拌した。反応溶液にｐ－ブロモアニリン（１３．４ｍｇ，０．０７７６ｍｍｏｌ）を添加し、室温で２２時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を合わせて硫酸ナトリウムで乾燥し、溶媒を減圧留去した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６０：４０）にて精製し、ＫＵＳＣ－５０３４（２１．２６ｍｇ，７５％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＤＭＳＯ－ｄ６　２．６３（３Ｈ，ｓ），６．６２（２Ｈ，ｓ），６．８７（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），６．９２（１Ｈ，ｓ），７．５１（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．７４（２Ｈ，ｄ，Ｊ＝９．５Ｈｚ），８．１８（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），１０．１５（１Ｈ，ｓ）
ＨＭＱＣ，ＨＭＢＣで相関を確認した。
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１５Ｈ１３ＢｒＮ６ＮａＯ３［Ｍ＋Ｎａ］＋，
４２９．０１０５，ｆｏｕｎｄ，４２９．０１０２　
Figure JPOXMLDOC01-appb-C000115
 ・ KUSC-5034
DIPEA (24.6 μL, 0.141 mmol) and HATU (27.0 mg, 0.0705 mmol) were added to 0.55 ml of a CH 2 Cl 2 solution of carboxylic acid intermediate 60 (17.73 mg, 0.0706 mmol). The mixture was stirred at room temperature for 30 minutes. P-Bromoaniline (13.4 mg, 0.07776 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 22 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 60: 40) to obtain KUSC-5034 (21.26 mg, 75%).
1 1 HNMR 500MHz in DMSO-d 6 2.63 (3H, s), 6.62 (2H, s), 6.87 (1H, d, J = 2.5Hz), 6.92 (1H, s), 7.51 (2H, d, J = 8.5Hz), 7.74 (2H, d, J = 9.5Hz), 8.18 (1H, d, J = 2.5Hz), 10.15 (1H) , S)
Correlation was confirmed by HMQC and HMBC.
HR-ESI-MS: calcd C 15 H 13 BrN 6 NaO 3 [M + Na] + ,
429.0105, found, 429.0102
Figure JPOXMLDOC01-appb-C000115
　・エステル体６１
　エステル体５８（３６．３５ｍｇ，０．１３０ｍｍｏｌ）のＭｅＯＨ（１．３５ｍＬ）とＴＨＦ（０．４５ｍＬ）の混合溶液に（Ｂｏｃ）２Ｏ（３３μＬ，０．１４４ｍｍｏｌ）と５％Ｐｄ／Ｃ（１８．１ｍｇ）を加えて、水素雰囲気下、２２時間反応させた。セライトでろ過し、溶媒を留去した。残渣を分取ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１：１）で精製した。エステル体６１（３１．９ｍｇ，７０％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．４５（９Ｈ，ｓ），２．３７（３Ｈ，ｓ），４．３７（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），６．３０（２Ｈ，ｓ），６．４０（１Ｈ，ｓ），６．７５（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．５４（１Ｈ，ｓ），８．３６（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ２３Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，
３７２．１６４３，ｆｏｕｎｄ，３７２．１６７５ -Ester body 61
In a mixed solution of ester 58 (36.35 mg, 0.130 mmol) of MeOH (1.35 mL) and THF (0.45 mL), (Boc) 2 O (33 μL, 0.144 mmol) and 5% Pd / C (18). .1 mg) was added, and the mixture was reacted for 22 hours under a hydrogen atmosphere. The solvent was distilled off by filtering with cerite. The residue was purified by preparative TLC (Hexane / AcOEt = 1: 1). Ester 61 (31.9 mg, 70%) was obtained.
1 1 HNMR 600MHz in CDCl 3 1.37 (3H, t, J = 7.2Hz), 1.45 (9H, s), 2.37 (3H, s), 4.37 (2H, q, J = 7) .2Hz), 6.30 (2H, s), 6.40 (1H, s), 6.75 (1H, d, J = 2.4Hz), 7.54 (1H, s), 8.36 ( 1H, s)
HR-ESI-MS: calcd C 16 H 23 N 5 NaO 4 [M + Na] + ,
372.1643, found, 372.167
　・カルボン酸中間体６２
　エステル中間体６１（２５．２５ｍｇ，０．０７２３ｍｍｏｌ）のＭｅＯＨ（１．２ｍＬ）と水（０．４ｍＬ）の混合溶液に２Ｍ水酸化ナトリウム水溶液（５４μＬ，０．１０８ｍｍｏｌ）を加えて、４５℃で２０時間反応させた。１Ｍ塩酸で反応を停止し、ｐＨ＝２としてＣＨＣｌ３で抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体６２（２０．６８ｍｇ，８９％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．４９（９Ｈ，ｓ），２．４３（３Ｈ，ｓ），６．１７（１Ｈ，ｓ），６．２４（２Ｈ，ｓ），６．７７（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．８１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１９Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，
３４４．１３３０，ｆｏｕｎｄ，３４４．１３０６ -Carboxylic acid intermediate 62
A 2M aqueous sodium hydroxide solution (54 μL, 0.108 mmol) was added to a mixed solution of MeOH (1.2 mL) and water (0.4 mL) of ester intermediate 61 (25.25 mg, 0.0723 mmol) at 45 ° C. It was allowed to react for 20 hours. The reaction was stopped with 1M hydrochloric acid, and extraction was performed with CHCl3 at pH = 2. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 62 (20.68 mg, 89%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 1.49 (9H, s), 2.43 (3H, s), 6.17 (1H, s), 6.24 (2H, s), 6.77 (1H, d, J = 1.8Hz), 7.81 (1H, d, J = 2.4Hz)
HR-ESI-MS: calcd C 14 H 19 N 5 NaO 4 [M + Na] + ,
344.1330, found, 344.1306
　・アミド体６３
　カルボン酸中間体６２（１５．０ｍｇ，０．０４６７ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（０．６３ｍＬ）にＤＩＰＥＡ（１６．３μＬ，０．０９３６ｍｍｏｌ），ＨＡＴＵ（１７．７ｍｇ，０．０４６６ｍｍｏｌ）を加えて、窒素雰囲気下、２０分攪拌した。４－トリフルオロメチルアニリン（９．０μＬ，０．０７１７ｍｍｏｌ）を加えて室温で１８時間攪拌した。水で反応を停止し、酢酸エチルで抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、残渣を分取ＴＬＣ（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１：１）で精製した。アミド体６３（１８．１ｍｇ，８６％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．４６（９Ｈ，ｓ），２．４３（３Ｈ，ｓ），６．１７（１Ｈ，ｓ），６．２６（２Ｈ，ｓ），６．８３（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．６１（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．８５（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），７．８９（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９１（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２１Ｈ２３Ｆ３Ｎ６ＮａＯ３［Ｍ＋Ｎａ］＋，
４８７．１６７６，ｆｏｕｎｄ，４８７．１７００ ・ Amide 63
Add DIPEA (16.3 μL, 0.0936 mmol) and HATU (17.7 mg, 0.0466 mmol) to a CH 2 Cl 2 solution (0.63 mL) of carboxylic acid intermediate 62 (15.0 mg, 0.0467 mmol). , Stirred for 20 minutes under a nitrogen atmosphere. 4-Trifluoromethylaniline (9.0 μL, 0.0717 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was stopped with water and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by preparative TLC (Hexane / AcOEt = 1: 1). An amide form 63 (18.1 mg, 86%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 1.46 (9H, s), 2.43 (3H, s), 6.17 (1H, s), 6.26 (2H, s), 6.83 (1H, d, J = 2.4Hz), 7.61 (1H, d, J = 9.0Hz), 7.85 (1H, d, J = 1.2Hz), 7.89 (2H, d, J = 9) .0Hz), 7.91 (1H, s)
HR-ESI-MS: calcd C 21 H 23 F 3 N 6 NaO 3 [M + Na] + ,
487.1676, found, 487.1700
　・アミン塩酸塩６４
　アミド体６３（１７．６４ｍｇ，０．０３８０ｍｍｏｌ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（０．３８ｍＬ）を窒素雰囲気下、室温で４時間攪拌した。溶媒を減圧留去した。アミン塩酸塩６４（１６．２２ｍｇ）を得た。　
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　２．５９（３Ｈ，ｓ），６．０９（１Ｈ，ｓ），６．４６（２Ｈ，ｓ），６．９０（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．６５（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９８（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ１５Ｆ３Ｎ６ＮａＯ［Ｍ－ＨＣｌ＋Ｎａ］＋，
３８７．１１５２，ｆｏｕｎｄ，３８７．１１６７　 ・ Amine hydrochloride 64
A 4MHCl in 1,4-dioxane solution (0.38 mL) of amide 63 (17.64 mg, 0.0380 mmol) was stirred at room temperature for 4 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure. Amine hydrochloride 64 (16.22 mg) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 2.59 (3H, s), 6.09 (1H, s), 6.46 (2H, s), 6.90 (1H, d, J = 2.4Hz), 7.65 (2H, d, J = 9.0Hz), 7.93 (2H, d, J = 9.0Hz), 7.98 (1H, d, J = 3.0Hz)
HR-ESI-MS: calcd C 16 H 15 F 3 N 6 NaO [M-HCl + Na] + ,
387.1152, found, 387.1167
　・ＫＵＳＣ－５０４８
　アミン塩酸塩６４（１６．２２ｍｇ，０．０４０５ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（０．４０ｍＬ）にトリエチルアミン（７．０μＬ，０．０５０４ｍｍｏｌ）を加えて、３０分間反応させた。塩化プロピオニル（３．９μＬ，０．０４４６ｍｍｏｌ）を加えて、室温で２３時間反応させた。水で反応を停止し、酢酸エチルで抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を留去した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝５０：５０）にて精製し、ＫＵＳＣ－５０４８（６．６９ｍｇ，４２％，２　ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１７（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），２．３６（２Ｈ，ｑ，Ｊ＝７．５Ｈｚ），６．３３（２Ｈ，ｓ），６．４０（１Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．８８（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．９３（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１９Ｈ１９Ｆ３Ｎ６ＮａＯ２　［Ｍ＋Ｎａ］＋，
４４３．１４１４，ｆｏｕｎｄ，４４３．１４２０ ・ KUSC-5048
Triethylamine (7.0 μL, 0.0504 mmol) was added to a CH 2 Cl 2 solution (0.40 mL) of amine hydrochloride 64 (16.22 mg, 0.0405 mmol), and the mixture was reacted for 30 minutes. Propionyl chloride (3.9 μL, 0.0446 mmol) was added and reacted at room temperature for 23 hours. The reaction was stopped with water, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate and the solvent was distilled off. Purified by preparative TLC (CHCl 3 / MeOH = 20: 1). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 50: 50), and KUSC-5048 (6.69 mg, 42%, 2 steps) was added. Obtained.
1 1 HNMR 500MHz in MeOH-d 4 1.17 (3H, t, J = 7.5Hz), 2.36 (2H, q, J = 7.5Hz), 6.33 (2H, s), 6.40 (1H, s), 6.86 (1H, d, J = 2.5Hz), 7.64 (2H, d, J = 8.5Hz), 7.88 (1H, d, J = 2.5Hz) , 7.93 (2H, d, J = 8.5Hz)
HR-ESI-MS: calcd C 19 H 19 F 3 N 6 NaO 2 [M + Na] + ,
443.1414, found, 443.1420
　・ＫＵＳＣ－５０５２
Figure JPOXMLDOC01-appb-C000116
 ・ KUSC-5052
Figure JPOXMLDOC01-appb-C000116
　・エステル体６５，６６
　３－メチルー４－ニトロピラゾール（２１．８ｍｇ，０．１７２ｍｍｏｌ）のＤＭＦ溶液（０．９５ｍＬ）にＫ２ＣＯ３（４７．４ｍｇ，０．３４３ｍｍｏｌ），１－（ブロモメチル）－３－カルボン酸エチル（４０．２ｍｇ，０．１７２ｍｍｏｌ）を加えて、室温で２１．８時間攪拌した。水で反応を停止し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝１：１）にて精製し 、エステル体６５（１４．２０ｍｇ，３０％），エステル体６６（１９．７３ｍｇ，４１％）を得た。 -Ester bodies 65, 66
K 2 CO 3 (47.4 mg, 0.343 mmol), ethyl 1- (bromomethyl) -3-carboxylate in a DMF solution (0.95 mL) of 3-methyl-4-nitropyrazole (21.8 mg, 0.172 mmol). (40.2 mg, 0.172 mmol) was added, and the mixture was stirred at room temperature for 21.8 hours. The reaction was stopped with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by SiO 2 flash color n chromatography (Hexane / AcOEt = 1: 1), and the ester body 65 (14.20 mg, 30%) and the ester body 66 (19. 73 mg, 41%) was obtained.
　　・エステル体６５
Figure JPOXMLDOC01-appb-C000117
 　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３９（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．８６（３Ｈ，ｓ），４．３９（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），６．３６（２Ｈ，ｓ），６．８４（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．７０（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），８．１１（１Ｈ，ｓ）
ＨＭＱＣ、ＨＭＢＣで相関を確認した。
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ１３Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，３０２．０８６０，ｆｏｕｎｄ，３０２．０８２９  -Ester body 65
Figure JPOXMLDOC01-appb-C000117
 1 1 HNMR 500MHz in CDCl 3 1.39 (3H, t, J = 7.2Hz), 2.86 (3H, s), 4.39 (2H, q, J = 7.2Hz), 6.36 (2H) , S), 6.84 (1H, d, J = 2.4Hz), 7.70 (1H, d, J = 2.4Hz), 8.11 (1H, s)
Correlation was confirmed by HMQC and HMBC.
HR-ESI-MS: calcd C 11 H 13 N 5 NaO 4 [M + Na] + , 302.0860, found, 302.0829
　・エステル体６６
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３９（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．５１（３Ｈ，ｓ），４．４１（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），６．２９（２Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．７４（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），８．４３（１Ｈ，ｓ）
ＨＭＱＣ、ＨＭＢＣで相関を確認した。
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ１３Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，３０２．０８６０，ｆｏｕｎｄ，３０２．０８２８ -Ester body 66
1 1 HNMR 500MHz in CDCl 3 1.39 (3H, t, J = 7.2Hz), 2.51 (3H, s), 4.41 (2H, q, J = 7.2Hz), 6.29 (2H) , S), 6.86 (1H, d, J = 3.0Hz), 7.74 (1H, d, J = 3.0Hz), 8.43 (1H, s)
Correlation was confirmed by HMQC and HMBC.
HR-ESI-MS: calcd C 11 H 13 N 5 NaO 4 [M + Na] + , 302.0860, found, 302.0828
　・エステル体６７
　エステル体６５（１１．６６ｍｇ，０．０４１８ｍｍｏｌ）のＭｅＯＨ（０．４２ｍＬ）とＴＨＦ（０．４２ｍＬ）の混合溶液に（Ｂｏｃ）２Ｏ（１１μＬ，０．２３５ｍｍｏｌ）と５％Ｐｄ／Ｃ（５．９１ｍｇ）を加えて、水素雰囲気下、９時間反応させた。セライトでろ過し、溶媒を減圧留去した。分取ＴＬＣ（ＣＨＣｌ３／ＡｃＯＥｔ＝９：１）で精製を行い、エステル体６７（１３．３７ｍｇ，９２％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．３９（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．４８（９Ｈ，ｓ），２．１７（３Ｈ，ｓ），４．４０（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），　５．９７（１Ｈ，ｂｒ），６．２０（２Ｈ，ｓ），６．７９（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．５９（１Ｈ，ｓ），７．８９（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ２３Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，３７２．１６４３，ｆｏｕｎｄ，３７２．１６１４ -Ester body 67
(Boc) 2 O (11 μL, 0.235 mmol) and 5% Pd / C (5) in a mixed solution of ester 65 (11.66 mg, 0.0418 mmol) in MeOH (0.42 mL) and THF (0.42 mL). .91 mg) was added, and the mixture was reacted for 9 hours under a hydrogen atmosphere. The mixture was filtered through cerite and the solvent was distilled off under reduced pressure. Purification was performed by preparative TLC (CHCl3 / AcOEt = 9: 1) to obtain ester 67 (13.37 mg, 92%).
1 1 HNMR 500MHz in CDCl 3 1.39 (3H, t, J = 7.2Hz), 1.48 (9H, s), 2.17 (3H, s), 4.40 (2H, q, J = 7) .2Hz), 5.97 (1H, br), 6.20 (2H, s), 6.79 (1H, d, J = 1.8Hz), 7.59 (1H, s), 7.89 ( 1H, br)
HR-ESI-MS: calcd C 16 H 23 N 5 NaO 4 [M + Na] + , 372.1643, found, 372.614
　・カルボン酸中間体６８
　エステル体６７（１３．３２ｍｇ，０．０３８１ｍｍｏｌ）のＭｅＯＨ（０．７２ｍＬ）と水（０．２４ｍＬ）の混合溶液に２Ｍ水酸化ナトリウム水溶液（２９μＬ，０．０５８ｍｍｏｌ）を加えて、４５℃で２０時間反応させた。１Ｍ塩酸で反応を停止し、ｐＨ＝２としてＣＨＣｌ３で抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体６８（１２．９２ｍｇ，９７％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．４９（９Ｈ，ｓ），２．１３（３Ｈ，ｓ），６．２８（２Ｈ，ｓ），６．７８（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．８６（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．９１（１Ｈ，ｓ），７．９３（１Ｈ，ｂｒ），８．４２（１Ｈ，ｂｒ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１４Ｈ１９Ｎ５ＮａＯ４［Ｍ＋Ｎａ］＋，３４４．１３３０，ｆｏｕｎｄ，３４４．１３０１ -Carboxylic acid intermediate 68
To a mixed solution of ester 67 (13.32 mg, 0.0381 mmol) with MeOH (0.72 mL) and water (0.24 mL), add 2 M aqueous sodium hydroxide solution (29 μL, 0.058 mmol) and add 20 at 45 ° C. Reacted for time. The reaction was stopped with 1M hydrochloric acid, and extraction was performed with CHCl 3 at pH = 2. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 68 (12.92 mg, 97%) was obtained.
1 1 HNMR 500MHz in MeOH-d 4 1.49 (9H, s), 2.13 (3H, s), 6.28 (2H, s), 6.78 (1H, d, J = 2.4Hz), 7.86 (1H, d, J = 3.0Hz), 7.91 (1H, s), 7.93 (1H, br), 8.42 (1H, br)
HR-ESI-MS: calcd C 14 H 19 N 5 NaO 4 [M + Na] + , 344.1330, found, 344.1301
　・アミド体６９
　カルボン酸中間体６８（１２．９２ｍｇ，０．０４１２ｍｍｏｌ）のジクロロメタン溶液（０．５６ｍＬ）にＤＩＰＥＡ（１４μＬ，０．０８０４ｍｍｏｌ），ＨＡＴＵ（１６．４ｍｇ，０．０４３２ｍｍｏｌ）を加えて、窒素雰囲気下、２０分攪拌した。４－トリフルオロメチルアニリン（５．７μＬ，０．０４５３ｍｍｏｌ）を加えて室温で１８時間攪拌した。水で反応を停止し、酢酸エチルで抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）にて精製し 、アミド体６９（１３．４１ｍｇ）を得た。 ・ Amide 69
DIPEA (14 μL, 0.0804 mmol) and HATU (16.4 mg, 0.0432 mmol) were added to a dichloromethane solution (0.56 mL) of carboxylic acid intermediate 68 (12.92 mg, 0.0412 mmol) under a nitrogen atmosphere. The mixture was stirred for 20 minutes. 4-Trifluoromethylaniline (5.7 μL, 0.0453 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was stopped with water and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off, and the obtained residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1) to obtain an amide compound 69 (13.41 mg).
　・アミン塩酸塩７０
　アミド体６９（１３．４１ｍｇ）の４ＭＨＣｌ　ｉｎ　１，４－ｄｉｏｘａｎｅ溶液（０．４０ｍＬ）を窒素雰囲気下、室温で４時間攪拌した。溶媒を減圧留去した。得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝６５：３５，０．０５％ＴＦＡ）にて精製し、アミン塩酸塩７０（５．４８ｍｇ，３４％，２　ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　２．２７（３Ｈ，ｓ），６．４３（２Ｈ，ｓ），６．８８（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．６６（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９７（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），８．０６（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１６Ｈ１５Ｆ３Ｎ６ＮａＯ［Ｍ－ＨＣｌ＋Ｎａ］＋，３８７．１１５２，ｆｏｕｎｄ，３８７．１１２５ ・ Amine hydrochloride 70
A 4MHCl in 1,4-dioxane solution (0.40 mL) of the amide compound 69 (13.41 mg) was stirred at room temperature for 4 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 65: 35, 0.05% TFA), and amine hydrochloride 70 (5.48 mg, 34%) was purified. , 2 steps).
1 1 HNMR 500MHz in MeOH-d 4 2.27 (3H, s), 6.43 (2H, s), 6.88 (1H, d, J = 2.4Hz), 7.66 (2H, d, J) = 9.0Hz), 7.94 (2H, d, J = 9.0Hz), 7.97 (1H, d, J = 1.8Hz), 8.06 (1H, s)
HR-ESI-MS: calcd C 16 H 15 F 3 N 6 NaO [M-HCl + Na] + , 387.1152 found, 387.11.125
　・ＫＵＳＣ－５０５２
　アミン塩酸塩７０（５．４８ｍｇ，０．０１３７ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（０．１４ｍＬ）にトリエチルアミン（４．８μＬ，０．０３４２ｍｍｏｌ）を加えて、３０分間反応させた。塩化プロピオニル（１．３μＬ，０．２１７ｍｍｏｌ）を加えて、室温で２日間反応させた。水で反応を停止し、ＣＨＣｌ３で抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を留去した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝４５：５５）にて精製し、ＫＵＳＣ－５０５２（３．３８ｍｇ，５９％）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．２３（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），２．３９（２Ｈ，ｑ，Ｊ＝７．５Ｈｚ），６．１８（２Ｈ，ｓ），６．８７（１Ｈ，ｓ），６．９０（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．６７（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．８４（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．２６（１Ｈ，ｂｒ），８．９０（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１９Ｈ１９Ｆ３Ｎ６ＮａＯ２　［Ｍ＋Ｎａ］＋，
　４４３．１４１４，ｆｏｕｎｄ，４４３．１４２８
Figure JPOXMLDOC01-appb-C000118
 ・ KUSC-5052
Triethylamine (4.8 μL, 0.0342 mmol) was added to CH 2 Cl 2 solution (0.14 mL) of amine hydrochloride 70 (5.48 mg, 0.0137 mmol), and the mixture was reacted for 30 minutes. Propionyl chloride (1.3 μL, 0.217 mmol) was added and reacted at room temperature for 2 days. The reaction was stopped with water, extracted with CHCl 3 , and washed with saturated brine. The organic layer was dried over sodium sulfate and the solvent was distilled off. Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 45: 55) to obtain KUSC-5052 (3.38 mg, 59%).
1 1 HNMR 500MHz in MeOH-d 4 1.23 (3H, t, J = 7.5Hz), 2.39 (2H, q, J = 7.5Hz), 6.18 (2H, s), 6.87 (1H, s), 6.90 (1H, d, J = 2.5Hz), 7.61 (2H, d, J = 8.0Hz), 7.67 (1H, d, J = 7.5Hz) , 7.84 (2H, d, J = 8.0Hz), 8.26 (1H, br), 8.90 (1H, s)
HR-ESI-MS: calcd C 19 H 19 F 3 N 6 NaO 2 [M + Na] + ,
443.1414, found, 443.1.1428
Figure JPOXMLDOC01-appb-C000118
・エステル体７１
　４－ピラゾールカルボン酸メチル（１００ｍｇ，０．７９３ｍｍｏｌ）のアセトン溶液（２．２ｍＬ）にＫ２ＣＯ３（５４７．９ｍｇ，３．９６ｍｍｏｌ）と臭化ベンジル（９４μＬ，０．７９０ｍｍｏｌ）を加えて、窒素雰囲気下５６℃で２２時間反応させた。水で反応を停止し、ＣＨＣｌ３で抽出し、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝７：３）にて精製し 、エステル体７１（１６２．５５ｍｇ，９５％）を得た。
　１ＨＮＭＲは文献値と一致した。 -Ester body 71
K 2 CO 3 (547.9 mg, 3.96 mmol) and benzyl bromide (94 μL, 0.790 mmol) were added to an acetone solution (2.2 mL) of methyl 4-pyrazolecarboxylate (100 mg, 0.793 mmol). The reaction was carried out at 56 ° C. for 22 hours under a nitrogen atmosphere. The reaction was stopped with water, extracted with CHCl 3 , and washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO 2 flash color n chromatography (Hexane / AcOEt = 7: 3) to obtain an ester body 71 (162.55 mg, 95%).
1 1 HNMR was in agreement with the literature value.
　・カルボン酸中間体７２
　エステル体７１（１５９．２１ｍｇ，０．７３６ｍｍｏｌ）のＭｅＯＨ（１１．１ｍＬ）と水（３．７ｍＬ）の混合溶液に２ＭＮａＯＨ溶液（０．５５ｍＬ，１．１１ｍｍｏｌ）を加えて、４５℃で１１時間反応させた。１Ｍ塩酸で反応を停止し、ｐＨ＝２としてＣＨＣｌ３で抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体７２（１５０．４９ｍｇ，１００％）を得た。
　１ＨＮＭＲは文献値と一致した。 -Carboxylic acid intermediate 72
A 2M NaOH solution (0.55 mL, 1.11 mmol) was added to a mixed solution of ester 71 (159.21 mg, 0.736 mmol) with MeOH (11.1 mL) and water (3.7 mL), and the mixture was added at 45 ° C. for 11 hours. It was reacted. The reaction was stopped with 1M hydrochloric acid, and extraction was performed with CHCl 3 at pH = 2. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 72 (150.49 mg, 100%) was obtained.
1 1 HNMR was in agreement with the literature value.
・アミド体７３
　カルボン酸中間体７２（１４９．２４ｍｇ，０．７４４ｍｍｏｌ）のジクロロメタン溶液（４．６ｍＬ）にＤＩＰＥＡ（１９３μＬ，１．１２ｍｍｏｌ），ＤＭＡＰ（１４．０ｍｇ，０．１１１ｍｍｏｌ）を加えて室温で５分攪拌した。ＥＤＣ・ＨＣｌ（２１２．２ｍｇ，１．１２ｍｍｏｌ）を加えて室温で２０時間反応させた。飽和重曹水で反応を停止し、ＣＨＣｌ３で抽出を行った。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）にて精製し 、アミド体７３（１５０．０９ｍｇ，８９％）を得た。
１ＨＮＭＲは文献値と一致した。　 -Amid body 73
Add DIPEA (193 μL, 1.12 mmol) and DMAP (14.0 mg, 0.111 mmol) to a dichloromethane solution (4.6 mL) of carboxylic acid intermediate 72 (149.24 mg, 0.744 mmol) and stir at room temperature for 5 minutes. did. EDC HCl (212.2 mg, 1.12 mmol) was added and reacted at room temperature for 20 hours. The reaction was stopped with saturated aqueous sodium hydrogen carbonate, and extraction was performed with CHCl 3 . The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 chloroform n chromatography (CHCl3 / MeOH = 20: 1) to obtain an amide form 73 (150.09 mg, 89%).
1 1 HNMR was in agreement with the literature value.
　・アミド体７４
　アミド体７３（７１．０２ｍｇ，０．３１０ｍｍｏｌ）のｔＢｕＯＨ溶液（１４．２ｍＬ）にギ酸（１．４２ｍＬ，０．０３７６ｍｍｏｌ），５％Ｐｄ／Ｃ（２８４ｍｇ）を加えて窒素雰囲気下、５０℃で１４時間反応させた。セライトろ過を行い、溶媒を減圧留去した。アミド体７４（５７．６ｍｇ）を得た。
　１ＨＮＭＲは文献値と一致した。 ・ Amide body 74
Formic acid (1.42 mL, 0.0376 mmol) and 5% Pd / C (284 mg) were added to a tBuOH solution (14.2 mL) of the amide 73 (71.02 mg, 0.310 mmol) at 50 ° C. under a nitrogen atmosphere. It was allowed to react for 14 hours. Cerite filtration was performed, and the solvent was distilled off under reduced pressure. An amide 74 (57.6 mg) was obtained.
1 1 HNMR was in agreement with the literature value.
　・エステル体７５
　アミド中間体７４（５７．６ｍｇ，０．４１４ｍｍｏｌ）のアセトン溶液（１．１５ｍＬ）にＫ２ＣＯ３（２８５．８ｍｇ，２．０７ｍｍｏｌ）１－（ブロモメチル）ピラゾールー３－カルボン酸エチル（９６．５ｍｇ，０．４１４ｍｍｏｌ）を加えて５０℃で2日間反応させた。水で反応を停止し、酢酸エチルで抽出を行った。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）にて精製し 、エステル体７５（５２．６８ｍｇ，５８％，　２　ｓｔｅｐｓ）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　１．１７（３Ｈ，ｔ，Ｊ＝６．６Ｈｚ），１．３８（３Ｈ，ｔ，Ｊ＝６．６Ｈｚ），３．３９（２Ｈ，ｑ，Ｊ＝６．６Ｈｚ），４．３８（２Ｈ，ｑ，Ｊ＝６．６Ｈｚ），６．０９（１Ｈ，ｂｒ）６．３３（２Ｈ，ｓ），６．８１（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．６９（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．８３（１Ｈ，ｓ），８．１２（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１３Ｈ１７Ｎ５Ｏ３［Ｍ＋Ｎａ］＋，
３１４．１２２４，ｆｏｕｎｄ，３１４．１２２３  -Ester body 75
Ethyl K 2 CO 3 (285.8 mg, 2.07 mmol) 1- (bromomethyl) pyrazole-3-carboxylate (96.5 mg) in an acetone solution (1.15 mL) of amide intermediate 74 (57.6 mg, 0.414 mmol). , 0.414 mmol) was added and the mixture was reacted at 50 ° C. for 2 days. The reaction was stopped with water and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by SiO 2 chloroform n chromatography (CHCl3 / MeOH = 20: 1) to obtain an ester 75 (52.68 mg, 58%, 2 steps).
1 1 HNMR 600MHz in CDCl 3 1.17 (3H, t, J = 6.6Hz), 1.38 (3H, t, J = 6.6Hz), 3.39 (2H, q, J = 6.6Hz) , 4.38 (2H, q, J = 6.6Hz), 6.09 (1H, br) 6.33 (2H, s), 6.81 (1H, d, J = 1.8Hz), 7. 69 (1H, d, J = 2.4Hz), 7.83 (1H, s), 8.12 (1H, s)
HR-ESI-MS: calcd C 13 H 17 N 5 O 3 [M + Na] + ,
314.1224, found, 314.1223
　・カルボン酸中間体７６
　エステル体７５（３４ｍｇ，０．１１７ｍｍｏｌ）のＭｅＯＨ（２．２５ｍＬ）と水（０．７５ｍＬ）の混合溶媒に２ＭＮａＯＨ水溶液（８８μＬ，０．１７６ｍｍｏｌ）を加えて５０℃で１３時間攪拌した。１ＭＨＣｌでｐＨ＝２とし、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体７６（３１．１６ｍｇ，１００％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１８（３Ｈ，ｔ，Ｊ＝６．６Ｈｚ），３．３３（２Ｈ，ｑ，Ｊ＝６．６Ｈｚ），６．４７（２Ｈ，ｓ），６．７９（１Ｈ，ｄ，Ｊ＝１．８Ｈｚ），７．９１（１Ｈ，ｓ），７．９５（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），８．３４（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１１Ｈ１４Ｎ５Ｏ３［Ｍ＋Ｈ］＋，
２６４．１０９１，ｆｏｕｎｄ，２６４．１０９３ -Carboxylic acid intermediate 76
A 2M NaOH aqueous solution (88 μL, 0.176 mmol) was added to a mixed solvent of MeOH (2.25 mL) of ester 75 (34 mg, 0.117 mmol) and water (0.75 mL), and the mixture was stirred at 50 ° C. for 13 hours. The pH was adjusted to 2 with 1 MHCl, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 76 (31.16 mg, 100%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 1.18 (3H, t, J = 6.6Hz), 3.33 (2H, q, J = 6.6Hz), 6.47 (2H, s), 6.79 (1H, d, J = 1.8Hz), 7.91 (1H, s), 7.95 (1H, d, J = 2.4Hz), 8.34 (1H, s)
HR-ESI-MS: calcd C 11 H 14 N 5 O 3 [M + H] + ,
264.1091, found, 264.1093
　・ＫＵＳＣ－５０５５
　カルボン酸中間体７６（２９．１３ｍｇ，０．１１１ｍｍｏｌ）のジクロロメタン溶液（１．５ｍＬ）にＤＩＰＥＡ（７８μＬ，０．２２１ｍｍｏｌ），ＨＡＴＵ（４２．６ｍｇ，０．１１２ｍｍｏｌ）を加えて、窒素雰囲気下、３０分攪拌した。４－トリフルオロメチルアニリン（１５．３μＬ，０．１２２ｍｍｏｌ）を加えて室温で１４時間攪拌した。水で反応を停止し、酢酸エチルで抽出を行った。有機層を飽和重曹水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去し、得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）にて精製し 、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝４５：５５）にて精製し、ＫＵＳＣ－５０５５（２３．８１ｍｇ，５３％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．１７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．３３（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），６．５２（２Ｈ，ｓ），６．８７（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．６４（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９４（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９７（１Ｈ，ｓ），７．９９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），　８．３７（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１８Ｈ１７Ｆ３Ｎ６ＮａＯ２［Ｍ＋Ｎａ］＋，
　４２９．１２５８，ｆｏｕｎｄ，４２９．１２８９
Figure JPOXMLDOC01-appb-C000119
 ・ KUSC-5055
DIPEA (78 μL, 0.221 mmol) and HATU (42.6 mg, 0.112 mmol) were added to a dichloromethane solution (1.5 mL) of carboxylic acid intermediate 76 (29.13 mg, 0.111 mmol) under a nitrogen atmosphere. The mixture was stirred for 30 minutes. 4-Trifluoromethylaniline (15.3 μL, 0.122 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction was stopped with water and extraction was performed with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off, and the obtained residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1), and then the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent:). Purification with CH 3 CN / H 2 O = 45: 55) gave KUSC-5055 (23.81 mg, 53%).
1 1 HNMR 600MHz in MeOH-d 4 1.17 (3H, t, J = 7.2Hz), 3.33 (2H, q, J = 7.2Hz), 6.52 (2H, s), 6.87 (1H, d, J = 3.0Hz), 7.64 (2H, d, J = 9.0Hz), 7.94 (2H, d, J = 9.0Hz), 7.97 (1H, s) , 7.99 (1H, d, J = 2.0Hz), 8.37 (1H, s)
HR-ESI-MS: calcd C 18 H 17 F 3 N 6 NaO 2 [M + Na] + ,
429.1258, found, 429.1289
Figure JPOXMLDOC01-appb-C000119
　・Ｎｓ保護体７７
　ＫＵＳＣ－５０３５（９．５ｍｇ，０．０２４６ｍｍｏｌ）のジクロロメタン溶液（０．１２ｍＬ）にトリエチルアミン（１７．１μＬ，０．１２３ｍｍｏｌ）を加えて窒素雰囲気下、室温で２５分間反応させた。塩化２－ニトロベンゼンスルホニル（５．５ｍｇ，０．０２４８ｍｍｏｌ）を加えて、室温で１３時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、Ｎｓ保護体７７（６．１２ｍｇ，４７％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＣＤＣｌ３　６．２２（２Ｈ，ｓ），６．９１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．０４（１Ｈ，ｓ），７．３２（１Ｈ，ｓ），７．５４（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．６２－６７（４Ｈ，ｍ），７．３２－４５（２Ｈ，ｍ），７．８３（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ２１Ｈ１６Ｆ３Ｎ７Ｏ５ＳＮａ［Ｍ＋Ｎａ］＋，
５５８．０７７８，ｆｏｕｎｄ，５５８．０７９６ ・ Ns protecting body 77
Triethylamine (17.1 μL, 0.123 mmol) was added to a dichloromethane solution (0.12 mL) of KUSC-5035 (9.5 mg, 0.0246 mmol), and the mixture was reacted at room temperature for 25 minutes under a nitrogen atmosphere. 2-Nitrobenzenesulfonyl chloride (5.5 mg, 0.0248 mmol) was added and the mixture was stirred at room temperature for 13 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layer was washed with saturated brine and dried over sodium sulfate. Purification with preparative TLC (CHCl 3 / MeOH = 20: 1) gave Ns-protected 77 (6.12 mg, 47%).
1 1 HNMR 600MHz in CDCl 3 6.22 (2H, s), 6.91 (1H, d, J = 2.4Hz), 7.04 (1H, s), 7.32 (1H, s), 7. 54 (1H, t, J = 7.8Hz), 7.62-67 (4H, m), 7.32-45 (2H, m), 7.83 (2H, d, J = 9.0Hz)
HR-ESI-MS: calcd C 21 H 16 F 3 N 7 O 5 SNa [M + Na] + ,
558.0778, found, 558.07796
　・ＫＵＳＣ－５０５６
　Ｎｓ保護体７７（６．１２ｍｇ，０．０１１４ｍｍｏｌ）のＤＭＦ溶液（０．１１ｍＬ）にＫ２ＣＯ３（５．１ｍｇ，０．０３６９ｍｍｏｌ），ヨウ化プロピル（１．６７μＬ，０．０１７１ｍｍｏｌ）とＴＢＡＩ（０．００２７１ｍｍｏｌ）を加えて４０℃で１３時間攪拌した。室温に冷却し、０．１Ｍチオフェノール　ｉｎ　ＤＭＦ（０．２９ｍＬ，０．０２９ｍｍｏｌ）を加えて２．３時間攪拌した。水で反応を停止し、ＣＨＣｌ３で抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。分取ＴＬＣ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製した。その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝３５：６５）にて精製し、ＫＵＳＣ－５０５６（２．０６ｍｇ，４６％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　０．９７（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．５９（２Ｈ，ｓｅｐｔｅｔ，Ｊ＝７．２Ｈｚ），２．８９（２Ｈ，ｔ，Ｊ＝７．２Ｈｚ），６．３４（２Ｈ，ｓ），６．８５（１Ｈ，ｄ，Ｊ＝１．２Ｈｚ），７．２７（１Ｈ，ｓ），７．４４（１Ｈ，ｓ），７．６５（２Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．８９（１Ｈ，ｄ，Ｊ＝３．０Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１８Ｈ１９Ｆ３Ｎ６ＮａＯ　［Ｍ＋Ｎａ］＋，４１５．１４６５，ｆｏｕｎｄ，４１５．１４８１ ・ KUSC-5056
K 2 CO 3 (5.1 mg, 0.0369 mmol), propyl iodide (1.67 μL, 0.0171 mmol) and TBAI in a DMF solution (0.11 mL) of Ns-protecting group 77 (6.12 mg, 0.0114 mmol). (0.00271 mmol) was added, and the mixture was stirred at 40 ° C. for 13 hours. The mixture was cooled to room temperature, 0.1 M thiophenol in DMF (0.29 mL, 0.029 mmol) was added, and the mixture was stirred for 2.3 hours. The reaction was stopped with water and extracted with CHCl 3 . The organic layer was washed with saturated brine and dried over sodium sulfate. Purified by preparative TLC (CHCl 3 / MeOH = 20: 1). Then, the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 35: 65) to obtain KUSC-5056 (2.06 mg, 46%).
1 1 HNMR 600MHz in MeOH-d 4 0.97 (3H, t, J = 7.2Hz), 1.59 (2H, septet, J = 7.2Hz), 2.89 (2H, t, J = 7. 2Hz), 6.34 (2H, s), 6.85 (1H, d, J = 1.2Hz), 7.27 (1H, s), 7.44 (1H, s), 7.65 (2H) , D, J = 8.4Hz), 7.89 (1H, d, J = 3.0Hz), 7.95 (2H, d, J = 9.0Hz)
HR-ESI-MS: calcd C 18 H 19 F 3 N 6 NaO [M + Na] + , 415.1465, found, 415.1481
　・ＫＵＳＣ－５０３３　　
Figure JPOXMLDOC01-appb-C000120
 ・ KUSC-5033
Figure JPOXMLDOC01-appb-C000120
　・エステル体７８
Figure JPOXMLDOC01-appb-C000121
 　１－（ブロモメチル）ピラゾールー３－カルボン酸エチル（５０ｍｇ，０．２１５ｍｍｏｌ)のアセトニトリル溶液に４－クロロピラゾール（４９．７ｍｇ，０．４８５ｍｍｏｌ）、Ｋ２ＣＯ３（６５．２ｍｇ，０．４７２ｍｍｏｌ）を添加し、室温で２３．５時間攪拌した。水で反応を停止させ、ＣＨＣｌ３で抽出を行い、有機層を合わせて、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ　（ＣＨＣｌ３／ＭｅＯＨ＝１００：３）にて精製し 、エステル体７８（５６．５８ｍｇ）を得た。
　１ＨＮＭＲ　５００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　１．３５（３Ｈ，ｔ，Ｊ＝７．５Ｈｚ），４．３３（２Ｈ，ｑ，Ｊ＝７．５Ｈｚ），６．４０（２Ｈ，ｓ），６．７９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ），８．００（１Ｈ，ｓ）
　ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１０Ｈ１１ＣｌＮ４ＮａＯ２［Ｍ＋Ｎａ］＋，
２７７．０４６３，ｆｏｕｎｄ，２７７．０４３５ -Ester body 78
Figure JPOXMLDOC01-appb-C000121
 4-Chloropyrazole (49.7 mg, 0.485 mmol) and K2 CO 3 (65.2 mg, 0.472 mmol) in an acetonitrile solution of 1- (bromomethyl) pyrazole- 3 -carboxylate (50 mg, 0.215 mmol). It was added and stirred at room temperature for 23.5 hours. The reaction was stopped with water, extraction was performed with CHCl 3 , the organic layers were combined, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 100: 3) to obtain an ester 78 (56.58 mg).
1 1 HNMR 500MHz in MeOH-d 4 1.35 (3H, t, J = 7.5Hz), 4.33 (2H, q, J = 7.5Hz), 6.40 (2H, s), 6.79 (1H, d, J = 2.0Hz), 8.00 (1H, s)
HR-ESI-MS: calcd C 10 H 11 ClN 4 NaO 2 [M + Na] + ,
277.0463, found, 277.0435
　・カルボン酸中間体７９
Figure JPOXMLDOC01-appb-C000122
 　エステル体７８（５６．５８ｍｇ）のＭｅＯＨ／水＝３：１混合溶媒（４．４ｍＬ）に２Ｍ水酸化ナトリウム水溶液（０．１７ｍＬ，０．３４０ｍｍｏｌ）を加えて、４５℃で２３．７時間反応させた。濃塩酸で反応を停止し、ｐＨ＝３から４として酢酸エチルで抽出を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。カルボン酸中間体７９（３６．０６ｍｇ，７２％）を得た。
　１ＨＮＭＲ　６００ＭＨｚ　ｉｎ　ＭｅＯＨ－ｄ４　６．４０（２Ｈ，ｓ），６．７９（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），７．５１（１Ｈ，ｓ），７．９１（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），８．００（１Ｈ，ｓ） -Carboxylic acid intermediate 79
Figure JPOXMLDOC01-appb-C000122
 A 2M aqueous sodium hydroxide solution (0.17 mL, 0.340 mmol) was added to a MeOH / water = 3: 1 mixed solvent (4.4 mL) of the ester 78 (56.58 mg), and the reaction was carried out at 45 ° C. for 23.7 hours. I let you. The reaction was stopped with concentrated hydrochloric acid, and extraction was performed with ethyl acetate at pH = 3 to 4. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Carboxylic acid intermediate 79 (36.06 mg, 72%) was obtained.
1 1 HNMR 600MHz in MeOH-d 4 6.40 (2H, s), 6.79 (1H, d, J = 1.5Hz), 7.51 (1H, s), 7.91 (1H, d, J) = 2.5Hz), 8.00 (1H, s)
　・ＫＵＳＣ－５０３３
Figure JPOXMLDOC01-appb-C000123
 　カルボン酸中間体７９（２０ｍｇ，０．０８８ｍｍｏｌ）のＣＨ２Ｃｌ２溶液（１．０ｍＬ）にＤＩＰＥＡ（３１μＬ，０．１８ｍｍｏｌ），ＨＡＴＵ（２８．３ｍｇ，０．０８９ｍｍｏｌ）を添加し、室温で２５分攪拌した。ｐ－ブロモアニリン（１６．７ｍｇ，０．０４４ｍｍｏｌ）を添加し、室温で２４時間反応させた。水で反応を停止し、酢酸エチルで抽出した。有機層を合わせて、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄を行った。硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＳｉＯ２　ｆｌａｓｈ　ｃｏｌｕｍ ｎ　ｃｈｒｏｍａｔｏｇｒａｐｈｙ（ＣＨＣｌ３／ＭｅＯＨ＝２０：１）で精製し、その後、得られた残渣をＨＰＬＣ（ｃｏｓｍｏｓｉｌ　ＭＳＩＩ，φ２０×２５０ｍｍ，　ｅｌｕｅｎｔ　：　ＣＨ３ＣＮ／Ｈ２Ｏ＝５０：５０）にて精製し、ＫＵＳＣ－５０３３（２５．０ｍｇ，７４％）を得た。
　１ＨＮＭＲ５００ＭＨｚ　ｉｎ　Ａｃｅｔｏｎｅ－ｄ６　６．４９（２Ｈ，ｓ），６．７０（１Ｈ，ｓ），６．８６（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ），７．１５（１Ｈ，ｓ），７．５０（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．０６（１Ｈ，ｓ）８．１５（１Ｈ，ｓ），８．０５（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），９．５７（１Ｈ，ｓ）
ＨＲ－ＥＳＩ－ＭＳ：ｃａｌｃｄ　Ｃ１4Ｈ１1ＢｒＣｌＮ５ＮａＯ［Ｍ＋Ｎａ］＋，
４０１．９７２８，ｆｏｕｎｄ，４０１．９７４３ ・ KUSC-5033
Figure JPOXMLDOC01-appb-C000123
 DIPEA (31 μL, 0.18 mmol) and HATU (28.3 mg, 0.089 mmol) were added to a CH 2 Cl 2 solution (1.0 mL) of carboxylic acid intermediate 79 (20 mg, 0.088 mmol), and 25 at room temperature. Stir for minutes. p-Bromoaniline (16.7 mg, 0.044 mmol) was added and reacted at room temperature for 24 hours. The reaction was stopped with water and extracted with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by SiO 2 chloroform n chromatography (CHCl 3 / MeOH = 20: 1), and then the obtained residue was purified by HPLC (cosmosil MSII, φ20 × 250 mm, eluent: CH 3 CN / H 2 O = 50 :). Purification in 50) gave KUSC-5033 (25.0 mg, 74%).
1 HNMR500MHz in Acetone-d 6 6.49 (2H, s), 6.70 (1H, s), 6.86 (1H, d, J = 2.5Hz), 7.15 (1H, s), 7 .50 (2H, d, J = 9.0Hz), 7.78 (2H, d, J = 8.5Hz), 8.06 (1H, s) 8.15 (1H, s), 8.05 ( 1H, d, J = 1.5Hz), 9.57 (1H, s)
HR-ESI-MS: calcd C 14 H 11 BrClN 5 NaO [M + Na] + ,
401.9728, found, 401.9743
実施例（各化合物の生物活性評価）
HIF-1転写阻害活性の測定
　Ｈｙｐｏｘｉａ　Ｒｅｓｐｏｎｓｅ　Ｅｌｅｍｅｎｔ（ＨＲＥ）配列の下流にホタルルシフェラーゼ遺伝子を挿入したプラスミドを安定に保持するヒト子宮頸がんＨｅＬａ細胞（ＨｅＬａ／５ＨＲＥ-Ｌｕｃ）を用いて、ＨＩＦ－１阻害活性を評価した。ＨｅＬａ／５ＨＲＥ-Ｌｕｃ細胞を９６ウェルプレートに播種し（６．０×１０３ｃｅｌｌ／ｗｅｌｌ）、通常酸素条件で２４時間培養した。上記のようにして取得した各化合物を添加し（ＤＭＳＯ終濃度：１％）、通常酸素条件で１時間培養した後、低酸素条件（１％Ｏ２）下で２４時間培養した。細胞をＰＢＳで洗浄し、ｌｙｓｉｓ　ｂｕｆｆｅｒ（２０ｍＭ　Ｔｒｉｓ／ＨＣｌ　ｐＨ７．５，１５０ｍＭ　ＮａＣｌ，１ｍＭ　ＥＤＴＡ，　０．１％Ｔｒｉｔｏｎ　Ｘ－１００）を加え（３０μＬ／ｗｅｌｌ）、２０分間振とうして細胞抽出液を得た。細胞抽出液１０μＬにＣｏｏｍａｓｓｉｅ　Ｂｒｉｌｌｉａｎｔ　Ｂｌｕｅ（ＣＢＢ）希釈溶液を１００μＬ添加し、吸光度（５９５ｎｍ）を測定して総タンパク量の変化を測定した。一方、細胞抽出液中のルシフェラーゼ活性は、細胞抽出液２０μＬにＬｕｃ　ｒｅａｃｔｉｏｎ　ｂｕｆｆｅｒ（５０ｍＭ　Ｔｒｉｓ／ＨＣｌ　ｐＨ８．０，５ｍＭ　ＭｇＳＯ４，０．１２５ｍＭ　Ｄ－ルシフェリン，０．５ｍＭ　ＡＴＰ，０．５ｍＭ　ＣｏＡ）を加え、化学発光をＥｎＶｉｓｉｏｎ（パーキンエルマー社製）またはＡＲＶＯ（パーキンエルマー社製）を用いて測定しHIF-1阻害活性を測定した。 Example (evaluation of biological activity of each compound)
Measurement of HIF-1 transcription inhibitory activity Using human cervical cancer HeLa cells (HeLa / 5HRE-Luc) that stably carry a plasmid in which the firefly luciferase gene is inserted downstream of the Hypoxia Response Element (HRE) sequence, HIF- 1 Inhibitory activity was evaluated. HeLa / 5HRE-Luc cells were seeded on 96-well plates (6.0 × 10 3 cell / well) and cultured under normal oxygen conditions for 24 hours. Each compound obtained as described above was added (DMSO final concentration: 1%), cultured under normal oxygen conditions for 1 hour, and then cultured under hypoxic conditions (1% O 2 ) for 24 hours. The cells are washed with PBS, lysis buffer (20 mM Tris / HCl pH 7.5,150 mM NaCl, 1 mM EDTA, 0.1% Triton X-100) is added (30 μL / well), and the cells are shaken for 20 minutes to extract the cell extract. Got 100 μL of Coomassie Brilliant Blue (CBB) diluted solution was added to 10 μL of the cell extract, and the absorbance (595 nm) was measured to measure the change in the total protein amount. On the other hand, the luciferase activity in the cell extract is as follows: Luciferase buffer (50 mM Tris / HCl pH 8.0, 5 mM ו 4 , 0.125 mM D-luciferin, 0.5 mM ATP, 0.5 mM CoA) in 20 μL of the cell extract. In addition, chemiluminescence was measured using EnVision (manufactured by PerkinElmer) or ARVO (manufactured by PerkinElmer) to measure HIF-1 inhibitory activity.
　各化合物のHIF-1阻害活性測定結果（IC50値：50%阻害濃度）を表３に示す。なお、表１に示す全ての化合物において、細胞毒性は検出されなかった。なお、８０％以上の生存率の場合に細胞毒性は検出されないと判断した。 Table 3 shows the measurement results of HIF-1 inhibitory activity (IC 50 value: 50% inhibitory concentration) of each compound. No cytotoxicity was detected in all the compounds shown in Table 1. It was determined that no cytotoxicity was detected when the survival rate was 80% or more.
ＨＢＶコアプロモーター阻害活性の測定
　ＨＢＶコアプロモーター下でルシフェラーゼを発現する配列を恒常的に発現する細胞株であるＨＢＶコアプロモーターレポーター細胞を１×１０４ ｃｅｌｌｓ／ｗｅｌｌの密度で９６ウェルプレートまたは４×１０３ /wellのｃｅｌｌｓ／ｗｅｌｌの密度で３８４ウェルプレートに撒き、３７℃、５％ＣＯ２の条件でＤＭＥＭ－ｈｉｇｈ　ｇｌｕｃｏｓｅ （Ｓｉｇｍａ－Ａｌｄｒｉｃｈ　Ｊａｐａｎ　Ｉｎｃ．社製)に１０％牛胎仔血清, １００Ｕ／ｍｌ　Ｐｅｎｉｃｉｌｌｉｎ，１００μｇ／ｍｌ　Ｓｔｒｅｐｔｏｍｙｃｉｎ（ＴｈｅｒｍｏＦｉｓｈｅｒ　Ｓｃｉｅｎｔｉｃ　Ｉｎｃ．社製)を含む培養液を用いて培養し、1日後に各化合物（０．１６，０．８，４，２０，１００μＭ）を加え1日間培養した。その後、９６ウェルプレートまたは ３８４ウェルプレートにそれぞれ新しい７５μＬまたは２５μＬの培養液へ交換し、さらに７５μＬまたは２５μＬの発光基質Ｓｔｅａｄｙ－ＧｌｏＬｕｃｉｆｅｒａｓｅＡｓｓａｙ　Ｓｙｓｔｅｍ (プロメガ社)を加え振盪し、30分後に発光強度をプレートリーダーのＥｎｓｉｇｈｔ (パーキンエルマー社)を用いて定量してＨＢＶコアプロモーターの阻害活性を決定した。また、同様に処理した細胞を用いて細胞生存率（細胞増殖抑制率）を細胞増殖キットＩＩ（ＸＴＴアッセイ：ロシュ・ダイアグノスティクス（株））を用いてミトコンドリア活性を発色に変換し、３０分後に４９０ｎｍの吸光度をプレートリーダーのＥｎｓｉｇｈｔ（Ｐｅｒｋｉｎ　Ｅｌｍｅｒ社製)を用いて定量して決定した。 Measurement of HBV core promoter inhibitory activity HBV core promoter reporter cells, which are cell lines that constitutively express sequences expressing luciferase under the HBV core promoter, are 96-well plates or 4 × 10 at a density of 1 × 10 4 cells / well. Sprinkle on 384-well plates at a density of 3 / well cells / well and add 10% bovine fetal serum to DMEM-high glucose (manufactured by Sigma-Aldrich Japan Inc.) at 37 ° C. and 5% CO 2 conditions, 100 U / ml. Cultivated using a culture solution containing Pencillin, 100 μg / ml Streptomycin (manufactured by Thermo Fisher Scientific Inc.), and after 1 day, each compound (0.16, 0.8, 4, 20, 100 μM) was added and cultured for 1 day. .. Then, the 96-well plate or the 384-well plate is replaced with a new 75 μL or 25 μL culture solution, respectively, and 75 μL or 25 μL of the luminescent substrate Steady-GloLuciphase Assay System (Promega) is added and shaken, and the luminescence intensity is adjusted to the plate reader after 30 minutes. The inhibitory activity of the HBV core promoter was determined by quantification using Ensight (PerkinElmer). In addition, the cell viability (cell proliferation inhibition rate) was converted to color using the cell proliferation kit II (XTT assay: Roche Diagnostics Co., Ltd.) using the cells treated in the same manner, and the mitochondrial activity was converted into color development for 30 minutes. Later, the absorbance at 490 nm was quantified and determined using a plate reader Ensight (manufactured by PerkinElmer).
　各化合物のＨＢＶコアプロモーターの阻害活性測定結果（ＩＣ５０値：５０％阻害濃度）を表３に併せて示す。なお、表１に示す全ての化合物において、細胞毒性は検出されなかった。なお、８０％以上の生存率の場合に細胞毒性は検出されないと判断した。
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-I000125
Figure JPOXMLDOC01-appb-I000126
Figure JPOXMLDOC01-appb-I000127
Table 3 also shows the results of measuring the inhibitory activity of the HBV core promoter of each compound (IC 50 value: 50% inhibitory concentration). No cytotoxicity was detected in all the compounds shown in Table 1. It was determined that no cytotoxicity was detected when the survival rate was 80% or more.
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-I000125
Figure JPOXMLDOC01-appb-I000126
Figure JPOXMLDOC01-appb-I000127
　表３に示されるように、各化合物は優れた低酸素誘導因子－１（ＨＩＦ－１）阻害効果及び優れた抗ＨＢＶ（抗Ｂ型肝炎ウイルス）活性を奏した。 As shown in Table 3, each compound exhibited an excellent hypoxia-inducible factor-1 (HIF-1) inhibitory effect and an excellent anti-HBV (anti-hepatitis B virus) activity.

Claims (9)

  1. 式（１）：
    Figure JPOXMLDOC01-appb-C000001
     〔式（１）中、
    Ｘは基Ｘ－１：
    Figure JPOXMLDOC01-appb-C000002
     （当該式中、
    Ｘ１は炭素原子又は窒素原子を示し、
    ＲＸ１、ＲＸ２、及びＲＸ３は、それぞれ独立して、水素原子、ハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示す）
    を示し、
    Ｙは基Ｙ－１：
    Figure JPOXMLDOC01-appb-C000003
     （当該式中、
    Ｙ１は炭素原子又は窒素原子を示し、
    ＲＹ１ａ、ＲＹ１ｂ、及びＲＹ１ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉ（当該式中、－Ｙ１ｉ－は－ＣＯ－、－ＳＯ２－、若しくは－ＣＨ２－を示し、－Ｙ１ｉｉはＣ１～Ｃ４アルキル基、フェニル基、若しくはベンジル基を示す）で表される基を示す）
    又は基Ｙ－２：
    Figure JPOXMLDOC01-appb-C000004
     （当該式中、
    Ｙ２は炭素原子又は窒素原子を示し、
    ＲＹ２ａ、ＲＹ２ｂ、及びＲＹ２ｃは、それぞれ独立して、水素原子、ハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ２ｉ－Ｙ２ｉｉ（当該式中、－Ｙ２ｉ－は－ＣＯ－、－ＳＯ２－、若しくは－ＣＨ２－を示し、－Ｙ２ｉｉはＣ１～Ｃ４アルキル基又はフェニル基若しくはベンジル基を示す）で表される基を示す）
    を示し、
    Ｚはメチレン基又は基Ｚ－１：
    Figure JPOXMLDOC01-appb-C000005
     （当該式中、Ａｒはベンゼン環、フラン環、若しくはピラゾール環を示す）
    を示し、
    ｍは０、１、又は２を示し、
    ｎは１、２、又は３を示す。〕
    で表される化合物。     Equation (1):
    Figure JPOXMLDOC01-appb-C000001
     [In equation (1),
    X is the base X-1:
    Figure JPOXMLDOC01-appb-C000002
     (In the formula,
    X 1 represents a carbon atom or a nitrogen atom,
    RX1 , RX2 , and RX3 independently indicate a hydrogen atom, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group).
    Show,
    Y is the base Y-1:
    Figure JPOXMLDOC01-appb-C000003
     (In the formula,
    Y 1 represents a carbon atom or a nitrogen atom.
    RY1a , RY1b , and RY1c are independently hydrogen atom, halogen atom, C1-C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or formula:-. NH-Y 1i -Y 1ii (in the formula, -Y 1i- indicates -CO-, -SO 2- , or -CH 2- , and -Y 1i is a C1-C4 alkyl group, phenyl group, or benzyl group. Indicates a group represented by))
    Or group Y-2:
    Figure JPOXMLDOC01-appb-C000004
     (In the formula,
    Y 2 indicates a carbon atom or a nitrogen atom.
    RY2a , RY2b , and RY2c are independently hydrogen atom, halogen atom, C1-C4 alkyl group, nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or formula:-. NH-Y 2i -Y 2ii (in the formula, -Y 2i- indicates -CO-, -SO 2- , or -CH 2- , and -Y 2ii is a C1-C4 alkyl group or a phenyl group or a benzyl group. Indicates a group represented by))
    Show,
    Z is a methylene group or a group Z-1:
    Figure JPOXMLDOC01-appb-C000005
     (In the formula, Ar indicates a benzene ring, a furan ring, or a pyrazole ring)
    Show,
    m indicates 0, 1, or 2,
    n indicates 1, 2, or 3. ]
    The compound represented by.
  2. Ｘが基Ｘ－１を示し、
    ＲＸ１、ＲＸ２、及びＲＸ３のいずれか１つが水素原子を示し、残りの２つが同じハロゲン原子を示すか、あるいは、
    ＲＸ１がハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示し、ＲＸ２及びＲＸ３が水素原子を示す、
    請求項１に記載の化合物。     X indicates the base X-1,
    Either one of RX1 , RX2 , and RX3 represents a hydrogen atom and the other two represent the same halogen atom, or
    RX1 represents a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group, and RX2 and RX3 represent a hydrogen atom.
    The compound according to claim 1.
  3. Ｙが基Ｙ－１又はＹ－２基を示し、
    Ｙが基Ｙ－１を示すとき、
    ＲＹ１ａが水素原子、ＲＹ１ｂがＣ１～Ｃ４アルキル基、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すか、
    ＲＹ１ａがＣ１～Ｃ４アルキル基、ＲＹ１ｂが水素原子、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すか、あるいは
    ＲＹ１ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ１ａ及びＲＹ１ｃが水素原子を示し、
    ＹがＹ－２基を示すとき、
    ＲＹ２ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ａ及びＲＹ２ｃが水素原子を示すか、あるいは、
    ＲＹ２ａがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ｂ及びＲＹ２ｃが水素原子を示す、
    請求項１又は２に記載の化合物     Y indicates a group Y-1 or a group Y-2,
    When Y indicates the base Y-1,
    Whether RY1a is a hydrogen atom, RY1b is a C1-C4 alkyl group, RY1c is a nitro group or a group represented by the formula: -NH- Y1i - Y1iii .
    RY1a is a C1-C4 alkyl group, RY1b is a hydrogen atom, RY1c is a nitro group or a group represented by the formula: -NH- Y1i - Y1ii , or RY1b is a halogen atom, C1 to C4. An alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , where RY1a and RY1c indicate hydrogen atoms. ,
    When Y indicates Y-2 groups
    RY2b represents a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , R Y2a and RY2c indicate hydrogen atoms, or
    RY2a represents a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , R Y2b and RY2c represent hydrogen atoms,
    The compound according to claim 1 or 2.
  4. Ｚがメチレン基又は基Ｚ－１を示し、
    Ｚが基Ｚ－１を示すとき、
    Ａｒがベンゼン環を示す場合、基Ｚ－１は、
    Figure JPOXMLDOC01-appb-C000006
     のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示し、
    Ａｒがフラン環を示す場合、基Ｚ－１は、
    Figure JPOXMLDOC01-appb-C000007
     のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示し、
    Ａｒがピラゾール環を示す場合、基Ｚ－１は、
    Figure JPOXMLDOC01-appb-C000008
     のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示す、
    請求項１～３のいずれかに記載の化合物。     Z indicates a methylene group or a group Z-1.
    When Z indicates the base Z-1,
    When Ar represents a benzene ring, the group Z-1 is
    Figure JPOXMLDOC01-appb-C000006
     (However, the asterisk side is the Y side in equation (1)).
    When Ar represents a furan ring, the group Z-1 is
    Figure JPOXMLDOC01-appb-C000007
     (However, the asterisk side is the Y side in equation (1)).
    When Ar represents a pyrazole ring, the group Z-1 is
    Figure JPOXMLDOC01-appb-C000008
     (However, the asterisk side is the Y side in the equation (1)).
    The compound according to any one of claims 1 to 3.
  5. Ｘが基Ｘ－１を示し、
    ＲＸ１、ＲＸ２、及びＲＸ３のいずれか１つが水素原子を示し、残りの２つが同じハロゲン原子を示すか、あるいは、
    ＲＸ１がハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１～Ｃ４アルキル基、Ｃ１～Ｃ４アルコキシ基、又はヒドロキシル基を示し、ＲＸ２及びＲＸ３が水素原子を示し、
    Ｙが基Ｙ－１又はＹ－２基を示し、
    Ｙが基Ｙ－１を示すとき、
    ＲＹ１ａが水素原子、ＲＹ１ｂがＣ１～Ｃ４アルキル基、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すか、
    ＲＹ１ａがＣ１～Ｃ４アルキル基、ＲＹ１ｂが水素原子、ＲＹ１ｃがニトロ基又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示すか、あるいは
    ＲＹ１ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ１ａ及びＲＹ１ｃが水素原子を示し、
    ＹがＹ－２基を示すとき、
    ＲＹ２ｂがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ａ及びＲＹ２ｃが水素原子を示すか、あるいは、
    ＲＹ２ａがハロゲン原子、Ｃ１～Ｃ４アルキル基、ニトロ基、－ＣＯ－ＮＨ－ＣＨ２ＣＨ３、－ＮＨ３Ｃｌ、又は式：－ＮＨ－Ｙ１ｉ－Ｙ１ｉｉで表される基を示し、ＲＹ２ｂ及びＲＹ２ｃが水素原子を示し、
    Ｚがメチレン基又は基Ｚ－１を示し、
    Ｚが基Ｚ－１を示すとき、
    Ａｒがベンゼン環を示す場合、基Ｚ－１は、
    Figure JPOXMLDOC01-appb-C000009
     のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示し、
    Ａｒがフラン環を示す場合、基Ｚ－１は、
    Figure JPOXMLDOC01-appb-C000010
     のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示し、
    Ａｒがピラゾール環を示す場合、基Ｚ－１は、
    Figure JPOXMLDOC01-appb-C000011
     のいずれかの基（但し、アスタリスク側が、式（１）におけるＹ側）を示す、
    請求項１に記載の化合物。     X indicates the base X-1,
    Either one of RX1 , RX2 , and RX3 represents a hydrogen atom and the other two represent the same halogen atom, or
    RX1 represents a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or a hydroxyl group, and RX2 and RX3 represent a hydrogen atom.
    Y indicates a group Y-1 or a group Y-2,
    When Y indicates the base Y-1,
    Whether RY1a is a hydrogen atom, RY1b is a C1-C4 alkyl group, RY1c is a nitro group or a group represented by the formula: -NH- Y1i - Y1iii .
    RY1a is a C1-C4 alkyl group, RY1b is a hydrogen atom, RY1c is a nitro group or a group represented by the formula: -NH- Y1i - Y1ii , or RY1b is a halogen atom, C1 to C4. An alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , where RY1a and RY1c indicate hydrogen atoms. ,
    When Y indicates Y-2 groups
    RY2b represents a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , R Y2a and RY2c indicate hydrogen atoms, or
    RY2a represents a halogen atom, a C1-C4 alkyl group, a nitro group, -CO-NH-CH 2 CH 3 , -NH 3 Cl, or a group represented by the formula: -NH-Y 1i -Y 1ii , R Y2b and RY2c indicate hydrogen atoms,
    Z indicates a methylene group or a group Z-1.
    When Z indicates the base Z-1,
    When Ar represents a benzene ring, the group Z-1 is
    Figure JPOXMLDOC01-appb-C000009
     (However, the asterisk side is the Y side in equation (1)).
    When Ar represents a furan ring, the group Z-1 is
    Figure JPOXMLDOC01-appb-C000010
     (However, the asterisk side is the Y side in equation (1)).
    When Ar represents a pyrazole ring, the group Z-1 is
    Figure JPOXMLDOC01-appb-C000011
     (However, the asterisk side is the Y side in the equation (1)).
    The compound according to claim 1.
  6. 以下の表に記載のいずれかの構造式で表される化合物。
    Figure JPOXMLDOC01-appb-T000012
    Figure JPOXMLDOC01-appb-I000013
    Figure JPOXMLDOC01-appb-I000014
    Figure JPOXMLDOC01-appb-I000015
    Figure JPOXMLDOC01-appb-I000016
    Figure JPOXMLDOC01-appb-I000017
    Figure JPOXMLDOC01-appb-I000018
    Figure JPOXMLDOC01-appb-I000019
    Figure JPOXMLDOC01-appb-I000020
    A compound represented by any of the structural formulas described in the table below.
    Figure JPOXMLDOC01-appb-T000012
    Figure JPOXMLDOC01-appb-I000013
    Figure JPOXMLDOC01-appb-I000014
    Figure JPOXMLDOC01-appb-I000015
    Figure JPOXMLDOC01-appb-I000016
    Figure JPOXMLDOC01-appb-I000017
    Figure JPOXMLDOC01-appb-I000018
    Figure JPOXMLDOC01-appb-I000019
    Figure JPOXMLDOC01-appb-I000020
  7. 請求項１～６のいずれかに記載の化合物の塩。 The salt of the compound according to any one of claims 1 to 6.
  8. 請求項１～６のいずれかに記載の化合物又はその塩を含有する抗がん剤。 An anticancer agent containing the compound according to any one of claims 1 to 6 or a salt thereof.
  9. 請求項１～６のいずれかに記載の化合物又はその塩を含有する抗Ｂ型肝炎ウイルス剤。 An anti-hepatitis B virus agent containing the compound according to any one of claims 1 to 6 or a salt thereof.
PCT/JP2021/045451 2020-12-17 2021-12-10 Nitrogen-containing heterocyclic compound WO2022131146A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020209649 2020-12-17
JP2020-209649 2020-12-17

Publications (1)

Publication Number Publication Date
WO2022131146A1 true WO2022131146A1 (en) 2022-06-23

Family

ID=82059101

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/045451 WO2022131146A1 (en) 2020-12-17 2021-12-10 Nitrogen-containing heterocyclic compound

Country Status (1)

Country Link
WO (1) WO2022131146A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060067738A (en) * 2004-12-15 2006-06-20 주식회사 대웅제약 Novel arylamide derivatives as vanilloid receptor antagonist showing excellent analgesic activity and pharmaceutical compositions containing the same
JP2007126454A (en) * 2005-10-06 2007-05-24 Taisho Pharmaceut Co Ltd Anilide derivative
WO2008044767A1 (en) * 2006-10-13 2008-04-17 Takeda Pharmaceutical Company Limited Aromatic amine derivative and use thereof
JP2010527378A (en) * 2007-05-18 2010-08-12 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト Heteroaryl-substituted pyrazole derivatives useful for the treatment of disorders associated with hyperproliferative disorders and angiogenesis
CN102270281A (en) * 2011-06-01 2011-12-07 山东大学 Screening method of anticancer medicament using cyclin-dependent kinases 1 (CDK1) as target
WO2014031928A2 (en) * 2012-08-24 2014-02-27 Philip Jones Heterocyclic modulators of hif activity for treatment of disease

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060067738A (en) * 2004-12-15 2006-06-20 주식회사 대웅제약 Novel arylamide derivatives as vanilloid receptor antagonist showing excellent analgesic activity and pharmaceutical compositions containing the same
JP2007126454A (en) * 2005-10-06 2007-05-24 Taisho Pharmaceut Co Ltd Anilide derivative
WO2008044767A1 (en) * 2006-10-13 2008-04-17 Takeda Pharmaceutical Company Limited Aromatic amine derivative and use thereof
JP2010527378A (en) * 2007-05-18 2010-08-12 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト Heteroaryl-substituted pyrazole derivatives useful for the treatment of disorders associated with hyperproliferative disorders and angiogenesis
CN102270281A (en) * 2011-06-01 2011-12-07 山东大学 Screening method of anticancer medicament using cyclin-dependent kinases 1 (CDK1) as target
WO2014031928A2 (en) * 2012-08-24 2014-02-27 Philip Jones Heterocyclic modulators of hif activity for treatment of disease

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
ANA GUARDIA, GULCIN GULTEN, RAQUEL FERNANDEZ, JESUS GóMEZ, FENG WANG, MAIRE CONVERY, DELIA BLANCO, MARíA MARTíNEZ, : "N -Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2- trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity", CHEMMEDCHEM COMMUNICATIONS, WILEY-VCH, DE, vol. 11, no. 7, 5 April 2016 (2016-04-05), DE , pages 687 - 701, XP055715233, ISSN: 1860-7179, DOI: 10.1002/cmdc.201600020 *
DATABASE REGISTRY 2 September 2009 (2009-09-02), ANONYMOUS : "1H-Pyrazole-3-carboxamide, 1-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-[[2- (trifluoromethyl)phenyl]methyl]-(CA INDEX NAME)", XP055942687, retrieved from STN Database accession no. 1179436-73-7 *
DATABASE REGISTRY 2 September 2009 (2009-09-02), ANONYMOUS : "1H-Pyrazole-3-carboxamide, 1-[(4-chloro-3,5-dimethyl-1H-pyrazol-1- yl)methyl]-N-[[2-(trifluoromethyl)phenyl]methyl]- (CA INDEX NAME) ", XP055942629, retrieved from STN Database accession no. 1179498-48-6 *
DATABASE REGISTRY 28 February 2008 (2008-02-28), ANONYMOUS : "1H-Pyrazole-3-carboxamide, N-(2,4-dichlorophenyl)-1-[(4-nitro-1H-pyrazol-1- yl)methyl]-(CA INDEX NAME) ", XP055942609, retrieved from STN Database accession no. 1005587-80-3 *
DATABASE REGISTRY 28 February 2008 (2008-02-28), ANONYMOUS : "1H-Pyrazole-3-carboxamide, N-(2-bromophenyl)-1-[(4-nitro-1H-pyrazol-1- yl)methyl]-(CA INDEX NAME)", XP055942605, retrieved from STN Database accession no. 1005613-38-6 *
DATABASE REGISTRY 28 February 2008 (2008-02-28), ANONYMOUS : "1H-Pyrazole-3-carboxamide, N-(3-bromophenyl)-1-[(4-nitro-1H-pyrazol-1- yl)methyl]-(CA INDEX NAME)", XP055942612, retrieved from STN Database accession no. 1005632-81-4 *
DATABASE REGISTRY 28 February 2008 (2008-02-28), ANONYMOUS : "1H-Pyrazole-3-carboxamide, N-(3-bromophenyl)-1-[(4-nitro-1H-pyrazol-1- yl)methyl]-(CA INDEX NAME)", XP055942617, retrieved from STN Database accession no. 1005632-81-4 *
DATABASE REGISTRY 28 February 2008 (2008-02-28), ANONYMOUS : "1H-Pyrazole-3-carboxamide, N-(4-bromophenyl)-1-[(4-nitro-1H-pyrazol-1- yl)methyl]-(CA INDEX NAME)", XP055942604, retrieved from STN Database accession no. 1005698-44-1 *
DATABASE REGISTRY 28 February 2008 (2008-02-28), ANONYMOUS : "1H-Pyrazole-3-carboxamide, N-(4-chlorophenyl)-1-[(4-nitro-1H-pyrazol-1- yl)methyl]-(CA INDEX NAME) ", XP055942625, retrieved from STN Database accession no. 1005584-42-8 *
DATABASE REGISTRY 29 April 2008 (2008-04-29), ANONYMOUS : "1H-Pyrazole-3-carboxamide, 1-[(4-bromo-3,5-dimethyl-1H-pyrazol-1- yl)methyl]-N-[2-fluoro-5-(trifluoromethyl)phenyl]- (CA INDEX NAME) ", XP055942689, retrieved from STN Database accession no. 1018025-79-0 *
YASUDA YORINOBU; ARAKAWA TAKEAKI; NAWATA YUMI; SHIMADA SAYAKA; OISHI SHINYA; FUJII NOBUTAKA; NISHIMURA SHINICHI; HATTORI AKIRA; KA: "Design, synthesis, and structure–activity relationships of 1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor (HIF)-1 inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 23, no. 8, 25 February 2015 (2015-02-25), AMSTERDAM, NL, pages 1776 - 1787, XP029209711, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2015.02.038 *

Similar Documents

Publication Publication Date Title
RU2142946C1 (en) Derivatives of pyrazole and pharmaceutical composition containing thereof
AU751139B2 (en) Amide derivative
ES2243598T3 (en) NEW DERIVATIVES OF PIRAZOLOPIRIDINE REPLACED WITH PIRIDINE.
FI88504B (en) PROTECTION OF THERAPEUTIC FRAME THERAPEUTIC 4-BENZYL-1- (2H) -Phthalazine derivative
US20060122230A1 (en) 1,5-Diaryl-pyrrole-3-carboxamide derivatives and their use as cannabinoid receptor modulators
CA2762916C (en) Salts of bicyclo-substituted pyrazolon azo derivatives, preparation method and use thereof
WO2004058255A1 (en) 4, 5-diarylthiazole derivatives as cb-1 ligands
FR2943669A1 (en) NICOTINAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
BR112020000564A2 (en) new heteroaryl amide derivatives as selective inhibitors of histone deacetylases 1 and / or 2 (hdac1-2)
JP2022521081A (en) Amide derivatives useful in the treatment of HBV infections or HBV-induced diseases
JP2019509272A (en) Combination therapy for the treatment of spinal muscular atrophy
JPH11240832A (en) Amide or amine derivative
US9078899B2 (en) Pyrazolyl-based carboxamides II
JP4469174B2 (en) New compounds for the treatment of impotence
CA3137869A1 (en) Protein kinase inhibitors and uses thereof for the treatment of diseases and conditions
JP2010501641A (en) 1H-pyrrolo [2,3-B] pyridine derivatives useful as HSP90 inhibitors
WO2022131146A1 (en) Nitrogen-containing heterocyclic compound
WO2020007729A1 (en) Triazole benzamide derivatives as gpr142 agonists
JPWO2008029912A1 (en) Compound having benzamide as skeleton having cyclooxygenase 1 (COX-1) selective inhibitory activity
WO2022173795A1 (en) OXADIAZOLYL DIHYDROPYRANO[2,3-b]PYRIDINE INHIBITORS OF HIPK2 FOR TREATING KIDNEY FIBROSIS
CA3210977A1 (en) Small molecule activators of yap transcriptional activity for regenerative organ repair
US20220298186A1 (en) Biaryl dialkyl phosphine oxide fpr2 agonists
KR102647513B1 (en) Pharmaceutical compositions and synthesis method of new cinnamic amide derivatives having FXR receptor activating effect
WO2022161423A1 (en) Cyclic amine derivative, preparation method therefor and use thereof
WO2021072028A1 (en) Activators of heme regulated inhibitor kinase (hri)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21906508

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21906508

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP