JP6533997B2

JP6533997B2 - Compound having ZNF143 inhibitory activity and use thereof

Info

Publication number: JP6533997B2
Application number: JP2014265812A
Authority: JP
Inventors: 雅弘小野; 恒之小林; 竜太山崎; 弘高灰原; 由紀子西山; 亜都子法橋; 西山　裕之; 裕之西山; 晃伸栗田; 松崎　健; 健松崎; 公俊河野; 弘人和泉
Original assignee: Yakult Honsha Co Ltd; University of Occupational and Environmental Health Japan
Current assignee: Yakult Honsha Co Ltd; University of Occupational and Environmental Health Japan
Priority date: 2014-12-26
Filing date: 2014-12-26
Publication date: 2019-06-26
Anticipated expiration: 2034-12-26
Also published as: JP2016124812A

Description

本発明は、ZNF143阻害活性を有する新規化合物およびその利用に関する。 The present invention relates to novel compounds having ZNF143 inhibitory activity and uses thereof.

Zinc finger protein 143（ZNF143）は、セレノシスティンtRNA遺伝子の転写に関与するツメガエル転写活性化因子（selenocystein tRNA gene transcription activating factor; Staf）のヒトホモログとして1998年に同定された（非特許文献１および２）。ZNF143は、その分子内に7個のジンクフィンガードメインを有し、このドメインを介して少なくとも18個以上の特定のDNA配列（Staf binding site; SBS）を認識してDNAに結合することで転写を促進するジンクフィンガー型の転写因子である。ZNF143のがんへの関わりについては、近年、シスプラチン、エトポシドおよびドキソルビシンなどの抗がん剤やγ線によるDNA損傷によってZNF143の発現が転写レベルで誘導されること、ZNF143がシスプラチン架橋DNAを認識してDNAに結合すること、シスプラチン耐性がん細胞でZNF143が高発現していること、ZNF143の発現抑制によりがん細胞がシスプラチン感受性になることなどが報告され（非特許文献３および４）、本転写因子ががん治療に対する感受性や耐性に重要な役割を果たしていることが推察された。さらに最近では、siRNAによるZNF143のノックダウンによって、ヒト前立腺がんPC-3細胞の増殖がアポトーシスを介して抑制されることや、細胞周期、細胞生存およびDNA修復などに関わる遺伝子群の発現が抑制されることが報告された（非特許文献５）。また、ZNF143特異的siRNAを用いた癌細胞の増殖阻害方法は既に知られている（特許文献１）。これらの報告から、ZNF143はがんの進展に深くかかわっていることがわかり、ZNF143はがん治療において魅力的な標的分子として考えられ、それを阻害する化合物は新規な抗がん剤として期待される。一方、これまでに低分子のZNF143阻害剤の報告はない。 Zinc finger protein 143 (ZNF143) was identified in 1998 as a human homolog of the Xenopus transcription factor (selenocystein tRNA gene transcription activating factor; Staf) involved in transcription of the selenocystine tRNA gene (Non-patent Documents 1 and 2) . ZNF143 has seven zinc finger domains in its molecule, through which it recognizes transcription by binding to DNA by recognizing at least 18 or more specific DNA sequences (Staf binding site; SBS). It is a zinc finger type transcription factor that promotes. Regarding the involvement of ZNF143 in cancer, recently, expression of ZNF143 is induced at the transcription level by DNA damage caused by anticancer agents such as cisplatin, etoposide and doxorubicin and γ-ray, ZNF143 recognizes cisplatin crosslinked DNA It has been reported that binding to DNA, high expression of ZNF143 in cisplatin-resistant cancer cells, and suppression of ZNF143 expression make the cancer cells sensitive to cisplatin (Non-patent Documents 3 and 4). It has been speculated that transcription factors play an important role in cancer treatment sensitivity and tolerance. More recently, knockdown of ZNF143 by siRNA suppresses the proliferation of human prostate cancer PC-3 cells via apoptosis, and suppresses the expression of genes involved in cell cycle, cell survival, DNA repair, etc. It was reported that it was done (nonpatent literature 5). In addition, methods for inhibiting the growth of cancer cells using ZNF143-specific siRNA are already known (Patent Document 1). From these reports, it is understood that ZNF143 is deeply involved in the development of cancer, and ZNF143 is considered as an attractive target molecule in cancer treatment, and a compound that inhibits it is expected as a novel anticancer agent Ru. On the other hand, there have been no reports of small molecule ZNF143 inhibitors to date.

特開２００９−１５９８６９号公報JP, 2009-159869, A

Schuster, C., et al., EMBO J. 1995, 14(15), 3777-87Schuster, C., et al., EMBO J. 1995, 14 (15), 3777-87 Myslinski, E., et al., J. Biol. Chem. 1998, 273(34), 21998-2006Myslinski, E., et al., J. Biol. Chem. 1998, 273 (34), 21998-2006 Ishiguchi, H., et al., Int. J. Cancer. 2004, 111(6), 900-9Ishiguchi, H., et al., Int. J. Cancer. 2004, 111 (6), 900-9 Wakasugi ,T., et al., Oncogene. 2007, 26(36), 5194-203Wakasugi, T., et al., Oncogene. 2007, 26 (36), 5194-203. Izumi, H., et al., Cancer Sci. 2010, 101(12), 2538-45Izumi, H., et al., Cancer Sci. 2010, 101 (12), 2538-45

本発明の目的は、ZNF143阻害効果を有する化合物ならびにこれを含むZNF143阻害剤および医薬組成物を提供することにある。 An object of the present invention is to provide a compound having a ZNF143 inhibitory effect, and a ZNF143 inhibitor and a pharmaceutical composition comprising the same.

本発明者らは上記課題を解決すべく広範な化合物を合成し、合成した化合物がZNF143阻害作用、アポトーシス誘導作用および抗腫瘍作用を有し、抗がん剤として有用であることを見出し、本発明を完成した。 The present inventors have synthesized a wide range of compounds to solve the above problems, and found that the synthesized compounds have ZNF143 inhibitory activity, apoptosis induction activity and antitumor activity and are useful as anticancer agents. Completed the invention.

すなわち、本発明は、以下に関する。
（１）式（Ｉ）
Ａ−Ｂ−Ｃ−Ｄ（Ｉ）
式中、
Ａは、Ｈ、ＣＨ_３、
または置換基を有していてもよいフェニル基もしくは単環のＮを含む複素芳香環であり、
Ｂは、
であり、
Ｃは、−ＣＯＮＨ−、−ＣＯＮ（ＣＨ_３）−または
であり、
Ｄは、置換基を有していてもよいフェニル基または単環のＮもしくはＳを含む複素芳香環であるか、
あるいは、
ＣおよびＤは共に、置換基を有していてもよい
を形成し、
Ａが、Ｈ、ＣＨ_３、
または置換基を有していてもよいフェニル基であるとき、
Ｃは、−ＣＯＮＨ−であり、
Ｄは、置換基を有するフェニル基であり、ただし、ハロゲン原子、ＣＮ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＯＯＨ、ＣＯＯＣＨ_３およびＣＯＯＣ_２Ｈ_５で一置換されず、ＯＣＨ_３およびＯＣＨ_３、ＯＣＨ_３およびＣＨ_３、ＯＣＨ_３およびＣｌ、ＯＨおよび置換基を有しないフェニル基、ならびにＢｒおよびＣＨ_３で二置換されず、ＯＣＨ_３で三置換されなく、
Ａが、置換基を有していてもよい単環のＮを含む複素芳香環であるとき、
Ｃは、−ＣＯＮＨ−、−ＣＯＮ（ＣＨ_３）−または
であり、
Ｄは、置換基を有していてもよいフェニル基または単環のＮもしくはＳを含む複素芳香環であり、
あるいは、
ＣおよびＤは共に、置換基を有していてもよい
を形成する、
で表される化合物またはその塩。 That is, the present invention relates to the following.
(1) Formula (I)
A-B-C-D (I)
During the ceremony
A is H, CH ₃ ,
Or a phenyl group which may have a substituent or a heteroaromatic ring containing monocyclic N,
B is
And
C is, -CONH -, - CON (CH 3) - or
And
D is a phenyl group which may have a substituent or a heteroaromatic ring containing a single ring N or S, or
Or
Both C and D may have a substituent
Form
A is H, CH ₃ ,
Or when it is a phenyl group which may have a substituent,
C is -CONH-,
D is a phenyl group having a substituent, provided that a halogen _{_{atom, CN, CH 3, CH 2}} OH, COOH, not monosubstituted by COOCH ₃ and COOC ₂ H _5, OCH ₃ and _OCH 3, OCH ₃ and CH ₃ , OCH ₃ and Cl, OH and phenyl groups having no substituent, and not substituted with Br and CH ₃ and trisubstituted with OCH ₃ ,
When A is a single ring N-containing heteroaromatic ring which may have a substituent,
C is, -CONH -, - CON (CH 3) - or
And
D is a phenyl group which may have a substituent or a heteroaromatic ring containing single ring N or S,
Or
Both C and D may have a substituent
Form
Or a salt thereof.

（２）Ａが、Ｈ、ＣＨ_３、
または置換基を有していてもよいフェニル基であり、
Ｂが、
であり、
Ｃが、−ＣＯＮＨ−であり、
Ｄが、置換基を有するフェニル基であり、ただし、ハロゲン原子、ＣＮ、ＣＨ_３、ＣＨ_２ＯＨ、ＣＯＯＨ、ＣＯＯＣＨ_３およびＣＯＯＣ_２Ｈ_５で一置換されず、ＯＣＨ_３およびＯＣＨ_３、ＯＣＨ_３およびＣＨ_３、ＯＣＨ_３およびＣｌ、ＯＨおよび置換基を有しないフェニル基、ならびにＢｒおよびＣＨ_３で二置換されず、ＯＣＨ_３で三置換されない、
上記（１）に記載の化合物またはその塩。 (2) A is H, CH ₃ ,
Or a phenyl group which may have a substituent,
B is
And
C is -CONH-,
D is a phenyl group having a substituent, provided that it is not monosubstituted by a halogen atom, CN, CH ₃ , CH ₂ OH, COOH, COOCH ₃ and COOC ₂ H ₅ , OCH ₃ and OCH ₃ , OCH ₃ and CH ₃ , OCH ₃ and Cl, OH and phenyl groups having no substituents, and not substituted with Br and CH ₃ and trisubstituted with OCH ₃ ,
The compound or its salt as described in said (1).

（３）Ａが、Ｈ、ＣＨ_３、
またはフェニル基であり、フェニル基の１個のＨは、ハロゲン原子、ＣＮ、直鎖状のアルキル基、ハロゲノアルキル基またはハロゲノアルコキシ基により置き換えられていてもよく、
Ｂが、
であり、
Ｃが、−ＣＯＮＨ−であり、
Ｄが、フェニル基であり、２個のＨはそれぞれ独立して、ハロゲン原子、アルコキシ基、アルコキシカルボニル基、ハロゲノアルキル基またはＣＮにより置き換えられていてもよく、ＯＣＨ_３およびＯＣＨ_３、ＯＣＨ_３およびＣｌで二置換されない、
上記（１）または（２）に記載の化合物またはその塩。 (3) A is H, CH ₃ ,
Or a phenyl group, and one H of the phenyl group may be replaced by a halogen atom, CN, a linear alkyl group, a halogenoalkyl group or a halogenoalkoxy group,
B is
And
C is -CONH-,
D is a phenyl group, and each of two H may be independently replaced by a halogen atom, an alkoxy group, an alkoxycarbonyl group, a halogenoalkyl group or CN, OCH ₃ and OCH ₃ , OCH ₃ and Not disubstituted with Cl,
The compound or its salt as described in said (1) or (2).

（４）Ａが、Ｈ、ＣＨ_３、
またはフェニル基であり、フェニル基の１個のＨは、Ｆ、ＣＮ、ＣＨ_３、ＣＦ_３またはＯＣＦ_３基により置き換えられていてもよく、
Ｂが、
であり、
Ｃが、−ＣＯＮＨ−であり、
Ｄが、フェニル基であり、２個のＨはそれぞれ独立して、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＣＨ_３、ＣＯＯＣＨ_３、ＣＦ_３またはＣＮにより置き換えられていてもよく、ＯＣＨ_３およびＯＣＨ_３、ＯＣＨ_３およびＣｌで二置換されない、
上記（１）〜（３）のいずれかに記載の化合物またはその塩。 (4) A is H, CH ₃ ,
Or a phenyl group, wherein one H of the phenyl group may be replaced by F, CN, CH ₃ , CF ₃ or OCF ₃ group,
B is
And
C is -CONH-,
D is a phenyl group, and each of two H may be independently replaced by F, Cl, Br, I, OCH ₃ , COOCH ₃ , CF ₃ or CN, OCH ₃ and OCH ₃ , Not disubstituted with OCH ₃ and Cl,
The compound or its salt in any one of said (1)-(3).

（５）Ａが、置換基を有していてもよい単環のＮを含む複素芳香環であり、
Ｂが、
であり、
Ｃが、−ＣＯＮＨ−、−ＣＯＮ（ＣＨ_３）−または
であり、
Ｄが、置換基を有していてもよいフェニル基または単環のＮもしくはＳを含む複素芳香環であり、
あるいは、
ＣおよびＤが共に、置換基を有していてもよい
を形成する、
上記（１）に記載の化合物またはその塩。 (5) A is a heteroaromatic ring containing a single ring N which may have a substituent,
B is
And
C is, -CONH -, - CON (CH 3) - or
And
D is a phenyl group which may have a substituent or a heteroaromatic ring containing a single ring of N or S,
Or
Both C and D may have a substituent
Form
The compound or its salt as described in said (1).

（６）Ａが、置換基を有していてもよいピリジル基またはピラジル基であり、
Ｂが、
であり、
Ｃが、−ＣＯＮＨ−、−ＣＯＮ（ＣＨ_３）−または
であり、
Ｄが、置換基を有していてもよいフェニル基、ピリジル基またはチオフェニル基であり、
あるいは、
ＣおよびＤが共に、置換基を有していてもよい
を形成する、
上記（１）または（５）に記載の化合物またはその塩。 (6) A is a pyridyl or pyrazyl group which may have a substituent,
B is
And
C is, -CONH -, - CON (CH 3) - or
And
D is a phenyl group which may have a substituent, a pyridyl group or a thiophenyl group,
Or
Both C and D may have a substituent
Form
The compound or its salt as described in said (1) or (5).

（７）Ａが、ピリジル基またはピラジル基であり、１個または２個以上のＨはそれぞれ独立して、ハロゲン原子、アミノ基、ＣＮ、直鎖状または分枝状のアルキル基、アルコキシ基、ハロゲノアルキル基、ハロゲノアルコキシ基、ヒドロキシアルキル基または直鎖状または分枝状のアルキルアミド基により置き換えられていてもよく、また、環中の１個のＮがＮ−オキシドであってもよく、
Ｂが、
であり、
Ｃが、−ＣＯＮＨ−、−ＣＯＮ（ＣＨ_３）−または
であり、
Ｄが、フェニル基、
であり、１個または２個以上のＨはそれぞれ独立して、ハロゲン原子、アミノ基、ＣＮ、直鎖状または分枝状のアルキル基、アルコキシ基、ハロゲノアルキル基またはハロゲノアルコキシ基、フェニル基、−ＮＨＣＯ−Ｘ、−ＳＯ−Ｘ、−ＣＯＯ−Ｘ、−ＯＣＯ−Ｘあるいは−Ｏ−Ｘにより置き換えられていてもよく、
Ｘは、直鎖状または分枝状アルキル基またはアルコキシ基あるいはフェニル基であり、アルキル基の末端は、ヒドロキシ基、−ＮＨＣＯ−Ｙ、−ＯＣＯ−Ｙ、５もしくは６員環からなる炭素原子のみの単素環基あるいは窒素原子、酸素原子および／または硫黄原子を含有する複素環基（該複素環基の１個または２個以上のＨは、Ｙにより置換されていてもよい）でもよく、
Ｙは、ハロゲン原子、直鎖状または分枝状のアルキル基またはアルコキシ基、−ＣＯ−Ｚあるいは−ＣＨ_２ＮＨＣＯ−Ｚであり、アルキル基の末端は、窒素原子に結合する１個または２個以上のＨが直鎖状または分枝状のアルキル基で置換されたアルキルアミノ基でもよく、
Ｚは、直鎖状または分枝状のアルコキシ基であり、
あるいは、
ＣおよびＤが共に、
を形成し、１個または２個以上のＨはそれぞれ独立して、ハロゲン原子、アミノ基、ヒドロキシ基、直鎖状または分枝状のアルキル基、アルケニル基、アルコキシ基、ハロゲノアルキル基、ハロゲノアルコキシ基、アルキルチオ基、ヒドロキシアルキル基または窒素原子に結合するＨが直鎖状または分枝状のアルキル基で置換されたアルキルアミド基、−ＣＯ−Ｒ、−Ｏ−Ｒ、−ＮＨＣＯ−Ｒあるいは―Ｌ―Ｍから選ばれる１個または２個以上の置換基により置き換えられてよく、
Ｌは、単結合、直鎖状または分枝状のアルキル基であり、
Ｍは、５〜７員環からなる窒素原子、酸素原子および／または硫黄原子を含有する単環、縮合環および架橋の複素環基であり、環を構成する硫黄原子はＳＯ_２であってもよく、環を構成する炭素原子の１つはＣ＝Ｏであってもよく、１個または２個以上のＨはそれぞれ独立して、直鎖状または分枝状のアルキル基（アルキル基の末端は、アルコキシ基、ジアルキルアミノ基または直鎖状もしくは分枝状のアルキル基が結合したシリル基で置換されていてもよい）またはアルコキシ基、−ＣＯ−Ｗ、−ＮＨＣＯ−Ｗまたは−ＣＯＮＨ−Ｗ、アミノ基、Ｈがハロゲン原子またはジアルキルアミノ基に置換されてもよい直鎖状または分枝状のアルキル基またはアルケニル基が結合したスルホニル基、あるいは非置換もしくは置換の６員環からなる窒素原子、酸素原子および／または硫黄原子を含有する複素環基により置き換えられてよく、
Ｒは、直鎖状または分枝状のアルキル基（アルキル基の末端は、直鎖状または分枝状のアルキル基で置換されたアルキルアミノ基あるいは非置換もしくは置換の６員環からなる窒素原子、酸素原子および／または硫黄原子を含有する複素環基でもよく、該複素環基の１個または２個以上のＨは、直鎖状または分枝状のアルキル基が結合したアルコキシ基を有するカルボニル基に置換されていてもよい）またはアルコキシ基、あるいは直鎖状または分枝状のアルキル基が結合したシリル基であり、
Ｗは、直鎖状または分枝状のアルキル基（アルキル基の末端は、アルコキシ基、アミノ基、ジアルキルアミノ基、直鎖状または分枝状のアルキルアミド基またはアルコキシアミド基、非置換の５または６員環からなる窒素原子、酸素原子および／または硫黄原子を含有する複素環基で置換されていてもよい）またはアルコキシ基、非置換もしくは置換の４または６員環からなる窒素原子、酸素原子および／または硫黄原子を含有する複素環基（該複素環基のＨは、直鎖状または分枝状のアルコキシ基を有するカルボニル基に置換されていてもよい）である、
上記（１）または（５）〜（６）のいずれかに記載の化合物またはその塩。 (7) A is a pyridyl group or a pyrazyl group, and one or more H atoms are each independently a halogen atom, an amino group, CN, a linear or branched alkyl group, an alkoxy group, It may be replaced by a halogenoalkyl group, a halogenoalkoxy group, a hydroxyalkyl group or a linear or branched alkylamide group, and one N in the ring may be an N-oxide,
B is
And
C is, -CONH -, - CON (CH 3) - or
And
D is a phenyl group,
And one or more H's are each independently a halogen atom, an amino group, CN, a linear or branched alkyl group, an alkoxy group, a halogenoalkyl group or a halogenoalkoxy group, a phenyl group, -NHCO-X, -SO-X, -COO-X, -OCO-X or -O-X may be substituted,
X is a linear or branched alkyl group, an alkoxy group or a phenyl group, and the terminal of the alkyl group is only a carbon atom consisting of a hydroxy group, -NHCO-Y, -OCO-Y or a 5- or 6-membered ring Or a heterocyclic group containing a nitrogen atom, an oxygen atom and / or a sulfur atom (one or more of H in the heterocyclic group may be substituted by Y),
Y is a halogen atom, a linear or branched alkyl group or an alkoxy group, -CO-Z or -CH ₂ NHCO-Z, and the end of the alkyl group is one or two bonded to a nitrogen atom The above H may be an alkylamino group substituted with a linear or branched alkyl group,
Z is a linear or branched alkoxy group,
Or
C and D both
And one or more H's are each independently a halogen atom, an amino group, a hydroxy group, a linear or branched alkyl group, an alkenyl group, an alkoxy group, a halogenoalkyl group, a halogenoalkoxy Alkylamido group in which H bonded to a group, alkylthio group, hydroxyalkyl group or nitrogen atom is substituted with a linear or branched alkyl group, -CO-R, -O-R, -NHCO-R or- May be replaced by one or more substituents selected from LM;
L is a single bond, a linear or branched alkyl group,
M is a 5-, 7-, or 7-membered nitrogen atom, a single ring containing an oxygen atom and / or a sulfur atom, a fused ring, and a crosslinked heterocyclic group, and the sulfur atom constituting the ring is SO ₂ Preferably, one of the carbon atoms constituting the ring may be C = O, and one or more H's are each independently a linear or branched alkyl group (terminal of alkyl group Is optionally substituted by an alkoxy group, a dialkylamino group or a silyl group to which a linear or branched alkyl group is bonded) or an alkoxy group, -CO-W, -NHCO-W or -CONH-W , An amino group, a sulfonyl group in which H is a halogen atom or a linear or branched alkyl group or alkenyl group which may be substituted, or an unsubstituted or substituted 6-membered ring It may be replaced by a heterocyclic group containing an atomic atom, an oxygen atom and / or a sulfur atom,
R represents a linear or branched alkyl group (the end of the alkyl group is an alkylamino group substituted with a linear or branched alkyl group or a nitrogen atom consisting of an unsubstituted or substituted 6-membered ring And a heterocyclic group containing an oxygen atom and / or a sulfur atom, and one or more of H in the heterocyclic group have a carbonyl having an alkoxy group to which a linear or branched alkyl group is bonded. A group which may be substituted) or an alkoxy group, or a silyl group to which a linear or branched alkyl group is bonded,
W represents a linear or branched alkyl group (the end of the alkyl group is alkoxy, amino, dialkylamino, linear or branched alkylamido or alkoxyamido, unsubstituted 5 Or a 6-membered nitrogen atom, optionally substituted by a heterocyclic group containing an oxygen atom and / or a sulfur atom), an alkoxy group, an unsubstituted or substituted 4- or 6-membered ring nitrogen atom, oxygen A heterocyclic group containing an atom and / or a sulfur atom (H in the heterocyclic group may be substituted by a carbonyl group having a linear or branched alkoxy group),
The compound or salt thereof according to any of the above (1) or (5) to (6).

（８）Ａが、ピリジル基またはピラジル基であり、１個または２個以上のＨはそれぞれ独立して、ＣＨ_３、ＯＣＨ_３、ＣＮ、ＣＦ_３、ＯＣＦ_３、ＮＨ_２、ＣＨ_２ＯＨ、ＮＨＣＯＣＨ_３により置き換えられていてもよく、または、環中の１個のＮがＮ−オキシドであってもよく、
Ｂが、
であり、
Ｃが、−ＣＯＮＨ−、−ＣＯＮ（ＣＨ_３）−または
であり、
Ｄが、置換フェニル基あるいは非置換または置換
であり、１個または２個以上のＨはそれぞれ独立して、Ｆ、Ｃｌ、Ｉ、Ｂｒ、ＯＨ、ＣＦ_３、ＯＣＨＦ_２、ＯＣＦ_３、ＣＮ、ＮＨ_２、Ｔ−フェニル基（Ｔは、単結合、−Ｏ−、−ＯＣＯ−、−ＮＨＣＯ−である）、あるいはＣ１〜１０の直鎖状または分枝状アルキル基により置き換えられてもよく、前記アルキル基中に存在する１個または２個以上のＣＨ_２基はそれぞれ独立して、−ＣＯＯ−、−ＯＣＯ−、−Ｏ−、−ＳＯ−、−ＮＨ−、
で置き換えられてもよく、前記アルキル基またはアルケニル基の末端のＣＨ_３基は、ＯＨ、ＮＨ_２、Ｎ（ＣＨ_３）_２、Ｎ（Ｃ_３Ｈ_７）_２、
で置き換えられてもよく、末端の
の１個のＨは、Ｆで置き換えられてもよく、
あるいは、
ＣおよびＤが共に、
を形成し、１個または２個以上のＨはそれぞれ独立して、Ｆ、Ｃｌ、Ｂｒ、ＯＨ、ＣＦ_３、ＯＣＦ_３、ＯＣ_２Ｈ_３、ＮＨ_２、
あるいはＣ１〜９の直鎖状または分枝状アルキル基またはアルケニル基により置き換えられてもよく、前記アルキル基またはアルケニル基中に存在する１個または２個以上のＣＨ_２基はそれぞれ独立して、−ＣＯＯ−、−ＣＯ−、−Ｏ−、−Ｓ−、−ＳＯ_２−、−ＮＨ−、−Ｓｉ（ＣＨ_３）_２−、
で置き換えられてもよく、前記アルキル基の末端のＣＨ_３基は、Ｃｌ、ＯＨ、ＮＨ_２、Ｎ（ＣＨ_３）_２、
で置き換えられてもよい、
上記（１）または（５）〜（７）のいずれかに記載の化合物またはその塩。 (8) A is a pyridyl group or a pyrazyl group, and one or more Hs are each independently CH ₃ , OCH ₃ , CN, CF ₃ , OCF ₃ , NH ₂ , CH ₂ OH, NHCOCH May be replaced by ₃ or one N in the ring may be N-oxide,
B is
And
C is, -CONH -, - CON (CH 3) - or
And
D is a substituted phenyl group or unsubstituted or substituted
And one or more H's are each independently F, Cl, I, Br, OH, CF ₃ , OCHF ₂ , OCF ₃ , CN, NH ₂ , T-phenyl group (T is A bond, -O-, -OCO-, -NHCO-), or C1-10 linear or branched alkyl group, which may be replaced by one or two of them in the alkyl group The above CH ₂ groups are each independently -COO-, -OCO-, -O-, -SO-, -NH-,
And the terminal CH ₃ group of the alkyl group or the alkenyl group is OH, NH ₂ , N (CH ₃ ) ₂ , N (C ₃ H ₇ ) ₂ ,
May be replaced by
One H of may be replaced by F,
Or
C and D both
And one or more H's are each independently F, Cl, Br, OH, CF ₃ , OCF ₃ , OC ₂ H ₃ , NH ₂ ,
Alternatively, it may be replaced by a C 1-9 linear or branched alkyl group or alkenyl group, and one or more CH ₂ groups present in the alkyl group or alkenyl group are each independently -COO-, -CO-, -O-, -S-, -SO _2- , -NH-, -Si (CH ₃ ) _2- ,
And the terminal CH ₃ group of the alkyl group may be Cl, OH, NH ₂ , N (CH ₃ ) ₂ ,
May be replaced by
The compound or salt thereof according to any one of the above (1) or (5) to (7).

（９）以下のものから選択される化合物又はその塩：
N-(5-クロロ-2-シアノフェニル)-3-フェニルプロピオールアミド、
N-(5-フルオロ-2-メトキシフェニル)-3-フェニルプロピオールアミド、
N-(5-ヨード-2-メトキシフェニル)-3-フェニルプロピオールアミド、
ジメチル2-(3-(p-トルイル)プロピオールアミド)テレフタレート、
ジメチル 2-(3-(m-トルイル)プロピオールアミド)テレフタレート、
N-(5-ブロモ-2-メトキシフェニル)-3-(ナフタレン-1-イル)プロピオールアミド、
ジメチル 2-(3-(4-シアノフェニル)プロピオールアミド)テレフタレート、
ジメチル 2-(3-(2-シアノフェニル)プロピオールアミド)テレフタレート、
N-(5-ブロモ-2-メトキシフェニル)-3-(2-(トリフルオロメチル)フェニル)プロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(4-(トリフルオロメチル)フェニル)プロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(4-(トリフルオロメトキシ)フェニル)プロピオールアミド、
N-(2-メトキシ-5-(トリフルオロメチル)フェニル)-3-フェニルプロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(2-シアノフェニル)プロピオールアミド、
N-(5-ブロモ-2-シアノフェニル)-3-フェニルプロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(2-フルオロフェニル)プロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-3-イル)プロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-4-イル)プロピオールアミド、
ジメチル 2-(3-(ピリジン-3-イル)プロピオールアミド)テレフタレート、
ジメチル 2-(3-(ピリジン-2-イル)プロピオールアミド)テレフタレート、
N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-2-イル)プロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(ピラジン-2-イル)プロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(2-メトキシピリジン-3-イル)プロピオールアミド、
3-(3-((5-ブロモ-2-メトキシフェニル)アミノ)-3-オキソプロピ-1-イン-1-イル)ピリジン 1-オキシド、
N-(5-フルオロ-2-メトキシフェニル)-3-(ピリジン-3-イル)プロピオールアミド、
N-(5-フルオロ-2-メトキシフェニル)-3-(ピリジン-4-イル)プロピオールアミド、
3-(6-アセトアミドピリジン-3-イル)-N-(5-ブロモ-2-メトキシフェニル)プロピオールアミド、
3-(6-アミノピリジン-3-イル)-N-(5-ブロモ-2-メトキシフェニル)プロピオールアミド、
N-(2-メトキシ-5-(トリフルオロメチル)フェニル)-3-(ピリジン-3-イル)プロピオールアミド、
N-(4-メトキシ-[1,1'-ビフェニル]-3-イル)-3-(ピリジン-3-イル)プロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-3-(6-メトキシピリジン-3-イル)プロピオールアミド、
N-(5-ブロモ-2-メトキシフェニル)-N-メチル-3-(ピリジン-3-イル)プロピオールアミド、
4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
5-フルオロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
5-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
2-(ピリジン-3-イルエチニル)オキサゾロ[4,5-b]ピリジン、
4-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
2-(ピリジン-3-イルエチニル)-5-(トリフルオロメチル)ベンゾ[d]オキサゾール、
2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-アミン、
7-フルオロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
7-ブロモ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
7-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-(メチルチオ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-((ターシャリーブチルジメチルシリル)オキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-オール、
7-((ターシャリーブチルジメチルシリル)オキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-オール、
4-モルホリノ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
ターシャリーブチル 2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシレート、
メチル 2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシレート、
(2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)メタノール、
ターシャリーブチル ((2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)メチル)カルバメート、
7-ブロモ-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
ターシャリーブチル 2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-カルボキシレート、
(2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)メタノール、
4-メトキシ-7-モルホリノ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
ターシャリーブチル 4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボキシレート、
4-メトキシ-7-(4-(2-メトキシエチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩、
4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)チオモルホリン 1,1-ジオキシド、
ターシャリーブチル (1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-イル)カルバメート、
1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-アミントリフルオロ酢酸塩、
ターシャリーブチル 4-(2-((2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレート、
7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩、
7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-メトキシ-7-(4-モルホリノピペリジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-オン、
4-ブロモ-7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
ターシャリーブチル 4-(7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)ピペラジン-1-カルボキシレート、
4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
ターシャリーブチル 4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)-1,4-ジアゼパン-1-カルボキシレート、
4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
7-(1,4-ジアゼパン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩、
2-(4-(7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)ピペラジン-1-イル)-N,N-ジメチルエタンアミン塩酸塩、
7-(1,4-ジアゼパン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-アミン塩酸塩、
4-メトキシ-7-(4-(2-メトキシエチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
ターシャリーブチル (2-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-オキソエチル)カルバメート、
2-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)エタノン塩酸塩、
2-アミノ-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)エタノン塩酸塩、
4-メトキシ-7-(モルホリノメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
ターシャリーブチル 4-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボニル)ピペリジン-1-カルボキシレート、
(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)(ピペリジン-4-イル)メタノン、
4-メトキシ-7-(モルホリノメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)(ピペリジン-4-イル)メタノン塩酸塩、
1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピペリジン-1-イル)エタノン、
3-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)プロパン-1-オン、
7-(2-(4-メチルピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピペリジン-1-イル)エタノン塩酸塩、
3-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)プロパン-1-オン塩酸塩、
ターシャリーブチル 4-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)メチル)ピペラジン-1-カルボキシレート、
4-メトキシ-7-(4-(メチルスルホニル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
ターシャリーブチル 3-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボニル)アゼチジン-1-カルボキシレート、
4-メトキシ-7-(ピペラジン-1-イルメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-メトキシ-7-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-メトキシ-7-(ピペラジン-1-イルメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
アゼチジン-3-イル(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)メタノン塩酸塩、
1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピロリジン-1-イル)エタノン、
ターシャリーブチル 4-(2-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレート、
1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピロリジン-1-イル)エタノン塩酸塩、
4-メトキシ-7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-メトキシ-7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
7-(4-((クロロメチル)スルホニル)ピペラジン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
ターシャリーブチル 5-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-カルボキシレート、
4-メトキシ-2-(ピリジン-3-イルエチニル)-7-(4-(ビニルスルホニル)ピペラジン-1-イル)ベンゾ[d]オキサゾール、
2-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-N,N-ジメチルエタンアミン、
2-((4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)スルホニル)-N,N-ジメチルエタンアミン、
2-((4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)スルホニル)-N,N-ジメチルエタンアミン塩酸塩、
7-ブロモ-4-メトキシ-2-(ピリジン-4-イルエチニル)ベンゾ[d]オキサゾール、
2-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)-N,N-ジメチルエタンアミン、
4-メトキシ-7-(2-(ピペリジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-メトキシ-7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4,7-ジメトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
7-ブロモ-4-エトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
7-ブロモ-4-イソプロポキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-メトキシ-7-(2-(ピペリジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
4-メトキシ-7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩、
4-メトキシ-7-(4-(2-(メチルスルホニル)エチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール、
4-メトキシ-2-(ピリジン-3-イルエチニル)-7-チオモルホリノベンゾ[d]オキサゾール、
4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-5,7-ジアミン、
4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン、
4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-5-アミン、
3-(ジメチルアミノ)-N-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)プロパンアミド、
4-メトキシ-N,N-ジメチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン、
4-メトキシ-N-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン、
7-ブロモ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-オール、
N-(2-(ジメチルアミノ)エチル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシアミド、
(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)(4-メチルピペラジン-1-イル)メタノン、
2-(2-メトキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(5-ブロモ-2-メトキシフェニル)-5-(ピリジン-3-イルエチンイル)-1,3,4-オキサジアゾール、
2-(5-ブロモ-2-(トリフルオロメチル)フェニル)-5-(ピリジン-3-イルエチンイル)-1,3,4-オキサジアゾール、
2-(ピリジン-3-イルエチニル)-5-(2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾール、
2-(2-エチルフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(ピリジン-3-イルエチニル)-5-(2-(トリフルオロメチル)フェニル)-1,3,4-オキサジアゾール、
2-(2-(ベンジルオキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)ベンゾニトリル、
2-(2-((4-フルオロベンジル)オキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(シクロヘキシルメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-フェノキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(3-(ベンジルオキシ)ピリジン-2-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(ベンジルオキシ)-5-クロロフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(ベンジルオキシ)-5-フルオロフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(ベンジルオキシ)-6-フルオロフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(ピリジン-2-イルメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(ピリジン-3-イルエチニル)-5-(2-(チオフェン-2-イルメトキシ)フェニル)-1,3,4-オキサジアゾール、
2-(3-(ベンジルオキシ)チオフェン-2-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(ベンジルスルフィニル)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(ベンジルオキシ)ピリジン-3-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニルベンゾエート、
2-(2-ブロモフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
N-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニル)ベンズアミド、
2-(2-フェネトキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(5-ブロモ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(ジフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(5-クロロ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(5-フルオロ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(3-(ジフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
ターシャリーブチル (2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニル)カルバメート、
2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)アニリン、
(5-((5-(2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾール-2-イル)エチニル)ピリジン-2-イル)メタノール、
ターシャリーブチル (2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)カルバメート、
4-(2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)モルホリン、
2-(2-(2-(ピペリジン-1-イル)エトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール、
2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチルアセテート、
ターシャリーブチル 4-(2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)ピペラジン-1-カルボキシレート、
2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エタノール、
ターシャリーブチル 4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)ベンジルカルバメート、
(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)フェニル)メタンアミン、
N,N-ジメチル-1-(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)フェニル)メタンアミン、
N-プロピル-N-(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)ベンジル)プロパン-1-アミン、
ジメチル 2-プロピオールアミドテレフタレート、
ジメチル2-(ブチ-2-イナミド)テレフタレート、
5-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]チアゾール、
ターシャリーブチル 2-(ピリジン-3-イルエチニル)-1H-ベンゾ[d]イミダゾール-1-カルボキシレート、
4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]チアゾール、
2-(ピリジン-3-イルエチニル)-1H-ベンゾ[d]イミダゾール。 (9) A compound selected from the following or a salt thereof:
N- (5-chloro-2-cyanophenyl) -3-phenylpropiolamide,
N- (5-Fluoro-2-methoxyphenyl) -3-phenylpropiolamide,
N- (5-iodo-2-methoxyphenyl) -3-phenylpropiolamide,
Dimethyl 2- (3- (p-toluyl) propiolamide) terephthalate,
Dimethyl 2- (3- (m-toluyl) propiolamide) terephthalate,
N- (5-bromo-2-methoxyphenyl) -3- (naphthalen-1-yl) propiolamide,
Dimethyl 2- (3- (4-cyanophenyl) propiolamide) terephthalate,
Dimethyl 2- (3- (2-cyanophenyl) propiolamide) terephthalate,
N- (5-bromo-2-methoxyphenyl) -3- (2- (trifluoromethyl) phenyl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (4- (trifluoromethyl) phenyl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (4- (trifluoromethoxy) phenyl) propiolamide,
N- (2-methoxy-5- (trifluoromethyl) phenyl) -3-phenylpropiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (2-cyanophenyl) propiolamide,
N- (5-bromo-2-cyanophenyl) -3-phenylpropiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (2-fluorophenyl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (pyridin-3-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (pyridin-4-yl) propiolamide,
Dimethyl 2- (3- (pyridin-3-yl) propiolamide) terephthalate,
Dimethyl 2- (3- (pyridin-2-yl) propiolamide) terephthalate,
N- (5-bromo-2-methoxyphenyl) -3- (pyridin-2-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (pyrazin-2-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (2-methoxypyridin-3-yl) propiolamide,
3- (3-((5-bromo-2-methoxyphenyl) amino) -3-oxoprop-1-yn-1-yl) pyridine 1-oxide,
N- (5-Fluoro-2-methoxyphenyl) -3- (pyridin-3-yl) propiolamide,
N- (5-fluoro-2-methoxyphenyl) -3- (pyridin-4-yl) propiolamide,
3- (6-acetamidopyridin-3-yl) -N- (5-bromo-2-methoxyphenyl) propiolamide,
3- (6-Aminopyridin-3-yl) -N- (5-bromo-2-methoxyphenyl) propiolamide,
N- (2-methoxy-5- (trifluoromethyl) phenyl) -3- (pyridin-3-yl) propiolamide,
N- (4-Methoxy- [1,1'-biphenyl] -3-yl) -3- (pyridin-3-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (6-methoxypyridin-3-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -N-methyl-3- (pyridin-3-yl) propiolamide,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) benzo [d] oxazole,
5-fluoro-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
5-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) oxazolo [4,5-b] pyridine,
4-Methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) -5- (trifluoromethyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-amine,
7-Fluoro-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-bromo-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-Methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4- (methylthio) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-((tert-butyldimethylsilyl) oxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-ol,
7-((tert-butyldimethylsilyl) oxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) benzo [d] oxazol-7-ol,
4-morpholino-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tertiary butyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxylate,
Methyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxylate,
(2- (Pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) methanol,
Tertiary butyl ((2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) methyl) carbamate,
7-bromo-4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert.-butyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-4-carboxylate,
(2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) methanol,
4-methoxy-7-morpholino-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carboxylate,
4-methoxy-7- (4- (2-methoxyethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate,
4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) thiomorpholine 1,1-dioxide,
Tert-butyl (1- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-yl) carbamate
1- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-amine trifluoroacetate salt,
Tert-butyl 4- (2-((2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate,
7- (2- (Piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate,
7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7- (4-morpholinopiperidin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
1- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-one,
4-bromo-7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 4- (7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazine-1-carboxylate,
4-methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) -1,4-diazepane-1-carboxylate,
4-Methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
7- (1,4-diazepan-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate,
2- (4- (7-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazin-1-yl) -N, N-dimethylethanamine hydrochloride,
7- (1,4-diazepan-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
1- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-amine hydrochloride,
4-methoxy-7- (4- (2-methoxyethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
7- (2- (Piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
Tert-butyl (2- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2-oxoethyl) carbamate
2- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone hydrochloride,
2-Amino-1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone hydrochloride,
4-methoxy-7- (morpholinomethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 4- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carbonyl) piperidine-1-carboxylate,
(4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) (piperidin-4-yl) methanone,
4-Methoxy-7- (morpholinomethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
(4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) (piperidin-4-yl) methanone hydrochloride,
1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (piperidin-1-yl) ethanone,
3- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) propan-1-one,
7- (2- (4-Methylpiperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (piperidin-1-yl) ethanone hydrochloride,
3- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) propan-1-one hydrochloride,
Tert-butyl 4-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) methyl) piperazine-1-carboxylate,
4-methoxy-7- (4- (methylsulfonyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 3- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carbonyl) azetidine-1-carboxylate,
4-methoxy-7- (piperazin-1-ylmethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7-((4- (methylsulfonyl) piperazin-1-yl) methyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7- (piperazin-1-ylmethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
Azetidin-3-yl (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) methanone hydrochloride,
1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (pyrrolidin-1-yl) ethanone,
Tert-butyl 4- (2-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate,
1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (pyrrolidin-1-yl) ethanone hydrochloride,
4-methoxy-7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-Methoxy-7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
7- (4-((chloromethyl) sulfonyl) piperazin-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 5- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate,
4-methoxy-2- (pyridin-3-ylethynyl) -7- (4- (vinylsulfonyl) piperazin-1-yl) benzo [d] oxazole,
2- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -N, N-dimethylethanamine,
2-((4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) sulfonyl) -N, N-dimethylethanamine,
2-((4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) sulfonyl) -N, N-dimethylethanamine hydrochloride,
7-bromo-4-methoxy-2- (pyridin-4-ylethynyl) benzo [d] oxazole,
2-((4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) -N, N-dimethylethanamine,
4-methoxy-7- (2- (piperidin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4,7-Dimethoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-Bromo-4-ethoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-bromo-4-isopropoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-Methoxy-7- (2- (piperidin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
4-methoxy-7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
4-methoxy-7- (4- (2- (methylsulfonyl) ethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-2- (pyridin-3-ylethynyl) -7-thiomorpholinobenzo [d] oxazole,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-5,7-diamine,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-amine,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-5-amine,
3- (dimethylamino) -N- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) propanamide,
4-methoxy-N, N-dimethyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-amine,
4-Methoxy-N-methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-amine,
7-Bromo-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-ol,
N- (2- (dimethylamino) ethyl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxamide,
(4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) (4-methylpiperazin-1-yl) methanone,
2- (2-methoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-bromo-2-methoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-bromo-2- (trifluoromethyl) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (Pyridin-3-ylethynyl) -5- (2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole,
2- (2-ethylphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (Pyridin-3-ylethynyl) -5- (2- (trifluoromethyl) phenyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) benzonitrile,
2- (2-((4-fluorobenzyl) oxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (Cyclohexylmethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2-Phenoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (3- (benzyloxy) pyridin-2-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) -5-chlorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) -5-fluorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) -6-fluorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (Pyridin-2-ylmethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (Pyridin-3-ylethynyl) -5- (2- (thiophen-2-ylmethoxy) phenyl) -1,3,4-oxadiazole,
2- (3- (benzyloxy) thiophen-2-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzylsulfinyl) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) pyridin-3-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl benzoate,
2- (2-bromophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
N- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl) benzamide,
2- (2-phenethoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-bromo-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (Difluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-chloro-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-fluoro-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (3- (Difluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
Tertiary butyl (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl) carbamate,
2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) aniline,
(5-((5- (2- (Trifluoromethoxy) phenyl) -1,3,4-oxadiazol-2-yl) ethynyl) pyridin-2-yl) methanol,
Tert-butyl (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) carbamate
4- (2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) morpholine,
2- (2- (2- (Piperidin-1-yl) ethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl acetate,
Tert-butyl 4- (2- (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) piperazine-1-carboxylate,
2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethanol;
Tert-butyl 4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) benzyl carbamate,
(4-((2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) phenyl) methanamine,
N, N-Dimethyl-1- (4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) phenyl) methanamine,
N-propyl-N- (4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) benzyl) propan-1-amine;
Dimethyl 2-propiolamide terephthalate,
Dimethyl 2- (but-2-ynamide) terephthalate,
5-methoxy-2- (pyridin-3-ylethynyl) benzo [d] thiazole,
Tert-butyl 2- (pyridin-3-ylethynyl) -1H-benzo [d] imidazole-1-carboxylate,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] thiazole,
2- (Pyridin-3-ylethynyl) -1H-benzo [d] imidazole.

（１０）上記（１）〜（９）のいずれかに記載の化合物またはその塩を１種または２種以上含む、ZNF143阻害剤。
（１１）上記（１）〜（９）のいずれかに記載の化合物またはその塩を１種または２種以上含む、抗癌剤。
（１２）上記（１）〜（９）のいずれかに記載の化合物またはその塩の１種または２種以上を有効成分とする医薬組成物。
（１３）がんの治療用である、上記（１２）に記載の医薬組成物。 (10) A ZNF143 inhibitor comprising one or more compounds of the above (1) to (9) or salts thereof.
(11) An anticancer agent comprising one or more compounds of the above (1) to (9) or a salt thereof.
(12) A pharmaceutical composition comprising as an active ingredient one or two or more of the compounds according to any one of the above (1) to (9) or salts thereof.
(13) The pharmaceutical composition according to (12), which is for the treatment of cancer.

本発明によれば、優れたZNF143阻害活性を有する化合物およびその塩を提供することができる。
本発明のZNF143阻害活性を有する化合物は、従来のZNF143特異的siRNAと異なり低分子であることから、化合物の製造および製剤化を容易に行うことができる。 According to the present invention, a compound having excellent ZNF143 inhibitory activity and a salt thereof can be provided.
The compounds having ZNF143 inhibitory activity of the present invention are small molecules unlike conventional ZNF143-specific siRNAs, so that the compounds can be easily manufactured and formulated.

本発明化合物のZNF143とSBSの相互作用阻害活性の試験結果を示す図である。It is a figure which shows the test result of the interaction inhibitory activity of ZNF143 of this invention compound and SBS. 本発明化合物によるZNF143標的遺伝子（BIRC5、PLK1およびRAD51）の発現抑制作用を示す図である。It is a figure which shows the expression suppression effect | action of ZNF143 target gene (BIRC5, PLK1 and RAD51) by this invention compound. 本発明化合物によるHCT116細胞のDNA断片量（アポトーシス誘導作用）を示す図である。It is a figure which shows the DNA fragment quantity (apoptosis induction effect | action) of HCT116 cell by this invention compound.

本発明のZNF143阻害活性を有する化合物の代表的な製造方法を、以下のスキーム１〜３に示す。当業者であれば、以下のスキームを適宜変更して、本発明の化合物を製造することができる。 Representative methods for producing the compounds having ZNF143 inhibitory activity of the present invention are shown in the following schemes 1 to 3. Those skilled in the art can appropriately modify the following scheme to produce the compound of the present invention.

（１）の工程において、化合物IIを溶媒に溶解し、そこへ触媒、化合物IIIおよび塩基を加え、攪拌することで化合物IVが得られる。
溶媒としては、極性溶媒を用いればよく、特にN,N-ジメチルホルムアミド(DMF)が好ましい。
触媒としては、通常、薗頭カップリングに用いられるパラジウムと銅を組み合わせた触媒を用いればよく、特にトリス(ジベンジリデンアセトン)パラジウムジクロライド(PdCl₂(dba)₃)、ヨウ化銅(I)(CuI)が好ましい。
触媒の使用量は、化合物IIに対して0.05〜0.1当量が好ましい。
塩基としては、無機塩やアミン類が挙げられ、特にトリエチルアミン(TEA)が好ましい。
塩基の使用量は、化合物IIに対して約0.5当量用いればよい。 In the step (1), the compound II is dissolved in a solvent, the catalyst, the compound III and the base are added thereto, and the compound IV is obtained by stirring.
As the solvent, a polar solvent may be used, and N, N-dimethylformamide (DMF) is particularly preferable.
As a catalyst, a catalyst combining palladium and copper generally used for Sonogashira coupling may be used, and tris (dibenzylideneacetone) palladium dichloride (PdCl ₂ (dba) ₃ ), copper iodide (I) (in particular, CuI) is preferred.
The amount of the catalyst used is preferably 0.05 to 0.1 equivalents relative to compound II.
Examples of the base include inorganic salts and amines, and triethylamine (TEA) is particularly preferable.
The amount of the base used may be about 0.5 equivalent to the compound II.

（２）の工程において、化合物IVを溶媒に溶解し、そこへクロロ化剤、触媒および化合物Vを加え、攪拌することで本発明の化合物である化合物VIが得られる。
溶媒としては、ハロゲン系溶媒、極性溶媒等が挙げられ、特にジクロロメタン(CH₂Cl₂)、DMFが好ましい。
クロロ化剤としては、特にオキサリルクロライド((COCl)₂)が好ましい。
クロロ化剤の使用量は、化合物IVに対して1.0〜1.5当量用いればよい。
触媒としては、少量のDMFが好ましい。 In the step (2), the compound IV is dissolved in a solvent, the chlorinating agent, the catalyst and the compound V are added thereto, and stirring is carried out to obtain the compound VI of the present invention.
Examples of the solvent include halogen solvents, polar solvents and the like, and dichloromethane (CH ₂ Cl ₂ ) and DMF are particularly preferable.
As the chlorinating agent, in particular, oxalyl chloride ((COCl) ₂ ) is preferable.
The amount of the chlorinating agent used may be 1.0 to 1.5 equivalents relative to compound IV.
As a catalyst, a small amount of DMF is preferred.

（３）の工程において、化合物VIIの溶液中に還元剤を加え、加熱し、攪拌することで化合物VIIIが得られる。
溶媒としては、アルコール系溶媒、極性溶媒等が挙げられ、特にH₂O、エタノール、テトラヒドロフラン(THF)、酢酸エチルが好ましい。
還元剤としては、特にパラジウム炭素(Pd/C)、塩化スズ(II)(SnCl₂)が好ましい。
反応時の温度は、パラジウム炭素を用いる場合は0℃から室温が好ましく、塩化スズ(II)を用いる場合は80〜100℃が好ましい。 In the step of (3), a reducing agent is added to the solution of compound VII, and heated and stirred to obtain compound VIII.
Examples of the solvent include alcohol solvents, polar solvents and the like, and H ₂ O, ethanol, tetrahydrofuran (THF) and ethyl acetate are particularly preferable.
In particular, palladium carbon (Pd / C) and tin (II) chloride (SnCl ₂ ) are preferable as the reducing agent.
The temperature at the time of reaction is preferably 0 ° C. to room temperature when using palladium carbon, and preferably 80 to 100 ° C. when using tin (II) chloride.

（４）の工程において、化合物VIIIの溶液中に酸触媒を加え、加熱し、攪拌することで化合物IXが得られる。
溶媒としては、オルトギ酸トリエチル(CH(OEt)₃)が好ましい。
溶媒の使用量は、化合物VIIIに対して6〜10当量用いるのがよい。
酸触媒としては、少量のパラトシル酸一水和物(TsOH H₂O)が好ましい。
反応時の温度は、約100℃が好ましい。 In the step (4), an acid catalyst is added to the solution of compound VIII, and heating and stirring give compound IX.
As a solvent, triethyl orthoformate (CH (OEt) ₃ ) is preferable.
The amount of solvent used is preferably 6 to 10 equivalents relative to compound VIII.
As an acid catalyst, a small amount of paratosyl acid monohydrate (TsOH H ₂ O) is preferred.
The reaction temperature is preferably about 100.degree.

（５）の工程において、化合物X、四臭化炭素(CBr₄)およびトリフェニルホスフィン(PPh3)を溶媒に溶解し、室温に昇温し、攪拌することで、化合物XIが得られる。
溶媒としては、ハロゲン系溶媒が挙げられ、特にクロロホルム、ジクロロメタンが好ましい。
トリフェニルホスフィンの使用量は、化合物Xに対して約2.2当量である。
四臭化炭素の使用量は、約1.1当量である。
反応時の温度は、約0℃から室温が好ましい。 In the step (5), compound X, carbon tetrabromide (CBr ₄ ) and triphenylphosphine (PPh 3) are dissolved in a solvent, and the mixture is warmed to room temperature and stirred to give compound XI.
Examples of the solvent include halogen solvents, and chloroform and dichloromethane are particularly preferable.
The amount of triphenylphosphine used is about 2.2 equivalents relative to compound X.
The amount of carbon tetrabromide used is about 1.1 equivalents.
The reaction temperature is preferably about 0 ° C. to room temperature.

（６）の工程において、化合物XIの溶液中に塩基を加え、室温に昇温し、攪拌することで、化合物XIIが得られる。
溶媒としては、極性溶媒等が挙げられ、特にTHFが好ましい。
塩基としては、無機塩等が挙げられ、特にカリウムターシャリーブトキシド(KO^tBu)が好ましい。
塩基の使用量は、約1当量である。
反応時の温度は0℃から室温が好ましい。 In the step (6), a base is added to the solution of compound XI, and the mixture is warmed to room temperature and stirred to give compound XII.
Examples of the solvent include polar solvents and the like, and THF is particularly preferable.
As a base, an inorganic salt etc. are mentioned, Especially potassium tertiary butoxide (KO ^t Bu) is preferable.
The amount of base used is about 1 equivalent.
The reaction temperature is preferably 0 ° C. to room temperature.

（７）の工程において、化合物IX、化合物XII、銅触媒、配位子および塩基を溶媒に溶解し、マイクロウェーブ照射下、加熱し、攪拌することで、本発明の化合物である化合物XIIIが得られる。
溶媒としては、1,4-ジオキサンが好ましい。
銅触媒としては、臭化銅ジメチルスルフィド錯体が好ましい。
銅触媒の使用量は、約0.1当量である。
配位子としては、特にビス［2-(ジフェニルホスフィノ)フェニル］エーテル(DPEPhos)が好ましい。
配位子の使用量は、約0.1当量である。
塩基としては、リチウムターシャリーブトキシド(LiO^tBu)が好ましい。
塩基の使用量は、約1〜2当量である。
反応時の温度は、特に、120℃が好ましい。 In the step (7), Compound IX, Compound XII, a copper catalyst, a ligand and a base are dissolved in a solvent, and heated and stirred under microwave irradiation to obtain Compound XIII, which is a compound of the present invention. Be
As a solvent, 1,4-dioxane is preferable.
As a copper catalyst, copper bromide dimethyl sulfide complex is preferable.
The amount of copper catalyst used is about 0.1 equivalent.
As the ligand, in particular, bis [2- (diphenylphosphino) phenyl] ether (DPEPhos) is preferable.
The amount of ligand used is about 0.1 equivalent.
As a base, lithium tertiary butoxide (LiO ^t Bu) is preferable.
The amount of base used is about 1 to 2 equivalents.
The temperature at the time of reaction is particularly preferably 120.degree.

（８）の工程において、化合物XIVを溶媒に懸濁し、そこへ（イソシアノイミノ）トリフェニルホスホランの溶液を加え、室温で攪拌することで、化合物XVが得られる。
溶媒としては、ハロゲン系溶媒等が挙げられ、特にジクロロメタンが好ましい。 In the step (8), the compound XIV is suspended in a solvent, a solution of (isocyanoimino) triphenylphosphorane is added thereto, and the mixture is stirred at room temperature to obtain a compound XV.
Examples of the solvent include halogen solvents and the like, and dichloromethane is particularly preferable.

（９）の工程において、化合物XII、化合物XV、銅触媒、配位子および塩基を溶媒に溶解し、マイクロウェーブ照射下、加熱し、攪拌することで、本発明の化合物である化合物XVIが得られる。使用される銅触媒、配位子、塩基および溶媒の種類と使用量ならびに反応条件は、（７）の工程と同一である。 In the step (9), the compound XII, the compound XV, the copper catalyst, the ligand and the base are dissolved in a solvent, and heated and stirred under microwave irradiation to obtain a compound XVI which is a compound of the present invention Be The type and amount of copper catalyst, ligand, base and solvent used and the reaction conditions used are the same as in step (7).

本発明はさらに、上記式（Ｉ）で表される化合物またはその塩を１種または２種以上含む、ZNF143阻害剤または医薬組成物に関する。
本発明のZNF143阻害剤または医薬組成物は、本発明の化合物を含む限り特に制限はされない。本発明の化合物またはその塩は、少なくとも１種含まれていればよく、２種以上含まれていてもよい。
本発明の医薬組成物は、特にがんを処置するのに有効である。したがって、本発明はさらに、がんの治療用である上記医薬組成物に関する。 The present invention further relates to a ZNF143 inhibitor or pharmaceutical composition comprising one or more compounds represented by the above formula (I) or salts thereof.
The ZNF143 inhibitor or pharmaceutical composition of the present invention is not particularly limited as long as it contains the compound of the present invention. The compound of the present invention or a salt thereof may be contained at least one kind, or two or more kinds.
The pharmaceutical composition of the present invention is particularly effective for treating cancer. Thus, the invention further relates to the above pharmaceutical composition for the treatment of cancer.

本発明の化合物の塩としては、塩酸、硫酸、リン酸、臭化水素酸、硝酸等の無機酸塩、酢酸、トリフルオロ酢酸、プロピオン酸、乳酸、リンゴ酸、クエン酸、フマル酸、シュウ酸、酒石酸、メタンスルホン酸、パラトルエンスルホン酸等の有機酸塩が挙げられ、塩酸塩およびトリフルオロ酢酸塩が好ましい。 As salts of the compounds of the present invention, inorganic acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, malic acid, citric acid, fumaric acid, oxalic acid And organic acid salts such as tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like, and hydrochloride and trifluoroacetate are preferable.

本発明におけるがんとしては、限定されずに、例えば、線維肉腫、悪性線維性組織球腫、脂肪肉腫、横紋筋肉腫、平滑筋肉腫、血管肉腫、カポジ肉腫、リンパ管肉腫、滑膜肉腫、軟骨肉腫、骨肉腫などの肉腫、脳腫瘍、頭頚部癌、乳癌、肺癌、食道癌、胃癌、十二指腸癌、虫垂癌、大腸癌、直腸癌、肝癌、膵癌、胆嚢癌、胆管癌、肛門癌、腎癌、尿管癌、膀胱癌、前立腺癌、陰茎癌、精巣癌、子宮癌、卵巣癌、外陰癌、膣癌、皮膚癌などの癌腫、さらには白血病や悪性リンパ腫などが挙げられる。なお、本発明では、「がん」は、上皮性悪性腫瘍および非上皮性悪性腫瘍を含む。本発明におけるがんは、身体の任意の部位、例えば、脳、頭頚部、胸部、四肢、肺、心臓、胸腺、食道、胃、小腸（十二指腸、空腸、回腸）、大腸（結腸、盲腸、虫垂、直腸）、肝臓、膵臓、胆嚢、肛門、腎、尿管、膀胱、前立腺、陰茎、精巣、子宮、卵巣、外陰、膣、皮膚、横紋筋、平滑筋、滑膜、軟骨、骨、甲状腺、副腎、腹膜、腸間膜、骨髄、血液、血管系、リンパ節等のリンパ系、リンパ液などに存在し得る。 The cancer in the present invention is not limited, for example, fibrosarcoma, malignant fibrohistocytoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, Kaposi's sarcoma, lymphangiosarcoma, synovial sarcoma , Chondrosarcoma, sarcomas such as osteosarcoma, brain tumor, head and neck cancer, breast cancer, lung cancer, esophagus cancer, gastric cancer, duodenal cancer, appendix cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, anal cancer, Renal cancer, ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, testicular cancer, uterine cancer, ovarian cancer, vulvar cancer, vaginal cancer, carcinomas such as skin cancer, leukemia, malignant lymphoma and the like. In the present invention, "cancer" includes epithelial malignancy and non-epithelial malignancy. The cancer in the present invention may be any part of the body such as brain, head and neck, chest, limbs, lung, heart, thymus, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (colon, cecum, appendix) , Rectum, liver, pancreas, gallbladder, anus, kidney, ureter, bladder, prostate, penis, testis, uterus, ovary, vulva, vagina, skin, striated muscle, smooth muscle, synovium, cartilage, bone, thyroid It may be present in the adrenal gland, peritoneum, mesentery, bone marrow, blood, vasculature, lymph system such as lymph node, lymph fluid, etc.

本発明のZNF143阻害剤または医薬組成物においては、本発明の化合物の効果を妨げない限り、他の任意成分を含んでもよい。そのような任意成分としては、他の化学治療剤、薬理学的に許容される担体、賦形剤、希釈剤、分散補助剤等が挙げられ、例えば、マンニトール、乳糖、デキストラン等の水溶性の単糖類ないしオリゴ糖もしくは多糖類；例えばヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース等のゲル形成性または水溶性のセルロース等；例えば結晶性セルロース、α−セルロース、架橋カルボキシメチルセルロースナトリウム、およびそれらの誘導体等の水吸収性でかつ水難溶性のセルロース類；例えばヒドロキシプロピル澱粉、カルボキシメチル澱粉、架橋澱粉、アミロース、アミロペクチン、ペクチンおよびそれらの誘導体等の水吸収性でかつ水難溶性の多糖類；例えばアラビアガム、トラガントガム、グリコマンナンおよびそれらの誘導体等の水吸収性でかつ水難溶性のガム類；例えばポリビニルピロリドン、架橋ポリアクリル酸およびその塩、架橋ポリビニルアルコール、ポリヒドロキシエチルメタクリレートおよびそれらの誘導体等の架橋ビニル重合体類；リン脂質、コレステロール等のリポソーム等分子集合体を形成する脂質類等を挙げることができる。 The ZNF143 inhibitor or pharmaceutical composition of the present invention may contain other optional components as long as the effects of the compound of the present invention are not impaired. Such optional ingredients include other chemotherapeutic agents, pharmacologically acceptable carriers, excipients, diluents, dispersion aids, etc. For example, water-soluble ones such as mannitol, lactose, dextran, etc. Mono- or oligosaccharides or polysaccharides; gel-forming or water-soluble celluloses such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose etc., eg crystalline cellulose, α-cellulose, crosslinked sodium carboxymethyl cellulose, and derivatives thereof etc. Water-absorbing and water-insoluble celluloses; water-absorbing and water-insoluble polysaccharides such as hydroxypropyl starch, carboxymethyl starch, cross-linked starch, cross-linked starch, amylose, amylopectin, pectin and their derivatives; gum arabic, Tragant gum, Guri Water-absorbing and poorly water-soluble gums such as mannan and their derivatives; cross-linked vinyl polymers such as polyvinyl pyrrolidone, cross-linked polyacrylic acid and its salts, cross-linked polyvinyl alcohol, polyhydroxyethyl methacrylate and their derivatives; There can be mentioned lipids and the like which form a molecular assembly such as liposome such as phospholipid and cholesterol.

本発明のZNF143阻害剤または医薬組成物の溶解性が低い場合には、可溶化処理を施すことができる。可溶化処理としては通常医薬に適用できる方法、例えば、ポリオキシエチレンアルコールエーテル等、ポリオキシエチレンアシルエステル類、ソルビタンアシルエステル類、ポリオキシエチレンソルビタンアシルエステル類等の界面活性剤を添加する方法、ポリエチレングリコール等の水溶性高分子を使用する方法等が挙げられる。また、必要により、可溶性の塩にする方法、シクロデキストリン等を用いて包接化合物を形成させる方法等も使用できる。
また、投与経路や薬物放出様式などに応じて、上記ZNF143阻害剤または医薬組成物を、適切な材料、例えば、腸溶性のコーティングや、時限崩壊性の材料で被覆してもよく、また、適切な薬物放出システムに組み込んでもよい。 When the solubility of the ZNF143 inhibitor or pharmaceutical composition of the present invention is low, a solubilization treatment can be performed. As a solubilization process, a method which is generally applicable to pharmaceuticals, for example, a method of adding a surfactant such as polyoxyethylene alcohol ether, polyoxyethylene acyl esters, sorbitan acyl esters, polyoxyethylene sorbitan acyl esters, etc. The method of using water soluble polymers, such as polyethylene glycol, etc. are mentioned. In addition, if necessary, a method of forming a soluble salt, a method of forming an inclusion compound using cyclodextrin or the like, and the like can also be used.
Also, depending on the administration route, drug release mode, etc., the above-mentioned ZNF143 inhibitor or pharmaceutical composition may be coated with a suitable material, for example, an enteric coating or a time-disintegrable material, and Drug delivery system.

本発明のZNF143阻害剤または医薬組成物は、経口および非経口の両方を包含する種々の経路、例えば、限定することなく、経口、静脈内、筋肉内、皮下、局所、腫瘍内、直腸、動脈内、門脈内、心室内、経粘膜、経皮、鼻内、腹腔内、肺内および子宮内等の経路で投与してもよく、各投与経路に適した剤形に製剤してもよい。かかる剤形および製剤方法は任意の公知のものを適宜採用することができる（例えば、標準薬剤学、渡辺喜照ら編、南江堂、２００３年などを参照）。
例えば、経口投与に適した剤形としては、限定することなく、散剤、顆粒剤、錠剤、カプセル剤、液剤、懸濁剤、乳剤、ゲル剤、シロップ剤などが挙げられ、また非経口投与に適した剤形としては、溶液性注射剤、懸濁性注射剤、乳濁性注射剤、用時調製型注射剤などの注射剤が挙げられる。非経口投与用製剤は、水性または非水性の等張性無菌溶液または懸濁液の形態であることができる。 ZNF143 inhibitors or pharmaceutical compositions of the present invention may be used in various routes including both oral and parenteral, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, topical, intratumoral, rectal, arterial It may be administered by the route such as intraportal, intraportal, intraventricular, transmucosal, transdermal, intranasal, intraperitoneal, intrapulmonary, intrapulmonary and intrauterine, and may be formulated into a dosage form suitable for each administration route. . Any known dosage form and preparation method can be appropriately adopted (see, for example, standard pharmaceutics, edited by Yoshiteru Watanabe, Minami-edo, 2003, etc.).
For example, dosage forms suitable for oral administration include, but are not limited to, powders, granules, tablets, capsules, solutions, suspensions, emulsions, gels, syrups etc. and also for parenteral administration Suitable dosage forms include injections such as solution injections, suspension injections, emulsion injections, and ready-to-use injections. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile solutions or suspensions.

本発明のZNF143阻害剤または医薬組成物における本発明の化合物の投与量は、疾患の程度、患者の体重、年齢、性別に応じて適宜選択し、改善の度合いに応じて適宜増減することができる。 The dose of the compound of the present invention in the ZNF143 inhibitor or pharmaceutical composition of the present invention can be appropriately selected according to the degree of disease, body weight, age and sex of the patient, and can be appropriately increased or decreased according to the degree of improvement .

具体的には、例えば静脈内投与の場合には、特に、副作用等のリスクを低減することが求められるため、できるだけ低濃度の注射用製剤を複数回に分けて分注するか、または適当な補液で希釈して持続注入することが好ましい。例えば、成人の場合、本発明の化合物を、1 ｍｇ〜30 ｇ、さらに100 ｍｇ〜30 ｇ、特に500 ｍｇ〜30 ｇ投与するのが好ましい。 Specifically, for example, in the case of intravenous administration, in particular, it is required to reduce the risk of side effects etc. It is preferable to dilute with replacement fluid and continuously inject. For example, in the case of adults, it is preferred to administer the compound of the present invention in an amount of 1 mg to 30 g, more preferably 100 mg to 30 g, particularly 500 mg to 30 g.

本明細書に記載される本発明の処置方法において投与する本発明の化合物の具体的な用量は、処置を要する対象に関する種々の条件、例えば、症状の重篤度、対象の一般健康状態、年齢、体重、対象の性別、食事、投与の時期および頻度、併用している医薬、治療への反応性、剤形、および治療に対するコンプライアンスなどを考慮して決定され得る。
投与経路としては、経口および非経口の両方を包含する種々の経路、例えば、経口、静脈内、筋肉内、皮下、局所、腫瘍内、直腸、動脈内、門脈内、心室内、経粘膜、経皮、鼻内、腹腔内、肺内および子宮内等の経路が含まれる。
投与頻度は、用いる剤や組成物の性状や、上記のものを含む対象の条件によって異なるが、例えば、１日多数回（すなわち１日２、３、４回または５回以上）、１日１回、数日毎（すなわち２、３、４、５、６、７日毎など）、１週間毎、数週間毎（すなわち２、３、４週間毎など）であってもよい。 Specific dosages of the compounds of the invention administered in the methods of treatment of the invention described herein will vary according to the various conditions associated with the subject requiring treatment, such as the severity of the condition, the general health of the subject, the age of the subject. Body weight, sex of the subject, diet, timing and frequency of administration, medication in combination, responsiveness to treatment, dosage form, compliance with treatment, etc. can be determined.
As the administration route, various routes including both oral and parenteral, for example, oral, intravenous, intramuscular, subcutaneous, local, intratumoral, rectal, intraarterial, intraportal, intraventricular, transmucosal, Percutaneous, intranasal, intraperitoneal, intrapulmonary and intrauterine routes are included.
The frequency of administration varies depending on the properties of the agent and composition used and the condition of the subject including the above, for example, many times a day (that is, two, three, four or more times a day), one day It may be once every few days (i.e. every 2, 3, 4, 5, 6, 7 days etc), every week, every few weeks (i.e. every 2, 3, 4 weeks etc).

本明細書で用いる場合、用語「対象」は、任意の生物個体を意味し、好ましくは動物、さらに好ましくは哺乳動物、さらに好ましくはヒトの個体である。本発明において、対象は健常であっても、何らかの疾患に罹患していてもよいものとするが、特定の疾患の処置が企図される場合には、典型的にはかかる疾患に罹患しているか、罹患するリスクを有する対象を意味する。
また、用語「処置」は、本明細書で用いる場合、疾患の治癒、一時的寛解または予防などを目的とする医学的に許容される全ての種類の予防的および／または治療的介入を包含するものとする。例えば、「処置」の用語は、疾患の進行の遅延または停止、病変の退縮または消失、発症の予防または再発の防止などを含む、種々の目的の医学的に許容される介入を包含する。 As used herein, the term "subject" refers to any living individual, preferably an animal, more preferably a mammal, more preferably a human individual. In the present invention, the subject may be healthy or may be suffering from any disease, but in cases where treatment of a specific disease is intended, is it typically affected by such a disease? , Means a subject at risk for suffering.
Also, as used herein, the term "treatment" encompasses all types of medically acceptable prophylactic and / or therapeutic interventions, such as for the purpose of curing, temporary remission or prevention of a disease. It shall be. For example, the term "treatment" encompasses medically acceptable interventions of various purposes, including delaying or halting disease progression, regression or disappearance of lesions, prevention of onset or prevention of recurrence.

また、本発明のZNF143阻害剤は、上記のような医薬品製剤として用いるだけでなく、飲食品等として用いることもできる。この場合には、上記式（Ｉ）で表される化合物またはその塩をそのまま、または各種の栄養成分を加えて、飲食品に含有せしめればよい。この飲食品は、がんの転移および装飾、関節リウマチ等の改善、予防等に有用な保健用食品または食品素材として利用でき、これらの飲食品またはその容器には、前期の効果を有する旨の表示を付してもよい。具体的に本発明のZNF143阻害剤を飲食品に配合する場合は、飲食品として使用可能な添加剤を適宜使用し、慣用の手段を用いて食用に適した形態、例えば、顆粒状、粒状、錠剤、カプセル、ペースト等に成形してもよく、また各種の食品、例えば、ハム、ソーセージ等の食肉加工品、かまぼこ、ちくわ等の水産加工物、パン、菓子、バター、粉乳、乳酸菌飲料、発酵乳、発酵豆乳などの発酵飲食品に添加して使用してもよい。なお、飲食品には動物飼料も含まれる。 Moreover, the ZNF143 inhibitor of the present invention can be used not only as a pharmaceutical preparation as described above, but also as food and drink and the like. In this case, the compound represented by the above formula (I) or a salt thereof may be contained in the food or drink as it is or after adding various nutritional components. This food and drink can be used as a health food or food material useful for cancer metastasis and decoration, improvement and prevention of rheumatoid arthritis etc. These food and drink or containers thereof have the effect of the previous term. A display may be attached. Specifically, when the ZNF143 inhibitor of the present invention is incorporated into food and drink, additives suitable for use as food and drink are suitably used, and a form suitable for food using conventional means, for example, granular, granular, It may be formed into tablets, capsules, pastes and the like, and various foods, for example, processed meat products such as ham and sausages, processed fish products such as kamabo and chikuwa, breads, sweets, butter, milk powder, lactic acid bacteria beverages, fermented You may add and use to fermented foods / drinks, such as milk and fermented soymilk. Food and drink also include animal feed.

本発明を以下の例でさらに詳細に説明するが、これらは例示に過ぎず、本発明を決して限定するものではない。 The invention will be further described in the following examples, which are illustrative only and do not limit the invention in any way.

製造例1：N-(5-クロロ-2-シアノフェニル)-3-フェニルプロピオールアミド[化合物No.1]の合成
実施例1-1：N-(5-クロロ-2-シアノフェニル)-3-フェニルプロピオールアミド[化合物No.1]の合成

3-フェニルプロピオール酸(185 mg, 1.27 mmol)をジクロロメタン(1.9 ml)に懸濁させた、そこへオキサリルクロライド(0.114 ml, 1.33 mmol)、DMF(1滴)を加えて室温で2時間撹拌した。そこへ2-アミノ-4-クロロベンゾニトリル(194 mg, 1.27 mmol)を加えて室温で一晩撹拌した。反応後、水を加えた。珪藻土カラム(VARIAN Chem Elute 12198006)を通し、クロロホルムで洗った。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(SNAP 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(268 mg,75.2%)を淡黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.29 (1H, br s), 7.93 (1H, d, J = 8.3 Hz), 7.74 (1H, s), 7.70-7.68 (2H, m), 7.58-7.50 (4H, m).
ESI-MS m/z:281[M+H]⁺. Preparation Example 1: Synthesis of N- (5-chloro-2-cyanophenyl) -3-phenylpropiolamide [Compound No. 1] Example 1-1: N- (5-chloro-2-cyanophenyl) -3 Of 2-phenylpropiolamide [compound No. 1]

3-phenylpropiolic acid (185 mg, 1.27 mmol) was suspended in dichloromethane (1.9 ml), to which was added oxalyl chloride (0.114 ml, 1.33 mmol), DMF (1 drop) and stirred at room temperature for 2 hours . The 2-amino 4- chloro benzonitrile (194 mg, 1.27 mmol) was added there, and it stirred at room temperature overnight. After the reaction, water was added. The mixture was passed through a diatomaceous earth column (VARIAN Chem Elute 12198006) and washed with chloroform. The solvent was evaporated, and the residue was purified by silica gel column chromatography (SNAP 25 g, hexane / ethyl acetate) to give the title compound (268 mg, 75.2%) as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.29 (1 H, br s), 7.93 (1 H, d, J = 8.3 Hz), 7.74 (1 H, s), 7.70-7.68 (2 H , m), 7.58-7.50 (4H, m).
ESI-MS m / z: 281 [M + H] ⁺ .

製造例2：N-(5-フルオロ-2-メトキシフェニル)-3-フェニルプロピオールアミド[化合物No.2]の合成
実施例2-1：N-(5-フルオロ-2-メトキシフェニル)-3-フェニルプロピオールアミド[化合物No.2]の合成
5-フルオロ-2-メトキシアニリン(0.150 ml, 1.27 mmol)を用いて実施例1-1と同様の操作を行うことで標記の化合物(265 mg,77.5%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.20 (1H, br s), 7.73 (1H, dd, J = 10.5, 2.9 Hz), 7.67 (2H, d, J = 7.1 Hz), 7.57-7.48 (3H, m), 7.09 (1H, dd, J = 9.0, 5.1 Hz), 7.00 (1H, td, J = 8.6, 3.0 Hz), 3.84 (3H, s).
ESI-MS m/z:270[M+H]⁺. Preparation Example 2: Synthesis of N- (5-fluoro-2-methoxyphenyl) -3-phenylpropiolamide [Compound No. 2] Example 2-1: N- (5-fluoro-2-methoxyphenyl) -3 Of 2-phenylpropiolamide [compound No. 2]
The title compound (265 mg, 77.5%) was obtained as a white solid by the same procedure as in Example 1-1 using 5-fluoro-2-methoxyaniline (0.150 ml, 1.27 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.20 (1 H, br s), 7.73 (1 H, dd, J = 10.5, 2.9 Hz), 7.67 (2 H, d, J = 7.1 Hz ), 7.57-7.48 (3H, m), 7.09 (1H, dd, J = 9.0, 5.1 Hz), 7.00 (1H, td, J = 8.6, 3.0 Hz), 3.84 (3H, s).
ESI-MS m / z: 270 [M + H] ⁺ .

製造例3：N-(5-ヨード-2-メトキシフェニル)-3-フェニルプロピオールアミド[化合物No.3]の合成
実施例3-1：N-(5-ヨード-2-メトキシフェニル)-3-フェニルプロピオールアミド[化合物No.3]の合成
5-ヨード-2-メトキシアニリン(321 mg, 1.29 mmol)を用いて実施例1-1と同様の操作を行うことで標記の化合物(408 mg,83.5%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.15 (1H, br s), 8.10 (1H, d, J = 1.7 Hz), 7.67 (2H, d, J = 7.1 Hz), 7.56-7.48 (4H, m), 6.93 (1H, d, J = 8.8 Hz), 3.83 (3H, s).
ESI-MS m/z:278[M+H]⁺. Preparation Example 3: Synthesis of N- (5-iodo-2-methoxyphenyl) -3-phenylpropiolamide [Compound No. 3] Example 3-1: N- (5-iodo-2-methoxyphenyl) -3 Of 2-phenylpropiolamide [compound No. 3]
The title compound (408 mg, 83.5%) was obtained as a brown solid by the same procedure as in Example 1-1 using 5-iodo-2-methoxyaniline (321 mg, 1.29 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.15 (1 H, br s), 8.10 (1 H, d, J = 1.7 Hz), 7.67 (2 H, d, J = 7.1 Hz), 7.56-7.48 (4H, m), 6.93 (1H, d, J = 8.8 Hz), 3.83 (3H, s).
ESI-MS m / z: 278 [M + H] ⁺ .

製造例4：ジメチル2-(3-(p-トルイル)プロピオールアミド)テレフタレート[化合物No.4]の合成
実施例4-1：3-(p-トルイル)プロピオール酸の合成
p-ヨードトルエン(238 mg, 1.09 mmol)をDMF(3.6 ml)に溶解した。そこへビス(トリフェニルホスフィン)パラジウム(II)ジクロライド(38 mg, 0.055 mmol)、ヨウ化銅(21 mg, 0.109 mmol)を加えた。さらにプロピオール酸(0.134 ml, 2.18 mmol)、トリエチルアミン(0.456 ml)を加えて室温で5.5時間撹拌した。反応後、溶媒を留去した。クロロホルムに溶解し、1 mol/l水酸化ナトリウム水溶液で抽出した。水層を1 mol/l塩酸でpH=2にした。生じた沈殿をろ過し、減圧乾燥した(60℃)。標記の化合物(43 mg, 24.6%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 13.71 (1H, br s), 7.52 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 2.36 (3H, s).
ESI-MS m/z:161[M+H]⁺. Preparation Example 4: Synthesis of dimethyl 2- (3- (p-toluyl) propiolamide) terephthalate [Compound No. 4] Example 4-1: Synthesis of 3- (p-toluyl) propiolic acid
p-iodotoluene (238 mg, 1.09 mmol) was dissolved in DMF (3.6 ml). Thereto were added bis (triphenylphosphine) palladium (II) dichloride (38 mg, 0.055 mmol) and copper iodide (21 mg, 0.109 mmol). Further, propiolic acid (0.134 ml, 2.18 mmol) and triethylamine (0.456 ml) were added and the mixture was stirred at room temperature for 5.5 hours. After the reaction, the solvent was distilled off. It was dissolved in chloroform and extracted with 1 mol / l aqueous sodium hydroxide solution. The aqueous layer was adjusted to pH 2 with 1 mol / l hydrochloric acid. The resulting precipitate was filtered and dried in vacuo (60 ° C.). The title compound (43 mg, 24.6%) was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 13.71 (1 H, br s), 7.52 (2 H, d, J = 8.1 Hz), 5.2 29 (2 H, d, J = 8.1 Hz), 2.36 (3H, s).
ESI-MS m / z: 161 [M + H] ⁺ .

実施例4-2：ジメチル2-(3-(p-トルイル)プロピオールアミド)テレフタレート[化合物No.4]の合成
実施例4-1で得られた化合物(42 mg, 0.26 mmol)とジメチル2-アミノテレフタレート(54 mg, 0.26 mmol)を用いて実施例1-1と同様の操作を行うことで標記の化合物(80 mg, 87.6%)を淡黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.18 (1H, br s), 8.59 (1H, s), 8.01 (1H, d, J = 8.1 Hz), 7.82 (1H, dd, J = 8.1, 1.7 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.32 (2H, d, J = 7.8 Hz), 3.90 (3H, s), 3.88 (3H, s), 2.38 (3H, s).
ESI-MS m/z:352[M+H]⁺. Example 4-2 Synthesis of Dimethyl 2- (3- (p-toluyl) propiolamido) terephthalate [Compound No. 4]
Using the compound (42 mg, 0.26 mmol) obtained in Example 4-1 and dimethyl 2-amino terephthalate (54 mg, 0.26 mmol), the same procedure as in Example 1-1 was carried out to give the title compound ( 80 mg, 87.6%) were obtained as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.18 (1 H, br s), 8.59 (1 H, s), 8.01 (1 H, d, J = 8.1 Hz), 7.82 (1 H, dd , J = 8.1, 1.7 Hz), 7.57 (2 H, d, J = 7.8 Hz), 7.32 (2 H, d, J = 7.8 Hz), 3. 90 (3 H, s), 3. 88 (3 H, s), 2. 38 (3 H) , s).
ESI-MS m / z: 352 [M + H] ⁺ .

製造例5：ジメチル2-(3-(m-トルイル)プロピオールアミド)テレフタレート[化合物No.5]の合成
実施例5-1：3-(m-トルイル)プロピオール酸の合成
m-ヨードトルエン(0.257 ml, 2 mmol)を用いて実施例4-1と同様の操作を行うことで標記の化合物(159 mg, 49.6%)を黒色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.40-7.32 (4H, m), 2.32 (3H, s).
ESI-MS m/z:161[M+H]⁺. Preparation Example 5 Synthesis of Dimethyl 2- (3- (m-toluyl) propiolamide) terephthalate [Compound No. 5] Example 5-1: Synthesis of 3- (m-toluyl) propiolate
The title compound (159 mg, 49.6%) was obtained as a black oil by the same procedure as in Example 4-1 using m-iodotoluene (0.257 ml, 2 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.40-7.32 (4H, m), 2.32 (3H, s).
ESI-MS m / z: 161 [M + H] ⁺ .

実施例5-2：ジメチル2-(3-(m-トルイル)プロピオールアミド)テレフタレート[化合物No.5]の合成
実施例5-1で得られた化合物(158 mg, 0.99 mmol)とジメチル2-アミノテレフタレート(54 mg, 0.26 mmol)を用いて実施例1-1と同様の操作を行うことで標記の化合物(172 mg, 49.4%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.21 (1H, br s), 8.60 (1H, s), 8.02 (1H, d, J = 8.3 Hz), 7.83 (1H, dd, J = 8.3, 1.5 Hz), 7.50-7.46 (2H, m), 7.40-7.39 (2H, m), 3.90 (3H, s), 3.89 (3H, s), 2.35 (3H, s).
ESI-MS m/z:352[M+H]⁺. Example 5-2 Synthesis of dimethyl 2- (3- (m-toluyl) propiolamido) terephthalate [Compound No. 5]
Using the compound (158 mg, 0.99 mmol) obtained in Example 5-1 and dimethyl 2-amino terephthalate (54 mg, 0.26 mmol), the same procedure as in Example 1-1 was carried out to obtain the title compound ( 172 mg, 49.4%) were obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.21 (1 H, br s), 8.60 (1 H, s), 8.02 (1 H, d, J = 8.3 Hz), 7.83 (1 H, dd , J = 8.3, 1.5 Hz), 7.50-1.46 (2 H, m), 7. 40-7. 39 (2 H, m), 3. 90 (3 H, s), 3. 89 (3 H, s), 2. 35 (3 H, s).
ESI-MS m / z: 352 [M + H] ⁺ .

製造例6：N-(5-ブロモ-2-メトキシフェニル)-3-(ナフタレン-1-イル)プロピオールアミド[化合物No.6]の合成
実施例6-1：3-(ナフタレン-1-イル)プロピオール酸の合成
1-ヨードナフタレン(0.292 ml, 2 mmol)を用いて実施例4-1と同様の操作を行うことで標記の化合物(253 mg, 60.0%)を黒色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 13.94 (1H, br s), 8.23 (1H, d, J = 8.3 Hz), 8.15 (1H, d, J = 8.3 Hz), 8.07 (1H, d, J = 8.3 Hz), 7.95 (1H, dd, J = 7.2, 1.1 Hz), 7.77-7.72 (1H, m), 7.69-7.59 (2H, m). Preparation Example 6: Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (naphthalen-1-yl) propiolamide [Compound No. 6] Example 6-1: 3- (naphthalene-1) Synthesis of (I) propiolic acid
The title compound (253 mg, 60.0%) was obtained as a black solid by the same procedure as in Example 4-1 using 1-iodonaphthalene (0.292 ml, 2 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 13.94 (1 H, br s), 8.23 (1 H, d, J = 8.3 Hz), 8.15 (1 H, d, J = 8.3 Hz), 8.07 (1 H, d, J = 8.3 Hz), 7.95 (1 H, dd, J = 7.2, 1.1 Hz), 7.77-7.72 (1 H, m), 7.69-7.59 (2 H, m).

実施例6-2：N-(5-ブロモ-2-メトキシフェニル)-3-(ナフタレン-1-イル)プロピオールアミド[化合物No.6]の合成
実施例6-1で得られた化合物(131 mg, 0.67 mmol)と5-ブロモ-2-メトキシアニリン(135 mg, 0.67 mmol)を用いて実施例1-1と同様の操作を行うことで標記の化合物(59 mg, 23.2%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.43 (1H, br s), 8.43 (1H, d, J = 8.3 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.04 (2H, dd, J = 14.5, 5.0 Hz), 7.97 (1H, d, J = 7.3 Hz), 7.74 (1H, t, J = 7.3 Hz), 7.68-7.60 (2H, m), 7.37 (1H, dd, J = 8.5, 2.3 Hz), 7.09 (1H, d, J = 8.5 Hz), 3.87 (3H, s).
ESI-MS m/z:380[M+H]⁺. Example 6-2 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (naphthalen-1-yl) propiolamide [Compound No. 6]
The title was obtained by the same procedure as in Example 1-1 using the compound (131 mg, 0.67 mmol) obtained in Example 6-1 and 5-bromo-2-methoxyaniline (135 mg, 0.67 mmol). The compound of (59 mg, 23.2%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.43 (1 H, br s), 8.43 (1 H, d, J = 8.3 Hz), 8.13 (1 H, d, J = 8.3 Hz), 8.04 (2H, dd, J = 14.5, 5.0 Hz), 7.97 (1H, d, J = 7.3 Hz), 7.74 (1H, t, J = 7.3 Hz), 7.68-7.60 (2H, m), 7.37 (1H , dd, J = 8.5, 2.3 Hz), 7.09 (1 H, d, J = 8.5 Hz), 3.87 (3 H, s).
ESI-MS m / z: 380 [M + H] ⁺ .

製造例7：ジメチル2-(3-(4-シアノフェニル)プロピオールアミド)テレフタレート[化合物No.7]の合成
実施例7-1：ジメチル2-(3-(トリメチルシリル)プロピオールアミド)テレフタレートの合成
3-(トリメチルシリル)プロピオール酸(947 mg, 6.66 mmol)を用いて実施例1-1と同様の操作を行うことで標記の化合物(1.531 g, 72.5%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.12 (1H, br s), 8.53 (1H, s), 7.99 (1H, d, J = 8.1 Hz), 7.81 (1H, dd, J = 8.1, 1.5 Hz), 3.89 (3H, s), 3.87 (3H, s), 0.28 (9H, s).
ESI-MS m/z:334[M+H]⁺. Preparation Example 7: Synthesis of dimethyl 2- (3- (4-cyanophenyl) propiolamide) terephthalate [compound No. 7] Example 7-1 of dimethyl 2- (3- (trimethylsilyl) propiolamide) terephthalate Synthesis
The title compound (1.531 g, 72.5%) was obtained as a white solid by the same procedure as in Example 1-1 using 3- (trimethylsilyl) propiolic acid (947 mg, 6.66 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.12 (1 H, br s), 8.53 (1 H, s), 7.99 (1 H, d, J = 8.1 Hz), 7.81 (1 H, dd , J = 8.1, 1.5 Hz), 3.89 (3 H, s), 3. 87 (3 H, s), 0.28 (9 H, s).
ESI-MS m / z: 334 [M + H] ⁺ .

実施例7-2：ジメチル2-プロピオールアミドテレフタレートの合成
実施例7-1で得られた化合物(1.036 g, 3.11 mmol)をクロロホルム(20 ml)、メタノール(20 ml)に溶解した。そこへ炭酸ナトリウム(43 mg, 0.31 mmol)を加えて室温で15分撹拌した。反応後、1 mol/l塩酸を加えてクロロホルム抽出した。硫酸マグネシウムで乾燥し、溶媒を留去し、標記の化合物(827 mg, quant.)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.14 (1H, br s), 8.53 (1H, s), 8.00 (1H, d, J = 8.3 Hz), 7.82 (1H, dd, J = 8.3, 1.7 Hz), 4.57 (1H, s), 3.89 (3H, s), 3.87 (3H, s).
ESI-MS m/z:262[M+H]⁺. Example 7-2 Synthesis of dimethyl 2-propiolamide terephthalate
The compound obtained in Example 7-1 (1.036 g, 3.11 mmol) was dissolved in chloroform (20 ml) and methanol (20 ml). Sodium carbonate (43 mg, 0.31 mmol) was added there, and it stirred at room temperature for 15 minutes. After the reaction, 1 mol / l hydrochloric acid was added to extract chloroform. The extract was dried over magnesium sulfate and evaporated to give the title compound (827 mg, quant.) As a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.14 (1 H, br s), 8.53 (1 H, s), 8.00 (1 H, d, J = 8.3 Hz), 7.82 (1 H, dd , J = 8.3, 1.7 Hz), 4.57 (1 H, s), 3. 89 (3 H, s), 3. 87 (3 H, s).
ESI-MS m / z: 262 [M + H] ⁺ .

実施例7-3：ジメチル2-(3-(4-シアノフェニル)プロピオールアミド)テレフタレート[化合物No.7]の合成
4-ヨードベンゾニトリル(63 mg, 0.27 mmol)をDMF(1 ml)に溶解した。そこへビス(トリフェニルホスフィン)パラジウム(II)ジクロライド(9.5 mg, 0.0135 mmol)、ヨウ化銅(5.1 mg, 0.027 mmol)を加えた。さらに実施例7-2で得られた化合物(86 mg, 0.33 mmol)、トリエチルアミン(0.113 ml, 0.81 mmol)を加えて室温で6時間撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(58 mg, 59.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.28 (1H, br s), 8.52 (1H, s), 8.02-7.98 (3H, m), 7.89-7.83 (3H, m), 3.90 (3H, s), 3.88 (3H, s).
ESI-MS m/z:363[M+H]⁺. Example 7-3 Synthesis of dimethyl 2- (3- (4-cyanophenyl) propiolamido) terephthalate [Compound No. 7]
4-iodobenzonitrile (63 mg, 0.27 mmol) was dissolved in DMF (1 ml). Thereto were added bis (triphenylphosphine) palladium (II) dichloride (9.5 mg, 0.0135 mmol) and copper iodide (5.1 mg, 0.027 mmol). The compound (86 mg, 0.33 mmol) obtained in Example 7-2 and triethylamine (0.113 ml, 0.81 mmol) were further added, and the mixture was stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 25 g, hexane / ethyl acetate) to give the title compound (58 mg, 59.3%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.28 (1H, br s), 8.52 (1H, s), 8.02-7.98 (3H, m), 7.89-7.83 (3H, m) , 3.90 (3H, s), 3.88 (3H, s).
ESI-MS m / z: 363 [M + H] ⁺ .

製造例8：ジメチル2-(3-(2-シアノフェニル)プロピオールアミド)テレフタレート[化合物No.8]の合成
実施例8-1：ジメチル2-(3-(2-シアノフェニル)プロピオールアミド)テレフタレート[化合物No.8]の合成
2-ヨードベンゾニトリル(66 mg, 0.29 mmol)を用いて実施例7-3と同様の操作を行うことで標記の化合物(34 mg, 34.8%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.33 (1H, br s), 8.57 (1H, br s), 8.06-8.01 (2H, m), 7.95 (1H, d, J = 8.3 Hz), 7.87-7.83 (2H, m), 7.77 (1H, t, J = 7.8 Hz), 3.90 (3H, s), 3.89 (3H, s).
ESI-MS m/z:363[M+H]⁺. Preparation Example 8 Synthesis of dimethyl 2- (3- (2-cyanophenyl) propiolamide) terephthalate [Compound No. 8] Example 8-1: Dimethyl 2- (3- (2-cyanophenyl) propiolamide ) Synthesis of terephthalate [compound No. 8]
The title compound (34 mg, 34.8%) was obtained as a yellow solid by the same procedure as in Example 7-3 using 2-iodobenzonitrile (66 mg, 0.29 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.33 (1 H, br s), 8.57 (1 H, br s), 8.06-8.01 (2 H, m), 7.95 (1 H, d, J = 8.3 Hz), 7.87-7.83 (2 H, m), 7. 77 (1 H, t, J = 7.8 Hz), 3. 90 (3 H, s), 3. 89 (3 H, s).
ESI-MS m / z: 363 [M + H] ⁺ .

製造例9：N-(5-ブロモ-2-メトキシフェニル)-3-(2-(トリフルオロメチル)フェニルプロピオールアミド[化合物No.9]の合成
実施例9-1：N-(5-ブロモ-2-メトキシフェニル)-3-(トリメチルシリル)プロピオールアミドの合成
5-ブロモ-2-メトキシアニリン(3.758 g, 18.6 mmol)を用いて実施例7-1と同様の操作を行うことにより標記の化合物(5.753 g, 94.8%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.05 (1H, br s), 7.83 (1H, d, J = 2.2 Hz), 7.33 (1H, dd, J = 8.8, 2.2 Hz), 7.04 (1H, d, J = 8.8 Hz), 6.75 (1H, d, J = 2.4 Hz), 6.71 (1H, d, J = 8.5 Hz), 6.61 (1H, dd, J = 8.5, 2.4 Hz), 5.00 (1H, s), 3.81 (3H, s), 3.74 (2H, s), 0.26 (9H, s).
ESI-MS m/z:326[M+H]⁺. Preparation Example 9 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (2- (trifluoromethyl) phenylpropiolamide [Compound No. 9] Example 9-1: N- (5-bromo) Synthesis of -2-methoxyphenyl) -3- (trimethylsilyl) propiolamide
The title compound (5.753 g, 94.8%) was obtained as a white solid by the same procedure as in Example 7-1 using 5-bromo-2-methoxyaniline (3.758 g, 18.6 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.05 (1 H, br s), 7.83 (1 H, d, J = 2.2 Hz), 7.33 (1 H, dd, J = 8.8, 2.2 Hz ), 7.04 (1 H, d, J = 8.8 Hz), 6.75 (1 H, d, J = 2.4 Hz), 6.71 (1 H, d, J = 8.5 Hz), 6.61 (1 H, dd, J = 8.5, 2.4 Hz) ), 5.00 (1H, s), 3.81 (3H, s), 3.74 (2H, s), 0.26 (9H, s).
ESI-MS m / z: 326 [M + H] ⁺ .

実施例9-2：N-(5-ブロモ-2-メトキシフェニル)プロピオールアミドの合成
実施例9-1で得られた化合物(5.753 g, 17.6 mmol)を用いて実施例7-2と同様の操作を行うことにより標記の化合物(3.058 g, 68.4%)を淡黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.12 (1H, br s), 7.86 (1H, d, J = 2.4 Hz), 7.34 (1H, dd, J = 8.8, 2.4 Hz), 7.04 (1H, d, J = 8.8 Hz), 4.41 (1H, s), 3.81 (3H, s).
ESI-MS m/z:254[M+H]⁺. Example 9-2 Synthesis of N- (5-bromo-2-methoxyphenyl) propiolamide
The title compound (3.058 g, 68.4%) was obtained as a pale yellow solid by performing the same procedure as in Example 7-2 using the compound (5.753 g, 17.6 mmol) obtained in Example 9-1 .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.12 (1 H, br s), 7.86 (1 H, d, J = 2.4 Hz), 7.34 (1 H, dd, J = 8.8, 2.4 Hz ), 7.04 (1 H, d, J = 8.8 Hz), 4.41 (1 H, s), 3.81 (3 H, s).
ESI-MS m / z: 254 [M + H] ⁺ .

実施例9-3：N-(5-ブロモ-2-メトキシフェニル)-3-(2-(トリフルオロメチル)フェニルプロピオールアミド[化合物No.9]の合成
1-ヨード-2-(トリフルオロメチル)ベンゼン(0.077 ml, 0.54 mmol)と実施例9-2で得られた化合物(180 mg, 0.71 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(23 mg, 10.7%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.29 (1H, br s), 7.98 (1H, d, J = 2.2 Hz), 7.96 (1H, d, J = 7.8 Hz), 7.90 (1H, d, J = 8.3 Hz), 7.81 (1H, t, J = 7.4 Hz), 7.75 (1H, t, J = 7.4 Hz), 7.36 (1H, dd, J = 8.8, 2.2 Hz), 7.08 (1H, d, J = 8.8 Hz), 3.85 (3H, s).
ESI-MS m/z:398[M+H]⁺. Example 9-3 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (2- (trifluoromethyl) phenylpropiolamide [Compound No. 9]
The procedure of Example 7-3 was repeated using 1-iodo-2- (trifluoromethyl) benzene (0.077 ml, 0.54 mmol) and the compound obtained in Example 9-2 (180 mg, 0.71 mmol). The work up gave the title compound (23 mg, 10.7%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.29 (1 H, br s), 7.98 (1 H, d, J = 2.2 Hz), 7.96 (1 H, d, J = 7.8 Hz), 7.90 (1 H, d, J = 8.3 Hz), 7.81 (1 H, t, J = 7.4 Hz), 7. 75 (1 H, t, J = 7.4 Hz), 7. 36 (1 H, dd, J = 8.8, 2.2 Hz), 7.08 (1H, d, J = 8.8 Hz), 3.85 (3H, s).
ESI-MS m / z: 398 [M + H] ⁺ .

製造例10：N-(5-ブロモ-2-メトキシフェニル)-3-(4-(トリフルオロメチル)フェニル)プロピオールアミド[化合物No.10]の合成
実施例10-1：N-(5-ブロモ-2-メトキシフェニル)-3-(4-(トリフルオロメチル)フェニル)プロピオールアミド[化合物No.10]の合成
1-ヨード-4-(トリフルオロメチル)ベンゼン(0.078 ml, 0.54 mmol)と実施例9-2で得られた化合物(180 mg, 0.71 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(143 mg, 66.5%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.37 (1H, br s), 8.00 (1H, d, J = 2.4 Hz), 7.91-7.86 (4H, m), 7.36 (1H, dd, J = 8.8, 2.4 Hz), 7.08 (1H, d, J = 8.8 Hz), 3.85 (3H, s).
ESI-MS m/z:398[M+H]⁺. Preparation Example 10 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (4- (trifluoromethyl) phenyl) propiolamide [Compound No. 10] Example 10-1: N- (5 Synthesis of -Bromo-2-methoxyphenyl) -3- (4- (trifluoromethyl) phenyl) propiolamide [Compound No. 10]
The procedure of Example 7-3 was repeated using 1-iodo-4- (trifluoromethyl) benzene (0.078 ml, 0.54 mmol) and the compound obtained in Example 9-2 (180 mg, 0.71 mmol). The title compound (143 mg, 66.5%) was obtained as a yellow solid by carrying out.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.37 (1 H, br s), 8.00 (1 H, d, J = 2.4 Hz), 7.91-7.86 (4 H, m), 7.36 (1 H , dd, J = 8.8, 2.4 Hz), 7.08 (1 H, d, J = 8.8 Hz), 3. 85 (3 H, s).
ESI-MS m / z: 398 [M + H] ⁺ .

製造例11：N-(5-ブロモ-2-メトキシフェニル)-3-(4-(トリフルオロメトキシ)フェニル)プロピオールアミド[化合物No.11]の合成
実施例11-1：N-(5-ブロモ-2-メトキシフェニル)-3-(4-(トリフルオロメトキシ)フェニル)プロピオールアミド[化合物No.11]の合成
1-ヨード-4-(トリフルオロメトキシ)ベンゼン(0.090 ml, 0.58 mmol)と実施例9-2で得られた化合物(192 mg, 0.76 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(20 mg, 8.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.28 (1H, br s), 8.00 (1H, d, J = 2.4 Hz), 7.83-7.81 (2H, m), 7.50 (2H, d, J = 8.1 Hz), 7.35 (1H, dd, J = 8.8, 2.4 Hz), 7.07 (1H, d, J = 8.8 Hz), 3.85 (3H, s).
ESI-MS m/z:414[M+H]⁺. Preparation Example 11 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (4- (trifluoromethoxy) phenyl) propiolamide [Compound No. 11] Example 11-1: N- (5 Synthesis of -Bromo-2-methoxyphenyl) -3- (4- (trifluoromethoxy) phenyl) propiolamide [Compound No. 11]
The procedure of Example 7-3 was repeated using 1-iodo-4- (trifluoromethoxy) benzene (0.090 ml, 0.58 mmol) and the compound obtained in Example 9-2 (192 mg, 0.76 mmol) The title compound (20 mg, 8.3%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.28 (1 H, br s), 8.00 (1 H, d, J = 2.4 Hz), 7.83-7.81 (2 H, m), 7. 50 (2 H , d, J = 8.1 Hz), 7.35 (1 H, dd, J = 8.8, 2.4 Hz), 7.07 (1 H, d, J = 8.8 Hz), 3.85 (3 H, s).
ESI-MS m / z: 414 [M + H] ⁺ .

製造例12：N-(2-メトキシ-5-(トリフルオロメチル)フェニル)-3-フェニルプロピオールアミド[化合物No.12]の合成
実施例12-1：N-(2-メトキシ-5-(トリフルオロメチル)フェニル)-3-フェニルプロピオールアミド[化合物No.12]の合成
3-フェニルプロピオ−ル酸(184 mg, 1.26 mmol)と2-メトキシ-5-トリフルオロメチルアニリン(241 mg, 1.26 mmol)を用いて実施例1-1と同様の操作を行うことにより標記の化合物(227 mg, 56.4%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.33 (1H, br s), 8.18 (1H, s), 7.69-7.67 (2H, m), 7.55-7.48 (4H, m), 7.28 (1H, d, J = 8.5 Hz), 3.94 (3H, s).
ESI-MS m/z:320[M+H]⁺. Preparation Example 12 Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -3-phenylpropiolamide [Compound No. 12] Example 12-1: N- (2-methoxy-5- ( Synthesis of trifluoromethyl) phenyl) -3-phenylpropiolamide [compound No. 12]
The title was obtained by the same procedure as in Example 1-1 using 3-phenylpropio-phosphoric acid (184 mg, 1.26 mmol) and 2-methoxy-5-trifluoromethylaniline (241 mg, 1.26 mmol). The compound (227 mg, 56.4%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.33 (1H, br s), 8.18 (1H, s), 7.69-7.67 (2H, m), 7.55-7.48 (4H, m) , 7.28 (1 H, d, J = 8.5 Hz), 3.94 (3 H, s).
ESI-MS m / z: 320 [M + H] ⁺ .

製造例13：N-(5-ブロモ-2-メトキシフェニル)-3-(2-シアノフェニル)プロピオールアミド[化合物No.13]の合成
実施例13-1：N-(5-ブロモ-2-メトキシフェニル)-3-(2-シアノフェニル)プロピオールアミド[化合物No.13]の合成
2-シアノ-ヨードベンゼン(128 mg, 0.56 mmol)と実施例9-2で得られた化合物(185 mg, 0.73 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(52 mg, 26.1%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.41 (1H, br s), 8.04-7.99 (2H, m), 7.92 (1H, d, J = 7.7 Hz), 7.84 (1H, t, J = 7.7 Hz), 7.73 (1H, t, J = 7.7 Hz), 7.37 (1H, dd, J = 8.8, 2.2 Hz), 7.08 (1H, d, J = 8.8 Hz), 3.85 (3H, s).
ESI-MS m/z:355[M+H]⁺. Preparation Example 13 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (2-cyanophenyl) propiolamide [Compound No. 13] Example 13-1: N- (5-bromo-2) Synthesis of -Methoxyphenyl) -3- (2-cyanophenyl) propiolamide [Compound No. 13]
The title compound was obtained by the same procedure as Example 7-3 using 2-cyano-iodobenzene (128 mg, 0.56 mmol) and the compound (185 mg, 0.73 mmol) obtained in Example 9-2. (52 mg, 26.1%) was obtained as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.41 (1 H, br s), 8.04-7.99 (2 H, m), 7. 92 (1 H, d, J = 7.7 Hz), 7.84 (1 H , t, J = 7.7 Hz), 7.73 (1 H, t, J = 7.7 Hz), 7. 37 (1 H, dd, J = 8.8, 2.2 Hz), 7.08 (1 H, d, J = 8.8 Hz), 3.85 (3 H) , s).
ESI-MS m / z: 355 [M + H] ⁺ .

製造例14：N-(5-ブロモ-2-シアノフェニル)-3-フェニルプロピオールアミド[化合物No.14]の合成
実施例14-1：N-(5-ブロモ-2-シアノフェニル)-3-フェニルプロピオールアミド[化合物No.14]の合成
3-フェニルプロピオール酸(161 mg, 1.10 mmol)と5-ブロモ-2-シアノアニリン(152 mg, 0.77 mmol)を用いて実施例1-1と同様の操作を行うことにより標記の化合物(59 mg, 16.5%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.29 (1H, br s), 7.87-7.84 (2H, m), 7.70-7.66 (3H, m), 7.60-7.50 (3H, m).
ESI-MS m/z:325[M+H]⁺. Preparation Example 14 Synthesis of N- (5-bromo-2-cyanophenyl) -3-phenylpropiolamide [Compound No. 14] Example 14-1: N- (5-bromo-2-cyanophenyl) -3 Of 2-phenylpropiol amide [compound No. 14]
The title compound (59 mg) was obtained by the same procedure as in Example 1-1 using 3-phenylpropiolic acid (161 mg, 1.10 mmol) and 5-bromo-2-cyanoaniline (152 mg, 0.77 mmol) , 16.5%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.29 (1 H, br s), 7.87-7.84 (2 H, m), 7.70-7.66 (3 H, m), 7.60-1.50 (3 H, m).
ESI-MS m / z: 325 [M + H] ⁺ .

製造例15：N-(5-ブロモ-2-メトキシフェニル)-3-(2-フルオロフェニル)プロピオールアミド[化合物No.15]の合成
実施例15-1：N-(5-ブロモ-2-メトキシフェニル)-3-(2-フルオロフェニル)プロピオールアミド[化合物No.15]の合成
2-フルオロ-ヨードベンゼン(0.071 ml, 0.62 mmol)と実施例9-2で得られた化合物(206 mg, 0.81 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(42 mg, 19.5%)を褐色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.30 (1H, br s), 7.96 (1H, d, J = 2.3 Hz), 7.74 (1H, t, J = 6.7 Hz), 7.61 (1H, q, J = 6.7 Hz), 7.41 (1H, t, J = 8.9 Hz), 7.37-7.32 (2H, m), 7.07 (1H, d, J = 8.9 Hz), 3.85 (3H, s).
ESI-MS m/z:348[M+H]⁺. Preparation Example 15 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (2-fluorophenyl) propiolamide [Compound No. 15] Example 15-1: N- (5-bromo-2) Synthesis of -Methoxyphenyl) -3- (2-fluorophenyl) propiolamide [Compound No. 15]
The title compound was obtained by the same procedure as in Example 7-3 using 2-fluoro-iodobenzene (0.071 ml, 0.62 mmol) and the compound (206 mg, 0.81 mmol) obtained in Example 9-2. (42 mg, 19.5%) was obtained as a brown oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.30 (1 H, br s), 7.96 (1 H, d, J = 2.3 Hz), 7.74 (1 H, t, J = 6.7 Hz), 7.61 (1H, q, J = 6.7 Hz), 7.41 (1H, t, J = 8.9 Hz), 7.37-7. 32 (2H, m), 7.07 (1 H, d, J = 8.9 Hz), 3.85 (3H, s) ).
ESI-MS m / z: 348 [M + H] ⁺ .

製造例16：N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-3-イル)プロピオールアミド[化合物No.16]の合成
実施例16-1：N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-3-イル)プロピオールアミド[化合物No.16]の合成
3-ヨードピリジン(42 mg, 0.21 mmol)と実施例9-2で得られた化合物(79 mg, 0.31 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(15 mg, 21.6%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.32 (1H, br s), 8.85 (1H, s), 8.70 (1H, dd, J = 4.8, 1.5 Hz), 8.10 (1H, d, J = 7.7 Hz), 8.00 (1H, d, J = 2.4 Hz), 7.54 (1H, dd, J = 7.7, 4.8 Hz), 7.35 (1H, dd, J = 8.7, 2.4 Hz), 7.07 (1H, d, J = 8.7 Hz), 3.85 (3H, s).
ESI-MS m/z:331[M+H]⁺. Preparation Example 16 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (pyridin-3-yl) propiolamide [Compound No. 16] Example 16-1: N- (5-bromo-) Synthesis of 2-Methoxyphenyl) -3- (pyridin-3-yl) propiolamide [Compound No. 16]
The title compound (15) was obtained by the same procedure as in Example 7-3 using 3-iodopyridine (42 mg, 0.21 mmol) and the compound obtained in Example 9-2 (79 mg, 0.31 mmol). mg, 21.6%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.32 (1 H, br s), 8. 85 (1 H, s), 8. 70 (1 H, dd, J = 4.8, 1.5 Hz), 8. 10 (1 H , d, J = 7.7 Hz), 8.00 (1 H, d, J = 2.4 Hz), 7.54 (1 H, dd, J = 7.7, 4.8 Hz), 7.35 (1 H, dd, J = 8.7, 2.4 Hz), 7.07 (1H, d, J = 8.7 Hz), 3.85 (3H, s).
ESI-MS m / z: 331 [M + H] ⁺ .

製造例17：N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-4-イル)プロピオールアミド[化合物No.17]の合成
実施例17-1：N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-4-イル)プロピオールアミド[化合物No.17]の合成
4-ヨードピリジン(74 mg, 0.36 mmol)と実施例9-2で得られた化合物(110 mg, 0.43 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(15 mg, 12.6%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.41 (1H, br s), 8.72 (1H, s), 8.70 (1H, s), 7.98 (1H, d, J = 2.2 Hz), 7.64-7.59 (3H, m), 7.57-7.53 (1H, m), 7.36 (1H, dd, J = 8.8, 2.4 Hz), 7.07 (1H, d, J = 8.8 Hz), 3.85 (3H, s).
ESI-MS m/z:331[M+H]⁺. Preparation Example 17 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (pyridin-4-yl) propiolamide [Compound No. 17] Example 17-1: N- (5-bromo-) Synthesis of 2-Methoxyphenyl) -3- (pyridin-4-yl) propiolamide [Compound No. 17]
The title compound (15) was obtained by the same procedure as in Example 7-3 using 4-iodopyridine (74 mg, 0.36 mmol) and the compound obtained in Example 9-2 (110 mg, 0.43 mmol). mg, 12.6%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.41 (1 H, br s), 8. 72 (1 H, s), 8. 70 (1 H, s), 7. 98 (1 H, d, J = 2.2 Hz ), 7.64-7.59 (3H, m), 7.57-7.53 (1H, m), 7.36 (1H, dd, J = 8.8, 2.4 Hz), 7.07 (1H, d, J = 8.8 Hz), 3.85 (3H, 3H, s).
ESI-MS m / z: 331 [M + H] ⁺ .

製造例18：ジメチル2-(3-(ピリジン-3-イル)プロピオールアミド)テレフタレート[化合物No.18]の合成
実施例18-1：ジメチル2-(3-(ピリジン-3-イル)プロピオールアミド)テレフタレート[化合物No.18]の合成
3-ヨードピリジン(67 mg, 0.33 mmol)と実施例7-2で得られた化合物(111 mg, 0.42 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(45 mg, 40.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.27 (1H, br s), 8.87 (1H, s), 8.73 (1H, dd, J = 5.0, 1.6 Hz), 8.53 (1H, s), 8.13 (1H, d, J = 7.7 Hz), 8.01 (1H, d, J = 8.2 Hz), 7.85 (1H, dd, J = 8.2, 1.6 Hz), 7.55 (1H, dd, J = 7.7, 5.0 Hz), 3.90 (3H, s), 3.88 (3H, s).
ESI-MS m/z:339[M+H]⁺. Preparation Example 18 Synthesis of dimethyl 2- (3- (pyridin-3-yl) propiolamido) terephthalate [Compound No. 18] Example 18-1: Dimethyl 2- (3- (pyridin-3-yl) propi Synthesis of Allamido) terephthalate [Compound No. 18]
The title compound (45) was obtained by the same procedure as in Example 7-3 using 3-iodopyridine (67 mg, 0.33 mmol) and the compound obtained in Example 7-2 (111 mg, 0.42 mmol). mg, 40.3%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.27 (1 H, br s), 8.87 (1 H, s), 8. 73 (1 H, dd, J = 5.0, 1.6 Hz), 8.53 (1 H , s), 8.13 (1 H, d, J = 7.7 Hz), 8.01 (1 H, d, J = 8.2 Hz), 7. 85 (1 H, dd, J = 8.2, 1.6 Hz), 7.55 (1 H, dd, J = 7.7, 5.0 Hz), 3.90 (3 H, s), 3. 88 (3 H, s).
ESI-MS m / z: 339 [M + H] ⁺ .

製造例19：ジメチル2-(3-(ピリジン-2-イル)プロピオールアミド)テレフタレート[化合物No.19]の合成
実施例19-1：ジメチル2-(3-(ピリジン-2-イル)プロピオールアミド)テレフタレート[化合物No.19]の合成
2-ヨードピリジン(0.034 ml, 0.33 mmol)と実施例7-2で得られた化合物(111 mg, 0.42 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(23 mg, 20.6%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.33 (1H, br s), 8.70 (1H, dd, J = 3.4, 1.0 Hz), 8.54 (1H, s), 8.01 (1H, d, J = 8.3 Hz), 7.95 (1H, td, J = 7.7, 1.8 Hz), 7.85 (1H, dd, J = 8.3, 1.7 Hz), 7.81 (1H, d, J = 7.3 Hz), 7.57 (1H, ddd, J = 7.6, 4.8, 1.2 Hz), 3.90 (3H, s), 3.89 (3H, s).
ESI-MS m/z:339[M+H]⁺. Preparation Example 19 Synthesis of Dimethyl 2- (3- (pyridin-2-yl) propiolamide) terephthalate [Compound No. 19] Example 19-1: Dimethyl 2- (3- (pyridin-2-yl) propi Synthesis of Allamide) Terephthalate [Compound No. 19]
The title compound (23) was obtained by the same procedure as in Example 7-3 using 2-iodopyridine (0.034 ml, 0.33 mmol) and the compound obtained in Example 7-2 (111 mg, 0.42 mmol). mg, 20.6%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.33 (1 H, br s), 8.70 (1 H, dd, J = 3.4, 1.0 Hz), 8.54 (1 H, s), 8.01 (1 H , d, J = 8.3 Hz), 7. 95 (1 H, td, J = 7.7, 1.8 Hz), 7. 85 (1 H, dd, J = 8.3, 1.7 Hz), 7.81 (1 H, d, J = 7.3 Hz), 7.57 (1H, ddd, J = 7.6, 4.8, 1.2 Hz), 3.90 (3H, s), 3.89 (3H, s).
ESI-MS m / z: 339 [M + H] ⁺ .

製造例20：N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-2-イル)プロピオールアミド[化合物No.20]の合成
実施例20-1：N-(5-ブロモ-2-メトキシフェニル)-3-(ピリジン-2-イル)プロピオールアミド[化合物No.20]の合成
2-ヨードピリジン(0.037 ml, 0.35 mmol)と実施例9-2で得られた化合物(117 mg, 0.46 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(66 mg, 56.9%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.38 (1H, br s), 8.68 (1H, d, J = 3.9 Hz), 7.97 (1H, d, J = 2.4 Hz), 7.93 (1H, td, J = 7.7, 1.4 Hz), 7.78 (1H, d, J = 7.7 Hz), 7.54 (1H, ddd, J = 7.1, 5.1, 0.5 Hz), 7.36 (1H, dd, J = 8.8, 2.4 Hz), 7.07 (1H, d, J = 8.8 Hz), 3.85 (3H, s).
ESI-MS m/z:331[M+H]⁺. Preparation Example 20 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (pyridin-2-yl) propiolamide [Compound No. 20] Example 20-1: N- (5-bromo-) Synthesis of 2-Methoxyphenyl) -3- (pyridin-2-yl) propiolamide [Compound No. 20]
The title compound (66) was obtained by the same procedure as in Example 7-3 using 2-iodopyridine (0.037 ml, 0.35 mmol) and the compound obtained in Example 9-2 (117 mg, 0.46 mmol). mg, 56.9%) was obtained as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.38 (1 H, br s), 8.68 (1 H, d, J = 3.9 Hz), 7.97 (1 H, d, J = 2.4 Hz), 7.93 (1H, td, J = 7.7, 1.4 Hz), 7.78 (1 H, d, J = 7.7 Hz), 7.54 (1 H, ddd, J = 7.1, 5.1, 0.5 Hz), 7.36 (1 H, dd, J = 8.8, 2.4 Hz), 7.07 (1 H, d, J = 8.8 Hz), 3.85 (3 H, s).
ESI-MS m / z: 331 [M + H] ⁺ .

製造例21：N-(5-ブロモ-2-メトキシフェニル)-3-(ピラジン-2-イル)プロピオールアミド[化合物No.21]の合成
実施例21-1：N-(5-ブロモ-2-メトキシフェニル)-3-(ピラジン-2-イル)プロピオールアミド[化合物No.21]の合成
2-ヨードピラジン(0.035 ml, 0.35 mmol)と実施例9-3で得られた化合物(117 mg, 0.46 mmol)を用いて実施例9-3と同様の操作を行うことにより標記の化合物(8 mg, 6.9%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.56 (1H, br s), 8.99 (1H, d, J = 1.2 Hz), 8.79-8.77 (2H, m), 7.97 (1H, d, J = 2.4 Hz), 7.37 (1H, dd, J = 8.8, 2.4 Hz), 7.08 (1H, d, J = 8.8 Hz), 3.85 (3H, s).
ESI-MS m/z:332[M+H]⁺. Preparation Example 21 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (pyrazin-2-yl) propiolamide [Compound No. 21] Example 21-1: N- (5-bromo-) Synthesis of 2-Methoxyphenyl) -3- (pyrazin-2-yl) propiolamide [Compound No. 21]
The title compound (8) was obtained by the same procedure as in Example 9-3 using 2-iodopyrazine (0.035 ml, 0.35 mmol) and the compound obtained in Example 9-3 (117 mg, 0.46 mmol). mg, 6.9%) was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.56 (1 H, br s), 8.99 (1 H, d, J = 1.2 Hz), 8.79-8.77 (2 H, m), 7.97 (1 H , d, J = 2.4 Hz), 7.37 (1 H, dd, J = 8.8, 2.4 Hz), 7.08 (1 H, d, J = 8.8 Hz), 3.85 (3 H, s).
ESI-MS m / z: 332 [M + H] ⁺ .

製造例22：N-(5-ブロモ-2-メトキシフェニル)-3-(2-メトキシピリジン-3-イル)プロピオールアミド[化合物No.22]の合成
実施例22-1: N-(5-ブロモ-2-メトキシフェニル)-3-(2-メトキシピリジン-3-イル)プロピオールアミド[化合物No.22]の合成
3-ヨード-2-メトキシピリジン(231 mg, 0.98 mmol)と実施例9-2で得られた化合物(324 mg, 1.27 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(113 mg, 31.9%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.20 (1H, br s), 8.31 (1H, dd, J = 4.9, 1.7 Hz), 8.04 (1H, dd, J = 7.1, 1.7 Hz), 7.96 (1H, d, J = 2.3 Hz), 7.35 (1H, dd, J = 8.7, 2.3 Hz), 7.12 (1H, dd, J = 7.3, 5.1 Hz), 7.07 (1H, d, J = 8.4 Hz), 3.97 (3H, s), 3.84 (3H, s).
ESI-MS m/z:361[M+H]⁺. Preparation Example 22 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (2-methoxypyridin-3-yl) propiolamide [Compound No. 22] Example 22-1: N- (5 Synthesis of -Bromo-2-methoxyphenyl) -3- (2-methoxypyridin-3-yl) propiolamide [Compound No. 22]
The title was obtained by the same procedure as in Example 7-3 using 3-iodo-2-methoxypyridine (231 mg, 0.98 mmol) and the compound obtained in Example 9-2 (324 mg, 1.27 mmol). The compound of (113 mg, 31.9%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.20 (1 H, br s), 8.31 (1 H, dd, J = 4.9, 1.7 Hz), 8.04 (1 H, dd, J = 7.1, 1.7 Hz), 7.96 (1 H, d, J = 2.3 Hz), 7. 35 (1 H, dd, J = 8.7, 2.3 Hz), 7.12 (1 H, dd, J = 7.3, 5.1 Hz), 7.07 (1 H, d, J = 8.4 Hz), 3.97 (3H, s), 3.84 (3H, s).
ESI-MS m / z: 361 [M + H] ⁺ .

製造例23：3-(3-((5-ブロモ-2-メトキシフェニル)アミノ)-3-オキソプロピ-1-イン-1-イル)ピリジン 1-オキシド[化合物No.23]の合成
実施例23-1：3-(3-((5-ブロモ-2-メトキシフェニル)アミノ)-3-オキソプロピ-1-イン-1-イル)ピリジン 1-オキシド[化合物No.23]の合成
実施例16-1で得られた化合物(29 mg, 0.088 mmol)をジクロロメタン(0.6 ml)に溶解した。そこへm-クロロ過安息香酸(33 mg, 0.132 mmol)を加えた。室温で一晩撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(18 mg, 58.9%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.38 (1H, br s), 8.56 (1H, s), 8.35 (1H, d, J = 6.3 Hz), 8.01 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.1 Hz), 7.52 (1H, t, J = 7.2 Hz), 7.36 (1H, dd, J = 8.8, 2.4 Hz), 7.08 (1H, d, J = 8.8 Hz), 3.86 (3H, s).
ESI-MS m/z:347[M+H]⁺. Preparation Example 23 Synthesis of 3- (3-((5-bromo-2-methoxyphenyl) amino) -3-oxoprop-1-yn-1-yl) pyridine 1-oxide [Compound No. 23] Example 23 Synthesis of 1-: 3- (3-((5-bromo-2-methoxyphenyl) amino) -3-oxoprop-1-yn-1-yl) pyridine 1-oxide [Compound No. 23]
The compound obtained in Example 16-1 (29 mg, 0.088 mmol) was dissolved in dichloromethane (0.6 ml). Thereto was added m-chloroperbenzoic acid (33 mg, 0.132 mmol). Stir at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 10 g, chloroform / methanol) to give the title compound (18 mg, 58.9%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.38 (1 H, br s), 8.56 (1 H, s), 8. 35 (1 H, d, J = 6.3 Hz), 8.01 (1 H, d , J = 2.4 Hz), 7.61 (1 H, d, J = 8.1 Hz), 7.52 (1 H, t, J = 7.2 Hz), 7.56 (1 H, dd, J = 8.8, 2.4 Hz), 7.08 (1 H, d , J = 8.8 Hz), 3.86 (3 H, s).
ESI-MS m / z: 347 [M + H] ⁺ .

製造例24：N-(5-フルオロ-2-メトキシフェニル)-3-(ピリジン-3-イル)プロピオールアミド[化合物No.24]の合成
実施例24-1：N-(5-フルオロ-2-メトキシフェニル)-3-(トリメチルシリル)プロピオールアミドの合成
3-(トリメチルシリル)プロピン酸(860 mg, 6.05 mmol)と5-フルオロ-2-メトキシアニリン(0.713 ml, 6.05 mmol)を用いて実施例1-1と同様の操作を行うことにより標記の化合物(638 mg, 39.7%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.05 (1H, s), 7.56 (1H, dd, J = 10.1, 2.8 Hz), 7.06 (1H, dd, J = 9.0, 5.1 Hz), 6.99 (1H, td, J = 8.7, 2.8 Hz), 3.81 (3H, s), 0.26 (9H, s).
ESI-MS m/z: 266[M+H]⁺. Preparation Example 24 Synthesis of N- (5-fluoro-2-methoxyphenyl) -3- (pyridin-3-yl) propiolamide [Compound No. 24] Example 24-1: N- (5-fluoro-) Synthesis of 2-methoxyphenyl) -3- (trimethylsilyl) propiolamide
The title compound was obtained by the same procedure as in Example 1-1 using 3- (trimethylsilyl) propynoic acid (860 mg, 6.05 mmol) and 5-fluoro-2-methoxyaniline (0.713 ml, 6.05 mmol). 638 mg, 39.7%) were obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.05 (1 H, s), 7.56 (1 H, dd, J = 10.1, 2.8 Hz), 7.06 (1 H, dd, J = 9.0, 5.1 Hz), 6.99 (1 H, td, J = 8.7, 2.8 Hz), 3.81 (3 H, s), 0.26 (9 H, s).
ESI-MS m / z: 266 [M + H] ⁺ .

実施例24-2：N-(5-フルオロ-2-メトキシフェニル)プロピオールアミドの合成
実施例24-1で得られた化合物 (638 mg, 2.4 mmol)を用いて実施例7-2と同様の操作を行うことにより標記の化合物(242 mg, 52.2%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.10 (1H, br s), 7.59 (1H, d, J = 10.5 Hz), 7.09-6.97 (2H, m), 4.41 (1H, s), 3.80 (3H, s).
ESI-MS m/z:266[M+H]⁺. Example 24-2 Synthesis of N- (5-fluoro-2-methoxyphenyl) propiolamide
The title compound (242 mg, 52.2%) was obtained as a yellow solid by the same procedure as that of Example 7-2 using the compound (638 mg, 2.4 mmol) obtained in Example 24-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.10 (1 H, br s), 7.59 (1 H, d, J = 10.5 Hz), 7.09-6.97 (2 H, m), 4.41 (1 H , s), 3.80 (3H, s).
ESI-MS m / z: 266 [M + H] ⁺ .

実施例24-3：N-(5-フルオロ-2-メトキシフェニル)-3-(ピリジン-3-イル)プロピオールアミド[化合物No.24]の合成
3-ヨードピリジン(96 mg, 0.47 mmol)と実施例24-2で得られた化合物(117 mg, 0.61 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(60 mg, 47.2%)を黄褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.32 (1H, br s), 8.85 (1H, s), 8.70 (1H, d, J = 4.4 Hz), 8.10 (1H, d, J = 7.8 Hz), 7.73 (1H, dd, J = 10.5, 2.9 Hz), 7.54 (1H, dd, J = 7.8, 5.1 Hz), 7.10 (1H, dd, J = 9.0, 5.1 Hz), 7.01 (1H, td, J = 8.7, 2.9 Hz), 3.84 (3H, s).
ESI-MS m/z:271[M+H]⁺. Example 24-3 Synthesis of N- (5-fluoro-2-methoxyphenyl) -3- (pyridin-3-yl) propiolamide [Compound No. 24]
The title compound (60) was obtained by the same procedure as in Example 7-3 using 3-iodopyridine (96 mg, 0.47 mmol) and the compound obtained in Example 24-2 (117 mg, 0.61 mmol). mg, 47.2%) was obtained as a tan solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.32 (1 H, br s), 8. 85 (1 H, s), 8. 70 (1 H, d, J = 4.4 Hz), 8. 10 (1 H, d , J = 7.8 Hz), 7.73 (1 H, dd, J = 10.5, 2.9 Hz), 7.54 (1 H, dd, J = 7.8, 5.1 Hz), 7.10 (1 H, dd, J = 9.0, 5.1 Hz), 7.01 (1H, td, J = 8.7, 2.9 Hz), 3.84 (3H, s).
ESI-MS m / z: 271 [M + H] ⁺ .

製造例25：N-(5-フルオロ-2-メトキシフェニル)-3-(ピリジン-4-イル)プロピオールアミド[化合物No.25]の合成
実施例25-1：N-(5-フルオロ-2-メトキシフェニル)-3-(ピリジン-4-イル)プロピオールアミド[化合物No.25]の合成
4-ヨードピリジン(96 mg, 0.47 mmol)と実施例24-2で得られた化合物(117 mg, 0.61 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(47 mg, 37.0%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.43 (1H, br s), 8.73 (2H, br s), 7.71 (1H, dd, J = 10.4, 3.3 Hz), 7.65-7.64 (2H, m), 7.10 (1H, dd, J = 9.1, 5.2 Hz), 7.02 (1H, td, J = 9.1, 3.3 Hz), 3.84 (3H, s).
ESI-MS m/z:271[M+H]⁺. Preparation Example 25 Synthesis of N- (5-fluoro-2-methoxyphenyl) -3- (pyridin-4-yl) propiolamide [Compound No. 25] Example 25-1: N- (5-fluoro-) Synthesis of 2-Methoxyphenyl) -3- (pyridin-4-yl) propiolamide [Compound No. 25]
The title compound (47) was obtained by the same procedure as in Example 7-3 using 4-iodopyridine (96 mg, 0.47 mmol) and the compound obtained in Example 24-2 (117 mg, 0.61 mmol). mg, 37.0%) was obtained as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.43 (1 H, br s), 8.73 (2 H, br s), 7.71 (1 H, dd, J = 10.4, 3.3 Hz), 7.65- 7.64 (2H, m), 7.10 (1 H, dd, J = 9.1, 5.2 Hz), 7.02 (1 H, td, J = 9.1, 3.3 Hz), 3.84 (3 H, s).
ESI-MS m / z: 271 [M + H] ⁺ .

製造例26：3-(6-アセトアミドピリジン-3-イル)-N-(5-ブロモ-2-メトキシフェニル)プロピオールアミド[化合物No.26]の合成
実施例26-1：N-(5-ヨードピリジン-2-イル)アセトアミドの合成
5-ヨードピリジン-2-アミン(170 mg, 0.77 mmol)を1,2-ジクロロエタン(3.4 ml)に溶解した。そこへ無水酢酸(0.087 ml, 0.924 mmol)、DMAP(10 mg, 0.077 mmol)を加えて60℃で5時間撹拌した。さらに無水酢酸(0.087 ml, 0.924 mmol)を加えて60℃で1時間撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(193 mg, 95.6%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.60 (1H, br s), 8.51 (1H, d, J = 2.2 Hz), 8.09 (1H, dd, J = 8.8, 2.2 Hz), 7.95 (1H, d, J = 8.8 Hz), 2.08 (3H, s).
ESI-MS m/z:263[M+H]⁺. Preparation Example 26 Synthesis of 3- (6-acetamidopyridin-3-yl) -N- (5-bromo-2-methoxyphenyl) propiolamide [Compound No. 26] Example 26-1: N- (5 Synthesis of -iodopyridin-2-yl) acetamide
5-iodopyridin-2-amine (170 mg, 0.77 mmol) was dissolved in 1,2-dichloroethane (3.4 ml). Acetic anhydride (0.087 ml, 0.924 mmol) and DMAP (10 mg, 0.077 mmol) were added there, and it stirred at 60 degreeC for 5 hours. Further, acetic anhydride (0.087 ml, 0.924 mmol) was added and the mixture was stirred at 60 ° C. for 1 hour. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 25 g, hexane / ethyl acetate) to give the title compound (193 mg, 95.6%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.60 (1 H, br s), 8.51 (1 H, d, J = 2.2 Hz), 8.09 (1 H, dd, J = 8.8, 2.2 Hz ), 7.95 (1 H, d, J = 8.8 Hz), 2.08 (3 H, s).
ESI-MS m / z: 263 [M + H] ⁺ .

実施例26-2：3-(6-アセトアミドピリジン-3-イル)-N-(5-ブロモ-2-メトキシフェニル)プロピオールアミド[化合物No.26]の合成
実施例26-1で得られた化合物(193 mg, 0.74 mmol)と実施例9-2で得られた化合物(244 mg, 0.962 mmol)を用いて実施例7-3と同様の操作を行うことで標記の化合物(100 mg, 34.8%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.84 (1H, br s), 10.21 (1H, br s), 8.60 (1H, d, J = 1.2 Hz), 8.18 (1H, d, J = 8.3 Hz), 8.05 (1H, dd, J = 8.8, 2.0 Hz), 8.01 (1H, d, J = 2.3 Hz), 7.34 (1H, dd, J = 8.8, 2.3 Hz), 7.07 (1H, d, J = 9.0 Hz), 3.85 (3H, s), 2.13 (3H, s).
ESI-MS m/z:388[M+H]⁺. Example 26-2 Synthesis of 3- (6-acetamidopyridin-3-yl) -N- (5-bromo-2-methoxyphenyl) propiolamide [Compound No. 26]
Using the compound (193 mg, 0.74 mmol) obtained in Example 26-1 and the compound (244 mg, 0.962 mmol) obtained in Example 9-2 in the same manner as in Example 7-3 The title compound (100 mg, 34.8%) was obtained as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.84 (1 H, br s), 10. 21 (1 H, br s), 8. ₆₀ (1 H, d, J = 1.2 Hz), 8. 18 (1 H, d, J = 8.3 Hz), 8.05 (1 H, dd, J = 8.8, 2.0 Hz), 8.01 (1 H, d, J = 2.3 Hz), 7.34 (1 H, dd, J = 8.8, 2.3 Hz), 7.07 (7 1H, d, J = 9.0 Hz), 3.85 (3H, s), 2.13 (3H, s).
ESI-MS m / z: 388 [M + H] ⁺ .

製造例27：3-(6-アミノピリジン-3-イル)-N-(5-ブロモ-2-メトキシフェニル)プロピオールアミド[化合物No.27]の合成
実施例27-1：3-(6-アミノピリジン-3-イル)-N-(5-ブロモ-2-メトキシフェニル)プロピオールアミド[化合物No.27]の合成
実施例26-2で得られた化合物(99 mg, 0.25 mmol)をメタノール(2 ml)、THF(1 ml)に溶解した。そこへ1 mol/l塩酸(0.765 ml, 0.765 mmol)を加えて1.5時間加熱還流した。反応後、1 mol/l水酸化ナトリウム水溶液を加えてクロロホルム抽出した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(41 mg, 47.4%)を淡褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.93 (1H, br s), 8.22 (1H, s), 8.01 (1H, s), 7.58 (1H, d, J = 7.6 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 9.0 Hz), 6.73 (2H, br s), 6.47 (1H, d, J = 8.5 Hz), 3.84 (3H, s).
ESI-MS m/z:346[M+H]⁺. Preparation Example 27 Synthesis of 3- (6-Aminopyridin-3-yl) -N- (5-bromo-2-methoxyphenyl) propiolamide [Compound No. 27] Example 27-1: 3- (6 Synthesis of -Aminopyridin-3-yl) -N- (5-bromo-2-methoxyphenyl) propiolamide [Compound No. 27]
The compound (99 mg, 0.25 mmol) obtained in Example 26-2 was dissolved in methanol (2 ml) and THF (1 ml). 1 mol / l hydrochloric acid (0.765 ml, 0.765 mmol) was added there, and it heated and refluxed for 1.5 hours. After the reaction, 1 mol / l aqueous sodium hydroxide solution was added to extract chloroform. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 10 g, chloroform / methanol) to give the title compound (41 mg, 47.4%) as a pale brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.93 (1 H, br s), 8.22 (1 H, s), 8.01 (1 H, s), 7.58 (1 H, d, J = 7.6 Hz ), 7.31 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 9.0 Hz), 6.73 (2H, br s), 6.47 (1 H, d, J = 8.5 Hz), 3.84 (3H, 3H) s).
ESI-MS m / z: 346 [M + H] ⁺ .

製造例28：N-(2-メトキシ-5-(トリフルオロメチル)フェニル)-3-(ピリジン-3-イル)プロピオールアミド[化合物No.28]の合成
実施例28-1：N-(2-メトキシ-5-(トリフルオロメチル)フェニル)-3-(トリメチルシリル)プロピオールアミドの合成
3-(トリメチルシリル)プロピオール酸(852 mg, 5.99 mmol)と5-トリフルオロメチル-2-メトキシアニリン(1.145 g, 5.99 mmol)を用いて実施例1-1と同様の操作を行うことにより標記の化合物(1.721 g, 91.1%)を淡褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.18 (1H, br s), 8.01 (1H, d, J = 1.4 Hz), 7.54 (1H, dd, J = 8.3, 1.4 Hz), 7.26 (1H, d, J = 8.3 Hz), 3.90 (3H, s), 0.26 (9H, s).
ESI-MS m/z: 316[M+H]⁺. Preparation Example 28 Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -3- (pyridin-3-yl) propiolamide [Compound No. 28] Example 28-1: N- ( Synthesis of 2-methoxy-5- (trifluoromethyl) phenyl) -3- (trimethylsilyl) propiolamide
The title was obtained by the same procedure as in Example 1-1 using 3- (trimethylsilyl) propiolic acid (852 mg, 5.99 mmol) and 5-trifluoromethyl-2-methoxyaniline (1.145 g, 5.99 mmol). The compound (1.721 g, 91.1%) was obtained as a pale brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.18 (1 H, br s), 8.01 (1 H, d, J = 1.4 Hz), 7.54 (1 H, dd, J = 8.3, 1.4 Hz ), 7.26 (1 H, d, J = 8.3 Hz), 3.90 (3 H, s), 0.26 (9 H, s).
ESI-MS m / z: 316 [M + H] ⁺ .

実施例28-2：N-(2-メトキシ-5-(トリフルオロメチル)フェニル)プロピオールアミドの合成
実施例28-1で得られた化合物(1.561 g, 4.95 mmol)を用いて実施例7-2と同様の操作を行うことにより標記の化合物(889 mg, 73.9%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.24 (1H, br s), 8.04 (1H, d, J = 1.6 Hz), 7.55 (1H, dd, J = 8.7, 1.6 Hz), 7.26 (1H, d, J = 8.7 Hz), 3.90 (3H, s).
ESI-MS m/z: 244[M+H]⁺. Example 28-2 Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) propiolamide
The title compound (889 mg, 73.9%) was obtained as a white solid by carrying out the same procedure as in Example 7-2 using the compound (1.561 g, 4.95 mmol) obtained in Example 28-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.24 (1 H, br s), 8.04 (1 H, d, J = 1.6 Hz), 7.55 (1 H, dd, J = 8.7, 1.6 Hz ), 7.26 (1 H, d, J = 8.7 Hz), 3.90 (3 H, s).
ESI-MS m / z: 244 [M + H] ⁺ .

実施例28-3：N-(2-メトキシ-5-(トリフルオロメチル)フェニル)-3-(ピリジン-3-イル)プロピオールアミド[化合物No.28]の合成
3-ヨードピリジン(128 mg, 0.62 mmol)と実施例28-2で得られた化合物(197 mg, 0.81 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(84 mg, 42.3%)を褐色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.44 (1H, br s), 8.86 (1H, d, J = 1.1 Hz), 8.70 (1H, dd, J = 4.9, 1.5 Hz), 8.19 (1H, d, J = 1.9 Hz), 8.11 (1H, dt, J = 7.9, 1.9 Hz), 7.57-7.53 (2H, m), 7.29 (1H, d, J = 8.5 Hz), 3.94 (3H, s).
ESI-MS m/z:321[M+H]⁺. Example 28-3 Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -3- (pyridin-3-yl) propiolamide [Compound No. 28]
The title compound (84) was obtained by the same procedure as in Example 7-3 using 3-iodopyridine (128 mg, 0.62 mmol) and the compound (197 mg, 0.81 mmol) obtained in Example 28-2. mg, 42.3%) was obtained as a brown oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.44 (1 H, br s), 8.86 (1 H, d, J = 1.1 Hz), 8.70 (1 H, dd, J = 4.9, 1.5 Hz ), 8.19 (1H, d, J = 1.9 Hz), 8.11 (1H, dt, J = 7.9, 1.9 Hz), 7.57-7.53 (2H, m), 7.29 (1 H, d, J = 8.5 Hz), 3.94 (3H, s).
ESI-MS m / z: 321 [M + H] ⁺ .

製造例29：N-(4-メトキシ-[1,1'-ビフェニル]-3-イル)-3-(ピリジン-3-イル)プロピオールアミド[化合物No.29]の合成
実施例29-1：N-(4-メトキシ-[1,1'-ビフェニル]-3-イル)-3-(トリメチルシリル)プロピオールアミドの合成
3-(トリメチルシリル)プロピン酸(848 mg, 5.96 mmol)と4-メトキシ-[1,1'-ビフェニル]-3-アミン(1.187 g, 5.96 mmol)を用いて実施例1-1と同様の操作を行うことにより標記の化合物(1.775 g, 92.1%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.99 (1H, br s), 7.88 (1H, d, J = 2.3 Hz), 7.56 (2H, d, J = 7.4 Hz), 7.49-7.47 (1H, m), 7.44 (2H, t, J = 7.7 Hz), 7.32 (1H, tt, J = 7.4, 1.3 Hz), 7.16 (1H, d, J = 8.6 Hz), 3.86 (3H, s), 0.26 (9H, s).
ESI-MS m/z:324[M+H]⁺. Production Example 29 Synthesis of N- (4-Methoxy- [1,1′-biphenyl] -3-yl) -3- (pyridin-3-yl) propiolamide [Compound No. 29] Example 29-1 : N- (4-Methoxy- [1,1'-biphenyl] -3-yl) -3- (trimethylsilyl) propiolamide
The same procedure as in Example 1-1, using 3- (trimethylsilyl) propynoic acid (848 mg, 5.96 mmol) and 4-methoxy- [1,1'-biphenyl] -3-amine (1.187 g, 5.96 mmol) The title compound (1.775 g, 92.1%) was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.99 (1 H, br s), 7.88 (1 H, d, J = 2.3 Hz), 7.56 (2 H, d, J = 7.4 Hz), 7.49-7.47 (1H, m), 7.44 (2H, t, J = 7.7 Hz), 7.32 (1H, tt, J = 7.4, 1.3 Hz), 7.16 (1 H, d, J = 8.6 Hz), 3.86 (3H , s), 0.26 (9H, s).
ESI-MS m / z: 324 [M + H] ⁺ .

実施例29-2：N-(4-メトキシ-[1,1'-ビフェニル]-3-イル)プロピオールアミドの合成
実施例29-1で得られた化合物(1.775 g, 5.49 mmol)を用いて実施例7-2と同様の操作を行うことにより標記の化合物(969 mg, 70.2%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.04 (1H, br s), 7.92 (1H, d, J = 2.3 Hz), 7.57 (2H, d, J = 7.3 Hz), 7.50-7.42 (3H, m), 7.32 (1H, tt, J = 7.3, 1.5 Hz), 7.16 (1H, d, J = 8.7 Hz), 4.36 (1H, s), 3.86 (3H, s).
ESI-MS m/z:252[M+H]⁺. Example 29-2 Synthesis of N- (4-Methoxy- [1,1′-biphenyl] -3-yl) propiolamide
The title compound (969 mg, 70.2%) was obtained as a yellow solid by the same procedure as that of Example 7-2 using the compound (1.775 g, 5.49 mmol) obtained in Example 29-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.04 (1 H, br s), 7. 92 (1 H, d, J = 2.3 Hz), 7.57 (2 H, d, J = 7.3 Hz), 7.50-7.42 (3 H, m), 7.32 (1 H, tt, J = 7.3, 1.5 Hz), 7.16 (1 H, d, J = 8.7 Hz), 4.36 (1 H, s), 3.86 (3 H, s).
ESI-MS m / z: 252 [M + H] ⁺ .

実施例29-3：N-(4-メトキシ-[1,1'-ビフェニル]-3-イル)-3-(ピリジン-3-イル)プロピオールアミド[化合物No.29]の合成
3-ヨードピリジン(139 mg, 0.68 mmol)と実施例29-2で得られた化合物(197 mg, 0.81 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(137 mg, 61.4%)を褐色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.26 (1H, br s), 8.87 (1H, s), 8.71 (1H, s), 8.11 (1H, d, J = 8.0 Hz), 8.05 (1H, d, J = 2.3 Hz), 7.59 (2H, d, J = 6.9 Hz), 7.55 (1H, d, J = 8.7 Hz), 7.49 (1H, dd, J = 8.7, 2.3 Hz), 7.45 (2H, t, J = 7.7 Hz), 7.33 (1H, t, J = 7.7 Hz), 7.19 (1H, d, J = 8.7 Hz), 3.90 (3H, s).
ESI-MS m/z:329[M+H]⁺. Example 29-3 Synthesis of N- (4-Methoxy- [1,1′-biphenyl] -3-yl) -3- (pyridin-3-yl) propiolamide [Compound No. 29]
The title compound (137) was obtained by the same procedure as in Example 7-3 using 3-iodopyridine (139 mg, 0.68 mmol) and the compound obtained in Example 29-2 (197 mg, 0.81 mmol). mg, 61.4%) was obtained as a brown oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.26 (1 H, br s), 8.87 (1 H, s), 8. 71 (1 H, s), 8.11 (1 H, d, J = 8.0 Hz ), 8.05 (1H, d, J = 2.3 Hz), 7.59 (2H, d, J = 6.9 Hz), 7.55 (1 H, d, J = 8.7 Hz), 7.49 (1 H, dd, J = 8.7, 2.3 Hz) ), 7.45 (2H, t, J = 7.7 Hz), 7.33 (1 H, t, J = 7.7 Hz), 7.19 (1 H, d, J = 8.7 Hz), 3.90 (3 H, s).
ESI-MS m / z: 329 [M + H] ⁺ .

製造例30：N-(5-ブロモ-2-メトキシフェニル)-3-(6-メトキシピリジン-3-イル)プロピオールアミド[化合物No.30]の合成
実施例30-1：N-(5-ブロモ-2-メトキシフェニル)-3-(6-メトキシピリジン-3-イル)プロピオールアミド[化合物No.30]の合成
5-ヨード-2-メトキシピリジン(204 mg, 0.87 mmol)と実施例9-2で得られた化合物(287 mg, 1.13 mmol)を用いて実施例7-3と同様の操作を行うことにより標記の化合物(77 mg, 24.5%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.18 (1H, br s), 8.51 (1H, d, J = 2.3 Hz), 8.00 (1H, d, J = 2.3 Hz), 7.97 (1H, dd, J = 8.8, 2.3 Hz), 7.34 (1H, dd, J = 8.8, 2.3 Hz), 7.06 (1H, d, J = 8.8 Hz), 6.95 (1H, d, J = 8.8 Hz), 3.92 (3H, s), 3.85 (3H, s).
ESI-MS m/z:361[M+H]⁺. Preparation Example 30 Synthesis of N- (5-bromo-2-methoxyphenyl) -3- (6-methoxypyridin-3-yl) propiolamide [Compound No. 30] Example 30-1: N- (5 Synthesis of -Bromo-2-methoxyphenyl) -3- (6-methoxypyridin-3-yl) propiolamide [Compound No. 30]
The title was obtained by the same procedure as in Example 7-3 using 5-iodo-2-methoxypyridine (204 mg, 0.87 mmol) and the compound obtained in Example 9-2 (287 mg, 1.13 mmol). The compound of (77 mg, 24.5%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.18 (1 H, br s), 8.51 (1 H, d, J = 2.3 Hz), 8.00 (1 H, d, J = 2.3 Hz), 7.97 (1 H, dd, J = 8.8, 2.3 Hz), 7.34 (1 H, dd, J = 8.8, 2.3 Hz), 7.06 (1 H, d, J = 8.8 Hz), 6.95 (1 H, d, J = 8.8 Hz ), 3.92 (3H, s), 3.85 (3H, s).
ESI-MS m / z: 361 [M + H] ⁺ .

製造例31：N-(5-ブロモ-2-メトキシフェニル)-N-メチル-3-(ピリジン-3-イル)プロピオールアミド[化合物No.31]の合成
実施例31-1：N-(5-ブロモ-2-メトキシフェニル)-N-メチル-3-(ピリジン-3-イル)プロピオールアミド[化合物No.31]の合成
実施例16-1で得られた化合物(37 mg, 0.11 mmol)をDMF(0.7 ml)に溶解した。そこへ炭酸セシウム(55 mg, 0.17 mmol)、ヨウ化メチル(0.008 ml, 0.13 mmol)を加えて室温で一晩撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, クロロホルム/酢酸エチル)で精製し、標記の化合物(30 mg, 79.0%)を褐色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.60 (1H, dd, J = 4.9, 1.7 Hz), 8.28 (1H, dd, J = 2.2, 0.8 Hz), 7.74 (1H, d, J = 2.2 Hz), 7.65 (1H, d, J = 3.7 Hz), 7.62 (1H, s), 7.18 (1H, d, J = 8.9 Hz), 3.84 (3H, s), 3.17 (3H, s).
ESI-MS m/z:345[M+H]⁺. Preparation Example 31 Synthesis of N- (5-bromo-2-methoxyphenyl) -N-methyl-3- (pyridin-3-yl) propiolamide [Compound No. 31] Example 31-1: N- ( Synthesis of 5-bromo-2-methoxyphenyl) -N-methyl-3- (pyridin-3-yl) propiolamide [compound No. 31]
The compound (37 mg, 0.11 mmol) obtained in Example 16-1 was dissolved in DMF (0.7 ml). Cesium carbonate (55 mg, 0.17 mmol) and methyl iodide (0.008 ml, 0.13 mmol) were added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 10 g, chloroform / ethyl acetate) to give the title compound (30 mg, 79.0%) as a brown oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.60 (1 H, dd, J = 4.9, 1.7 Hz), 8.28 (1 H, dd, J = 2.2, 0.8 Hz), 7.74 (1 H, 1 H, d, J = 2.2 Hz), 7. 65 (1 H, d, J = 3.7 Hz), 7.62 (1 H, s), 7. 18 (1 H, d, J = 8.9 Hz), 3. 84 (3 H, s), 3. 17 (3 H, s) s).
ESI-MS m / z: 345 [M + H] ⁺ .

製造例32：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.32]の合成
実施例32-1：2-アミノベンゼン-1,3-ジオールの合成
2-ニトロベンゼン-1,3-ジオール(1.00 g, 6.5 mmol)のエタノール(20 ml)溶液中にパラジウム炭素(200 mg)をアルゴン雰囲気下0℃で添加した。水素置換したのち、室温で4時間撹拌した。反応終了後、セライトろ過し、ろ液を減圧下濃縮し、標記の化合物(827 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96-8.64 (2H, m), 6.30-6.17 (3H, m), 3.95-3.60 (2H, m).
ESI-MS m/z:126[M+H]⁺. Preparation Example 32 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 32] Example 32 Synthesis of 2-aminobenzene-1,3-diol
Palladium carbon (200 mg) was added to a solution of 2-nitrobenzene-1,3-diol (1.00 g, 6.5 mmol) in ethanol (20 ml) at 0 ° C. under an argon atmosphere. After hydrogen substitution, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (827 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96-8.64 (2H, m), 6.30-6.17 (3H, m), 3.95-3.60 (2H, m).
ESI-MS m / z: 126 [M + H] ⁺ .

実施例32-2：ベンゾ[d]オキサゾール-4-オールの合成
実施例32-1で得られた化合物(400 mg, 3.20 mmol)のオルトギ酸トリエチル(3.2 ml, 19.2 mmol)溶液中に、パラトシル酸一水和物(30 mg, 0.16 mmol)を滴下した。アルゴン雰囲気下、還流条件で30分撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(232 mg, 54 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.51-10.08 (1H, m), 8.57 (1H, s), 7.21 (1H, dd, J = 8.0, 7.8 Hz), 7.15 (1H, d, J = 8.0 Hz), 6.77 (1H, d, J = 7.8 Hz).
ESI-MS m/z:136[M+H]⁺. Example 32-2: Synthesis of benzo [d] oxazol-4-ol
In a solution of the compound (400 mg, 3.20 mmol) obtained in Example 32-1 in triethyl orthoformate (3.2 ml, 19.2 mmol), paratosylate monohydrate (30 mg, 0.16 mmol) was dropped. After stirring for 30 minutes under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (232 mg, 54%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.51-10.08 (1 H, m), 8.57 (1 H, s), 7.21 (1 H, dd, J = 8.0, 7.8 Hz), 7.15 (7 1H, d, J = 8.0 Hz), 6.77 (1 H, d, J = 7.8 Hz).
ESI-MS m / z: 136 [M + H] ⁺ .

実施例32-3：4-メトキシベンゾ[d]オキサゾールの合成
実施例32-2で得られた化合物(100 mg, 0.74 mmol)のアセトン(4 ml)溶液中に、炭酸カリウム(113 mg, 0.81 mmol)、ヨウ化メタン(69 μl, 1.11 mmol)を添加した。80℃で2時間撹拌した後、反応終了後、セライトろ過し、ろ液を減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(26 mg, 24 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.63 (1H, s), 7.40-7.31 (2H, m), 6.95 (1H, dd, J = 7.6, 1.1 Hz), 3.97 (3H, s).
ESI-MS m/z:150[M+H]⁺. Example 32-3: Synthesis of 4-methoxybenzo [d] oxazole
Potassium carbonate (113 mg, 0.81 mmol) and iodomethane (69 μl, 1.11 mmol) were added to a solution of the compound (100 mg, 0.74 mmol) obtained in Example 32-2 in acetone (4 ml) . After stirring at 80 ° C. for 2 hours, after completion of the reaction, the mixture was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (26 mg, 24%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.63 (1 H, s), 7.40-7.31 (2 H, m), 6.95 (1 H, dd, J = 7.6, 1.1 Hz), 3.97 (3 3H, s).
ESI-MS m / z: 150 [M + H] ⁺ .

実施例32-4：4-(2,2-ジブロモビニル)ピリジンの合成
トリフェニルホスフィン(8.08 g, 30.8 mmol)のクロロホルム(40 ml)溶液中に、四臭化炭素(5.11 g, 15.4 mmol)をアルゴン雰囲気下、0℃で添加した。30分撹拌した後、ニコチンアルデヒド(1.32 ml, 14 mmol)を滴下した。室温に昇温して１時間撹拌した後、反応終了後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物(2.62 g, 71 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.72 (1H, s), 8.56 (1H, d, J = 10.0 Hz), 8.05 (1H, d, J = 9.0 Hz), 7.84 (1H, s), 7.46 (1H, dd, J = 10.0, 9.0 Hz).
ESI-MS m/z:262[M+H]⁺. Example 32-4 Synthesis of 4- (2,2-dibromovinyl) pyridine
Carbon tetrabromide (5.11 g, 15.4 mmol) was added to a solution of triphenylphosphine (8.08 g, 30.8 mmol) in chloroform (40 ml) at 0 ° C. under an argon atmosphere. After stirring for 30 minutes, nicotinaldehyde (1.32 ml, 14 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 1 hour. After completion of the reaction, saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (2.62 g, 71%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (1 H, s), 8.56 (1 H, d, J = 10.0 Hz), 8.05 (1 H, d, J = 9.0 Hz), 7.84 (1H, s), 7.46 (1H, dd, J = 10.0, 9.0 Hz).
ESI-MS m / z: 262 [M + H] ⁺ .

実施例32-5：4-(ブロモエチンイル)ピリジンの合成
実施例32-4で得られた化合物(2.62 g, 10.0 mmol)のTHF(20 ml)溶液中に、カリウムターシャリーブトキシド(1.17 g, 10.5 mmol)をアルゴン雰囲気下、0℃で添加した。室温に昇温し6時間撹拌した後、反応終了後、飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物(1.58 g, 87 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.69 (1H, s), 8.59 (1H, d, J = 4.8 Hz), 7.93 (1H, d, J = 7.8 Hz), 7.44-7.41 (1H, m).
ESI-MS m/z:182[M+H]⁺. Example 32-5: Synthesis of 4- (bromoethynyl) pyridine
In a solution of the compound (2.62 g, 10.0 mmol) obtained in Example 32-4 in THF (20 ml), potassium tertiary butoxide (1.17 g, 10.5 mmol) was added at 0 ° C. under an argon atmosphere. The mixture was warmed to room temperature and stirred for 6 hours. After completion of the reaction, saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (1.58 g, 87%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.69 (1 H, s), 8. 59 (1 H, d, J = 4.8 Hz), 7.93 (1 H, d, J = 7.8 Hz), 7.44 -7.41 (1 H, m).
ESI-MS m / z: 182 [M + H] ⁺ .

実施例32-6：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.32]の合成
実施例32-3で得られた化合物(26 mg, 0.17 mmol)、実施例32-5で得られた化合物(64 mg, 0.35 mmol)、臭化銅ジメチルスルフィド錯体(6 mg, 0.03 mmol)、DPEPhos(15 mg, 0.03 mmol)、リチウムターシャリーブトキシド (29 mg, 0.36 mmol)の1,4-ジオキサン(1.0 ml)溶液を、マイクロウェーブ照射下、120℃で1時間撹拌した。飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(37 mg, 85 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, br s), 8.74 (1H, d, J = 5.0 Hz), 8.21 (1H, d, J = 8.0 Hz), 7.57 (1H, dd, J = 8.0, 5.0 Hz), 7.48 (1H, dd, J = 8.2, 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.03 (1H, d, J = 8.2 Hz), 4.00 (3H, s).
ESI-MS m/z:251[M+H]⁺. Example 32-6 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 32]
Compound obtained in Example 32-3 (26 mg, 0.17 mmol), compound obtained in Example 32-5 (64 mg, 0.35 mmol), copper bromide dimethyl sulfide complex (6 mg, 0.03 mmol), A solution of DPEPhos (15 mg, 0.03 mmol), lithium tertiary butoxide (29 mg, 0.36 mmol) in 1,4-dioxane (1.0 ml) was stirred at 120 ° C. for 1 hour under microwave irradiation. Saturated brine was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (37 mg, 85%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, br s), 8.74 (1 H, d, J = 5.0 Hz), 8.21 (1 H, d, J = 8.0 Hz), 7.57 (1H, dd, J = 8.0, 5.0 Hz), 7.48 (1 H, dd, J = 8.2, 7.8 Hz), 7.35 (1 H, d, J = 7.8 Hz), 7.03 (1 H, d, J = 8.2 Hz ), 4.00 (3H, s).
ESI-MS m / z: 251 [M + H] ⁺ .

製造例33：2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.33]の合成
実施例33-1：2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.33]の合成
ベンゾオキサゾール(223 mg, 1.87 mmol)と実施例32-5で得られた化合物(682 mg, 3.74 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(237 mg, 57.5%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, dd, J = 2.1, 0.7 Hz), 8.75 (1H, dd, J = 4.9, 1.7 Hz), 8.22 (1H, ddd, J = 8.0, 2.1, 1.7 Hz), 7.86 (1H, dq, J = 8.0, 0.7 Hz), 7.81 (1H, dq, J = 8.0, 0.7 Hz), 7.60-7.54 (2H, m), 7.49 (1H, ddd, J = 8.3, 7.0, 0.7 Hz).
ESI-MS m/z:221[M+H]⁺. Preparation Example 33 Synthesis of 2- (Pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 33] Example 33-1: 2- (Pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 33] Synthesis
By performing the same operation as in Example 32-6 using benzoxazole (223 mg, 1.87 mmol) and the compound obtained in Example 32-5 (682 mg, 3.74 mmol), the title compound (237 mg, 57.5%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, dd, J = 2.1, 0.7 Hz), 8. 75 (1 H, dd, J = 4.9, 1.7 Hz), 8.22 (1 H, 1 H, ddd, J = 8.0, 2.1, 1.7 Hz), 7.86 (1 H, dq, J = 8.0, 0.7 Hz), 7.81 (1 H, dq, J = 8.0, 0.7 Hz), 7.60-7.54 (2 H, m), 7.49 (1H, ddd, J = 8.3, 7.0, 0.7 Hz).
ESI-MS m / z: 221 [M + H] ⁺ .

製造例34：5-フルオロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.34]の合成
実施例34-1：5-フルオロベンゾ[d]オキサゾールの合成
4-フルオロ-2-ニトロフェノール(1.00 g, 6.5 mmol)のエタノール(20 ml)溶液中にパラジウム炭素(200 mg)をアルゴン雰囲気下0℃で添加した。水素置換したのち、室温で5時間撹拌した。反応終了後、セライトろ過し、ろ液を減圧下濃縮した。残渣物のオルトギ酸トリエチル(6.5 ml, 39 mmol)溶液中に、パラトシル酸一水和物(62 mg, 0.33 mmol)を滴下した。アルゴン雰囲気下、還流条件で7時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(100 mg, 11 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.82 (1H, s), 7.84-7.82 (1H, m), 7.71-7.69 (1H, m), 7.34-7.31 (1H, m).
ESI-MS m/z:138[M+H]⁺. Preparation Example 34 Synthesis of 5-fluoro-2- (pyridin-3-ylethynyl) benzo [d] oxazole [compound No. 34] Example 34-1: Synthesis of 5-fluorobenzo [d] oxazole
Palladium on carbon (200 mg) was added to a solution of 4-fluoro-2-nitrophenol (1.00 g, 6.5 mmol) in ethanol (20 ml) at 0 ° C. under an argon atmosphere. After hydrogen substitution, the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Into a solution of the residue in triethyl orthoformate (6.5 ml, 39 mmol), paratosylate monohydrate (62 mg, 0.33 mmol) was added dropwise. After stirring for 7 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (100 mg, 11%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.82 (1 H, s), 7.84-7.82 (1 H, m), 7.71-7.69 (1 H, m), 7.34-7. 31 (1 H, m) ).
ESI-MS m / z: 138 [M + H] ⁺ .

実施例34-2：5-フルオロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.34]の合成
実施例34-1で得られた化合物(100 mg, 0.73 mmol)と実施例32-5で得られた化合物(266 mg, 1.46 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(41 mg, 24 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, br s), 8.75 (1H, dd, J = 4.8, 1.6 Hz), 8.24-8.22 (1H, m), 7.86 (1H, dd, J = 8.9, 4.4 Hz), 7.77 (1H, dd, J = 8.7, 2.3 Hz), 7.59-7.57 (1H, m), 7.46-7.41 (1H, m).
ESI-MS m/z:239[M+H]⁺. Example 34-2 Synthesis of 5-fluoro-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 34]
Using the compound (100 mg, 0.73 mmol) obtained in Example 34-1 and the compound (266 mg, 1.46 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (41 mg, 24%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, br s), 8.75 (1 H, dd, J = 4.8, 1.6 Hz), 8.24-8.22 (1 H, m), 7.86 (1H, dd, J = 8.9, 4.4 Hz), 7.77 (1 H, dd, J = 8.7, 2.3 Hz), 7.59-7.57 (1 H, m), 7.46-7.41 (1 H, m).
ESI-MS m / z: 239 [M + H] ⁺ .

製造例35：7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.35]の合成
実施例35-1：3-アミノベンゼン-1,2-ジオールの合成
2,3-ジメトキシアニリン(438 μl, 3.26 mmol)のジクロロメタン(5.0 ml)溶液中に、1mol/l三臭化ホウ素/ジクロロメタン溶液(11.4ml, 11.4 mmol)をアルゴン雰囲気下、-78℃で滴下漏斗からゆっくり滴下した。室温に昇温し、一晩撹拌した。飽和炭酸水素ナトリウム水溶液で反応を停止し、飽和塩化アンモニウム水溶液で中和した。酢酸エチルで抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(67 mg, 16 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.70 (1H, s), 7.78 (1H, s), 6.35 (1H, dd, J = 8.0, 7.8 Hz), 6.10 (1H, d, J = 7.8 Hz), 6.06 (1H, d, J = 8.0 Hz), 4.40 (2H, s).
ESI-MS m/z:126[M+H]⁺. Production Example 35 Synthesis of 7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 35] Example 35-1: Synthesis of 3-aminobenzene-1,2-diol
In a solution of 2,3-dimethoxyaniline (438 μl, 3.26 mmol) in dichloromethane (5.0 ml), 1 mol / l boron tribromide / dichloromethane solution (11.4 ml, 11.4 mmol) was added dropwise at -78 ° C under an argon atmosphere It slowly dripped from the funnel. The temperature was raised to room temperature and stirred overnight. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution and neutralized with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (67 mg, 16%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.70 (1 H, s), 7.78 (1 H, s), 6.35 (1 H, dd, J = 8.0, 7.8 Hz), 6.10 ( ¹ H, ¹ H, s) d, J = 7.8 Hz), 6.06 (1 H, d, J = 8.0 Hz), 4.40 (2 H, s).
ESI-MS m / z: 126 [M + H] ⁺ .

実施例35-2：ベンゾ[d]オキサゾール-7-オールの合成
実施例35-1で得られた化合物(67 mg, 0.54 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(41 mg, 57 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.38 (1H, s), 8.64 (1H, s), 7.23-7.15 (2H, m), 6.88-6.84 (1H, m).
ESI-MS m/z:136[M+H]⁺. Example 35-2 Synthesis of Benzo [d] oxazol-7-ol
The title compound (41 mg, 57%) was obtained by the same procedure as in Example 32-2 using the compound (67 mg, 0.54 mmol) obtained in Example 35-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.38 (1 H, s), 8.64 (1 H, s), 7.23-7.15 (2 H, m), 6.88-6.84 (1 H, m).
ESI-MS m / z: 136 [M + H] ⁺ .

実施例35-3：7-メトキシベンゾ[d]オキサゾールの合成
実施例35-2で得られた化合物(41 mg, 0.30 mmol)を用いて実施例32-3と同様の操作を行うことにより標記の化合物(44 mg, 97 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.71 (1H, s), 7.36-7.31 (2H, m), 7.07 (1H, dd, J = 7.8, 1.4 Hz), 3.97 (3H, s).
ESI-MS m/z:150[M+H]⁺. Example 35-3 Synthesis of 7-methoxybenzo [d] oxazole
The title compound (44 mg, 97%) was obtained by the same procedure as in Example 32-3 using the compound (41 mg, 0.30 mmol) obtained in Example 35-2.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.71 (1 H, s), 7.36-7.31 (2 H, m), 7.07 (1 H, dd, J = 7.8, 1.4 Hz), 3.97 (3 3H, s).
ESI-MS m / z: 150 [M + H] ⁺ .

実施例35-4：7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.35]の合成
実施例35-3で得られた化合物(44 mg, 0.30 mmol)と実施例32-5で得られた化合物(107 mg, 0.59 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(12 mg, 16 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.75 (1H, dd, J = 4.8, 1.6 Hz), 8.23-8.22 (1H, m), 7.58 (1H, ddd, J = 7.8, 5.0, 0.9 Hz), 7.42-7.40 (2H, m), 7.18-7.17 (1H, m), 4.00 (3H, s).
ESI-MS m/z:251[M+H]⁺. Example 35-4 Synthesis of 7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 35]
Using the compound (44 mg, 0.30 mmol) obtained in Example 35-3 and the compound (107 mg, 0.59 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (12 mg, 16%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.75 (1 H, dd, J = 4.8, 1.6 Hz), 8.23-8.22 (1 H, m), 7.58 (1H, ddd, J = 7.8, 5.0, 0.9 Hz), 7.42-7.40 (2H, m), 7.18-7.17 (1 H, m), 4.00 (3 H, s).
ESI-MS m / z: 251 [M + H] ⁺ .

製造例36：5-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.36]の合成
実施例36-1：5-メトキシベンゾ[d]オキサゾールの合成
2-アミノ-4-メトキシフェノール(239 mg, 1.72 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(182 mg, 70.9%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.68 (1H, s), 7.66 (1H, dd, J = 8.9, 0.5 Hz), 7.35 (1H, d, J = 2.5 Hz), 7.02 (1H, ddd, J = 8.9, 2.5, 0.5 Hz), 3.81 (3H, s).
ESI-MS m/z:150[M+H]⁺. Preparation Example 36 Synthesis of 5-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 36] Example 36-1: Synthesis of 5-methoxybenzo [d] oxazole
The title compound (182 mg, 70.9%) was obtained as a yellow solid by the same procedure as in Example 32-2 using 2-amino-4-methoxyphenol (239 mg, 1.72 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.68 (1 H, s), 7.66 (1 H, dd, J = 8.9, 0.5 Hz), 7.35 (1 H, d, J = 2.5 Hz) , 7.02 (1H, ddd, J = 8.9, 2.5, 0.5 Hz), 3.81 (3H, s).
ESI-MS m / z: 150 [M + H] ⁺ .

実施例36-2：5-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.36]の合成
実施例36-1で得られた化合物(99 mg, 0.66 mmol)と実施例32-5で得られた化合物(242 mg, 1.33 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(109 mg, 66.0%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, dd, J = 2.3, 0.9 Hz), 8.74 (1H, dd, J = 4.8, 1.7 Hz), 8.21 (1H, ddd, J = 8.0, 2.3, 1.7 Hz), 7.70 (1H, dd, J = 9.0, 0.5 Hz), 7.57 (1H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.38 (1H, d, J = 2.3 Hz), 7.13 (1H, dd, J = 9.0, 2.3 Hz), 3.84 (3H, s).
ESI-MS m/z:251[M+H]⁺. Example 36-2 Synthesis of 5-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 36]
Using the compound (99 mg, 0.66 mmol) obtained in Example 36-1 and the compound (242 mg, 1.33 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 Gave the title compound (109 mg, 66.0%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, dd, J = 2.3, 0.9 Hz), 8.74 (1 H, dd, J = 4.8, 1.7 Hz), 8.21 (1 H, 1 H, ddd, J = 8.0, 2.3, 1.7 Hz), 7.70 (1H, dd, J = 9.0, 0.5 Hz), 7.57 (1H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.38 (1H, d, J = 2.3 Hz), 7.13 (1 H, dd, J = 9.0, 2.3 Hz), 3.84 (3 H, s).
ESI-MS m / z: 251 [M + H] ⁺ .

製造例37：2-(ピリジン-3-イルエチニル)オキサゾロ[4,5-b]ピリジン[化合物No.37]の合成
実施例37-1：オキサゾロ[4,5-b]ピリジンの合成
2-アミノピリジン-3-オール(400 mg, 3.63 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(366 mg, 83.9%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.04 (1H, s), 8.58 (1H, dd, J = 4.7, 1.6 Hz), 8.27 (1H, dd, J = 8.4, 1.6 Hz), 7.50 (1H, dd, J = 8.4, 4.7 Hz).
ESI-MS m/z:121[M+H]⁺. Preparation Example 37 Synthesis of 2- (Pyridin-3-ylethynyl) oxazolo [4,5-b] pyridine [Compound No. 37] Example 37-1: Synthesis of Oxazolo [4,5-b] pyridine
The title compound (366 mg, 83.9%) was obtained as a white solid by the same procedure as in Example 32-2 using 2-aminopyridin-3-ol (400 mg, 3.63 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.04 (1 H, s), 8. 58 (1 H, dd, J = 4.7, 1.6 Hz), 8.27 (1 H, dd, J = 8.4, 1.6 Hz), 7.50 (1 H, dd, J = 8.4, 4.7 Hz).
ESI-MS m / z: 121 [M + H] ⁺ .

実施例37-2：2-(ピリジン-3-イルエチニル)オキサゾロ[4,5-b]ピリジン[化合物No.37]の合成
実施例37-1で得られた化合物(74 mg, 0.62 mmol)と実施例32-5で得られた化合物(224 mg, 1.23 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(7 mg, 5.1%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.00 (1H, br s), 8.77 (1H, br s), 8.66 (1H, dd, J = 4.8, 1.4 Hz), 8.32-8.28 (1H, m), 8.26 (1H, dt, J = 8.0, 1.9 Hz), 7.62-7.58 (2H, m).
ESI-MS m/z:222[M+H]⁺. Example 37-2 Synthesis of 2- (pyridin-3-ylethynyl) oxazolo [4,5-b] pyridine [Compound No. 37]
Using the compound (74 mg, 0.62 mmol) obtained in Example 37-1 and the compound (224 mg, 1.23 mmol) obtained in Example 32-5, the same procedure as in Example 32-6 is performed. The title compound (7 mg, 5.1%) was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.00 (1 H, br s), 8.77 (1 H, br s), 8. 66 (1 H, dd, J = 4.8, 1.4 Hz), 8.32- 8.28 (1 H, m), 8.26 (1 H, dt, J = 8.0, 1.9 Hz), 7.62-7.58 (2 H, m).
ESI-MS m / z: 222 [M + H] ⁺ .

製造例38：4-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.38]の合成
実施例38-1：4-メチルベンゾ[d]オキサジアゾールの合成
2-アミノ-3-メチルフェノール(300 mg, 2.44 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(152 mg, 27 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.69 (1H, s), 7.56 (1H, d, J = 7.8 Hz), 7.32 (1H, dd, J = 7.8, 7.3 Hz), 7.22 (1H, d, J = 7.3 Hz), 2.55 (3H, s).
ESI-MS m/z:134[M+H]⁺. Preparation Example 38 Synthesis of 4-methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 38] Example 38-1: Synthesis of 4-methylbenzo [d] oxadiazole
The title compound (152 mg, 27%) was obtained by the same procedure as in Example 32-2 using 2-amino-3-methylphenol (300 mg, 2.44 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.69 (1 H, s), 7.56 (1 H, d, J = 7.8 Hz), 7.32 (1 H, dd, J = 7.8, 7.3 Hz) , 7.22 (1 H, d, J = 7.3 Hz), 2.55 (3 H, s).
ESI-MS m / z: 134 [M + H] ⁺ .

実施例38-2：4-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.38]の合成
実施例38-1で得られた化合物(100 mg, 0.75 mmol)と実施例32-5で得られた化合物 (273 mg, 1.50 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(85 mg, 48 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.75 (1H, d, J = 4.8 Hz), 8.24-8.20 (1H, m), 7.62-7.55 (2H, m), 7.46-7.40 (1H, m), 7.30 (1H, d, J = 7.3 Hz), 2.57 (3H, s).
ESI-MS m/z:235[M+H]⁺. Example 38-2 Synthesis of 4-methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 38]
Using the compound (100 mg, 0.75 mmol) obtained in Example 38-1 and the compound (273 mg, 1.50 mmol) obtained in Example 32-5, the same procedure as in Example 32-6 is performed. The title compound (85 mg, 48%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.75 (1 H, d, J = 4.8 Hz), 8.24-8.20 (1 H, m), 7.62-7.55 (2H, m), 7.46-7.40 (1H, m), 7.30 (1H, d, J = 7.3 Hz), 2.57 (3H, s).
ESI-MS m / z: 235 [M + H] ⁺ .

製造例39：2-(ピリジン-3-イルエチニル)-5-(トリフルオロメチル)ベンゾ[d]オキサゾール[化合物No.39]の合成
実施例39-1：5-(トリフルオロメチル)ベンゾ[d]オキサゾールの合成
2-ニトロ-4-(トリフルオロメチル)フェノール(500 mg, 2.41 mmol)のエタノール(10 ml)溶液中にパラジウム炭素(200 mg)をアルゴン雰囲気下0℃で添加した。水素置換したのち、室温で一晩撹拌した。反応終了後、セライトろ過し、ろ液を減圧下濃縮した。残渣物のオルトギ酸トリエチル(2.4 ml, 14.5 mmol)溶液中に、パラトシル酸一水和物(23 mg, 0.12 mmol)を滴下した。アルゴン雰囲気下、還流条件で3時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(182 mg, 40 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, s), 8.26 (1H, s), 8.04 (1H, d, J = 8.7 Hz), 7.83 (1H, d, J = 8.7 Hz).
ESI-MS m/z:188[M+H]⁺. Preparation Example 39 Synthesis of 2- (Pyridin-3-ylethynyl) -5- (trifluoromethyl) benzo [d] oxazole [Compound No. 39] Example 39-1: 5- (Trifluoromethyl) benzo [d Synthesis of oxazole
Palladium on carbon (200 mg) was added to a solution of 2-nitro-4- (trifluoromethyl) phenol (500 mg, 2.41 mmol) in ethanol (10 ml) at 0 ° C. under an argon atmosphere. After hydrogen substitution, the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Into a solution of the residue in triethyl orthoformate (2.4 ml, 14.5 mmol), paratosylate monohydrate (23 mg, 0.12 mmol) was dropped. After stirring for 3 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (182 mg, 40%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, s), 8.26 (1 H, s), 8.04 (1 H, d, J = 8.7 Hz), 7.83 (1 H, d, J = 8.7 Hz).
ESI-MS m / z: 188 [M + H] ⁺ .

実施例39-2：2-(ピリジン-3-イルエチニル)-5-(トリフルオロメチル)ベンゾ[d]オキサゾール[化合物No.39]の合成
実施例39-1で得られた化合物(182 mg, 0.97 mmol)と実施例32-5で得られた化合物 (354 mg, 1.95 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(36 mg, 13 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.99 (1H, br s), 8.77 (1H, dd, J = 4.8, 1.6 Hz), 8.32 (1H, br s), 8.27-8.23 (1H, m), 8.05 (1H, d, J = 8.9 Hz), 7.93 (1H, d, J = 8.9 Hz), 7.62-7.58 (1H, m).
ESI-MS m/z:289[M+H]⁺. Example 39-2 Synthesis of 2- (pyridin-3-ylethynyl) -5- (trifluoromethyl) benzo [d] oxazole [Compound No. 39]
Using the compound (182 mg, 0.97 mmol) obtained in Example 39-1 and the compound (354 mg, 1.95 mmol) obtained in Example 32-5, the same procedure as in Example 32-6 is performed. The title compound (36 mg, 13%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.99 (1 H, br s), 8.77 (1 H, dd, J = 4.8, 1.6 Hz), 8.32 (1 H, br s), 8.27- 8.23 (1 H, m), 8.05 (1 H, d, J = 8.9 Hz), 7.93 (1 H, d, J = 8.9 Hz), 7.62-7.58 (1 H, m).
ESI-MS m / z: 289 [M + H] ⁺ .

製造例40：2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-アミン[化合物No.40]の合成
実施例40-1：4-ニトロベンゾ[d]オキサゾールの合成
2-アミノ-3-ニトロフェノール(1 g, 6.40 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(1.06 g, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.09 (1H, s), 8.30 (1H, d, J = 8.2 Hz), 8.25 (1H, d, J = 8.2 Hz), 7.71 (1H, dd, J = 8.2, 8.2 Hz).
ESI-MS m/z:165[M+H]⁺. Preparation Example 40 Synthesis of 2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-amine [Compound No. 40] Example 40-1: Synthesis of 4-Nitrobenzo [d] oxazole
The title compound (1.06 g, 100%) was obtained by the same procedure as in Example 32-2 using 2-amino-3-nitrophenol (1 g, 6.40 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.09 (1 H, s), 8.30 (1 H, d, J = 8.2 Hz), 8.25 (1 H, d, J = 8.2 Hz), 7.71 (1H, dd, J = 8.2, 8.2 Hz).
ESI-MS m / z: 165 [M + H] ⁺ .

実施例40-2：ベンゾ[d]オキサゾール-4-アミンの合成
実施例40-1で得られた化合物(600 mg, 3.66 mmol)のエタノール(10 ml)溶液中にパラジウム炭素(300 mg)をアルゴン雰囲気下0℃で添加した。水素置換したのち、室温で一晩撹拌した。反応終了後、セライトろ過し、ろ液を減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(404 mg, 82 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.47 (1H, s), 7.07 (1H, dd, J = 7.8, 7.8 Hz), 6.82 (1H, d, J = 7.8 Hz), 6.52 (1H, d, J = 7.8 Hz), 5.63 (2H, br s).
ESI-MS m/z:135[M+H]⁺. Example 40-2 Synthesis of Benzo [d] oxazol-4-amine
Palladium carbon (300 mg) was added to a solution of the compound obtained in Example 40-1 (600 mg, 3.66 mmol) in ethanol (10 ml) at 0 ° C. under an argon atmosphere. After hydrogen substitution, the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (404 mg, 82%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.47 (1 H, s), 7.07 (1 H, dd, J = 7.8, 7.8 Hz), 6.82 (1 H, d, J = 7.8 Hz) , 6.52 (1H, d, J = 7.8 Hz), 5.63 (2H, br s).
ESI-MS m / z: 135 [M + H] ⁺ .

実施例40-3：ターシャリーブチルベンゾ[d]オキサゾール-4-イルカルバメートの合成
実施例40-2で得られた化合物(80 mg, 0.60 mmol)のTHF(2.0 ml)溶液中に、ジターシャリーブチルジカーボネイト(277 μl, 1.19 mmol)、ジイソプロピルエチルアミン(419 μl, 2.38 mmol)を室温下滴下した。70℃で一晩撹拌した後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(140 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.04 (1H, s), 8.69 (1H, s), 7.67 (1H, d, J = 7.8 Hz), 7.42 (1H, d, J = 8.2 Hz), 7.35 (1H, dd, J = 8.2, 7.8 Hz), 1.49 (9H, s).
ESI-MS m/z:235[M+H]⁺. Example 40-3 Synthesis of tert-butyl benzo [d] oxazol-4-ylcarbamate
In a solution of the compound (80 mg, 0.60 mmol) obtained in Example 40-2 in THF (2.0 ml), ditertiary butyl dicarbonate (277 μl, 1.19 mmol), diisopropylethylamine (419 μl, 2.38 mmol) It dripped under room temperature. After stirring overnight at 70 ° C., the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (140 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.04 (1 H, s), 8.69 (1 H, s), 7.67 (1 H, d, J = 7.8 Hz), 7.42 (1 H, d, J = 8.2 Hz), 7.35 (1 H, dd, J = 8.2, 7.8 Hz), 1.49 (9 H, s).
ESI-MS m / z: 235 [M + H] ⁺ .

実施例40-4：ターシャリーブチル (2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)カルバメートの合成
実施例40-3で得られた化合物 (140 mg, 0.60 mmol)と実施例32-5で得られた化合物(218 mg, 1.19 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(6 mg, 3 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.30 (1H, s), 8.94 (1H, br s), 8.75 (1H, dd, J = 4.8, 1.6 Hz), 8.21-8.19 (1H, m), 7.77-7.71 (1H, m), 7.61-7.56 (1H, m), 7.49-7.41 (2H, m), 1.49 (9H, s).
ESI-MS m/z:336[M+H]⁺. Example 40-4 Synthesis of tert-butyl (2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) carbamate
Using the compound (140 mg, 0.60 mmol) obtained in Example 40-3 and the compound (218 mg, 1.19 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (6 mg, 3%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.30 (1 H, s), 8.94 (1 H, br s), 8.75 (1 H, dd, J = 4.8, 1.6 Hz), 8.21-8.19 (1H, m), 7.77-7.71 (1H, m), 7.61-7.56 (1H, m), 7.49-7.41 (2H, m), 1.49 (9H, s).
ESI-MS m / z: 336 [M + H] ⁺ .

実施例40-5：2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-アミン[化合物No.40]の合成
実施例40-4で得られた化合物(16 mg, 0.05 mmol)のジクロロメタン(620 μl)溶液中に、トリフルオロ酢酸(77 μl, 1.00 mmol)を0℃で滴下した。室温で6時間撹拌した後、反応終了後、飽和炭酸水素ナトリウム水溶液で中和した。酢酸エチルで抽出し、無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(5 mg, 45 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.92 (1H, br s), 8.72 (1H, dd, J = 4.8, 1.6 Hz), 8.18-8.16 (1H, m), 7.57-7.55 (1H, m), 7.17 (1H, dd, J = 8.2, 8.2 Hz), 6.81 (1H, d, J = 8.2 Hz), 6.57 (1H, d, J = 8.2 Hz), 5.92-5.85 (2H, m).
ESI-MS m/z:236[M+H]⁺. Example 40-5: Synthesis of 2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-amine [Compound No. 40]
Trifluoroacetic acid (77 μl, 1.00 mmol) was dropped at 0 ° C. into a solution of the compound (16 mg, 0.05 mmol) obtained in Example 40-4 in dichloromethane (620 μl). After stirring at room temperature for 6 hours, after completion of the reaction, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (5 mg, 45%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.92 (1 H, br s), 8. 72 (1 H, dd, J = 4.8, 1.6 Hz), 8.18-8.16 (1 H, m), 7.57 -7.55 (1H, m), 7.17 (1H, dd, J = 8.2, 8.2 Hz), 6.81 (1H, d, J = 8.2 Hz), 6.57 (1 H, d, J = 8.2 Hz), 5.92-5.85 ( 2H, m).
ESI-MS m / z: 236 [M + H] ⁺ .

製造例41：7-フルオロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.41]の合成
実施例41-1：2-アミノ-6-フルオロフェノールの合成
2-フルオロ-6-ニトロフェノール(322 mg, 2.05 mmol)をTHF(6.4 ml)、水(6.4 ml)に溶解し、そこへ塩化スズ(1.943 g, 10.25 mmol)を加えて一晩加熱還流した。反応後、飽和重曹水と酢酸エチルを加えた。沈殿物をろ過した。ろ液を酢酸エチルで抽出した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去し、標記の化合物(144 mg, 55.3%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.87 (1H, br s), 6.52 (1H, td, J = 8.2, 6.0 Hz), 6.40 (1H, dt, J = 8.2, 1.5 Hz), 6.31 (1H, ddd, J = 10.7, 8.2, 1.5 Hz), 4.83 (2H, br s).
ESI-MS m/z:128[M+H]⁺. Preparation Example 41 Synthesis of 7-fluoro-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 41] Example 41-1 Synthesis of 2-amino-6-fluorophenol
2-Fluoro-6-nitrophenol (322 mg, 2.05 mmol) was dissolved in THF (6.4 ml) and water (6.4 ml), and tin chloride (1.943 g, 10.25 mmol) was added thereto and heated to reflux overnight . After the reaction, saturated aqueous sodium bicarbonate solution and ethyl acetate were added. The precipitate was filtered off. The filtrate was extracted with ethyl acetate. Washed with saturated saline. Drying over magnesium sulfate and evaporation of the solvent gave the title compound (144 mg, 55.3%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.87 (1 H, br s), 6.52 (1 H, td, J = 8.2, 6.0 Hz), 6.40 (1 H, dt, J = 8.2, 1.5 Hz), 6.31 (1 H, ddd, J = 10.7, 8.2, 1.5 Hz), 4.83 (2 H, br s).
ESI-MS m / z: 128 [M + H] ⁺ .

実施例41-2：7-フルオロベンゾ[d]オキサゾールの合成
実施例41-1で得られた化合物(144 mg, 1.13 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(70 mg, 45.2%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.86 (1H, s), 7.68 (1H, dd, J = 7.6, 1.5 Hz), 7.42 (1H, t, J = 2.0 Hz).
ESI-MS m/z:138[M+H]⁺. Example 41-2 Synthesis of 7-fluorobenzo [d] oxazole
The title compound (70 mg, 45.2%) was obtained as a yellow oil by carrying out the same procedure as in Example 32-2 using the compound (144 mg, 1.13 mmol) obtained in Example 41-1 .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.86 (1 H, s), 7.68 (1 H, dd, J = 7.6, 1.5 Hz), 7.42 (1 H, t, J = 2.0 Hz) .
ESI-MS m / z: 138 [M + H] ⁺ .

実施例41-3：7-フルオロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.41]の合成
実施例41-2で得られた化合物(70 mg, 0.51 mmol)と実施例32-5で得られた化合物(186 mg, 1.02 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(15 mg, 12.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.99 (1H, t, J = 1.1 Hz), 8.76 (1H, dd, J = 4.9, 1.5 Hz), 8.25 (1H, dt, J = 7.9, 1.8 Hz), 7.72 (1H, dd, J = 5.6, 3.5 Hz), 7.59 (1H, ddd, J = 7.9, 4.9, 0.9 Hz), 7.51-7.48 (2H, m).
ESI-MS m/z:239[M+H]⁺. Example 41-3 Synthesis of 7-fluoro-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 41]
Using the compound (70 mg, 0.51 mmol) obtained in Example 41-2 and the compound (186 mg, 1.02 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 Gave the title compound (15 mg, 12.3%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.99 (1 H, t, J = 1.1 Hz), 8.76 (1 H, dd, J = 4.9, 1.5 Hz), 8.25 (1 H, dt, J = 7.9, 1.8 Hz), 7.72 (1 H, dd, J = 5.6, 3.5 Hz), 7.59 (1 H, ddd, J = 7.9, 4.9, 0.9 Hz), 7.51-7.48 (2 H, m).
ESI-MS m / z: 239 [M + H] ⁺ .

製造例42：7-ブロモ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.42]の合成
実施例42-1：2-アミノ-6-ブロロモフェノールの合成
2-ブロモ-6-ニトロフェノール(434 mg, 1.99 mmol)を用いて実施例41-1と同様の操作を行うことにより標記の化合物(288 mg, 76.9%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 6.66 (1H, dd, J = 7.8, 1.7 Hz), 6.59 (1H, dd, J = 7.8, 1.7 Hz), 6.52 (1H, t, J = 7.8 Hz).
ESI-MS m/z:188[M+H]⁺. Preparation Example 42 Synthesis of 7-bromo-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 42] Example 42 Synthesis of 2-amino-6-bromomophenol
The title compound (288 mg, 76.9%) was obtained as a white solid by the same procedure as in Example 41-1 using 2-bromo-6-nitrophenol (434 mg, 1.99 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 6.66 (1 H, dd, J = 7.8, 1.7 Hz), 6.59 (1 H, dd, J = 7.8, 1.7 Hz), 6.52 (1 H, t, J = 7.8 Hz).
ESI-MS m / z: 188 [M + H] ⁺ .

実施例42-2：7-ブロモベンゾ[d]オキサゾールの合成
実施例42-1で得られた化合物(288 mg, 1.53 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(332 mg, quant.)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.87 (1H, s), 7.83 (1H, dd, J = 7.9, 0.9 Hz), 7.69 (1H, dd, J = 7.9, 0.9 Hz), 7.38 (1H, t, J = 7.9 Hz).
ESI-MS m/z:198[M+H]⁺. Example 42-2 Synthesis of 7-bromobenzo [d] oxazole
The title compound (332 mg, quant.) Was obtained as a yellow solid by carrying out the same procedure as in Example 32-2 using the compound (288 mg, 1.53 mmol) obtained in Example 42-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.87 (1 H, s), 7.83 (1 H, dd, J = 7.9, 0.9 Hz), 7.69 (1 H, dd, J = 7.9, 0.9) Hz), 7.38 (1 H, t, J = 7.9 Hz).
ESI-MS m / z: 198 [M + H] ⁺ .

実施例42-3：7-ブロモ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.42]の合成
実施例42-2で得られた化合物(117 mg, 0.59 mmol)と実施例32-5で得られた化合物(215 mg, 1.18 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(54 mg, 30.6%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.00 (1H, d, J = 1.9 Hz), 8.76 (1H, dd, J = 4.9, 0.9 Hz), 8.26 (1H, dt, J = 8.0, 1.9 Hz), 7.87 (1H, dd, J = 8.0, 0.9 Hz), 7.79 (1H, dd, J = 8.0, 0.9 Hz), 7.59 (1H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.44 (1H, t, J = 8.0 Hz).
ESI-MS m/z:298[M+H]⁺. Example 42-3 Synthesis of 7-bromo-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 42]
Using the compound (117 mg, 0.59 mmol) obtained in Example 42-2 and the compound (215 mg, 1.18 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 Gave the title compound (54 mg, 30.6%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.00 (1 H, d, J = 1.9 Hz), 8.76 (1 H, dd, J = 4.9, 0.9 Hz), 8.26 (1 H, dt, J = 8.0, 1.9 Hz), 7.87 (1 H, dd, J = 8.0, 0.9 Hz), 7.79 (1 H, dd, J = 8.0, 0.9 Hz), 7.59 (1 H, ddd, J = 8.0, 4.9, 0.9 Hz ), 7.44 (1 H, t, J = 8.0 Hz).
ESI-MS m / z: 298 [M + H] ⁺ .

製造例43：7-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.43]の合成
実施例43-1：2-アミノ-6-メチルフェノールの合成
2-メチル-6-ニトロフェノール(342 mg, 2.23 mmol)を用いて実施例41-1と同様の操作を行うことにより標記の化合物(108 mg, 39.3%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.78 (1H, br s), 6.50-6.43 (2H, m), 6.30 (1H, ddd, J = 6.7, 2.4, 0.6 Hz), 4.53 (2H, br s), 2.09 (3H, s).
ESI-MS m/z:124[M+H]⁺. Preparation Example 43 Synthesis of 7-methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 43] Example 43-1 Synthesis of 2-amino-6-methylphenol
The title compound (108 mg, 39.3%) was obtained as a white solid by the same procedure as in Example 41-1 using 2-methyl-6-nitrophenol (342 mg, 2.23 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.78 (1 H, br s), 6.50-6.43 (2 H, m), 6.30 (1 H, ddd, J = 6.7, 2.4, 0.6 Hz) , 4.53 (2H, br s), 2.09 (3H, s).
ESI-MS m / z: 124 [M + H] ⁺ .

実施例43-2：7-メチルベンゾ[d]オキサゾールの合成
実施例43-1で得られた化合物(108 mg, 0.88 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(46 mg, 39.3%)を褐色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.72 (1H, s), 7.61 (1H, dq, J = 7.6, 0.7 Hz), 7.48 (1H, dd, J = 8.7, 0.7 Hz), 7.30 (1H, t, J = 7.6 Hz), 2.51 (3H, s).
ESI-MS m/z:134[M+H]⁺. Example 43-2 Synthesis of 7-methylbenzo [d] oxazole
The title compound (46 mg, 39.3%) was obtained as a brown oil by the same procedure as in Example 32-2 using the compound (108 mg, 0.88 mmol) obtained in Example 43-1. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (1 H, s), 7.61 (1 H, dq, J = 7.6, 0.7 Hz), 7.48 (1 H, dd, J = 8.7, 0.7 Hz), 7.30 (1 H, t, J = 7.6 Hz), 2.51 (3 H, s).
ESI-MS m / z: 134 [M + H] ⁺ .

実施例43-3：7-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.43]の合成
実施例43-2で得られた化合物(46 mg, 0.35 mmol)と実施例32-5で得られた化合物(126 mg, 0.69 mmol)を用いて実施例32-6と同様の操作を行うことで標記の化合物(29 mg, 35.4%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, dd, J = 2.2, 0.9 Hz), 8.75 (1H, dd, J = 4.9, 1.7 Hz), 8.23 (1H, ddd, J = 7.9, 2.2, 1.7 Hz), 7.67-7.64 (1H, m), 7.58 (1H, ddd, J = 7.9, 4.9, 0.9 Hz), 7.38 (2H, d, J = 6.4 Hz), 2.53 (3H, s).
ESI-MS m/z:235[M+H]⁺. Example 43-3 Synthesis of 7-methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 43]
Using the compound (46 mg, 0.35 mmol) obtained in Example 43-2 and the compound (126 mg, 0.69 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (29 mg, 35.4%) was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, dd, J = 2.2, 0.9 Hz), 8.75 (1 H, dd, J = 4.9, 1.7 Hz), 8.23 (1 H, 1 H, ddd, J = 7.9, 2.2, 1.7 Hz), 7.67-7.64 (1 H, m), 7.58 (1 H, ddd, J = 7.9, 4.9, 0.9 Hz), 7.38 (2 H, d, J = 6.4 Hz), 2.53 (3H, s).
ESI-MS m / z: 235 [M + H] ⁺ .

製造例44：4-(メチルチオ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.44]の合成
実施例44-1：3-(メチルチオ)-2-ニトロフェノールの合成
3-フルオロ-2-ニトロフェノール(175 mg, 1.11 mmol)のDMF(3 ml)溶液中に、ナトリウムメタンチオレート(86 mg, 1.23 mmol)を室温下添加した。80℃で一晩撹拌した後、反応終了後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(66 mg, 24 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.03 (1H, s), 7.36 (1H, dd, J = 8.2, 7.3 Hz), 6.95 (1H, d, J = 7.3 Hz), 6.88 (1H, d, J = 8.2 Hz), 3.33 (3H, s). Preparation Example 44 Synthesis of 4- (methylthio) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 44] Example 44-1: Synthesis of 3- (methylthio) -2-nitrophenol
Sodium methanethiolate (86 mg, 1.23 mmol) was added to a solution of 3-fluoro-2-nitrophenol (175 mg, 1.11 mmol) in DMF (3 ml) at room temperature. After stirring overnight at 80 ° C., after completion of the reaction, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (66 mg, 24%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.03 (1 H, s), 7.36 (1 H, dd, J = 8.2, 7.3 Hz), 6.95 (1 H, d, J = 7.3 Hz) , 6.88 (1 H, d, J = 8.2 Hz), 3.33 (3 H, s).

実施例44-2：4-(メチルチオ)ベンゾ[d]オキサゾールの合成
実施例44-1で得られた化合物(66 mg, 0.36 mmol)のエタノール(5 ml)溶液中にパラジウム炭素(80 mg)をアルゴン雰囲気下0℃で添加した。水素置換したのち、室温で一晩撹拌した。反応終了後、セライトろ過し、ろ液を減圧下濃縮した。残渣物のオルトギ酸トリエチル(360 μl, 2.16 mmol)溶液中に、パラトシル酸一水和物(4 mg, 0.02 mmol)を滴下した。アルゴン雰囲気下、還流条件で1時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(55 mg, 92 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.74 (1H, s), 7.55 (1H, d, J = 8.2 Hz), 7.41 (1H, dd, J = 8.2, 7.3 Hz), 7.23 (1H, d, J = 7.3 Hz), 2.61 (3H, s).
ESI-MS m/z:166[M+H]⁺. Example 44-2 Synthesis of 4- (methylthio) benzo [d] oxazole
Palladium carbon (80 mg) was added to a solution of the compound (66 mg, 0.36 mmol) obtained in Example 44-1 in ethanol (5 ml) at 0 ° C. under an argon atmosphere. After hydrogen substitution, the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Into a solution of the residue in triethyl orthoformate (360 μl, 2.16 mmol), paratosylate monohydrate (4 mg, 0.02 mmol) was dropped. After stirring for 1 hour under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (55 mg, 92%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.74 (1 H, s), 7.55 (1 H, d, J = 8.2 Hz), 7.41 (1 H, dd, J = 8.2, 7.3 Hz) , 7.23 (1 H, d, J = 7.3 Hz), 2.61 (3 H, s).
ESI-MS m / z: 166 [M + H] ⁺ .

実施例44-3：4-(メチルチオ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.44]の合成
実施例44-2で得られた化合物(55 mg, 0.33 mmol)と実施例32-5で得られた化合物(121 mg, 0.67 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(43 mg, 49 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, br s), 8.75 (1H, d, J = 4.8 Hz), 8.26-8.20 (1H, m), 7.60-7.54 (2H, m), 7.51 (1H, dd, J = 8.0, 7.6 Hz), 7.29 (1H, dd, J = 7.6, 1.1 Hz), 2.62 (3H, s).
ESI-MS m/z: 267[M+H]⁺ Example 44-3 Synthesis of 4- (methylthio) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 44]
Using the compound (55 mg, 0.33 mmol) obtained in Example 44-2 and the compound (121 mg, 0.67 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (43 mg, 49%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, br s), 8.75 (1 H, d, J = 4.8 Hz), 8.26-8.20 (1 H, m), 7.60-7.54 (2H, m), 7.51 (1 H, dd, J = 8.0, 7.6 Hz), 7.29 (1 H, dd, J = 7.6, 1.1 Hz), 2.62 (3 H, s).
ESI-MS m / z: 267 [M + H] ⁺

製造例45：4-((ターシャリーブチルジメチルシリル)オキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.45]の合成
実施例45-1：4-((ターシャリーブチルジメチルシリル)オキシ)ベンゾ[d]オキサゾールの合成
実施例32-2で得られた化合物(150 mg, 1.11 mmol)のジクロロメタン(5 ml)溶液中に、ターシャリーブチルジメチルシリルクロライド(218 mg, 1.44 mmol)、N,N-ジメチル-4-アミノピリジン(7 mg, 0.06 mmol)、トリエチルアミン(201 μl, 1.44 mmol)を室温で添加した。一晩撹拌した後、さらにターシャリーブチルジメチルシリルクロライド(218 mg, 1.44 mmol)、N,N-ジメチル-4-アミノピリジン(7 mg, 0.06 mmol)、トリエチルアミン(201 μl, 1.44 mmol)を添加し、50℃で3時間後撹拌した。反応終了後、飽和食塩水を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(277 mg, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.64 (1H, s), 7.37 (1H, d, J = 8.0 Hz), 7.31 (1H, dd, J = 8.0, 7.8 Hz), 6.87 (1H, d, J = 7.8 Hz), 1.01 (9H, s), 0.25 (6H, s).
ESI-MS m/z: 250[M+H]⁺. Preparation Example 45 Synthesis of 4-((tertiary butyldimethylsilyl) oxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 45] Example 45-1: 4-((Tasha Synthesis of (L-butyldimethylsilyl) oxy) benzo [d] oxazole
In a solution of the compound (150 mg, 1.11 mmol) obtained in Example 32-2 in dichloromethane (5 ml), tert-butyldimethylsilyl chloride (218 mg, 1.44 mmol), N, N-dimethyl-4-amino Pyridine (7 mg, 0.06 mmol), triethylamine (201 μl, 1.44 mmol) were added at room temperature. After stirring overnight, tertiary butyldimethylsilyl chloride (218 mg, 1.44 mmol), N, N-dimethyl-4-aminopyridine (7 mg, 0.06 mmol) and triethylamine (201 μl, 1.44 mmol) were further added. After stirring for 3 hours at 50 ° C. After completion of the reaction, brine was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (277 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.64 (1 H, s), 7.37 (1 H, d, J = 8.0 Hz), 7.31 (1 H, dd, J = 8.0, 7.8 Hz) , 6.87 (1 H, d, J = 7.8 Hz), 1.01 (9 H, s), 0.25 (6 H, s).
ESI-MS m / z: 250 [M + H] ⁺ .

実施例45-2：4-((ターシャリーブチルジメチルシリル)オキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.45]の合成
実施例45-1で得られた化合物(250 mg, 1.00 mmol)と実施例32-5で得られた化合物(365 mg, 2.00 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(60 mg, 17 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, br s), 8.74 (1H, dd, J = 5.0, 1.4 Hz), 8.25-8.21 (1H, m), 7.61-7.55 (1H, m), 7.44-7.35 (2H, m), 6.94 (1H, dd, J = 7.1, 1.6 Hz), 1.01 (9H, s), 0.27 (6H, s).
ESI-MS m/z: 351[M+H]⁺. Example 45-2 Synthesis of 4-((tert-butyldimethylsilyl) oxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 45]
Using the compound (250 mg, 1.00 mmol) obtained in Example 45-1 and the compound (365 mg, 2.00 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 Gave the title compound (60 mg, 17%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, br s), 8.74 (1 H, dd, J = 5.0, 1.4 Hz), 8.25-8.21 (1 H, m), 7.61 -7.55 (1 H, m), 7.44-7. 35 (2 H, m), 6.94 (1 H, dd, J = 7.1, 1.6 Hz), 1.01 (9 H, s), 0.27 (6 H, s).
ESI-MS m / z: 351 [M + H] ⁺ .

製造例46：2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-オール[化合物No.46]の合成
実施例46-1：2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-オール[化合物No.46]の合成
実施例45-2で得られた化合物(33mg, 0.09mmol)のTHF(6 ml)溶液中に、テトラブチルアンモニウムフルオリド(26 mg, 0.10 mmol)を室温下添加した。3時間撹拌した後、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(2 mg, 9 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.65 (1H, s), 8.94 (1H, br s), 8.74 (1H, dd, J = 5.0, 1.8 Hz), 8.21-8.19 (1H, m), 7.58-7.57 (1H, m), 7.33 (1H, dd, J = 8.2, 8.2 Hz), 7.18 (1H, d, J = 8.2 Hz), 6.84 (1H, d, J = 8.2 Hz).
ESI-MS m/z: 237[M+H]⁺. Preparation Example 46 Synthesis of 2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-ol [Compound No. 46] Example 46-1: 2- (Pyridin-3-ylethynyl) benzo [d] oxazole Synthesis of -4-ol [compound No. 46]
Tetrabutylammonium fluoride (26 mg, 0.10 mmol) was added to a solution of the compound (33 mg, 0.09 mmol) obtained in Example 45-2 in THF (6 ml) at room temperature. After stirring for 3 hours, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2 mg, 9%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.65 (1 H, s), 8.94 (1 H, br s), 8.74 (1 H, dd, J = 5.0, 1.8 Hz), 8.21-8.19 (1H, m), 7.58-7.57 (1 H, m), 7.33 (1 H, dd, J = 8.2, 8.2 Hz), 7.18 (1 H, d, J = 8.2 Hz), 6.84 (1 H, d, J = 8.2 Hz).
ESI-MS m / z: 237 [M + H] ⁺ .

製造例47：7-((ターシャリーブチルジメチルシリル)オキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.47]の合成
実施例47-1：7-((ターシャリーブチルジメチルシリル)オキシ)ベンゾ[d]オキサゾールの合成
実施例35-2で得られた化合物(77 mg, 0.57 mmol)をDMF(1.5 ml)に溶解した。そこへターシャリーブチルジメチルシリルクロライド(103 mg, 0.68 mmol)、イミダゾール(46 mg, 0.68 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(57 mg, 40.1%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.71 (1H, s), 7.40 (1H, dd, J = 7.9, 0.8 Hz), 7.26 (1H, t, J = 7.9 Hz), 6.95 (1H, dd, J = 7.9, 0.8 Hz), 1.00 (9H, s), 0.24 (6H, s).
ESI-MS m/z:250[M+H]⁺. Preparation Example 47 Synthesis of 7-((tert-butyldimethylsilyl) oxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 47] Example 47-1: 7-((Tasha Synthesis of (L-butyldimethylsilyl) oxy) benzo [d] oxazole
The compound (77 mg, 0.57 mmol) obtained in Example 35-2 was dissolved in DMF (1.5 ml). The tertiary butyl dimethyl silyl chloride (103 mg, 0.68 mmol) and the imidazole (46 mg, 0.68 mmol) were added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 10 g, hexane / ethyl acetate) to give the title compound (57 mg, 40.1%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.71 (1 H, s), 7.40 (1 H, dd, J = 7.9, 0.8 Hz), 7.26 (1 H, t, J = 7.9 Hz) , 6.95 (1 H, dd, J = 7.9, 0.8 Hz), 1.00 (9 H, s), 0.24 (6 H, s).
ESI-MS m / z: 250 [M + H] ⁺ .

実施例47-2：7-((ターシャリーブチルジメチルシリル)オキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.47]の合成
実施例47-1で得られた化合物(57 mg, 0.23 mmol)と実施例32-5で得られた化合物(83 mg, 0.46 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(40 mg, 49.6%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, dd, J = 2.2, 0.8 Hz), 8.75 (1H, dd, J = 5.0, 1.7 Hz), 8.23 (1H, ddd, J = 8.0, 2.2, 1.7 Hz), 7.58 (1H, ddd, J = 8.0, 5.0, 0.8 Hz), 7.44 (1H, dd, J = 8.0, 1.1 Hz), 7.35 (1H, t, J = 8.0 Hz), 7.06 (1H, dd, J = 8.0, 1.1 Hz), 1.01 (9H, s), 0.28 (6H, s).
ESI-MS m/z:351[M+H]⁺. Example 47-2 Synthesis of 7-((tert-butyldimethylsilyl) oxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 47]
Using the compound (57 mg, 0.23 mmol) obtained in Example 47-1 and the compound (83 mg, 0.46 mmol) obtained in Example 32-5, the same operation as in Example 32-6 is performed. Gave the title compound (40 mg, 49.6%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, dd, J = 2.2, 0.8 Hz), 8. 75 (1 H, dd, J = 5.0, 1.7 Hz), 8.23 (1 H, 1 H, ddd, J = 8.0, 2.2, 1.7 Hz), 7.58 (1 H, ddd, J = 8.0, 5.0, 0.8 Hz), 7.44 (1 H, dd, J = 8.0, 1.1 Hz), 7.35 (1 H, t, J = 8.0 Hz), 7.06 (1 H, dd, J = 8.0, 1.1 Hz), 1.01 (9 H, s), 0.28 (6 H, s).
ESI-MS m / z: 351 [M + H] ⁺ .

製造例48：2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-オール[化合物No.48]の合成
実施例48-1：2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-オール[化合物No.48]の合成
実施例47-2で得られた化合物(37 mg, 0.11 mmol)をTHF(0.7 ml)に溶解した。そこへ1 mol/lテトラアンモニウムフルオライドTHF溶液(0.127 ml, 0.13 mmol)を加えて室温で1時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(10 mg, 38.5%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.63 (1H, br s), 8.96 (1H, dd, J = 2.1, 0.9 Hz), 8.75 (1H, dd, J = 4.9, 1.5 Hz), 8.22 (1H, dq, J = 8.0, 1.5 Hz), 7.58 (1H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.26 (1H, d, J = 3.1 Hz), 7.25 (1H, s), 6.95 (1H, dd, J = 5.8, 3.1 Hz).
ESI-MS m/z:237[M+H]⁺. Preparation Example 48 Synthesis of 2- (Pyridin-3-ylethynyl) benzo [d] oxazol-7-ol [Compound No. 48] Example 48-1: 2- (Pyridin-3-ylethynyl) benzo [d] oxazole Synthesis of -7-ol [compound No. 48]
The compound (37 mg, 0.11 mmol) obtained in Example 47-2 was dissolved in THF (0.7 ml). The 1 mol / l tetra ammonium fluoride THF solution (0.127 ml, 0.13 mmol) was added there, and it stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, hexane / ethyl acetate) to give the title compound (10 mg, 38.5%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.63 (1 H, br s), 8.96 (1 H, dd, J = 2.1, 0.9 Hz), 8.75 (1 H, dd, J = 4.9, 1.5 Hz), 8.22 (1 H, dq, J = 8.0, 1.5 Hz), 7.58 (1 H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.26 (1 H, d, J = 3.1 Hz), 7.25 (1 H, 1 H, d s), 6.95 (1 H, dd, J = 5.8, 3.1 Hz).
ESI-MS m / z: 237 [M + H] ⁺ .

製造例49：4-モルホリノ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.49]の合成
実施例49-1：4-(3-(ベンジロキシ)-2-ニトロフェニル)モルホリンの合成
1-(ベンジロキシ)-3-フルオロ-2-ニトロベンゼン(0.5 g, 2.02 mmol)のDMF(10 ml)溶液中に、モルホリン(211μl, 2.43 mmol)、炭酸カリウム(1.118g, 8.09 mmol)を添加した。80℃で撹拌した後、反応終了後、減圧下濃縮乾固した。飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(100 mg, 16 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.47 (1H, dd, J = 8.7, 7.8 Hz), 7.43-7.31 (5H, m), 7.13 (1H, d, J = 8.7 Hz), 7.01 (1H, d, J = 7.8 Hz), 5.24 (2H, s), 3.63-3.62 (4H, m), 2.90-2.88 (4H, m).
ESI-MS m/z: 315[M+H]⁺. Preparation Example 49 Synthesis of 4-morpholino-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 49] Example 49-1: 4- (3- (benzyloxy) -2-nitrophenyl) Synthesis of morpholine
Morpholine (211 μl, 2.43 mmol) and potassium carbonate (1.118 g, 8.09 mmol) were added to a solution of 1- (benzyloxy) -3-fluoro-2-nitrobenzene (0.5 g, 2.02 mmol) in DMF (10 ml) . After stirring at 80 ° C., after completion of the reaction, it was concentrated to dryness under reduced pressure. Saturated brine was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (100 mg, 16%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.47 (1 H, dd, J = 8.7, 7.8 Hz), 7.43-7.31 (5 H, m), 7.13 (1 H, d, J = 8.7 Hz), 7.01 (1 H, d, J = 7.8 Hz), 5.24 (2 H, s), 3.63-3.62 (4 H, m), 2. 90-2.88 (4 H, m).
ESI-MS m / z: 315 [M + H] ⁺ .

実施例49-2：2-アミノ-3-モルホリノフェノールの合成
実施例49-1で得られた化合物(100mg, 0.32 mmol)を用いて実施例32-1と同様の操作を行うことにより標記の化合物(45 mg, 73 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.05 (1H, s), 6.51-6.39 (3H, m), 4.21-4.08 (2H, m), 3.73 (4H, t, J = 4.4 Hz), 2.78 (4H, t, J = 4.4 Hz).
ESI-MS m/z: 195[M+H]⁺. Example 49-2 Synthesis of 2-amino-3-morpholinophenol
The title compound (45 mg, 73%) was obtained by the same procedure as in Example 32-1 using the compound (100 mg, 0.32 mmol) obtained in Example 49-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.05 (1 H, s), 6.51 to 6.39 (3 H, m), 4.21-4.08 (2 H, m), 3.73 (4 H, t, J = 4.4 Hz), 2.78 (4 H, t, J = 4.4 Hz).
ESI-MS m / z: 195 [M + H] ⁺ .

実施例49-3：4-モルホリノベンゾ[d]オキサゾールの合成
実施例49-2で得られた化合物(45 mg, 0.23 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(23 mg, 49 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.61 (1H, s), 7.29 (1H, dd, J = 8.2, 7.8 Hz), 7.22 (1H, d, J = 8.2 Hz), 6.74 (1H, d, J = 7.8 Hz), 3.80 (4H, t, J = 4.6 Hz), 3.49 (4H, t, J = 4.6 Hz).
ESI-MS m/z:205[M+H]⁺. Example 49-3: Synthesis of 4-morpholinobenzo [d] oxazole
The title compound (23 mg, 49%) was obtained by the same procedure as that of Example 32-2 using the compound (45 mg, 0.23 mmol) obtained in Example 49-2.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.61 (1 H, s), 7.29 (1 H, dd, J = 8.2, 7.8 Hz), 7.22 (1 H, d, J = 8.2 Hz) , 6.74 (1 H, d, J = 7.8 Hz), 3.80 (4 H, t, J = 4.6 Hz), 3. 49 (4 H, t, J = 4.6 Hz).
ESI-MS m / z: 205 [M + H] ⁺ .

実施例49-4：4-モルホリノ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.49]の合成
実施例49-3で得られた化合物(16 mg, 0.08 mmol)と実施例32-5で得られた化合物 (29 mg, 0.16 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(5mg, 21 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, br s), 8.74-8.73 (1H, br m), 8.24-8.20 (1H, m), 7.60-7.54 (1H, m), 7.39 (1H, dd, J = 8.2, 7.8 Hz), 7.22 (1H, d, J = 8.2 Hz), 6.80 (1H, d, J = 7.8 Hz), 3.81 (4H, t, J = 4.8 Hz), 3.52 (4H, t, J = 4.8 Hz).
ESI-MS m/z: 306[M+H]⁺. Example 49-4 Synthesis of 4-morpholino-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 49]
Using the compound (16 mg, 0.08 mmol) obtained in Example 49-3 and the compound (29 mg, 0.16 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 Gave the title compound (5 mg, 21%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, br s), 8.74-8.73 (1 H, br m), 8.24-8.20 (1 H, m), 7.60-7.54 (1 H , m), 7.39 (1 H, dd, J = 8.2, 7.8 Hz), 7.22 (1 H, d, J = 8.2 Hz), 6.80 (1 H, d, J = 7.8 Hz), 3.81 (4 H, t, J = 4.8 Hz), 3.52 (4 H, t, J = 4.8 Hz).
ESI-MS m / z: 306 [M + H] ⁺ .

製造例50：4-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.50]の合成
実施例50-1：4-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.50]の合成
実施例46-1で得られた化合物(20 mg, 0.09 mmol)のDMF(2 ml)溶液中に、炭酸セシウム(83 mg, 0.25 mmol)、4-(2-クロロエチル)モルホリン塩酸塩(17mg, 0.09 mmol)を室温下添加した。70℃で一晩撹拌した後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(4 mg, 14 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, br s), 8.74 (1H, dd, J = 5.0, 1.4 Hz), 8.22-8.20 (1H, m), 7.61-7.55 (1H, m), 7.45 (1H, dd, J = 8.2, 8.2 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.04 (1H, d, J = 8.2 Hz), 4.38 (2H, t, J = 5.5 Hz), 3.59 (4H, t, J = 4.8 Hz), 2.78 (2H, t, J = 5.5 Hz), 2.56-2.52 (4H, m).
ESI-MS m/z: 350[M+H]⁺. Preparation Example 50 Synthesis of 4- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 50] Example 50-1: 4- (2-morpholinoethoxy)- Synthesis of 2- (Pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 50]
In a solution of the compound (20 mg, 0.09 mmol) obtained in Example 46-1 in DMF (2 ml), cesium carbonate (83 mg, 0.25 mmol), 4- (2-chloroethyl) morpholine hydrochloride (17 mg, 0.09 mmol) was added at room temperature. After stirring overnight at 70 ° C., the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (4 mg, 14%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, br s), 8. 74 (1 H, dd, J = 5.0, 1.4 Hz), 8.22-8.20 (1 H, m), 7.61 -7.55 (1 H, m), 7. 45 (1 H, dd, J = 8.2, 8.2 Hz), 7. 35 (1 H, d, J = 8.2 Hz), 7.04 (1 H, d, J = 8.2 Hz), 4.38 (2 H, 2 H, t, J = 5.5 Hz), 3.59 (4 H, t, J = 4.8 Hz), 2. 78 (2 H, t, J = 5.5 Hz), 2.56-2.52 (4 H, m).
ESI-MS m / z: 350 [M + H] ⁺ .

製造例51: ターシャリーブチル2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシレート[化合物No.51]の合成
実施例51-1：メチル 3-アミノ-2-ヒドロキシベンゾエートの合成
メチル2-ヒドロキシ-3-ニトロベンゾエート(1.404 g, 7.12 mmol)をエタノール(70 ml)、酢酸エチル(40 ml)、THF(40 ml)に溶解した。そこへ10%パラジウム炭素(140 mg)を加えて水素雰囲気下室温で一晩攪拌した。反応後、セライトろ過して溶媒を留去し、標記の化合物(1.174 g, 98.6%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.63 (1H, br s), 7.02 (1H, t, J = 8.2 Hz), 6.88 (1H, t, J = 8.2 Hz), 6.69 (1H, dd, J = 16.0, 8.2 Hz), 4.98 (2H, br s), 3.88 (3H, s). Preparation Example 51: Synthesis of tert-butyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxylate [Compound No. 51] Example 51-1: Methyl 3-amino-2-hydroxybenzoate Synthesis
Methyl 2-hydroxy-3-nitrobenzoate (1.404 g, 7.12 mmol) was dissolved in ethanol (70 ml), ethyl acetate (40 ml), THF (40 ml). The 10% palladium carbon (140 mg) was added there, and it stirred at room temperature under hydrogen atmosphere overnight. After the reaction, the mixture was filtered through Celite and the solvent was evaporated to give the title compound (1.174 g, 98.6%) as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.63 (1 H, br s), 7.02 (1 H, t, J = 8.2 Hz), 6.88 (1 H, t, J = 8.2 Hz), 6.69 (1H, dd, J = 16.0, 8.2 Hz), 4.98 (2H, br s), 3.88 (3H, s).

実施例51-2：メチルベンゾ[d]オキサゾール-7-カルボキシレートの合成
実施例51-1で得られた化合物(1.174 g, 7.02 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(1.221 g, 98.2%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.91 (1H, s), 8.12 (1H, dd, J = 7.9, 0.9 Hz), 8.01-7.99 (1H, m), 7.55 (1H, t, J = 7.9 Hz), 3.95 (3H, s).
ESI-MS m/z:178[M+H]⁺. Example 51-2: Synthesis of methyl benzo [d] oxazole-7-carboxylate
The title compound (1.221 g, 98.2%) was obtained as a yellow solid by carrying out the same procedure as in Example 32-2 using the compound (1.174 g, 7.02 mmol) obtained in Example 51-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.91 (1 H, s), 8.12 (1 H, dd, J = 7.9, 0.9 Hz), 8.01-7.99 (1 H, m), 7.55 1 H, t, J = 7.9 Hz), 3.95 (3 H, s).
ESI-MS m / z: 178 [M + H] ⁺ .

実施例51-3：ターシャリーブチル2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシレート[化合物No.51]の合成
実施例51-2で得られた化合物(246 mg, 1.39 mmol)と実施例32-5で得られた化合物(505 mg, 2.78 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(28 mg, 6.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, dd, J = 2.1, 0.9 Hz), 8.76 (1H, dd, J = 4.9, 1.8 Hz), 8.25 (1H, dq, J = 7.9, 1.2 Hz), 8.11 (1H, dd, J = 7.9, 1.2 Hz), 7.99 (1H, dd, J = 7.6, 1.2 Hz), 7.61-7.57 (2H, m), 1.62 (9H, s).
ESI-MS m/z:321[M+H]⁺. Example 51-3 Synthesis of tert-butyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxylate [Compound No. 51]
Using the compound (246 mg, 1.39 mmol) obtained in Example 51-2 and the compound (505 mg, 2.78 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 Gave the title compound (28 mg, 6.3%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, dd, J = 2.1, 0.9 Hz), 8. 76 (1 H, dd, J = 4.9, 1.8 Hz), 8. 25 (1 H, 1 H, dq, J = 7.9, 1.2 Hz), 8.11 (1 H, dd, J = 7.9, 1.2 Hz), 7.99 (1 H, dd, J = 7.6, 1.2 Hz), 7.61-7.57 (2 H, m), 1.62 (9 H) , s).
ESI-MS m / z: 321 [M + H] ⁺ .

製造例52：メチル 2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシレート[化合物No.52]の合成
実施例52-1：メチル 2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシレート[化合物No.52]の合成
実施例51-2で得られた化合物(246 mg, 1.39 mmol)と実施例32-5で得られた化合物(505 mg, 2.78 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物 (21 mg, 5.4%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.00 (1H, dd, J = 2.1, 0.9 Hz), 8.76 (1H, dd, J = 4.9, 1.5 Hz), 8.26 (1H, dq, J = 7.9, 1.3 Hz), 8.15 (1H, dd, J = 7.9, 1.2 Hz), 8.08 (1H, dd, J = 7.9, 1.1 Hz), 7.64-7.58 (2H, m), 3.97 (3H, s).
ESI-MS m/z:279[M+H]⁺. Preparation Example 52 Synthesis of methyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxylate [Compound No. 52] Example 52-1: Methyl 2- (pyridin-3-ylethynyl) benzo [ Synthesis of d] oxazole-7-carboxylate [Compound No. 52]
Using the compound (246 mg, 1.39 mmol) obtained in Example 51-2 and the compound (505 mg, 2.78 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (21 mg, 5.4%) was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.00 (1 H, dd, J = 2.1, 0.9 Hz), 8.76 (1 H, dd, J = 4.9, 1.5 Hz), 8.26 (1 H, 1 H, dq, J = 7.9, 1.3 Hz), 8. 15 (1 H, dd, J = 7.9, 1.2 Hz), 8.08 (1 H, dd, J = 7.9, 1.1 Hz), 7.64-7.58 (2 H, m), 3. 97 (3 H , s).
ESI-MS m / z: 279 [M + H] ⁺ .

製造例53：(2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)メタノール[化合物No.53]の合成
実施例53-1：ベンゾ[d]オキサゾール-7-イルメタノールの合成
実施例51-2で得られた化合物(1.221 g, 6.89 mmol)をTHF(24 ml)、エタノール(24 ml)に溶解し、氷冷した。そこへ塩化カルシウム(1.529 g, 13.78 mmol)、水素化ホウ素ナトリウム(1.043 g, 27.56 mmol)を加えて室温で2時間攪拌した。反応後、1 mol/l 塩酸を加えて酢酸エチルで抽出した。飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(149 mg, 14.5%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.74 (1H, s), 7.69 (1H, dd, J = 7.9, 1.2 Hz), 7.44 (1H, dd, J = 7.5, 0.8 Hz), 7.38 (1H, t, J = 7.6 Hz), 5.42 (1H, t, J = 5.8 Hz), 4.80 (3H, d, J = 5.8 Hz).
ESI-MS m/z:150[M+H]⁺. Preparation Example 53 Synthesis of (2- (Pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) methanol [Compound No. 53] Example 53-1: benzo [d] oxazol-7-ylmethanol Synthesis
The compound obtained in Example 51-2 (1.221 g, 6.89 mmol) was dissolved in THF (24 ml) and ethanol (24 ml) and ice-cooled. Calcium chloride (1.529 g, 13.78 mmol) and sodium borohydride (1.043 g, 27.56 mmol) were added there, and it stirred at room temperature for 2 hours. After the reaction, 1 mol / l hydrochloric acid was added and extracted with ethyl acetate. Washed with saturated sodium bicarbonate water. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (149 mg, 14.5%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.74 (1 H, s), 7.69 (1 H, dd, J = 7.9, 1.2 Hz), 7.44 (1 H, dd, J = 7.5, 0.8 Hz), 7.38 (1 H, t, J = 7.6 Hz), 5.42 (1 H, t, J = 5.8 Hz), 4.80 (3 H, d, J = 5.8 Hz).
ESI-MS m / z: 150 [M + H] ⁺ .

実施例53-2：7-(((ターシャリーブチルジメチルシリル)オキシ)メチル)ベンゾ[d]オキサゾールの合成
実施例53-1で得られた化合物(155 mg, 1.04 mmol)をDMF(3 ml)に溶解した。そこへターシャリーブチルジメチルシリルクロライド(188 mg, 1.25mmol)、イミダゾール(106 mg, 1.56 mmol)を加えて室温で1.5時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物409 mg, quant.)を無色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.76 (1H, s), 7.72 (1H, dd, J = 7.3, 1.8 Hz), 7.44-7.38 (2H, m), 5.01 (2H, s), 0.90 (9H, s), 0.10 (6H, s).
ESI-MS m/z:264[M+H]⁺. Example 53-2 Synthesis of 7-(((tert-butyldimethylsilyl) oxy) methyl) benzo [d] oxazole
The compound (155 mg, 1.04 mmol) obtained in Example 53-1 was dissolved in DMF (3 ml). The tertiary butyl dimethyl silyl chloride (188 mg, 1.25 mmol) and the imidazole (106 mg, 1.56 mmol) were added there, and it stirred at room temperature for 1.5 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 10 g, hexane / ethyl acetate) to give the title compound 409 mg, quant.) As a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.76 (1 H, s), 7.72 (1 H, dd, J = 7.3, 1.8 Hz), 7.44-7.38 (2 H, m), 5.01 (5.0 H) 2H, s), 0.90 (9H, s), 0.10 (6H, s).
ESI-MS m / z: 264 [M + H] ⁺ .

実施例53-3：7-(((ターシャリーブチルジメチルシリル)オキシ)メチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールの合成
実施例53-2で得られた化合物(213 mg, 0.81 mmol)と実施例32-5で得られた化合物(294 mg, 1.62 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(127 mg, 43.0%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, dd, J = 2.3, 0.8 Hz), 8.75 (1H, dd, J = 4.9, 1.5 Hz), 8.22 (1H, dt, J = 8.0, 2.0 Hz), 7.76 (1H, dd, J = 7.6, 1.5 Hz), 7.58 (1H, ddd, J = 7.0, 4.9, 0.9 Hz), 7.54-7.52 (1H, m), 7.48 (1H, t, J = 7.6 Hz), 5.04 (2H, s), 0.92 (9H, s), 0.13 (6H, s).
ESI-MS m/z:365[M+H]⁺. Example 53-3 Synthesis of 7-(((tert-butyldimethylsilyl) oxy) methyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole
Using the compound (213 mg, 0.81 mmol) obtained in Example 53-2 and the compound (294 mg, 1.62 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (127 mg, 43.0%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, dd, J = 2.3, 0.8 Hz), 8.75 (1 H, dd, J = 4.9, 1.5 Hz), 8.22 (1 H, 1 H, dt, J = 8.0, 2.0 Hz), 7. 76 (1 H, dd, J = 7.6, 1.5 Hz), 7.58 (1 H, ddd, J = 7.0, 4.9, 0.9 Hz), 7.54-7.52 (1 H, m), 7.48 (1H, t, J = 7.6 Hz), 5.04 (2H, s), 0.92 (9H, s), 0.13 (6H, s).
ESI-MS m / z: 365 [M + H] ⁺ .

実施例53-4：(2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)メタノール[化合物No.53]の合成
実施例53-3で得られた化合物(111 mg, 0.3 mmol)をTHF(2 ml)に溶解した。そこへ1 mol/lテトラアンモニウムフルオライドTHF溶液(0.365 ml, 0.37 mmol)を加えて室温で1時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(11 mg, 14.7%)を淡黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 1.5 Hz), 8.75 (1H, dd, J = 4.9, 1.5 Hz), 8.23 (1H, dt, J = 8.0, 2.0 Hz), 7.74 (1H, dd, J = 8.0, 1.5 Hz), 7.58 (1H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.54 (1H, dd, J = 7.8, 1.2 Hz), 7.46 (1H, t, J = 7.8 Hz), 5.49 (1H, t, J = 5.8 Hz), 4.81 (2H, d, J = 5.8 Hz).
ESI-MS m/z:251[M+H]⁺. Example 53-4 Synthesis of (2- (Pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) methanol [Compound No. 53]
The compound (111 mg, 0.3 mmol) obtained in Example 53-3 was dissolved in THF (2 ml). The 1 mol / l tetraammonium fluoride THF solution (0.365 ml, 0.37 mmol) was added there, and it stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, hexane / ethyl acetate) to give the title compound (11 mg, 14.7%) as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 1.5 Hz), 8.75 (1 H, dd, J = 4.9, 1.5 Hz), 8.23 (1 H, dt, J = 8.0, 2.0 Hz), 7.74 (1 H, dd, J = 8.0, 1.5 Hz), 7.58 (1 H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.54 (1 H, dd, J = 7.8, 1.2 Hz ), 7.46 (1 H, t, J = 7.8 Hz), 5. 49 (1 H, t, J = 5.8 Hz), 4.81 (2 H, d, J = 5.8 Hz).
ESI-MS m / z: 251 [M + H] ⁺ .

製造例54：ターシャリーブチル((2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)メチル)カルバメート[化合物No.54]の合成
実施例54-1：4-(ブロモエチル)ベンゾ[d]オキサゾールの合成
実施例38-1で得られた化合物(1.376 g, 10.3 mmol)のジクロロメタン(28 ml)溶液中に、アゾビスイソブチルニトリル(34 mg, 0.21 mmol)、N-ブロモスクシンイミド(2.391 g, 13.4 mmol)を室温下添加した。還流条件下、一晩撹拌した後、反応終了後減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(1.364 mg, 62 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.83 (1H, s), 7.76 (1H, d, J = 8.2 Hz), 7.52 (1H, d, J = 7.3 Hz), 7.44 (1H, dd, J = 8.2, 7.3 Hz), 4.99 (3H, s).
ESI-MS m/z: 212[M+H]⁺. Preparation Example 54 Synthesis of tert-butyl ((2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) carbamate [Compound No. 54] Example 54-1: 4- (Bromoethyl) Synthesis of benzo [d] oxazole
Azobisisobutylonitrile (34 mg, 0.21 mmol), N-bromosuccinimide (2.391 g, 13.4 mmol) in a solution of the compound (1.376 g, 10.3 mmol) obtained in Example 38-1 in dichloromethane (28 ml) Was added at room temperature. After stirring overnight under reflux conditions, the reaction was concentrated to dryness under reduced pressure after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.364 mg, 62%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.83 (1 H, s), 7. 76 (1 H, d, J = 8.2 Hz), 7.52 (1 H, d, J = 7.3 Hz), 7.44 (1H, dd, J = 8.2, 7.3 Hz), 4.99 (3H, s).
ESI-MS m / z: 212 [M + H] ⁺ .

実施例54-2：4-(アジドベンジル)ベンゾ[d]オキサゾールの合成
実施例54-1で得られた化合物(700 mg, 3.3 mmol)のDMF(16 ml)溶液中に、アジ化ナトリウム(1.07 g, 16.5 mmol)を室温下添加した。60℃で一晩撹拌した後、減圧下濃縮乾固した。飽和炭酸水素ナトリウム水溶液、飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物( 488 mg, 85 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.82 (1H, s), 7.80 (1H, d, J = 8.2 Hz), 7.53-7.40 (2H, m), 4.79 (2H, s).
ESI-MS m/z: 175[M+H]⁺. Example 54-2 Synthesis of 4- (azidobenzyl) benzo [d] oxazole
Sodium azide (1.07 g, 16.5 mmol) was added to a solution of the compound (700 mg, 3.3 mmol) obtained in Example 54-1 in DMF (16 ml) at room temperature. After stirring overnight at 60 ° C., the solution was concentrated to dryness under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution and saturated brine were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (488 mg, 85%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.82 (1 H, s), 7.80 (1 H, d, J = 8.2 Hz), 7.53-7. s).
ESI-MS m / z: 175 [M + H] ⁺ .

実施例54-3：ターシャリーブチル(ベンゾ[d]オキサゾール-4-イルメチル)カルバメートの合成
実施例54-2で得られた化合物(178 mg, 1.02 mmol)のテトラヒドロフラン(1 ml)溶液中に、トリフェニルホスフィン(348 mg, 1.33 mmol)を添加した。室温下8時間撹拌した後、水(1 ml)を滴下した。一晩撹拌した後、減圧下濃縮乾固した。残渣物のテトラヒドロフラン(5 ml)溶液中に、ジイソプロピルエチルアミン(536 μl, 3.07 mmol)、ジターシャリーブチルジカーボネイト(712 μl, 3.07 mmol)を添加した。80℃で2時間撹拌した後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(124 mg, 49 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.73 (1H, s), 7.64 (1H, d, J = 8.7 Hz), 7.49-7.38 (2H, m), 7.26 (1H, d, J = 7.3 Hz), 4.51 (2H, d, J = 6.4 Hz), 1.42 (9H, s).
ESI-MS m/z: 249[M+H]⁺. Example 54-3 Synthesis of tert-butyl (benzo [d] oxazol-4-ylmethyl) carbamate
Triphenylphosphine (348 mg, 1.33 mmol) was added to a solution of the compound (178 mg, 1.02 mmol) obtained in Example 54-2 in tetrahydrofuran (1 ml). After stirring at room temperature for 8 hours, water (1 ml) was added dropwise. After stirring overnight, it was concentrated to dryness under reduced pressure. To a solution of the residue in tetrahydrofuran (5 ml) was added diisopropylethylamine (536 μl, 3.07 mmol) and ditertiary butyl dicarbonate (712 μl, 3.07 mmol). After stirring at 80 ° C. for 2 hours, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (124 mg, 49%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.73 (1 H, s), 7.64 (1 H, d, J = 8.7 Hz), 7.49-7.38 (2 H, m), 7.26 (1 H, s) d, J = 7.3 Hz), 4.51 (2 H, d, J = 6.4 Hz), 1.42 (9 H, s).
ESI-MS m / z: 249 [M + H] ⁺ .

実施例54-4：ターシャリーブチル((2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)メチル)カルバメート[化合物No.54]の合成
実施例54-3で得られた化合物(124 mg, 0.50 mmol)と実施例32-5で得られた化合物(182 mg, 1.00 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(31 mg, 18 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, br s), 8.75 (1H, dd, J = 5.0, 1.8 Hz), 8.23 (1H, d, J = 8.2 Hz), 7.67 (1H, d, J = 7.8 Hz), 7.60-7.57 (1H, m), 7.55-7.48 (2H, m), 7.33 (1H, d, J = 7.8 Hz), 4.51 (2H, d, J = 6.0 Hz), 1.41 (9H, s).
ESI-MS m/z: 350[M+H]⁺. Example 54-4 Synthesis of tertiary butyl ((2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) methyl carbamate [Compound No. 54]
Using the compound (124 mg, 0.50 mmol) obtained in Example 54-3 and the compound (182 mg, 1.00 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (31 mg, 18%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, br s), 8.75 (1 H, dd, J = 5.0, 1.8 Hz), 8.23 (1 H, d, J = 8.2 Hz ), 7.67 (1H, d, J = 7.8 Hz), 7.60-7.57 (1H, m), 7.55-7.48 (2H, m), 7.33 (1H, d, J = 7.8 Hz), 4.51 (2H, d, 7) J = 6.0 Hz), 1.41 (9 H, s).
ESI-MS m / z: 350 [M + H] ⁺ .

製造例55：7-ブロモ-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.55]の合成
実施例55-1：7-ブロモ-4-メトキシベンゾ[d]オキサゾールの合成
実施例32-3で得られた化合物(41 mg, 0.28 mmol)のアセトニトリル(2.5 ml)溶液中に、N-ブロモスクシンイミド(54 mg, 0.30 mmol)を添加した。100℃で8時間撹拌した後、反応終了後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(33 mg, 53 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.75 (1H, s), 7.59 (1H, d, J = 8.7 Hz), 6.96 (1H, d, J = 8.7 Hz), 3.98 (3H, s).
ESI-MS m/z: 228[M+H]⁺. Preparation Example 55 Synthesis of 7-bromo-4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 55] Example 55-1: 7-bromo-4-methoxybenzo [d Synthesis of oxazole
N-bromosuccinimide (54 mg, 0.30 mmol) was added to a solution of the compound (41 mg, 0.28 mmol) obtained in Example 32-3 in acetonitrile (2.5 ml). After stirring at 100 ° C. for 8 hours, after completion of the reaction, the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (33 mg, 53%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.75 (1 H, s), 7.59 (1 H, d, J = 8.7 Hz), 6.96 (1 H, d, J = 8.7 Hz), 3.98 (3H, s).
ESI-MS m / z: 228 [M + H] ⁺ .

実施例55-2：7-ブロモ-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.55]の合成
実施例55-1で得られた化合物(33 mg, 0.15 mmol)と実施例32-5で得られた化合物(53 mg, 0.29 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(26 mg, 55 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, br s), 8.75 (1H, dd, J = 5.0, 1.8 Hz), 8.26-8.24 (1H, m), 7.69 (1H, d, J = 8.7 Hz), 7.60-7.56 (1H, m), 7.02 (1H, d, J = 8.7 Hz), 4.00 (3H, s).
ESI-MS m/z: 329[M+H]⁺. Example 55-2 Synthesis of 7-bromo-4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 55]
Using the compound (33 mg, 0.15 mmol) obtained in Example 55-1 and the compound (53 mg, 0.29 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (26 mg, 55%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, br s), 8.75 (1 H, dd, J = 5.0, 1.8 Hz), 8.26-8.24 (1 H, m), 7.69 (1H, d, J = 8.7 Hz), 7.60-7.56 (1 H, m), 7.02 (1 H, d, J = 8.7 Hz), 4.00 (3 H, s).
ESI-MS m / z: 329 [M + H] ⁺ .

製造例56：ターシャリーブチル 2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-カルボキシレート[化合物No.56]の合成
実施例56-1：メチル 2-アミノ-3-ヒドロキシベンゾエートの合成
メチル 3-ヒドロキシ-2-ニトロベンゾエート(2.0 g, 10.1 mmol)を用いて実施例32-1と同様の操作を行うことにより標記の化合物(1.696 g, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.76-10.42 (1H, m), 7.01 (1H, dd, J = 8.0, 1.8 Hz), 6.86 (1H, dd, J = 7.8, 1.8 Hz), 6.68 (1H, dd, J = 8.0, 7.8 Hz), 5.11-4.78 (2H, m), 3.88 (3H, s). Production Example 56: Synthesis of tert-butyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-4-carboxylate [Compound No. 56] Example 56-1: Methyl 2-amino-3-hydroxybenzoate Synthesis
The title compound (1.696 g, 100%) was obtained by the same procedure as in Example 32-1 using methyl 3-hydroxy-2-nitrobenzoate (2.0 g, 10.1 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.76 to 10.42 (1 H, m), 7.01 (1 H, dd, J = 8.0, 1.8 Hz), 6.86 (1 H, dd, J = 7.8) , 1.8 Hz), 6.68 (1 H, dd, J = 8.0, 7.8 Hz), 5.11-4.78 (2 H, m), 3. 88 (3 H, s).

実施例56-2：メチルベンゾ[d]オキサゾール-4-カルボキシレートの合成
実施例56-1で得られた化合物(1.696 g, 10.23 mmol)を用いて実施例32-2と同様の操作を行うことにより標記の化合物(1.67 g, 93 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.91 (1H, s), 8.12 (1H, dd, J = 8.0, 1.1 Hz), 8.00 (1H, dd, J = 7.8, 1.1 Hz), 7.55 (1H, dd, J = 8.0, 7.8 Hz), 3.95 (3H, s). Example 56-2 Synthesis of Methyl Benzo [d] oxazole-4-carboxylate
The title compound (1.67 g, 93%) was obtained by the same procedure as in Example 32-2 using the compound (1.696 g, 10.23 mmol) obtained in Example 56-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.91 (1 H, s), 8.12 (1 H, dd, J = 8.0, 1.1 Hz), 8.00 (1 H, dd, J = 7.8, 1.1 Hz), 7.55 (1 H, dd, J = 8.0, 7.8 Hz), 3.95 (3 H, s).

実施例56-3：ターシャリーブチル 2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-カルボキシレート[化合物No.56]の合成
実施例56-2で得られた化合物(100 mg, 0.56 mmol)と実施例32-5で得られた化合物(205 mg, 1.13 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(7 mg, 4 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, d, J = 2.3 Hz), 8.76 (1H, dd, J = 4.8, 1.6 Hz), 8.27-8.22 (1H, m), 8.11 (1H, d, J = 8.2 Hz), 7.99 (1H, d, J = 7.8 Hz), 7.62-7.56 (2H, m), 1.62 (9H, s).
ESI-MS m/z: 321[M+H]⁺. Example 56-3 Synthesis of tert-butyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-4-carboxylate [Compound No. 56]
Using the compound (100 mg, 0.56 mmol) obtained in Example 56-2 and the compound (205 mg, 1.13 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (7 mg, 4%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, d, J = 2.3 Hz), 8.76 (1 H, dd, J = 4.8, 1.6 Hz), 8.27-8.22 (1 H, m), 8.11 (1 H, d, J = 8.2 Hz), 7.99 (1 H, d, J = 7.8 Hz), 7.62-7.56 (2 H, m), 1.62 (9 H, s).
ESI-MS m / z: 321 [M + H] ⁺ .

製造例57：(2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)メタノール[化合物No.57]の合成
実施例57-1：ベンゾ[d]オキサゾール-4-イルメタノールの合成
実施例56-2で得られた化合物(500 mg, 2.82 mmol)のテトラヒドロフラン(10 ml)、エタノール(10 ml)溶液中に、塩化カルシウム(626 mg, 5.64 mmol)を0℃で添加し溶解した。水素化ホウ素ナトリウム(427 mg, 11.29 mmol)を添加し室温で2時間撹拌した。反応終了後、1mol/l塩酸を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(154 mg, 37 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.74 (1H, s), 7.69 (1H, d, J = 7.8 Hz), 7.44 (1H, d, J = 6.9 Hz), 7.38 (1H, dd, J = 7.8, 6.9 Hz), 5.41 (1H, t, J = 5.7 Hz), 4.80 (2H, d, J = 5.7 Hz). Preparation Example 57 Synthesis of (2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) methanol [Compound No. 57] Example 57-1: Preparation of benzo [d] oxazol-4-ylmethanol Synthesis
In a solution of the compound (500 mg, 2.82 mmol) obtained in Example 56-2 in tetrahydrofuran (10 ml) and ethanol (10 ml), calcium chloride (626 mg, 5.64 mmol) was added at 0 ° C. for dissolution . Sodium borohydride (427 mg, 11.29 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, 1 mol / l hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (154 mg, 37%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.74 (1 H, s), 7.69 (1 H, d, J = 7.8 Hz), 7.44 (1 H, d, J = 6.9 Hz), 7.38 (1H, dd, J = 7.8, 6.9 Hz), 5.41 (1 H, t, J = 5.7 Hz), 4.80 (2 H, d, J = 5.7 Hz).

実施例57-2：4-(((ターシャリーブチルジメチルシリル)オキシ)メチル)ベンゾ[d]オキサゾールの合成
実施例57-1で得られた化合物(154 mg, 1.03 mmol)のジクロロメタン(4 ml)溶液中に、ターシャリーブチルクロロジメチルシラン(202 mg, 1.34 mmol)、N,N-ジメチル-4-アミノピリジン(6 mg, 0.05 mmol)、トリエチルアミン(187 μl, 1.34 mmol)を室温下添加した。室温で一晩撹拌した後、反応終了後、飽和食塩水を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(245 mg, 90 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.76 (1H, s), 7.72 (1H, dd, J = 7.3, 1.8 Hz), 7.45-7.37 (2H, m), 5.01 (2H, s), 0.90 (9H, s), 0.11 (6H, s).
ESI-MS m/z: 264[M+H]⁺. Example 57-2 Synthesis of 4-(((tert-butyldimethylsilyl) oxy) methyl) benzo [d] oxazole
In a solution of the compound (154 mg, 1.03 mmol) obtained in Example 57-1 in dichloromethane (4 ml), tert-butylchlorodimethylsilane (202 mg, 1.34 mmol), N, N-dimethyl-4-amino Pyridine (6 mg, 0.05 mmol) and triethylamine (187 μl, 1.34 mmol) were added at room temperature. After stirring overnight at room temperature, saturated saline was added after completion of the reaction, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (245 mg, 90%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.76 (1 H, s), 7.72 (1 H, dd, J = 7.3, 1.8 Hz), 7.45-7.37 (2 H, m), 5.01 (5 2H, s), 0.90 (9H, s), 0.11 (6H, s).
ESI-MS m / z: 264 [M + H] ⁺ .

実施例57-3：4-(((ターシャリーブチルジメチルシリル)オキシ)メチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールの合成
実施例57-4で得られた化合物(245 mg, 0.93 mmol)と実施例32-5で得られた化合物(339 mg, 1.86 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(259 mg, 76 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, br s), 8.75 (1H, dd, J = 4.8, 1.6 Hz), 8.25-8.19 (1H, m), 7.76 (1H, d, J = 7.6 Hz), 7.61-7.56 (1H, m), 7.56-7.45 (2H, m), 5.04 (2H, s), 0.92 (9H, s), 0.13 (6H, s).
ESI-MS m/z: 365[M+H]⁺. Example 57-3 Synthesis of 4-(((tert-butyldimethylsilyl) oxy) methyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole
Using the compound (245 mg, 0.93 mmol) obtained in Example 57-4 and the compound (339 mg, 1.86 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 Gave the title compound (259 mg, 76%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, br s), 8.75 (1 H, dd, J = 4.8, 1.6 Hz), 8.25-8.19 (1 H, m), 7.76 (1H, d, J = 7.6 Hz), 7.61-7.56 (1H, m), 7.56-7.45 (2H, m), 5.04 (2H, s), 0.92 (9H, s), 0.13 (6H, s).
ESI-MS m / z: 365 [M + H] ⁺ .

実施例57-4:(2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)メタノール[化合物No.57]の合成
実施例57-3で得られた化合物(100 mg, 0.27 mmol)のテトラヒドロフラン(5 ml)溶液中に、テトラブチルアンモニウムフロリド(79 mg, 0.30 mmol)を室温下添加した。1時間撹拌した後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(26 mg, 38 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, br s), 8.75 (1H, dd, J = 4.8, 1.6 Hz), 8.24-8.22 (1H, m), 7.74 (1H, d, J = 7.8 Hz), 7.65-7.52 (2H, m), 7.46 (1H, dd, J = 7.8, 7.8 Hz), 5.49 (1H, t, J = 5.5 Hz), 4.81 (2H, d, J = 5.5 Hz).
ESI-MS m/z: 251[M+H]⁺. Example 57-4 Synthesis of (2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) methanol [Compound No. 57]
Tetrabutylammonium fluoride (79 mg, 0.30 mmol) was added to a solution of the compound (100 mg, 0.27 mmol) obtained in Example 57-3 in tetrahydrofuran (5 ml) at room temperature. After stirring for 1 hour, the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (26 mg, 38%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, br s), 8.75 (1 H, dd, J = 4.8, 1.6 Hz), 8.24-8.22 (1 H, m), 7.74 (1H, d, J = 7.8 Hz), 7.65-7.52 (2H, m), 7.46 (1H, dd, J = 7.8, 7.8 Hz), 5.49 (1 H, t, J = 5.5 Hz), 4.81 (2H, 2H, t d, J = 5.5 Hz).
ESI-MS m / z: 251 [M + H] ⁺ .

製造例58：4-メトキシ-7-モルホリノ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.58]の合成
実施例58-1：4-メトキシ-7-モルホリノ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.58]の合成
実施例55-2で得られた化合物(30 mg, 0.09 mmol)のトルエン(1 ml) 溶液中に、モルホリン(79 μl, 0.90 mmol)、酢酸パラジウム(2 mg, 9.11 μmol)、ジシクロホスフィル(2',4',6'-トリイソプロピル-[1,1'-ビフェニル]-2-イル)ホスフィン(13 mg, 0.03 mmol)、ターシャリーブトキシナトリウム(18 mg, 0.18 mmol)を添加した。アルゴン雰囲気下110℃で4時間撹拌した後、セライトろ過し酢酸エチルで洗浄、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(17 mg, 56 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, d, J = 1.4 Hz), 8.74 (1H, dd, J = 5.0, 1.4 Hz), 8.23-8.21 (1H, m), 7.57 (1H, dd, J = 7.8, 5.0 Hz), 6.93 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.81 (4H, t, J = 4.6 Hz), 3.15 (4H, t, J = 4.6 Hz).
ESI-MS m/z: 336[M+H]⁺. Preparation Example 58 Synthesis of 4-methoxy-7-morpholino-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 58] Example 58-1: 4-methoxy-7-morpholino-2- Synthesis of (Pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 58]
In a solution of the compound (30 mg, 0.09 mmol) obtained in Example 55-2 in toluene (1 ml), morpholine (79 μl, 0.90 mmol), palladium acetate (2 mg, 9.11 μmol), dicyclophosphyl (2 ′, 4 ′, 6′-triisopropyl- [1,1′-biphenyl] -2-yl) phosphine (13 mg, 0.03 mmol) and tertiary butoxy sodium (18 mg, 0.18 mmol) were added. After stirring at 110 ° C. for 4 hours under an argon atmosphere, the mixture was filtered through celite, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (17 mg, 56%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, d, J = 1.4 Hz), 8.74 (1 H, dd, J = 5.0, 1.4 Hz), 8.23-8.21 (1 H, m), 7.57 (1 H, dd, J = 7.8, 5.0 Hz), 6.93 (1 H, d, J = 8.7 Hz), 6.90 (1 H, d, J = 8.7 Hz), 3.93 (3 H, s), 3.81 ( 4H, t, J = 4.6 Hz), 3.15 (4H, t, J = 4.6 Hz).
ESI-MS m / z: 336 [M + H] ⁺ .

製造例59：ターシャリーブチル4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボキシレート[化合物No.59]の合成
実施例59-1：ターシャリーブチル4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボキシレート[化合物No.59]の合成
実施例55-2で得られた化合物(30 mg, 0.09 mmol)とターシャリーブチルピペラジン-1-カルボキシレート (85 mg, 0.46 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(20 mg, 51 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.74 (1H, dd, J = 5.0, 1.8 Hz), 8.25-8.19 (1H, m), 7.61-7.54 (1H, m), 6.96 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.54 (4H, t, J = 4.6 Hz), 3.10 (4H, t, J = 4.6 Hz), 1.43 (9H, s).
ESI-MS m/z: 435[M+H]⁺. Preparation Example 59: Synthesis of tert-butyl 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carboxylate [Compound No. 59] Example 59 -1: Synthesis of tert-butyl 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carboxylate [Compound No. 59]
By performing the same operation as in Example 58-1 using the compound (30 mg, 0.09 mmol) obtained in Example 55-2 and tertiary butyl piperazine-1-carboxylate (85 mg, 0.46 mmol) The title compound (20 mg, 51%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.74 (1 H, dd, J = 5.0, 1.8 Hz), 8.25-8.19 (1 H, m), 7.61 -7.54 (1 H, m), 6.96 (1 H, d, J = 8.7 Hz), 6.90 (1 H, d, J = 8.7 Hz), 3.93 (3 H, s), 3.54 (4 H, t, J = 4.6 Hz) , 3.10 (4H, t, J = 4.6 Hz), 1.43 (9H, s).
ESI-MS m / z: 435 [M + H] ⁺ .

製造例60：4-メトキシ-7-(4-(2-メトキシエチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.60]の合成
実施例60-1：4-メトキシ-7-(4-(2-メトキシエチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.60]の合成
実施例55-2で得られた化合物(30 mg, 0.09 mmol)と1-(2-メトキシエチル)ピペラジン(68 μl, 0.46 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(13 mg, 36 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, d, J = 1.8 Hz), 8.74 (1H, dd, J = 4.8, 1.6 Hz), 8.25-8.19 (1H, m), 7.61-7.54 (1H, m), 6.91 (1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 8.7 Hz), 3.92 (3H, s), 3.48 (2H, t, J = 5.7 Hz), 3.26 (3H, s), 3.14 (4H, t, J = 4.6 Hz), 2.63 (4H, t, J = 4.6 Hz), 2.55 (2H, t, J = 5.7 Hz).
ESI-MS m/z: 393[M+H]⁺. Preparation Example 60 Synthesis Example of 4-methoxy-7- (4- (2-methoxyethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 60] Synthesis of 60-1: 4-methoxy-7- (4- (2-methoxyethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [compound No. 60]
By performing the same operation as in Example 58-1 using the compound (30 mg, 0.09 mmol) obtained in Example 55-2 and 1- (2-methoxyethyl) piperazine (68 μl, 0.46 mmol) The title compound (13 mg, 36%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, d, J = 1.8 Hz), 8.74 (1 H, dd, J = 4.8, 1.6 Hz), 8.25-8.19 (1 H, m), 7.61-7.54 (1H, m), 6.91 (1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 8.7 Hz), 3.92 (3H, s), 3.48 (2H, t, J = 5.7 Hz), 3.26 (3 H, s), 3.14 (4 H, t, J = 4.6 Hz), 2. 63 (4 H, t, J = 4.6 Hz), 2.55 (2 H, t, J = 5.7 Hz).
ESI-MS m / z: 393 [M + H] ⁺ .

製造例61：4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩[化合物No.61]の合成
実施例61-1：4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩 [化合物No.61]の合成
実施例59-1で得られた化合物(12 mg, 0.03 mmol)のジクロロメタン(720 μl)溶液中に、2,2,2-トリフルオロ酢酸(96 μl, 1.16 mmol)を滴下した。4時間撹拌した後、反応終了後、減圧下濃縮乾固した。標記の化合物(12 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, d, J = 2.3 Hz), 8.84-8.68 (2H, m), 8.24-8.18 (1H, m), 7.62-7.56 (1H, m), 7.02 (1H, d, J = 8.7 Hz), 6.93 (1H, d, J = 8.7 Hz), 6.02-5.03 (8H, m), 3.94 (3H, s).
ESI-MS m/z: 335[M+H]⁺. Production Example 61 Synthesis of 4-methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate [Compound No. 61] Example 61-1: Synthesis of 4-methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate [Compound No. 61]
In a solution of the compound (12 mg, 0.03 mmol) obtained in Example 59-1 in dichloromethane (720 μl), 2,2,2-trifluoroacetic acid (96 μl, 1.16 mmol) was dropped. After stirring for 4 hours, after completion of the reaction, the solution was concentrated to dryness under reduced pressure. The title compound (12 mg, 100%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, d, J = 2.3 Hz), 8.84-8.68 (2 H, m), 8.24-8.18 (1 H, m), 7.62- 7.56 (1 H, m), 7.02 (1 H, d, J = 8.7 Hz), 6.93 (1 H, d, J = 8.7 Hz), 6.02-5.03 (8 H, m), 3.94 (3 H, s).
ESI-MS m / z: 335 [M + H] ⁺ .

製造例62：4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)チオモルホリン 1,1-ジオキシド[化合物No.62]の合成
実施例62-1: 4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)チオモルホリン 1,1-ジオキシド[化合物No.62]の合成
実施例55-2で得られた化合物(30 mg, 0.09 mmol)とチオモルホリン1,1-ジオキシド (62 mg, 0.46 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(12 mg, 34 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, d, J = 1.8 Hz), 8.75-8.74 (1H, m), 8.25-8.19 (1H, m), 7.61-7.55 (1H, m), 7.08 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.73-3.66 (4H, m), 3.32-3.26 (4H, m).
ESI-MS m/z: 384[M+H]⁺. Production Example 62 Synthesis of 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) thiomorpholine 1,1-dioxide [Compound No. 62] Example 62-1 Synthesis of 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) thiomorpholine 1,1-dioxide [Compound No. 62]
The title compound was obtained by the same procedures as in Example 58-1 using the compound (30 mg, 0.09 mmol) obtained in Example 55-2 and thiomorpholine 1,1-dioxide (62 mg, 0.46 mmol). The compound (12 mg, 34%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, d, J = 1.8 Hz), 8.75-8.74 (1 H, m), 8.25-8. 19 (1 H, m), 7.61- 7.55 (1H, m), 7.08 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.73-3.66 (4H, m), 3.32-3.26 (4H, m).
ESI-MS m / z: 384 [M + H] ⁺ .

製造例63：ターシャリーブチル(1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-イル)カルバメート[化合物No.63]の合成
実施例63-1：ターシャリーブチル(1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-イル)カルバメート[化合物No.63]の合成
実施例55-2で得られた化合物(30 mg, 0.09 mmol)とターシャリーブチルピペリジン-4-イルカルバメート (91 mg, 0.46 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(25 mg, 61 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, br s), 8.74 (1H, dd, J = 5.0, 1.4 Hz), 8.27-8.19 (1H, m), 7.61-7.54 (1H, m), 6.96-6.91 (2H, m), 6.88 (1H, d, J = 8.7 Hz), 3.92 (3H, s), 3.58-3.50 (2H, m), 3.47-3.37 (1H, m), 2.81-2.72 (2H, m), 1.91-1.82 (2H, m), 1.65-1.53 (2H, m), 1.40 (9H, s).
ESI-MS m/z: 449[M+H]⁺. Preparation Example 63 Synthesis of tert-butyl (1- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-yl) carbamate [Compound No. 63] Example 63-1: Synthesis of tert-butyl (1- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-yl) carbamate [Compound No. 63]
By performing the same operation as in Example 58-1 using the compound (30 mg, 0.09 mmol) obtained in Example 55-2 and tert-butylpiperidin-4-ylcarbamate (91 mg, 0.46 mmol) The title compound (25 mg, 61%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, br s), 8.74 (1 H, dd, J = 5.0, 1.4 Hz), 8.27-8.19 (1 H, m), 7.61 -7.54 (1H, m), 6.96-6.91 (2H, m), 6.88 (1H, d, J = 8.7 Hz), 3.92 (3H, s), 3.58-3.50 (2H, m), 3.47-3.37 (1H , m), 2.81-2.72 (2H, m), 1.91-1.82 (2H, m), 1.65-1.53 (2H, m), 1.40 (9H, s).
ESI-MS m / z: 449 [M + H] ⁺ .

製造例64：1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-アミントリフルオロ酢酸塩[化合物No.64]の合成
実施例64-1：1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-アミントリフルオロ酢酸塩[化合物No.64]の合成
実施例63-1で得られた化合物(20 mg, 0.05 mmol)のジクロロメタン(1.16 ml)溶液中に、2,2,2-トリフルオロ酢酸(144 μl, 1.88 mmol)を滴下した。2時間撹拌した後、反応終了後、減圧下濃縮乾固した。標記の化合物(21 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 1.8 Hz), 8.75 (1H, dd, J = 4.8, 1.6 Hz), 8.26-8.20 (1H, m), 8.00-7.80 (3H, m), 7.62-7.56 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.69-3.60 (2H, m), 3.27-3.18 (1H, m), 2.86-2.77 (2H, m), 2.08-1.99 (2H, m), 1.78-1.64 (2H, m).
ESI-MS m/z: 349[M+H]⁺. Preparation Example 64 Synthesis of 1- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-amine Trifluoroacetic Acid Salt [Compound No. 64] Example 64 -1-(4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidine-4-amine Synthesis of trifluoroacetate [compound No. 64]
In a solution of the compound (20 mg, 0.05 mmol) obtained in Example 63-1 in dichloromethane (1.16 ml), 2,2,2-trifluoroacetic acid (144 μl, 1.88 mmol) was dropped. After stirring for 2 hours, after completion of the reaction, it was concentrated to dryness under reduced pressure. The title compound (21 mg, 100%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 1.8 Hz), 8.75 (1 H, dd, J = 4.8, 1.6 Hz), 8.26-8.20 (1 H, 1 H, m), 8.00-7.80 (3H, m), 7.62-7.56 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 3.93 (3H, s) ), 3.69-3.60 (2H, m), 3.27-3.18 (1H, m), 2.86-2.77 (2H, m), 2.08-1.99 (2H, m), 1.78-1.64 (2H, m).
ESI-MS m / z: 349 [M + H] ⁺ .

製造例65：ターシャリーブチル 4-(2-((2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレート[化合物No.65]の合成
実施例65-1：ターシャリーブチル 4-(2-(ベンゾ[d]オキサゾール-7-イルオキシ)エチル)ピペラジン-1-カルボキシレートの合成
実施例35-2で得られた化合物(74 mg, 0.55 mmol)をDMF(1.5 ml)に溶解した。そこへ炭酸セシウム(214 mg, 0.66 mmol)、ターシャリーブチル 4-(2-ブロモメチル)ピペラジン-1-カルボキシレート(323 mg, 1.1 mmol)、ヨウ化カリウム(183 mg, 1.1 mmol)を加えて70 ℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Chromatorex NH 20 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(184 mg, 96.3%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.70 (1H, s), 8.32 (1H, br s), 7.36 (1H, dd, J = 7.9, 0.9 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.09 (1H, d, J = 7.9 Hz), 4.32 (2H, t, J = 5.6 Hz), 2.81-2.77 (2H, m), 2.58-2.54 (2H, m), 2.48-2.45 (4H, m), 2.36 (2H, t, J = 5.0 Hz), 1.39 (9H, s).
ESI-MS m/z:348[M+H]⁺. Production Example 65: Tertiary butyl 4- (2-((2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate [Compound No. 65] Synthesis Example 65-1: Synthesis of tert-butyl 4- (2- (benzo [d] oxazol-7-yloxy) ethyl) piperazine-1-carboxylate
The compound (74 mg, 0.55 mmol) obtained in Example 35-2 was dissolved in DMF (1.5 ml). Cesium carbonate (214 mg, 0.66 mmol), tert-butyl 4- (2-bromomethyl) piperazine-1-carboxylate (323 mg, 1.1 mmol), and potassium iodide (183 mg, 1.1 mmol) are added thereto. Stir overnight at ° C. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Chromatorex NH 20 g, hexane / ethyl acetate) to give the title compound (184 mg, 96.3%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.70 (1 H, s), 8.32 (1 H, br s), 7.36 (1 H, dd, J = 7.9, 0.9 Hz), 7.30 (1 H , t, J = 7.9 Hz), 7.09 (1 H, d, J = 7.9 Hz), 4.32 (2 H, t, J = 5.6 Hz), 2.81-2.77 (2 H, m), 2.58-2.54 (2 H, m) , 2.48-2.45 (4H, m), 2.36 (2H, t, J = 5.0 Hz), 1.39 (9H, s).
ESI-MS m / z: 348 [M + H] ⁺ .

実施例65-2：ターシャリーブチル 4-(2-((2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレート[化合物No.65]の合成
実施例65-1で得られた化合物(184 mg, 0.53 mmol)と実施例32-5で得られた化合物(193 mg, 1.06 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(30 mg, 12.6%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 2.0 Hz), 8.75 (1H, dd, J = 4.9, 1.5 Hz), 8.23 (1H, dt, J = 7.9, 2.0 Hz), 7.58 (1H, dd, J = 7.9, 4.9 Hz), 7.41-7.36 (2H, m), 7.19 (1H, dd, J = 6.7, 2.4 Hz), 4.34 (2H, t, J = 5.5 Hz), 2.81 (2H, t, J = 5.5 Hz), 2.55-2.53 (1H, m), 2.48-2.46 (7H, m), 1.39 (9H, s).
ESI-MS m/z:449[M+H]⁺. Example 65-2: tert-butyl 4- (2-((2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate [Compound No. 65] ] Synthesis
Using the compound (184 mg, 0.53 mmol) obtained in Example 65-1 and the compound (193 mg, 1.06 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 Gave the title compound (30 mg, 12.6%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 2.0 Hz), 8.75 (1 H, dd, J = 4.9, 1.5 Hz), 8.23 (1 H, dt, J = 7.9, 2.0 Hz), 7.58 (1 H, dd, J = 7.9, 4.9 Hz), 7.41-7.36 (2 H, m), 7.19 (1 H, dd, J = 6.7, 2.4 Hz), 4.34 (2 H, t , J = 5.5 Hz), 2.81 (2 H, t, J = 5.5 Hz), 2.55-2.53 (1 H, m), 2.48-2.46 (7 H, m), 1. 39 (9 H, s).
ESI-MS m / z: 449 [M + H] ⁺ .

製造例66：7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩[化合物No.66]の合成
実施例66-1：7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩[化合物No.66]の合成
実施例65-2で得られた化合物(27 mg, 0.06 mmol)をジクロロメタン(1 ml)に溶解した。そこへトリフルオロ酢酸(1 ml)を加えて室温で40分攪拌した。反応後、溶媒を留去し、標記の化合物(54 mg, quant.)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, d, J = 2.1 Hz), 8.77 (1H, d, J = 1.2 Hz), 8.76 (1H, d, J = 1.8 Hz), 8.22 (1H, dt, J = 7.9, 1.8 Hz), 7.59 (1H, dd, J = 7.9, 4.9 Hz), 7.47-7.41 (2H, m), 7.22 (1H, d, J = 7.9 Hz), 4.50-4.47 (2H, m), 3.19-3.06 (4H, m).
ESI-MS m/z:349[M+H]⁺. Preparation Example 66 Synthesis of 7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate [Compound No. 66] Example 66-1 Synthesis of 7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate [compound No. 66]
The compound (27 mg, 0.06 mmol) obtained in Example 65-2 was dissolved in dichloromethane (1 ml). Thereto was added trifluoroacetic acid (1 ml) and the mixture was stirred at room temperature for 40 minutes. After the reaction, the solvent was evaporated to give the title compound (54 mg, quant.) As a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, d, J = 2.1 Hz), 8.77 (1 H, d, J = 1.2 Hz), 8. 76 (1 H, d, J = 1.8 Hz), 8.22 (1 H, dt, J = 7.9, 1.8 Hz), 7.59 (1 H, dd, J = 7.9, 4.9 Hz), 7.47-7.41 (2 H, m), 7.22 (1 H, d, J = 7.9) Hz), 4.50-4.47 (2H, m), 3.19-3.06 (4H, m).
ESI-MS m / z: 349 [M + H] ⁺ .

製造例67：7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.67]の合成
実施例67-1：7-(2-モルホリノエトキシ)ベンゾ[d]オキサゾールの合成
実施例35-2で得られた化合物(67 mg, 0.49 mmol)をDMF(1.3 ml)に溶解した。そこへ炭酸セシウム(388 mg, 1.19 mmol)、4-(2-クロロエチル)モルホリン塩酸塩(184 mg, 0.99 mmol)、ヨウ化カリウム(164 mg, 0.99 mmol)を加えて70 ℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Chromatorex NH 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(60 mg, 49.3%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.69 (1H, s), 7.36 (1H, d, J = 7.9 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.08 (1H, d, J = 7.9 Hz), 4.32 (2H, t, J = 5.6 Hz), 3.59-3.54 (6H, m), 2.77 (2H, t, J = 5.6 Hz), 2.56-2.53 (2H, m), 2.41-2.39 (2H, m).
ESI-MS m/z:249[M+H]⁺. Preparation Example 67 Synthesis of 7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 67] Example 67-1: 7- (2-morpholinoethoxy) benzo Synthesis of [d] oxazole
The compound obtained in Example 35-2 (67 mg, 0.49 mmol) was dissolved in DMF (1.3 ml). Cesium carbonate (388 mg, 1.19 mmol), 4- (2-chloroethyl) morpholine hydrochloride (184 mg, 0.99 mmol), potassium iodide (164 mg, 0.99 mmol) were added thereto, and the mixture was stirred overnight at 70 ° C. . After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Chromatorex NH 10 g, hexane / ethyl acetate) to give the title compound (60 mg, 49.3%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.69 (1 H, s), 7.36 (1 H, d, J = 7.9 Hz), 7.30 (1 H, t, J = 7.9 Hz), 7.08 (1H, d, J = 7.9 Hz), 4.32 (2H, t, J = 5.6 Hz), 3.59-3.54 (6H, m), 2.77 (2H, t, J = 5.6 Hz), 2.56-2.53 (2H, 2H, t) m), 2.41-2.39 (2H, m).
ESI-MS m / z: 249 [M + H] ⁺ .

実施例67-2：7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.67]の合成
実施例67-1で得られた化合物(60 mg, 0.24 mmol)と実施例32-5で得られた化合物(88 mg, 0.48 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(16 mg, 19.1%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 1.8 Hz), 8.75 (1H, dd, J = 4.9, 1.5 Hz), 8.23 (1H, dt, J = 7.8, 1.9 Hz), 7.58 (1H, dd, J = 7.9, 5.2 Hz), 7.40-7.38 (2H, m), 7.20 (1H, dd, J = 6.7, 2.4 Hz), 4.34 (2H, t, J = 5.6 Hz), 3.60-3.57 (5H, m), 2.78 (2H, t, J = 5.5 Hz), 2.55-2.53 (2H, m), 2.47-2.46 (1H, m).
ESI-MS m/z:350[M+H]⁺. Example 67-2 Synthesis of 7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 67]
Using the compound (60 mg, 0.24 mmol) obtained in Example 67-1 and the compound (88 mg, 0.48 mmol) obtained in Example 32-5, the same procedure as in Example 32-6 is performed. This gave the title compound (16 mg, 19.1%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 1.8 Hz), 8.75 (1 H, dd, J = 4.9, 1.5 Hz), 8.23 (1 H, dt, J = 7.8, 1.9 Hz), 7.58 (1 H, dd, J = 7.9, 5.2 Hz), 7.40-7.38 (2 H, m), 7.20 (1 H, dd, J = 6.7, 2.4 Hz), 4.34 (2 H, t , J = 5.6 Hz), 3.60-3.57 (5 H, m), 2. 78 (2 H, t, J = 5.5 Hz), 2.55-2.53 (2 H, m), 2.47-2.46 (1 H, m).
ESI-MS m / z: 350 [M + H] ⁺ .

製造例68：4-メトキシ-7-(4-モルホリノピペリジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.68]の合成
実施例68-1：4-メトキシ-7-(4-モルホリノピペリジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.68]の合成
実施例55-2で得られた化合物(30 mg, 0.09 mmol)と4-(ピペリジン-4-イル)モルホリン(78 mg, 0.46 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(2 mg, 5 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, s), 8.74 (1H, d, J = 4.6 Hz), 8.22 (1H, d, J = 7.8 Hz), 7.62-7.54 (1H, m), 6.92 (1H, d, J = 8.7 Hz), 6.87 (1H, d, J = 8.7 Hz), 3.92 (3H, s), 3.68-3.54 (7H, m), 2.77-2.64 (4H, m), 2.35-2.27 (2H, m), 1.96-1.88 (2H, m), 1.67-1.53 (2H, m).
ESI-MS m/z: 419[M+H]⁺. Preparation Example 68 Synthesis of 4-methoxy-7- (4-morpholinopiperidin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 68] Example 68-1: 4 Synthesis of -Methoxy-7- (4-morpholinopiperidin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 68]
Performing the same procedure as in Example 58-1 using the compound (30 mg, 0.09 mmol) obtained in Example 55-2 and 4- (piperidin-4-yl) morpholine (78 mg, 0.46 mmol) The title compound (2 mg, 5%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, s), 8. 74 (1 H, d, J = 4.6 Hz), 8.22 (1 H, d, J = 7.8 Hz), 7.62 -7.54 (1H, m), 6.92 (1H, d, J = 8.7 Hz), 6.87 (1H, d, J = 8.7 Hz), 3.92 (3H, s), 3.68-3.54 (7H, m), 2.77- 2.64 (4H, m), 2.35-2.27 (2H, m), 1.96-1.88 (2H, m), 1.67-1.53 (2H, m).
ESI-MS m / z: 419 [M + H] ⁺ .

製造例69：1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-オン[化合物No.69]の合成
実施例69-1：1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-オン[化合物No.69]の合成
実施例55-2で得られた化合物(30 mg, 0.09 mmol)とピペリジン-4-オン塩酸塩水和物 (70 mg, 0.46 mmol)を用いて同様の操作を行うことにより標記の化合物(4 mg, 13 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.74 (1H, dd, J = 4.8, 1.6 Hz), 8.25-8.19 (1H, m), 7.61-7.55 (1H, m), 7.03 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.54 (4H, t, J = 6.2 Hz), 2.54 (4H, t, J = 6.2 Hz).
ESI-MS m/z: 348[M+H]⁺. Preparation Example 69 Synthesis of 1- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-one [Compound No. 69] Example 69-1: 1 Synthesis of-(4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-one [Compound No. 69]
The title compound (4 mg) was obtained by the same procedure using the compound (30 mg, 0.09 mmol) obtained in Example 55-2 and piperidin-4-one hydrochloride hydrate (70 mg, 0.46 mmol). , 13%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.74 (1 H, dd, J = 4.8, 1.6 Hz), 8.25-8.19 (1 H, m), 7.61 -7.55 (1 H, m), 7.03 (1 H, d, J = 8.7 Hz), 6.91 (1 H, d, J = 8.7 Hz), 3.94 (3 H, s), 3.54 (4 H, t, J = 6.2 Hz) , 2.54 (4H, t, J = 6.2 Hz).
ESI-MS m / z: 348 [M + H] ⁺ .

製造例70：4-ブロモ-7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.70]の合成
実施例70-1：4-ブロモ-7-メトキシベンゾ[d]オキサゾールの合成
実施例35-3で得られた化合物(530 mg, 3.55 mmol)を用いて実施例55-1と同様の操作を行うことにより標記の化合物(770 mg, 95.1%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.83 (1H, s), 7.55 (1H, d, J = 8.5 Hz), 7.07 (1H, d, J = 8.5 Hz), 3.97 (3H, s).
ESI-MS m/z:228[M+H]⁺. Preparation Example 70 Synthesis of 4-bromo-7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 70] Example 70-1: 4-Bromo-7-methoxybenzo [d Synthesis of oxazole
The title compound (770 mg, 95.1%) was obtained as a white solid by the same procedure as in Example 55-1 using the compound (530 mg, 3.55 mmol) obtained in Example 35-3.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.83 (1 H, s), 7.55 (1 H, d, J = 8.5 Hz), 7.07 (1 H, d, J = 8.5 Hz), 3.97 (3H, s).
ESI-MS m / z: 228 [M + H] ⁺ .

実施例70-2：4-ブロモ-7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.70]の合成
実施例70-1で得られた化合物(770 mg, 3.38 mmol)と実施例32-5で得られた化合物(1.229 mg, 6.75 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(642 mg, 57.7%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, d, J = 1.8 Hz), 8.76 (1H, dd, J = 5.0, 1.8 Hz), 8.24 (1H, dt, J = 7.8, 1.8 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.59 (1H, dd, J = 7.8, 5.0 Hz), 7.15 (1H, d, J = 8.5 Hz), 3.99 (3H, s).
ESI-MS m/z:329[M+H]⁺. Example 70-2 Synthesis of 4-bromo-7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 70]
Using the compound (770 mg, 3.38 mmol) obtained in Example 70-1 and the compound (1.229 mg, 6.75 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (642 mg, 57.7%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, d, J = 1.8 Hz), 8. 76 (1 H, dd, J = 5.0, 1.8 Hz), 8.24 (1 H, dt, J = 7.8, 1.8 Hz), 7.63 (1 H, d, J = 8.5 Hz), 7. 59 (1 H, dd, J = 7.8, 5.0 Hz), 7.15 (1 H, d, J = 8.5 Hz), 3.99 (3 H, s).
ESI-MS m / z: 329 [M + H] ⁺ .

製造例71：ターシャリーブチル 4-(7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)ピペラジン-1-カルボキシレート[化合物No.71]の合成
実施例71-1：ターシャリーブチル 4-(7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)ピペラジン-1-カルボキシレート[化合物No.71]の合成
実施例70-2で得られた化合物(88 mg, 0.27 mmol)と1-(ターシャリーブトキシカルボニル)ピペラジン(503 mg, 2.7 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(55 mg, 46.9%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 1.5 Hz), 8.74 (1H, dd, J = 4.9, 1.5 Hz), 8.23 (1H, dt, J = 7.9, 1.8 Hz), 7.58 (1H, dd, J = 7.9, 5.5 Hz), 7.04 (1H, d, J = 8.9 Hz), 6.74 (1H, d, J = 8.9 Hz), 3.91 (3H, s), 3.55-3.52 (4H, m), 3.30-3.26 (4H, m), 1.43 (9H, s).
ESI-MS m/z:435[M+H]⁺. Preparation Example 71: Synthesis of tert-butyl 4- (7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazine-1-carboxylate [Compound No. 71] Example 71 -1: Synthesis of tert-butyl 4- (7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazine-1-carboxylate [Compound No. 71]
By performing the same operation as in Example 58-1 using the compound (88 mg, 0.27 mmol) obtained in Example 70-2 and 1- (tert-butoxycarbonyl) piperazine (503 mg, 2.7 mmol) The title compound (55 mg, 46.9%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 1.5 Hz), 8.74 (1 H, dd, J = 4.9, 1.5 Hz), 8.23 (1 H, dt, J = 7.9, 1.8 Hz), 7.58 (1 H, dd, J = 7.9, 5.5 Hz), 7.04 (1 H, d, J = 8.9 Hz), 6.74 (1 H, d, J = 8.9 Hz), 3.91 (3 H, s), 3.55-3.52 (4H, m), 3.30-1.26 (4H, m), 1.43 (9H, s).
ESI-MS m / z: 435 [M + H] ⁺ .

製造例72：4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.72]の合成
実施例72-1：4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.72]の合成
実施例59-1で得られた化合物(151 mg, 0.35 mmol)のジクロロメタン(4.5 ml)溶液中に、2,2,2-トリフルオロ酢酸(1.12 ml, 14.6 mmol)を滴下した。4時間撹拌した後、反応終了後、減圧下濃縮乾固した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(63 mg, 54 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, d, J = 1.8 Hz), 8.76-8.71 (1H, m), 8.26-8.19 (1H, m), 7.61-7.53 (1H, m), 6.93-6.85 (2H, m), 3.92 (3H, s), 3.07 (4H, t, J = 4.8 Hz), 2.91 (4H, t, J = 4.8 Hz).
ESI-MS m/z: 335[M+H]⁺. Preparation Example 72 Synthesis of 4-methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 72] Example 72-1: 4-methoxy- Synthesis of 7- (Piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 72]
In a solution of the compound (151 mg, 0.35 mmol) obtained in Example 59-1 in dichloromethane (4.5 ml), 2,2,2-trifluoroacetic acid (1.12 ml, 14.6 mmol) was dropped. After stirring for 4 hours, after completion of the reaction, the solution was concentrated to dryness under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (63 mg, 54%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, d, J = 1.8 Hz), 8.76-8.71 (1 H, m), 8.26-8.19 (1 H, m), 7.61- 7.53 (1 H, m), 6.93-6.85 (2 H, m), 3.92 (3 H, s), 3.07 (4 H, t, J = 4.8 Hz), 2. 91 (4 H, t, J = 4.8 Hz).
ESI-MS m / z: 335 [M + H] ⁺ .

製造例73：ターシャリーブチル 4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)-1,4-ジアゼパン-1-カルボキシレート[化合物No.73]の合成
実施例73-1：ターシャリーブチル 4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)-1,4-ジアゼパン-1-カルボキシレート[化合物No.73]の合成
実施例55-2で得られた化合物(20 mg, 0.06 mmol)とターシャリーブチル1,4-ジアゼパン-1-カルボキシレート(60 μl, 0.30 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(5 mg, 18 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, s), 8.78-8.69 (1H, m), 8.25-8.17 (1H, m), 7.60-7.53 (1H, m), 6.88-6.73 (2H, m), 3.88 (3H, s), 3.75-3.69 (1H, m), 3.68-3.61 (1H, m), 3.60-3.49 (5H, m), 1.92-1.80 (2H, m), 1.32 (4H, s), 1.27-1.21 (1H, m), 1.14 (5H, s).
ESI-MS m/z: 449[M+H]⁺. Preparation Example 73: tert-butyl 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) -1,4-diazepane-1-carboxylate [Compound No. 73] Synthesis Example 73-1: Tertiary butyl 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) -1,4-diazepane-1-carboxylate [compound No. 73] Synthesis
Operation similar to Example 58-1 using the compound (20 mg, 0.06 mmol) obtained in Example 55-2 and tertiary butyl 1,4-diazepane-1-carboxylate (60 μl, 0.30 mmol) Gave the title compound (5 mg, 18%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, s), 8.78-8.69 (1 H, m), 8.25-8.17 (1 H, m), 7.60-7.53 (1 H, m) ), 6.88-6.73 (2H, m), 3.88 (3H, s), 3.75-3.69 (1H, m), 3.68-3.61 (1H, m), 3.60-3.49 (5H, m), 1.92-1.80 (2H) , m), 1.32 (4H, s), 1.27-1.21 (1H, m), 1.14 (5H, s).
ESI-MS m / z: 449 [M + H] ⁺ .

製造例74：4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.74]の合成
実施例74-1：4-メトキシ-7-(ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.74]の合成
実施例72-1で得られた化合物(60 mg, 0.18 mmol)のクロロホルム(2 ml)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(47 μl, 0.19 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、標記の化合物(66 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, d, J = 1.4 Hz), 8.77-8.73 (1H, m), 8.32 (1H, s), 8.23-8.18 (1H, m), 7.61-7.55 (1H, m), 6.99 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.31-3.27 (4H, m), 3.27-3.21 (4H, m).
ESI-MS m/z: 335[M+H]⁺. Preparation Example 74 Synthesis of 4-methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 74] Example 74-1: 4- Synthesis of Methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 74]
In a solution of the compound (60 mg, 0.18 mmol) obtained in Example 72-1 in chloroform (2 ml), 4 mol / l hydrogen chloride / ethyl acetate solution (47 μl, 0.19 mmol) was dropped. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the title compound (66 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, d, J = 1.4 Hz), 8.77-8.73 (1 H, m), 8.32 (1 H, s), 8.23-8.18 ( 1H, m), 7.61-7.55 (1H, m), 6.99 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.31-3.27 (4H , m), 3.27-3.21 (4H, m).
ESI-MS m / z: 335 [M + H] ⁺ .

製造例75：7-(1,4-ジアゼパン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩[化合物No.75]の合成
実施例75-1：7-(1,4-ジアゼパン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールトリフルオロ酢酸塩[化合物No.75]の合成
実施例73-1で得られた化合物(4 mg, 0.01 mmol)のジクロロメタン(232 μl)溶液中に、2,2,2-トリフルオロ酢酸(28 μl, 0.46 mmol)を滴下した。2時間撹拌した後、反応終了後、減圧下濃縮乾固した。標記の化合物(3.6 mg, 86 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, d, J = 2.3 Hz), 8.78-8.72 (1H, m), 8.69-8.59 (2H, m), 8.23-8.17 (1H, m), 7.62-7.55 (1H, m), 6.89 (1H, d, J = 9.0 Hz), 6.84 (1H, d, J = 9.0 Hz), 3.91 (3H, s), 3.75-3.69 (2H, m), 3.57-3.49 (2H, m), 3.42-3.34 (2H, m), 3.28-3.21 (2H, m), 2.18-2.09 (2H, m).
ESI-MS m/z: 349[M+H]⁺. Preparation Example 75 Synthesis of 7- (1,4-diazepan-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate [compound No. 75] Synthesis of 75-1: 7- (1,4-diazepan-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate [compound No. 75]
In a solution of the compound (4 mg, 0.01 mmol) obtained in Example 73-1 in dichloromethane (232 μl), 2,2,2-trifluoroacetic acid (28 μl, 0.46 mmol) was dropped. After stirring for 2 hours, after completion of the reaction, it was concentrated to dryness under reduced pressure. The title compound (3.6 mg, 86%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, d, J = 2.3 Hz), 8.78-8.72 (1 H, m), 8.69-8.59 (2 H, m), 8.23- 8.17 (1 H, m), 7.62-7.55 (1 H, m), 6.89 (1 H, d, J = 9.0 Hz), 6.84 (1 H, d, J = 9.0 Hz), 3.91 (3 H, s), 3.75-3.69 (2H, m), 3.57-3.49 (2H, m), 3.42-3.34 (2H, m), 3.28-3.21 (2H, m), 2.18-2.09 (2H, m).
ESI-MS m / z: 349 [M + H] ⁺ .

製造例76：2-(4-(7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)ピペラジン-1-イル)-N,N-ジメチルエタンアミン塩酸塩[化合物No.76]の合成
実施例76-1：2-(4-(7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)ピペラジン-1-イル)-N,N-ジメチルエタンアミンの合成
実施例70-2で得られた化合物(54 mg, 0.16 mmol)と1-[2-(ジメチルアミノ)エチル]ピペラジン(258 mg, 1.6 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(23 mg, 35.5%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, d, J = 1.5 Hz), 8.74 (1H, dd, J = 4.9, 1.5 Hz), 8.22 (1H, dt, J = 7.9, 2.0 Hz), 7.57 (1H, ddd, J = 7.9, 4.9, 0.6 Hz), 7.02 (1H, d, J = 8.9 Hz), 6.69 (1H, d, J = 8.9 Hz), 3.90 (3H, s), 2.68-2.53 (6H, m), 2.47-2.32 (6H, m), 2.16 (6H, s).
ESI-MS m/z:406[M+H]⁺. Preparation Example 76: 2- (4- (7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazin-1-yl) -N, N-dimethylethanamine hydrochloride [ Synthesis of Compound No. 76] Example 76-1: 2- (4- (7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazin-1-yl) -N , N-Dimethylethanamine Synthesis
The procedure of Example 58-1 is repeated using the compound (54 mg, 0.16 mmol) obtained in Example 70-2 and 1- [2- (dimethylamino) ethyl] piperazine (258 mg, 1.6 mmol) The title compound (23 mg, 35.5%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, d, J = 1.5 Hz), 8.74 (1 H, dd, J = 4.9, 1.5 Hz), 8.22 (1 H, dt, J = 7.9, 2.0 Hz), 7.57 (1 H, ddd, J = 7.9, 4.9, 0.6 Hz), 7.02 (1 H, d, J = 8.9 Hz), 6.69 (1 H, d, J = 8.9 Hz), 3.90 (3 3H, s), 2.68-2.53 (6H, m), 2.47-2. 32 (6H, m), 2.16 (6H, s).
ESI-MS m / z: 406 [M + H] ⁺ .

実施例76-2：2-(4-(7-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-イル)ピペラジン-1-イル)-N,N-ジメチルエタンアミン塩酸塩[化合物No.76]の合成
実施例76-1で得られた化合物(22 mg, 0.054 mmol)をメタノール(0.2 ml)、クロロホルム(0.2 ml)に溶解した。そこへ4 mol/l塩化水素-酢酸エチル溶液(0.033 ml, 0.13 mmol)を加えた。溶媒を留去し、標記の化合物(25 mg, 96.7%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 2.1 Hz), 8.75 (1H, dd, J = 4.9, 1.5 Hz), 8.22 (1H, dt, J = 7.9, 1.8 Hz), 7.58 (1H, dd, J = 7.9, 4.9 Hz), 7.04 (1H, d, J = 8.5 Hz), 6.73 (1H, d, J = 6.1 Hz), 3.92 (3H, s), 3.27-3.13 (4H, m), 2.81 (6H, s), 2.74-2.65 (5H, m), 2.55-2.53 (1H, m), 2.47-2.31 (2H, m).
ESI-MS m/z:406[M+H]⁺. Example 76-2: 2- (4- (7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazin-1-yl) -N, N-dimethylethanamine hydrochloride Synthesis of salt [compound No. 76]
The compound (22 mg, 0.054 mmol) obtained in Example 76-1 was dissolved in methanol (0.2 ml) and chloroform (0.2 ml). Thereto was added 4 mol / l hydrogen chloride-ethyl acetate solution (0.033 ml, 0.13 mmol). The solvent was evaporated to give the title compound (25 mg, 96.7%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 2.1 Hz), 8.75 (1 H, dd, J = 4.9, 1.5 Hz), 8.22 (1 H, dt, J = 7.9, 1.8 Hz), 7.58 (1 H, dd, J = 7.9, 4.9 Hz), 7.04 (1 H, d, J = 8.5 Hz), 6.73 (1 H, d, J = 6.1 Hz), 3.92 (3 H, s), 3.27-3.13 (4H, m), 2.81 (6H, s), 2.74-2.65 (5H, m), 2.55-2.53 (1H, m), 2.47-2.31 (2H, m).
ESI-MS m / z: 406 [M + H] ⁺ .

製造例77：7-(1,4-ジアゼパン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.77]の合成
実施例77-1：7-(1,4-ジアゼパン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.77]の合成
実施例73-1で得られた化合物(150 mg, 0.33 mmol)のジクロロメタン(4.3 ml)溶液中に、2,2,2-トリフルオロ酢酸(1.08 ml, 14.0 mmol)を滴下した。2時間撹拌した後、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製した。これをクロロホルム(4 ml)に溶解し、4 mol/l塩化水素/酢酸エチル溶液(72.3 μl, 0.29 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、酢酸エチルで洗浄後、減圧下乾燥し、標記の化合物(91 mg, 85 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, d, J = 2.3 Hz), 8.75 (1H, dd, J = 4.8, 1.6 Hz), 8.72-8.50 (1H, m), 8.23-8.16 (1H, m), 7.61-7.54 (1H, m), 6.88 (1H, d, J = 9.2 Hz), 6.82 (1H, d, J = 9.2 Hz), 3.91 (3H, s), 3.72 (2H, t, J = 5.0 Hz), 3.54 (2H, t, J = 6.0 Hz), 3.32-3.28 (2H, m), 3.19 (2H, t, J = 5.0 Hz), 2.16-2.07 (2H, m).
ESI-MS m/z: 349[M+H]⁺. Preparation Example 77 Synthesis of 7- (1,4-diazepan-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 77] Example 77- Synthesis of 1: 7- (1,4-diazepan-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [compound No. 77]
In a solution of the compound (150 mg, 0.33 mmol) obtained in Example 73-1 in dichloromethane (4.3 ml), 2,2,2-trifluoroacetic acid (1.08 ml, 14.0 mmol) was dropped. After stirring for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added after completion of the reaction, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol). This was dissolved in chloroform (4 ml), and 4 mol / l hydrogen chloride / ethyl acetate solution (72.3 μl, 0.29 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, washed with ethyl acetate and dried under reduced pressure to obtain the title compound (91 mg, 85%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, d, J = 2.3 Hz), 8.75 (1 H, dd, J = 4.8, 1.6 Hz), 8.72-8.50 (1 H, m), 8.23-8.16 (1H, m), 7.61-7.54 (1H, m), 6.88 (1H, d, J = 9.2 Hz), 6.82 (1H, d, J = 9.2 Hz), 3.91 (3H, s) ), 3.72 (2H, t, J = 5.0 Hz), 3.54 (2H, t, J = 6.0 Hz), 3.32-3.28 (2H, m), 3.19 (2H, t, J = 5.0 Hz), 2.16-2.07 (2H, m).
ESI-MS m / z: 349 [M + H] ⁺ .

製造例78：1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-アミン塩酸塩[化合物No.78]の合成
実施例78-1：1-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペリジン-4-アミン塩酸塩[化合物No.78]の合成
実施例63-1で得られた化合物(82 mg, 0.18 mmol)のジクロロメタン(4.8 ml)溶液中に、2,2,2-トリフルオロ酢酸(0.888 ml, 11.5 mmol)を滴下した。2時間撹拌した後、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製した。これをクロロホルム(2 ml)に溶解し、4 mol/l塩化水素/酢酸エチル溶液(38 μl, 0.15 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、酢酸エチルで洗浄後、減圧下乾燥し、標記の化合物(42 mg, 76 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.19 (1H, m), 7.74-7.42 (3H, m), 6.95 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.68-3.58 (2H, m), 3.22-3.12 (1H, m), 2.86-2.76 (2H, m), 2.06-1.97 (2H, m), 1.77-1.63 (2H, m).
ESI-MS m/z: 349[M+H]⁺. Preparation Example 78 Synthesis Example of 1- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidine-4-amine hydrochloride [Compound No. 78] Example 78-1 Synthesis of 1- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidine-4-amine hydrochloride [Compound No. 78]
In a solution of the compound obtained in Example 63-1 (82 mg, 0.18 mmol) in dichloromethane (4.8 ml), 2,2,2-trifluoroacetic acid (0.888 ml, 11.5 mmol) was dropped. After stirring for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added after completion of the reaction, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol). This was dissolved in chloroform (2 ml), and 4 mol / l hydrogen chloride / ethyl acetate solution (38 μl, 0.15 mmol) was added dropwise. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure, washed with ethyl acetate and dried under reduced pressure to give the title compound (42 mg, 76%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.19 (1 H, m), 7.74-7.42 (3 H, m), 6.95 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.68-3.58 (2H, m), 3.22-3.12 (1H, m) ), 2.86-2.76 (2H, m), 2.06-1.97 (2H, m), 1.77-1.63 (2H, m).
ESI-MS m / z: 349 [M + H] ⁺ .

製造例79：4-メトキシ-7-(4-(2-メトキシエチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.79]の合成
実施例79-1：4-メトキシ-7-(4-(2-メトキシエチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.79]の合成
実施例60-1で得られた化合物(166 mg, 0.47 mmol)のクロロホルム(6.14 ml)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(111 μl, 0.49 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、酢酸エチルで洗浄後、減圧下乾燥し、標記の化合物(127 mg, 70 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.15-10.02 (1H, m), 8.95 (1H, br s), 8.78-8.73 (1H, m), 8.25-8.16 (1H, m), 7.63-7.55 (1H, m), 7.02 (1H, d, J = 8.2 Hz), 6.93 (1H, d, J = 8.2 Hz), 3.94 (3H, s), 3.78-3.68 (4H, m), 3.67-3.59 (2H, m), 3.45-3.38 (2H, m), 3.34 (3H, s), 3.32-3.26 (2H, m), 3.24-3.14 (2H, m).
ESI-MS m/z: 393[M+H]⁺. Preparation Example 79 Synthesis of 4-methoxy-7- (4- (2-methoxyethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 79] Example 79-1: 4-methoxy-7- (4- (2-methoxyethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 79] Synthesis of
In a solution of the compound (166 mg, 0.47 mmol) obtained in Example 60-1 in chloroform (6.14 ml), a 4 mol / l hydrogen chloride / ethyl acetate solution (111 μl, 0.49 mmol) was dropped. The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, washed with ethyl acetate and dried under reduced pressure to give the title compound (127 mg, 70%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.15-12.02 (1H, m), 8.95 (1 H, br s), 8.78-8.73 (1 H, m), 8.25-8.16 (1 H, m), 7.63-7.55 (1H, m), 7.02 (1H, d, J = 8.2 Hz), 6.93 (1H, d, J = 8.2 Hz), 3.94 (3H, s), 3.78-3.68 (4H, m) ), 3.67-3.59 (2H, m), 3.45-3.38 (2H, m), 3.34 (3H, s), 3.32-3.26 (2H, m), 3.24-3.14 (2H, m).
ESI-MS m / z: 393 [M + H] ⁺ .

製造例80：7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.80]の合成
実施例80-1：7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.80]の合成
実施例67-2で得られた化合物(541 mg, 1.55 mmol)をメタノール(5 ml)、クロロホルム(5 ml)に溶解した。そこへ4 mol/l塩化水素-酢酸エチル溶液(0.816 ml, 3.26 mmol)を加えた。溶媒を留去し、酢酸エチルで洗った。減圧乾燥して、標記の化合物(379 mg, 58.0%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.41 (2H, br s), 8.97 (1H, d, J = 1.8 Hz), 8.76 (1H, dd, J = 4.9, 1.5 Hz), 8.23 (1H, dt, J = 7.9, 1.8 Hz), 7.60 (1H, dd, J = 7.9, 4.9 Hz), 7.48-7.42 (2H, m), 7.25 (1H, d, J = 7.6 Hz), 4.67-4.64 (2H, m), 3.72-3.62 (4H, m), 3.60-3.56 (2H, m), 2.55-2.53 (2H, m), 2.47-2.46 (2H, m).
ESI-MS m/z:349[M+H]⁺. Preparation Example 80 Synthesis of 7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 80] Example 80-1: 7 Synthesis of-(2- (Piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 80]
The compound (541 mg, 1.55 mmol) obtained in Example 67-2 was dissolved in methanol (5 ml) and chloroform (5 ml). Thereto was added 4 mol / l hydrogen chloride-ethyl acetate solution (0.816 ml, 3.26 mmol). The solvent was evaporated and washed with ethyl acetate. Drying under reduced pressure gave the title compound (379 mg, 58.0%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.41 (2 H, br s), 8. 97 (1 H, d, J = 1.8 Hz), 8.76 (1 H, dd, J = 4.9, 1.5 Hz ), 8.23 (1H, dt, J = 7.9, 1.8 Hz), 7.60 (1H, dd, J = 7.9, 4.9 Hz), 7.48-7.42 (2H, m), 7.25 (1 H, d, J = 7.6 Hz) , 4.67-4.64 (2H, m), 3.72-3.62 (4H, m), 3.60-3.56 (2H, m), 2.55-2.53 (2H, m), 2.47-2.46 (2H, m).
ESI-MS m / z: 349 [M + H] ⁺ .

製造例81：ターシャリーブチル (2-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-オキソエチル)カルバメート[化合物No.81]の合成
実施例81-1：ターシャリーブチル (2-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-オキソエチル)カルバメート[化合物No.81]の合成
実施例72-1で得られた化合物(40 mg, 0.12 mmol)のDMF(600 μl)溶液中に、2-((ターシャリーブトキシカルボニル)アミノ)酢酸(21 mg, 0.12 mmol)、2-(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)-1,1,3,3-テトラメチルイソウロニウムヘキサフルオロホスフェート(V)(50 mg, 0.13 mmol)、N-エチル-N-イソプロピルプロパン-2-アミン(21 μl, 0.12 mmol)を室温下添加した。一晩撹拌した後、減圧下濃縮乾固した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(56 mg, 95 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.76-8.71 (1H, m), 8.26-8.19 (1H, m), 7.61-7.54 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 6.80 (1H, t, J = 5.7 Hz), 3.93 (3H, s), 3.85 (2H, d, J = 5.7 Hz), 3.71-3.60 (4H, m), 3.18-3.06 (4H, m), 1.39 (9H, s).
ESI-MS m/z:492[M+H]⁺. Preparation Example 81: Tertiary butyl (2- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2-oxoethyl) carbamate [Cer. Synthesis of Compound No. 81] Example 81-1: Tertiary butyl (2- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-) Synthesis of (yl) -2-oxoethyl) carbamate [Compound No. 81]
In a solution of the compound (40 mg, 0.12 mmol) obtained in Example 72-1 in DMF (600 μl), 2-((tertiary butoxycarbonyl) amino) acetic acid (21 mg, 0.12 mmol), 2- ( 3H- [1,2,3] Triazolo [4,5-b] pyridin-3-yl) -1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (50 mg, 0.13 mmol) , N-ethyl-N-isopropylpropan-2-amine (21 μl, 0.12 mmol) was added at room temperature. After stirring overnight, it was concentrated to dryness under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (56 mg, 95%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.76-8.71 (1 H, m), 8.26-8.19 (1 H, m), 7.61-7.54 (1 H, 1 H, m), 6.95 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 6.80 (1 H, t, J = 5.7 Hz), 3.93 (3H, s), 3.85 (2H, 2H, s) d, J = 5.7 Hz), 3.71-3.60 (4H, m), 3.18-3.06 (4H, m), 1. 39 (9H, s).
ESI-MS m / z: 492 [M + H] ⁺ .

製造例82：2-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)エタノン塩酸塩[化合物No.82]の合成
実施例82-1：2-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)エタノンの合成
実施例72-1で得られた化合物(20 mg, 0.06 mmol)とN,N'-ジメチルグリシン(6 mg, 0.06 mmol)を用いて実施例81-1と同様の操作を行うことにより標記の化合物(17 mg, 68 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.78-8.72 (1H, m), 8.26-8.18 (1H, m), 7.61-7.53 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.79-3.72 (2H, m), 3.70-3.63 (2H, m), 3.20-3.07 (6H, m), 2.21 (6H, s).
ESI-MS m/z:420[M+H]⁺. Preparation Example 82: 2- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone hydrochloride [ Synthesis of Compound No. 82] Example 82-1: 2- (dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine -1-yl) Ethanone synthesis
The title compound was obtained by the same procedure as in Example 81-1 using the compound (20 mg, 0.06 mmol) obtained in Example 72-1 and N, N′-dimethylglycine (6 mg, 0.06 mmol). The compound (17 mg, 68%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.78-8.72 (1 H, m), 8.26-8.18 (1 H, m), 7.61-7.53 (1 H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.79-3.72 (2H, m), 3.70-3.63 (2H, m ), 3.20-3.07 (6H, m), 2.21 (6H, s).
ESI-MS m / z: 420 [M + H] ⁺ .

実施例82-2：2-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)エタノン塩酸塩[化合物No.82]の合成
実施例82-1で得られた化合物(17 mg, 0.04 mmol)のクロロホルム(0.59 ml)溶液中に、4N塩酸/酢酸エチル溶液(11 μl, 0.04 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、標記の化合物(18 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.64-9.50 (1H, m), 8.96 (1H, br s), 8.78-8.72 (1H, m), 8.26-8.19 (1H, m), 7.63-7.50 (1H, m), 6.97 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.72 (2H, t, J = 4.8 Hz), 3.62 (2H, t, J = 4.8 Hz), 3.34 (2H, s), 3.19 (2H, t, J = 4.8 Hz), 3.14 (2H, t, J = 4.8 Hz), 2.62 (6H, s).
ESI-MS m/z: 420[M+H]⁺. Example 82-2: 2- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone hydrochloride Synthesis of salt [compound No. 82]
In a solution of the compound (17 mg, 0.04 mmol) obtained in Example 82-1 in chloroform (0.59 ml), 4N hydrochloric acid / ethyl acetate solution (11 μl, 0.04 mmol) was dropped. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the title compound (18 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.64-9.50 (1 H, m), 8.96 (1 H, br s), 8. 78-8. 72 (1 H, m), 8. 26-8. 19 (1 H, m), 7.63-7.50 (1H, m), 6.97 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.72 (2H, t, J = 4.8 Hz), 3.62 (2H, t, J = 4.8 Hz), 3.34 (2H, s), 3.19 (2H, t, J = 4.8 Hz), 3.14 (2H, t, J = 4.8 Hz), 2.62 ( 6H, s).
ESI-MS m / z: 420 [M + H] ⁺ .

製造例83：2-アミノ-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)エタノン塩酸塩[化合物No.83]の合成
実施例83-1：2-アミノ-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)エタノンの合成
実施例81-1で得られた化合物(50 mg, 0.10 mmol)のジクロロメタン(1.3 ml)溶液中に、2,2,2-トリフルオロ酢酸(165 μl, 2.14 mmol)を滴下した。2時間撹拌した後、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(34 mg, 85 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.19 (1H, m), 7.61-7.54 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.73-3.64 (2H, m), 3.61-3.53 (2H, m), 3.39 (2H, s), 3.20-3.06 (4H, m), 1.70-1.50 (2H, m).
ESI-MS m/z: 392[M+H]⁺. Preparation Example 83: 2-amino-1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone hydrochloride [Compound No. Synthesis of 83] Example 83-1: 2-amino-1- (4- (4-methoxy-4- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone Synthesis of
In a solution of the compound (50 mg, 0.10 mmol) obtained in Example 81-1 in dichloromethane (1.3 ml), 2,2,2-trifluoroacetic acid (165 μl, 2.14 mmol) was dropped. After stirring for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added after completion of the reaction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (34 mg, 85%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.19 (1 H, m), 7.61-7.54 (1 H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.73-3.64 (2H, m), 3.61-3.53 (2H, m ), 3.39 (2H, s), 3.20-3.06 (4H, m), 1. 70-1. 50 (2H, m).
ESI-MS m / z: 392 [M + H] ⁺ .

実施例83-2：2-アミノ-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)エタノン塩酸塩[化合物No.83]の合成
実施例83-1で得られた化合物(34 mg, 0.09 mmol)のクロロホルム(1.26 ml)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(23 μl, 0.09 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、酢酸エチルで洗浄後、減圧下乾燥し、標記の化合物(16 mg, 43 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, s), 8.77-8.73 (1H, m), 8.26-8.18 (1H, m), 7.62-7.55 (1H, m), 6.96 (1H, d, J = 9.2 Hz), 6.92 (1H, d, J = 9.2 Hz), 3.94 (3H, s), 3.76-3.65 (4H, m), 3.63-3.55 (2H, m), 3.20-3.03 (4H, m).
ESI-MS m/z: 392[M+H]⁺. Example 83-2: 2-amino-1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone hydrochloride [compound No. 83] Synthesis
In a solution of the compound (34 mg, 0.09 mmol) obtained in Example 83-1 in chloroform (1.26 ml), 4 mol / l hydrogen chloride / ethyl acetate solution (23 μl, 0.09 mmol) was dropped. The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, washed with ethyl acetate and dried under reduced pressure to give the title compound (16 mg, 43%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, s), 8.77-8.73 (1 H, m), 8.26-8.18 (1 H, m), 7.62-7.55 (1 H, m) ), 6.96 (1H, d, J = 9.2 Hz), 6.92 (1H, d, J = 9.2 Hz), 3.94 (3H, s), 3.76-3.65 (4H, m), 3.63-3.55 (2H, m) , 3.20-3.03 (4H, m).
ESI-MS m / z: 392 [M + H] ⁺ .

製造例84：4-メトキシ-7-(モルホリノメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.84]の合成
実施例84-1：4-メトキシ-7-ビニルベンゾ[d]オキサゾールの合成
実施例55-1で得られた化合物(20 mg, 0.09 mmol)の1,4-ジオキサン(1.1 ml)、水(158 μl)溶液中に、4,4,5,5-テトラメチル-2-ビニル-1,3,2-ジオキサボロラン(23 μl, 0.13 mmol)、酢酸パラジウム(2 mg, 8.77 μmol)、ジシクロヘキシル(2',6'-ジメトキシ-[1,1'-ビフェニル]-2-イル)ホスフィン(7 mg, 0.018 mmol)、リン酸カリウム(140 mg, 0.66 mmol)を添加した。アルゴン置換した後、還流条件下一晩撹拌した。反応終了後、セライトろ過し、酢酸エチルで洗浄後、減圧下濃縮乾固した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物 (16 mg, 99 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.71 (1H, s), 7.43 (1H, d, J = 8.7 Hz), 6.95 (1H, d, J = 8.7 Hz), 6.86 (1H, dd, J = 17.9, 11.4 Hz), 6.05 (1H, dd, J = 17.9, 1.1 Hz), 5.44 (1H, dd, J = 11.4, 1.1 Hz), 3.98 (3H, s).
ESI-MS m/z: 176[M+H]⁺. Preparation Example 84 Synthesis of 4-methoxy-7- (morpholinomethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 84] Example 84-1: 4-methoxy-7-vinylbenzo Synthesis of [d] oxazole
In a solution of the compound (20 mg, 0.09 mmol) obtained in Example 55-1 in 1,4-dioxane (1.1 ml) in water (158 μl), 4,4,5,5-tetramethyl-2- Vinyl-1,3,2-dioxaborolane (23 μl, 0.13 mmol), palladium acetate (2 mg, 8.77 μmol), dicyclohexyl (2 ', 6'-dimethoxy- [1,1'-biphenyl] -2-yl) Phosphine (7 mg, 0.018 mmol) and potassium phosphate (140 mg, 0.66 mmol) were added. After argon substitution, the solution was stirred overnight under reflux. After completion of the reaction, the reaction solution was filtered through Celite, washed with ethyl acetate and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (16 mg, 99%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.71 (1 H, s), 7.43 (1 H, d, J = 8.7 Hz), 6.95 (1 H, d, J = 8.7 Hz), 6.86 (1H, dd, J = 17.9, 11.4 Hz), 6.05 (1 H, dd, J = 17.9, 1.1 Hz), 5.44 (1 H, dd, J = 11.4, 1.1 Hz), 3.98 (3 H, s).
ESI-MS m / z: 176 [M + H] ⁺ .

実施例84-2：4-メトキシベンゾ[d]オキサゾール-7-カルボアルデヒドの合成
実施例84-1で得られた化合物(23 mg, 0.13 mmol)の1,4-ジオキサン(1 ml)、水(200 μl)の混合溶液中に、2.5 wt% 四酸化オスミウムターシャリーブタノール溶液(33 μl, 2.63 μmol)、2,6-ルチジン(31 μl, 0.26 mmol)、過ヨウ素酸ナトリウム(112 mg, 0.53 mmol)を添加した。アルゴン置換した後、室温で6時間撹拌した。反応終了後、セライトろ過した後、酢酸エチルで洗浄し、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物 (17 mg,73 %, 0.096 mmol)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.09 (1H, s), 8.82 (1H, s), 7.99 (1H, d, J = 8.7 Hz), 7.19 (1H, d, J = 8.7 Hz), 4.10 (3H, s).
ESI-MS m/z: 178[M+H]⁺. Example 84-2 Synthesis of 4-methoxybenzo [d] oxazole-7-carbaldehyde
2.5 wt% osmium tetraoxide tertiary butanol solution (in a mixed solution of the compound (23 mg, 0.13 mmol) obtained in Example 84-1 in 1,4-dioxane (1 ml) and water (200 μl) 33 μl, 2.63 μmol), 2,6-lutidine (31 μl, 0.26 mmol) and sodium periodate (112 mg, 0.53 mmol) were added. After argon substitution, the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was filtered through celite, washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (17 mg, 73%, 0.096 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.09 (1 H, s), 8.82 (1 H, s), 7.99 (1 H, d, J = 8.7 Hz), 7.19 (1 H, d, J = 8.7 Hz), 4.10 (3 H, s).
ESI-MS m / z: 178 [M + H] ⁺ .

実施例84-3：4-メトキシ-7-(モルホリノメチル)ベンゾ[d]オキサゾールの合成
実施例84-2で得られた化合物(17 mg, 0.10 mmol)のジクロロメタン(1 ml)溶液中に、モルホリン(9 μl, 0.10 mmol)、酢酸(6 μl, 0.10 mmol)を室温下添加した。トリアセトキシ水素化ホウ素ナトリウム(26 mg, 0.13 mmol)を添加した後、室温で3時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物 (14 mg, 59%)を得た。
¹H-NMR (CDCl₃) δ: 8.63 (1H, s), 7.28 (1H, d, J = 8.2 Hz), 6.92 (1H, d, J = 8.2 Hz), 3.96 (3H, s), 3.68 (2H, s), 3.54 (4H, t, J = 4.6 Hz), 2.37 (4H, t, J = 4.6 Hz).
ESI-MS m/z:249[M+H]⁺. Example 84-3 Synthesis of 4-methoxy-7- (morpholinomethyl) benzo [d] oxazole
In a solution of the compound (17 mg, 0.10 mmol) obtained in Example 84-2 in dichloromethane (1 ml), morpholine (9 μl, 0.10 mmol) and acetic acid (6 μl, 0.10 mmol) were added at room temperature. After adding sodium triacetoxyborohydride (26 mg, 0.13 mmol), the mixture was stirred at room temperature for 3 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (14 mg, 59%).
¹ H-NMR (CDCl ₃ ) δ: 8.63 (1 H, s), 7.28 (1 H, d, J = 8.2 Hz), 6. 92 (1 H, d, J = 8.2 Hz), 3.96 (3 H, s), 3.68 (3 2H, s), 3.54 (4H, t, J = 4.6 Hz), 2.37 (4H, t, J = 4.6 Hz).
ESI-MS m / z: 249 [M + H] ⁺ .

実施例84-4：4-メトキシ-7-(モルホリノメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.84]の合成
実施例84-3で得られた化合物(14 mg, 0.06 mmol)と実施例32-5で得られた化合物 (21 mg, 0.11 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(8 mg, 41 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.71 (1H, m), 8.24-8.19 (1H, m), 7.61-7.54 (1H, m), 7.39 (1H, d, J = 8.2 Hz), 6.99 (1H, d, J = 8.2 Hz), 3.99 (3H, s), 3.69 (2H, s), 3.56 (4H, t, J = 4.4 Hz), 2.39 (4H, t, J = 4.4 Hz).
ESI-MS m/z: 350[M+H]⁺. Example 84-4 Synthesis of 4-methoxy-7- (morpholinomethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 84]
Using the compound (14 mg, 0.06 mmol) obtained in Example 84-3 and the compound (21 mg, 0.11 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (8 mg, 41%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.71 (1 H, m), 8.24-8.19 (1 H, m), 7.61-7.54 (1 H, 1 H, m) m), 7.39 (1 H, d, J = 8.2 Hz), 6.99 (1 H, d, J = 8.2 Hz), 3.99 (3 H, s), 3.69 (2 H, s), 3.56 (4 H, t, J = 4.4) Hz), 2.39 (4H, t, J = 4.4 Hz).
ESI-MS m / z: 350 [M + H] ⁺ .

製造例85：ターシャリーブチル 4-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボニル)ピペリジン-1-カルボキシレート[化合物No.85]の合成
実施例85-1：ターシャリーブチル 4-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボニル)ピペリジン-1-カルボキシレート[化合物No.85]の合成
実施例72-1で得られた化合物(20 mg, 0.06 mmol)と1-(ターシャリーブトキシカルボニル)ピペリジン-4-アセチックアシド(13 mg, 0.06 mmol)を用いて実施例81-1と同様の操作を行うことにより標記の化合物(31 mg, 95 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, s), 8.78-8.72 (1H, m), 8.25-8.19 (1H, m), 7.61-7.55 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 4.00-3.89 (5H, m), 3.78-3.63 (4H, m), 3.21-3.06 (4H, m), 2.94-2.70 (3H, m), 1.69-1.60 (2H, m), 1.47-1.36 (11H, m).
ESI-MS m/z:546[M+H]⁺. Preparation Example 85: Tertiary butyl 4- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carbonyl) piperidine-1-carboxylate [Compound Synthesis of No. 85] Example 85-1: Tertiary butyl 4- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carbonyl) Synthesis of piperidine-1-carboxylate [Compound No. 85]
The same procedure as in Example 81-1 using the compound (20 mg, 0.06 mmol) obtained in Example 72-1 and 1- (tert-butoxycarbonyl) piperidine-4-acetic acid (13 mg, 0.06 mmol) Gave the title compound (31 mg, 95%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, s), 8. 78-8. 72 (1 H, m), 8.25-8. 19 (1 H, m), 7.61-7. 55 (1 H, m) ), 6.95 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 4.00 to 3.89 (5H, m), 3.78 to 3.63 (4H, m), 3.21 to 3.06 (4H, m) m), 2.94-2.70 (3H, m), 1.69-1.60 (2H, m), 1.47-1.36 (11H, m).
ESI-MS m / z: 546 [M + H] ⁺ .

製造例86：(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)(ピペリジン-4-イル)メタノン[化合物No.86]の合成
実施例86-1：(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)(ピペリジン-4-イル)メタノン[化合物No.86]の合成
実施例85-1で得られた化合物(25 mg, 0.05 mmol)のジクロロメタン(596 μl)溶液中に、2,2,2-トリフルオロ酢酸(74 μl, 0.96 mmol)を滴下した。1時間撹拌した後、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(20 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.20 (1H, m), 7.62-7.55 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.76-3.62 (4H, m), 3.19-3.05 (4H, m), 2.98-2.88 (2H, m), 2.78-2.64 (1H, m), 2.60-2.53 (2H, m), 1.60-1.40 (4H, m).
ESI-MS m/z: 446[M+H]⁺. Preparation Example 86: (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) (piperidin-4-yl) methanone [Compound No. 86 Synthesis of Example 86-1: (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) (piperidin-4-yl) methanone Synthesis of [compound No. 86]
In a solution of the compound (25 mg, 0.05 mmol) obtained in Example 85-1 in dichloromethane (596 μl), 2,2,2-trifluoroacetic acid (74 μl, 0.96 mmol) was dropped. After stirring for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added after completion of the reaction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (20 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.20 (1 H, m), 7.62-7.55 (1 H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.76-3.62 (4H, m), 3.19-3.05 (4H, m) ), 2.98-2.88 (2H, m), 2.78-2.64 (1H, m), 2.60-2.53 (2H, m), 1.60-1. 40 (4H, m).
ESI-MS m / z: 446 [M + H] ⁺ .

製造例87：4-メトキシ-7-(モルホリノメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.87]の合成
実施例87-1：4-メトキシ-7-(モルホリノメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.87]の合成
実施例84-4で得られた化合物(6 mg, 0.02 mmol)のクロロホルム(249 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(5 μl, 0.02 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、標記の化合物(7 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.23-10.10 (1H, m), 8.96 (1H, s), 8.81-8.71 (1H, m), 8.27-8.15 (1H, m), 7.62-7.54 (1H, m), 7.40 (1H, d, J = 8.7 Hz), 7.00 (1H, d, J = 8.7 Hz), 3.99 (3H, s), 3.69 (2H, s), 3.60-3.49 (4H, m), 2.44-2.34 (4H, m).
ESI-MS m/z: 350[M+H]⁺. Preparation Example 87 Synthesis of 4-methoxy-7- (morpholinomethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 87] Example 87-1: 4-methoxy-7 Synthesis of-(morpholinomethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 87]
In a solution of the compound (6 mg, 0.02 mmol) obtained in Example 84-4 in chloroform (249 μl), 4 mol / l hydrogen chloride / ethyl acetate solution (5 μl, 0.02 mmol) was dropped. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the title compound (7 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.23-10.10 (1H, m), 8.96 (1 H, s), 8.81-8.71 (1 H, m), 8.27-8.15 (1 H, m) ), 7.62-7.54 (1 H, m), 7. 40 (1 H, d, J = 8.7 Hz), 7.00 (1 H, d, J = 8.7 Hz), 3.99 (3 H, s), 3.69 (2 H, s), 3.60 -3.49 (4H, m), 2.44-2.34 (4H, m).
ESI-MS m / z: 350 [M + H] ⁺ .

製造例88：(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)(ピペリジン-4-イル)メタノン塩酸塩[化合物No.88]の合成
実施例88-1：(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)(ピペリジン-4-イル)メタノン塩酸塩[化合物No.88]の合成
実施例86-1で得られた化合物(20 mg, 0.05 mmol)のクロロホルム(652 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(12 μl, 0.05 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、標記の化合物(19 mg, 88 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.24-8.18 (1H, m), 7.62-7.55 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.78-3.63 (4H, m), 3.26-3.06 (6H, m), 3.04-2.90 (2H, m), 2.89-2.79 (1H, m), 1.80-1.59 (4H, m).
ESI-MS m/z: 446[M+H]⁺. Preparation Example 88: (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) (piperidin-4-yl) methanone hydrochloride [Compound No. Synthesis of Example 88-1: (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) (piperidin-4-yl ) Synthesis of Methanone Hydrochloride [Compound No. 88]
In a solution of the compound (20 mg, 0.05 mmol) obtained in Example 86-1 in chloroform (652 μl), a 4 mol / l hydrogen chloride / ethyl acetate solution (12 μl, 0.05 mmol) was dropped. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the title compound (19 mg, 88%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.24-8.18 (1 H, m), 7.62-7.55 (1 H, m), 6.95 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.78-3.63 (4H, m), 3.26-3.06 (6H, m) ), 3.04-2.90 (2H, m), 2.89-2.79 (1H, m), 1.80-1.59 (4H, m).
ESI-MS m / z: 446 [M + H] ⁺ .

製造例89：1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピペリジン-1-イル)エタノン[化合物No.89]の合成
実施例89-1：1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピペリジン-1-イル)エタノン[化合物No.89]の合成
実施例72-1で得られた化合物(20 mg, 0.06 mmol)と2-(ピペリジン-1-イル)アセチックアシド (9 mg, 0.06 mmol)を用いて実施例81-1と同様の操作を行うことにより標記の化合物(25 mg, 91 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.71 (1H, m), 8.25-8.19 (1H, m), 7.61-7.54 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.82-3.75 (2H, m), 3.71-3.63 (2H, m), 3.21-3.15 (2H, m), 3.13 (2H, s), 3.12-3.05 (2H, m), 2.42-2.31 (4H, m), 1.55-1.45 (4H, m), 1.40-1.32 (2H, m).
ESI-MS m/z:460[M+H]⁺. Preparation Example 8: 1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (piperidin-1-yl) ethanone Synthesis of [Compound No. 89] Example 89-1: 1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl)- Synthesis of 2- (Piperidin-1-yl) ethanone [Compound No. 89]
Using the compound (20 mg, 0.06 mmol) and 2- (piperidin-1-yl) acetic acid (9 mg, 0.06 mmol) obtained in Example 72-1 and performing the same operation as in Example 81-1 Gave the title compound (25 mg, 91%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.71 (1 H, m), 8.25-8.19 (1 H, m), 7.61-7.54 (1 H, 1 H, m) m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.82-3.75 (2H, m), 3.71-3.63 (2H, m) ), 3.21-3.15 (2H, m), 3.13 (2H, s), 3.12-3.05 (2H, m), 2.42-2.31 (4H, m), 1.55-1.45 (4H, m), 1.40-1.32 (2H) , m).
ESI-MS m / z: 460 [M + H] ⁺ .

製造例90：3-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)プロパン-1-オン[化合物No.90]の合成
実施例90-1：3-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)プロパン-1-オン[化合物No.90]の合成
実施例72-1で得られた化合物(20 mg, 0.06 mmol)と3-(ジメチルアミノ)プロパノイックアシド塩酸塩(10 mg, 0.06 mmol)を用いて実施例81-1と同様の操作を行うことにより標記の化合物(14 mg, 54 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.76-8.72 (1H, m), 8.25-8.19 (1H, m), 7.61-7.54 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.72-3.63 (4H, m), 3.34-3.31 (4H, m), 3.19-3.05 (4H, m), 2.15 (6H, s).
ESI-MS m/z:434[M+H]⁺. Preparation Example 90: 3- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) propane-1-yl Synthesis of On [Compound No. 90] Example 90-1: 3- (dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl )) Synthesis of piperazin-1-yl) propan-1-one [compound No. 90]
The same procedure as in Example 81-1 was performed using the compound (20 mg, 0.06 mmol) obtained in Example 72-1 and 3- (dimethylamino) propanoic acid hydrochloride (10 mg, 0.06 mmol). The title compound (14 mg, 54%) was obtained by carrying out.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.76-8.72 (1 H, m), 8.25-8.19 (1 H, m), 7.61-7.54 (1 H, 1 H, m) m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.72-3.63 (4H, m), 3.34-3. 31 (4H, m) ), 3.19-3.05 (4H, m), 2.15 (6H, s).
ESI-MS m / z: 434 [M + H] ⁺ .

製造例91：7-(2-(4-メチルピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチンイル)ベンゾ[d]オキサゾール塩酸塩[化合物No.91]の合成
実施例91-1：7-(2-(4-メチルピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチンイル)ベンゾ[d]オキサゾール塩酸塩[化合物No.91]の合成
実施例80-1で得られた化合物(60 mg, 0.14 mmol)をメタノール(1.8 ml)に溶解し、そこへ37%ホルムアルデヒド水溶液(0.021 ml, 0.28 mmol)、シアノ水素化ホウ素ナトリウム(59 mg, 0.28 mmol)、トリエチルアミン(0.059 ml, 0.42 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, クロロホルム/酢酸エチル)で精製した。これをメタノール(1 ml)、クロロホルム(1 ml)に溶解し、そこへ4 mol/l塩化水素-酢酸エチル溶液(0.066 ml, 0.265 mmol)を加えた。溶媒を留去し、標記の化合物(36 mg, 60.9%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 2.1 Hz), 8.76 (1H, dd, J = 4.9, 1.5 Hz), 8.23 (1H, dt, J = 7.9, 1.8 Hz), 7.59 (1H, dd, J = 7.9, 4.9 Hz), 7.45 (1H, s), 7.43 (1H, d, J = 7.6 Hz), 7.23 (1H, d, J = 7.3 Hz), 4.61-4.51 (2H, m), 3.72-3.47 (8H, m), 2.82-2.78 (5H, m).
ESI-MS m/z:363[M+H]⁺. Production Example 91 Synthesis of 7- (2- (4-Methylpiperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 91] Example 91- Synthesis of 1: 7- (2- (4-Methylpiperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 91]
The compound (60 mg, 0.14 mmol) obtained in Example 80-1 is dissolved in methanol (1.8 ml), to which a 37% aqueous formaldehyde solution (0.021 ml, 0.28 mmol), sodium cyanoborohydride (59 mg, 0.28 mmol) and triethylamine (0.059 ml, 0.42 mmol) were added and stirred overnight at room temperature. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, chloroform / ethyl acetate). This was dissolved in methanol (1 ml) and chloroform (1 ml), and 4 mol / l hydrogen chloride-ethyl acetate solution (0.066 ml, 0.265 mmol) was added thereto. The solvent was evaporated to give the title compound (36 mg, 60.9%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 2.1 Hz), 8.76 (1 H, dd, J = 4.9, 1.5 Hz), 8.23 (1 H, dt, J = 7.9, 1.8 Hz), 7.59 (1 H, dd, J = 7.9, 4.9 Hz), 7.45 (1 H, s), 7.43 (1 H, d, J = 7.6 Hz), 7.23 (1 H, d, J = 7.3 Hz), 4.61-4.51 (2H, m), 3.72-3.47 (8H, m), 2.82-2.78 (5H, m).
ESI-MS m / z: 363 [M + H] ⁺ .

製造例92：1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピペリジン-1-イル)エタノン塩酸塩[化合物No.92]の合成
実施例92-1：1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピペリジン-1-イル)エタノン塩酸塩[化合物No.92]の合成
実施例89-1で得られた化合物(22 mg, 0.05 mmol)のクロロホルム(695 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(13 μl, 0.05 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、標記の化合物(24 mg, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.46-9.37 (1H, m), 8.96 (1H, s), 8.78-8.73 (1H, m), 8.26-8.20 (1H, m), 7.61-7.55 (1H, m), 6.97 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.82-3.53 (4H, m), 3.27-3.02 (6H, m), 1.89-1.30 (10H, m).
ESI-MS m/z: 460[M+H]⁺. Preparation Example 2: 2- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (piperidin-1-yl) ethanone Synthesis of Hydrochloride [Compound No. 92] Example 92-1: 1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl ) Synthesis of (2- (piperidin-1-yl) ethanone hydrochloride [Compound No. 92]
In a solution of the compound (22 mg, 0.05 mmol) obtained in Example 89-1 in chloroform (695 μl), a 4 mol / l hydrogen chloride / ethyl acetate solution (13 μl, 0.05 mmol) was dropped. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the title compound (24 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.46-9.37 (1 H, m), 8. 96 (1 H, s), 8. 78-8. 73 (1 H, m), 8. 26-8. 20 (1 H, m) ), 7.61-7.55 (1H, m), 6.97 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.82-3.53 (4H, m) , 3.27-3.02 (6H, m), 1.89-1.30 (10H, m).
ESI-MS m / z: 460 [M + H] ⁺ .

製造例93：3-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)プロパン-1-オン塩酸塩[化合物No.93]の合成
実施例93-1：3-(ジメチルアミノ)-1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)プロパン-1-オン塩酸塩[化合物No.93]の合成
実施例90-1で得られた化合物(11 mg, 0.025 mmol)のクロロホルム(368 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(7 μl, 0.027 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、標記の化合物(11 mg, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.34-9.19 (1H, m), 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.26-8.19 (1H, m), 7.61-7.55 (1H, m), 6.96 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.73-3.64 (4H, m), 3.21-3.08 (4H, m), 3.05-2.92 (2H, m), 2.79-2.71 (2H, m), 2.54 (6H, br s).
ESI-MS m/z: 434[M+H]⁺. Production Example 93: 3- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) propane-1-yl Synthesis of On Hydrochloride [Compound No. 93] Example 93-1: 3- (dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7 Synthesis of (yl) piperazin-1-yl) propan-1-one hydrochloride [Compound No. 93]
In a solution of the compound (11 mg, 0.025 mmol) obtained in Example 90-1 in chloroform (368 μl), a 4 mol / l hydrogen chloride / ethyl acetate solution (7 μl, 0.027 mmol) was dropped. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the title compound (11 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.34-9.19 (1 H, m), 8. 96 (1 H, br s), 8. 77-8. 72 (1 H, m), 8. 26-8. 19 (1 H, m), 7.61-7.55 (1H, m), 6.96 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.73-3.64 (4H, m) ), 3.21-3.08 (4H, m), 3.05-2.92 (2H, m), 2.79-2.71 (2H, m), 2.54 (6H, br s).
ESI-MS m / z: 434 [M + H] ⁺ .

製造例94：ターシャリーブチル 4-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)メチル)ピペラジン-1-カルボキシレート[化合物No.94]の合成
実施例94-1：ターシャリーブチル 4-((4-メトキシベンゾ[d]オキサゾール-7-イル)メチル)ピペラジン-1-カルボキシレートの合成
実施例84-2で得られた化合物(80 mg, 0.45 mmol)とターシャリーブチルピペラジン-1-カルボキシレート (84 mg, 0.45 mmol)を用いて実施例84-3と同様の操作を行うことにより標記の化合物 (94 mg, 60 %)を得た。
¹H-NMR (CDCl₃) δ: 8.62 (1H, s), 7.28 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.96 (3H, s), 3.70 (2H, s), 3.28 (4H, t, J = 4.8 Hz), 2.33 (4H, t, J = 4.8 Hz), 1.37 (9H, s).
ESI-MS m/z:348[M+H]⁺. Production Example 94: Synthesis of tert-butyl 4-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) methyl) piperazine-1-carboxylate [Compound No. 94] Example 94-1: Synthesis of tert-butyl 4-((4-methoxybenzo [d] oxazol-7-yl) methyl) piperazine-1-carboxylate
By performing the same operation as in Example 84-3 using the compound (80 mg, 0.45 mmol) obtained in Example 84-2 and tertiary butyl piperazine-1-carboxylate (84 mg, 0.45 mmol) The title compound (94 mg, 60%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.62 (1 H, s), 7.28 (1 H, d, J = 8.7 Hz), 6. 92 (1 H, d, J = 8.7 Hz), 3.96 (3 H, s), 3.70 2H, s), 3.28 (4H, t, J = 4.8 Hz), 2.33 (4H, t, J = 4.8 Hz), 1.37 (9 H, s).
ESI-MS m / z: 348 [M + H] ⁺ .

実施例94-2：ターシャリーブチル 4-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)メチル)ピペラジン-1-カルボキシレート[化合物No.94]の合成
実施例94-1で得られた化合物(94 mg, 0.27 mmol)と実施例32-5で得られた化合物(98 mg, 0.54 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(82 mg, 68 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, s), 8.78-8.71 (1H, m), 8.26-8.19 (1H, m), 7.61-7.53 (1H, m), 7.39 (1H, d, J = 8.7 Hz), 7.00 (1H, d, J = 8.7 Hz), 3.99 (3H, s), 3.71 (2H, s), 3.31-3.27 (4H, m), 2.38-2.32 (4H, m), 1.38 (9H, s).
ESI-MS m/z: 449[M+H]⁺. Example 94-2 Tertiary butyl 4-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) methyl) piperazine-1-carboxylate [Compound No. 94] Synthesis of
Using the compound (94 mg, 0.27 mmol) obtained in Example 94-1 and the compound (98 mg, 0.54 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (82 mg, 68%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, s), 8.78-8.71 (1 H, m), 8.26-8.19 (1 H, m), 7.61-7.53 (1 H, m) ), 7.39 (1H, d, J = 8.7 Hz), 7.00 (1H, d, J = 8.7 Hz), 3.99 (3H, s), 3.71 (2H, s), 3.31-3.27 (4H, m), 2.38 -2.32 (4H, m), 1.38 (9H, s).
ESI-MS m / z: 449 [M + H] ⁺ .

製造例95：4-メトキシ-7-(4-(メチルスルホニル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.95]の合成
実施例95-1：4-メトキシ-7-(4-(メチルスルホニル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.95]の合成
実施例72-1で得られた化合物(20 mg, 0.06 mmol)のジクロロメタン(1 ml)溶液中に、メタンスルホニルクロライド(7 μl, 0.09 mmol)、N-エチル-N-イソプロピルプロパン-2-アミン(31 μl, 0.18 mmol)を0℃で添加した。室温で一晩撹拌した後、飽和食塩水を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物 (16 mg, 65 %)を得た。
¹H-NMR (CDCl₃) δ: 8.96 (1H, s), 8.78-8.72 (1H, m), 8.25-8.17 (1H, m), 7.61-7.53 (1H, m), 6.98 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.37-3.33 (4H, m), 3.27-3.22 (4H, m), 2.96 (3H, s).
ESI-MS m/z:413[M+H]⁺. Preparation Example 95 Synthesis of 4-methoxy-7- (4- (methylsulfonyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 95] Example 95- Synthesis of 1: 4-methoxy-7- (4- (methylsulfonyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [compound No. 95]
In a solution of the compound (20 mg, 0.06 mmol) obtained in Example 72-1 in dichloromethane (1 ml), methanesulfonyl chloride (7 μl, 0.09 mmol), N-ethyl-N-isopropylpropan-2-amine (31 μl, 0.18 mmol) was added at 0 ° C. After stirring overnight at room temperature, brine was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (16 mg, 65%).
¹ H-NMR (CDCl ₃ ) δ: 8.96 (1 H, s), 8. 78-8. 72 (1 H, m), 8.25-8. 17 (1 H, m), 7.61-7.53 (1 H, m), 6. 98 (1 H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.37-3.33 (4H, m), 3.27-3.22 (4H, m), 2.96 (3H, s).
ESI-MS m / z: 413 [M + H] ⁺ .

製造例96：ターシャリーブチル 3-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボニル)アゼチジン-1-カルボキシレート[化合物No.96]の合成
実施例96-1：ターシャリーブチル 3-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-カルボニル)アゼチジン-1-カルボキシレート[化合物No.96]の合成
実施例72-1で得られた化合物(20 mg, 0.06 mmol)と1-(ターシャリーブトキシカルボニル)アゼチジン-3-カルボキシリックアシド(12 mg, 0.06 mmol)を用いて実施例81-1と同様の操作を行うことにより標記の化合物(33 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.19 (1H, m), 7.62-7.54 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 4.07-3.95 (4H, m), 3.93 (3H, s), 3.75-3.66 (3H, m), 3.52-3.45 (2H, m), 3.16-3.08 (4H, m), 1.38 (9H, s).
ESI-MS m/z:518[M+H]⁺. Preparation Example 96: Tertiary butyl 3- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carbonyl) azetidine-1-carboxylate [Compound Synthesis of No. 96] Example 96-1: Tertiary butyl 3- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carbonyl) Synthesis of azetidine-1-carboxylate [Compound No. 96]
As in Example 81-1, using the compound (20 mg, 0.06 mmol) obtained in Example 72-1 and 1- (tertiary butoxycarbonyl) azetidine-3-carboxylic acid (12 mg, 0.06 mmol) The title compound (33 mg, 100%) was obtained by the operation of
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.19 (1 H, m), 7.62-7.54 (1 H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 4.07-3.95 (4H, m), 3.93 (3H, s), 3.75-3.66 (3H, m) ), 3.52-3.45 (2H, m), 3.16-3.08 (4H, m), 1.38 (9H, s).
ESI-MS m / z: 518 [M + H] ⁺ .

製造例97：4-メトキシ-7-(ピペラジン-1-イルメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.97]の合成
実施例97-1：4-メトキシ-7-(ピペラジン-1-イルメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.97]の合成
実施例94-2で得られた化合物(80 mg, 0.18 mmol)のジクロロメタン(2.3 ml)溶液中に、2,2,2-トリフルオロ酢酸(578 μl, 7.50 mmol)を滴下した。1時間撹拌した後、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(24 mg, 39 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.71 (1H, m), 8.26-8.18 (1H, m), 7.61-7.54 (1H, m), 7.38 (1H, d, J = 8.7 Hz), 6.99 (1H, d, J = 8.7 Hz), 3.99 (3H, s), 3.65 (2H, s), 2.69-2.63 (4H, m), 2.36-2.27 (4H, m).
ESI-MS m/z: 349[M+H]⁺. Preparation Example 97 Synthesis of 4-methoxy-7- (piperazin-1-ylmethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 97] Example 97-1: 4-methoxy- Synthesis of 7- (Piperazine-1-ylmethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 97]
In a solution of the compound (80 mg, 0.18 mmol) obtained in Example 94-2 in dichloromethane (2.3 ml), 2,2,2-trifluoroacetic acid (578 μl, 7.50 mmol) was dropped. After stirring for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added after completion of the reaction, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (24 mg, 39%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.71 (1 H, m), 8.26-8.18 (1 H, m), 7.61-7.54 (1 H, 1 H, m), 7.38 (1H, d, J = 8.7 Hz), 6.99 (1H, d, J = 8.7 Hz), 3.99 (3H, s), 3.65 (2H, s), 2.69-2.63 (4H, m), 2.36- 2.27 (4H, m).
ESI-MS m / z: 349 [M + H] ⁺ .

製造例98：4-メトキシ-7-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.98]の合成
実施例98-1：4-メトキシ-7-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.98]の合成
実施例97-1で得られた化合物(16 mg, 0.05 mmol)のジクロロメタン(1 ml)溶液中に、メタンスルホニルクロライド(5.4 μl, 0.07 mmol)、N-エチル-N-イソプロピルプロパン-2-アミン(24 μl, 0.14 mmol)を0℃で添加した。室温で一晩撹拌した後、飽和食塩水を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物 (18 mg, 92 %)を得た。
¹H-NMR (CDCl₃) δ: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.18 (1H, m), 7.62-7.53 (1H, m), 7.40 (1H, d, J = 8.7 Hz), 7.01 (1H, d, J = 8.7 Hz), 3.99 (3H, s), 3.75 (2H, s), 3.13-3.07 (4H, m), 2.86 (3H, s), 2.53-2.48 (4H, m).
ESI-MS m/z:427[M+H]⁺. Preparation Example 98 Synthesis of 4-methoxy-7-((4- (methylsulfonyl) piperazin-1-yl) methyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 98] Example 98-1 Synthesis of 4-methoxy-7-((4- (methylsulfonyl) piperazin-1-yl) methyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 98]
In a solution of the compound (16 mg, 0.05 mmol) obtained in Example 97-1 in dichloromethane (1 ml), methanesulfonyl chloride (5.4 μl, 0.07 mmol), N-ethyl-N-isopropylpropan-2-amine (24 μl, 0.14 mmol) was added at 0 ° C. After stirring overnight at room temperature, brine was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (18 mg, 92%).
¹ H-NMR (CDCl ₃ ) δ: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.18 (1 H, m), 7.62-7.53 (1 H, m), 7.40 (1 H, d , J = 8.7 Hz), 7.01 (1 H, d, J = 8.7 Hz), 3.99 (3 H, s), 3.75 (2 H, s), 3.13-3.07 (4 H, m), 2.86 (3 H, s), 2.53 -2.48 (4H, m).
ESI-MS m / z: 427 [M + H] ⁺ .

製造例99：4-メトキシ-7-(ピペラジン-1-イルメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.99]の合成
実施例99-1：4-メトキシ-7-(ピペラジン-1-イルメチル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.99]の合成
実施例97-1で得られた化合物(6 mg, 0.02 mmol)のクロロホルム(250 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(4.5 μl, 0.02 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮し、標記の化合物(3 mg, 45%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.26-8.18 (1H, m), 7.62-7.55 (1H, m), 7.38 (1H, d, J = 8.2 Hz), 6.99 (1H, d, J = 8.2 Hz), 3.99 (3H, s), 3.68 (2H, s), 2.79-2.72 (4H, m), 2.41-2.34 (4H, m).
ESI-MS m/z: 349[M+H]⁺. Preparation Example 99 Synthesis of 4-methoxy-7- (piperazin-1-ylmethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 99] Example 99-1: 4- Synthesis of Methoxy-7- (piperazin-1-ylmethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 99]
In a solution of the compound (6 mg, 0.02 mmol) obtained in Example 97-1 in chloroform (250 μl), a 4 mol / l hydrogen chloride / ethyl acetate solution (4.5 μl, 0.02 mmol) was dropped. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the title compound (3 mg, 45%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.26-8.18 (1 H, m), 7.62-7.55 (1 H, m), 7.38 (1 H, d, J = 8.2 Hz), 6.99 (1 H, d, J = 8.2 Hz), 3.99 (3 H, s), 3.68 (2 H, s), 2. 79-2.72 (4 H, m), 2.41-2.34 (4H, m).
ESI-MS m / z: 349 [M + H] ⁺ .

製造例100：アゼチジン-3-イル(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)メタノン塩酸塩[化合物No.100]の合成
実施例100-1：アゼチジン-3-イル(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)メタノンの合成
実施例96-1で得られた化合物(30 mg, 0.06 mmol)のジクロロメタン(753 μl)溶液中に、2,2,2-トリフルオロ酢酸(188 μl, 2.44 mmol)を滴下した。3時間撹拌した後、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(24 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.76-8.72 (1H, m), 8.25-8.18 (1H, m), 7.61-7.54 (1H, m), 6.98-6.86 (2H, m), 4.38-4.24 (2H, m), 3.95 (3H, s), 3.87-3.78 (2H, m), 3.74-3.65 (3H, m), 3.54-3.47 (2H, m), 3.15-3.07 (4H, m).
ESI-MS m/z: 418[M+H]⁺. Preparation Example 100: azetidin-3-yl (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) methanone hydrochloride [Compound No. 100 Synthesis of azetidin-3-yl (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) methanone
In a solution of the compound (30 mg, 0.06 mmol) obtained in Example 96-1 in dichloromethane (753 μl), 2,2,2-trifluoroacetic acid (188 μl, 2.44 mmol) was dropped. After stirring for 3 hours, saturated aqueous sodium hydrogen carbonate solution was added after completion of the reaction, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (24 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.76-8.72 (1 H, m), 8.25-8.18 (1 H, m), 7.61-7.54 (1 H, 1 H, m) m), 6.98-6.86 (2H, m), 4.38-4.24 (2H, m), 3.95 (3H, s), 3.87-3.78 (2H, m), 3.74-3.65 (3H, m), 3.54-3.47 ( 2H, m), 3.15-3.07 (4H, m).
ESI-MS m / z: 418 [M + H] ⁺ .

実施例100-2：アゼチジン-3-イル(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)メタノン塩酸塩[化合物No.100]の合成
実施例100-1で得られた化合物(24 mg, 0.06 mmol)のクロロホルム(835 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(15 μl, 0.06 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮した。酢酸エチルで洗浄した後、減圧下乾燥した。標記の化合物(5 mg, 19%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.73 (1H, m), 8.24-8.19 (1H, m), 7.61-7.56 (1H, m), 6.97-6.89 (2H, m), 4.18-4.08 (4H, m), 3.93 (3H, s), 3.74-3.69 (3H, m), 3.52-3.45 (2H, m), 3.18-3.10 (4H, m).
ESI-MS m/z: 418[M+H]⁺. Example 100-2: azetidin-3-yl (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) methanone hydrochloride [Compound No. .100] synthesis
In a solution of the compound (24 mg, 0.06 mmol) obtained in Example 100-1 in chloroform (835 μl), 4 mol / l hydrogen chloride / ethyl acetate solution (15 μl, 0.06 mmol) was dropped. After stirring at room temperature for 1 hour, the solution was concentrated under reduced pressure. After washing with ethyl acetate, it was dried under reduced pressure. The title compound (5 mg, 19%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.73 (1 H, m), 8.24-8.19 (1 H, m), 7.61-7.56 (1 H, 1 H, m) m), 6.97-6.89 (2H, m), 4.18-4.08 (4H, m), 3.93 (3H, s), 3.74-3.69 (3H, m), 3.52-3.45 (2H, m), 3.18-3. 4H, m).
ESI-MS m / z: 418 [M + H] ⁺ .

製造例101：1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピロリジン-1-イル)エタノン[化合物No.101]の合成
実施例101-1：1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピロリジン-1-イル)エタノン[化合物No.101]の合成
実施例72-1で得られた化合物(20 mg, 0.06 mmol)と2-(ピロリジン-1-イル)アセチックアシド(8 mg, 0.06 mmol)を用いて実施例81-1と同様の操作を行うことにより標記の化合物(25 mg, 94 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.71 (1H, m), 8.24-8.19 (1H, m), 7.61-7.53 (1H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.78-3.72 (2H, m), 3.70-3.63 (2H, m), 3.31 (2H, s), 3.15-3.13 (2H, m), 3.11-3.09 (2H, m), 2.57-2.45 (4H, m), 1.73-1.65 (4H, m).
ESI-MS m/z:446[M+H]⁺. Preparation Example 1 1: 1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (pyrrolidin-1-yl) ethanone Synthesis of [Compound No. 101] Example 10 1-1-(4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl)- Synthesis of 2- (pyrrolidin-1-yl) ethanone [compound No. 101]
Performing the same procedure as in Example 81-1 using the compound (20 mg, 0.06 mmol) obtained in Example 72-1 and 2- (pyrrolidin-1-yl) acetic acid (8 mg, 0.06 mmol) Gave the title compound (25 mg, 94%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.71 (1 H, m), 8.24-8.19 (1 H, m), 7.61-7.53 (1 H, m), 6.95 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.78-3.72 (2H, m), 3.70-3.63 (2H, m) ), 3.31 (2H, s), 3.15-3.13 (2H, m), 3.11-3.09 (2H, m), 2.57-2.45 (4H, m), 1.73-1.65 (4H, m).
ESI-MS m / z: 446 [M + H] ⁺ .

製造例102：ターシャリーブチル 4-(2-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレート[化合物No.102]の合成
実施例102-1：4-メトキシベンゾ[d]オキサゾール-7-オールの合成
実施例84-2で得られた化合物(100 mg, 0.56 mmol)のジクロロメタン(5 ml)溶液中に、3-クロロベンゾペロキソイックアシド(165 mg, 0.62 mmol)を0℃で添加した。室温に昇温し、一晩撹拌した。反応終了後、飽和チオ硫酸ナトリウム水溶液を加えクロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のメタノール(5 ml)溶液中に、1mol/l水酸化ナトリウム水溶液(1.13 ml, 1.13 mmol)を室温下滴下した。1時間撹拌した後、1mol/l塩酸で酸性にし、飽和塩化ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(45 mg, 48 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.84 (1H, s), 8.57 (1H, s), 6.76 (1H, d, J = 8.7 Hz), 6.72 (1H, d, J = 8.7 Hz), 3.87 (3H, s).
ESI-MS m/z:166[M+H]⁺. Preparation Example 102: tert-butyl 4- (2-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate [Compound No. Example 102-1: Synthesis of 4-methoxybenzo [d] oxazol-7-ol
In a solution of the compound (100 mg, 0.56 mmol) obtained in Example 84-2 in dichloromethane (5 ml), 3-chlorobenzoperoxoic acid (165 mg, 0.62 mmol) was added at 0 ° C. The temperature was raised to room temperature and stirred overnight. After completion of the reaction, a saturated aqueous sodium thiosulfate solution was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Into a solution of the residue in methanol (5 ml), 1 mol / l aqueous sodium hydroxide solution (1.13 ml, 1.13 mmol) was added dropwise at room temperature. After stirring for 1 hour, the mixture was acidified with 1 mol / l hydrochloric acid, saturated aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (45 mg, 48%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.84 (1 H, s), 8. 57 (1 H, s), 6. 76 (1 H, d, J = 8.7 Hz), 6.72 (1 H, d, J = 8.7 Hz), 3.87 (3 H, s).
ESI-MS m / z: 166 [M + H] ⁺ .

実施例102-2：ターシャリーブチル 4-(2-((4-メトキシベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレートの合成
実施例102-1で得られた化合物(45 mg, 0.27 mmol)のDMF(1 ml)溶液中に、ターシャリーブチル 4-(2-ブロモエチル)ピペラジン-1-カルボキシレート (88 mg, 0.30 mmol)、炭酸セシウム(107 mg, 0.33 mmol)を添加した。70℃で一晩撹拌し、反応終了後減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(95 mg, 92 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.62 (1H, s), 6.99 (1H, d, J = 8.7 Hz), 6.82 (1H, d, J = 8.7 Hz), 4.24 (2H, t, J = 5.7 Hz), 3.90 (3H, s), 3.32-3.24 (4H, m), 2.76 (2H, t, J = 5.7 Hz), 2.48-2.39 (4H, m), 1.39 (9H, s).
ESI-MS m/z:378[M+H]⁺. Example 102-2: Synthesis of tert-butyl 4- (2-((4-methoxybenzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate
Tertiary butyl 4- (2-bromoethyl) piperazine-1-carboxylate (88 mg, 0.30 mmol) in a solution of the compound obtained in Example 102-1 (45 mg, 0.27 mmol) in DMF (1 ml) And cesium carbonate (107 mg, 0.33 mmol) were added. The mixture was stirred at 70 ° C. overnight, and after completion of the reaction, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (95 mg, 92%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.62 (1 H, s), 6.99 (1 H, d, J = 8.7 Hz), 6.82 (1 H, d, J = 8.7 Hz), 4.24 (2H, t, J = 5.7 Hz), 3.90 (3H, s), 3.32-3.24 (4H, m), 2.76 (2H, t, J = 5.7 Hz), 2.48-2.39 (4H, m), 1.39 ( 9H, s).
ESI-MS m / z: 378 [M + H] ⁺ .

実施例102-3：ターシャリーブチル 4-(2-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレート[化合物No.102]の合成
実施例102-2で得られた化合物(95 mg, 0.25 mmol)と実施例32-5で得られた化合物(92 mg,0.50 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(21 mg, 17 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.24-8.18 (1H, m), 7.61-7.54 (1H, m), 7.11 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 4.25 (2H, t, J = 5.5 Hz), 3.93 (3H, s), 3.32-3.28 (4H, m), 2.77 (2H, t, J = 5.5 Hz), 2.48-2.43 (4H, m), 1.39 (9H, s).
ESI-MS m/z: 479[M+H]⁺. Example 102-3: tert-butyl 4- (2-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate Synthesis of Compound No. 102]
Using the compound (95 mg, 0.25 mmol) obtained in Example 102-2 and the compound (92 mg, 0.50 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (21 mg, 17%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.24-8.18 (1 H, m), 7.61-7.54 (1 H, 1 H, m) m), 7.11 (1 H, d, J = 8.7 Hz), 6.89 (1 H, d, J = 8.7 Hz), 4.25 (2 H, t, J = 5.5 Hz), 3.93 (3 H, s), 3.32-3.28 ( 4H, m), 2.77 (2H, t, J = 5.5 Hz), 2.48-2.43 (4H, m), 1.39 (9H, s).
ESI-MS m / z: 479 [M + H] ⁺ .

製造例103：1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピロリジン-1-イル)エタノン塩酸塩[化合物No.103]の合成
実施例103-1：1-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-2-(ピロリジン-1-イル)エタノン塩酸塩[化合物No.103]の合成
実施例101-1で得られた化合物(25 mg, 0.06 mmol)のクロロホルム(815 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(15 μl, 0.06 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮した。酢酸エチルで洗浄した後、減圧下乾燥した。標記の化合物(11 mg, 41%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.90-9.81 (1H, m), 8.96 (1H, br s), 8.77-8.73 (1H, m), 8.26-8.18 (1H, m), 7.62-7.55 (1H, m), 6.97 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 4.40-4.29 (2H, m), 3.94 (3H, s), 3.78-3.69 (2H, m), 3.62-3.53 (2H, m), 3.24-3.13 (4H, m), 2.53-2.48 (4H, m), 1.98-1.88 (4H, m).
ESI-MS m/z: 446[M+H]⁺. Preparation example 103: 1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (pyrrolidin-1-yl) ethanone Synthesis of Hydrochloride [Compound No. 103] Example 103-1: 1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl )) Synthesis of 2- (Pyrrolidin-1-yl) ethanone hydrochloride [Compound No. 103]
In a solution of the compound (25 mg, 0.06 mmol) obtained in Example 101-1 in chloroform (815 μl), a 4 mol / l hydrogen chloride / ethyl acetate solution (15 μl, 0.06 mmol) was dropped. After stirring at room temperature for 1 hour, the solution was concentrated under reduced pressure. After washing with ethyl acetate, it was dried under reduced pressure. The title compound (11 mg, 41%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.90-9.81 (1H, m), 8.96 (1H, br s), 8.77-8.73 (1H, m), 8.26-8.18 (1H, 1 H, m) m), 7.62-7.55 (1H, m), 6.97 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 4.40-4.29 (2H, m), 3.94 (3H, s) ), 3.78-3.69 (2H, m), 3.62-3.53 (2H, m), 3.24-3.13 (4H, m), 2.53-2.48 (4H, m), 1.98-1.88 (4H, m).
ESI-MS m / z: 446 [M + H] ⁺ .

製造例104：4-メトキシ-7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.104]の合成
実施例104-1：ターシャリーブチル 4-(2-((4-メトキシベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレートの合成
実施例102-1で得られた化合物(45 mg, 0.27 mmol)のDMF(1 ml)溶液中に、ターシャリーブチル 4-(2-ブロモエチル)ピペラジン-1-カルボキシレート (88 mg, 0.30 mmol)、炭酸セシウム(107 mg, 0.33 mmol)を添加した。70℃で一晩撹拌し、反応終了後減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(95 mg, 92 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.62 (1H, s), 6.99 (1H, d, J = 8.7 Hz), 6.82 (1H, d, J = 8.7 Hz), 4.24 (2H, t, J = 5.7 Hz), 3.90 (3H, s), 3.32-3.24 (4H, m), 2.76 (2H, t, J = 5.7 Hz), 2.48-2.39 (4H, m), 1.39 (9H, s).
ESI-MS m/z:378[M+H]⁺. Preparation Example 104 Synthesis Example of 4-methoxy-7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 104] : Synthesis of tert-butyl 4- (2-((4-methoxybenzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate
Tertiary butyl 4- (2-bromoethyl) piperazine-1-carboxylate (88 mg, 0.30 mmol) in a solution of the compound obtained in Example 102-1 (45 mg, 0.27 mmol) in DMF (1 ml) And cesium carbonate (107 mg, 0.33 mmol) were added. The mixture was stirred at 70 ° C. overnight, and after completion of the reaction, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (95 mg, 92%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.62 (1 H, s), 6.99 (1 H, d, J = 8.7 Hz), 6.82 (1 H, d, J = 8.7 Hz), 4.24 (2H, t, J = 5.7 Hz), 3.90 (3H, s), 3.32-3.24 (4H, m), 2.76 (2H, t, J = 5.7 Hz), 2.48-2.39 (4H, m), 1.39 ( 9H, s).
ESI-MS m / z: 378 [M + H] ⁺ .

実施例104-2：ターシャリーブチル 4-(2-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)エチル)ピペラジン-1-カルボキシレートの合成
実施例104-1で得られた化合物(95 mg, 0.25 mmol)と実施例32-5で得られた化合物(92 mg,0.50 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(21 mg, 17 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.24-8.18 (1H, m), 7.61-7.54 (1H, m), 7.11 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 4.25 (2H, t, J = 5.5 Hz), 3.93 (3H, s), 3.32-3.28 (4H, m), 2.77 (2H, t, J = 5.5 Hz), 2.48-2.43 (4H, m), 1.39 (9H, s).
ESI-MS m/z: 479[M+H]⁺. Example 104-2 Tertiary butyl 4- (2-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate Synthesis
Using the compound (95 mg, 0.25 mmol) obtained in Example 104-1 and the compound (92 mg, 0.50 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (21 mg, 17%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.24-8.18 (1 H, m), 7.61-7.54 (1 H, 1 H, m) m), 7.11 (1 H, d, J = 8.7 Hz), 6.89 (1 H, d, J = 8.7 Hz), 4.25 (2 H, t, J = 5.5 Hz), 3.93 (3 H, s), 3.32-3.28 ( 4H, m), 2.77 (2H, t, J = 5.5 Hz), 2.48-2.43 (4H, m), 1.39 (9H, s).
ESI-MS m / z: 479 [M + H] ⁺ .

実施例104-3：4-メトキシ-7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.104]の合成
実施例104-2で得られた化合物(20 mg, 0.04 mmol)のジクロロメタン(543 μl)溶液中に、2,2,2-トリフルオロ酢酸(68 μl, 0.88 mmol)を滴下した。3時間撹拌した後、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(12 mg, 76 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.76-8.70 (1H, m), 8.25-8.17 (1H, m), 7.60-7.53 (1H, m), 7.10 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 4.23 (2H, t, J = 5.7 Hz), 3.93 (3H, s), 2.73-2.63 (6H, m), 2.44-2.36 (4H, m).
ESI-MS m/z: 379[M+H]⁺. Example 104-3 Synthesis of 4-methoxy-7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 104]
In a solution of the compound (20 mg, 0.04 mmol) obtained in Example 104-2 in dichloromethane (543 μl), 2,2,2-trifluoroacetic acid (68 μl, 0.88 mmol) was dropped. After stirring for 3 hours, saturated aqueous sodium hydrogen carbonate solution was added after completion of the reaction, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (12 mg, 76%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.76-8.70 (1 H, m), 8.25-8.17 (1 H, m), 7.60-7.53 (1 H, m), 7.10 (1 H, d, J = 8.7 Hz), 6.89 (1 H, d, J = 8.7 Hz), 4.23 (2 H, t, J = 5.7 Hz), 3.93 (3 H, s), 2.73-2.63 (2. 6H, m), 2.44-2.36 (4H, m).
ESI-MS m / z: 379 [M + H] ⁺ .

製造例105：4-メトキシ-7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.105]の合成
実施例105-1：4-メトキシ-7-(2-(ピペラジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.105]の合成
実施例104-4で得られた化合物(10 mg, 0.026 mmol)のクロロホルム(384 μl)溶液中に、4mol/l塩化水素/酢酸エチル溶液(7 μl, 0.026 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮した。標記の化合物(11 mg, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.24-8.18 (1H, m), 7.62-7.55 (1H, m), 7.10 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 4.30-4.25 (2H, m), 3.94 (3H, s), 3.17-3.04 (4H, m), 2.83-2.81 (2H, m), 2.76-2.62 (4H, m).
ESI-MS m/z: 379[M+H]⁺. Preparation Example 105 Synthesis of 4-methoxy-7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 105] Example 105 Synthesis of -1: 4-methoxy-7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 105]
In a solution of the compound (10 mg, 0.026 mmol) obtained in Example 104-4 in chloroform (384 μl), a 4 mol / l hydrogen chloride / ethyl acetate solution (7 μl, 0.026 mmol) was dropped. After stirring at room temperature for 1 hour, the solution was concentrated under reduced pressure. The title compound (11 mg, 100%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.24-8.18 (1 H, m), 7.62-7.55 (1 H, m), 7.10 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 4.30-4.25 (2H, m), 3.94 (3H, s), 3.17-3.04 (4H, m) ), 2.83-2.81 (2H, m), 2.76-2.62 (4H, m).
ESI-MS m / z: 379 [M + H] ⁺ .

製造例106：7-(4-((クロロメチル)スルホニル)ピペラジン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[dオキサゾール[化合物No.106]の合成
実施例106-1：7-(4-((クロロメチル)スルホニル)ピペラジン-1-イル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[dオキサゾール[化合物No.106]の合成
実施例72-1で得られた化合物(25 mg, 0.08 mmol)のクロロホルム(500 μl)溶液中に、トリエチルアミン(12 μl, 0.08 mmol)、クロロメタンスルホニルクロライド(7 μl, 0.08 mmol)をアルゴン雰囲気下0℃で滴下した。4時間撹拌した後、反応終了後、飽和食塩水を加え酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(16 mg, 48 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.19 (1H, m), 7.61-7.54 (1H, m), 6.98 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 5.19 (2H, s), 3.94 (3H, s), 3.59-3.51 (4H, m), 3.26-3.19 (4H, m).
ESI-MS m/z: 447[M+H]⁺. Preparation Example 106 Synthesis Example of 7- (4-((chloromethyl) sulfonyl) piperazin-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d oxazole [Compound No. 106] 106-1: Synthesis of 7- (4-((chloromethyl) sulfonyl) piperazin-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d oxazole [compound No. 106]
Triethylamine (12 μl, 0.08 mmol), chloromethanesulfonyl chloride (7 μl, 0.08 mmol) in an argon atmosphere in a solution of the compound (25 mg, 0.08 mmol) obtained in Example 72-1 in chloroform (500 μl) It dripped at 0 degreeC below. After stirring for 4 hours, after completion of the reaction, saturated brine was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (16 mg, 48%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.19 (1 H, m), 7.61-7.54 (1 H, 1 H, m) m), 6.98 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 5.19 (2H, s), 3.94 (3H, s), 3.59-3.51 (4H, m), 3.26-3.19 (4H, m).
ESI-MS m / z: 447 [M + H] ⁺ .

製造例107：ターシャリーブチル5-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-カルボキシレート[化合物No.107]の合成
実施例107-1：ターシャリーブチル5-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-カルボキシレート[化合物No.107]の合成
実施例55-2で得られた化合物(25 mg, 0.08 mmol)とターシャリーブチル 2,5-ジアザビシクロ[2.2.1]ヘプタン-2-カルボキシレート(38 mg, 0.19 mmol)を用いて実施例58-1と同様の操作を行うことにより標記の化合物(4 mg, 12 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, br s), 8.78-8.72 (1H, m), 8.27-8.18 (1H, m), 7.62-7.54 (1H, m), 6.86 (1H, d, J = 8.2 Hz), 6.65 (1H, d, J = 8.2 Hz), 4.74-4.64 (1H, m), 4.50-4.40 (1H, m), 3.89 (3H, s), 3.79-3.69 (1H, m), 3.29-3.19 (2H, m), 2.01-1.88 (2H, m), 1.38 (5H, s), 1.32 (4H, s), 1.27-1.21 (1H, m).
ESI-MS m/z: 447[M+H]⁺. Preparation Example 107: tert-butyl 5- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate Synthesis of [Compound No. 107] Example 107-1 Tertiary butyl 5- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) -2,5-diazabicyclo [ 2.2.1] Synthesis of heptane-2-carboxylate [Compound No. 107]
Example 58 using the compound obtained in Example 55-2 (25 mg, 0.08 mmol) and tert-butyl 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (38 mg, 0.19 mmol) The title compound (4 mg, 12%) was obtained by the same procedure as -1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, br s), 8.78-8.72 (1 H, m), 8.27-8.18 (1 H, m), 7.62-7.54 (1 H, m), 6.86 (1H, d, J = 8.2 Hz), 6.65 (1 H, d, J = 8.2 Hz), 4.74-4.64 (1 H, m), 4.54-4.40 (1 H, m), 3.89 (3 H, s) ), 3.79-3.69 (1H, m), 3.29-3.19 (2H, m), 2.01-1.88 (2H, m), 1.38 (5H, s), 1.32 (4H, s), 1.27-1.21 (1H, m) ).
ESI-MS m / z: 447 [M + H] ⁺ .

製造例108：4-メトキシ-2-(ピリジン-3-イルエチニル)-7-(4-(ビニルスルホニル)ピペラジン-1-イル)ベンゾ[d]オキサゾール[化合物No.108]の合成
実施例108-1：4-メトキシ-2-(ピリジン-3-イルエチニル)-7-(4-(ビニルスルホニル)ピペラジン-1-イル)ベンゾ[d]オキサゾール[化合物No.108]の合成
実施例72-1で得られた化合物(50 mg, 0.15 mmol)のジクロロメタン(1 ml)溶液中に、ジイソプロピルエチルアミン(65 μl, 0.37 mmol)、2-クロロエタンスルホニルクロライド(20 μl, 0.18 mmol)をアルゴン雰囲気下0℃で添加した。0℃で1時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(19 mg, 30 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, br s), 8.78-8.70 (1H, m), 8.25-8.17 (1H, m), 7.62-7.52 (1H, m), 7.02-6.84 (3H, m), 6.25 (1H, d, J = 10.1 Hz), 6.18 (1H, d, J = 16.5 Hz), 3.93 (3H, s), 3.35-3.32 (4H, m), 3.27-3.24 (4H, m).
ESI-MS m/z: 425[M+H]⁺. Preparation Example 108 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) -7- (4- (vinylsulfonyl) piperazin-1-yl) benzo [d] oxazole [Compound No. 108] Example 108- Synthesis of 1: 4-methoxy-2- (pyridin-3-ylethynyl) -7- (4- (vinylsulfonyl) piperazin-1-yl) benzo [d] oxazole [compound No. 108]
Diisopropylethylamine (65 μl, 0.37 mmol) and 2-chloroethanesulfonyl chloride (20 μl, 0.18 mmol) in a solution of the compound (50 mg, 0.15 mmol) obtained in Example 72-1 in dichloromethane (1 ml) It was added at 0 ° C. under argon atmosphere. After stirring at 0 ° C. for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (19 mg, 30%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, br s), 8.78-8.70 (1 H, m), 8.25-8.17 (1 H, m), 7.62-7.52 (1 H, m), 7.02-6.84 (3H, m), 6.25 (1H, d, J = 10.1 Hz), 6.18 (1H, d, J = 16.5 Hz), 3.93 (3H, s), 3.35-3. 32 (4H, m) ), 3.27-3.24 (4H, m).
ESI-MS m / z: 425 [M + H] ⁺ .

製造例109：2-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-N,N-ジメチルエタンアミン[化合物No.109]の合成
実施例109-1：2-(4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)-N,N-ジメチルエタンアミン[化合物No.109]の合成
実施例72-1で得られた化合物(25 mg, 0.08 mmol)のDMF(1ml)溶液中に、2-クロロ-N,N-ジメチルエタンアミン塩酸塩(12 mg, 0.08 mmol)、炭酸ナトリウム(34 mg, 0.25 mmol)、ヨウ化ナトリウム(2 mg, 0.015 mmol)を室温下添加した。アルゴン雰囲気下、80℃で一晩撹拌し、反応終了後減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(19 mg, 63 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.76-8.71 (1H, m), 8.25-8.18 (1H, m), 7.61-7.54 (1H, m), 6.95-6.86 (2H, m), 3.92 (3H, s), 3.17-3.11 (4H, m), 2.65-2.59 (4H, m), 2.47-2.43 (2H, m), 2.41-2.37 (2H, m), 2.15 (6H, s).
ESI-MS m/z:406 [M+H]⁺. Preparation Example 109: 2- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -N, N-dimethylethanamine [compound No. Synthesis of Example 109-1: 2- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -N, N -Synthesis of dimethylethanamine [compound No. 109]
2-Chloro-N, N-dimethylethanamine hydrochloride (12 mg, 0.08 mmol), sodium carbonate (12 mg, 0.08 mmol) in a solution of the compound (25 mg, 0.08 mmol) obtained in Example 72-1 in DMF (1 ml) 34 mg (0.25 mmol) and sodium iodide (2 mg, 0.015 mmol) were added at room temperature. The mixture was stirred overnight at 80 ° C. under an argon atmosphere, and after completion of the reaction, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (19 mg, 63%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.76-8.71 (1 H, m), 8.25-8.18 (1 H, m), 7.61-7.54 (1 H, 1 H, m) m), 6.95-6.86 (2H, m), 3.92 (3H, s), 3.17-3.11 (4H, m), 2.65-2.59 (4H, m), 2.47-2.43 (2H, m), 2.41-2.37 ( 2H, m), 2.15 (6H, s).
ESI-MS m / z: 406 [M + H] ⁺ .

製造例110：2-((4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)スルホニル)-N,N-ジメチルエタンアミン[化合物No.110]の合成
実施例110-1：2-((4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)スルホニル)-N,N-ジメチルエタンアミン[化合物No.110]の合成
実施例108-1で得られた化合物(15 mg, 0.04 mmol)のTHF(1 ml)溶液中に、50%ジメチルアミン溶液(7 μl, 0.08 mmol)を室温下滴下した。30分撹拌した後、50%ジメチルアミン溶液(28 μl, 0.32 mmol)を添加した。さらに30分撹拌した後、50%ジメチルアミン溶液(28 μl, 0.32 mmol)を添加し一晩撹拌した。反応終了後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(19 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.19 (1H, m), 7.62-7.55 (1H, m), 6.98 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.43-3.39 (4H, m), 3.27 (2H, t, J = 7.3 Hz), 3.24-3.19 (4H, m), 2.66 (2H, t, J = 7.3 Hz), 2.19 (6H, s).
ESI-MS m/z:470[M+H]⁺. Preparation Example 110: 2-((4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) sulfonyl) -N, N-dimethylethanamine Synthesis of [Compound No. 110] Example 110-1-2-(((4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) Synthesis of sulfonyl) -N, N-dimethylethanamine [compound No. 110]
In a solution of the compound (15 mg, 0.04 mmol) obtained in Example 108-1 in THF (1 ml), 50% dimethylamine solution (7 μl, 0.08 mmol) was added dropwise at room temperature. After stirring for 30 minutes, 50% dimethylamine solution (28 μl, 0.32 mmol) was added. After stirring for another 30 minutes, 50% dimethylamine solution (28 μl, 0.32 mmol) was added and stirred overnight. After completion of the reaction, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (19 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.19 (1 H, m), 7.62-7.55 (1 H, m), 6.98 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.43-3.39 (4H, m), 3.27 (2H, t, J = 7.3 Hz), 3.24-3.19 (4H, m), 2.66 (2H, t, J = 7.3 Hz), 2.19 (6H, s).
ESI-MS m / z: 470 [M + H] ⁺ .

製造例111：2-((4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)スルホニル)-N,N-ジメチルエタンアミン塩酸塩[化合物No.111]の合成
実施例111-1：2-((4-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)ピペラジン-1-イル)スルホニル)-N,N-ジメチルエタンアミン塩酸塩[化合物No.111]の合成
実施例110-1で得られた化合物(19 mg, 0.04 mmol)のクロロホルム(587 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(11 μl, 0.042 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮した。標記の化合物(20 mg, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, s), 8.77-8.74 (1H, m), 8.24-8.19 (1H, m), 7.62-7.56 (1H, m), 6.99 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.53-3.47 (2H, m), 3.47-3.41 (4H, m), 3.28-3.20 (4H, m), 2.62-2.55 (2H, m), 2.50 (9H, s).
ESI-MS m/z:470[M+H]⁺. Preparation Example 111: 2-((4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) sulfonyl) -N, N-dimethylethanamine Synthesis of Hydrochloride [Compound No. 111] Example 111-1-2-((4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1 Synthesis of (yl) sulfonyl) -N, N-dimethylethanamine hydrochloride [Compound No. 111]
In a solution of the compound (19 mg, 0.04 mmol) obtained in Example 110-1 in chloroform (587 μl), a 4 mol / l hydrogen chloride / ethyl acetate solution (11 μl, 0.042 mmol) was dropped. After stirring at room temperature for 1 hour, the solution was concentrated under reduced pressure. The title compound (20 mg, 100%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, s), 8.77-8.74 (1 H, m), 8.24-8.19 (1 H, m), 7.62-7.56 (1 H, m) ), 6.99 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 8.7 Hz), 3.94 (3H, s), 3.53-3.47 (2H, m), 3.47-3. 41 (4H, m) , 3.28-3.20 (4H, m), 2.62-2.55 (2H, m), 2.50 (9H, s).
ESI-MS m / z: 470 [M + H] ⁺ .

製造例112：7-ブロモ-4-メトキシ-2-(ピリジン-4-イルエチニル)ベンゾ[d]オキサゾール[化合物No.112]の合成
実施例112-1：4-(2,2-ジブロモビニル)ピリジンの合成
イソニコチンアルデヒド(3.737 g, 34.9 mmol)、四臭化炭素(13.89 g, 41.9 mmol)をジクロロメタン(75 ml)に溶解し、氷冷した。そこへトリフェニルホスフィン(20.14 g, 76.8 mmol)のジクロロメタン溶液(80 ml)を加えた。室温で一晩攪拌した。反応後、1mol/l水酸化ナトリウム水溶液、飽和食塩水で洗った。硫酸マグネシウムで乾燥して、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 100 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(260 mg, 2.8%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]:8.63 (2H, dd, J = 4.6, 1.5 Hz), 7.85 (1H, s), 7.56 (2H, dd, J = 4.6, 1.5 Hz).
ESI-MS m/z:263, 265[M+H, M+2+H]⁺. Preparation Example 112 Synthesis of 7-bromo-4-methoxy-2- (pyridin-4-ylethynyl) benzo [d] oxazole [Compound No. 112] Example 112-1: 4- (2,2-dibromovinyl) Synthesis of pyridine
Isonicotinaldehyde (3.737 g, 34.9 mmol) and carbon tetrabromide (13.89 g, 41.9 mmol) were dissolved in dichloromethane (75 ml) and ice cooled. Thereto was added a solution of triphenylphosphine (20.14 g, 76.8 mmol) in dichloromethane (80 ml). Stir at room temperature overnight. After the reaction, it was washed with 1 mol / l aqueous sodium hydroxide solution and saturated brine. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 100 g, hexane / ethyl acetate) to give the title compound (260 mg, 2.8%) as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.63 (2 H, dd, J = 4.6, 1.5 Hz), 7.85 (1 H, s), 7.56 (2 H, dd, J = 4.6, 1.5 Hz).
ESI-MS m / z: 263, 265 [M + H, M + 2 + H] ⁺ .

実施例112-2：4-(ブロモエチニル)ピリジンの合成
実施例112-1で得られた化合物(260 mg, 0.99 mmol)をTHF(4 ml)に溶解し、氷冷した。そこへカリウムt-ブトキシド(117 mg, 1.04 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。水を加えてクロロホルムで抽出した。硫酸マグネシウムで乾燥して、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(85 mg, 47.2%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.60 (2H, dd, J = 4.6, 1.7 Hz), 7.48 (2H, dd, J = 4.6, 1.7 Hz).
ESI-MS m/z:183, 185[M+H, M+2+H]⁺. Example 112-2 Synthesis of 4- (bromoethynyl) pyridine
The compound (260 mg, 0.99 mmol) obtained in Example 112-1 was dissolved in THF (4 ml) and ice-cooled. The potassium t-butoxide (117 mg, 1.04 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. Water was added and extracted with chloroform. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, hexane / ethyl acetate) to give the title compound (85 mg, 47.2%) as a brown solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.60 (2 H, dd, J = 4.6, 1.7 Hz), 7.48 (2 H, dd, J = 4.6, 1.7 Hz).
ESI-MS m / z: 183, 185 [M + H, M + 2 + H] ⁺ .

実施例112-3：7-ブロモ-4-メトキシ-2-(ピリジン-4-イルエチニル)ベンゾ[d]オキサゾール[化合物No.112]の合成
実施例55-1で得られた化合物(53 mg, 0.23 mmol)と実施例112-2で得られた化合物(85 mg, 0.47 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(60 mg, 79.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.77 (2H, d, J = 4.6 Hz), 7.78 (2H, dd, J = 4.6, 1.5 Hz), 7.71 (1H, d, J = 8.5 Hz), 7.03 (1H, d, J = 8.5 Hz), 4.00 (3H, s).
ESI-MS m/z: 330, 332[M+H, M+2+H]⁺. Example 112-3 Synthesis of 7-bromo-4-methoxy-2- (pyridin-4-ylethynyl) benzo [d] oxazole [Compound No. 112]
Using the compound (53 mg, 0.23 mmol) obtained in Example 55-1 and the compound (85 mg, 0.47 mmol) obtained in Example 112-2 in the same manner as in Example 32-6 Gave the title compound (60 mg, 79.3%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.77 (2 H, d, J = 4.6 Hz), 7.78 (2 H, dd, J = 4.6, 1.5 Hz), 7.71 (1 H, d, J = 8.5 Hz), 7.03 (1 H, d, J = 8.5 Hz), 4.00 (3 H, s).
ESI-MS m / z: 330, 332 [M + H, M + 2 + H] ⁺ .

製造例113：2-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)-N,N-ジメチルエタンアミン[化合物No.113]の合成
実施例113-1：2-((4-メトキシベンゾ[d]オキサゾール-7-イル)オキシ)-N,N-ジメチルエタンアミンの合成
実施例102-1で得られた化合物(40 mg, 0.24 mmol)のDMF(1 ml)溶液中に、2-クロロ-N,N-ジメチルエタンアミン塩酸塩(38 mg, 0.27 mmol)、炭酸セシウム(237 mg, 0.73 mmol)を室温下添加した。アルゴン雰囲気下80℃で一晩撹拌した後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(16 mg, 28 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.63 (1H, s), 6.99 (1H, d, J = 8.7 Hz), 6.82 (1H, d, J = 8.7 Hz), 4.20 (2H, t, J = 5.7 Hz), 3.90 (3H, s), 2.69-2.65 (2H, m), 2.23 (6H, s).
ESI-MS m/z:237[M+H]⁺. Production Example 113 Synthesis of 2-((4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) -N, N-dimethylethanamine [Compound No. 113] Example 113-1 Synthesis of 2-((4-methoxybenzo [d] oxazol-7-yl) oxy) -N, N-dimethylethanamine
2-Chloro-N, N-dimethylethanamine hydrochloride (38 mg, 0.27 mmol) in a solution of the compound (40 mg, 0.24 mmol) obtained in Example 102-1 in DMF (1 ml), cesium carbonate (237 mg, 0.73 mmol) was added at room temperature. After stirring overnight at 80 ° C. under an argon atmosphere, the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (16 mg, 28%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.63 (1 H, s), 6.99 (1 H, d, J = 8.7 Hz), 6.82 (1 H, d, J = 8.7 Hz), 4.20 (2H, t, J = 5.7 Hz), 3.90 (3H, s), 2.69-2.65 (2H, m), 2.23 (6H, s).
ESI-MS m / z: 237 [M + H] ⁺ .

実施例113-2：2-((4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)オキシ)-N,N-ジメチルエタンアミン[化合物No.113]の合成
実施例113-1で得られた化合物(16 mg, 0.07 mmol)と実施例32-5で得られた化合物(25 mg, 0.14 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(3 mg, 13 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.26-8.19 (1H, m), 7.61-7.55 (1H, m), 7.11 (1H, d, J = 9.2 Hz), 6.90 (1H, d, J = 9.2 Hz), 4.25-4.19 (2H, m), 3.93 (3H, s), 2.66-2.64 (2H, m), 2.25 (6H, s).
ESI-MS m/z: 338[M+H]⁺. Example 113-2: 2-((4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) -N, N-dimethylethanamine [Compound No. 113] Synthesis
Using the compound (16 mg, 0.07 mmol) obtained in Example 113-1 and the compound (25 mg, 0.14 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (3 mg, 13%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.26-8.19 (1 H, m), 7.61-7.55 (1 H, m), 7.11 (1H, d, J = 9.2 Hz), 6.90 (1H, d, J = 9.2 Hz), 4.25-4.19 (2H, m), 3.93 (3H, s), 2.66-2.64 (2H, m) ), 2.25 (6H, s).
ESI-MS m / z: 338 [M + H] ⁺ .

製造例114：4-メトキシ-7-(2-(ピペリジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.114]の合成
実施例114-1：4-メトキシ-7-(2-(ピペリジン-1-イル)エトキシ)ベンゾ[d]オキサゾールの合成
実施例102-1で得られた化合物(40 mg, 0.24 mmol)のDMF(1 ml)溶液中に、1-(2-クロロエチル)ピペリジン塩酸塩(49 mg, 0.27 mmol)、炭酸セシウム(237 mg, 0.73 mmol)を室温下添加した。アルゴン雰囲気下80℃で一晩撹拌した後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(20 mg, 30 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.62 (1H, s), 6.99 (1H, d, J = 8.7 Hz), 6.82 (1H, d, J = 8.7 Hz), 4.21 (2H, t, J = 5.7 Hz), 3.91 (3H, s), 2.75-2.65 (2H, m), 2.48-2.39 (4H, m), 1.55-1.44 (4H, m), 1.41-1.32 (2H, m).
ESI-MS m/z:277[M+H]⁺. Preparation Example 114 Synthesis of 4-methoxy-7- (2- (piperidin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 114] Example 114-1 : Synthesis of 4-methoxy-7- (2- (piperidin-1-yl) ethoxy) benzo [d] oxazole
1- (2-chloroethyl) piperidine hydrochloride (49 mg, 0.27 mmol), cesium carbonate (237 mg) in a solution of the compound (40 mg, 0.24 mmol) obtained in Example 102-1 in DMF (1 ml) , 0.73 mmol) was added at room temperature. After stirring overnight at 80 ° C. under an argon atmosphere, the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (20 mg, 30%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.62 (1 H, s), 6.99 (1 H, d, J = 8.7 Hz), 6.82 (1 H, d, J = 8.7 Hz), 4.21 (2H, t, J = 5.7 Hz), 3.91 (3H, s), 2.75-2.65 (2H, m), 2.48-2.39 (4H, m), 1.55-1.44 (4H, m), 1.41-1.32 (2H , m).
ESI-MS m / z: 277 [M + H] ⁺ .

実施例114-2：4-メトキシ-7-(2-(ピペリジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.114]の合成
実施例114-1で得られた化合物(20 mg, 0.07 mmol)、実施例32-5で得られた化合物(26 mg, 0.15 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(19 mg, 70 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.19 (1H, m), 7.62-7.55 (1H, m), 7.11 (1H, d, J = 9.2 Hz), 6.89 (1H, d, J = 9.2 Hz), 4.25-4.18 (2H, m), 3.93 (3H, s), 2.74-2.64 (2H, m), 2.46-2.39 (4H, m), 1.55-1.45 (4H, m), 1.42-1.34 (2H, m).
ESI-MS m/z: 378[M+H]⁺. Example 114-2 Synthesis of 4-methoxy-7- (2- (piperidin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 114]
Using the compound (20 mg, 0.07 mmol) obtained in Example 114-1 and the compound (26 mg, 0.15 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (19 mg, 70%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.19 (1 H, m), 7.62-7.55 (1 H, m), 7.11 (1H, d, J = 9.2 Hz), 6.89 (1H, d, J = 9.2 Hz), 4.25-4.18 (2H, m), 3.93 (3H, s), 2.74-2.64 (2H, m) ), 2.46-2.39 (4H, m), 1.55-1.45 (4H, m), 1.42-1.34 (2H, m).
ESI-MS m / z: 378 [M + H] ⁺ .

製造例115：4-メトキシ-7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.115]の合成
実施例115-1：4-メトキシ-7-(2-モルホリノエトキシ)ベンゾ[d]オキサゾールの合成
実施例102-1で得られた化合物(40 mg, 0.24 mmol)のDMF(1 ml)溶液中に、4-(2-クロロエチル)モルホリン塩酸塩(50 mg, 0.27 mmol)、炭酸セシウム(237 mg, 0.73 mmol)、ヨウ化ナトリウム(2 mg, 0.01 mmol)を室温下添加した。アルゴン雰囲気下80℃で一晩撹拌した後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(37 mg, 55 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.63 (1H, s), 6.99 (1H, d, J = 8.7 Hz), 6.82 (1H, d, J = 8.7 Hz), 4.24 (2H, t, J = 5.5 Hz), 3.90 (3H, s), 3.57 (4H, t, J = 4.6 Hz), 2.73 (2H, t, J = 5.5 Hz), 2.50-2.45 (4H, m).
ESI-MS m/z:279[M+H]⁺. Preparation Example 115 Synthesis of 4-methoxy-7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 115] Example 115-1: 4-methoxy-7 Synthesis of-(2-morpholinoethoxy) benzo [d] oxazole
4- (2-chloroethyl) morpholine hydrochloride (50 mg, 0.27 mmol) and cesium carbonate (237 mg) in a solution of the compound (40 mg, 0.24 mmol) obtained in Example 102-1 in DMF (1 ml) , 0.73 mmol) and sodium iodide (2 mg, 0.01 mmol) were added at room temperature. After stirring overnight at 80 ° C. under an argon atmosphere, the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (37 mg, 55%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.63 (1 H, s), 6.99 (1 H, d, J = 8.7 Hz), 6.82 (1 H, d, J = 8.7 Hz), 4.24 (2H, t, J = 5.5 Hz), 3.90 (3H, s), 3.57 (4H, t, J = 4.6 Hz), 2.73 (2H, t, J = 5.5 Hz), 2.50-2.45 (4H, m) .
ESI-MS m / z: 279 [M + H] ⁺ .

実施例115-2：4-メトキシ-7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.115]の合成
実施例115-1で得られた化合物(37 mg, 0.13 mmol)と実施例32-5で得られた化合物(48 mg, 0.27 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(40 mg, 79 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.20 (1H, m), 7.61-7.54 (1H, m), 7.11 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 4.25 (2H, t, J = 5.7 Hz), 3.93 (3H, s), 3.60-3.56 (4H, m), 2.74 (2H, t, J = 5.7 Hz), 2.51-2.47 (4H, m).
ESI-MS m/z: 380[M+H]⁺. Example 115-2 Synthesis of 4-methoxy-7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 115]
Using the compound (37 mg, 0.13 mmol) obtained in Example 115-1 and the compound (48 mg, 0.27 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 Gave the title compound (40 mg, 79%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.20 (1 H, m), 7.61-7.54 (1 H, m), 7.11 (1 H, d, J = 8.7 Hz), 6.89 (1 H, d, J = 8.7 Hz), 4.25 (2 H, t, J = 5.7 Hz), 3.93 (3 H, s), 3.60-3.56 (6 4H, m), 2.74 (2H, t, J = 5.7 Hz), 2.51-2.47 (4H, m).
ESI-MS m / z: 380 [M + H] ⁺ .

製造例116：4,7-ジメトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.116]の合成
実施例116-1：4,7-ジメトキシベンゾ[d]オキサゾールの合成
実施例102-1で得られた化合物(40 mg, 0.24 mmol)のDMF(1 ml)溶液中に、ヨードメタン(17 μl, 0.26 mmol)、炭酸セシウム(118 mg, 0.36 mmol)を室温下添加した。アルゴン雰囲気下80℃で一晩撹拌した後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(16 mg, 37 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.63 (1H, s), 6.97 (1H, d, J = 8.7 Hz), 6.84 (1H, d, J = 8.7 Hz), 3.90 (6H, s).
ESI-MS m/z:180[M+H]⁺. Preparation Example 116 Synthesis of 4,7-dimethoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 116] Example 116-1: Synthesis of 4,7-dimethoxybenzo [d] oxazole
In a solution of the compound (40 mg, 0.24 mmol) obtained in Example 102-1 in DMF (1 ml), iodomethane (17 μl, 0.26 mmol) and cesium carbonate (118 mg, 0.36 mmol) were added at room temperature. . After stirring overnight at 80 ° C. under an argon atmosphere, the solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (16 mg, 37%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.63 (1 H, s), 6.97 (1 H, d, J = 8.7 Hz), 6.84 (1 H, d, J = 8.7 Hz), 3.90 (6H, s).
ESI-MS m / z: 180 [M + H] ⁺ .

実施例116-2：4,7-ジメトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.116]の合成
実施例116-1で得られた化合物(16 mg, 0.09 mmol)と実施例32-5で得られた化合物 (33 mg,0.18 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(10 mg, 40 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.25-8.19 (1H, m), 7.61-7.55 (1H, m), 7.08 (1H, d, J = 8.7 Hz), 6.91 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.93 (3H, s).
ESI-MS m/z: 281[M+H]⁺. Example 116-2 Synthesis of 4,7-dimethoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 116]
Using the compound (16 mg, 0.09 mmol) obtained in Example 116-1 and the compound (33 mg, 0.18 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (10 mg, 40%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.25-8.19 (1 H, m), 7.61-7.55 (1 H, m), 7.08 (1 H, d, J = 8.7 Hz), 6.91 (1 H, d, J = 8.7 Hz), 3.93 (3 H, s), 3.93 (3 H, s).
ESI-MS m / z: 281 [M + H] ⁺ .

製造例117：7-ブロモ-4-エトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.117]の合成
実施例117-1：4-エトキシベンゾ[d]オキサゾールの合成
実施例32-2で得られた化合物(521 mg, 3.86 mmol)をDMF(10 ml)に溶解した。そこへ炭酸セシウム(1.508 g, 4.63 mmol)、ヨウ化エチル(0.621 ml, 7.72 mmol)を加えて70℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(529 mg, 83.9%)を無色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.63 (1H, s), 7.37-7.31 (2H, m), 6.93 (1H, dd, J = 7.3, 1.5 Hz), 4.29 (2H, q, J = 7.0 Hz), 1.40 (3H, t, J = 7.0 Hz).
ESI-MS m/z: 164[M+H]⁺. Preparation Example 117 Synthesis of 7-bromo-4-ethoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 117] Example 117-1: Synthesis of 4-ethoxybenzo [d] oxazole
The compound (521 mg, 3.86 mmol) obtained in Example 32-2 was dissolved in DMF (10 ml). Cesium carbonate (1.508 g, 4.63 mmol) and ethyl iodide (0.621 ml, 7.72 mmol) were added there, and it stirred at 70 degreeC overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, hexane / ethyl acetate) to give the title compound (529 mg, 83.9%) as a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.63 (1 H, s), 7.37-7.31 (2 H, m), 6.93 (1 H, dd, J = 7.3, 1.5 Hz), 4.29 (4 2H, q, J = 7.0 Hz), 1.40 (3H, t, J = 7.0 Hz).
ESI-MS m / z: 164 [M + H] ⁺ .

実施例117-2：7-ブロモ-4-エトキシベンゾ[d]オキサゾールの合成
実施例117-1で得られた化合物(529 mg, 3.24 mmol)をアセトニトリル(26 ml)に溶解し、氷冷した。そこへN-ブロモコハク酸イミド(635 mg, 3.57 mmol)を加えて室温で1時間攪拌し、その後1時間加熱還流した。反応後、水を加えて酢酸エチルで抽出した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(603 mg, 76.9%)を無色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.75 (1H, s), 7.56 (1H, d, J = 8.9 Hz), 6.94 (1H, d, J = 8.9 Hz), 4.29 (2H, q, J = 6.9 Hz), 1.40 (3H, t, J = 6.9 Hz).
ESI-MS m/z: 243, 245[M+H, M+2+H]⁺. Example 117-2 Synthesis of 7-bromo-4-ethoxybenzo [d] oxazole
The compound (529 mg, 3.24 mmol) obtained in Example 117-1 was dissolved in acetonitrile (26 ml) and ice-cooled. N-bromosuccinimide (635 mg, 3.57 mmol) was added there, and it stirred at room temperature for 1 hour, and heated and refluxed for 1 hour after that. After the reaction, water was added and extracted with ethyl acetate. Washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (603 mg, 76.9%) as a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.75 (1 H, s), 7.56 (1 H, d, J = 8.9 Hz), 6.94 (1 H, d, J = 8.9 Hz), 4.29 (2H, q, J = 6.9 Hz), 1.40 (3H, t, J = 6.9 Hz).
ESI-MS m / z: 243, 245 [M + H, M + 2 + H] ⁺ .

実施例117-3：7-ブロモ-4-エトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.117]の合成
実施例117-2で得られた化合物(214 mg, 0.88 mmol)と実施例32-5で得られた化合物(322 mg, 1.77 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(148 mg, 49.0%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, s), 8.76 (1H, d, J = 3.7 Hz), 8.24 (1H, dt, J = 7.6, 1.8 Hz), 7.66 (1H, d, J = 8.9 Hz), 7.59 (1H, dd, J = 7.6, 4.9 Hz), 7.00 (1H, d, J = 8.9 Hz), 4.31 (2H, q, J = 7.0 Hz), 1.41 (3H, t, J = 7.0 Hz).
ESI-MS m/z: 344, 346[M+H, M+2+H]⁺. Example 117-3 Synthesis of 7-bromo-4-ethoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 117]
Using the compound (214 mg, 0.88 mmol) obtained in Example 117-2 and the compound (322 mg, 1.77 mmol) obtained in Example 32-5, the same procedure as in Example 32-6 is performed. Gave the title compound (148 mg, 49.0%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, s), 8. 76 (1 H, d, J = 3.7 Hz), 8.24 (1 H, dt, J = 7.6, 1.8 Hz) , 7.66 (1H, d, J = 8.9 Hz), 7.59 (1 H, dd, J = 7.6, 4.9 Hz), 7.00 (1 H, d, J = 8.9 Hz), 4.31 (2 H, q, J = 7.0 Hz) , 1.41 (3H, t, J = 7.0 Hz).
ESI-MS m / z: 344, 346 [M + H, M + 2 + H] ⁺ .

製造例118：7-ブロモ-4-イソプロポキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.118]の合成
実施例118-1：4-イソプロポキシベンゾ[d]オキサゾールの合成
実施例32-2で得られた化合物(520 mg, 3.85 mmol)をDMF(10 ml)に溶解した。そこへ炭酸セシウム(1.505 g, 4.62 mmol)、2-ヨードプロパン(0.765 ml, 7.7 mmol)を加えて70℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(556 mg, 81.5%)を無色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.62 (1H, s), 7.35-7.29 (2H, m), 6.93 (1H, dd, J = 7.2, 2.0 Hz), 5.09-5.03 (1H, m), 1.33 (6H, d, J = 6.1 Hz).
ESI-MS m/z: 178[M+H]⁺. Preparation Example 118 Synthesis of 7-bromo-4-isopropoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 118] Example 118-1: 4-isopropoxybenzo [d] oxazole Synthesis of
The compound (520 mg, 3.85 mmol) obtained in Example 32-2 was dissolved in DMF (10 ml). Cesium carbonate (1.505 g, 4.62 mmol) and 2-iodopropane (0.765 ml, 7.7 mmol) were added there, and it stirred at 70 degreeC overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, hexane / ethyl acetate) to give the title compound (556 mg, 81.5%) as a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.62 (1 H, s), 7. 35-7. 29 (2 H, m), 6. 93 (1 H, dd, J = 7.2, 2.0 Hz), 5.09- 5.03 (1 H, m), 1.33 (6 H, d, J = 6.1 Hz).
ESI-MS m / z: 178 [M + H] ⁺ .

実施例118-2：7-ブロモ-4-イソプロポキシベンゾ[d]オキサゾールの合成
実施例118-1で得られた化合物(556 mg, 3.14 mmol)をアセトニトリル(27 ml)に溶解し、氷冷した。そこへN-ブロモコハク酸イミド(614 mg, 3.45 mmol)を加えて室温で1時間攪拌し、その後1時間加熱還流した。反応後、水を加えて酢酸エチルで抽出した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(533 mg, 66.2%)を無色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.75 (1H, s), 7.54 (1H, d, J = 8.5 Hz), 6.94 (1H, d, J = 8.5 Hz), 5.06-5.00 (1H, m), 1.33 (6H, d, J = 6.1 Hz).
ESI-MS m/z: 257, 259[M+H, M+2+H]⁺. Example 118-2 Synthesis of 7-bromo-4-isopropoxybenzo [d] oxazole
The compound (556 mg, 3.14 mmol) obtained in Example 118-1 was dissolved in acetonitrile (27 ml) and ice-cooled. Thereto was added N-bromosuccinimide (614 mg, 3.45 mmol), and the mixture was stirred at room temperature for 1 hour and then heated under reflux for 1 hour. After the reaction, water was added and extracted with ethyl acetate. Washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (533 mg, 66.2%) as a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.75 (1 H, s), 7.54 (1 H, d, J = 8.5 Hz), 6.94 (1 H, d, J = 8.5 Hz), 5.06 -5.00 (1 H, m), 1.33 (6 H, d, J = 6.1 Hz).
ESI-MS m / z: 257, 259 [M + H, M + 2 + H] ⁺ .

実施例118-3：7-ブロモ-4-イソプロポキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.118]の合成
実施例118-2で得られた化合物(259 mg, 1.01 mmol)と実施例32-5で得られた化合物(368 mg, 2.02 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(146 mg, 40.5%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, s), 8.76 (1H, d, J = 3.7 Hz), 8.24 (1H, dt, J = 7.6, 1.7 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.59 (1H, dd, J = 7.6, 4.9 Hz), 7.00 (1H, d, J = 8.5 Hz), 5.07-5.01 (1H, m), 1.35 (6H, d, J = 6.1 Hz).
ESI-MS m/z: 358, 360[M+H, M+2+H]⁺. Example 118-3 Synthesis of 7-bromo-4-isopropoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 118]
Using the compound (259 mg, 1.01 mmol) obtained in Example 118-2 and the compound (368 mg, 2.02 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (146 mg, 40.5%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, s), 8. 76 (1 H, d, J = 3.7 Hz), 8.24 (1 H, dt, J = 7.6, 1.7 Hz) , 7.63 (1H, d, J = 8.5 Hz), 7.59 (1 H, dd, J = 7.6, 4.9 Hz), 7.00 (1 H, d, J = 8.5 Hz), 5.07-5.01 (1 H, m), 1.35 ( 6H, d, J = 6.1 Hz).
ESI-MS m / z: 358, 360 [M + H, M + 2 + H] ⁺ .

製造例119：4-メトキシ-7-(2-(ピペリジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.119]の合成
実施例119-1：4-メトキシ-7-(2-(ピペリジン-1-イル)エトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.119]の合成
実施例114-2で得られた化合物(12 mg, 0.03 mmol)のクロロホルム(462 μl)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(9 μl, 0.03 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮した。標記の化合物(14 mg, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.81-9.64 (1H, m), 8.96 (1H, br s), 8.78-8.73 (1H, m), 8.24-8.18 (1H, m), 7.63-7.55 (1H, m), 7.21-7.11 (1H, m), 6.98-6.89 (1H, m), 4.62-4.41 (2H, m), 3.95 (3H, s), 3.68-3.43 (4H, m), 3.13-2.91 (2H, m), 1.89-1.32 (6H, m).
ESI-MS m/z:378[M+H]⁺. Preparation Example 119 Synthesis of 4-methoxy-7- (2- (piperidin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 119] Example 119 Synthesis of 1-: 4-Methoxy-7- (2- (piperidin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 119]
In a solution of the compound (12 mg, 0.03 mmol) obtained in Example 114-2 in chloroform (462 μl), a 4 mol / l hydrogen chloride / ethyl acetate solution (9 μl, 0.03 mmol) was dropped. After stirring at room temperature for 1 hour, the solution was concentrated under reduced pressure. The title compound (14 mg, 100%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.81-9.64 (1 H, m), 8.96 (1 H, br s), 8.78-8.73 (1 H, m), 8.24-8.18 (1 H, m), 7.63-7.55 (1H, m), 7.21-7.11 (1H, m), 6.98-6.89 (1H, m), 4.62-4.41 (2H, m), 3.95 (3H, s), 3.68-3.43 ( 4H, m), 3.13-2.91 (2H, m), 1.89-1.32 (6H, m).
ESI-MS m / z: 378 [M + H] ⁺ .

製造例120：4-メトキシ-7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.120]の合成
実施例120-1：4-メトキシ-7-(2-モルホリノエトキシ)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール塩酸塩[化合物No.120]の合成
実施例115-2で得られた化合物(30 mg, 0.08 mmol)のクロロホルム(1.15 ml)溶液中に、4 mol/l塩化水素/酢酸エチル溶液(21 μl, 0.08 mmol)を滴下した。室温下1時間撹拌した後、減圧下濃縮した。標記の化合物(33 mg, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, s), 8.78-8.73 (1H, m), 8.24-8.18 (1H, m), 7.62-7.56 (1H, m), 7.54-7.46 (1H, m), 7.23-7.14 (1H, m), 4.62-4.52 (2H, m), 3.95 (3H, s), 3.81-3.49 (8H, m), 3.30-3.19 (2H, m).
ESI-MS m/z:380[M+H]⁺. Preparation Example 120: Synthesis of 4-methoxy-7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 120] Example 120-1: 4-methoxy Synthesis of -7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride [Compound No. 120]
In a solution of the compound (30 mg, 0.08 mmol) obtained in Example 115-2 in chloroform (1.15 ml), a 4 mol / l hydrogen chloride / ethyl acetate solution (21 μl, 0.08 mmol) was dropped. After stirring at room temperature for 1 hour, the solution was concentrated under reduced pressure. The title compound (33 mg, 100%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, s), 8.78-8.73 (1 H, m), 8.24-8.18 (1 H, m), 7.62-7.56 (1 H, m) ), 7.54-7.46 (1H, m), 7.23-7.14 (1H, m), 4.62-4.52 (2H, m), 3.95 (3H, s), 3.81-3.49 (8H, m), 3.30-3.19 (2H) , m).
ESI-MS m / z: 380 [M + H] ⁺ .

製造例121：4-メトキシ-7-(4-(2-(メチルスルホニル)エチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.121]の合成
実施例121-1：4-メトキシ-7-(4-(2-(メチルスルホニル)エチル)ピペラジン-1-イル)-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール[化合物No.121]の合成
実施例72-1で得られた化合物(25 mg, 0.08 mmol)のDMF(1ml)溶液中に、1-クロロ-2-(メチルスルホニル)エタン(30 mg, 0.20 mmol)、炭酸ナトリウム(21 mg, 0.15 mmol)、ヨウ化ナトリウム(3 mg, 0.015 mmol)を室温下添加した。アルゴン雰囲気下、80℃で一晩撹拌し、反応終了後減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(31 mg, 94 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.76-8.72 (1H, m), 8.26-8.20 (1H, m), 7.62-7.55 (1H, m), 6.92 (1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 8.7 Hz), 3.92 (3H, s), 3.36 (2H, t, J = 6.6 Hz), 3.20-3.13 (4H, m), 3.06 (3H, s), 2.79 (2H, t, J = 6.6 Hz), 2.70-2.62 (4H, m).
ESI-MS m/z:441 [M+H]⁺. Preparation Example 121: 4-methoxy-7- (4- (2- (methylsulfonyl) ethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 121] Synthesis Example 12 1-1: 4-methoxy-7- (4- (2- (methylsulfonyl) ethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole [Compound No. 121] synthesis
1-Chloro-2- (methylsulfonyl) ethane (30 mg, 0.20 mmol) and sodium carbonate (21 mg) in a solution of the compound (25 mg, 0.08 mmol) obtained in Example 72-1 in DMF (1 ml) , 0.15 mmol) and sodium iodide (3 mg, 0.015 mmol) were added at room temperature. The mixture was stirred overnight at 80 ° C. under an argon atmosphere, and after completion of the reaction, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (31 mg, 94%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.76-8.72 (1 H, m), 8.26-8.20 (1 H, m), 7.62-7.55 (1 H, m), 6.92 (1H, d, J = 8.7 Hz), 6.88 (1H, d, J = 8.7 Hz), 3.92 (3H, s), 3.36 (2H, t, J = 6.6 Hz), 3.20-3.13 ( 4H, m), 3.06 (3H, s), 2.79 (2H, t, J = 6.6 Hz), 2.70-2.62 (4H, m).
ESI-MS m / z: 441 [M + H] ⁺ .

製造例122：4-メトキシ-2-(ピリジン-3-イルエチニル)-7-チオモルホリノベンゾ[d]オキサゾール[化合物No.122]の合成
実施例122-1：4-メトキシ-2-(ピリジン-3-イルエチニル)-7-チオモルホリノベンゾ[d]オキサゾール[化合物No.122]の合成
実施例55-2で得られた化合物(25 mg, 0.08 mmol)とチオモルホリン(18 μl, 0.19 mmol)を用いて実施例58-1と同様の操作を行うことにより、標記の化合物(3 mg, 11 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.72 (1H, m), 8.26-8.19 (1H, m), 7.61-7.54 (1H, m), 6.99 (1H, d, J = 8.7 Hz), 6.90 (1H, d, J = 8.7 Hz), 3.93 (3H, s), 3.43-3.37 (4H, m), 2.84-2.78 (4H, m).
ESI-MS m/z: 352[M+H]⁺. Preparation Example 122 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) -7-thiomorpholinobenzo [d] oxazole [compound No. 122] Example 122-1: 4-methoxy-2- (pyridine- Synthesis of 3-ylethynyl) -7-thiomorpholinobenzo [d] oxazole [compound No. 122]
Using the compound (25 mg, 0.08 mmol) obtained in Example 55-2 and thiomorpholine (18 μl, 0.19 mmol) in the same manner as in Example 58-1, the title compound (3 mg) , 11%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.72 (1 H, m), 8.26-8.19 (1 H, m), 7.61-7.54 (1 H, m), 6.99 (1 H, d, J = 8.7 Hz), 6.90 (1 H, d, J = 8.7 Hz), 3.93 (3 H, s), 3.43-3.37 (4 H, m), 2.84-2.67 (4 H, m) ).
ESI-MS m / z: 352 [M + H] ⁺ .

製造例123：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-5,7-ジアミン[化合物No.123]の合成
実施例123-1：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-5,7-ジアミン[化合物No.123]の合成
実施例32-6で得られた化合物(50 mg, 0.20 mmol)のアセトニトリル(2.3 ml)溶液中に、0.5mol/lニトロニウムテトラフルオロボレートのスルホラン溶液(1.2 ml, 0.60 mmol)をアルゴン雰囲気下、0℃で滴下した。室温に昇温して一晩撹拌し、反応終了後飽和食塩水を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、4-メトキシ-7-ニトロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールと4-メトキシ-5,7-ジニトロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールの混合物(70 mg)を得た。この混合物のエタノール(1 ml)、水(1 ml)溶液中に、鉄粉(112 mg, 2.00 mmol)、塩化アンモニウム(160 mg, 3.00 mmol)を添加した。110℃で3時間撹拌した後、セライトろ過しクロロホルムで洗浄した。減圧下濃縮乾固した後、残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製した。標記の化合物(2 mg, 17 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.91 (1H, br s), 8.77-8.69 (1H, m), 8.21-8.13 (1H, m), 7.60-7.52 (1H, m), 6.18 (1H, s), 5.16 (2H, s), 4.63 (2H, s), 3.88 (3H, s).
ESI-MS m/z: 281[M+H]⁺. Preparation Example 123 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-5,7-diamine [Compound No. 123] Example 123-1: 4-methoxy-2- (pyridine) Synthesis of -3-ylethynyl) benzo [d] oxazole-5,7-diamine [compound No. 123]
In a solution of the compound (50 mg, 0.20 mmol) obtained in Example 32-6 in acetonitrile (2.3 ml), a sulfolane solution (1.2 ml, 0.60 mmol) of 0.5 mol / l nitronium tetrafluoroborate under an argon atmosphere At 0 ° C. The mixture was warmed to room temperature and stirred overnight, and after completion of the reaction, brine was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform / methanol), 4-methoxy-7-nitro-2- (pyridin-3-ylethynyl) benzo [d] oxazole and 4-methoxy-5,7-dinitro- A mixture (70 mg) of 2- (pyridin-3-ylethynyl) benzo [d] oxazole was obtained. Iron powder (112 mg, 2.00 mmol) and ammonium chloride (160 mg, 3.00 mmol) were added to a solution of this mixture in ethanol (1 ml) and water (1 ml). After stirring at 110 ° C. for 3 hours, the mixture was filtered through celite and washed with chloroform. After concentration to dryness under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol). The title compound (2 mg, 17%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.91 (1 H, br s), 8.77-8.69 (1 H, m), 8.21-8.13 (1 H, m), 7.60-7.52 (1 H, m), 6.18 (1 H, s), 5.16 (2 H, s), 4.63 (2 H, s), 3. 88 (3 H, s).
ESI-MS m / z: 281 [M + H] ⁺ .

製造例124：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン[化合物No.124]の合成
実施例124-1：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン[化合物No.124]の合成
実施例32-6で得られた化合物(784 mg, 3.13 mmol)のアセトニトリル(36 ml)溶液中に、0.5mol/lニトロニウムテトラフルオロボレートのスルホラン溶液(9.40 ml, 4.7 mmol)をアルゴン雰囲気下、0℃で滴下した。室温に昇温して一晩撹拌し、反応終了後飽和食塩水を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、4-メトキシ-7-ニトロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールと4-メトキシ-5-ニトロ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾールの混合物(924 mg)を得た。この混合物のエタノール(15 ml)、水(15 ml)溶液中に、鉄粉(1.75 g, 31 mmol)、塩化アンモニウム(2.51 g, 47 mmol)を添加した。110℃で4時間撹拌した後、セライトろ過し飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製した。標記の化合物(173 mg, 21 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.93 (1H, br s), 8.74-8.73 (1H, m), 8.20-8.18 (1H, m), 7.58-7.57 (1H, m), 6.75 (1H, d, J = 8.7 Hz), 6.67 (1H, d, J = 8.7 Hz), 5.22 (2H, s), 3.87 (3H, s).
ESI-MS m/z: 266[M+H]⁺. Preparation Example 124 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-amine [Compound No. 124] Example 124-1: 4-methoxy-2- (pyridine-3) Of 1-ylethynyl) benzo [d] oxazole-7-amine [compound No. 124]
In a solution of the compound (784 mg, 3.13 mmol) obtained in Example 32-6 in acetonitrile (36 ml), a sulfolane solution (9.40 ml, 4.7 mmol) of 0.5 mol / l nitronium tetrafluoroborate under an argon atmosphere At 0 ° C. The mixture was warmed to room temperature and stirred overnight, and after completion of the reaction, brine was added and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform / methanol), 4-methoxy-7-nitro-2- (pyridin-3-ylethynyl) benzo [d] oxazole and 4-methoxy-5-nitro-2- A mixture (924 mg) of (pyridin-3-ylethynyl) benzo [d] oxazole was obtained. Iron powder (1.75 g, 31 mmol) and ammonium chloride (2.51 g, 47 mmol) were added to a solution of this mixture in ethanol (15 ml) and water (15 ml). After stirring at 110 ° C. for 4 hours, the mixture was filtered through Celite, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). The title compound (173 mg, 21%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.93 (1 H, br s), 8.74-8.73 (1 H, m), 8.20-8.18 (1 H, m), 7.58-7.57 (1 H, m), 6.75 (1 H, d, J = 8.7 Hz), 6.67 (1 H, d, J = 8.7 Hz), 5.22 (2 H, s), 3. 87 (3 H, s).
ESI-MS m / z: 266 [M + H] ⁺ .

製造例125：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-5-アミン[化合物No.125]の合成
実施例125-1：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-5-アミン[化合物No.125]の合成
実施例124-1から副生し、標記の化合物(121 mg, 15 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, br s), 8.75-8.71 (1H, m), 8.23-8.17 (1H, m), 7.60-7.54 (1H, m), 7.15 (1H, d, J = 8.7 Hz), 6.89 (1H, d, J = 8.7 Hz), 4.84 (2H, s), 4.17 (3H, s).
ESI-MS m/z: 266[M+H]⁺. Production Example 125 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-5-amine [Compound No. 125] Example 125-1: 4-Methoxy-2- (pyridine-3) Synthesis of (-ylethynyl) benzo [d] oxazol-5-amine [Compound No. 125]
The title compound (121 mg, 15%) was obtained as a by-product from Example 124-1.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, br s), 8.75-8.71 (1 H, m), 8.23-8.17 (1 H, m), 7.60-7.54 (1 H, m), 7.15 (1 H, d, J = 8.7 Hz), 6.89 (1 H, d, J = 8.7 Hz), 4.84 (2 H, s), 4. 17 (3 H, s).
ESI-MS m / z: 266 [M + H] ⁺ .

製造例126：3-(ジメチルアミノ)-N-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)プロパンアミド[化合物No.126]の合成
実施例126-1：3-(ジメチルアミノ)-N-(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)プロパンアミド[化合物No.126]の合成
実施例124-1で得られた化合物(20 mg, 0.08 mmol)のDMF(1 ml)溶液中に、3-(ジメチルアミノ)プロパノイックアシッド塩酸塩(15 mg, 0.10 mmol)、2-(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)-1,1,3,3-テトラメチルイソウロニウムヘキサフルオロホスフェート(V)(43 mg, 0.11 mmol)、N-エチル-N-イソプロピルプロパン-2-アミン(79 μl, 0.45 mmol)を室温下添加した。一晩撹拌した後、減圧下濃縮乾固した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(5 mg, 18 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.37 (1H, s), 8.95 (1H, br s), 8.78-8.72 (1H, m), 8.24-8.15 (1H, m), 7.76 (1H, d, J = 8.7 Hz), 7.62-7.54 (1H, m), 6.97 (1H, d, J = 8.7 Hz), 3.97 (3H, s), 2.60-2.56 (2H, m), 2.56-2.53 (2H, m), 2.21 (6H, s).
ESI-MS m/z:365[M+H]⁺. Preparation Example 126 Synthesis of 3- (dimethylamino) -N- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) propanamide [Compound No. 126] Example 126 Synthesis of -1: 3- (Dimethylamino) -N- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) propanamide [Compound No. 126]
3- (Dimethylamino) propanoic acid hydrochloride (15 mg, 0.10 mmol) in a solution of the compound (20 mg, 0.08 mmol) obtained in Example 124-1 in DMF (1 ml), 2- ( 3H- [1,2,3] Triazolo [4,5-b] pyridin-3-yl) -1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (43 mg, 0.11 mmol) , N-ethyl-N-isopropylpropan-2-amine (79 μl, 0.45 mmol) was added at room temperature. After stirring overnight, it was concentrated to dryness under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (5 mg, 18%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.37 (1H, s), 8.95 (1H, br s), 8.78-8.72 (1H, m), 8.24-8.15 (1H, m) , 7.76 (1 H, d, J = 8.7 Hz), 7.62-7.54 (1 H, m), 6.97 (1 H, d, J = 8.7 Hz), 3. 97 (3 H, s), 2.60-2.56 (2 H, m), 2.56-2.53 (2H, m), 2.21 (6H, s).
ESI-MS m / z: 365 [M + H] ⁺ .

製造例127：4-メトキシ-N,N-ジメチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン[化合物No.127]の合成
実施例127-1：4-メトキシ-N,N-ジメチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン[化合物No.127]の合成
実施例124-1で得られた化合物(30 mg, 0.11 mmol)のジクロロメタン(2 ml)溶液中に、37%パラホルムアルデヒド水溶液(18.6 μl, 0.24 mmol)、トリアセトキシ水素化ホウ素ナトリウム(72 mg, 0.34 mmol)を添加した後、室温で2時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物 (15 mg, 45 %)を得た。
¹H-NMR (CDCl₃) δ: 8.96 (1H, br s), 8.76-8.71 (1H, m), 8.24-8.19 (1H, m), 7.61-7.54 (1H, m), 6.88 (1H, d, J = 8.7 Hz), 6.79 (1H, d, J = 8.7 Hz), 3.91 (3H, s), 2.91 (6H, s).
ESI-MS m/z:294[M+H]⁺. Production Example 127 Synthesis of 4-Methoxy-N, N-dimethyl-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-amine [Compound No. 127] Example 127-1: 4-Methoxy- Synthesis of N, N-Dimethyl-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-amine [Compound No. 127]
In a solution of the compound (30 mg, 0.11 mmol) obtained in Example 124-1 in dichloromethane (2 ml), 37% aqueous paraformaldehyde solution (18.6 μl, 0.24 mmol), sodium triacetoxyborohydride (72 mg, After addition of 0.34 mmol), the mixture was stirred at room temperature for 2 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (15 mg, 45%).
¹ H-NMR (CDCl ₃ ) δ: 8.96 (1 H, br s), 8.76-8.71 (1 H, m), 8.24-8. 19 (1 H, m), 7.61-7.54 (1 H, m), 6.88 (1 H, d , J = 8.7 Hz), 6.79 (1 H, d, J = 8.7 Hz), 3.91 (3 H, s), 2. 91 (6 H, s).
ESI-MS m / z: 294 [M + H] ⁺ .

製造例128：4-メトキシ-N-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン[化合物No.128]の合成
実施例128-1：4-メトキシ-N-メチル-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-アミン[化合物No.128]の合成
実施例124-1で得られた化合物(30 mg, 0.11 mmol)のジクロロメタン(2 ml)溶液中に、37%パラホルムアルデヒド水溶液(18.6 μl, 0.24 mmol)、トリアセトキシ水素化ホウ素ナトリウム(72 mg, 0.34 mmol)を添加した後、室温で2時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物 (9 mg, 29 %)を得た。
¹H-NMR (CDCl₃) δ: 8.93 (1H, br s), 8.76-8.72 (1H, m), 8.22-8.16 (1H, m), 7.61-7.54 (1H, m), 6.83 (1H, d, J = 8.7 Hz), 6.54 (1H, d, J = 8.7 Hz), 5.73 (1H, q, J = 5.0 Hz), 3.88 (3H, s), 2.78 (3H, d, J = 5.0 Hz).
ESI-MS m/z:280[M+H]⁺. Preparation Example 128 Synthesis of 4-Methoxy-N-methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-amine [Compound No. 128] Example 128-1: 4-Methoxy-N- Synthesis of methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-amine [compound No. 128]
In a solution of the compound (30 mg, 0.11 mmol) obtained in Example 124-1 in dichloromethane (2 ml), 37% aqueous paraformaldehyde solution (18.6 μl, 0.24 mmol), sodium triacetoxyborohydride (72 mg, After addition of 0.34 mmol), the mixture was stirred at room temperature for 2 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (9 mg, 29%).
¹ H-NMR (CDCl ₃ ) δ: 8.93 (1 H, br s), 8.76-8.72 (1 H, m), 8.22-8.16 (1 H, m), 7.61-7.54 (1 H, m), 6.83 (1 H, d , J = 8.7 Hz), 6.54 (1 H, d, J = 8.7 Hz), 5.73 (1 H, q, J = 5.0 Hz), 3.88 (3 H, s), 2. 78 (3 H, d, J = 5.0 Hz).
ESI-MS m / z: 280 [M + H] ⁺ .

製造例129：7-ブロモ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-オール[化合物No.129]の合成
実施例129-1：4-((ターシャリーブチルジメチルシリル)オキシ)ベンゾ[d]オキサゾールの合成
実施例32-2で得られた化合物(622 mg, 4.6 mmol)をDMF(13 ml)に溶解した。そこへターシャリーブチルジメチルシリルクロリド(1.387 g, 9.2 mmol)、イミダゾール(470 mg, 6.9 mmol)を加えて70℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(1.112 g, 96.9%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.63 (1H, s), 7.36 (1H, dd, J = 8.2, 0.9 Hz), 7.30 (1H, t, J = 7.9 Hz), 6.86 (1H, dd, J = 7.9, 0.9 Hz), 1.00 (9H, s), 0.24 (6H, s).
ESI-MS m/z: 250[M+H]⁺. Preparation Example 129 Synthesis of 7-bromo-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-ol [Compound No. 129] Example 129-1: 4-((tertiary butyldimethylsilyl) Synthesis of oxy) benzo [d] oxazole
The compound (622 mg, 4.6 mmol) obtained in Example 32-2 was dissolved in DMF (13 ml). Tertiary butyl dimethyl silyl chloride (1.387 g, 9.2 mmol) and imidazole (470 mg, 6.9 mmol) were added there, and it stirred at 70 degreeC overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (1.112 g, 96.9%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.63 (1 H, s), 7.36 (1 H, dd, J = 8.2, 0.9 Hz), 7.30 (1 H, t, J = 7.9 Hz) , 6.86 (1 H, dd, J = 7.9, 0.9 Hz), 1.00 (9 H, s), 0.24 (6 H, s).
ESI-MS m / z: 250 [M + H] ⁺ .

実施例129-2：7-ブロモ-4-((ターシャリーブチルジメチルシリル)オキシ)ベンゾ[d]オキサゾールの合成
実施例129-1で得られた化合物(1.112 g, 4.46 mmol)をアセトニトリル(50 ml)に溶解し、氷冷した。そこへN-ブロモコハク酸イミド(873 mg, 4.90 mmol)を加えて室温で1時間攪拌し、その後2時間加熱還流した。反応後、水を加えて酢酸エチルで抽出した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(464 mg, 31.7%)を無色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.75 (1H, s), 7.52 (1H, d, J = 8.5 Hz), 6.86 (1H, d, J = 8.5 Hz), 1.00 (9H, s), 0.24 (6H, s).
ESI-MS m/z: 329, 331[M+H, M+2+H]⁺. Example 129-2 Synthesis of 7-bromo-4-((tertiary butyldimethylsilyl) oxy) benzo [d] oxazole
The compound (1.112 g, 4.46 mmol) obtained in Example 129-1 was dissolved in acetonitrile (50 ml) and ice-cooled. N-bromosuccinimide (873 mg, 4.90 mmol) was added there, and it stirred at room temperature for 1 hour, and heated and refluxed for 2 hours after that. After the reaction, water was added and extracted with ethyl acetate. Washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (464 mg, 31.7%) as a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.75 (1 H, s), 7.52 (1 H, d, J = 8.5 Hz), 6.86 (1 H, d, J = 8.5 Hz), 1.00 (9H, s), 0.24 (6H, s).
ESI-MS m / z: 329, 331 [M + H, M + 2 + H] ⁺ .

実施例129-3：7-ブロモ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-4-オール[化合物No.129]の合成
実施例129-2で得られた化合物(464 mg, 1.41 mmol)と実施例32-5で得られた化合物(515 mg, 2.83 mmol)を用いて実施例32-6と同様の操作を行い、残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製した。
これをTHF(2.5 ml)に溶解し、1mol/l テトラブチルアンモニウムフルオリド溶液(0.44 ml)を加えて室温で3時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, ヘキサン/酢酸エチル)で精製し標記の化合物(19 mg, 20.0%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.97 (1H, s), 8.98 (1H, d, J = 1.8 Hz), 8.74 (1H, d, J = 1.5 Hz), 8.24 (1H, dt, J = 7.9, 1.8 Hz), 7.58 (1H, dd, J = 7.9, 4.9 Hz), 7.52 (1H, d, J = 8.5 Hz), 6.82 (1H, d, J = 8.5 Hz).
ESI-MS m/z: 316, 318[M+H, M+2+H]⁺. Example 129-3 Synthesis of 7-bromo-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-ol [Compound No. 129]
The same procedure as in Example 32-6 is performed using the compound (464 mg, 1.41 mmol) obtained in Example 129-2 and the compound (515 mg, 2.83 mmol) obtained in Example 32-5, The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate).
This was dissolved in THF (2.5 ml), 1 mol / l tetrabutylammonium fluoride solution (0.44 ml) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, hexane / ethyl acetate) to give the title compound (19 mg, 20.0%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.97 (1 H, s), 8. 98 (1 H, d, J = 1.8 Hz), 8.74 (1 H, d, J = 1.5 Hz), 8.24 (1H, dt, J = 7.9, 1.8 Hz), 7.58 (1 H, dd, J = 7.9, 4.9 Hz), 7.52 (1 H, d, J = 8.5 Hz), 6.82 (1 H, d, J = 8.5 Hz) .
ESI-MS m / z: 316, 318 [M + H, M + 2 + H] ⁺ .

製造例130：N-(2-(ジメチルアミノ)エチル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシアミド[化合物No.130]の合成
実施例130-1：4-メトキシベンゾ[d]オキサゾール-7-カルボキシリックアシッドの合成
実施例84-2で得られた化合物(394 mg, 2.22 mmol)のターシャリーブチルアルコール(12 ml)、水(4 ml)溶液中に、亜塩素酸ナトリウム(402 mg, 4.45 mmol)、リン酸二水素ナトリウム(1.334 g, 11.12 mmol)、2-メチル-2-ブテン(1.89 ml, 17.79 mmol)を室温下添加した。一晩撹拌した後、減圧下濃縮乾固した。1N水酸化ナトリウム水溶液でPH>8とし、酢酸エチルで分液した。分取した水層に6mol/l塩酸を加え、PH<1とし酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記の化合物 (123 mg, 29 %)を得た。
¹H-NMR (CDCl₃) δ: 8.75 (1H, s), 7.94 (1H, d, J = 8.7 Hz), 7.07 (1H, d, J = 8.7 Hz), 4.05 (3H, s).
ESI-MS m/z:194[M+H]⁺. Production Example 130 Synthesis of N- (2- (Dimethylamino) ethyl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxamide [Compound No. 130] Example 130 Synthesis of 4-methoxybenzo [d] oxazole-7-carboxylic acid
Sodium chlorite (402 mg, 4.45 mmol), phosphoric acid in a solution of the compound obtained in Example 84-2 (394 mg, 2.22 mmol) in tertiary butyl alcohol (12 ml), water (4 ml) Sodium dihydrogen (1.334 g, 11.12 mmol) and 2-methyl-2-butene (1.89 ml, 17.79 mmol) were added at room temperature. After stirring overnight, it was concentrated to dryness under reduced pressure. The pH was adjusted to> 8 with a 1 N aqueous solution of sodium hydroxide, and the layers were separated with ethyl acetate. To the separated aqueous layer was added 6 mol / l hydrochloric acid to adjust pH <1, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (123 mg, 29%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.75 (1 H, s), 7.94 (1 H, d, J = 8.7 Hz), 7.07 (1 H, d, J = 8.7 Hz), 4.05 (3 H, s).
ESI-MS m / z: 194 [M + H] ⁺ .

実施例130-2：N-(2-(ジメチルアミノ)エチル)-4-メトキシベンゾ[d]オキサゾール-7-カルボキシアミドの合成
実施例130-1で得られた化合物(60 mg, 0.31 mmol)のDMF(2.6 ml)溶液中に、2-(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)-1,1,3,3-テトラメチルイソウロニウムヘキサフルオロホスフェート(V)(177 mg, 0.47 mmol)、N-エチル-N-イソプロピルプロパン-2-アミン(163 μl, 0.93 mmol)を室温下添加した。30分撹拌した後、N1,N1-ジメチルエタン-1,2-ジアミン(37 μl, 0.34 mmol)を滴下した。一晩撹拌した後、飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(17 mg, 21 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.78 (1H, s), 8.07-7.99 (1H, m), 7.82 (1H, d, J = 8.7 Hz), 7.06 (1H, d, J = 8.7 Hz), 4.03 (3H, s), 3.45-3.38 (2H, m), 2.45-2.41 (2H, m), 2.20 (6H, s).
ESI-MS m/z:264[M+H]⁺. Example 130-2 Synthesis of N- (2- (dimethylamino) ethyl) -4-methoxybenzo [d] oxazol-7-carboxamide
In a solution of the compound (60 mg, 0.31 mmol) obtained in Example 130-1 in DMF (2.6 ml), 2- (3H- [1,2,3] triazolo [4,5-b] pyridine-3 -Yl) -1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (177 mg, 0.47 mmol), N-ethyl-N-isopropylpropan-2-amine (163 μl, 0.93 mmol) Was added at room temperature. After stirring for 30 minutes, N1, N1-dimethylethane-1,2-diamine (37 μl, 0.34 mmol) was added dropwise. After stirring overnight, saturated brine was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (17 mg, 21%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.78 (1 H, s), 8.07-7.99 (1 H, m), 7.82 (1 H, d, J = 8.7 Hz), 7.06 (1 H, d, J = 8.7 Hz), 4.03 (3H, s), 3.45-3.38 (2H, m), 2.45-2.41 (2H, m), 2.20 (6H, s).
ESI-MS m / z: 264 [M + H] ⁺ .

実施例130-3：N-(2-(ジメチルアミノ)エチル)-4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-カルボキシアミド[化合物No.130]の合成
実施例130-2で得られた化合物(17 mg, 0.07 mmol)と実施例32-5で得られた化合物(24 mg, 0.13 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(7 mg, 30 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.77-8.74 (1H, m), 8.24-8.20 (1H, m), 8.05-8.01 (1H, m), 7.88 (1H, d, J = 8.7 Hz), 7.62-7.56 (1H, m), 7.12 (2H, d, J = 8.7 Hz), 4.05 (3H, s), 3.44-3.40 (2H, m), 2.44-2.41 (2H, m), 2.21 (6H, s).
ESI-MS m/z: 365[M+H]⁺. Example 130-3 Synthesis of N- (2- (dimethylamino) ethyl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxamide [Compound No. 130]
Using the compound (17 mg, 0.07 mmol) obtained in Example 130-2 and the compound (24 mg, 0.13 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (7 mg, 30%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.77-8.74 (1 H, m), 8.24-8.20 (1 H, m), 8.05-8.01 (1 H, 1 H, m) m), 7.88 (1 H, d, J = 8.7 Hz), 7.62-7.56 (1 H, m), 7.12 (2 H, d, J = 8.7 Hz), 4.05 (3 H, s), 3.44-3. 40 (2 H, m) ), 2.44-2.41 (2H, m), 2.21 (6H, s).
ESI-MS m / z: 365 [M + H] ⁺ .

製造例131：(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)(4-メチルピペラジン-1-イル)メタノン[化合物No.131]の合成
実施例131-1：(4-メトキシベンゾ[d]オキサゾール-7-イル)(4-メチルピペラジン-1-イル)メタノンの合成
実施例130-1で得られた化合物(60 mg, 0.31 mmol)のDMF(2.6 ml)溶液中に、2-(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イル)-1,1,3,3-テトラメチルイソウロニウムヘキサフルオロホスフェート(V)(177 mg, 0.47 mmol)、N-エチル-N-イソプロピルプロパン-2-アミン(163 μl, 0.93 mmol)を室温下添加した。30分撹拌した後、1-メチルピペラジン(38 μl, 0.34 mmol)を滴下した。一晩撹拌した後、飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(37 mg, 43 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.71 (1H, s), 7.43 (1H, d, J = 8.7 Hz), 7.02 (1H, d, J = 8.7 Hz), 4.01 (3H, s), 3.71-3.59 (1H, m), 3.32-3.24 (1H, m), 2.43-2.22 (6H, m), 2.20 (3H, s).
ESI-MS m/z: 276[M+H]⁺. Preparation Example 131 Synthesis of (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) (4-methylpiperazin-1-yl) methanone [Compound No. 131] Example 131 -1: Synthesis of (4-Methoxybenzo [d] oxazol-7-yl) (4-methylpiperazin-1-yl) methanone
In a solution of the compound (60 mg, 0.31 mmol) obtained in Example 130-1 in DMF (2.6 ml), 2- (3H- [1,2,3] triazolo [4,5-b] pyridine-3 -Yl) -1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (177 mg, 0.47 mmol), N-ethyl-N-isopropylpropan-2-amine (163 μl, 0.93 mmol) Was added at room temperature. After stirring for 30 minutes, 1-methylpiperazine (38 μl, 0.34 mmol) was added dropwise. After stirring overnight, saturated brine was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (37 mg, 43%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.71 (1 H, s), 7.43 (1 H, d, J = 8.7 Hz), 7.02 (1 H, d, J = 8.7 Hz), 4.01 (3H, s), 3.71-3.59 (1H, m), 3.32-3.24 (1H, m), 2.43-2.22 (6H, m), 2.20 (3H, s).
ESI-MS m / z: 276 [M + H] ⁺ .

実施例131-2：(4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]オキサゾール-7-イル)(4-メチルピペラジン-1-イル)メタノン[化合物No.131]の合成
実施例131-1で得られた化合物(37 mg, 0.13 mmol)と実施例32-5で得られた化合物(49 mg, 0.27 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(7 mg, 14 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, br s), 8.79-8.74 (1H, m), 8.27-8.19 (1H, m), 7.63-7.56 (1H, m), 7.52 (1H, d, J = 8.2 Hz), 7.08 (1H, d, J = 8.2 Hz), 4.04 (3H, s), 2.44-2.24 (8H, m), 2.20 (3H, d, J = 2.7 Hz).
ESI-MS m/z: 377[M+H]⁺. Example 131-2: Synthesis of (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) (4-methylpiperazin-1-yl) methanone [Compound No. 131]
Using the compound (37 mg, 0.13 mmol) obtained in Example 131-1 and the compound (49 mg, 0.27 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (7 mg, 14%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, br s), 8.79-8.74 (1 H, m), 8.27-8.19 (1 H, m), 7.63-7.56 (1 H, m), 7.52 (1 H, d, J = 8.2 Hz), 7.08 (1 H, d, J = 8.2 Hz), 4.04 (3 H, s), 2.44-2.24 (8 H, m), 2.20 (3 H, d, J = 2.7 Hz).
ESI-MS m / z: 377 [M + H] ⁺ .

製造例132：2-(2-メトキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.132]の合成
実施例132-1：ベンジル2-(5-ブロモ-2-メトキシベンゾイル)ヒドラジンカルボキシレートの合成
5-ブロモ-2-メトキシ安息香酸(841 mg, 3.64 mmol)をジクロロメタン(17 ml)に溶解した。そこへオキサリルクロリド(0.328 ml, 3.82 mmol)、DMF(1滴)を加えて室温で1.5時間撹拌した。そこへベンジルヒドラジンカルボキシレート(665 mg, 4 mmol)を加えて室温で一晩撹拌した。反応後、クロロホルム/メタノール溶液を加えて飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 25 g, クロロホルム/メタノール)で精製し、標記の化合物(1.048 g, 75.9%)を白色固体として得た。
ESI-MS m/z:379[M+H]⁺. Preparation Example 132: Synthesis of 2- (2-methoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 132] Example 132-1: Benzyl 2- ( Synthesis of 5-bromo-2-methoxybenzoyl) hydrazine carboxylate
5-bromo-2-methoxybenzoic acid (841 mg, 3.64 mmol) was dissolved in dichloromethane (17 ml). The oxalyl chloride (0.328 ml, 3.82 mmol) and DMF (1 drop) were added there, and it stirred at room temperature for 1.5 hours. The benzyl hydrazine carboxylate (665 mg, 4 mmol) was added there, and it stirred at room temperature overnight. After the reaction, a chloroform / methanol solution was added and washed with saturated brine. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 25 g, chloroform / methanol) to give the title compound (1.048 g, 75.9%) as a white solid.
ESI-MS m / z: 379 [M + H] ⁺ .

実施例132-2：2-メトキシベンゾヒドラジドの合成
実施例132-1で得られた化合物(1.048 g, 2.76 mmol)をメタノール(60 ml)、酢酸エチル(40 ml)に溶解した。10%パラジウム炭素(105 mg)を加えた。水素雰囲気下、室温で1時間撹拌した。反応後、セライトろ過し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 50 g, クロロホルム/メタノール)で精製し、標記の化合物(228 mg, 49.7%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.21 (1H, br s), 7.67 (1H, dd, J = 7.6, 1.5 Hz), 7.45 (1H, ddd, J = 8.4, 7.0, 1.5 Hz), 7.11 (1H, dd, J = 8.4, 1.1 Hz), 7.02 (1H, td, J = 7.6, 1.1 Hz), 4.64 (2H, br s), 3.85 (3H, s).
ESI-MS m/z:167[M+H]⁺. Example 132-2: Synthesis of 2-methoxybenzohydrazide
The compound obtained in Example 132-1 (1.048 g, 2.76 mmol) was dissolved in methanol (60 ml) and ethyl acetate (40 ml). 10% palladium on carbon (105 mg) was added. It stirred at room temperature under hydrogen atmosphere for 1 hour. After the reaction, the mixture was filtered through celite and the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 50 g, chloroform / methanol) to give the title compound (228 mg, 49.7%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.21 (1 H, br s), 7.67 (1 H, dd, J = 7.6, 1.5 Hz), 7.45 (1 H, ddd, J = 8.4, 7.0, 1.5 Hz), 7.11 (1 H, dd, J = 8.4, 1.1 Hz), 7.02 (1 H, td, J = 7.6, 1.1 Hz), 4.64 (2 H, br s), 3. 85 (3 H, s).
ESI-MS m / z: 167 [M + H] ⁺ .

実施例132-3：2-メトキシ-N'-(3-(トリメチルシリル)プロピオロイル)ベンゾヒドラジドの合成
3-(トリメチルシリル)プロピン酸(195 mg, 1.37 mmol)をジクロロメタン(4 ml)に溶解した。そこへオキサリルクロリド(0.123 ml, 1.44 mmol)、DMF(1滴)を加えて室温で2時間撹拌した。そこへ実施例132-2で得られた化合物(228 mg, 1.37 mmol)、トリエチルアミン(0.229 ml, 1.64 mmol)を加えて室温で一晩撹拌した。反応後、クロロホルムを加えて飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP Ultra 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(225 mg, 56.6%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.72 (1H, d, J = 0.6 Hz), 9.93 (1H, br s), 7.71 (1H, dd, J = 7.9, 1.8 Hz), 7.52 (1H, ddd, J = 8.6, 6.9, 1.4 Hz), 7.16 (1H, dd, J = 8.6, 0.9 Hz), 7.07-7.03 (1H, m), 3.87 (3H, s), 0.25 (9H, s).
ESI-MS m/z:291[M+H]⁺. Example 132-3: Synthesis of 2-methoxy-N '-(3- (trimethylsilyl) propionoyl) benzohydrazide
3- (Trimethylsilyl) propynoic acid (195 mg, 1.37 mmol) was dissolved in dichloromethane (4 ml). The oxalyl chloride (0.123 ml, 1.44 mmol) and DMF (1 drop) were added there, and it stirred at room temperature for 2 hours. The compound (228 mg, 1.37 mmol) obtained in Example 132-2 and a triethylamine (0.229 ml, 1.64 mmol) were added there, and it stirred at room temperature overnight. After the reaction, chloroform was added and washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP Ultra 25 g, hexane / ethyl acetate) to give the title compound (225 mg, 56.6%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.72 (1 H, d, J = 0.6 Hz), 9. 93 (1 H, br s), 7.71 (1 H, dd, J = 7.9, 1.8 Hz ), 7.52 (1H, ddd, J = 8.6, 6.9, 1.4 Hz), 7.16 (1H, dd, J = 8.6, 0.9 Hz), 7.07-7.03 (1H, m), 3.87 (3H, s), 0.25 (0.25) 9H, s).
ESI-MS m / z: 291 [M + H] ⁺ .

実施例132-4：2-(2-メトキシフェニル)-5-((トリメチルシリル)エチニル)-1,3,4-オキサジアゾールの合成
実施例132-3で得られた化合物(225 mg, 0.77 mmol)をジクロロメタン(4.5 ml)に溶解した。そこへメシルクロライド(0.125 ml, 1.62 mmol)、トリエチルアミン(0.622 ml, 4.47 mmol)を加えて室温で一晩撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP Ultra 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(51 mg, 24.3%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.89 (1H, dd, J = 7.8, 1.6 Hz), 7.64 (1H, ddd, J = 8.8, 7.8, 1.6 Hz), 7.29 (1H, dd, J = 8.8, 0.8 Hz), 7.14 (1H, td, J = 7.8, 0.8 Hz), 3.91 (3H, s), 0.33 (9H, s).
ESI-MS m/z:273[M+H]⁺. Example 132-4: Synthesis of 2- (2-methoxyphenyl) -5-((trimethylsilyl) ethynyl) -1,3,4-oxadiazole
The compound obtained in Example 132-3 (225 mg, 0.77 mmol) was dissolved in dichloromethane (4.5 ml). The mesyl chloride (0.125 ml, 1.62 mmol) and the triethylamine (0.622 ml, 4.47 mmol) were added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP Ultra 25 g, hexane / ethyl acetate) to give the title compound (51 mg, 24.3%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.89 (1 H, dd, J = 7.8, 1.6 Hz), 7.64 (1 H, ddd, J = 8.8, 7.8, 1.6 Hz), 7.29 (7 1 H, dd, J = 8.8, 0.8 Hz), 7.14 (1 H, td, J = 7.8, 0.8 Hz), 3.91 (3 H, s), 0.33 (9 H, s).
ESI-MS m / z: 273 [M + H] ⁺ .

実施例132-5：2-エチニル-5-(2-メトキシフェニル)-1,3,4-オキサジアゾールの合成
実施例132-4で得られた化合物(50 mg, 0.18 mmol)を用いて実施例7-2と同様の操作を行うことにより、標記の化合物(23 mg, 63.8%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.89 (1H, dd, J = 7.9, 1.5 Hz), 7.64 (1H, ddd, J = 8.8, 7.2, 1.5 Hz), 7.29 (1H, dd, J = 8.8, 1.1 Hz), 7.15 (1H, td, J = 7.9, 1.1 Hz), 5.35 (1H, s), 3.91 (3H, s).
ESI-MS m/z:201[M+H]⁺. Example 132-5: Synthesis of 2-ethynyl-5- (2-methoxyphenyl) -1,3,4-oxadiazole
The title compound (23 mg, 63.8%) was obtained as a white solid by the same procedure as in Example 7-2 using the compound (50 mg, 0.18 mmol) obtained in Example 132-4. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.89 (1 H, dd, J = 7.9, 1.5 Hz), 7.64 (1 H, ddd, J = 8.8, 7.2, 1.5 Hz), 7.29 ( 1H, dd, J = 8.8, 1.1 Hz), 7.15 (1 H, td, J = 7.9, 1.1 Hz), 5.35 (1 H, s), 3.91 (3 H, s).
ESI-MS m / z: 201 [M + H] ⁺ .

実施例132-6：2-(2-メトキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.132]の合成
3-ヨードピリジン(27 mg, 0.13 mmol)と実施例132-5で得られた化合物(22 mg, 0.11 mmol)を用いて実施例7-3と同様の操作を行うことにより、標記の化合物(5 mg, 16.4%)を淡黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, dd, J = 2.1, 0.7 Hz), 8.76 (1H, dd, J = 4.9, 1.7 Hz), 8.24 (1H, ddd, J = 8.0, 2.2, 1.7 Hz), 7.94 (1H, dd, J = 8.0, 1.7 Hz), 7.66 (1H, ddd, J = 8.9, 7.0, 1.4 Hz), 7.59 (1H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.31 (1H, dd, J = 8.6, 0.9 Hz), 7.17 (1H, td, J = 7.6, 0.9 Hz), 3.93 (3H, s).
ESI-MS m/z:278[M+H]⁺. Example 132-6: Synthesis of 2- (2-methoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 132]
The title compound was obtained by the same procedure as in Example 7-3 using 3-iodopyridine (27 mg, 0.13 mmol) and the compound obtained in Example 132-5 (22 mg, 0.11 mmol). 5 mg, 16.4%) were obtained as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, dd, J = 2.1, 0.7 Hz), 8. 76 (1 H, dd, J = 4.9, 1.7 Hz), 8.24 (1 H, 1 H, ddd, J = 8.0, 2.2, 1.7 Hz), 7.94 (1H, dd, J = 8.0, 1.7 Hz), 7.66 (1H, ddd, J = 8.9, 7.0, 1.4 Hz), 7.59 (1H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.31 (1 H, dd, J = 8.6, 0.9 Hz), 7.17 (1 H, td, J = 7.6, 0.9 Hz), 3.93 (3 H, s).
ESI-MS m / z: 278 [M + H] ⁺ .

製造例133：2-(5-ブロモ-2-メトキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.133]の合成
実施例133-1：メチル5-ブロモ-2-メトキシベンゾエートの合成
5-ブロモ-2-メトキシ安息香酸(942 mg, 4.08 mmol)をジクロロメタン(10 ml)に溶解した。そこへオキサリルクロリド(0.367 ml, 4.28 mmol)、DMF(2滴)を加えた。室温で1.5時間撹拌した。そこへメタノール(5 ml)を加えて室温で30分撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(903 mg, 90.3%)を無色油状物として得た。
ESI-MS m/z:246[M+H]⁺. Preparation Example 133 Synthesis of 2- (5-bromo-2-methoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 133] Example 133-1: Synthesis of methyl 5-bromo-2-methoxybenzoate
5-bromo-2-methoxybenzoic acid (942 mg, 4.08 mmol) was dissolved in dichloromethane (10 ml). Thereto, oxalyl chloride (0.367 ml, 4.28 mmol) and DMF (2 drops) were added. Stir at room temperature for 1.5 hours. Methanol (5 ml) was added there, and it stirred at room temperature for 30 minutes. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 10 g, hexane / ethyl acetate) to give the title compound (903 mg, 90.3%) as a colorless oil.
ESI-MS m / z: 246 [M + H] ⁺ .

実施例133-2：5-ブロモ-2-メトキシベンゾヒドラジドの合成
実施例133-1で得られた化合物(903 mg, 3.68 mmol)をエタノール(0.5 ml)に溶解した。そこへヒドラジン一水和物(0.536 ml, 11.04 mmol)を加えた。マイクロウェーブ照射下100℃で2時間撹拌した。反応後、沈殿物をろ過してエタノールで洗った。減圧乾燥することで標記の化合物(737 mg, 81.7%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.31 (1H, t, J = 3.7 Hz), 7.72 (1H, d, J = 2.7 Hz), 7.62 (1H, dd, J = 8.9, 2.7 Hz), 7.10 (1H, d, J = 8.9 Hz), 4.55 (2H, d, J = 4.6 Hz), 3.85 (3H, s).
ESI-MS m/z:245[M+H]⁺. Example 133-2 Synthesis of 5-bromo-2-methoxybenzohydrazide
The compound (903 mg, 3.68 mmol) obtained in Example 133-1 was dissolved in ethanol (0.5 ml). Hydrazine monohydrate (0.536 ml, 11.04 mmol) was added there. The mixture was stirred at 100 ° C. for 2 hours under microwave irradiation. After the reaction, the precipitate was filtered and washed with ethanol. Drying under reduced pressure gave the title compound (737 mg, 81.7%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.31 (1 H, t, J = 3.7 Hz), 7.72 (1 H, d, J = 2.7 Hz), 7.62 (1 H, dd, J = 8.9, 2.7 Hz), 7.10 (1 H, d, J = 8.9 Hz), 4.55 (2 H, d, J = 4.6 Hz), 3. 85 (3 H, s).
ESI-MS m / z: 245 [M + H] ⁺ .

実施例133-3：5-ブロモ-2-メトキシ-N'-(3-(トリメチルシリル)プロピオロイル)ベンズヒドラジドの合成
3-(トリメチルシリル)プロピン酸(427 mg, 3 mmol)と実施例133-2で得られた化合物(737 mg, 3 mmol)を用いて実施例132-3と同様の操作を行うことにより、標記の化合物(653 mg, 58.9%)を黄褐色固体として得た。
ESI-MS m/z:369[M+H]⁺. Example 133-3 Synthesis of 5-bromo-2-methoxy-N '-(3- (trimethylsilyl) propionoyl) benzhydrazide
By performing the same operation as in Example 132-3 using 3- (trimethylsilyl) propynoic acid (427 mg, 3 mmol) and the compound (737 mg, 3 mmol) obtained in Example 133-2 to give the title The compound of (653 mg, 58.9%) was obtained as a tan solid.
ESI-MS m / z: 369 [M + H] ⁺ .

実施例133-4：2-(5-ブロモ-2-メトキシフェニル)-5-((トリメチルシリル)エチニル)-1,3,4-オキサジアゾールの合成
実施例133-3で得られた化合物(653 mg, 1.77 mmol)をジクロロメタン(13 ml)に溶解した。そこへトシルクロライド(708 mg, 3.71 mmol)、トリエチルアミン(0.74 ml, 5.31 mmol)を加えた。室温で一晩撹拌した。反応後、クロロホルムを加えて飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP Ultra 50 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(549 mg, 88.3%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.99 (1H, d, J = 2.5 Hz), 7.81 (1H, dd, J = 8.9, 2.5 Hz), 7.27 (1H, d, J = 8.9 Hz), 3.91 (3H, s), 0.32 (9H, s).
ESI-MS m/z:351[M+H]⁺. Example 133-4 Synthesis of 2- (5-bromo-2-methoxyphenyl) -5-((trimethylsilyl) ethynyl) -1,3,4-oxadiazole
The compound obtained in Example 133-3 (653 mg, 1.77 mmol) was dissolved in dichloromethane (13 ml). Thereto were added tosyl chloride (708 mg, 3.71 mmol) and triethylamine (0.74 ml, 5.31 mmol). Stir at room temperature overnight. After the reaction, chloroform was added and washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP Ultra 50 g, hexane / ethyl acetate) to give the title compound (549 mg, 88.3%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.99 (1 H, d, J = 2.5 Hz), 7.81 (1 H, dd, J = 8.9, 2.5 Hz), 7.27 (1 H, d, J = 8.9 Hz), 3.91 (3 H, s), 0.32 (9 H, s).
ESI-MS m / z: 351 [M + H] ⁺ .

実施例133-5：2-(5-ブロモ-2-メトキシフェニル)-5-エチニル-1,3,4-オキサジアゾールの合成
実施例133-4で得られた化合物(548 mg, 1.56 mmol)を用いて実施例7-2と同様の操作を行うことにより、標記の化合物(255 mg, 58.6%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.99 (1H, d, J = 2.5 Hz), 7.82 (1H, dd, J = 8.9, 2.5 Hz), 7.28 (1H, d, J = 8.9 Hz), 5.37 (1H, s), 3.92 (3H, s).
ESI-MS m/z:279[M+H]⁺. Example 133-5: Synthesis of 2- (5-bromo-2-methoxyphenyl) -5-ethynyl-1,3,4-oxadiazole
The title compound (255 mg, 58.6%) was obtained as a white solid by the same procedure as in Example 7-2 using the compound (548 mg, 1.56 mmol) obtained in Example 133-4. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.99 (1 H, d, J = 2.5 Hz), 7.82 (1 H, dd, J = 8.9, 2.5 Hz), 7.28 (1 H, d, J = 8.9 Hz), 5.37 (1 H, s), 3.92 (3 H, s).
ESI-MS m / z: 279 [M + H] ⁺ .

実施例133-6：2-(5-ブロモ-2-メトキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.133]の合成
実施例133-5で得られた化合物(73 mg, 0.26 mmol)を用いて実施例132-6と同様の操作を行うことにより、標記の化合物(8 mg, 11.2%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, dd, J = 2.2, 0.8 Hz), 8.76 (1H, dd, J = 5.0, 1.7 Hz), 8.24 (1H, ddd, J = 7.9, 2.2, 1.7 Hz), 8.03 (1H, d, J = 2.6 Hz), 7.83 (1H, dd, J = 9.0, 2.6 Hz), 7.59 (1H, ddd, J = 8.0, 5.0, 0.9 Hz), 7.30 (1H, d, J = 9.0 Hz), 3.94 (3H, s).
ESI-MS m/z:356[M+H]⁺. Example 133-6: Synthesis of 2- (5-bromo-2-methoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 133]
The title compound (8 mg, 11.2%) was obtained as a yellow solid by the same procedure as in Example 132-6 using the compound (73 mg, 0.26 mmol) obtained in Example 133-5. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, dd, J = 2.2, 0.8 Hz), 8. 76 (1 H, dd, J = 5.0, 1.7 Hz), 8.24 (1 H, 1 H, ddd, J = 7.9, 2.2, 1.7 Hz), 8.03 (1 H, d, J = 2.6 Hz), 7. 83 (1 H, dd, J = 9.0, 2.6 Hz), 7.59 (1 H, ddd, J = 8.0, 5.0, 0.9 Hz), 7.30 (1 H, d, J = 9.0 Hz), 3.94 (3 H, s).
ESI-MS m / z: 356 [M + H] ⁺ .

製造例134：2-(5-ブロモ-2-(トリフルオロメチル)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.134]の合成
実施例134-1：メチル5-ブロモ-2-(トリフルオロメチル)ベンゾエートの合成
メチル5-ブロモ-2-ヨードベンゾエート(1.950 g, 5.72 mmol)をNMP(4.0 ml)に溶解した。そこへメチル2,2-ジフルオロ-2-(フルオロスルホニル)アセテート(1.09 ml, 8.58 mmol)、臭化銅(I)(99 mg, 0.69 mmol)を加えてsealed tubeで120℃一晩撹拌した。反応後、水を加えて酢酸エチルで抽出した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 100 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(1.214 g, 75.0%)を黄褐色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.08 (1H, dd, J = 1.5, 0.6 Hz), 8.03-7.99 (1H, m), 7.83 (1H, d, J = 8.5 Hz), 3.88 (3H, s).
ESI-MS m/z:283[M+H]⁺. Preparation Example 134 Synthesis Example of 2- (5-bromo-2- (trifluoromethyl) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 134] 134-1: Synthesis of methyl 5-bromo-2- (trifluoromethyl) benzoate
Methyl 5-bromo-2-iodobenzoate (1.950 g, 5.72 mmol) was dissolved in NMP (4.0 ml). Thereto, methyl 2,2-difluoro-2- (fluorosulfonyl) acetate (1.09 ml, 8.58 mmol) and copper (I) bromide (99 mg, 0.69 mmol) were added, and the mixture was stirred overnight at 120 ° C. in a sealed tube. After the reaction, water was added and extracted with ethyl acetate. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 100 g, hexane / ethyl acetate) to give the title compound (1.214 g, 75.0%) as a yellow-brown oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.08 (1 H, dd, J = 1.5, 0.6 Hz), 8.03-7.99 (1 H, m), 7.83 (1 H, d, J = 8.5 Hz), 3.88 (3H, s).
ESI-MS m / z: 283 [M + H] ⁺ .

実施例134-2：5-ブロモ-2-(トリフルオロメチル)-N'-(3-(トリメチルシリル)プロピオロイル)ベンズアヒドラジドの合成
実施例134-1で得られた化合物(1.214 g, 4.29 mmol)をエタノール(0.7 ml)に溶解した。そこへヒドラジン一水和物(0.624 ml, 12.87 mmol)を加えた。マイクロウェーブ照射下100℃で2時間撹拌した。反応後、溶媒を留去した。
3-(トリメチルシリル)プロピン酸(610 mg, 4.29 mmol)をジクロロメタン(6 ml)に溶解した。そこへオキサリルクロリド(0.386 ml, 4.50 mmol)、DMF(2滴)を加えて室温で2時間撹拌した。そこへ上記で合成したヒドラジド、トリエチルアミン(0.658 ml, 4.72 mmol)を加えて室温で一晩撹拌した。反応後、クロロホルムを加えて飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP Ultra 50 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(439 mg, 25.1%)を白色固体として得た。
ESI-MS m/z:407[M+H]⁺. Example 134-2 Synthesis of 5-bromo-2- (trifluoromethyl) -N '-(3- (trimethylsilyl) propionoyl) benzhydrazide
The compound obtained in Example 134-1 (1.214 g, 4.29 mmol) was dissolved in ethanol (0.7 ml). Hydrazine monohydrate (0.624 ml, 12.87 mmol) was added there. The mixture was stirred at 100 ° C. for 2 hours under microwave irradiation. After the reaction, the solvent was distilled off.
3- (Trimethylsilyl) propynoic acid (610 mg, 4.29 mmol) was dissolved in dichloromethane (6 ml). The oxalyl chloride (0.386 ml, 4.50 mmol) and DMF (2 drops) were added there, and it stirred at room temperature for 2 hours. The hydrazide and the triethylamine (0.658 ml, 4.72 mmol) which were synthesize | combined above were added there, and it stirred at room temperature overnight. After the reaction, chloroform was added and washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP Ultra 50 g, hexane / ethyl acetate) to give the title compound (439 mg, 25.1%) as a white solid.
ESI-MS m / z: 407 [M + H] ⁺ .

実施例134-3：2-(5-ブロモ-2-(トリフルオロメチル)フェニル)-5-((トリメチルシリル)エチニル)-1,3,4-オキサジアゾールの合成
実施例134-2で得られた化合物(439 mg, 1.08 mmol)を用いて実施例133-4と同様の操作を行うことにより、標記の化合物(447 mg, quant.)を白色固体として得た。 Example 134-3: Synthesis of 2- (5-bromo-2- (trifluoromethyl) phenyl) -5-((trimethylsilyl) ethynyl) -1,3,4-oxadiazole
The title compound (447 mg, quant.) Was obtained as a white solid by the same procedure as in Example 133-4 using the compound (439 mg, 1.08 mmol) obtained in Example 134-2. .

実施例134-4：2-(5-ブロモ-2-(トリフルオロメチル)フェニル)-5-エチニル-1,3,4-オキサジアゾールの合成
実施例134-3で得られた化合物(447 mg, 1.15 mmol)を用いて実施例7-2と同様の操作を行うことにより、標記の化合物(328 mg, 90.0%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.30 (1H, d, J = 2.1 Hz), 8.15 (1H, dq, J = 8.5, 0.9 Hz), 7.99 (1H, d, J = 8.5 Hz), 5.47 (1H, s).
ESI-MS m/z:317[M+H]⁺. Example 134-4 Synthesis of 2- (5-bromo-2- (trifluoromethyl) phenyl) -5-ethynyl-1,3,4-oxadiazole
The title compound (328 mg, 90.0%) was obtained as a yellow solid by the same procedure as in Example 7-2 using the compound (447 mg, 1.15 mmol) obtained in Example 134-3. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.30 (1 H, d, J = 2.1 Hz), 8.15 (1 H, dq, J = 8.5, 0.9 Hz), 7.99 (1 H, d, J = 8.5 Hz), 5.47 (1 H, s).
ESI-MS m / z: 317 [M + H] ⁺ .

実施例134-5：2-(5-ブロモ-2-(トリフルオロメチル)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.134]の合成
実施例134-4で得られた化合物(328 mg, 1.03 mmol)を用いて実施例132-6と同様の操作を行うことにより、標記の化合物(4 mg, 1.2%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.99 (1H, s), 8.77 (1H, s), 8.34 (1H, s), 8.27-8.24 (1H, m), 8.16 (1H, d, J = 6.2 Hz), 8.01-7.99 (1H, m), 7.62-7.57 (1H, m).
ESI-MS m/z:394[M+H]⁺. Example 134-5: Synthesis of 2- (5-bromo-2- (trifluoromethyl) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 134]
The title compound (4 mg, 1.2%) was obtained as a white solid by the same procedure as in Example 132-6 using the compound (328 mg, 1.03 mmol) obtained in Example 134-4. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.99 (1 H, s), 8.77 (1 H, s), 8.34 (1 H, s), 8.27-8.24 (1 H, m), 8.16 (1 H, s) 1 H, d, J = 6.2 Hz), 8.01-7.99 (1 H, m), 7.62-7.57 (1 H, m).
ESI-MS m / z: 394 [M + H] ⁺ .

製造例135：2-(ピリジン-3-イルエチニル)-5-(2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾール[化合物No.135]の合成
実施例135-1：メチル2-(トリフルオロメトキシ)ベンゾエートの合成
2-(トリフルオロメトキシ)安息香酸(2.160 g, 10.48 mmol)をジクロロメタン(22 ml)に溶解した。そこへオキサリルクロリド(0.944 ml, 11.00 mmol)、DMF(2滴)を加えて室温で2時間撹拌した。そこへメタノール(10 ml)を加えた。反応後、飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去し、標記の化合物(2.607 g, quant.)を無色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.95 (1H, dd, J = 7.8, 1.8 Hz), 7.76 (1H, ddd, J = 8.8, 7.0, 1.3 Hz), 7.58-7.52 (2H, m), 3.86 (3H, s).
ESI-MS m/z:221[M+H]⁺. Preparation Example 135 Synthesis of 2- (Pyridin-3-ylethynyl) -5- (2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole [Compound No. 135] Example 135-1 Synthesis of methyl 2- (trifluoromethoxy) benzoate
2- (Trifluoromethoxy) benzoic acid (2.160 g, 10.48 mmol) was dissolved in dichloromethane (22 ml). The oxalyl chloride (0.944 ml, 11.00 mmol) and DMF (2 drops) were added there, and it stirred at room temperature for 2 hours. Methanol (10 ml) was added there. After the reaction, it was washed with saturated aqueous sodium bicarbonate solution. The extract was dried over magnesium sulfate and the solvent was evaporated to give the title compound (2.607 g, quant.) As a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.95 (1 H, dd, J = 7.8, 1.8 Hz), 7.76 (1 H, ddd, J = 8.8, 7.0, 1.3 Hz), 7.58 7.52 (2H, m), 3.86 (3H, s).
ESI-MS m / z: 221 [M + H] ⁺ .

実施例135-2：2-(トリフルオロメトキシ)ベンゾヒドラジドの合成
実施例135-1で得られた化合物(2.607 g, 10.48 mmol)をエタノール(26 ml)に溶解した。そこへヒドラジン一水和物(5.09 ml, 104.8 mmol)を加えて3時間加熱還流した。反応後、溶媒を留去した。クロロホルム/メタノール溶液に溶解し、飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去し、標記の化合物(2.063 g, 79.1%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.59 (1H, br s), 7.58 (1H, ddd, J = 8.7, 6.9, 1.5 Hz), 7.52 (1H, dd, J = 7.6, 1.5 Hz), 7.46 (1H, t, J = 3.8 Hz), 7.43 (1H, tt, J = 4.7, 1.9 Hz), 4.50 (2H, d, J = 4.6 Hz).
ESI-MS m/z:221[M+H]⁺. Example 135-2: Synthesis of 2- (trifluoromethoxy) benzohydrazide
The compound obtained in Example 135-1 (2.607 g, 10.48 mmol) was dissolved in ethanol (26 ml). Hydrazine monohydrate (5.09 ml, 104.8 mmol) was added there, and it heated and refluxed for 3 hours. After the reaction, the solvent was distilled off. It was dissolved in chloroform / methanol solution and washed with saturated saline. The extract was dried over magnesium sulfate and evaporated to give the title compound (2.063 g, 79.1%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.59 (1 H, br s), 7.58 (1 H, ddd, J = 8.7, 6.9, 1.5 Hz), 7.52 (1 H, dd, J = 7.6, 1.5 Hz), 7.46 (1 H, t, J = 3.8 Hz), 7.43 (1 H, tt, J = 4.7, 1.9 Hz), 4.50 (2 H, d, J = 4.6 Hz).
ESI-MS m / z: 221 [M + H] ⁺ .

実施例135-3：2-(トリフルオロメトキシ)-N'-(3-(トリメチルシリル)プロピオロイル)ベンゾヒドラジドの合成
3-(トリメチルシリル)プロピン酸(1.332 g, 9.37 mmol)をジクロロメタン(13 ml)に溶解した。そこへオキサリルクロリド(0.844 ml, 9.84 mmol)、DMF(2滴)を加えて室温で2時間撹拌した。そこへ実施例135-2で得られた化合物(2.063 g, 9.37 mmol)、トリエチルアミン(1.44 ml, 10.31 mmol)を加えて室温で一晩撹拌した。反応後、クロロホルムを加えて飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP Ultra 50 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(1.742 g, 54.0%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.75 (1H, br s), 10.43 (1H, br s), 7.67-7.58 (2H, m), 7.52-7.46 (2H, m), 0.25 (9H, s).
ESI-MS m/z:345[M+H]⁺. Example 135-3: Synthesis of 2- (trifluoromethoxy) -N '-(3- (trimethylsilyl) propionoyl) benzohydrazide
3- (trimethylsilyl) propynoic acid (1.332 g, 9.37 mmol) was dissolved in dichloromethane (13 ml). The oxalyl chloride (0.844 ml, 9.84 mmol) and DMF (2 drops) were added there, and it stirred at room temperature for 2 hours. The compound (2.063 g, 9.37 mmol) obtained in Example 135-2 and triethylamine (1.44 ml, 10.31 mmol) were added thereto, and the mixture was stirred overnight at room temperature. After the reaction, chloroform was added and washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP Ultra 50 g, hexane / ethyl acetate) to give the title compound (1.742 g, 54.0%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.75 (1 H, br s), 10.43 (1 H, br s), 7.67-7.58 (2 H, m), 7.52-7.46 (2 H, m ), 0.25 (9H, s).
ESI-MS m / z: 345 [M + H] ⁺ .

実施例135-4：2-(2-(トリフルオロメトキシ)フェニル)-5-((トリメチルシリル)エチニル)-1,3,4-オキサジアゾールの合成
実施例135-3で得られた化合物(1.742 g, 5.06 mmol)を用いて実施例133-4と同様の操作を行うことにより、標記の化合物(2.358 g, quant.)を褐色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.16 (1H, dd, J = 8.1, 1.7 Hz), 7.82 (1H, ddd, J = 8.8, 7.0, 1.7 Hz), 7.68-7.66 (2H, m), 0.33 (9H, s).
ESI-MS m/z:327[M+H]⁺. Example 135-4 Synthesis of 2- (2- (trifluoromethoxy) phenyl) -5-((trimethylsilyl) ethynyl) -1,3,4-oxadiazole
The title compound (2.358 g, quant.) Was obtained as a brown oil by the same procedure as that of Example 133-4 using the compound (1.742 g, 5.06 mmol) obtained in Example 135-3. The
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.16 (1 H, dd, J = 8.1, 1.7 Hz), 7.82 (1 H, ddd, J = 8.8, 7.0, 1.7 Hz), 7.68 7.66 (2H, m), 0.33 (9H, s).
ESI-MS m / z: 327 [M + H] ⁺ .

実施例135-5：2-エチニル-5-(2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾールの合成
実施例135-4で得られた化合物(2.385 g, 5.06 mmol)を用いて実施例7-2と同様の操作を行うことにより、標記の化合物(1.867 g, quant.)を褐色油状物として得た。
ESI-MS m/z:255[M+H]⁺. Example 135-5: Synthesis of 2-ethynyl-5- (2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole
The title compound (1.867 g, quant.) Was obtained as a brown oil by the same procedure as in Example 7-2 using the compound (2.385 g, 5.06 mmol) obtained in Example 135-4. The
ESI-MS m / z: 255 [M + H] ⁺ .

実施例135-6：2-(ピリジン-3-イルエチニル)-5-(2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾール[化合物No.135]の合成
実施例135-5で得られた化合物(312 mg, 1.23 mmol)を用いて実施例132-6と同様の操作を行うことにより、標記の化合物(24 mg, 7.7%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, br s), 8.77 (1H, d, J = 4.4 Hz), 8.25 (1H, dt, J = 8.0, 1.9 Hz), 8.20 (1H, dd, J = 8.1, 1.7 Hz), 7.84 (1H, ddd, J = 8.8, 7.0, 1.4 Hz), 7.70 (2H, d, J = 7.3 Hz), 7.59 (1H, dd, J = 7.9, 4.9 Hz).
ESI-MS m/z:332[M+H]⁺. Example 135-6: Synthesis of 2- (Pyridin-3-ylethynyl) -5- (2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole [Compound No. 135]
The title compound (24 mg, 7.7%) was obtained as a brown solid by performing the same procedure as in Example 132-6 using the compound (312 mg, 1.23 mmol) obtained in Example 135-5. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, br s), 8.77 (1 H, d, J = 4.4 Hz), 8.25 (1 H, dt, J = 8.0, 1.9 Hz ), 8.20 (1H, dd, J = 8.1, 1.7 Hz), 7.84 (1 H, ddd, J = 8.8, 7.0, 1.4 Hz), 7.70 (2 H, d, J = 7.3 Hz), 7.59 (1 H, dd, J = 7.9, 4.9 Hz).
ESI-MS m / z: 332 [M + H] ⁺ .

製造例136：2-(2-エチルフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.136]の合成
実施例136-1：2-エチルベンゾヒドラジドの合成
2-エチニル安息香酸(1.0 g, 6.66 mmol)のメタノール(30 ml)中に、濃塩酸(202 μl, 6.66 mmol)を室温下、滴下した。アルゴン置換した後、還流条件下一晩加熱撹拌した。減圧下濃縮乾固した後、エタノール(1 ml)に溶解し、ヒドラジン一水和物(969 μl, 19.98 mmol)を添加した。マイクロウェーブ照射下、100℃で2時間撹拌した。さらにヒドラジン一水和物(969 μl, 19.98 mmol)を添加し、マイクロウェーブ照射下、100℃で2時間撹拌した。減圧下濃縮乾固した後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記の化合物(783 mg, 72 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.40 (1H, s), 7.39-7.31 (1H, m), 7.31-7.17 (3H, m), 4.44 (2H, s), 2.68 (2H, q, J = 7.6 Hz), 1.13 (3H, t, J = 7.6 Hz).
ESI-MS m/z:165[M+H]⁺. Preparation Example 136 Synthesis of 2- (2-ethylphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 136] Example 136-1: 2-ethylbenzo Hydrazide synthesis
Concentrated hydrochloric acid (202 μl, 6.66 mmol) was added dropwise to methanol (30 ml) of 2-ethynylbenzoic acid (1.0 g, 6.66 mmol) at room temperature. After argon substitution, the mixture was heated and stirred overnight under reflux conditions. After concentration to dryness under reduced pressure, the residue was dissolved in ethanol (1 ml) and hydrazine monohydrate (969 μl, 19.98 mmol) was added. The mixture was stirred at 100 ° C. for 2 hours under microwave irradiation. Additional hydrazine monohydrate (969 μl, 19.98 mmol) was added and stirred at 100 ° C. for 2 hours under microwave irradiation. After concentration to dryness under reduced pressure, saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (783 mg, 72%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.40 (1 H, s), 7.39-7.31 (1 H, m), 7.31-7.17 (3 H, m), 4.44 (2 H, s), 2.68 (2H, q, J = 7.6 Hz), 1.13 (3H, t, J = 7.6 Hz).
ESI-MS m / z: 165 [M + H] ⁺ .

実施例136-2：2-エチル-N'-(3-(トリメチルシリル)プロピオロイル)ベンゾヒドラジドの合成
3-(トリメチルシリル)プロピン酸(678 mg, 4.77 mmol)のクロロホルム (10 ml)溶液中に、オキサリルクロリド(438 μl, 5.01 mmol)をアルゴン雰囲気下、室温で滴下した。さらにDMF(4 μl, 0.05 mmol)を滴下し、2時間撹拌した。実施例136-1で得られた化合物(783 mg, 4.77 mmol)、トリエチルアミン(731 μl, 5.25 mmol)を添加し、さらに2時間撹拌した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物(770 mg, 56 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.61 (1H, s), 10.19 (1H, s), 7.48-7.22 (4H, m), 2.81-2.65 (2H, m), 1.24-1.08 (3H, m), 0.25 (9H, s).
ESI-MS m/z:289[M+H]⁺. Example 136-2: Synthesis of 2-ethyl-N '-(3- (trimethylsilyl) propionoyl) benzohydrazide
Oxalyl chloride (438 μl, 5.01 mmol) was dropped into a solution of 3- (trimethylsilyl) propynoic acid (678 mg, 4.77 mmol) in chloroform (10 ml) at room temperature under an argon atmosphere. Further, DMF (4 μl, 0.05 mmol) was added dropwise and stirred for 2 hours. The compound (783 mg, 4.77 mmol) obtained in Example 136-1 and triethylamine (731 μl, 5.25 mmol) were added, and the mixture was further stirred for 2 hours. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (770 mg, 56%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.61 (1H, s), 10.19 (1H, s), 7.48-7.22 (4H, m), 2.81-2.65 (2H, m), 1.24-1.08 (3H, m), 0.25 (9H, s).
ESI-MS m / z: 289 [M + H] ⁺ .

実施例136-3：2-(2-エチルフェニル)-5-エチニル-1,3,4-オキサジアゾールの合成
実施例136-2で得られた化合物(770 mg, 2.67 mmol)のクロロホルム (15 ml)溶液に、パラトシル酸クロライド一水和物(1.069 g, 5.61 mmol)、トリエチルアミン(1.12 ml, 8.01 mmol)をアルゴン雰囲気下、室温で添加した。一晩撹拌した後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のメタノール(10 ml)、クロロホルム(10 ml)混合溶液中に、炭酸カリウム(443 mg, 3.20 mmol)をアルゴン雰囲気下、室温で添加した。30分撹拌した後、さらに炭酸カリウム(443 mg, 3.20 mmol)を添加した。30分撹拌した後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物(410 mg, 77 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.89 (1H, d, J = 7.8 Hz), 7.59 (1H, dd, J = 7.8, 1.2 Hz), 7.50 (1H, d, J = 7.8 Hz), 7.44 (1H, dd, J = 7.8, 1.2 Hz), 5.38 (1H, s), 3.03 (2H, q, J = 7.6 Hz), 1.20 (3H, t, J = 7.6 Hz).
ESI-MS m/z:199[M+H]⁺. Example 136-3: Synthesis of 2- (2-ethylphenyl) -5-ethynyl-1,3,4-oxadiazole
A solution of the compound (770 mg, 2.67 mmol) obtained in Example 136-2 in chloroform (15 ml) was added with paratosylate chloride monohydrate (1.069 g, 5.61 mmol) and triethylamine (1.12 ml, 8.01 mmol). It was added at room temperature under argon atmosphere. After stirring overnight, saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Potassium carbonate (443 mg, 3.20 mmol) was added to a mixed solution of the residue in methanol (10 ml) and chloroform (10 ml) at room temperature under an argon atmosphere. After stirring for 30 minutes, more potassium carbonate (443 mg, 3.20 mmol) was added. After stirring for 30 minutes, saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (410 mg, 77%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.89 (1 H, d, J = 7.8 Hz), 7.59 (1 H, dd, J = 7.8, 1.2 Hz), 7.50 (1 H, d, J = 7.8 Hz), 7.44 (1 H, dd, J = 7.8, 1.2 Hz), 5.38 (1 H, s), 3.03 (2 H, q, J = 7.6 Hz), 1.20 (3 H, t, J = 7.6 Hz) .
ESI-MS m / z: 199 [M + H] ⁺ .

実施例136-4：2-(2-エチニルフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.136]の合成
実施例136-3で得られた化合物(58 mg, 0.29 mmol)を用いて実施例132-6と同様の操作を行うことにより、標記の化合物(9 mg, 13 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, br s), 8.76 (1H, br s), 8.24 (1H, d, J = 7.8 Hz), 7.93 (1H, d, J = 7.8 Hz), 7.63-7.56 (2H, m), 7.51 (1H, d, J = 6.9 Hz), 7.46-7.44 (1H, m), 3.07 (2H, q, J = 7.5 Hz), 1.22 (3H, t, J = 7.5 Hz).
ESI-MS m/z:276[M+H]⁺. Example 136-4 Synthesis of 2- (2-ethynylphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 136]
The title compound (9 mg, 13%) was obtained by the same procedure as that of Example 132-6 using the compound (58 mg, 0.29 mmol) obtained in Example 136-3.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, br s), 8. 76 (1 H, br s), 8.24 (1 H, d, J = 7.8 Hz), 7.93 (1 H, d, J = 7.8 Hz), 7.63-7.56 (2H, m), 7.51 (1 H, d, J = 6.9 Hz), 7.46-7.44 (1 H, m), 3.07 (2 H, q, J = 7.5 Hz), 1.22 (3H, t, J = 7.5 Hz).
ESI-MS m / z: 276 [M + H] ⁺ .

製造例137：2-(ピリジン-3-イルエチニル)-5-(2-(トリフルオロメチル)フェニル)-1,3,4-オキサジアゾール[化合物No.137]の合成
実施例137-1：メチル2-(トリフルオロメチル)ベンゾエートの合成
2-(トリフルオロメチル)安息香酸(2.025 g, 10.65 mmol)をジクロロメタン(20 ml)に溶解した。そこへオキサリルクロリド(0.959 ml, 11.18 mmol)、DMF(2滴)を加えて室温で2時間撹拌した。そこへメタノール(10 ml)を加えた。反応後、飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去し、標記の化合物(2.064 g, 94.9%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.90-7.78 (4H, m), 3.87 (3H, s). Preparation Example 137 Synthesis of 2- (Pyridin-3-ylethynyl) -5- (2- (trifluoromethyl) phenyl) -1,3,4-oxadiazole [Compound No. 137] Example 137-1: Synthesis of methyl 2- (trifluoromethyl) benzoate
2- (trifluoromethyl) benzoic acid (2.025 g, 10.65 mmol) was dissolved in dichloromethane (20 ml). The oxalyl chloride (0.959 ml, 11.18 mmol) and DMF (2 drops) were added there, and it stirred at room temperature for 2 hours. Methanol (10 ml) was added there. After the reaction, it was washed with saturated aqueous sodium bicarbonate solution. The extract was dried over magnesium sulfate and the solvent was evaporated to give the title compound (2.064 g, 94.9%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.90-7.78 (4H, m), 3.87 (3H, s).

実施例137-2：2-(トリフルオロメチル)ベンゾヒドラジドの合成
実施例137-1で得られた化合物(853 mg, 4.18 mmol)をエタノール(2 ml)に溶解した。そこへヒドラジン一水和物(1.22 ml, 25.07 mmol)を加えて3時間加熱還流した。反応後、溶媒を留去した。クロロホルム/メタノール溶液に溶解し、飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去し、標記の化合物(288 mg, 33.8%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.60 (1H, br s), 7.78 (1H, dt, J = 7.8, 0.7 Hz), 7.73-7.69 (1H, m), 7.65 (1H, dtd, J = 10.1, 3.1, 2.1 Hz), 7.48 (1H, dt, J = 7.4, 0.7 Hz), 4.48 (2H, d, J = 4.0 Hz).
ESI-MS m/z:205[M+H]⁺. Example 137-2 Synthesis of 2- (trifluoromethyl) benzohydrazide
The compound (853 mg, 4.18 mmol) obtained in Example 137-1 was dissolved in ethanol (2 ml). The hydrazine monohydrate (1.22 ml, 25.07 mmol) was added there, and it heated and refluxed for 3 hours. After the reaction, the solvent was distilled off. It was dissolved in chloroform / methanol solution and washed with saturated saline. The extract was dried over magnesium sulfate and evaporated to give the title compound (288 mg, 33.8%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.60 (1 H, br s), 7.78 (1 H, dt, J = 7.8, 0.7 Hz), 7.73-7.69 (1 H, m), 7.65 (1H, dtd, J = 10.1, 3.1, 2.1 Hz), 7.48 (1 H, dt, J = 7.4, 0.7 Hz), 4.48 (2 H, d, J = 4.0 Hz).
ESI-MS m / z: 205 [M + H] ⁺ .

実施例137-3：2-(トリフルオロメチル)-N'-(3-(トリメチルシリル)プロピオロイル)ベンゾヒドラジドの合成
3-(トリメチルシリル)プロピン酸(200 mg, 1.41 mmol)をジクロロメタン(2 ml)に溶解した。そこへオキサリルクロリド(0.127 ml, 1.48 mmol)、DMF(1滴)を加えて室温で3時間撹拌した。そこへ実施例137-2で得られた化合物(288 mg, 1.41 mmol)、トリエチルアミン(0.216 ml, 1.55 mmol)を加えて室温で一晩撹拌した。反応後、クロロホルムを加えて飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(339 mg, 73.2%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.78 (1H, d, J = 1.2 Hz), 10.48 (1H, d, J = 1.2 Hz), 7.83 (1H, dd, J = 7.6, 0.6 Hz), 7.77 (1H, dd, J = 7.6, 0.8 Hz), 7.72 (1H, dd, J = 7.6, 0.6 Hz), 7.58 (1H, d, J = 7.6 Hz), 0.26 (9H, s).
ESI-MS m/z:329[M+H]⁺. Example 137-3: Synthesis of 2- (trifluoromethyl) -N '-(3- (trimethylsilyl) propionoyl) benzohydrazide
3- (Trimethylsilyl) propynoic acid (200 mg, 1.41 mmol) was dissolved in dichloromethane (2 ml). Thereto, oxalyl chloride (0.127 ml, 1.48 mmol) and DMF (1 drop) were added and stirred at room temperature for 3 hours. The compound (288 mg, 1.41 mmol) obtained in Example 137-2 and a triethylamine (0.216 ml, 1.55 mmol) were added there, and it stirred at room temperature overnight. After the reaction, chloroform was added and washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 10 g, hexane / ethyl acetate) to give the title compound (339 mg, 73.2%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.78 (1 H, d, J = 1.2 Hz), 10. 48 (1 H, d, J = 1.2 Hz), 7.83 (1 H, dd, J = 7.6, 0.6 Hz), 7.77 (1 H, dd, J = 7.6, 0.8 Hz), 7.72 (1 H, dd, J = 7.6, 0.6 Hz), 7.58 (1 H, d, J = 7.6 Hz), 0.26 (9 H, s).
ESI-MS m / z: 329 [M + H] ⁺ .

実施例137-4：2-エチニル-5-(2-(トリフルオロメチル)フェニル)-1,3,4-オキサジアゾールの合成
実施例137-3で得られた化合物(399 mg, 1.03 mmol)をジクロロメタン(7 ml)に溶解した。そこへトシルクロライド(413 mg, 2.17 mmol)、トリエチルアミン(0.431 ml, 3.09 mmol)を加えた。室温で一晩撹拌した。反応後、溶媒を留去した。これをメタノール(6 ml)、クロロホルム(6 ml)に溶解した。そこへ炭酸ナトリウム(142 mg, 1.03 mmol)を加えて室温で10分撹拌した。反応後、1 mol/l塩酸を加えた。クロロホルム抽出した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(438 mg, quant.)を無色油状物として得た。
ESI-MS m/z:239[M+H]⁺. Example 137-4: Synthesis of 2-ethynyl-5- (2- (trifluoromethyl) phenyl) -1,3,4-oxadiazole
The compound (399 mg, 1.03 mmol) obtained in Example 137-3 was dissolved in dichloromethane (7 ml). Thereto, tosyl chloride (413 mg, 2.17 mmol) and triethylamine (0.431 ml, 3.09 mmol) were added. Stir at room temperature overnight. After the reaction, the solvent was distilled off. This was dissolved in methanol (6 ml) and chloroform (6 ml). The sodium carbonate (142 mg, 1.03 mmol) was added there, and it stirred at room temperature for 10 minutes. After the reaction, 1 mol / l hydrochloric acid was added. Chloroform extracted. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 25 g, hexane / ethyl acetate) to give the title compound (438 mg, quant.) As a colorless oil.
ESI-MS m / z: 239 [M + H] ⁺ .

実施例137-5：2-(ピリジン-3-イルエチニル)-5-(2-(トリフルオロメチル)フェニル)-1,3,4-オキサジアゾール[化合物No.137]の合成
実施例137-4で得られた化合物(438 mg, 1.03 mmol)を用いて実施例132-6と同様の操作を行うことにより、標記の化合物(19 mg, 5.9%)を褐色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, d, J = 0.9 Hz), 8.77 (1H, dd, J = 4.7, 1.3 Hz), 8.25 (1H, ddd, J = 8.0, 2.1, 1.7 Hz), 8.14 (1H, dt, J = 5.3, 1.9 Hz), 8.08-8.06 (1H, m), 7.99-7.93 (2H, m), 7.59 (1H, ddd, J = 7.9, 4.9, 0.8 Hz).
ESI-MS m/z:316[M+H]⁺. Example 137-5: Synthesis of 2- (pyridin-3-ylethynyl) -5- (2- (trifluoromethyl) phenyl) -1,3,4-oxadiazole [Compound No. 137]
The title compound (19 mg, 5.9%) was obtained as a brown solid by the same procedure as in Example 132-6 using the compound (438 mg, 1.03 mmol) obtained in Example 137-4. .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, d, J = 0.9 Hz), 8.77 (1 H, dd, J = 4.7, 1.3 Hz), 8.25 (1 H, ddd, J = 8.0, 2.1, 1.7 Hz), 8.14 (1 H, dt, J = 5.3, 1.9 Hz), 8.08-8.06 (1 H, m), 7.99-7.93 (2 H, m), 7.59 (1 H, dd, J = 7.9, 4.9, 0.8 Hz).
ESI-MS m / z: 316 [M + H] ⁺ .

製造例138：2-(2-(ベンジルオキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.138]の合成
実施例138-1：2-メトキシベンゾヒドラジドの合成
2-メトキシ安息香酸(4 g, 26.3 mmol)のクロロホルム (50 ml)溶液に、アルゴン雰囲気下、室温でオキサリルクロリド(2.42 ml, 27.6 mmol)を滴下した。DMF(20 μl, 0.26 mmol)を滴下して2時間撹拌した。メタノール(25 ml)を滴下し、一晩撹拌した後、減圧下濃縮乾固した。残渣物のエタノール(4 ml)溶液にヒドラジン一水和物(3.83 ml, 79 mmol)を滴下し、マイクロウェーブ照射下、100℃で2時間撹拌した。減圧下濃縮乾固した後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記の化合物(4.16 g, 95 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.22 (1H, s), 7.68 (1H, d, J = 7.6 Hz), 7.46-7.44 (1H, m), 7.11 (1H, d, J = 8.2 Hz), 7.03-7.01 (1H, m), 4.53 (2H, s), 3.85 (3H, s).
ESI-MS m/z:167[M+H]⁺. Preparation Example 138 Synthesis of 2- (2- (benzyloxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 138] Example 138-1: 2 Of 2-methoxybenzohydrazide
To a solution of 2-methoxybenzoic acid (4 g, 26.3 mmol) in chloroform (50 ml) was dropwise added oxalyl chloride (2.42 ml, 27.6 mmol) at room temperature under an argon atmosphere. DMF (20 μl, 0.26 mmol) was added dropwise and stirred for 2 hours. Methanol (25 ml) was added dropwise, stirred overnight, and concentrated to dryness under reduced pressure. Hydrazine monohydrate (3.83 ml, 79 mmol) was added dropwise to a solution of the residue in ethanol (4 ml), and the mixture was stirred at 100 ° C. for 2 hours under microwave irradiation. After concentration to dryness under reduced pressure, saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (4.16 g, 95%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.22 (1 H, s), 7.68 (1 H, d, J = 7.6 Hz), 7.46-7.44 (1 H, m), 7.11 (1 H, d, J = 8.2 Hz), 7.03-7.01 (1 H, m), 4.53 (2 H, s), 3. 85 (3 H, s).
ESI-MS m / z: 167 [M + H] ⁺ .

実施例138-2：エチニル N'-(2-メトキシベンゾイル)ホルモヒドラゾネートの合成
実施例138-1で得られた化合物(300 mg, 1.81 mmol)のオルトギ酸トリエチル(5 ml, 30.0 mmol)溶液を、アルゴン雰囲気下還流条件で3時間撹拌した。反応終了後、減圧下濃縮乾固した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物(314 mg, 78 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.04 (1H, s), 8.00 (1H, d, J = 7.8 Hz), 7.56-7.54 (1H, m), 7.23 (1H, d, J = 7.8 Hz), 7.13-7.09 (1H, m), 7.08 (1H, s), 4.24 (2H, q, J = 7.2 Hz), 3.99 (3H, s), 1.33 (3H, t, J = 7.2 Hz).
ESI-MS m/z:223[M+H]⁺. Example 138-2 Synthesis of ethynyl N '-(2-methoxybenzoyl) formohydrazonate
A solution of the compound (300 mg, 1.81 mmol) obtained in Example 138-1 in triethyl orthoformate (5 ml, 30.0 mmol) was stirred under reflux conditions for 3 hours under an argon atmosphere. After completion of the reaction, it was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (314 mg, 78%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.04 (1 H, s), 8.00 (1 H, d, J = 7.8 Hz), 7.56-7.54 (1 H, m), 7.23 (1 H, d, J = 7.8 Hz), 7.13-7.09 (1 H, m), 7.08 (1 H, s), 4. 24 (2 H, q, J = 7.2 Hz), 3.99 (3 H, s), 1.33 (3 H, t, J = 7.2 Hz).
ESI-MS m / z: 223 [M + H] ⁺ .

実施例138-3：2-(2-メトキシフェニル)-1,3,4-オキサジアゾールの合成
実施例138-2で得られた化合物(314 mg, 1.41 mmol)の2-ブタノール(5 ml)溶液中に、DBU(213 μl, 1.4 mmol)を滴下した。アルゴン雰囲気下、還流条件で一晩撹拌した後、反応終了後、減圧下濃縮乾固した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物(185 mg, 74 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.33 (1H, s), 7.85 (1H, d, J = 7.6 Hz), 7.64-7.60 (1H, m), 7.28 (1H, d, J = 8.7 Hz), 7.15-7.13 (1H, m), 3.90 (3H, s).
ESI-MS m/z:177[M+H]⁺. Example 138-3 Synthesis of 2- (2-methoxyphenyl) -1,3,4-oxadiazole
DBU (213 μl, 1.4 mmol) was dropped into a solution of the compound obtained in Example 138-2 (314 mg, 1.41 mmol) in 2-butanol (5 ml). After stirring under reflux conditions overnight under an argon atmosphere, after completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (185 mg, 74%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.33 (1 H, s), 7. 85 (1 H, d, J = 7.6 Hz), 7.64-7.60 (1 H, m), 7.28 (1 H, 1 d, J = 8.7 Hz), 7.15-7.13 (1 H, m), 3. 90 (3 H, s).
ESI-MS m / z: 177 [M + H] ⁺ .

実施例138-4：2-(1,3,4-オキサジアゾール-2-イル)フェノールの合成
実施例138-3で得られた化合物(100 mg, 0.57 mmol)のクロロホルム (10 ml)溶液中に、三臭化ホウ素(3.41 ml, 1M in クロロホルム)をアルゴン雰囲気下、-78℃で滴下した。室温に昇温し2時間撹拌した後、反応終了後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加えて中和し、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をフラッシュカラムクロマトグラフ法(ヘキサン/酢酸エチル)にて精製し、標記の化合物(92 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.31 (1H, s), 9.35 (1H, s), 7.80 (1H, d, J = 7.8 Hz), 7.47 (1H, dd, J = 8.7, 6.9 Hz), 7.09 (1H, d, J = 8.7 Hz), 7.02 (1H, dd, J = 7.8, 6.9 Hz).
ESI-MS m/z:163[M+H]⁺. Example 138-4 Synthesis of 2- (1,3,4-oxadiazol-2-yl) phenol
In a solution of the compound (100 mg, 0.57 mmol) obtained in Example 138-3 in chloroform (10 ml), boron tribromide (3.41 ml, 1 M in chloroform) was dropped at -78 ° C under an argon atmosphere. . The reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was neutralized with saturated brine and saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / ethyl acetate) to give the title compound (92 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.31 (1 H, s), 9.35 (1 H, s), 7.80 (1 H, d, J = 7.8 Hz), 7.47 (1 H, dd, J = 8.7, 6.9 Hz), 7.09 (1 H, d, J = 8.7 Hz), 7.02 (1 H, dd, J = 7.8, 6.9 Hz).
ESI-MS m / z: 163 [M + H] ⁺ .

実施例138-5：2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノールの合成
実施例138-4で得られた化合物(30 mg, 0.19 mmol)と実施例32-5で得られた化合物(67 mg, 0.37 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(12 mg, 25 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.48 (1H, s), 8.98 (1H, s), 8.75 (1H, d, J = 4.8 Hz), 8.24 (1H, d, J = 7.9 Hz), 7.86 (1H, d, J = 7.8 Hz), 7.59-7.57 (1H, m), 7.52-7.47 (1H, m), 7.11 (1H, d, J = 4.4 Hz), 7.05-7.01 (1H, m).
ESI-MS m/z:264[M+H]⁺. Example 138-5: Synthesis of 2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenol
Using the compound (30 mg, 0.19 mmol) obtained in Example 138-4 and the compound (67 mg, 0.37 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (12 mg, 25%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.48 (1 H, s), 8. 98 (1 H, s), 8. 75 (1 H, d, J = 4.8 Hz), 8.24 (1 H, d, J = 7.9 Hz), 7.86 (1 H, d, J = 7.8 Hz), 7.59-7.57 (1 H, m), 7.52-7.47 (1 H, m), 7.11 (1 H, d, J = 4.4 Hz), 7.05- 7.01 (1 H, m).
ESI-MS m / z: 264 [M + H] ⁺ .

実施例138-6：2-(2-(ベンジルオキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.138]の合成
実施例138-5で得られた化合物(50 mg, 0.19 mmol)のDMF(3.0 ml)溶液中に、炭酸セシウム(74 mg, 0.23 mmol)、(ブロモメチル)ベンゼン(50 μl, 0.42 mmol)を室温下添加した。アルゴン雰囲気下4時間撹拌した後、濃縮乾固した。残渣物に飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(52 mg, 77 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, br s), 8.77 (1H, dd, J = 5.0, 1.8 Hz), 8.23-8.20 (1H, m), 7.98 (1H, dd, J = 7.8, 1.8 Hz), 7.67-7.53 (4H, m), 7.42-7.36 (3H, m), 7.34-7.32 (1H, m), 7.20-7.18 (1H, m), 5.34 (2H, s).
ESI-MS m/z:354[M+H]⁺. Example 138-6 Synthesis of 2- (2- (benzyloxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 138]
Cesium carbonate (74 mg, 0.23 mmol), (bromomethyl) benzene (50 μl, 0.42 mmol) in a solution of the compound (50 mg, 0.19 mmol) obtained in Example 138-5 in DMF (3.0 ml) at room temperature The bottom was added. After stirring for 4 hours under argon atmosphere, it was concentrated to dryness. To the residue was added saturated brine and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (52 mg, 77%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, br s), 8.77 (1 H, dd, J = 5.0, 1.8 Hz), 8.23-8.20 (1 H, m), 7.98 (1H, dd, J = 7.8, 1.8 Hz), 7.67-7.53 (4H, m), 7.42-7.36 (3H, m), 7.34-7.32 (1 H, m), 7.20-7.18 (1 H, m), 5.34 (2H, s).
ESI-MS m / z: 354 [M + H] ⁺ .

製造例139：2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)ベンゾニトリル[化合物No.139]の合成
実施例139-1：2-(1,3,4-オキサジアゾール-2-イル)ベンゾニトリルの合成
2-シアノ安息香酸(149 mg, 1.01 mmol)をジクロロメタン(3 ml)に懸濁した。そこへ(イソシアノイミノ)トリフェニルホスホラン(305 mg, 1.01 mmol)のジクロロメタン溶液(6 ml)を加えて室温で一晩撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP Ultra 50 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(33 mg, 19.1%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.53 (1H, s), 8.22 (1H, dq, J = 7.8, 0.6 Hz), 8.13 (1H, dq, J = 7.8, 0.6 Hz), 7.95 (1H, td, J = 7.8, 1.3 Hz), 7.84 (1H, td, J = 7.8, 1.3 Hz).
ESI-MS m/z: 172[M+H]⁺. Preparation Example 139 Synthesis of 2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) benzonitrile [Compound No. 139] Example 139-1: 2- ( Synthesis of 1,3,4-Oxadiazol-2-yl) benzonitrile
2-Cyanobenzoic acid (149 mg, 1.01 mmol) was suspended in dichloromethane (3 ml). The dichloromethane solution (6 ml) of (isocyanoimino) triphenylphosphorane (305 mg, 1.01 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP Ultra 50 g, hexane / ethyl acetate) to give the title compound (33 mg, 19.1%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.53 (1 H, s), 8.22 (1 H, dq, J = 7.8, 0.6 Hz), 8.13 (1 H, dq, J = 7.8, 0.6 Hz), 7.95 (1 H, td, J = 7.8, 1.3 Hz), 7.84 (1 H, td, J = 7.8, 1.3 Hz).
ESI-MS m / z: 172 [M + H] ⁺ .

実施例139-2：2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)ベンゾニトリル[化合物No.139]の合成
実施例139-1で得られた化合物(33 mg, 0.19 mmol)と実施例32-5で得られた化合物(70 mg, 0.39 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(11 mg, 21.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.99 (1H, dd, J = 2.1, 0.7 Hz), 8.77 (1H, dd, J = 4.8, 1.6 Hz), 8.27-8.23 (2H, m), 8.15 (1H, dd, J = 7.8, 0.9 Hz), 7.97 (1H, td, J = 7.8, 1.3 Hz), 7.87 (1H, td, J = 7.7, 1.3 Hz), 7.60 (1H, ddd, J = 8.0, 4.8, 0.9 Hz).
ESI-MS m/z: 273[M+H]⁺. Example 139-2 Synthesis of 2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) benzonitrile [Compound No. 139]
Using the compound (33 mg, 0.19 mmol) obtained in Example 139-1 and the compound (70 mg, 0.39 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (11 mg, 21.3%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.99 (1 H, dd, J = 2.1, 0.7 Hz), 8.77 (1 H, dd, J = 4.8, 1.6 Hz), 8.27-8.23 (8 2H, m), 8.15 (1H, dd, J = 7.8, 0.9 Hz), 7.97 (1H, td, J = 7.8, 1.3 Hz), 7.87 (1H, td, J = 7.7, 1.3 Hz), 7.60 (1H , ddd, J = 8.0, 4.8, 0.9 Hz).
ESI-MS m / z: 273 [M + H] ⁺ .

製造例140：2-(2-((4-フルオロベンジル)オキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.140]の合成
実施例140-1：2-(2-((4-フルオロベンジル)オキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.140]の合成
実施例138-5で得られた化合物(30 mg, 0.11 mmol)のDMF(1.0 ml)溶液中に、炭酸セシウム(45 mg, 0.14 mmol)、1-(ブロモメチル)-4-フルオロベンゼン(31 μl, 0.25 mmol)を室温下添加した。アルゴン雰囲気下2時間撹拌した後、濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(41 mg, 97 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, dd, J = 2.3, 0.9 Hz), 8.76 (1H, dd, J = 4.8, 1.6 Hz), 8.21 (1H, dt, J = 8.1, 1.9 Hz), 7.98 (1H, dd, J = 7.8, 1.8 Hz), 7.69-7.56 (4H, m), 7.39 (1H, d, J = 7.8 Hz), 7.26-7.15 (3H, m), 5.32 (2H, s).
ESI-MS m/z:372[M+H]⁺. Preparation Example 140 Synthesis Example of 2- (2-((4-Fluorobenzyl) oxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 140] Synthesis of 140-1: 2- (2-((4-fluorobenzyl) oxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 140]
Cesium carbonate (45 mg, 0.14 mmol), 1- (bromomethyl) -4-fluorobenzene (31 μl) in a solution of the compound (30 mg, 0.11 mmol) obtained in Example 138-5 in DMF (1.0 ml) , 0.25 mmol) was added at room temperature. After stirring for 2 hours under an argon atmosphere, the solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (41 mg, 97%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, dd, J = 2.3, 0.9 Hz), 8.76 (1 H, dd, J = 4.8, 1.6 Hz), 8.21 (1 H, 1 H, dt, J = 8.1, 1.9 Hz), 7. 98 (1 H, dd, J = 7.8, 1.8 Hz), 7.69-7.56 (4 H, m), 7. 39 (1 H, d, J = 7.8 Hz), 7.26-7.15 (3 H) , m), 5.32 (2H, s).
ESI-MS m / z: 372 [M + H] ⁺ .

製造例141：2-(2-(シクロヘキシルメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.141]の合成
実施例141-1：2-(2-(シクロヘキシルメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.141]の合成
実施例138-5で得られた化合物(30 mg, 0.11 mmol)のDMF(1.0 ml)溶液中に、炭酸セシウム(45 mg, 0.14 mmol)、(ブロモメチル)シクロヘキサン(35 μl, 0.25 mmol)を室温下添加した。アルゴン雰囲気下3時間撹拌した後、さらに60℃で一晩加熱した。反応終了後、濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(23 mg, 56 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.92 (1H, d, J = 2.3 Hz), 8.76 (1H, dd, J = 4.8, 2.4 Hz), 8.19 (1H, d, J = 7.8 Hz), 7.96 (1H, dd, J = 7.8, 1.8 Hz), 7.65-7.57 (2H, m), 7.27 (1H, d, J = 7.8 Hz), 7.15-7.13 (1H, m), 3.97 (2H, d, J = 5.5 Hz), 1.90-1.68 (5H, m), 1.66-1.57 (1H, m), 1.33-1.10 (5H, m).
ESI-MS m/z:360[M+H]⁺. Preparation Example 14 Synthesis of 2- (2- (cyclohexylmethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 141] Example 141-1: 2 Synthesis of-(2- (Cyclohexylmethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 141]
Cesium carbonate (45 mg, 0.14 mmol), (bromomethyl) cyclohexane (35 μl, 0.25 mmol) in a solution of the compound obtained in Example 138-5 (30 mg, 0.11 mmol) in DMF (1.0 ml) at room temperature The bottom was added. After stirring for 3 hours under an argon atmosphere, the mixture was further heated at 60 ° C. overnight. After completion of the reaction, the mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (23 mg, 56%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.92 (1 H, d, J = 2.3 Hz), 8.76 (1 H, dd, J = 4.8, 2.4 Hz), 8.19 (1 H, d, J = 7.8 Hz), 7.96 (1 H, dd, J = 7.8, 1.8 Hz), 7.65-7.57 (2 H, m), 7.27 (1 H, d, J = 7.8 Hz), 7.15-7.13 (1 H, m), 3.97 (2H, d, J = 5.5 Hz), 1.90-1.68 (5H, m), 1.66-1.57 (1 H, m), 1.33-1.10 (5 H, m).
ESI-MS m / z: 360 [M + H] ⁺ .

製造例142：2-(2-フェノキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.142]の合成
実施例142-1：2-(2-フェノキシフェニル)-1,3,4-オキサジアゾールの合成
2-フェノキシ安息香酸(488 mg, 2.28 mmol)を用いて実施例139-1と同様の操作を行うことにより、標記の化合物(80 mg, 14.7%)を褐色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.33 (1H, s), 8.05 (1H, dd, J = 7.8, 1.8 Hz), 7.64 (1H, ddd, J = 8.7, 6.9, 1.4 Hz), 7.42-7.36 (4H, m), 7.16 (1H, dq, J = 11.4, 2.6 Hz), 7.10 (1H, dd, J = 8.2, 0.9 Hz), 7.04-7.01 (2H, m).
ESI-MS m/z: 239[M+H]⁺. Preparation Example 142: Synthesis of 2- (2-Phenoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 142] Example 142-1: 2- (2 Synthesis of (Phenoxyphenyl) -1,3,4-oxadiazole
The title compound (80 mg, 14.7%) was obtained as a brown oil by the same procedure as in Example 139-1 using 2-phenoxybenzoic acid (488 mg, 2.28 mmol).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.33 (1 H, s), 8.05 (1 H, dd, J = 7.8, 1.8 Hz), 7.64 (1 H, ddd, J = 8.7, 6.9 , 1.4 Hz), 7.42-7.36 (4 H, m), 7. 16 (1 H, dq, J = 11.4, 2.6 Hz), 7. 10 (1 H, dd, J = 8.2, 0.9 Hz), 7.04-7.01 (2 H, m) .
ESI-MS m / z: 239 [M + H] ⁺ .

実施例142-2：2-(2-フェノキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.142]の合成
実施例142-1で得られた化合物(80 mg, 0.34 mmol)と実施例32-5で得られた化合物(122 mg, 0.67 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(33 mg, 28.6%)を淡黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, dd, J = 2.2, 1.0 Hz), 8.74 (1H, dd, J = 5.0, 1.6 Hz), 8.21 (1H, ddd, J = 8.0, 2.2, 1.6 Hz), 8.11 (1H, dd, J = 8.0, 1.6 Hz), 7.66 (1H, ddd, J = 8.8, 7.0, 1.4 Hz), 7.57 (1H, ddd, J = 8.0, 5.0, 1.0 Hz), 7.45-7.37 (3H, m), 7.20 (1H, tt, J = 7.4, 1.0 Hz), 7.10-7.07 (3H, m).
ESI-MS m/z: 340[M+H]⁺. Example 142-2 Synthesis of 2- (2-phenoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 142]
Using the compound (80 mg, 0.34 mmol) obtained in Example 142-1 and the compound (122 mg, 0.67 mmol) obtained in Example 32-5, the same procedure as in Example 32-6 is performed. The title compound (33 mg, 28.6%) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, dd, J = 2.2, 1.0 Hz), 8.74 (1 H, dd, J = 5.0, 1.6 Hz), 8.21 (1 H, 1 H, ddd, J = 8.0, 2.2, 1.6 Hz), 8.11 (1 H, dd, J = 8.0, 1.6 Hz), 7.66 (1 H, ddd, J = 8.8, 7.0, 1.4 Hz), 7.57 (1 H, ddd, J = 8.0, 5.0, 1.0 Hz), 7.45-7.37 (3H, m), 7.20 (1H, tt, J = 7.4, 1.0 Hz), 7.10-7.07 (3H, m).
ESI-MS m / z: 340 [M + H] ⁺ .

製造例143：2-(3-(ベンジルオキシ)ピリジン-2-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.143]の合成
実施例143-1：メチル 3-ヒドロキシピコリネートの合成
3-ヒドロキシピコリン酸(1.0 g, 7.19 mmol)のメタノール(15 ml)溶液中に、濃硫酸(200 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記の化合物(250 mg, 23 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.56 (1H, d, J = 4.6 Hz), 7.83-7.81 (1H, m), 7.56 (1H, d, J = 7.9 Hz), 7.35-7.33 (1H, m), 4.69 (3H, s).
ESI-MS m/z:154[M+H]⁺. Production Example 143 Synthesis of 2- (3- (benzyloxy) pyridin-2-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 143] Example 143 -1: Synthesis of methyl 3-hydroxypicolinate
Concentrated sulfuric acid (200 μl) was added dropwise to a solution of 3-hydroxypicolinic acid (1.0 g, 7.19 mmol) in methanol (15 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (250 mg, 23%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.56 (1 H, d, J = 4.6 Hz), 7.83-7.81 (1 H, m), 7.56 (1 H, d, J = 7.9 Hz) , 7.35-7.33 (1H, m), 4.69 (3H, s).
ESI-MS m / z: 154 [M + H] ⁺ .

実施例143-2：メチル 3-(ベンジロキシ)ピコリネートの合成
実施例143-1で得られた化合物(250 mg, 1.63 mmol)のDMF(5.0 ml)溶液中に、炭酸セシウム(638 mg, 1.96 mmol)、(ブロモメチル)ベンゼン(427 μl, 3.59 mmol)を室温下添加した。アルゴン雰囲気下1時間撹拌した後、さらに70℃に加熱して2時間撹拌した。反応終了後、濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(397 mg, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.19 (1H, dd, J = 4.6, 0.9 Hz), 7.72 (1H, dd, J = 8.7, 1.4 Hz), 7.53 (1H, dd, J = 8.7, 4.6 Hz), 7.47-7.38 (4H, m), 7.36-7.30 (1H, m), 5.26 (2H, s), 3.84 (3H, s).
ESI-MS m/z:244[M+H]⁺. Example 143-2: Synthesis of methyl 3- (benzyloxy) picolinate
Cesium carbonate (638 mg, 1.96 mmol), (bromomethyl) benzene (427 μl, 3.59 mmol) in a solution of the compound (250 mg, 1.63 mmol) obtained in Example 143-1 in DMF (5.0 ml) at room temperature The bottom was added. After stirring for 1 hour under an argon atmosphere, the mixture was further heated to 70 ° C. and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (397 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.19 (1 H, dd, J = 4.6, 0.9 Hz), 7.72 (1 H, dd, J = 8.7, 1.4 Hz), 7.53 (1 H, dd, J = 8.7, 4.6 Hz), 7.47-7.38 (4 H, m), 7. 36-7. 30 (1 H, m), 5. 26 (2 H, s), 3. 84 (3 H, s).
ESI-MS m / z: 244 [M + H] ⁺ .

実施例143-3：2-(3-(ベンジルオキシ)ピリジン-2-イル)-1,3,4-オキサジアゾールの合成
実施例143-2で得られた化合物(492 mg, 2.02 mmol)のエタノール(5.0 ml)溶液中に、ヒドラジン一水和物(981 μl, 20 mmol)を滴下した。アルゴン雰囲気下、還流条件で2時間撹拌した後、反応終了後濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のオルトギ酸トリエチル(2.0 ml, 12.12 mmol)溶液中に、パラトシル酸一水和物(4 mg, 0.20 mmol)を滴下した。アルゴン雰囲気下、還流条件で2時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(385 mg, 75%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.42 (1H, br s), 8.42-8.32 (1H, m), 7.92-7.81 (1H, m), 7.70-7.59 (1H, m), 7.59-7.47 (2H, m), 7.47-7.24 (3H, m), 5.38 (2H, br s).
ESI-MS m/z:254[M+H]⁺. Example 143-3 Synthesis of 2- (3- (benzyloxy) pyridin-2-yl) -1,3,4-oxadiazole
Hydrazine monohydrate (981 μl, 20 mmol) was dropped into a solution of the compound (492 mg, 2.02 mmol) obtained in Example 143-2 in ethanol (5.0 ml). After stirring for 2 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To a solution of the residue in triethyl orthoformate (2.0 ml, 12.12 mmol), paratosylate monohydrate (4 mg, 0.20 mmol) was added dropwise. After stirring for 2 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (385 mg, 75%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.42 (1 H, br s), 8.42-8.32 (1 H, m), 7.92-7. m), 7.59-7.47 (2H, m), 7.47-7. 24 (3H, m), 5.38 (2H, br s).
ESI-MS m / z: 254 [M + H] ⁺ .

実施例143-4：2-(3-(ベンジルオキシ)ピリジン-2-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.143]の合成
実施例143-3で得られた化合物(50 mg, 0.19 mmol)と実施例32-5で得られた化合物(72 mg, 0.40 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(24 mg, 34 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, dd, J = 2.3, 0.9 Hz), 8.77 (1H, dd, J = 5.0, 1.8 Hz), 8.40 (1H, dd, J = 4.6, 1.4 Hz), 8.27-8.21 (1H, m), 7.90 (1H, dd, J = 8.7, 1.4 Hz), 7.68 (1H, dd, J = 8.7, 4.6 Hz), 7.62-7.55 (3H, m), 7.45-7.38 (2H, m), 7.37-7.31 (1H, m), 5.41 (2H, s).
ESI-MS m/z:355[M+H]⁺. Example 143-4 Synthesis of 2- (3- (benzyloxy) pyridin-2-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 143]
Using the compound (50 mg, 0.19 mmol) obtained in Example 143-3 and the compound (72 mg, 0.40 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (24 mg, 34%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, dd, J = 2.3, 0.9 Hz), 8.77 (1 H, dd, J = 5.0, 1.8 Hz), 8.40 (1 H, 1 H, dd, J = 4.6, 1.4 Hz), 8. 27-8. 21 (1 H, m), 7. 90 (1 H, dd, J = 8.7, 1.4 Hz), 7. 68 (1 H, dd, J = 8.7, 4.6 Hz), 7.62-7.55 (3H, m), 7.45-7.38 (2H, m), 7.37-7. 31 (1H, m), 5.41 (2H, s).
ESI-MS m / z: 355 [M + H] ⁺ .

製造例144：2-(2-(ベンジルオキシ)-5-クロロフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.144]の合成
実施例144-1：メチル 5-クロロ-2-ヒドロキシベンゾエートの合成
5-クロロ-2-ヒドロキシ安息香酸 (1.0 g, 5.79 mmol)のメタノール(15 ml)溶液中に、濃硫酸(200 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。標記の化合物(850 mg, 79 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.48 (1H, s), 7.72 (1H, d, J = 2.7 Hz), 7.55 (1H, dd, J = 8.7, 2.7 Hz), 7.03 (1H, d, J = 8.7 Hz), 3.88 (3H, s).
ESI-MS m/z:187[M+H]⁺. Production Example 144 Synthesis of 2- (2- (benzyloxy) -5-chlorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 144] Example 144- 1: Synthesis of methyl 5-chloro-2-hydroxybenzoate
Concentrated sulfuric acid (200 μl) was added dropwise to a solution of 5-chloro-2-hydroxybenzoic acid (1.0 g, 5.79 mmol) in methanol (15 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound (850 mg, 79%) was obtained.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.48 (1 H, s), 7.72 (1 H, d, J = 2.7 Hz), 7.55 (1 H, dd, J = 8.7, 2.7 Hz) , 7.03 (1H, d, J = 8.7 Hz), 3.88 (3H, s).
ESI-MS m / z: 187 [M + H] ⁺ .

実施例144-2：メチル 2-(ベンジルオキシ)-5-クロロベンゾエートの合成
実施例144-1で得られた化合物(850 mg, 4.56 mmol)のDMF(10 ml)溶液中に、炭酸セシウム(1.78 g, 5.47 mmol)、(ブロモメチル)ベンゼン(1.19 ml, 10.02 mmol)を室温下添加した。アルゴン雰囲気下1時間撹拌した後、さらに70℃に加熱して3時間撹拌した。反応終了後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(1.26 g, 100%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.68 (1H, d, J = 2.7 Hz), 7.59 (1H, dd, J = 8.5, 2.5 Hz), 7.49-7.45 (2H, m), 7.43-7.37 (2H, m), 7.35-7.30 (1H, m), 7.29-7.25 (1H, m), 5.22 (2H, s), 3.82 (3H, s).
ESI-MS m/z:277[M+H]⁺. Example 144-2: Synthesis of methyl 2- (benzyloxy) -5-chlorobenzoate
In a solution of the compound (850 mg, 4.56 mmol) obtained in Example 144-1 in DMF (10 ml), cesium carbonate (1.78 g, 5.47 mmol), (bromomethyl) benzene (1.19 ml, 10.02 mmol) at room temperature The bottom was added. After stirring for 1 hour under an argon atmosphere, the mixture was further heated to 70 ° C. and stirred for 3 hours. After completion of the reaction, saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.26 g, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.68 (1 H, d, J = 2.7 Hz), 7.59 (1 H, dd, J = 8.5, 2.5 Hz), 7.49-7.45 (2 H, 2 H, d m), 7.43-7.37 (2H, m), 7.35-7.30 (1H, m), 7.29-7.25 (1H, m), 5.22 (2H, s), 3.82 (3H, s).
ESI-MS m / z: 277 [M + H] ⁺ .

実施例144-3：2-(2-(ベンジルオキシ)-5-クロロフェニル)-1,3,4-オキサジアゾールの合成
実施例144-2で得られた化合物(1.44 g, 5.20 mmol)のエタノール(10 ml)溶液中に、ヒドラジン一水和物(2.52 ml, 52 mmol)を滴下した。アルゴン雰囲気下、還流条件で4時間撹拌した後、反応終了後濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のオルトギ酸トリエチル(5.20 ml, 31.2 mmol)溶液中に、パラトシル酸一水和物(10 mg, 0.52 mmol)を滴下した。アルゴン雰囲気下、還流条件で2時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(1.25 g, 84%)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.40 (1H, s), 7.89 (1H, d, J = 2.7 Hz), 7.70-7.64 (1H, m), 7.53-7.46 (2H, m), 7.43-7.36 (3H, m), 7.36-7.29 (1H, m), 5.32 (2H, s).
ESI-MS m/z:287[M+H]⁺. Example 144-3 Synthesis of 2- (2- (benzyloxy) -5-chlorophenyl) -1,3,4-oxadiazole
Hydrazine monohydrate (2.52 ml, 52 mmol) was dropped into a solution of the compound (1.44 g, 5.20 mmol) obtained in Example 144-2 in ethanol (10 ml). After stirring under reflux conditions for 4 hours under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Into a solution of the residue in triethyl orthoformate (5.20 ml, 31.2 mmol), paratosylate monohydrate (10 mg, 0.52 mmol) was added dropwise. After stirring for 2 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.25 g, 84%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.40 (1 H, s), 7.89 (1 H, d, J = 2.7 Hz), 7.70-7.64 (1 H, m), 7.53-7.46 ( 2H, m), 7.43-7.36 (3H, m), 7.36-7. 29 (1H, m), 5.32 (2H, s).
ESI-MS m / z: 287 [M + H] ⁺ .

実施例144-4：2-(2-(ベンジルオキシ)-5-クロロフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.144]の合成
実施例144-3で得られた化合物(100 mg, 0.35 mmol)と実施例32-5で得られた化合物(127 mg, 0.70 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(52 mg, 38 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, d, J = 1.4 Hz), 8.77 (1H, dd, J = 4.8, 1.6 Hz), 8.22 (1H, dt, J = 7.9, 1.9 Hz), 7.97 (1H, d, J = 2.7 Hz), 7.71 (1H, dd, J = 9.2, 2.7 Hz), 7.62-7.59 (1H, m), 7.54 (2H, d, J = 7.3 Hz), 7.45-7.37 (3H, m), 7.35-7.29 (1H, m), 5.36 (2H, s).
ESI-MS m/z:388[M+H]⁺. Example 144-4 Synthesis of 2- (2- (benzyloxy) -5-chlorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 144]
Using the compound (100 mg, 0.35 mmol) obtained in Example 144-3 and the compound (127 mg, 0.70 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (52 mg, 38%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, d, J = 1.4 Hz), 8.77 (1 H, dd, J = 4.8, 1.6 Hz), 8.22 (1 H, dt, J = 7.9, 1.9 Hz), 7.97 (1 H, d, J = 2.7 Hz), 7.71 (1 H, dd, J = 9.2, 2.7 Hz), 7.62-7.59 (1 H, m), 7.54 (2 H, d, J = 7.3 Hz), 7.45-7.37 (3 H, m), 7. 35-7. 29 (1 H, m), 5. 36 (2 H, s).
ESI-MS m / z: 388 [M + H] ⁺ .

製造例145：2-(2-(ベンジルオキシ)-5-フルオロフェニル)-5-(ピリジン-3-インエチニル)-1,3,4-オキサジアゾール[化合物No.145]の合成
実施例145-1：メチル 2-(ベンジルオキシ)-5-フルオロベンゾエートの合成
5-フルオロ-2-ヒドロキシ安息香酸(500 mg, 3.2 mmol)のメタノール(20 ml)溶液中に、濃硫酸(300 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のDMF(8 ml)溶液中に、炭酸セシウム(1.25 g, 3.80 mmol)、(ブロモメチル)ベンゼン(837 μl, 7.00 mmol)を室温下添加した。アルゴン雰囲気下70℃に加熱して2時間撹拌した。反応終了後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(631 mg, 76 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.51-7.45 (3H, m), 7.44-7.38 (3H, m), 7.35-7.30 (1H, m), 7.29-7.24 (1H, m), 5.19 (2H, s), 3.82 (3H, s).
ESI-MS m/z:261[M+H]⁺. Preparation Example 145 Synthesis Example of 2- (2- (benzyloxy) -5-fluorophenyl) -5- (pyridin-3-inethynyl) -1,3,4-oxadiazole [Compound No. 145] 145-1: Synthesis of methyl 2- (benzyloxy) -5-fluorobenzoate
Concentrated sulfuric acid (300 μl) was added dropwise to a solution of 5-fluoro-2-hydroxybenzoic acid (500 mg, 3.2 mmol) in methanol (20 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Cesium carbonate (1.25 g, 3.80 mmol) and (bromomethyl) benzene (837 μl, 7.00 mmol) were added to a solution of the residue in DMF (8 ml) at room temperature. The mixture was heated to 70 ° C. under an argon atmosphere and stirred for 2 hours. After completion of the reaction, saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (631 mg, 76%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.51-7.45 (3H, m), 7.44-7.38 (3H, m), 7.35-7.30 (1H, m), 7.29-7.24 (1H , m), 5.19 (2H, s), 3.82 (3H, s).
ESI-MS m / z: 261 [M + H] ⁺ .

実施例145-2：2-(2-(ベンジルオキシ)-5-フルオロフェニル)-1,3,4-オキサジアゾールの合成
実施例145-1で得られた化合物(631 mg, 2.42 mmol)のエタノール(5 ml)溶液中に、ヒドラジン一水和物(1.18 ml, 24 mmol)を滴下した。アルゴン雰囲気下、還流条件で1時間撹拌した後、反応終了後濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のオルトギ酸トリエチル(2.40 ml, 14.5 mmol)溶液中に、パラトシル酸一水和物(5 mg, 0.24 mmol)を滴下した。アルゴン雰囲気下、還流条件で一晩撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(346 mg, 53 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.40 (1H, s), 7.71 (1H, dd, J = 8.7, 3.2 Hz), 7.55-7.45 (3H, m), 7.44-7.36 (3H, m), 7.36-7.29 (1H, m), 5.29 (2H, s).
ESI-MS m/z:271[M+H]⁺. Example 145-2: Synthesis of 2- (2- (benzyloxy) -5-fluorophenyl) -1,3,4-oxadiazole
Hydrazine monohydrate (1.18 ml, 24 mmol) was dropped into a solution of the compound (631 mg, 2.42 mmol) obtained in Example 145-1 in ethanol (5 ml). After stirring for 1 hour under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The paratosilic acid monohydrate (5 mg, 0.24 mmol) was added dropwise to a solution of the residue in triethyl orthoformate (2.40 ml, 14.5 mmol). After stirring overnight under an argon atmosphere under reflux conditions, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (346 mg, 53%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.40 (1 H, s), 7.71 (1 H, dd, J = 8.7, 3.2 Hz), 7.55-7.45 (3 H, m), 7.44 7.36 (3H, m), 7.36-7.29 (1H, m), 5.29 (2H, s).
ESI-MS m / z: 271 [M + H] ⁺ .

実施例145-3：2-(2-(ベンジルオキシ)-5-フルオロフェニル)-5-(ピリジン-3-インエチニル)-1,3,4-オキサジアゾール[化合物No.145]の合成
実施例145-2で得られた化合物(100 mg, 0.37 mmol)と実施例32-5で得られた化合物(135 mg, 0.74 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(33 mg, 24 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97-8.94 (1H, m), 8.81-8.75 (1H, m), 8.24-8.19 (1H, m), 7.79 (1H, dd, J = 8.7, 3.2 Hz), 7.63-7.58 (1H, m), 7.58-7.51 (3H, m), 7.45-7.41 (1H, m), 7.41-7.36 (2H, m), 7.35-7.29 (1H, m), 5.33 (2H, s).
ESI-MS m/z:372[M+H]⁺. Example 145-3 Synthesis of 2- (2- (benzyloxy) -5-fluorophenyl) -5- (pyridin-3-inethynyl) -1,3,4-oxadiazole [Compound No. 145]
Using the compound (100 mg, 0.37 mmol) obtained in Example 145-2 and the compound (135 mg, 0.74 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (33 mg, 24%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97-8.94 (1 H, m), 8.81-8.75 (1 H, m), 8.24-8.19 (1 H, m), 7.79 (1 H, dd) , J = 8.7, 3.2 Hz), 7.63-7.58 (1H, m), 7.58-7.51 (3H, m), 7.45-7.41 (1H, m), 7.41-7.36 (2H, m), 7.35-7.29 (1H , m), 5.33 (2H, s).
ESI-MS m / z: 372 [M + H] ⁺ .

製造例146：2-(2-(ベンジルオキシ)-6-フルオロフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.146]の合成
実施例146-1：メチル 2-(ベンジルオキシ)-6-フルオロベンゾエートの合成
2-フルオロ-6-ヒドロキシ安息香酸(500 mg, 3.2 mmol)のメタノール(20 ml)溶液中に、濃硫酸(300 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のDMF(8 ml)溶液中に、炭酸セシウム(1.25 g, 3.80 mmol)、(ブロモメチル)ベンゼン(837 μl, 7.00 mmol)を室温下添加した。アルゴン雰囲気下70℃に加熱して2時間撹拌した。反応終了後、飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(577 mg, 69 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.52-7.44 (1H, m), 7.43-7.29 (5H, m), 7.06 (1H, d, J = 8.7 Hz), 6.95-6.89 (1H, m), 5.22 (2H, s), 3.84 (3H, s).
ESI-MS m/z:261[M+H]⁺. Preparation Example 146 Synthesis of 2- (2- (benzyloxy) -6-fluorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 146] Example 146 -1: Synthesis of methyl 2- (benzyloxy) -6-fluorobenzoate
Concentrated sulfuric acid (300 μl) was added dropwise to a solution of 2-fluoro-6-hydroxybenzoic acid (500 mg, 3.2 mmol) in methanol (20 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Cesium carbonate (1.25 g, 3.80 mmol) and (bromomethyl) benzene (837 μl, 7.00 mmol) were added to a solution of the residue in DMF (8 ml) at room temperature. The mixture was heated to 70 ° C. under an argon atmosphere and stirred for 2 hours. After completion of the reaction, saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (577 mg, 69%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.52 to 7.44 (1 H, m), 7.43-7.29 (5 H, m), 7.06 (1 H, d, J = 8.7 Hz), 6.95- 6.89 (1 H, m), 5.22 (2 H, s), 3. 84 (3 H, s).
ESI-MS m / z: 261 [M + H] ⁺ .

実施例146-2：2-(2-(ベンジルオキシ)-6-フルオロフェニル)-1,3,4-オキサジアゾールの合成
実施例146-1で得られた化合物(577 mg, 2.22 mmol)のエタノール(5 ml)溶液中に、ヒドラジン一水和物(1.08 ml, 22 mmol)を滴下した。アルゴン雰囲気下、還流条件で一晩撹拌した後、反応終了後濃縮乾固した。飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のオルトギ酸トリエチル(2.20 ml, 13.3 mmol)溶液中に、パラトシル酸一水和物(5 mg, 0.24 mmol)を滴下した。アルゴン雰囲気下、還流条件で一晩撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(109 mg, 18 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.48 (1H, s), 7.70-7.61 (1H, m), 7.45-7.28 (5H, m), 7.23-7.18 (1H, m), 7.10-7.00 (1H, m), 5.27 (2H, s).
ESI-MS m/z:271[M+H]⁺. EXAMPLE 146-2 Synthesis of 2- (2- (benzyloxy) -6-fluorophenyl) -1,3,4-oxadiazole
Hydrazine monohydrate (1.08 ml, 22 mmol) was dropped into a solution of the compound (577 mg, 2.22 mmol) obtained in Example 146-1 in ethanol (5 ml). After stirring overnight under an argon atmosphere under reflux conditions, the reaction was concentrated to dryness after completion of the reaction. Saturated brine was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The paratosilic acid monohydrate (5 mg, 0.24 mmol) was added dropwise to a solution of the residue in triethyl orthoformate (2.20 ml, 13.3 mmol). After stirring overnight under an argon atmosphere under reflux conditions, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (109 mg, 18%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.48 (1H, s), 7.70-7.61 (1H, m), 7.45-7.28 (5H, m), 7.23-7.18 (1H, m) ), 7.10-7.00 (1 H, m), 5. 27 (2 H, s).
ESI-MS m / z: 271 [M + H] ⁺ .

実施例146-3：2-(2-(ベンジルオキシ)-6-フルオロフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.146]の合成
実施例146-2で得られた化合物(109 mg, 0.40 mmol)と実施例32-5で得られた化合物(147 mg, 0.81 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(8 mg, 5 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, br s), 8.79-8.75 (1H, m), 8.25-8.21 (1H, m), 7.75-7.66 (1H, m), 7.62-7.58 (1H, m), 7.46-7.42 (2H, m), 7.41-7.35 (2H, m), 7.34-7.28 (1H, m), 7.24 (1H, d, J = 8.2 Hz), 7.11 (1H, t, J = 9.2 Hz), 5.32 (2H, s).
ESI-MS m/z:372[M+H]⁺. Example 146-3 Synthesis of 2- (2- (benzyloxy) -6-fluorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 146]
Using the compound (109 mg, 0.40 mmol) obtained in Example 146-2 and the compound (147 mg, 0.81 mmol) obtained in Example 32-5, the same operation as in Example 32-6 is performed. The title compound (8 mg, 5%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, br s), 8.79-8.75 (1 H, m), 8.25-8.21 (1 H, m), 7.75-7.66 (1 H, m), 7.62-7.58 (1 H, m), 7.46-7.42 (2 H, m), 7.41-7. 35 (2 H, m), 7.24-7. 28 (1 H, m), 7.24 (1 H, d, J = 8.2 Hz) , 7.11 (1 H, t, J = 9.2 Hz), 5.32 (2 H, s).
ESI-MS m / z: 372 [M + H] ⁺ .

製造例147：2-(2-(ピリジン-2-イルメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.147]の合成
実施例147-1：2-(2-(ピリジン-2-イルメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.147]の合成
実施例138-5で得られた化合物(50 mg, 0.19 mmol)のDMF(2.0 ml)溶液中に、炭酸セシウム(371 mg, 1.14 mmol)、2-(クロロメチル)ピリジン塩酸塩(63 mg, 0.38 mmol)を室温下添加した。アルゴン雰囲気下70℃で一晩撹拌した後、濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(20 mg, 30 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, s), 8.77 (1H, dd, J = 4.8, 1.6 Hz), 8.59-8.58 (1H, m), 8.23-8.21 (1H, m), 8.00 (1H, dd, J = 7.8, 1.4 Hz), 7.86-7.84 (1H, m), 7.79 (1H, d, J = 7.8 Hz), 7.69-7.57 (1H, m), 7.40 (1H, d, J = 8.2 Hz), 7.37-7.33 (1H, m), 7.23-7.19 (1H, m), 5.40 (2H, s).
ESI-MS m/z: 355[M+H]⁺. Preparation Example 147: Synthesis of 2- (2- (pyridin-2-ylmethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 147] Example 147- Synthesis of 1: 2- (2- (pyridin-2-ylmethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [compound No. 147]
In a solution of the compound (50 mg, 0.19 mmol) obtained in Example 138-5 in DMF (2.0 ml), cesium carbonate (371 mg, 1.14 mmol), 2- (chloromethyl) pyridine hydrochloride (63 mg, 0.38 mmol) was added at room temperature. After stirring overnight at 70 ° C. under an argon atmosphere, the solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (20 mg, 30%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, s), 8. 77 (1 H, dd, J = 4.8, 1.6 Hz), 8.59-8.58 (1 H, m), 8.23- 8.21 (1 H, m), 8.00 (1 H, dd, J = 7.8, 1.4 Hz), 7.86-7.84 (1 H, m), 7.79 (1 H, d, J = 7.8 Hz), 7.69 7.57 (1 H, m) , 7.40 (1H, d, J = 8.2 Hz), 7.37-7.33 (1H, m), 7.23-7.19 (1H, m), 5.40 (2H, s).
ESI-MS m / z: 355 [M + H] ⁺ .

製造例148：2-(ピリジン-3-イルエチニル)-5-(2-(チオフェン-2-イルメトキシ)フェニル)-1,3,4-オキサジアゾール[化合物No.148]の合成
実施例148-1：2-(ブロモメチル)チオフェンの合成
チオフェン-2-イルメタノール(249 μl, 2.63 mmol)のジクロロメタン(10 ml)溶液中に、トリフェニルホスフィン(827 mg, 3.15 mmol)、四臭化炭素(1.394 g, 4.20 mmol)をアルゴン雰囲気下、0℃で添加した。室温に昇温し、3時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(465 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.59 (1H, dd, J = 5.0, 1.4 Hz), 7.23 (1H, dd, J = 3.5, 1.4 Hz), 6.98 (1H, dd, J = 5.0, 3.5 Hz), 5.02 (2H, s). Preparation Example 148 Synthesis of 2- (Pyridin-3-ylethynyl) -5- (2- (thiophen-2-ylmethoxy) phenyl) -1,3,4-oxadiazole [Compound No. 148] Example 148- Synthesis of 1: 2-(bromomethyl) thiophene
Triphenylphosphine (827 mg, 3.15 mmol) and carbon tetrabromide (1.394 g, 4.20 mmol) in a solution of thiophen-2-ylmethanol (249 μl, 2.63 mmol) in dichloromethane (10 ml) under an argon atmosphere It was added at 0 ° C. The temperature was raised to room temperature and stirred for 3 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (465 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.59 (1 H, dd, J = 5.0, 1.4 Hz), 7.23 (1 H, dd, J = 3.5, 1.4 Hz), 6.98 (1 H, 1 H, dd, J = 5.0, 3.5 Hz), 5.02 (2H, s).

実施例148-2：2-(ピリジン-3-イルエチニル)-5-(2-(チオフェン-2-イルメトキシ)フェニル)-1,3,4-オキサジアゾール[化合物No.148]の合成
実施例138-5で得られた化合物(50 mg, 0.19 mmol)のDMF(2.0 ml)溶液中に、炭酸セシウム(74 mg, 0.23 mmol)、実施例148-1で得られた化合物(74 mg, 0.42 mmol)を室温下添加した。アルゴン雰囲気下70℃で一晩撹拌した後、濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(61 mg, 89 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, br s), 8.76 (1H, dd, J = 4.8, 1.6 Hz), 8.22-8.20 (1H, m), 7.95 (1H, dd, J = 7.8, 1.6 Hz), 7.68-7.63 (1H, m), 7.60 (1H, dd, J = 7.8, 4.8 Hz), 7.55 (1H, dd, J = 5.0, 1.4 Hz), 7.45 (1H, d, J = 10.0 Hz), 7.26-7.25 (1H, m), 7.21-7.19 (1H, m), 7.03 (1H, dd, J = 5.0, 3.2 Hz), 5.51 (2H, s).
ESI-MS m/z: 360[M+H]⁺. Example 148-2: Synthesis of 2- (pyridin-3-ylethynyl) -5- (2- (thiophen-2-ylmethoxy) phenyl) -1,3,4-oxadiazole [Compound No. 148]
In a solution of the compound (50 mg, 0.19 mmol) obtained in Example 138-5 in DMF (2.0 ml), cesium carbonate (74 mg, 0.23 mmol), the compound obtained in Example 148-1 (74 mg) , 0.42 mmol) was added at room temperature. After stirring overnight at 70 ° C. under an argon atmosphere, the solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (61 mg, 89%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, br s), 8. 76 (1 H, dd, J = 4.8, 1.6 Hz), 8.22-8.20 (1 H, m), 7.95 (1H, dd, J = 7.8, 1.6 Hz), 7.68-7.63 (1 H, m), 7.60 (1 H, dd, J = 7.8, 4.8 Hz), 7.55 (1 H, dd, J = 5.0, 1.4 Hz), 7.45 (1H, d, J = 10.0 Hz), 7.26-7.25 (1 H, m), 7.21-7.19 (1 H, m), 7.03 (1 H, dd, J = 5.0, 3.2 Hz), 5.51 (2 H, s) .
ESI-MS m / z: 360 [M + H] ⁺ .

製造例149：2-(3-(ベンジルオキシ)チオフェン-2-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.149]の合成
実施例149-1：メチル 3-(ベンジルオキシ)チオフェン-2-カルボキシレートの合成
メチル 3-ヒドロキシチオフェン-2-カルボキシレート(500 mg, 3.16 mmol)のDMF(8 ml)溶液中に、(ブロモメチル)ベンゼン(827 μl, 6.95 mmol)、炭酸カリウム(481 mg, 3.48 mmol)を添加した。70℃で3時間撹拌し、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(781 mg, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.82 (1H, d, J = 5.5 Hz), 7.49-7.44 (2H, m), 7.43-7.37 (2H, m), 7.36-7.30 (1H, m), 7.18 (1H, d, J = 5.5 Hz), 5.28 (2H, s), 3.74 (3H, s).
ESI-MS m/z:249[M+H]⁺. Preparation Example 149 Synthesis Example of 2- (3- (benzyloxy) thiophen-2-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 149] Example 149 -1: Synthesis of methyl 3- (benzyloxy) thiophene-2-carboxylate
(Bromomethyl) benzene (827 μl, 6.95 mmol) and potassium carbonate (481 mg, 3.48 mmol) were added to a solution of methyl 3-hydroxythiophene-2-carboxylate (500 mg, 3.16 mmol) in DMF (8 ml) did. The mixture was stirred at 70 ° C. for 3 hours and concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (781 mg, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.82 (1 H, d, J = 5.5 Hz), 7.49-7.44 (2 H, m), 7.43-7.37 (2 H, m), 7.36 7.30 (1 H, m), 7.18 (1 H, d, J = 5.5 Hz), 5.28 (2 H, s), 3.74 (3 H, s).
ESI-MS m / z: 249 [M + H] ⁺ .

実施例149-2：2-(3-(ベンジルオキシ)チオフェン-2-イル)-1,3,4-オキサジアゾールの合成
実施例149-1で得られた化合物(781 mg, 3.15 mmol)のエタノール(6 ml)溶液中に、ヒドラジン一水和物(1.22 ml, 25.2 mmol)を滴下した。アルゴン雰囲気下、還流条件で6時間撹拌した後、反応終了後濃縮乾固した。飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のオルトギ酸トリエチル(3.7 ml, 27.9 mmol)溶液中に、パラトシル酸一水和物(6 mg, 0.03 mmol)を滴下した。アルゴン雰囲気下、還流条件で一晩撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(338 mg, 43 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.22 (1H, s), 7.86 (1H, d, J = 5.5 Hz), 7.49 (2H, d, J = 7.3 Hz), 7.43-7.38 (2H, m), 7.37-7.32 (1H, m), 7.29 (1H, d, J = 5.5 Hz), 5.35 (2H, s).
ESI-MS m/z:259[M+H]⁺. Example 149-2 Synthesis of 2- (3- (benzyloxy) thiophen-2-yl) -1,3,4-oxadiazole
Hydrazine monohydrate (1.22 ml, 25.2 mmol) was dropped into a solution of the compound (781 mg, 3.15 mmol) obtained in Example 149-1 in ethanol (6 ml). After stirring under reflux conditions for 6 hours under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. Saturated brine was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. In a solution of the residue in triethyl orthoformate (3.7 ml, 27.9 mmol), paratosylate monohydrate (6 mg, 0.03 mmol) was dropped. After stirring overnight under an argon atmosphere under reflux conditions, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (338 mg, 43%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.22 (1 H, s), 7.86 (1 H, d, J = 5.5 Hz), 7.49 (2 H, d, J = 7.3 Hz), 7.43 -7.38 (2H, m), 7.37-7.32 (1H, m), 7.29 (1H, d, J = 5.5 Hz), 5.35 (2H, s).
ESI-MS m / z: 259 [M + H] ⁺ .

実施例149-3：2-(3-(ベンジルオキシ)チオフェン-2-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.149]の合成
実施例149-2で得られた化合物(200 mg, 0.77 mmol)と実施例32-5で得られた化合物(282 mg, 1.55 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(73 mg, 26 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, br s), 8.75 (1H, d, J = 4.8 Hz), 8.21 (1H, d, J = 8.0 Hz), 7.93 (1H, d, J = 5.5 Hz), 7.58 (1H, dd, J = 8.0, 4.8 Hz), 7.51 (2H, t, J = 4.4 Hz), 7.43-7.39 (2H, m), 7.36-7.34 (1H, m), 7.30 (1H, d, J = 5.5 Hz), 5.40 (2H, s).
ESI-MS m/z:360[M+H]⁺. Example 149-3 Synthesis of 2- (3- (benzyloxy) thiophen-2-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 149]
Using the compound (200 mg, 0.77 mmol) obtained in Example 149-2 and the compound (282 mg, 1.55 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (73 mg, 26%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, br s), 8.75 (1 H, d, J = 4.8 Hz), 8.21 (1 H, d, J = 8.0 Hz), 7.93 (1 H, d, J = 5.5 Hz), 7.58 (1 H, dd, J = 8.0, 4.8 Hz), 7.51 (2 H, t, J = 4.4 Hz), 7.43-7.39 (2 H, m), 7.36-7. (1H, m), 7.30 (1H, d, J = 5.5 Hz), 5.40 (2H, s).
ESI-MS m / z: 360 [M + H] ⁺ .

製造例150：2-(2-(ベンジルスルフィニル)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.150]の合成
実施例150-1：メチル 2-(ベンジルチオ)ベンゾエートの合成
メチル 2-メルカプトベンゾエート(818 μl, 5.94 mmol)のDMF(15 ml)溶液中に、炭酸カリウム(904 mg, 6.54 mmol)、(1-ブロモエチル)ベンゼン(1.56 ml, 13.08 mmol)を室温下添加した。アルゴン雰囲気下90℃で一晩撹拌した後、濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(1.533 g, 100 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.82 (1H, d, J = 5.5 Hz), 7.49-7.44 (2H, m), 7.43-7.37 (2H, m), 7.36-7.30 (1H, m), 7.18 (1H, d, J = 5.5 Hz), 5.28 (2H, s), 3.74 (3H, s).
ESI-MS m/z: 259[M+H]⁺. Preparation Example 150: Synthesis of 2- (2- (benzylsulfinyl) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 150] Example 150-1: Methyl Synthesis of 2- (benzylthio) benzoate
Potassium carbonate (904 mg, 6.54 mmol), (1-bromoethyl) benzene (1.56 ml, 13.08 mmol) was added to a solution of methyl 2-mercaptobenzoate (818 μl, 5.94 mmol) in DMF (15 ml) at room temperature . After stirring overnight at 90 ° C. under an argon atmosphere, the solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.533 g, 100%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.82 (1 H, d, J = 5.5 Hz), 7.49-7.44 (2 H, m), 7.43-7.37 (2 H, m), 7.36 7.30 (1 H, m), 7.18 (1 H, d, J = 5.5 Hz), 5.28 (2 H, s), 3.74 (3 H, s).
ESI-MS m / z: 259 [M + H] ⁺ .

実施例150-2：2-(2-(ベンジルチオ)フェニル)-1,3,4-オキサジアゾールの合成
実施例150-1で得られた化合物(1.533 g, 5.93 mmol)のエタノール(8 ml)溶液中に、ヒドラジン一水和物(2.30 ml, 47.5 mmol)を滴下した。アルゴン雰囲気下、還流条件で6時間撹拌した後、反応終了後濃縮乾固した。飽和食塩水を加え、酢酸エチルで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のオルトギ酸トリエチル(4.94 ml, 29.7 mmol)溶液中に、パラトシル酸一水和物(11 mg, 0.06 mmol)を滴下した。アルゴン雰囲気下、還流条件で一晩撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(766 mg, 48 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.37 (1H, s), 7.87 (1H, dd, J = 7.8, 1.4 Hz), 7.67-7.61 (1H, m), 7.60-7.54 (1H, m), 7.43-7.38 (2H, m), 7.37-7.29 (3H, m), 7.29-7.23 (1H, m), 4.33 (2H, s).
ESI-MS m/z:269[M+H]⁺. Example 150-2 Synthesis of 2- (2- (benzylthio) phenyl) -1,3,4-oxadiazole
Hydrazine monohydrate (2.30 ml, 47.5 mmol) was added dropwise to a solution of the compound obtained in Example 150-1 (1.533 g, 5.93 mmol) in ethanol (8 ml). After stirring under reflux conditions for 6 hours under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. Saturated brine was added and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Into a solution of the residue in triethyl orthoformate (4.94 ml, 29.7 mmol), paratosyl acid monohydrate (11 mg, 0.06 mmol) was dropped. After stirring overnight under an argon atmosphere under reflux conditions, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (766 mg, 48%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.37 (1 H, s), 7.87 (1 H, dd, J = 7.8, 1.4 Hz), 7.67-7.61 (1 H, m), 7.60- 7.54 (1 H, m), 7.43-7.38 (2 H, m), 7. 37-7. 29 (3 H, m), 7. 29-7. 23 (1 H, m), 4.33 (2 H, s).
ESI-MS m / z: 269 [M + H] ⁺ .

実施例150-3：2-(2-(ベンジルスルフィニル)フェニル)-1,3,4-オキサジアゾールの合成
実施例150-2で得られた化合物(50 mg, 0.19 mmol)のクロロホルム(3.7 ml)溶液中に、メタクロロ過安息香酸(65 wt%, 50 mg, 0.19 mmol)を0℃で添加した。40分撹拌し、反応終了後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(41 mg, 77 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.50 (1H, s), 8.17-8.11 (1H, m), 7.81-7.73 (3H, m), 7.34-7.28 (3H, m), 7.21-7.15 (2H, m), 4.55 (1H, d, J = 12.8 Hz), 3.98 (1H, d, J = 12.8 Hz).
ESI-MS m/z:285[M+H]⁺. Example 150-3 Synthesis of 2- (2- (benzylsulfinyl) phenyl) -1,3,4-oxadiazole
Metachloroperbenzoic acid (65 wt%, 50 mg, 0.19 mmol) was added at 0 ° C. to a solution of the compound (50 mg, 0.19 mmol) obtained in Example 150-2 in chloroform (3.7 ml). The mixture was stirred for 40 minutes, and after completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (41 mg, 77%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.50 (1 H, s), 8.17-8.11 (1 H, m), 7.81-7. 73 (3 H, m), 7.34-7. 28 (3 H, m) ), 7.21-7.15 (2H, m), 4.55 (1H, d, J = 12.8 Hz), 3.98 (1 H, d, J = 12.8 Hz).
ESI-MS m / z: 285 [M + H] ⁺ .

実施例150-4：2-(2-(ベンジルスルフィニル)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.150]の合成
実施例150-3で得られた化合物(103 mg, 0.36 mmol)と実施例32-5で得られた化合物(132 mg, 0.73 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(10 mg, 7 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.00 (1H, dd, J = 2.3, 0.9 Hz), 8.78 (1H, dd, J = 5.0, 1.8 Hz), 8.27 (1H, dt, J = 7.9, 1.9 Hz), 8.18 (1H, dt, J = 7.6, 1.0 Hz), 7.84-7.74 (3H, m), 7.64-7.58 (1H, m), 7.33-7.27 (3H, m), 7.22-7.16 (2H, m), 4.57 (1H, d, J = 12.8 Hz), 3.99 (1H, d, J = 12.8 Hz).
ESI-MS m/z:386[M+H]⁺. Example 150-4: Synthesis of 2- (2- (benzylsulfinyl) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 150]
Using the compound (103 mg, 0.36 mmol) obtained in Example 150-3 and the compound (132 mg, 0.73 mmol) obtained in Example 32-5, the same procedure as in Example 32-6 is performed. The title compound (10 mg, 7%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.00 (1 H, dd, J = 2.3, 0.9 Hz), 8.78 (1 H, dd, J = 5.0, 1.8 Hz), 8.27 (1 H, 1 H, dt, J = 7.9, 1.9 Hz), 8.18 (1 H, dt, J = 7.6, 1.0 Hz), 7.84-7.74 (3 H, m), 7.64-7. 58 (1 H, m), 7.33-7. 27 (3 H, m) , 7.22-7.16 (2H, m), 4.57 (1H, d, J = 12.8 Hz), 3.99 (1 H, d, J = 12.8 Hz).
ESI-MS m / z: 386 [M + H] ⁺ .

製造例151：2-(2-(ベンジルオキシ)ピリジン-3-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.151]の合成
実施例151-1：メチル 2-ヒドロキシニコチネートの合成
2-ヒドロキシニコチン酸(1.763 g, 12.7 mmol)をメタノール(18 ml)に懸濁させた。そこへ濃硫酸(0.54 ml)、トルエン(4 ml)を加えてDienstarkを用いて一晩加熱還流した。反応後、炭酸カリウム水溶液でquenchした。溶媒を留去した。クロロホルムと飽和重曹水を加え、クロロホルム抽出した。硫酸マグネシウムで乾燥し、溶媒を留去し、標記の化合物(522 mg, 26.8%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 12.08 (1H, br s), 8.05 (1H, dd, J = 7.0, 2.1 Hz), 7.66 (1H, d, J = 4.9 Hz), 6.27 (1H, dd, J = 7.0, 6.4 Hz), 3.73 (3H, s). Preparation Example 151 Synthesis of 2- (2- (benzyloxy) pyridin-3-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 151] Example 151 -1: Synthesis of methyl 2-hydroxy nicotinate
2-hydroxynicotinic acid (1.763 g, 12.7 mmol) was suspended in methanol (18 ml). Concentrated sulfuric acid (0.54 ml) and toluene (4 ml) were added thereto, and the mixture was heated to reflux overnight using Dienstark. After the reaction, it was quenched with aqueous potassium carbonate solution. The solvent was distilled off. Chloroform and saturated aqueous sodium bicarbonate were added, and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and the solvent was evaporated to give the title compound (522 mg, 26.8%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 12.08 (1 H, br s), 8.05 (1 H, dd, J = 7.0, 2.1 Hz), 7.66 (1 H, d, J = 4.9 Hz ), 6.27 (1 H, dd, J = 7.0, 6.4 Hz), 3.73 (3 H, s).

実施例151-2：メチル 2-(ベンジルオキシ)ニコチネートの合成
実施例151-1で得られた化合物(522 mg, 3.41 mmol)をDMF(8 ml)に溶解した。そこへ炭酸セシウム(1.333 g, 4.09 mmol)、ベンジルブロマイド(0.891 ml, 7.50 mmol)を加えて70℃で一晩撹拌した。反応後、溶媒を留去した。水を加えてクロロホルム抽出した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP Ultra 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(889 mg, quant.)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.16 (1H, dd, J = 6.9, 2.1 Hz), 8.04 (1H, dd, J = 7.3, 2.1 Hz), 7.37-7.27 (5H, m), 6.36 (1H, t, J = 6.9 Hz), 5.14 (2H, s), 3.73 (3H, s).
ESI-MS m/z: 244[M+H]⁺. Example 151-2: Synthesis of methyl 2- (benzyloxy) nicotinate
The compound (522 mg, 3.41 mmol) obtained in Example 151-1 was dissolved in DMF (8 ml). Cesium carbonate (1.333 g, 4.09 mmol) and benzyl bromide (0.891 ml, 7.50 mmol) were added there, and it stirred at 70 degreeC overnight. After the reaction, the solvent was distilled off. Water was added and chloroform extracted. Washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP Ultra 25 g, hexane / ethyl acetate) to give the title compound (889 mg, quant.) As a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.16 (1 H, dd, J = 6.9, 2.1 Hz), 8.04 (1 H, dd, J = 7.3, 2.1 Hz), 7.37-7.27 ( 5H, m), 6.36 (1 H, t, J = 6.9 Hz), 5.14 (2 H, s), 3.73 (3 H, s).
ESI-MS m / z: 244 [M + H] ⁺ .

実施例151-3：2-(2-(ベンジルオキシ)ピリジン-3-イル)-1,3,4-オキサジアゾールの合成
実施例151-2で得られた化合物(889 mg, 3.41 mmol)をエタノール(9 ml)に溶解し、そこへヒドラジン一水和物(1.66 ml, 34.1 mmol)を加えて4時間加熱還流した。反応後、溶媒を留去し、水を加えてクロロホルム/メタノール=5/1で抽出した。硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残渣をオルトギ酸トリエチル(3.41 ml, 20.46 mmol)、パラトシル酸一水和物(65 mg, 0.341 mmol)を加えて120℃で一晩撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP Ultra 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(203 mg, 23.5%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.30 (1H, s), 8.41-8.38 (1H, m), 8.23-8.18 (2H, m), 7.39-7.30 (5H, m), 5.22 (2H, s).
ESI-MS m/z: 254[M+H]⁺. Example 15 1-3 Synthesis of 2- (2- (benzyloxy) pyridin-3-yl) -1,3,4-oxadiazole
The compound (889 mg, 3.41 mmol) obtained in Example 151-2 was dissolved in ethanol (9 ml), and thereto was added hydrazine monohydrate (1.66 ml, 34.1 mmol), and the mixture was heated under reflux for 4 hours. After the reaction, the solvent was distilled off, water was added, and the mixture was extracted with chloroform / methanol = 5/1. Dry over magnesium sulfate and evaporate the solvent. The obtained residue was added with triethyl orthoformate (3.41 ml, 20.46 mmol) and paratosyl acid monohydrate (65 mg, 0.341 mmol) and stirred at 120 ° C. overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP Ultra 25 g, hexane / ethyl acetate) to give the title compound (203 mg, 23.5%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.30 (1 H, s), 8.41-8.38 (1 H, m), 8.23-8.18 (2 H, m), 7.39-7.30 (5 H, m) ), 5.22 (2H, s).
ESI-MS m / z: 254 [M + H] ⁺ .

実施例151-4：2-(2-(ベンジルオキシ)ピリジン-3-イル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.151]の合成
実施例151-3で得られた化合物(200 mg, 0.79 mmol)と実施例32-5で得られた化合物(287 mg, 1.58 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(3 mg, 1.1%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, d, J = 1.4 Hz), 8.75 (1H, dd, J = 4.8, 1.6 Hz), 8.32 (1H, d, J = 1.4 Hz), 8.29 (1H, dd, J = 4.1, 2.1 Hz), 8.22 (1H, dt, J = 7.9, 1.9 Hz), 7.58 (1H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.37-7.36 (5H, m), 6.54 (1H, t, J = 7.0 Hz), 5.23 (2H, s).
ESI-MS m/z: 355[M+H]⁺. Example 15 1-4 Synthesis of 2- (2- (benzyloxy) pyridin-3-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 151]
Using the compound (200 mg, 0.79 mmol) obtained in Example 151-3 and the compound (287 mg, 1.58 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (3 mg, 1.1%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, d, J = 1.4 Hz), 8.75 (1 H, dd, J = 4.8, 1.6 Hz), 8.32 (1 H, d, J = 1.4 Hz), 8.29 (1 H, dd, J = 4.1, 2.1 Hz), 8.22 (1 H, dt, J = 7.9, 1.9 Hz), 7.58 (1 H, ddd, J = 8.0, 4.9, 0.9 Hz), 7.37-7.36 (5H, m), 6.54 (1H, t, J = 7.0 Hz), 5.23 (2H, s).
ESI-MS m / z: 355 [M + H] ⁺ .

製造例152：2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニルベンゾエート[化合物No.152]の合成
実施例152-1：2-(1,3,4-オキサジアゾール-2-イル)フェニルベンゾエートの合成
実施例138-4で得られた化合物(200 mg, 1.42 mmol)のDMF(4 ml)溶液中に、炭酸セシウム(482 mg, 1.48 mmol)、ベンゾイルクロライド(573 μl, 4.20 mmol)を添加した。アルゴン雰囲気下、70℃で一晩撹拌した。反応終了後、減圧下濃縮乾固し、残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(202 mg, 62 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.32 (1H, s), 8.18-8.11 (3H, m), 7.82-7.73 (2H, m), 7.67-7.54 (4H, m).
ESI-MS m/z:267[M+H]⁺. Preparation Example 152 Synthesis of 2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenylbenzoate [Compound No. 152] Example 152-1: 2- ( Synthesis of 1,3,4-Oxadiazol-2-yl) phenylbenzoate
Cesium carbonate (482 mg, 1.48 mmol) and benzoyl chloride (573 μl, 4.20 mmol) were added to a solution of the compound (200 mg, 1.42 mmol) obtained in Example 138-4 in DMF (4 ml). Stir at 70 ° C. overnight under an argon atmosphere. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (202 mg, 62%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.32 (1 H, s), 8.18-8.11 (3 H, m), 7.82-7. 73 (2 H, m), 7.67-7.54 (4 H, m) ).
ESI-MS m / z: 267 [M + H] ⁺ .

実施例152-2：2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニルベンゾエート[化合物No.152]の合成
実施例152-1で得られた化合物(202 mg, 0.76 mmol)と実施例32-5で得られた化合物 (276 mg, 1.52 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(31 mg, 11 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.80 (1H, br s), 8.76-8.73 (1H, m), 8.27-8.16 (3H, m), 8.12-8.06 (1H, m), 7.87-7.74 (2H, m), 7.71-7.54 (5H, m).
ESI-MS m/z:368[M+H]⁺. Example 152-2 Synthesis of 2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenylbenzoate [Compound No. 152]
Using the compound (202 mg, 0.76 mmol) obtained in Example 152-1 and the compound (276 mg, 1.52 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (31 mg, 11%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.80 (1 H, br s), 8.76-8.73 (1 H, m), 8.27-8.16 (3 H, m), 8.12-8.06 (1 H, 1 H, m) m), 7.87-7.74 (2H, m), 7.71-7.54 (5H, m).
ESI-MS m / z: 368 [M + H] ⁺ .

製造例153：2-(2-ブロモフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.153]の合成
実施例153-1：2-(2-ブロモフェニル)-1,3,4-オキサジアゾールの合成
2-ブロモ安息香酸(1.00 g, 4.97 mmol)のジクロロメタン(60 ml)溶液中に、(イソシアノイミノ)トリフェニルホスホラン(1.509 g, 4.97 mmol)を添加した。アルゴン雰囲気下、室温で一晩撹拌した後、減圧下濃縮した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(173 mg, 15 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.48 (1H, s), 7.93-7.89 (2H, m), 7.61-7.59 (2H, m).
ESI-MS m/z:225[M+H]⁺. Preparation Example 153 Synthesis of 2- (2-bromophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 153] Example 153-1: 2- (2 Synthesis of (Bromophenyl) -1,3,4-oxadiazole
To a solution of 2-bromobenzoic acid (1.00 g, 4.97 mmol) in dichloromethane (60 ml) was added (isocyanoimino) triphenylphosphorane (1.509 g, 4.97 mmol). After stirring overnight at room temperature under an argon atmosphere, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (173 mg, 15%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.48 (1 H, s), 7.93-7.89 (2 H, m), 7.61-7.59 (2 H, m).
ESI-MS m / z: 225 [M + H] ⁺ .

実施例153-2：2-(2-ブロモフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.153]の合成
実施例153-1で得られた化合物(86 mg, 0.38 mmol)と実施例32-5で得られた化合物(139 mg, 0.76 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(40 mg, 32 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, d, J = 1.4 Hz), 8.77 (1H, dd, J = 5.0, 1.4 Hz), 8.25 (1H, d, J = 5.0 Hz), 8.01 (1H, dd, J = 7.6, 2.3 Hz), 7.93 (1H, dd, J = 7.6, 1.6 Hz), 7.68-7.56 (3H, m).
ESI-MS m/z:326[M+H]⁺. Example 153-2 Synthesis of 2- (2-bromophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 153]
Using the compound (86 mg, 0.38 mmol) obtained in Example 153-1 and the compound (139 mg, 0.76 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (40 mg, 32%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, d, J = 1.4 Hz), 8.77 (1 H, dd, J = 5.0, 1.4 Hz), 8.25 (1 H, d, J = 5.0 Hz), 8.01 (1 H, dd, J = 7.6, 2.3 Hz), 7.93 (1 H, dd, J = 7.6, 1.6 Hz), 7.68-7.56 (3 H, m).
ESI-MS m / z: 326 [M + H] ⁺ .

製造例154：N-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニル)ベンズアミド[化合物No.154]の合成
実施例154-1：2-ベンズアミド安息香酸の合成
アントラニル酸(1.038 g, 7.57 mmol)をジクロロメタン(20 ml)に懸濁させた。そこへトリエチルアミン(2.11 ml, 15.13 mmol)、ベンゾイルクロライド(0.872 ml, 7.57 mmol)を加えて、室温で一晩撹拌した。反応後、1mol/ll塩酸を加えて、クロロホルム/メタノール=10/1で抽出した。硫酸マグネシウムで乾燥した。溶媒を留去し、標記の化合物(1.865 g, quant.)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 13.79 (1H, br s), 12.20 (1H, br s), 8.72 (1H, dt, J = 8.4, 1.4 Hz), 8.07 (1H, dd, J = 7.9, 1.8 Hz), 7.96 (2H, dd, J = 8.4, 1.4 Hz), 7.68-7.60 (4H, m), 7.24-7.20 (1H, m).
ESI-MS m/z: 242[M+H]⁺. Preparation Example 154 Synthesis Example of N- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl) benzamide [Compound No. 154] Example 154-1 : Synthesis of 2-benzamidobenzoic acid
Anthranilic acid (1.038 g, 7.57 mmol) was suspended in dichloromethane (20 ml). The triethylamine (2.11 ml, 15.13 mmol) and the benzoyl chloride (0.872 ml, 7.57 mmol) were added there, and it stirred at room temperature overnight. After the reaction, 1 mol / l hydrochloric acid was added, and extracted with chloroform / methanol = 10/1. Dried over magnesium sulfate. The solvent was evaporated to give the title compound (1.865 g, quant.) As a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 13.79 (1 H, br s), 12.20 (1 H, br s), 8. 72 (1 H, dt, J = 8.4, 1.4 Hz), 8.07 ( 1H, dd, J = 7.9, 1.8 Hz), 7.96 (2H, dd, J = 8.4, 1.4 Hz), 7.68-7.60 (4H, m), 7.24-7.20 (1 H, m).
ESI-MS m / z: 242 [M + H] ⁺ .

実施例154-2：N-(2-(1,3,4-オキサジアゾール-2-イル)フェニル)ベンズアミドの合成
実施例154-1で得られた化合物(377 mg, 1.56 mmol)をジクロロメタン(7 ml)に懸濁させた。そこへ(イソシアノイミノ)トリフェニルホスホラン(472 mg, 1.56 mmol)のジクロロメタン溶液(9 ml)を加えて室温で5時間撹拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(77 mg, 18.6%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.43 (1H, br s), 9.47 (1H, s), 8.63 (1H, dd, J = 8.5, 1.1 Hz), 8.07-8.03 (3H, m), 7.72-7.62 (4H, m), 7.39 (1H, ddd, J = 8.2, 7.1, 0.8 Hz).
ESI-MS m/z: 266[M+H]⁺. Example 154-2: Synthesis of N- (2- (1,3,4-oxadiazol-2-yl) phenyl) benzamide
The compound (377 mg, 1.56 mmol) obtained in Example 154-1 was suspended in dichloromethane (7 ml). The dichloromethane solution (9 ml) of (isocyanoimino) triphenylphosphorane (472 mg, 1.56 mmol) was added there, and it stirred at room temperature for 5 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 25 g, hexane / ethyl acetate) to give the title compound (77 mg, 18.6%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.43 (1 H, br s), 9.47 (1 H, s), 8.63 (1 H, dd, J = 8.5, 1.1 Hz), 8.07-8.03 (3H, m), 7.72-7. 62 (4H, m), 7.39 (1 H, ddd, J = 8.2, 7.1, 0.8 Hz).
ESI-MS m / z: 266 [M + H] ⁺ .

実施例154-3：N-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニル)ベンズアミド[化合物No.154]の合成
実施例154-2で得られた化合物(77 mg, 0.29 mmol)と実施例32-5で得られた化合物(106 mg, 0.58 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(11 mg, 10.4%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.19 (1H, br s), 8.95 (1H, dd, J = 2.1, 0.9 Hz), 8.77 (1H, dd, J = 4.9, 1.5 Hz), 8.52 (1H, dd, J = 8.5, 0.9 Hz), 8.22 (1H, dt, J = 8.0, 1.8 Hz), 8.05 (3H, dd, J = 8.2, 1.2 Hz), 7.75-7.71 (1H, m), 7.69-7.58 (4H, m), 7.41 (1H, td, J = 7.6, 0.9 Hz).
ESI-MS m/z: 367[M+H]⁺. Example 154-3 Synthesis of N- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl) benzamide [Compound No. 154]
Using the compound (77 mg, 0.29 mmol) obtained in Example 154-2 and the compound (106 mg, 0.58 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (11 mg, 10.4%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.19 (1 H, br s), 8.95 (1 H, dd, J = 2.1, 0.9 Hz), 8.77 (1 H, dd, J = 4.9, 1.5 Hz), 8.52 (1 H, dd, J = 8.5, 0.9 Hz), 8.22 (1 H, dt, J = 8.0, 1.8 Hz), 8.05 (3 H, dd, J = 8.2, 1.2 Hz), 7.55-7.71 ( 1H, m), 7.69-7.58 (4H, m), 7.41 (1H, td, J = 7.6, 0.9 Hz).
ESI-MS m / z: 367 [M + H] ⁺ .

製造例155：2-(2-フェネトキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.155]の合成
実施例155：2-(2-フェネトキシフェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.155]の合成
実施例138-5で得られた化合物(90 mg, 0.34 mmol)をDMF(1.8 ml)に溶解し、炭酸セシウム(134 mg, 0.41 mmol)、(2-ブロモエチル)ベンゼン(0.092 ml, 0.68 mmol)を加えて70℃で一晩撹拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(53 mg, 42.4%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, dd, J = 2.2, 0.8 Hz), 8.77 (1H, dd, J = 4.9, 1.7 Hz), 8.24 (1H, dt, J = 7.8, 1.9 Hz), 7.92 (1H, dd, J = 7.8, 1.8 Hz), 7.62-7.59 (2H, m), 7.38 (2H, d, J = 6.9 Hz), 7.30 (1H, d, J = 8.5 Hz), 7.25 (2H, t, J = 7.6 Hz), 7.18-7.14 (2H, m), 4.35 (2H, t, J = 6.2 Hz), 3.09 (2H, t, J = 6.2 Hz).
ESI-MS m/z: 367[M+H]⁺. Preparation Example 155: 2- (2-phenethoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 155] Synthesis Example 155: 2- (2- (2-phenethylphenyl)) Synthesis of phenetoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [compound No. 155]
The compound (90 mg, 0.34 mmol) obtained in Example 138-5 is dissolved in DMF (1.8 ml), cesium carbonate (134 mg, 0.41 mmol), (2-bromoethyl) benzene (0.092 ml, 0.68 mmol) Was added and stirred at 70.degree. C. overnight. After the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography (SNAP 10 g, hexane / ethyl acetate) to obtain the title compound (53 mg, 42.4%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, dd, J = 2.2, 0.8 Hz), 8.77 (1 H, dd, J = 4.9, 1.7 Hz), 8.24 (1 H, 1 H, dt, J = 7.8, 1.9 Hz), 7. 92 (1 H, dd, J = 7.8, 1.8 Hz), 7.62-7.59 (2 H, m), 7.38 (2 H, d, J = 6.9 Hz), 7.30 (1 H, d , J = 8.5 Hz, 7.25 (2 H, t, J = 7.6 Hz), 7. 18-7. 14 (2 H, m), 4. 35 (2 H, t, J = 6.2 Hz), 3.09 (2 H, t, J = 6.2 Hz) ).
ESI-MS m / z: 367 [M + H] ⁺ .

製造例156：2-(5-ブロモ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.156]の合成
実施例156-1：2-(5-ブロモ-2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾールの合成
5-ブロモ-2-(トリフルオロメトキシ)安息香酸(3.00 g, 10.53 mmol)のメタノール(30 ml)溶液中に、濃硫酸(300 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のエタノール(30 ml)溶液中に、ヒドラジン一水和物(4.1 ml, 84 mmol)を滴下した。アルゴン雰囲気下、還流条件で5時間撹拌した後、反応終了後濃縮乾固した。残渣物のオルトギ酸トリエチル(10.5 ml, 63 mmol)溶液中に、パラトシル酸一水和物(200 mg, 1.1 mmol)を滴下した。アルゴン雰囲気下、還流条件で6時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(2.096 g, 65 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.52 (1H, s), 8.28 (1H, d, J = 2.3 Hz), 8.01 (1H, dd, J = 8.9, 2.3 Hz), 7.65 (1H, dd, J = 8.9, 1.6 Hz).
ESI-MS m/z:308[M+H]⁺. Preparation Example 156 Synthesis Example of 2- (5-bromo-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 156] 156-1: Synthesis of 2- (5-bromo-2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole
Concentrated sulfuric acid (300 μl) was dropped into a solution of 5-bromo-2- (trifluoromethoxy) benzoic acid (3.00 g, 10.53 mmol) in methanol (30 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Hydrazine monohydrate (4.1 ml, 84 mmol) was dropped into a solution of the residue in ethanol (30 ml). After stirring for 5 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The paratosilic acid monohydrate (200 mg, 1.1 mmol) was added dropwise to a solution of the residue in triethyl orthoformate (10.5 ml, 63 mmol). After stirring under reflux conditions for 6 hours under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.096 g, 65%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.52 (1 H, s), 8.28 (1 H, d, J = 2.3 Hz), 8.01 (1 H, dd, J = 8.9, 2.3 Hz) , 7.65 (1H, dd, J = 8.9, 1.6 Hz).
ESI-MS m / z: 308 [M + H] ⁺ .

実施例156-2：2-(5-ブロモ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.156]の合成
実施例156-1で得られた化合物(100 mg, 0.32 mmol)と実施例32-5で得られた化合物(118 mg, 0.65 mmol)を用いて実施例32-6と同様の操作を行うことにより標記の化合物(20 mg, 15 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, br s), 8.77 (1H, dd, J = 4.8, 1.6 Hz), 8.31 (1H, d, J = 2.3 Hz), 8.26-8.24 (1H, m), 8.04 (1H, dd, J = 8.9, 2.5 Hz), 7.67 (1H, dd, J = 8.7, 1.4 Hz), 7.61-7.58 (1H, m).
ESI-MS m/z:410[M+H]⁺. Example 156-2 Synthesis of 2- (5-bromo-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 156]
Using the compound (100 mg, 0.32 mmol) obtained in Example 156-1 and the compound (118 mg, 0.65 mmol) obtained in Example 32-5, the same operation as in Example 32-6 is performed. The title compound (20 mg, 15%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, br s), 8.77 (1 H, dd, J = 4.8, 1.6 Hz), 8.31 (1 H, d, J = 2.3 Hz ), 8.26-8.24 (1H, m), 8.04 (1H, dd, J = 8.9, 2.5 Hz), 7.67 (1H, dd, J = 8.7, 1.4 Hz), 7.61-7.58 (1H, m).
ESI-MS m / z: 410 [M + H] ⁺ .

製造例157：2-(2-(ジフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.157]の合成
実施例157-1：2-(ジフルオロメトキシ)ベンゾヒドラジドの合成
2-(ジフルオロメトキシ)安息香酸(400 mg, 2.13 mmol)のメタノール(15 ml)溶液中に、濃硫酸(64 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のエタノール(6 ml)溶液中に、ヒドラジン一水和物(827 μl, 17.0 mmol)を滴下した。アルゴン雰囲気下、還流条件で4時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(クロロホルム/メタノール)で精製し、標記の化合物(180 mg, 42 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.44 (1H, s), 7.56-7.44 (2H, m), 7.37-7.21 (2H, m), 7.06 (1H, d, J = 74.2 Hz), 4.49 (2H, s).
ESI-MS m/z:203[M+H]⁺. Preparation Example 157: Synthesis of 2- (2- (difluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 157] Example 157-1: 2 Synthesis of-(Difluoromethoxy) benzohydrazide
Concentrated sulfuric acid (64 μl) was added dropwise to a solution of 2- (difluoromethoxy) benzoic acid (400 mg, 2.13 mmol) in methanol (15 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Hydrazine monohydrate (827 μl, 17.0 mmol) was added dropwise to a solution of the residue in ethanol (6 ml). After stirring under reflux conditions for 4 hours under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (180 mg, 42%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.44 (1 H, s), 7.56-7.44 (2 H, m), 7. 37-7.2 1 (2 H, m), 7.06 (1 H, d, J = 74.2 Hz), 4.49 (2H, s).
ESI-MS m / z: 203 [M + H] ⁺ .

実施例157-2：2-(2-(ジフルオロメトキシ)フェニル)-1,3,4-オキサジアゾールの合成
実施例157-1で得られた化合物(180 mg, 0.89 mmol)のオルトギ酸トリエチル(890 μl, 5.34 mmol)溶液中に、パラトシル酸一水和物(10 mg, 0.05 mmol)を滴下した。アルゴン雰囲気下、還流条件で3時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(148 mg, 78 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.44 (1H, s), 8.05 (1H, dd, J = 7.8, 1.8 Hz), 7.73 (1H, td, J = 7.8, 1.5 Hz), 7.53-7.44 (2H, m), 7.24 (1H, d, J = 73.7 Hz).
ESI-MS m/z:213[M+H]⁺. Example 157-2: Synthesis of 2- (2- (difluoromethoxy) phenyl) -1,3,4-oxadiazole
In a solution of the compound (180 mg, 0.89 mmol) obtained in Example 157-1 in triethyl orthoformate (890 μl, 5.34 mmol), paratosylate monohydrate (10 mg, 0.05 mmol) was dropped. After stirring for 3 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (148 mg, 78%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.44 (1 H, s), 8.05 (1 H, dd, J = 7.8, 1.8 Hz), 7.73 (1 H, td, J = 7.8, 1.5 Hz), 7.53-7.44 (2 H, m), 7.24 (1 H, d, J = 73.7 Hz).
ESI-MS m / z: 213 [M + H] ⁺ .

実施例157-3：2-(2-(ジフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.157]の合成
実施例157-2で得られた化合物(148 mg, 0.70 mmol)と実施例32-5で得られた化合物(254 mg, 1.40 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(47 mg, 22 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, br s), 8.76 (1H, dd, J = 4.8, 1.6 Hz), 8.24 (1H, dt, J = 7.9, 1.9 Hz), 8.11 (1H, dd, J = 7.8, 1.4 Hz), 7.78-7.74 (1H, m), 7.61-7.56 (1H, m), 7.53 (1H, dd, J = 7.6, 1.1 Hz), 7.50-7.48 (1H, m), 7.26 (1H, d, J = 73.7 Hz).
ESI-MS m/z:314[M+H]⁺. Example 157-3: Synthesis of 2- (2- (difluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 157]
Performing the same operation as in Example 32-6, using the compound (148 mg, 0.70 mmol) obtained in Example 157-2 and the compound (254 mg, 1.40 mmol) obtained in Example 32-5 The title compound (47 mg, 22%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, br s), 8. 76 (1 H, dd, J = 4.8, 1.6 Hz), 8.24 (1 H, dt, J = 7.9, 1.9 Hz), 8.11 (1 H, dd, J = 7.8, 1.4 Hz), 7.78-7.74 (1 H, m), 7.61-7.56 (1 H, m), 7.53 (1 H, dd, J = 7.6, 1.1 Hz), 7.50-7.48 (1 H, m), 7.26 (1 H, d, J = 73.7 Hz).
ESI-MS m / z: 314 [M + H] ⁺ .

製造例158：2-(5-クロロ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.158]の合成
実施例158-1：2-(5-クロロ-2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾールの合成
5-クロロ-2-(トリフルオロメトキシ)安息香酸(400 mg, 1.66 mmol)のメタノール(15 ml)溶液中に、濃硫酸(100 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のエタノール(5 ml)溶液中に、ヒドラジン一水和物(644 μl, 13.3 mmol)を滴下した。アルゴン雰囲気下、還流条件で5時間撹拌した後、反応終了後濃縮乾固した。残渣物のオルトギ酸トリエチル(1.7 ml, 9.96 mmol)溶液中に、パラトシル酸一水和物(16 mg, 0.08 mmol)を滴下した。アルゴン雰囲気下、還流条件で1時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(428 mg, 97 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.52 (1H, s), 8.17 (1H, d, J = 2.7 Hz), 7.88 (1H, dd, J = 8.9, 2.7 Hz), 7.73 (1H, d, J = 8.9 Hz).
ESI-MS m/z:265[M+H]⁺. Preparation Example 158 Synthesis Example of 2- (5-Chloro-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 158] Synthesis of 158-1: 2- (5-chloro-2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole
Concentrated sulfuric acid (100 μl) was added dropwise to a solution of 5-chloro-2- (trifluoromethoxy) benzoic acid (400 mg, 1.66 mmol) in methanol (15 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Hydrazine monohydrate (644 μl, 13.3 mmol) was added dropwise to a solution of the residue in ethanol (5 ml). After stirring for 5 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. In a solution of the residue in triethyl orthoformate (1.7 ml, 9.96 mmol), paratosylate monohydrate (16 mg, 0.08 mmol) was added dropwise. After stirring for 1 hour under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (428 mg, 97%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.52 (1 H, s), 8. 17 (1 H, d, J = 2.7 Hz), 7.88 (1 H, dd, J = 8.9, 2.7 Hz) , 7.73 (1 H, d, J = 8.9 Hz).
ESI-MS m / z: 265 [M + H] ⁺ .

実施例158-2：2-(5-クロロ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.158]の合成
実施例158-1で得られた化合物(150 mg, 0.57 mmol)と実施例32-5で得られた化合物(206 mg, 1.13 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(6 mg, 3 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, br s), 8.77 (1H, dd, J = 5.0, 1.8 Hz), 8.26-8.23 (1H, m), 8.20 (1H, br s), 7.91 (1H, d, J = 9.0 Hz), 7.75 (1H, d, J = 9.0 Hz), 7.63-7.57 (1H, m).
ESI-MS m/z:366[M+H]⁺. Example 158-2 Synthesis of 2- (5-chloro-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 158]
Using the compound (150 mg, 0.57 mmol) obtained in Example 158-1 and the compound (206 mg, 1.13 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (6 mg, 3%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, br s), 8.77 (1 H, dd, J = 5.0, 1.8 Hz), 8.26-8.23 (1 H, m), 8.20 (1H, br s), 7.91 (1 H, d, J = 9.0 Hz), 7.75 (1 H, d, J = 9.0 Hz), 7.63-7.57 (1 H, m).
ESI-MS m / z: 366 [M + H] ⁺ .

製造例159：2-(5-フルオロ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.159]の合成
実施例159-1：2-(5-フルオロ-2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾールの合成
5-フルオロ-2-(トリフルオロメトキシ)安息香酸(400 mg, 1.79 mmol)のメタノール(15 ml)溶液中に、濃硫酸(100 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のエタノール(5 ml)溶液中に、ヒドラジン一水和物(695 μl, 14.3 mmol)を滴下した。アルゴン雰囲気下、還流条件で3時間撹拌した後、反応終了後濃縮乾固した。残渣物のオルトギ酸トリエチル(1.8 ml, 10.7 mmol)溶液中に、パラトシル酸一水和物(17 mg, 0.09 mmol)を滴下した。アルゴン雰囲気下、還流条件で5時間撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(274 mg, 62 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.53 (1H, s), 7.99 (1H, dd, J = 8.5, 3.0 Hz), 7.81-7.73 (1H, m), 7.73-7.65 (1H, m).
ESI-MS m/z:249[M+H]⁺. Preparation Example 159 Synthesis Example of 2- (5-Fluoro-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 159] 159-1: Synthesis of 2- (5-fluoro-2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole
Concentrated sulfuric acid (100 μl) was dropped into a solution of 5-fluoro-2- (trifluoromethoxy) benzoic acid (400 mg, 1.79 mmol) in methanol (15 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Hydrazine monohydrate (695 μl, 14.3 mmol) was added dropwise to a solution of the residue in ethanol (5 ml). After stirring for 3 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. To a solution of the residue in triethyl orthoformate (1.8 ml, 10.7 mmol), paratosylate monohydrate (17 mg, 0.09 mmol) was added dropwise. After stirring for 5 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (274 mg, 62%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.53 (1 H, s), 7.99 (1 H, dd, J = 8.5, 3.0 Hz), 7.81-7.73 (1 H, m), 7.73 7.65 (1 H, m).
ESI-MS m / z: 249 [M + H] ⁺ .

実施例159-2：2-(5-フルオロ-2-(トリフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.159]の合成
実施例159-1で得られた化合物(150 mg, 0.61 mmol)と実施例32-5で得られた化合物(220 mg, 1.21 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(46 mg, 22 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, br s), 8.77 (1H, dd, J = 4.8, 1.6 Hz), 8.27-8.22 (1H, m), 8.03 (1H, dd, J = 8.7, 3.2 Hz), 7.82-7.76 (1H, m), 7.75-7.69 (1H, m), 7.61-7.58 (1H, m).
ESI-MS m/z:350[M+H]⁺. Example 159-2: Synthesis of 2- (5-fluoro-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 159]
Using the compound (150 mg, 0.61 mmol) obtained in Example 159-1 and the compound (220 mg, 1.21 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (46 mg, 22%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, br s), 8.77 (1 H, dd, J = 4.8, 1.6 Hz), 8.27-8.22 (1 H, m), 8.03 (1H, dd, J = 8.7, 3.2 Hz), 7.82-7.76 (1H, m), 7.75-7.69 (1H, m), 7.61-7.58 (1H, m).
ESI-MS m / z: 350 [M + H] ⁺ .

製造例160：2-(3-(ジフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.160]の合成
実施例160-1：2-(3-(ジフルオロメトキシ)フェニル)-1,3,4-オキサジアゾールの合成
3-(ジフルオロメトキシ)安息香酸(400 mg, 2.13 mmol)のメタノール(15 ml)溶液中に、濃硫酸(64 μl)を滴下した。アルゴン雰囲気下、還流条件下一晩撹拌し、反応終了後、濃縮乾固した。飽和食塩水、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。無水硫酸ナトリウムにより乾燥し、ろ過、減圧下濃縮した。残渣物のエタノール(6 ml)溶液中に、ヒドラジン一水和物(827 μl, 17.0 mmol)を滴下した。アルゴン雰囲気下、還流条件で3時間撹拌した後、反応終了後濃縮乾固した。残渣物のオルトギ酸トリエチル(2.1 ml, 12.8 mmol)溶液中に、パラトシル酸一水和物(20 mg, 0.11 mmol)を滴下した。アルゴン雰囲気下、還流条件で一晩撹拌した後、反応終了後濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(352 mg, 78 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.40 (1H, s), 7.91 (1H, d, J = 7.8 Hz), 7.78 (1H, br s), 7.69 (1H, dd, J = 8.2, 7.8 Hz), 7.47 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 73.3 Hz).
ESI-MS m/z:213[M+H]⁺. Preparation Example 160 Synthesis of 2- (3- (difluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 160] Example 160-1: 2 Synthesis of-(3- (Difluoromethoxy) phenyl) -1,3,4-oxadiazole
Concentrated sulfuric acid (64 μl) was added dropwise to a solution of 3- (difluoromethoxy) benzoic acid (400 mg, 2.13 mmol) in methanol (15 ml). The mixture was stirred overnight under an argon atmosphere under reflux conditions, and after completion of the reaction, it was concentrated to dryness. Saturated brine and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Hydrazine monohydrate (827 μl, 17.0 mmol) was added dropwise to a solution of the residue in ethanol (6 ml). After stirring for 3 hours under reflux conditions under an argon atmosphere, the reaction was concentrated to dryness after completion of the reaction. In a solution of the residue in triethyl orthoformate (2.1 ml, 12.8 mmol), paratosylate monohydrate (20 mg, 0.11 mmol) was added dropwise. After stirring overnight under an argon atmosphere under reflux conditions, the reaction was concentrated to dryness after completion of the reaction. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (352 mg, 78%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.40 (1 H, s), 7.91 (1 H, d, J = 7.8 Hz), 7.78 (1 H, br s), 7.69 (1 H, dd , J = 8.2, 7.8 Hz), 7.47 (1 H, d, J = 8.2 Hz), 7.31 (1 H, d, J = 73.3 Hz).
ESI-MS m / z: 213 [M + H] ⁺ .

実施例160-2：2-(3-(ジフルオロメトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.160]の合成
実施例160-1で得られた化合物(150 mg, 0.71 mmol)と実施例32-5で得られた化合物(257 mg, 1.42 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(33 mg, 15 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.98 (1H, br s), 8.77 (1H, dd, J = 4.8, 1.6 Hz), 8.24 (1H, dt, J = 8.1, 1.9 Hz), 7.95 (1H, d, J = 7.9 Hz), 7.82 (1H, br s), 7.71 (1H, dd, J = 8.0, 7.9 Hz), 7.62-7.57 (1H, m), 7.51 (1H, d, J = 8.0 Hz), 7.33 (1H, d, J = 73.7 Hz).
ESI-MS m/z:314[M+H]⁺. Example 160-2 Synthesis of 2- (3- (difluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 160]
Using the compound (150 mg, 0.71 mmol) obtained in Example 160-1 and the compound (257 mg, 1.42 mmol) obtained in Example 32-5, the same procedure as in Example 32-6 is performed. The title compound (33 mg, 15%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.98 (1 H, br s), 8.77 (1 H, dd, J = 4.8, 1.6 Hz), 8.24 (1 H, dt, J = 8.1, 1.9 Hz), 7.95 (1 H, d, J = 7.9 Hz), 7.82 (1 H, br s), 7.71 (1 H, dd, J = 8.0, 7.9 Hz), 7.62-7.57 (1 H, m), 7.51 (1 H , d, J = 8.0 Hz), 7.33 (1 H, d, J = 73.7 Hz).
ESI-MS m / z: 314 [M + H] ⁺ .

製造例161：ターシャリーブチル (2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニル)カルバメート[化合物No.161]の合成
実施例161-1：2-((ターシャリーブトキシカルボニル)アミノ)安息香酸の合成
2-アミノ安息香酸(1.587 g, 11.6 mmol)をTHF(16 ml)、水(16 ml)に懸濁させた。そこへ1 mol/l水酸化ナトリウム水溶液をpH=10になるまで加えた。そこへジ-ターシャリーブチルジカルボネート(2.772 g, 12.7 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。そこへ15%クエン酸水溶液を加えてpH=4にした。沈殿物をろ過して減圧乾燥し、標記の化合物(2.075 g, 75.4%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.25 (1H, br s), 8.24 (1H, dd, J = 8.2, 0.9 Hz), 7.96 (1H, dd, J = 8.2, 1.5 Hz), 7.50-7.46 (1H, m), 7.02 (1H, ddd, J = 8.2, 6.9, 0.9 Hz), 1.48 (9H, s). Preparation Example 161: Tertiary butyl (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl) carbamate [Compound No. 161] Synthesis Example 161- Synthesis of 1: 2-((tertiary butoxycarbonyl) amino) benzoic acid
2-Aminobenzoic acid (1.587 g, 11.6 mmol) was suspended in THF (16 ml), water (16 ml). The 1 mol / l sodium hydroxide aqueous solution was added there until it was set to pH = 10. The di-tertiary butyl dicarbonate (2.772 g, 12.7 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. Thereto was added a 15% aqueous citric acid solution to adjust to pH = 4. The precipitate was filtered and dried under reduced pressure to give the title compound (2.075 g, 75.4%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.25 (1 H, br s), 8.24 (1 H, dd, J = 8.2, 0.9 Hz), 7.96 (1 H, dd, J = 8.2, 1.5 Hz), 7.50-7.46 (1 H, m), 7.02 (1 H, ddd, J = 8.2, 6.9, 0.9 Hz), 1.48 (9 H, s).

実施例161-2：ターシャリーブチル(2-(1,3,4-オキサジアゾール-2-イル)フェニル)カルバメートの合成
実施例161-1で得られた化合物(637 mg, 2.68 mmol)をジクロロメタン(13 ml)に溶解した。そこへ(イソシアノイミノ)トリフェニルホスホラン(974 mg, 3.22 mmol)を加えて室温で3日間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(183 mg, 26.1%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 10.11 (1H, br s), 9.43 (1H, s), 8.29 (1H, dd, J = 8.5, 0.6 Hz), 7.95-7.92 (1H, m), 7.62-7.58 (1H, m), 7.26-7.22 (1H, m), 1.50 (9H, s). Example 161-2 Synthesis of tert-butyl (2- (1,3,4-oxadiazol-2-yl) phenyl) carbamate
The compound (637 mg, 2.68 mmol) obtained in Example 161-1 was dissolved in dichloromethane (13 ml). The (isocyanoimino) triphenylphosphorane (974 mg, 3.22 mmol) was added there, and it stirred at room temperature for 3 days. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (183 mg, 26.1%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 10.11 (1 H, br s), 9.43 (1 H, s), 8. 29 (1 H, dd, J = 8.5, 0.6 Hz), 7.95-7.92 (1H, m), 7.62-7.58 (1H, m), 7.26-7.22 (1H, m), 1.50 (9H, s).

実施例161-3：ターシャリーブチル (2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェニル)カルバメート[化合物No.161]の合成
実施例161-2で得られた化合物(182 mg, 0.69 mmol)と実施例32-5で得られた化合物(254 mg, 1.39 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(75 mg, 30.0%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.93 (1H, br s), 8.98 (1H, dd, J = 2.1, 0.9 Hz), 8.77 (1H, dd, J = 4.9, 1.8 Hz), 8.24 (1H, dt, J = 7.9, 1.8 Hz), 8.18 (1H, d, J = 8.2 Hz), 7.94 (1H, dd, J = 7.9, 1.8 Hz), 7.65-7.58 (2H, m), 7.29-7.25 (1H, m), 1.49 (9H, s).
ESI-MS m/z:363[M+H]⁺. Example 161-3 Synthesis of tert-butyl (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl) carbamate [Compound No. 161]
Using the compound (182 mg, 0.69 mmol) obtained in Example 161-2 and the compound (254 mg, 1.39 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (75 mg, 30.0%) was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.93 (1 H, br s), 8. 98 (1 H, dd, J = 2.1, 0.9 Hz), 8.77 (1 H, dd, J = 4.9, 1.8 Hz), 8.24 (1H, dt, J = 7.9, 1.8 Hz), 8.18 (1 H, d, J = 8.2 Hz), 7.94 (1 H, dd, J = 7.9, 1.8 Hz), 7.65-7.58 (2H, 2H) m), 7.29-7.25 (1 H, m), 1. 49 (9 H, s).
ESI-MS m / z: 363 [M + H] ⁺ .

製造例162：2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)アニリン[化合物No.162]の合成
実施例162-1：2-(1,3,4-オキサジアゾール-2-イル)アニリンの合成
2-アミノ安息香酸(374 mg, 2.73 mmol)をジクロロメタン(7.4 ml)に懸濁させた。そこへ(イソシアノイミノ)トリフェニルホスホラン(989 mg, 3.27 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(115 mg, 26.1%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.27 (1H, s), 7.68 (1H, dd, J = 8.1, 1.4 Hz), 7.30-7.25 (1H, m), 6.91 (1H, dt, J = 8.1, 0.6 Hz), 6.75 (2H, br s), 6.70-6.66 (1H, m).
ESI-MS m/z:162[M+H]⁺. Preparation Example 162 Synthesis of 2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) aniline [Compound No. 162] Example 162-1: 2- (1 Of 3,4-Oxadiazol-2-yl) aniline
2-Aminobenzoic acid (374 mg, 2.73 mmol) was suspended in dichloromethane (7.4 ml). The (isocyano imino) triphenyl phosphorane (989 mg, 3.27 mmol) was added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (115 mg, 26.1%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.27 (1 H, s), 7.68 (1 H, dd, J = 8.1, 1.4 Hz), 7.30-7.25 (1 H, m), 6.91 ( 1 H, dt, J = 8.1, 0.6 Hz), 6.75 (2 H, br s), 6.70-6. 66 (1 H, m).
ESI-MS m / z: 162 [M + H] ⁺ .

実施例162-2：2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)アニリン[化合物No.162]の合成
実施例162-1で得られた化合物(115 mg, 0.99 mmol)と実施例32-5で得られた化合物(360 mg, 1.98 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(2.1 mg, 0.8%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, dd, J = 2.1, 0.9 Hz), 8.76 (1H, dd, J = 5.0, 1.5 Hz), 8.23 (1H, dt, J = 8.0, 2.0 Hz), 7.68 (1H, dd, J = 8.0, 1.2 Hz), 7.59 (1H, ddd, J = 8.0, 5.0, 0.9 Hz), 7.33-7.29 (1H, m), 6.93 (1H, dd, J = 8.5, 0.6 Hz), 6.81 (2H, br s), 6.72-6.68 (1H, m).
ESI-MS m/z:263[M+H]⁺. Example 162-2 Synthesis of 2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) aniline [Compound No. 162]
Using the compound (115 mg, 0.99 mmol) obtained in Example 162-1 and the compound (360 mg, 1.98 mmol) obtained in Example 32-5, the same operation as in Example 32-6 The title compound (2.1 mg, 0.8%) was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, dd, J = 2.1, 0.9 Hz), 8. 76 (1 H, dd, J = 5.0, 1.5 Hz), 8.23 (1 H, 1 H, dt, J = 8.0, 2.0 Hz), 7.68 (1 H, dd, J = 8.0, 1.2 Hz), 7.59 (1 H, ddd, J = 8.0, 5.0, 0.9 Hz), 7.33-7.29 (1 H, m), 6.93 (1H, dd, J = 8.5, 0.6 Hz), 6.81 (2H, br s), 6.72-6.68 (1 H, m).
ESI-MS m / z: 263 [M + H] ⁺ .

製造例163：(5-((5-(2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾール-2-イル)エチニル)ピリジン-2-イル)メタノール[化合物No.163]の合成
実施例163-1：(5-ヨードピリジン-2-イル)メタノールの合成
2,5-ジヨードピリジン(2.616 g, 7.91 mmol)をトルエン(94 ml)に溶解し、-78℃で攪拌した。そこへ1.6 mol/l n-ブチルリチウムヘキサン溶液(5.93 ml, 9.49 mmol)を加えて-78℃で2時間攪拌した。そこへDMF(1 ml)を加えて1時間攪拌した。-10℃まで昇温して、水素化ホウ素ナトリウム(598 mg, 15.82 mmol)を加えて氷冷下で30分攪拌した。飽和塩化アンモニウム水溶液を加えて有機層を分離した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, クロロホルム/メタノール)で精製し、標記の化合物(894 mg, 48.1%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.78 (1H, d, J = 2.1 Hz), 8.00 (1H, dd, J = 8.2, 2.1 Hz), 7.10 (1H, d, J = 8.2 Hz), 4.72 (2H, s).
ESI-MS m/z:236[M+H]⁺. Production Example 163: (5-((5- (2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazol-2-yl) ethynyl) pyridin-2-yl) methanol [Compound No. 163] Synthesis of (5-iodopyridin-2-yl) methanol
2,5-diiodopyridine (2.616 g, 7.91 mmol) was dissolved in toluene (94 ml) and stirred at -78.degree. A 1.6 mol / l n-butyllithium hexane solution (5.93 ml, 9.49 mmol) was added there, and it stirred at -78 degreeC for 2 hours. The DMF (1 ml) was added there, and it stirred for 1 hour. The temperature was raised to −10 ° C., sodium borohydride (598 mg, 15.82 mmol) was added, and the mixture was stirred for 30 minutes under ice cooling. Saturated aqueous ammonium chloride solution was added and the organic layer was separated. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, chloroform / methanol) to give the title compound (894 mg, 48.1%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.78 (1 H, d, J = 2.1 Hz), 8.00 (1 H, dd, J = 8.2, 2.1 Hz), 7.10 (1 H, d, J = 8.2 Hz), 4.72 (2H, s).
ESI-MS m / z: 236 [M + H] ⁺ .

実施例163-2：2-(((ターシャリーブチルジメチルシリル)オキシ)メチル)-5-ヨードピリジンの合成
実施例163-1で得られた化合物(894 mg, 3.8 mmol)をDMF(18 ml)に溶解した。そこへターシャリーブチルジメチルシリルクロライド(688 mg, 4.56 mmol)、イミダゾール(388 mg, 5.7 mmol)を加えて室温で3時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(1.450 g, quant.)を無色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.72 (1H, d, J = 2.1 Hz), 8.20 (1H, dd, J = 8.2, 2.1 Hz), 7.29 (1H, d, J = 8.2 Hz), 4.70 (2H, s), 0.91 (9H, s), 0.09 (6H, s).
ESI-MS m/z:350[M+H]⁺. Example 163-2 Synthesis of 2-(((tert-butyldimethylsilyl) oxy) methyl) -5-iodopyridine
The compound obtained in Example 163-1 (894 mg, 3.8 mmol) was dissolved in DMF (18 ml). The tertiary butyl dimethyl silyl chloride (688 mg, 4.56 mmol) and the imidazole (388 mg, 5.7 mmol) were added there, and it stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 25 g, hexane / ethyl acetate) to give the title compound (1.450 g, quant.) As a colorless oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.72 (1 H, d, J = 2.1 Hz), 8.20 (1 H, dd, J = 8.2, 2.1 Hz), 7.29 (1 H, d, J = 8.2 Hz), 4.70 (2 H, s), 0.91 (9 H, s), 0.09 (6 H, s).
ESI-MS m / z: 350 [M + H] ⁺ .

実施例163-3：2-((6-(((ターシャリーブチルジメチルシリル)オキシ)メチル)ピリジン-3-イル)エチニル)-5-(2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾールの合成
実施例163-2で得られた化合物(497 mg, 1.42 mmol)をDMF(10 ml)に溶解した。そこへビストリフェニルホスフィンパラジウムクロライド(60 mg, 0.085 mmol)、ヨウ化銅(I)(54 mg, 0.284 mmol)、実施例135-5で得られた化合物(541 mg, 2.13 mmol)、トリエチルアミン(0.594 ml, 4.26 mmol)を加えて70℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(58 mg, 8.6%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]:8.90 (1H, d, J = 1.8 Hz), 8.27 (1H, dd, J = 8.2, 2.1 Hz), 8.19 (1H, dd, J = 7.6, 1.8 Hz), 7.84 (1H, dt, J = 11.1, 4.0 Hz), 7.70 (2H, d, J = 7.3 Hz), 7.60 (1H, d, J = 8.2 Hz), 4.84 (2H, s), 0.94 (9H, s), 0.13 (6H, s).
ESI-MS m/z:476[M+H]⁺. Example 163-3: 2- (2-((6-(((tert-butyldimethylsilyl) oxy) methyl) pyridin-3-yl) ethynyl) -5- (2- (trifluoromethoxy) phenyl) -1,3) , 4-Oxadiazole Synthesis
The compound (497 mg, 1.42 mmol) obtained in Example 163-2 was dissolved in DMF (10 ml). There, bis triphenyl phosphine palladium chloride (60 mg, 0.085 mmol), copper (I) iodide (54 mg, 0.284 mmol), the compound obtained in Example 135-5 (541 mg, 2.13 mmol), triethylamine (0.594) ml, 4.26 mmol) was added and stirred at 70 ° C. overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (58 mg, 8.6%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.90 (1 H, d, J = 1.8 Hz), 8.27 (1 H, dd, J = 8.2, 2.1 Hz), 8.19 (1 H, dd, J = 7.6, 1.8 Hz), 7.84 (1 H, dt, J = 11.1, 4.0 Hz), 7.70 (2 H, d, J = 7.3 Hz), 7.60 (1 H, d, J = 8.2 Hz), 4.84 (2 H, 2 H, d s), 0.94 (9H, s), 0.13 (6H, s).
ESI-MS m / z: 476 [M + H] ⁺ .

実施例163-4：(5-((5-(2-(トリフルオロメトキシ)フェニル)-1,3,4-オキサジアゾール-2-イル)エチニル)ピリジン-2-イル)メタノール[化合物No.163]の合成
実施例163-3で得られた化合物(54 mg, 0.113 mmol)をTHF(1 ml)に溶解した。そこへ1 mol/lテトラアンモニウムフルオライドTHF溶液(0.136 ml, 0.136 mmol)を加えて室温で30分間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, クロロホルム/メタノール)で精製し、さらにWaters社製MSトリガー付き分取LCシステムで精製し、標記の化合物(21 mg, 39.1%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.89 (1H, d, J = 1.7 Hz), 8.24 (1H, dd, J = 8.2, 2.1 Hz), 8.19 (1H, dd, J = 7.8, 1.7 Hz), 7.86-7.82 (1H, m), 7.70 (2H, d, J = 7.6 Hz), 7.65 (1H, t, J = 8.5 Hz), 4.65 (2H, s).
ESI-MS m/z:362[M+H]⁺. Example 163-4: (5-((5- (2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazol-2-yl) ethynyl) pyridin-2-yl) methanol [Compound No .163] synthesis
The compound (54 mg, 0.113 mmol) obtained in Example 163-3 was dissolved in THF (1 ml). The 1 mol / l tetraammonium fluoride THF solution (0.136 ml, 0.136 mmol) was added there, and it stirred at room temperature for 30 minutes. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 10 g, chloroform / methanol) and further purified by Waters MS triggered preparative LC system to obtain the title compound (21 mg, 39.1%) as a white solid .
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.89 (1 H, d, J = 1.7 Hz), 8.24 (1 H, dd, J = 8.2, 2.1 Hz), 8.19 (1 H, dd, J = 7.8, 1.7 Hz), 7.86-7.82 (1 H, m), 7. 70 (2 H, d, J = 7.6 Hz), 7. 65 (1 H, t, J = 8.5 Hz), 4. 65 (2 H, s).
ESI-MS m / z: 362 [M + H] ⁺ .

製造例164：ターシャリーブチル (2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)カルバメート[化合物No.164]の合成
実施例164-1：ターシャリーブチル (2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)カルバメート[化合物No.164]の合成
実施例138-5で得られた化合物(95 mg, 0.36 mmol)をDMF(2 ml)に溶解した。そこへ炭酸セシウム(141 mg, 0.43 mmol)、2-(ターシャリーブトキシカルボニルアミノ)エチルブロマイド(161 mg, 0.72 mmol)を加えて70℃で4時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(47 mg, 32.1%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 1.9 Hz), 8.75 (1H, dd, J = 4.9, 1.5 Hz), 8.23 (1H, dt, J = 8.0, 1.9 Hz), 7.92 (1H, dd, J = 7.8, 1.8 Hz), 7.65-7.61 (1H, m), 7.59 (1H, tt, J = 6.4, 1.8 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.17 (1H, t, J = 7.5 Hz), 6.93 (1H, t, J = 5.5 Hz), 4.16 (2H, t, J = 5.8 Hz), 3.35 (2H, t, J = 7.3 Hz), 1.33 (9H, s).
ESI-MS m/z:407[M+H]⁺. Preparation Example 164: tert-butyl (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) carbamate [Compound No. 164] Synthesis Example 164-1: Tertiary butyl (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) carbamate [Compound No. 164] synthesis
The compound (95 mg, 0.36 mmol) obtained in Example 138-5 was dissolved in DMF (2 ml). Cesium carbonate (141 mg, 0.43 mmol) and 2- (tertiary butoxycarbonylamino) ethyl bromide (161 mg, 0.72 mmol) were added thereto, and the mixture was stirred at 70 ° C. for 4 hours. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, hexane / ethyl acetate) to give the title compound (47 mg, 32.1%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 1.9 Hz), 8.75 (1 H, dd, J = 4.9, 1.5 Hz), 8.23 (1 H, dt, J = 8.0, 1.9 Hz), 7.92 (1 H, dd, J = 7.8, 1.8 Hz), 7.65-7.61 (1 H, m), 7.59 (1 H, tt, J = 6.4, 1.8 Hz), 7.31 (1 H, d , J = 8.2 Hz), 7.17 (1 H, t, J = 7.5 Hz), 6. 93 (1 H, t, J = 5.5 Hz), 4. 16 (2 H, t, J = 5.8 Hz), 3. 35 (2 H, t, J = 7.3 Hz), 1.33 (9 H, s).
ESI-MS m / z: 407 [M + H] ⁺ .

製造例165：4-(2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)モルホリン[化合物No.165]の合成
実施例165-1：4-(2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)モルホリン[化合物No.165]の合成
実施例138-5で得られた化合物(183 mg, 0.7 mmol)をDMF(3.6 ml)に溶解した。そこへ炭酸セシウム(544 mg, 1.67 mmol)、4-(2-クロロエチル)モルホリン塩酸塩(261 mg, 1.40 mmol)、ヨウ化カリウム(232 mg, 1.40 mmol)を加えて70 ℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, クロロホルム/酢酸エチル)で精製し、標記の化合物(105 mg, 39.9%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, d, J = 1.8 Hz), 8.76 (1H, dd, J = 4.9, 1.5 Hz), 8.22 (1H, s), 7.95 (1H, s), 7.66-7.62 (1H, m), 7.61-7.57 (1H, m), 7.32 (1H, d, J = 8.5 Hz), 7.16 (1H, t, J = 7.5 Hz), 4.27 (2H, t, J = 5.3 Hz), 4.20 (1H, t, J = 5.6 Hz), 3.55 (6H, t, J = 4.1 Hz), 2.76 (2H, t, J = 5.3 Hz).
ESI-MS m/z:377[M+H]⁺. Preparation Example 165: Synthesis of 4- (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) morpholine [Compound No. 165] Example 165-1: 4- (2- (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) morpholine [Compound No. 165] Synthesis of
The compound (183 mg, 0.7 mmol) obtained in Example 138-5 was dissolved in DMF (3.6 ml). Cesium carbonate (544 mg, 1.67 mmol), 4- (2-chloroethyl) morpholine hydrochloride (261 mg, 1.40 mmol), and potassium iodide (232 mg, 1.40 mmol) were added thereto, and stirred overnight at 70 ° C . After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, chloroform / ethyl acetate) to give the title compound (105 mg, 39.9%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, d, J = 1.8 Hz), 8. 76 (1 H, dd, J = 4.9, 1.5 Hz), 8.22 (1 H, s) , 7.95 (1H, s), 7.66-7.62 (1H, m), 7.61-7.57 (1H, m), 7.32 (1H, d, J = 8.5 Hz), 7.16 (1 H, t, J = 7.5 Hz), 4.27 (2H, t, J = 5.3 Hz), 4.20 (1 H, t, J = 5.6 Hz), 3.55 (6 H, t, J = 4.1 Hz), 2. 76 (2 H, t, J = 5.3 Hz).
ESI-MS m / z: 377 [M + H] ⁺ .

製造例166：2-(2-(2-(ピペリジン-1-イル)エトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.166]の合成
実施例166-1：2-(2-(2-(ピペリジン-1-イル)エトキシ)フェニル)-5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール[化合物No.166]の合成
実施例138-5で得られた化合物(109 mg, 0.41 mmol)をDMF(2.2 ml)に溶解した。そこへ炭酸セシウム(324 mg, 0.99 mmol)、1-(2-クロロエチル)ピペリジン塩酸塩(151 mg, 0.82 mmol)、ヨウ化カリウム(136 mg, 0.82 mmol)を加えて70 ℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, クロロホルム/酢酸エチル)で精製し、標記の化合物(107 mg, 69.7%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, t, J = 0.9 Hz), 8.76 (1H, dd, J = 5.0, 1.7 Hz), 8.20 (1H, dt, J = 7.9, 1.8 Hz), 7.93 (1H, dd, J = 7.8, 1.7 Hz), 7.65-7.58 (2H, m), 7.31 (1H, d, J = 8.5 Hz), 7.17-7.14 (1H, m), 4.24 (2H, t, J = 5.5 Hz), 2.72-2.70 (2H, m), 2.54 (2H, q, J = 7.9 Hz), 2.47-2.45 (4H, m), 1.48-1.42 (4H, m), 1.31 (2H, d, J = 18.0 Hz).
ESI-MS m/z:375[M+H]⁺. Preparation Example 166: 2- (2- (2- (piperidin-1-yl) ethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 166] Synthesis Example 166-1: 2- (2- (2- (piperidin-1-yl) ethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole [Compound No. 1] 166] synthesis
The compound (109 mg, 0.41 mmol) obtained in Example 138-5 was dissolved in DMF (2.2 ml). Cesium carbonate (324 mg, 0.99 mmol), 1- (2-chloroethyl) piperidine hydrochloride (151 mg, 0.82 mmol), and potassium iodide (136 mg, 0.82 mmol) were added thereto, and the mixture was stirred overnight at 70 ° C. . After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, chloroform / ethyl acetate) to give the title compound (107 mg, 69.7%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, t, J = 0.9 Hz), 8. 76 (1 H, dd, J = 5.0, 1.7 Hz), 8.20 (1 H, dt, J = 7.9, 1.8 Hz), 7.93 (1 H, dd, J = 7.8, 1.7 Hz), 7.65-7.58 (2 H, m), 7.31 (1 H, d, J = 8.5 Hz), 7.17-7.14 (1 H, m) ), 4.24 (2H, t, J = 5.5 Hz), 2.72-2.70 (2H, m), 2.54 (2H, q, J = 7.9 Hz), 2.47-2.45 (4H, m), 1.48-1.42 (4H, 4) m), 1.31 (2H, d, J = 18.0 Hz).
ESI-MS m / z: 375 [M + H] ⁺ .

製造例167：2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチルアセテート[化合物No.167]の合成
実施例167-1：2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチルアセテート[化合物No.167]の合成
実施例138-5で得られた化合物(112 mg, 0.43 mmol)をDMF(2.2 ml)に溶解した。そこへ炭酸セシウム(166 mg, 0.51 mmol)、2-ブロモエチルアセテート(0.094 ml, 0.86 mmol)、ヨウ化カリウム(143 g, 0.86 mmol)を加えて70 ℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, クロロホルム/酢酸エチル)で精製し、標記の化合物(107 mg, 69.7%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 1.8 Hz), 8.76 (1H, dd, J = 4.9, 1.5 Hz), 8.22 (1H, dt, J = 7.9, 1.8 Hz), 7.95 (1H, dd, J = 7.8, 1.7 Hz), 7.67-7.63 (1H, m), 7.59 (1H, ddd, J = 7.9, 4.9, 0.6 Hz), 7.33 (1H, d, J = 8.5 Hz), 7.19 (1H, t, J = 7.3 Hz), 4.42-4.40 (2H, m), 4.38-4.36 (2H, m), 2.01 (3H, s).
ESI-MS m/z:350[M+H]⁺. Preparation Example 167 Synthesis of 2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl acetate [Compound No. 167] Example 167- Synthesis of 1: 2- (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl acetate [Compound No. 167]
The compound obtained in Example 138-5 (112 mg, 0.43 mmol) was dissolved in DMF (2.2 ml). Cesium carbonate (166 mg, 0.51 mmol), 2-bromoethyl acetate (0.094 ml, 0.86 mmol) and potassium iodide (143 g, 0.86 mmol) were added thereto, and the mixture was stirred at 70 ° C. overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, chloroform / ethyl acetate) to give the title compound (107 mg, 69.7%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 1.8 Hz), 8. 76 (1 H, dd, J = 4.9, 1.5 Hz), 8.22 (1 H, dt, J = 7.9, 1.8 Hz), 7.95 (1 H, dd, J = 7.8, 1.7 Hz), 7.67-7.63 (1 H, m), 7.59 (1 H, ddd, J = 7.9, 4.9, 0.6 Hz), 7.33 (1 H , d, J = 8.5 Hz), 7.19 (1 H, t, J = 7.3 Hz), 4.42-4.40 (2 H, m), 4.38-4.36 (2 H, m), 2.01 (3 H, s).
ESI-MS m / z: 350 [M + H] ⁺ .

製造例168：ターシャリーブチル 4-(2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)ピペラジン-1-カルボキシレート[化合物No.168]の合成
実施例168-1：ターシャリーブチル 4-(2-ブロモメチル)ピペラジン-1-カルボキシレートの合成
四臭化炭素(1.681 g, 5.07 mmol)をジクロロメタン(17 ml)に溶解し、氷冷した。そこへターシャリーブチル 4-(2-ヒドロキシメチル)ピペラジン-1-カルボキシレート(1.062 g, 4.61 mmol)、トリフェニルホスフィン(1.329 g, 5.07 mmol)、ジクロロメタン(11 ml)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(1.131 g, 83.7%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 3.64-3.53 (2H, m), 3.31-3.22 (4H, m), 2.73-2.67 (2H, m), 2.42-2.35 (4H, m), 1.39 (9H, s).
ESI-MS m/z:293[M+H]⁺. Preparation Example 168: tert-butyl 4- (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) piperazine-1-carboxylate Synthesis of [Compound No. 168] Example 168-1: Synthesis of tertiary butyl 4- (2-bromomethyl) piperazine-1-carboxylate
Carbon tetrabromide (1.681 g, 5.07 mmol) was dissolved in dichloromethane (17 ml) and ice-cooled. Tertiary butyl 4- (2-hydroxymethyl) piperazine-1-carboxylate (1.062 g, 4.61 mmol), triphenylphosphine (1.329 g, 5.07 mmol) and dichloromethane (11 ml) were added thereto, and the mixture was allowed to stand overnight at room temperature. It stirred. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (1.131 g, 83.7%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.64-3.53 (2H, m), 3.31-3.22 (4H, m), 2.73-2.67 (2H, m), 2.42-2.35 (4H , m), 1.39 (9H, s).
ESI-MS m / z: 293 [M + H] ⁺ .

実施例168-2：ターシャリーブチル 4-(2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エチル)ピペラジン-1-カルボキシレート[化合物No.168]の合成
実施例138-5で得られた化合物(141 mg, 0.54 mmol)をDMF(2.8 ml)に溶解した。そこへ炭酸セシウム(209 mg, 0.64 mmol)、ターシャリーブチル 4-(2-ブロモメチル)ピペラジン-1-カルボキシレート(317 mg, 1.08 mmol)、ヨウ化カリウム(179 mg, 1.08 mmol)を加えて70 ℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Chromatorex NH 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(246 mg, 95.8%)を黄色油状物として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, d, J = 1.8 Hz), 8.75 (1H, dd, J = 4.9, 1.5 Hz), 8.21 (1H, dt, J = 8.0, 1.7 Hz), 7.95 (1H, d, J = 1.2 Hz), 7.66-7.62 (1H, m), 7.58 (1H, dd, J = 7.9, 4.9 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.16 (1H, t, J = 7.6 Hz), 4.26 (2H, t, J = 5.0 Hz), 3.30-3.26 (6H, m), 2.79 (2H, t, J = 5.2 Hz), 2.38-2.32 (2H, m), 1.32 (9H, s).
ESI-MS m/z:475[M+H]⁺. Example 168-2: Tertiary butyl 4- (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) piperazine-1 Synthesis of Carboxylate [Compound No. 168]
The compound (141 mg, 0.54 mmol) obtained in Example 138-5 was dissolved in DMF (2.8 ml). Cesium carbonate (209 mg, 0.64 mmol), tert-butyl 4- (2-bromomethyl) piperazine-1-carboxylate (317 mg, 1.08 mmol), and potassium iodide (179 mg, 1.08 mmol) are added thereto to obtain 70 Stir overnight at ° C. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Chromatorex NH 10 g, hexane / ethyl acetate) to give the title compound (246 mg, 95.8%) as a yellow oil.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, d, J = 1.8 Hz), 8.75 (1 H, dd, J = 4.9, 1.5 Hz), 8.21 (1 H, dt, J = 8.0, 1.7 Hz), 7.95 (1 H, d, J = 1.2 Hz), 7.66-7.62 (1 H, m), 7.58 (1 H, dd, J = 7.9, 4.9 Hz), 7.31 (1 H, d, J = 8.5 Hz), 7.16 (1 H, t, J = 7.6 Hz), 4. 26 (2 H, t, J = 5.0 Hz), 3. 30-3. 26 (6 H, m), 2. 79 (2 H, t, J = 5.2 Hz), 2.38-2.32 (2H, m), 1.32 (9H, s).
ESI-MS m / z: 475 [M + H] ⁺ .

製造例169：2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エタノール[化合物No.169]の合成
実施例169-1：2-(2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)エタノール[化合物No.169]の合成
実施例167-1で得られた化合物(75 mg, 0.21 mmol)をメタノール(1.5 ml)に溶解した。そこへナトリウムメトキシド(23 mg, 0.42 mmol)を加えて室温で30分間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SANP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(48 mg, 74.4%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.97 (1H, d, J = 2.1 Hz), 8.76 (1H, dd, J = 4.7, 1.7 Hz), 8.23 (1H, dt, J = 7.9, 1.7 Hz), 7.91 (1H, dd, J = 7.8, 1.7 Hz), 7.65-7.61 (1H, m), 7.61-7.57 (1H, m), 7.33 (1H, d, J = 8.5 Hz), 7.16 (1H, t, J = 7.5 Hz), 4.86 (1H, t, J = 5.6 Hz), 4.20 (2H, t, J = 5.0 Hz), 3.79-3.75 (2H, m).
ESI-MS m/z:308[M+H]⁺. Preparation Example 169 Synthesis of 2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethanol [Compound No. 169] Example 169-1 Synthesis of 2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethanol [Compound No. 169]
The compound obtained in Example 167-1 (75 mg, 0.21 mmol) was dissolved in methanol (1.5 ml). Thereto, sodium methoxide (23 mg, 0.42 mmol) was added and stirred at room temperature for 30 minutes. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SANP 10 g, chloroform / methanol) to give the title compound (48 mg, 74.4%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.97 (1 H, d, J = 2.1 Hz), 8.76 (1 H, dd, J = 4.7, 1.7 Hz), 8.23 (1 H, dt, J = 7.9, 1.7 Hz), 7. 91 (1 H, dd, J = 7.8, 1.7 Hz), 7.65-7.61 (1 H, m), 7.61-7. 57 (1 H, m), 7.33 (1 H, d, J = 8.5 Hz ), 7.16 (1 H, t, J = 7.5 Hz), 4.86 (1 H, t, J = 5.6 Hz), 4.20 (2 H, t, J = 5.0 Hz), 3.79-3. 75 (2 H, m).
ESI-MS m / z: 308 [M + H] ⁺ .

製造例170：ターシャリーブチル 4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)ベンジルカルバメート[化合物No.170]の合成
実施例170-1：ターシャリーブチル 4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)ベンジルカルバメート[化合物No.170]の合成
実施例138-5で得られた化合物(156 mg, 0.59 mmol)をDMF(3.2 ml)に溶解した。そこへ炭酸セシウム(231 mg, 0.708 mmol)、ターシャリーブチル4-(ブロモエチル)ベンジルカルバメート(354 mg, 1.18 mmol)を加えて70 ℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(171 mg, 60.1%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.96 (1H, d, J = 1.8 Hz), 8.77 (1H, dd, J = 4.9, 1.5 Hz), 8.21 (1H, dt, J = 7.9, 1.8 Hz), 7.96 (1H, dd, J = 7.8, 1.8 Hz), 7.65-7.59 (2H, m), 7.49 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.17 (1H, t, J = 7.5 Hz), 5.32 (2H, s), 4.10 (2H, d, J = 5.8 Hz), 1.36 (9H, s).
ESI-MS m/z:483[M+H]⁺. Preparation Example 170: tert-butyl 4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) benzyl carbamate [Compound No. 170] Synthesis Example 170-1: Tertiary butyl 4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) benzyl carbamate [compound No.170] synthesis
The compound (156 mg, 0.59 mmol) obtained in Example 138-5 was dissolved in DMF (3.2 ml). Cesium carbonate (231 mg, 0.708 mmol) and tert-butyl 4- (bromoethyl) benzyl carbamate (354 mg, 1.18 mmol) were added thereto, and the mixture was stirred at 70 ° C. overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 10 g, hexane / ethyl acetate) to give the title compound (171 mg, 60.1%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.96 (1 H, d, J = 1.8 Hz), 8.77 (1 H, dd, J = 4.9, 1.5 Hz), 8.21 (1 H, dt, J = 7.9, 1.8 Hz), 7.96 (1 H, dd, J = 7.8, 1.8 Hz), 7.65-7.59 (2 H, m), 7.49 (2 H, d, J = 8.2 Hz), 7.37 (2 H, d, J = 8.2 Hz), 7.24 (2H, d, J = 7.9 Hz), 7.17 (1 H, t, J = 7.5 Hz), 5.32 (2 H, s), 4.10 (2 H, d, J = 5.8 Hz), 1.36 (1. 9H, s).
ESI-MS m / z: 483 [M + H] ⁺ .

製造例171：(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)フェニル)メタンアミン[化合物No.171]の合成
実施例171-1：(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)フェニル)メタンアミン[化合物No.171]の合成
実施例170-1で得られた化合物(158 mg, 0.33 mmol)をジクロロメタン(1.5 ml)に溶解した。そこへトリフルオロ酢酸(0.7 ml)を加えて室温で1時間攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(Chromatorex NH 10 g, クロロホルム/酢酸エチル)で精製し、標記の化合物(113 mg, 89.5%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.95 (1H, d, J = 2.1 Hz), 8.77 (1H, dd, J = 4.9, 1.5 Hz), 8.22 (1H, dt, J = 7.9, 1.8 Hz), 7.97 (1H, dd, J = 7.9, 1.8 Hz), 7.66-7.58 (2H, m), 7.49 (2H, d, J = 7.9 Hz), 7.38 (1H, d, J = 8.5 Hz), 7.35 (2H, d, J = 7.9 Hz), 7.18 (1H, t, J = 7.5 Hz), 5.31 (2H, s), 4.10 (2H, br s), 3.72 (2H, s).
ESI-MS m/z:383[M+H]⁺. Preparation Example 171: (4-((2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) phenyl) methanamine [Compound No. 171] Synthesis Example 171-1: (4-((2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) phenyl) methanamine [Compound No. 171] synthesis
The compound obtained in Example 170-1 (158 mg, 0.33 mmol) was dissolved in dichloromethane (1.5 ml). Trifluoroacetic acid (0.7 ml) was added there, and it stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (Chromatorex NH 10 g, chloroform / ethyl acetate) to give the title compound (113 mg, 89.5%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.95 (1 H, d, J = 2.1 Hz), 8.77 (1 H, dd, J = 4.9, 1.5 Hz), 8.22 (1 H, dt, J = 7.9, 1.8 Hz), 7.97 (1 H, dd, J = 7.9, 1.8 Hz), 7.66-7.58 (2 H, m), 7.49 (2 H, d, J = 7.9 Hz), 7.38 (1 H, d, J = 8.5 Hz), 7. 35 (2 H, d, J = 7.9 Hz), 7. 18 (1 H, t, J = 7.5 Hz), 5.31 (2 H, s), 4. 10 (2 H, br s), 3.72 (2 H, s) .
ESI-MS m / z: 383 [M + H] ⁺ .

製造例172：N,N-ジメチル-1-(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)フェニル)メタンアミン[化合物No.172]の合成
実施例172-1：N,N-ジメチル-1-(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)フェニル)メタンアミン[化合物No.172]の合成
実施例171-1で得られた化合物(50 mg, 0.13 mmol)をメタノール(1.5 ml)に溶解した。そこへ37%ホルムアルデヒド水溶液(0.029 ml, 0.39 mmol)、トリアセトキシ水素化ホウ素ナトリウム(83 mg, 0.39 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。1 mol/l水酸化ナトリウム水溶液を加えてクロロホルム:メタノール=10:1で抽出した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, クロロホルム/メタノール)で精製し、標記の化合物(52 mg, 97.4%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, d, J = 2.1 Hz), 8.77 (1H, dd, J = 4.9, 1.5 Hz), 8.21 (1H, dt, J = 7.9, 2.1 Hz), 7.99 (1H, dd, J = 7.9, 1.5 Hz), 7.67-7.63 (1H, m), 7.60 (1H, dd, J = 7.9, 4.9 Hz), 7.51 (2H, d, J = 7.9 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.29 (2H, d, J = 7.9 Hz), 7.19 (1H, t, J = 7.6 Hz), 5.31 (2H, s), 3.34 (2H, s), 2.09 (6H, s).
ESI-MS m/z:411[M+H]⁺. Preparation Example 172: N, N-dimethyl-1- (4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) phenyl) Synthesis of Methaneamine [Compound No. 172] Example 172-1: N, N-Dimethyl-1- (4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole) Synthesis of -2-yl) phenoxy) methyl) phenyl) methanamine [compound No. 172]
The compound (50 mg, 0.13 mmol) obtained in Example 171-1 was dissolved in methanol (1.5 ml). Thereto were added 37% aqueous formaldehyde solution (0.029 ml, 0.39 mmol) and sodium triacetoxyborohydride (83 mg, 0.39 mmol), and the mixture was stirred overnight at room temperature. After the reaction, the solvent was distilled off. A 1 mol / l aqueous solution of sodium hydroxide was added and extracted with chloroform: methanol = 10: 1. Washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, chloroform / methanol) to give the title compound (52 mg, 97.4%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, d, J = 2.1 Hz), 8.77 (1 H, dd, J = 4.9, 1.5 Hz), 8.21 (1 H, dt, J = 7.9, 2.1 Hz), 7.99 (1 H, dd, J = 7.9, 1.5 Hz), 7.67-7.63 (1 H, m), 7.60 (1 H, dd, J = 7.9, 4.9 Hz), 7.51 (2 H, d , J = 7.9 Hz), 7.39 (1 H, d, J = 8.5 Hz), 7. 29 (2 H, d, J = 7.9 Hz), 7.19 (1 H, t, J = 7.6 Hz), 5.31 (2 H, s), 3.34 (2H, s), 2.09 (6H, s).
ESI-MS m / z: 411 [M + H] ⁺ .

製造例173：N-プロピル-N-(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)ベンジル)プロパン-1-アミン[化合物No.173]の合成
実施例173-1：N-プロピル-N-(4-((2-(5-(ピリジン-3-イルエチニル)-1,3,4-オキサジアゾール-2-イル)フェノキシ)メチル)ベンジル)プロパン-1-アミン[化合物No.173]の合成
実施例171-1で得られた化合物(55 mg, 0.14 mmol)をメタノール(1.6 ml)に溶解した。そこへプロピオンアルデヒド(0.031 ml, 0.43 mmol)、トリアセトキシ水素化ホウ素ナトリウム(91 mg, 0.43 mmol)を加えて室温で一晩攪拌した。反応後、溶媒を留去した。1 mol/l水酸化ナトリウム水溶液を加えてクロロホルム:メタノール=10:1で抽出した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 10 g, クロロホルム/メタノール)で精製し、標記の化合物(51 mg, 78.1%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.94 (1H, d, J = 2.0 Hz), 8.77 (1H, dd, J = 4.9, 1.5 Hz), 8.21 (1H, dt, J = 7.9, 2.0 Hz), 7.99 (1H, dd, J = 7.9, 1.5 Hz), 7.67-7.63 (1H, m), 7.59 (1H, dd, J = 7.9, 4.9 Hz), 7.49 (2H, d, J = 7.9 Hz), 7.39 (1H, d, J = 8.5 Hz), 7.30 (2H, d, J = 7.9 Hz), 7.19 (1H, t, J = 7.5 Hz), 5.30 (2H, s), 3.47 (2H, s), 2.27 (4H, t, J = 7.3 Hz), 1.40-1.31 (4H, m), 0.76 (6H, t, J = 7.3 Hz).
ESI-MS m/z:467[M+H]⁺. Preparation Example 173: N-propyl-N- (4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) benzyl) propane- Synthesis of 1-Amine [Compound No. 173] Example 173-1: N-propyl-N- (4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole) Synthesis of -2-yl) phenoxy) methyl) benzyl) propan-1-amine [Compound No. 173]
The compound (55 mg, 0.14 mmol) obtained in Example 171-1 was dissolved in methanol (1.6 ml). The propionaldehyde (0.031 ml, 0.43 mmol) and sodium triacetoxyborohydride (91 mg, 0.43 mmol) were added there, and it stirred at room temperature overnight. After the reaction, the solvent was distilled off. A 1 mol / l aqueous solution of sodium hydroxide was added and extracted with chloroform: methanol = 10: 1. Washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP ULTRA 10 g, chloroform / methanol) to give the title compound (51 mg, 78.1%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.94 (1 H, d, J = 2.0 Hz), 8.77 (1 H, dd, J = 4.9, 1.5 Hz), 8.21 (1 H, dt, J = 7.9, 2.0 Hz), 7.99 (1 H, dd, J = 7.9, 1.5 Hz), 7.67-7.63 (1 H, m), 7.59 (1 H, dd, J = 7.9, 4.9 Hz), 7.49 (2 H, d , J = 7.9 Hz), 7.39 (1 H, d, J = 8.5 Hz), 7.30 (2 H, d, J = 7.9 Hz), 7.19 (1 H, t, J = 7.5 Hz), 5.30 (2 H, s), 3.47 (2H, s), 2.27 (4H, t, J = 7.3 Hz), 1.40-1. 31 (4H, m), 0.76 (6 H, t, J = 7.3 Hz).
ESI-MS m / z: 467 [M + H] ⁺ .

製造例174：ジメチル2-プロピオールアミドテレフタレート[化合物No.174]の合成
実施例174-1：ジメチル2-プロピオールアミドテレフタレート[化合物No.174]の合成
プロピオール酸(185 mg, 2.64 mmol)をジクロロメタン(2 ml)にけん濁させた。そこへオキサリルクロリド(0.238 ml, 2.77 mmol)、DMF(1滴)を加えて室温で3時間撹拌した。そこへジメチル2-アミノテレフタレート(552 mg, 2.64 mmol)を加えて一晩室温で撹拌した。反応後、水を加えてクロロホルム抽出した。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 50 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(56 mg, 8.1%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.14 (1H, br s), 8.53 (1H, s), 8.00 (1H, d, J = 8.3 Hz), 7.82 (1H, dd, J = 8.3, 1.0 Hz), 4.57 (1H, s), 3.89 (3H, d, J = 0.7 Hz), 3.87 (3H, d, J = 0.7 Hz).
ESI-MS m/z:262[M+H]⁺. Preparation Example 174: Synthesis of dimethyl 2-propiolamide terephthalate [compound No. 174] Example 174-1: Synthesis of dimethyl 2-propiolamide terephthalate [compound No. 174]
Propiolic acid (185 mg, 2.64 mmol) was suspended in dichloromethane (2 ml). The oxalyl chloride (0.238 ml, 2.77 mmol) and DMF (1 drop) were added there, and it stirred at room temperature for 3 hours. The dimethyl 2-amino terephthalate (552 mg, 2.64 mmol) was added there, and it stirred at room temperature overnight. After the reaction, water was added and extracted with chloroform. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 50 g, hexane / ethyl acetate) to give the title compound (56 mg, 8.1%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.14 (1 H, br s), 8.53 (1 H, s), 8.00 (1 H, d, J = 8.3 Hz), 7.82 (1 H, dd , J = 8.3, 1.0 Hz), 4.57 (1 H, s), 3.89 (3 H, d, J = 0.7 Hz), 3.87 (3 H, d, J = 0.7 Hz).
ESI-MS m / z: 262 [M + H] ⁺ .

製造例175：ジメチル2-(ブチ-2-イナミド)テレフタレート[化合物No.175]の合成
実施例175-1：ジメチル2-(ブチ-2-イナミド)テレフタレート[化合物No.175]の合成
ブチ-2-イン酸(159 mg, 1.89 mmol)をジクロロメタン(1.6 ml)にけん濁させた。そこへオキサリルクロリド(0.170 ml, 1.99 mmol)、DMF(1滴)を加えて室温で3時間撹拌した。そこへジメチル2-アミノテレフタレート(395 mg, 1.89 mmol)を加えて一晩室温で撹拌した。反応後、水を加えてクロロホルム抽出した。硫酸マグネシウムで乾燥し、溶媒を留去した。酢酸エチルで再結晶し、標記の化合物(344 mg, 66.1%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.01 (1H, br s), 8.63 (1H, s), 8.01 (1H, d, J = 8.3 Hz), 7.78 (1H, dd, J = 8.3, 1.7 Hz), 3.89 (3H, s), 3.87 (3H, s), 2.08 (3H, s).
ESI-MS m/z:276[M+H]⁺. Preparation Example 175: Synthesis of dimethyl 2- (but-2-ynamide) terephthalate [compound No. 175] Example 175-1: Synthesis of dimethyl 2- (but-2-ynamide) terephthalate [compound No. 175]
Buty-2-ynoic acid (159 mg, 1.89 mmol) was suspended in dichloromethane (1.6 ml). Thereto, oxalyl chloride (0.170 ml, 1.99 mmol) and DMF (1 drop) were added and stirred at room temperature for 3 hours. The dimethyl 2-amino terephthalate (395 mg, 1.89 mmol) was added there, and it stirred at room temperature overnight. After the reaction, water was added and extracted with chloroform. Dry over magnesium sulfate and evaporate the solvent. Recrystallization from ethyl acetate gave the title compound (344 mg, 66.1%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 11.01 (1 H, br s), 8.63 (1 H, s), 8.01 (1 H, d, J = 8.3 Hz), 7.78 (1 H, dd J = 8.3, 1.7 Hz), 3.89 (3H, s), 3.87 (3H, s), 2.08 (3H, s).
ESI-MS m / z: 276 [M + H] ⁺ .

製造例176：5-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]チアゾール[化合物No.176]の合成
実施例176-1：5-メトキシベンゾ[d]チアゾールの合成
5-メトキシベンゾ[d]チアゾール-2-アミン(397 mg, 2.2 mmol)をTHF(16 ml)に溶解した。そこへターシャリーブチルナイトライト(0.375 ml, 3.17 mmol)を加えて60℃で一晩攪拌した。反応後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(281 mg, 77.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.26 (1H, s), 7.69 (1H, dd, J = 8.0, 0.9 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.07 (1H, dd, J = 8.0, 0.9 Hz), 3.97 (3H, s).
ESI-MS m/z:166[M+H]⁺. Preparation Example 176 Synthesis of 5-methoxy-2- (pyridin-3-ylethynyl) benzo [d] thiazole [Compound No. 176] Example 176-1: Synthesis of 5-methoxybenzo [d] thiazole
5-methoxybenzo [d] thiazol-2-amine (397 mg, 2.2 mmol) was dissolved in THF (16 ml). The tertiary butyl nitrite (0.375 ml, 3.17 mmol) was added there, and it stirred at 60 degreeC overnight. After the reaction, the solvent was distilled off. The residue was purified by silica gel column chromatography (SNAP 10 g, hexane / ethyl acetate) to give the title compound (281 mg, 77.3%) as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.26 (1 H, s), 7.69 (1 H, dd, J = 8.0, 0.9 Hz), 7.43 (1 H, t, J = 8.0 Hz) , 7.07 (1H, dd, J = 8.0, 0.9 Hz), 3.97 (3H, s).
ESI-MS m / z: 166 [M + H] ⁺ .

実施例176-2：5-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]チアゾール[化合物No.176]の合成
実施例176-1で得られた化合物(121 mg, 0.73 mmol)と実施例32-5で得られた化合物(267 mg, 1.46 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(59 mg, 30.3%)を黄色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.92 (1H, dd, J = 2.3, 0.9 Hz), 8.71 (1H, dd, J = 4.8, 1.6 Hz), 8.18-8.15 (1H, m), 7.70 (1H, dd, J = 8.0, 0.9 Hz), 7.57-7.50 (2H, m), 7.14 (1H, dd, J = 8.0, 0.9 Hz), 3.99 (3H, s).
ESI-MS m/z:267[M+H]⁺. Example 176-2 Synthesis of 5-methoxy-2- (pyridin-3-ylethynyl) benzo [d] thiazole [Compound No. 176]
Using the compound (121 mg, 0.73 mmol) obtained in Example 176-1 and the compound (267 mg, 1.46 mmol) obtained in Example 32-5 in the same manner as in Example 32-6 The title compound (59 mg, 30.3%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.92 (1 H, dd, J = 2.3, 0.9 Hz), 8.71 (1 H, dd, J = 4.8, 1.6 Hz), 8.18-8.15 (8 1H, m), 7.70 (1H, dd, J = 8.0, 0.9 Hz), 7.57-7.50 (2H, m), 7.14 (1 H, dd, J = 8.0, 0.9 Hz), 3.99 (3H, s).
ESI-MS m / z: 267 [M + H] ⁺ .

製造例177: ターシャリーブチル 2-(ピリジン-3-イルエチニル)-1H-ベンゾ[d]イミダゾール-1-カルボキシレート[化合物No.177]の合成
実施例177-1：ターシャリーブチル 2-ブロモ-1H-ベンゾ[d]イミダゾール-1-カルボキレートの合成
2-ブロモ-1H-ベンズイミダゾール(700 mg, 3.55 mmol)をDMF(14 ml)、アセトニトリル(14 ml)に溶解し、トリエチルアミン(0.594 ml, 4.26 mmol)を加え、室温で30分攪拌した。そこへジ-ターシャリーブチルジカルボネート(1.162 g, 5.33 mmol)のDMF(10 ml)溶液を加えて室温で一晩攪拌した。反応後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(SNAP ULTRA 25 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(1.262 g, quant.)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.89 (1H, d, J = 7.3 Hz), 7.68 (1H, d, J = 7.3 Hz), 7.44-7.35 (2H, m), 1.68 (9H, s).
ESI-MS m/z:297[M+H]⁺. Preparation Example 177: Synthesis of tert-butyl 2- (pyridin-3-ylethynyl) -1H-benzo [d] imidazole-1-carboxylate [Compound No. 177] Example 177-1: Tertiary butyl 2-bromo- Synthesis of 1H-benzo [d] imidazole-1-carboxylate
2-Bromo-1H-benzimidazole (700 mg, 3.55 mmol) was dissolved in DMF (14 ml) and acetonitrile (14 ml), triethylamine (0.594 ml, 4.26 mmol) was added and stirred at room temperature for 30 minutes. A solution of di-tert-butyl dicarbonate (1.162 g, 5.33 mmol) in DMF (10 ml) was added thereto, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was evaporated and the residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (1.262 g, quant.) As a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 7.89 (1 H, d, J = 7.3 Hz), 7.68 (1 H, d, J = 7.3 Hz), 7.44-7. 35 (2 H, m) , 1.68 (9H, s).
ESI-MS m / z: 297 [M + H] ⁺ .

実施例177-2：ターシャリーブチル 2-(ピリジン-3-イルエチニル)-1H-ベンゾ[d]イミダゾール-1-カルボキシレート[化合物No.177]の合成
実施例177-1で得られた化合物(253 mg, 0.85 mmol)をトリエチルアミン(7.6 ml)に溶解した。そこへ酢酸パラジウム(19 mg, 0.085 mmol)、ヨウ化銅(I)(24 mg, 0.1275 mmol)、トリフェニルホスフィン(45 mg, 0.17 mmol)、3-エチニルピリジン(131 mg, 1.275 mmol)を加えて室温で一晩攪拌した。反応後、セライトろ過して、酢酸エチルで洗った。溶媒を留去した。酢酸エチルに溶かして1 mol/l塩酸、飽和重曹水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, ヘキサン/酢酸エチル)で精製し、標記の化合物(220 mg, 81.0%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.87 (1H, dd, J = 2.1, 0.9 Hz), 8.71 (1H, dd, J = 4.9, 1.5 Hz), 8.11 (1H, dq, J = 7.9, 1.5 Hz), 8.01-7.98 (1H, m), 7.77 (1H, dq, J = 7.9, 0.6 Hz), 7.56 (1H, ddd, J = 7.9, 4.9, 0.9 Hz), 7.53-7.49 (1H, m), 7.44 (1H, ddd, J = 8.2, 7.0, 0.9 Hz), 1.67 (9H, s).
ESI-MS m/z:320[M+H]⁺. Example 177-2: Synthesis of tertiary butyl 2- (pyridin-3-ylethynyl) -1H-benzo [d] imidazole-1-carboxylate [Compound No. 177]
The compound (253 mg, 0.85 mmol) obtained in Example 177-1 was dissolved in triethylamine (7.6 ml). Palladium acetate (19 mg, 0.085 mmol), copper (I) iodide (24 mg, 0.1275 mmol), triphenylphosphine (45 mg, 0.17 mmol) and 3-ethynylpyridine (131 mg, 1.275 mmol) were added thereto. Stir at room temperature overnight. After the reaction, the mixture was filtered through celite and washed with ethyl acetate. The solvent was distilled off. It was dissolved in ethyl acetate and washed with 1 mol / l hydrochloric acid and saturated aqueous sodium bicarbonate. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 10 g, hexane / ethyl acetate) to give the title compound (220 mg, 81.0%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.87 (1 H, dd, J = 2.1, 0.9 Hz), 8.71 (1 H, dd, J = 4.9, 1.5 Hz), 8.11 (1 H, 1 H, dq, J = 7.9, 1.5 Hz), 8.01-7.98 (1H, m), 7. 77 (1 H, dq, J = 7.9, 0.6 Hz), 7.56 (1 H, ddd, J = 7.9, 4.9, 0.9 Hz), 7.53 -7.49 (1 H, m), 7.44 (1 H, ddd, J = 8.2, 7.0, 0.9 Hz), 1.67 (9 H, s).
ESI-MS m / z: 320 [M + H] ⁺ .

製造例178：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]チアゾール[化合物No.178]の合成
実施例178-1：4-メトキシベンゾ[d]チアゾールの合成
4-メトキシベンゾ[d]チアゾール-2-アミン(300 mg, 1.66 mmol)のTHF(10 ml)溶液中に、ターシャリーブチルニトリル(394 μl, 3.32 mmol)を室温下滴下した。60℃で一晩撹拌した後、反応終了後、減圧下濃縮乾固した。残渣物をシリカゲルカラムクロマトグラフ法(ヘキサン/酢酸エチル)で精製し、標記の化合物(211 mg, 77 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.25 (1H, s), 7.69 (1H, d, J = 8.2 Hz), 7.43 (1H, dd, J = 8.2, 8.2 Hz), 7.07 (1H, d, J = 8.2 Hz), 3.97 (3H, s).
ESI-MS m/z:166[M+H]⁺. Preparation Example 178 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] thiazole [Compound No. 178] Example 178-1: Synthesis of 4-methoxybenzo [d] thiazole
Tertiary butyl nitrile (394 μl, 3.32 mmol) was added dropwise to a solution of 4-methoxybenzo [d] thiazol-2-amine (300 mg, 1.66 mmol) in THF (10 ml) at room temperature. After stirring overnight at 60 ° C., after completion of the reaction, it was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (211 mg, 77%).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 9.25 (1 H, s), 7.69 (1 H, d, J = 8.2 Hz), 7.43 (1 H, dd, J = 8.2, 8.2 Hz) , 7.07 (1H, d, J = 8.2 Hz), 3.97 (3H, s).
ESI-MS m / z: 166 [M + H] ⁺ .

実施例178-2：4-メトキシ-2-(ピリジン-3-イルエチニル)ベンゾ[d]チアゾール[化合物No.178]の合成
実施例178-1で得られた化合物(100 mg, 0.61 mmol)と実施例32-5で得られた化合物(220 mg, 1.21 mmol)を用いて実施例32-6と同様の操作を行うことにより、標記の化合物(36 mg, 22 %)を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.92 (1H, br s), 8.71-8.70 (1H, m), 8.18-8.16 (1H, m), 7.70 (1H, d, J = 8.2 Hz), 7.57-7.50 (2H, m), 7.14 (1H, d, J = 8.2 Hz), 3.99 (3H, s).
ESI-MS m/z:267[M+H]⁺. Example 178-2 Synthesis of 4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] thiazole [Compound No. 178]
Using the compound (100 mg, 0.61 mmol) obtained in Example 178-1 and the compound (220 mg, 1.21 mmol) obtained in Example 32-5, performing the same operation as in Example 32-6 The title compound (36 mg, 22%) was obtained by
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 8.92 (1 H, br s), 8.71-8.70 (1 H, m), 8.18-8.16 (1 H, m), 7.70 (1 H, d, J = 8.2 Hz), 7.57-7.50 (2 H, m), 7. 14 (1 H, d, J = 8.2 Hz), 3.99 (3 H, s).
ESI-MS m / z: 267 [M + H] ⁺ .

製造例179：2-(ピリジン-3-イルエチニル)-1H-ベンゾ[d]イミダゾール[化合物No.179]の合成
実施例179-1：2-(ピリジン-3-イルエチニル)-1H-ベンゾ[d]イミダゾール[化合物No.179]の合成
実施例177-2で得られた化合物(185 mg, 0.58 mmol)をジクロロメタン(4 ml)に溶解した。トリフルオロ酢酸(1 ml)を加えて室温で1時間攪拌した。反応後、溶媒を留去した。1 mol/l水酸化ナトリウム水溶液を加えてクロロホルム抽出した。飽和食塩水で洗った。硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(SNAP 10 g, クロロホルム/メタノール)で精製し、標記の化合物(45 mg, 35.4%)を白色固体として得た。
¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]: 13.28 (1H, br s), 8.86 (1H, dd, J = 2.3, 0.8 Hz), 8.69 (1H, dd, J = 4.9, 1.5 Hz), 8.10 (1H, dq, J = 7.9, 1.2 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.55 (1H, ddd, J = 7.9, 5.0, 0.8 Hz), 7.51 (1H, d, J = 7.6 Hz), 7.28 (2H, tt, J = 16.3, 3.3 Hz).
ESI-MS m/z:220[M+H]⁺. Production Example 179 Synthesis of 2- (Pyridin-3-ylethynyl) -1H-benzo [d] imidazole [Compound No. 179] Example 179-1: 2- (Pyridin-3-ylethynyl) -1H-benzo [d Synthesis of Imidazole [Compound No. 179]
The compound (185 mg, 0.58 mmol) obtained in Example 177-2 was dissolved in dichloromethane (4 ml). Trifluoroacetic acid (1 ml) was added and stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off. An aqueous solution of 1 mol / l sodium hydroxide was added and extracted with chloroform. Washed with saturated saline. Dry over magnesium sulfate and evaporate the solvent. The residue was purified by silica gel column chromatography (SNAP 10 g, chloroform / methanol) to give the title compound (45 mg, 35.4%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 13.28 (1 H, br s), 8.86 (1 H, dd, J = 2.3, 0.8 Hz), 8.69 (1 H, dd, J = 4.9, 1.5 Hz), 8.10 (1 H, dq, J = 7.9, 1.2 Hz), 7.67 (1 H, d, J = 7.6 Hz), 7.55 (1 H, ddd, J = 7.9, 5.0, 0.8 Hz), 7.51 (1 H, d, J = 7.6 Hz), 7.28 (2 H, tt, J = 16.3, 3.3 Hz).
ESI-MS m / z: 220 [M + H] ⁺ .

試験例1
ZNF143活性に対する阻害作用
ZNF143活性におよぼす本発明の化合物の作用をルシフェラーゼアッセイ法により検討した。ZNF143応答配列（Staf binding site；SBS）の2回タンデムリピートをpGL3-Basicベクター（Promega社）のルシフェラーゼ遺伝子上流にあるMluI-XhoI制限酵素認識サイトに挿入してpGL3-SBSx2-Lucベクターを構築した。ヒト前立腺がんPC-3細胞にpGL3-SBSx2-LucベクターおよびSV40プロモーターをルシフェラーゼ遺伝子の上流に組み込んだレポーターベクターpGL3-Controlベクター（Promega社）を、Lipofectamine 2000（Invitrogen）を用いて添付の操作手順に従ってそれぞれトランスフェクションした。さらに細胞を10% FBS、100 U/mLペニシリン、100 μg/mLストレプトマイシンおよび0.5 mg/ml G418を含有したRPMI1640培地にて培養することにより、それぞれのベクターを安定的に導入した細胞、PC-3/SBSx2-LucおよびPC-3/SV40-Lucを作製した。PC-3/SBSx2-LucまたはPC-3/SV40-Luc細胞を10% FBS、100 U/mLペニシリンおよび100μg/mLストレプトマイシンを含有したRPMI1640培地（10% FBS/RPMI1640）に浮遊させ、96ウェルハーフエリア白色プレートまたは透明プレートに播種して5% CO₂、37℃条件下で培養した（5000 細胞/ウェル）。一晩培養後、DMSOに溶解した本発明の化合物を希釈した培地を加えてさらに16時間培養した。培養後、白色プレートで培養した細胞にBright-Glo Luciferase Assay System試薬（Promega社）を10 μL/ウェル加え、高感度発光測定用検出器を搭載したEnVisionマルチラベルリーダー（PerkinElmer社）を使用して細胞内のルシフェラーゼ活性を測定した。また、透明プレートで培養した細胞にはTetraColor ONE試薬（キシダ化学社）を5 μL/ウェル加え、SpectraMax Plus384（Molecular Devices社）を使用して生細胞数を測定した。なお本発明化合物のZNF143活性またはSV40プロモーター活性に対する阻害作用の結果は、PC-3/SBSx2-LucおよびPC-3/SV40-Luc細胞のルシフェラーゼ活性の測定値をそれぞれの生細胞数の測定値で割ることにより標準化後、ルシフェラーゼ活性の誘導を30%抑制する被験化合物の濃度としてIC₃₀値で表した。結果を表１〜５に示す（ＮＴ：ｎｏｔｔｅｓｔｅｄ）。
表１〜５に示すように、本発明化合物はZNF143活性に阻害作用を示した。また、SV40プロモーター活性にほとんど影響を与えず、ZNF143に対して特異的に作用する化合物も確認された。 Test Example 1
Inhibitory effect on ZNF143 activity
The effects of the compounds of the present invention on ZNF143 activity were examined by luciferase assay. The pGL3-SBSx2-Luc vector was constructed by inserting the double tandem repeat of the ZNF143 response element (Staf binding site; SBS) into the MluI-XhoI restriction enzyme recognition site upstream of the luciferase gene of the pGL3-Basic vector (Promega). . Reporter operation procedure using Lipofectamine 2000 (Invitrogen) with reporter vector pGL3-Control vector (Promega) in which pGL3-SBSx2-Luc vector and SV40 promoter were integrated upstream of luciferase gene in human prostate cancer PC-3 cells Each was transfected according to. Furthermore, cells in which each vector has been stably introduced by culturing the cells in RPMI 1640 medium containing 10% FBS, 100 U / mL penicillin, 100 μg / mL streptomycin and 0.5 mg / mL G418, PC-3 / SBSx2-Luc and PC-3 / SV40-Luc were prepared. PC-3 / SBSx2-Luc or PC-3 / SV40-Luc cells are suspended in RPMI 1640 medium (10% FBS / RPMI 1640) containing 10% FBS, 100 U / mL penicillin and 100 μg / mL streptomycin, and then 96-well half The cells were seeded in an area white plate or a transparent plate and cultured at 37 ° C. under 5% CO ₂ (5000 cells / well). After overnight culture, the medium to which the compound of the present invention dissolved in DMSO was diluted was added and cultured for further 16 hours. After culture, add 10 μl / well of Bright-Glo Luciferase Assay System reagent (Promega) to the cells cultured on a white plate, and use EnVision multi-label reader (PerkinElmer) equipped with a detector for high sensitivity luminescence measurement. The intracellular luciferase activity was measured. In addition, 5 μL / well of TetraColor ONE reagent (Kishida Chemical Co., Ltd.) was added to the cells cultured on a transparent plate, and the number of viable cells was measured using SpectraMax Plus 384 (Molecular Devices). The results of the inhibitory effect of the compounds of the present invention on ZNF143 activity or SV40 promoter activity can be obtained by measuring the luciferase activity of PC-3 / SBSx2-Luc and PC-3 / SV40-Luc cells as the number of viable cells. After normalization by division, the concentration of the test compound which inhibits induction of luciferase activity by 30% was expressed as an IC ₃₀ value. The results are shown in Tables 1 to 5 (NT: not tested).
As shown in Tables 1 to 5, the compounds of the present invention exhibited an inhibitory effect on ZNF143 activity. In addition, compounds that acted specifically on ZNF143 with little effect on SV40 promoter activity were also identified.

試験例2
がん細胞の増殖に対する抑制作用
ヒト大腸がんHT-29細胞、HCT116細胞およびヒト非小細胞肺がんA549細胞の増殖に及ぼす本発明化合物の作用を検討した。HT-29細胞（1,000 細胞/ウェル）、HCT116細胞（500 細胞/ウェル）またはA549細胞（1,000 細胞/ウェル）を10% FBS/RPMI1640に浮遊させ、96ウェルプレートに播種して5% CO₂、37℃にて一晩培養後、DMSOに溶解した本発明化合物に希釈した培地を加えてさらに5% CO₂、37℃にて96時間培養した。培養後、TetraColor ONE（キシダ化学社）を使用して、添付の操作手順に従って生細胞数を測定した。結果はIC₅₀値（細胞生存を50%抑制する被験化合物の濃度）で表した。その結果、表６〜１０に示すように本発明化合物はHT-29細胞、HCT116細胞およびA549細胞の増殖に対し抑制作用を示した。 Test example 2
Inhibitory effect on proliferation of cancer cells The effect of the compound of the present invention on proliferation of human colon cancer HT-29 cells, HCT116 cells and human non-small cell lung cancer A549 cells was examined. HT-29 cells (1,000 cells / well), HCT116 cells (500 cells / well) or A549 cells (1,000 cells / well) are suspended in 10% FBS / RPMI 1640 and seeded in a 96-well plate at 5% CO ₂ , After overnight culture at 37 ° C., the diluted medium was added to the compound of the present invention dissolved in DMSO, and the cells were further cultured at 37 ° C. for 96 hours at 5% CO ₂ . After culture, the number of viable cells was determined according to the attached operating procedure using TetraColor ONE (Kishida Chemical Co., Ltd.). The results were expressed as IC ₅₀ values (the concentration of a test compound that inhibits cell survival by 50%). As a result, as shown in Tables 6 to 10, the compounds of the present invention exhibited an inhibitory effect on the proliferation of HT-29 cells, HCT116 cells and A549 cells.

試験例3
本発明化合物のZNF143とSBSの相互作用阻害活性
ZNF143とSBSの相互作用に及ぼす本発明化合物の作用を検討した。3 x FLAG標識ZNF143遺伝子を安定導入されたヒト前立腺がんPC-3細胞（PC-3/ZNF143）（非特許文献4）を10 cmディッシュに1,000,000 細胞を播種して5% CO₂、37℃にて一晩培養後、培地を除去し、化合物135または化合物138を含むRPMI1640培地を加えた。さらに24時間培養後、ホルムアルデヒド（最終濃度1%）を加え蛋白質間の架橋処理を行い、PBSで2回洗浄後、セルスクレイパーを用いて細胞を1.5 mLチューブに回収した。回収した細胞は、遠心により上清を除去し、細胞にプロテアーゼインヒビターカクテル（ナカライテスク社）を含むLysisバッファー（50 mM Tris-HCl、pH 8.1、10 mM EDTA、1% SDS）を加えて細胞を溶解し、ソニケーションによりDNAを切断後、溶解液中のタンパク量を測定した。100μgのタンパクを含む細胞溶解液を、プロテアーゼインヒビターカクテルを含む希釈バッファー（16.7 mM Tris-HCl、pH 8.1、167 mM NaCl、1.2 mM EDTA、1.1% Triton X-100、0.01% SDS）で希釈後に、抗FLAG M2 Affinity Gel抗体（Sigma-Aldrich社）を加えて4℃にて一晩回転混和した。その後、各チューブからゲルを回収し、各種バッファーを用いてゲルを洗浄した。洗浄したゲルに溶出バッファー（1% SDS、0.1 M NaHCO₃）を加えて溶出液を回収後、1/25（v/v）量の0.5 M NaClを加えて65℃で一晩インキュベートし、DNAとタンパク間の脱架橋処理を行った。さらに、Proteinase K（ナカライテスク社）およびRNase A（Novagen社）によりタンパクおよびRNAを分解し、DNAの精製処理を行った後、ZNF143応答配列（SBS）の存在をPCR法により確認した。PCRプライマーは、PLK1のプロモーター領域に存在するSBSを標的として表１１に示す配列をデザインした。その結果、化合物135と化合物138はZNF143とSBSの相互作用を阻害することが分かった（図1）。 Test Example 3
Interaction inhibition activity of ZNF143 and SBS of the compound of the present invention
The effects of the compounds of the present invention on the interaction between ZNF143 and SBS were examined. Human prostate cancer PC-3 cells (PC-3 / ZNF143) (non-patent document 4) stably transfected with 3 x FLAG-tagged ZNF143 gene (non-patent document 4) are seeded with 1,000,000 cells in a 10 cm dish and 5% CO ₂ at 37 ° C After overnight culture, the medium was removed and RPMI 1640 medium containing Compound 135 or Compound 138 was added. After further culture for 24 hours, formaldehyde (final concentration 1%) was added to crosslink the proteins, and after washing twice with PBS, cells were collected into 1.5 mL tubes using a cell scraper. The collected cells are centrifuged to remove the supernatant, and the cells are added with Lysis buffer (50 mM Tris-HCl, pH 8.1, 10 mM EDTA, 1% SDS) containing a protease inhibitor cocktail (Nacalai Tesque). After dissolving and cleaving the DNA by sonication, the amount of protein in the lysate was measured. After diluting a cell lysate containing 100 μg of protein with a dilution buffer (16.7 mM Tris-HCl, pH 8.1, 167 mM NaCl, 1.2 mM EDTA, 1.1% Triton X-100, 0.01% SDS) containing a protease inhibitor cocktail Anti-FLAG M2 Affinity Gel antibody (Sigma-Aldrich) was added and vortexed overnight at 4 ° C. Thereafter, the gel was collected from each tube, and the gel was washed using various buffers. After adding elution buffer (1% SDS, 0.1 M NaHCO ₃ ) to the washed gel and collecting the eluate, add 1/25 (v / v) of 0.5 M NaCl and incubate overnight at 65 ° C. And the protein were decrosslinked. Furthermore, protein and RNA were digested with Proteinase K (Nacalai Tesque) and RNase A (Novagen), and after purification of DNA, the presence of ZNF143 response element (SBS) was confirmed by PCR. The PCR primers were designed to target the SBS present in the promoter region of PLK1 and the sequences shown in Table 11 were designed. As a result, Compound 135 and Compound 138 were found to inhibit the interaction between ZNF143 and SBS (FIG. 1).

試験例4
ZNF143標的遺伝子発現抑制作用
ZNF143標的遺伝子の発現に及ぼす本発明化合物の作用を検討した。HCT116細胞を6 cmディッシュに200,000 細胞を播種し、一晩培養後、培地を取り除き、化合物135または化合物138を含む培地を加え、24時間培養後細胞を回収した。回収した細胞よりRNA spin mini（GE）を用いて全RNAを抽出した。抽出した全RNAを鋳型として、GoScript Reverse Transcription System（Promega）を用いて逆転写反応を行いcDNAを合成した。さらに合成されたcDNAを用い、GoTaq qPCR Master Mix（Promega）および7500 Fast Real-Time PCR System（Applied Biosystems）を使用して添付の操作手順に従いリアルタイムPCRを行った。測定結果は、7500 Software Version 2.0.2により解析した。なお、ZNF143標的遺伝子としてBIRC5、PLK1およびRAD51を選択した。各標的遺伝子に対するプライマーは、公知のmRNA塩基配列よりPrimer Express Software Version 3.0（Applied Biosystems）を使用して表１２のようにデザインした。また、各遺伝子の発現量はハウスキーピング遺伝子であるGAPDHの発現量で補正した。その結果、化合物135は10μM以上、化合物138は0.5μM以上において、検討したすべての遺伝子の発現を50%以上抑制した（図２）。 Test Example 4
ZNF143 target gene expression suppression action
The effects of the compounds of the present invention on the expression of ZNF143 target gene were examined. HCT116 cells were seeded at 200,000 cells in a 6 cm dish, and after overnight culture, the medium was removed, medium containing compound 135 or compound 138 was added, and cells were harvested after culture for 24 hours. Total RNA was extracted from the collected cells using RNA spin mini (GE). Reverse transcription was carried out using GoScript Reverse Transcription System (Promega) using the extracted total RNA as a template to synthesize cDNA. Furthermore, real-time PCR was performed using GoTaq qPCR Master Mix (Promega) and 7500 Fast Real-Time PCR System (Applied Biosystems) according to the attached operating procedure using the synthesized cDNA. The measurement results were analyzed by 7500 Software Version 2.0.2. In addition, BIRC5, PLK1 and RAD51 were selected as ZNF143 target genes. Primers for each target gene were designed as shown in Table 12 using Primer Express Software Version 3.0 (Applied Biosystems) from known mRNA base sequences. In addition, the expression level of each gene was corrected by the expression level of the housekeeping gene GAPDH. As a result, the compound 135 suppressed the expression of all the examined genes by 50% or more at 10 μM or more and the compound 138 at 0.5 μM or more (FIG. 2).

試験例5
アポトーシス誘導作用
本発明化合物のアポトーシス誘導作用を検討した。HCT116細胞（5,000 細胞/ウェル）を10% FBS/RPMI1640に浮遊させ、96ウェルプレートに播種して5% CO₂、37℃にて一晩培養後、DMSOに溶解した化合物16に希釈した培地を加えてさらに5% CO₂、37℃にて24時間培養した。培養後、Cell Death Detection ELISA PLUS（Roche社）を使用して、添付の操作手順に従って細胞内のDNA断片量を測定した。その結果、化合物16はDNAを断片化しており、アポトーシスを誘導していることがわかった（図３）。 Test Example 5
Apoptosis inducing activity The apoptosis inducing activity of the compound of the present invention was examined. HCT116 cells (5,000 cells / well) are suspended in 10% FBS / RPMI 1640, seeded in a 96-well plate and cultured overnight at 37 ° C. in 5% CO ₂ , and diluted with compound 16 in DMSO dissolved in medium In addition, the cells were further cultured at 37 ° C. for 24 hours in 5% CO ₂ . After culture, the amount of DNA fragment in cells was measured according to the attached operating procedure using Cell Death Detection ELISA PLUS (Roche). As a result, Compound 16 fragmented DNA and was found to induce apoptosis (FIG. 3).

試験例6
ヒト大腸がんHCT116細胞移植マウスにおける抗腫瘍効果
本発明化合物のin vivoにおける抗腫瘍効果をヒト大腸がんHCT116細胞移植マウスを用いて検討した。6週齢の雄BALB/c slc-nu/nuマウス左肢鼠頚部皮下に2×10⁶個のHCT116細胞懸濁液0.1 mLを移植し、経時的に腫瘍の長径および短径をノギスで測定し、1/2× (長径) × (短径)²から求めた腫瘍体積が約100〜200mm³前後になった時点で各群（5匹/群）の腫瘍体積が均等になるように群分けを行った（Day 1）。化合物135はDay 1、2、3、8、9、12および16に、化合物138はDay 1、2、3、4、5および16にマウス腹腔内から20 mL/kgずつ投与した。Day 16に腫瘍を摘出し腫瘍重量を測定した後、次式により腫瘍増殖阻止率（IR）を求めた。

腫瘍増殖阻止率IR（%）=（1 − 投与群の平均腫瘍重量 ÷ 対照群の平均腫瘍重量）× 100その結果、表１３に示す。 Test Example 6
Antitumor effect in human colon cancer HCT116 cell-transplanted mice The in vivo antitumor effect of the compound of the present invention was examined using human colon cancer HCT116 cell-transplanted mice. A 6-week-old male BALB / c slc-nu / nu mouse is implanted with 0.1 mL of 2 × 10 ⁶ HCT116 cell suspensions subcutaneously in the left neck of the left limb, and the major axis and minor axis of the tumor are measured with calipers over time And the tumor volume of each group (5 animals / group) is equal when the tumor volume calculated from ^1/2 × (long diameter) × (short diameter) ² becomes about 100 to 200 mm ³ I did the division (Day 1). Compound 135 was administered on Days 1, 2, 3, 8, 9, 12 and 16 and Compound 138 on Days 1, 2, 3, 4, 5 and 16 from the intraperitoneal route of the mouse 20 mL / kg. After removing the tumor on Day 16 and measuring the tumor weight, the tumor growth inhibition rate (IR) was determined by the following equation.

Tumor growth inhibition rate IR (%) = (average tumor weight of 1− administration group ÷ average tumor weight of control group) × 100 The results are shown in Table 13.

上記より本発明化合物は、ヒト大腸がんHCT116細胞移植マウスにおいて抗腫瘍効果を発揮することが示された。 From the above, it was shown that the compound of the present invention exerts an antitumor effect in human colon cancer HCT116 cell-transplanted mice.

本発明化合物は、ZNF143阻害作用、アポトーシス誘導作用および抗腫瘍作用を有し、ZNF143阻害およびがんの治療用の医薬組成物として有用である。また、従来のZNF143阻害活性および細胞傷害活性を有する化合物と比較して、低分子であることから、より少数の工程で製造することができる。 The compounds of the present invention have ZNF143 inhibitory activity, apoptosis induction activity and antitumor activity, and are useful as pharmaceutical compositions for ZNF143 inhibition and treatment of cancer. Moreover, compared with the compound which has conventional ZNF143 inhibitory activity and cytotoxic activity, since it is a small molecule, it can be manufactured by fewer processes.

Claims

Formula (I)
A-B-C-D (I)
During the ceremony
A is an unsubstituted or monosubstituted pyridine ring, and the substituent is a methoxy group, a hydroxymethyl group, an amino group or an acetylamino group, or an N-oxide group,
B is
And
C is, -CONH -, - CON (CH 3) - and is,
D is a phenyl group, and each of two H may be independently replaced by a halogen atom, an alkoxy group, an alkoxycarbonyl group, a halogenoalkyl group or CN, provided that OCH ₃ and OCH ₃ , or , Not substituted with OCH ₃ and Cl,
Or
C is
And
D is a substituted phenyl group or unsubstituted or substituted
And
One or more H atoms are each independently F, Cl, I, Br, OH, CF ₃ , OCHF ₂ , OCF ₃ , CN, NH ₂ , T-phenyl group (T is a single bond,- O-, -OCO-, -NHCO-), or C1-5 linear or branched alkyl group, which may be replaced by one or more CH present in the alkyl group ₂ groups are each independently -COO-, -OCO-, -O-, -SO-, -NH-,
And the terminal CH ₃ group of the alkyl group or the alkenyl group is OH, NH ₂ , N (CH ₃ ) ₂ , N (C ₃ H ₇ ) ₂ ,
May be replaced by
One H of may be replaced by F,
Or
C and D both
And at least one has a substituent,
One or more H atoms are each independently F, Cl, Br, OH, CF ₃ , OCF ₃ , OCH ₃ , NH ₂ ,
Or may be replaced by a C1-9 linear or branched alkyl group or alkenyl group (with the exception of methyl group and fluoroethyl group); one or two or more present in the alkyl group or alkenyl group Or more CH ₂ groups each independently represent —COO—, —CO—, —O—, —S—, —SO ₂ —, —NH—, —Si (CH ₃ ) ₂ —,
And the terminal CH ₃ group of the alkyl or alkenyl group may be Cl, OH, NH ₂ , N (CH ₃ ) ₂ ,
May be replaced by
Or a salt thereof.

The compound selected from the following or a salt thereof:
N- (5-bromo-2-methoxyphenyl) -3- (pyridin-3-yl) propiolamide,
4-methoxy-7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) -5- (2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole.

The compound selected from the following or a salt thereof:
N- (5-chloro-2-cyanophenyl) -3-phenylpropiolamide,
N- (5-Fluoro-2-methoxyphenyl) -3-phenylpropiolamide,
N- (5-iodo-2-methoxyphenyl) -3-phenylpropiolamide,
Dimethyl 2- (3- (p-toluyl) propiolamide) terephthalate,
Dimethyl 2- (3- (m-toluyl) propiolamide) terephthalate,
N- (5-bromo-2-methoxyphenyl) -3- (naphthalen-1-yl) propiolamide,
Dimethyl 2- (3- (4-cyanophenyl) propiolamide) terephthalate,
Dimethyl 2- (3- (2-cyanophenyl) propiolamide) terephthalate,
N- (5-bromo-2-methoxyphenyl) -3- (2- (trifluoromethyl) phenyl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (4- (trifluoromethyl) phenyl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (4- (trifluoromethoxy) phenyl) propiolamide,
N- (2-methoxy-5- (trifluoromethyl) phenyl) -3-phenylpropiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (2-cyanophenyl) propiolamide,
N- (5-bromo-2-cyanophenyl) -3-phenylpropiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (2-fluorophenyl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (pyridin-3-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (pyridin-4-yl) propiolamide,
Dimethyl 2- (3- (pyridin-3-yl) propiolamide) terephthalate,
Dimethyl 2- (3- (pyridin-2-yl) propiolamide) terephthalate,
N- (5-bromo-2-methoxyphenyl) -3- (pyridin-2-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (pyrazin-2-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (2-methoxypyridin-3-yl) propiolamide,
3- (3-((5-bromo-2-methoxyphenyl) amino) -3-oxoprop-1-yn-1-yl) pyridine 1-oxide,
N- (5-Fluoro-2-methoxyphenyl) -3- (pyridin-3-yl) propiolamide,
N- (5-fluoro-2-methoxyphenyl) -3- (pyridin-4-yl) propiolamide,
3- (6-acetamidopyridin-3-yl) -N- (5-bromo-2-methoxyphenyl) propiolamide,
3- (6-Aminopyridin-3-yl) -N- (5-bromo-2-methoxyphenyl) propiolamide,
N- (2-methoxy-5- (trifluoromethyl) phenyl) -3- (pyridin-3-yl) propiolamide,
N- (4-Methoxy- [1,1'-biphenyl] -3-yl) -3- (pyridin-3-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -3- (6-methoxypyridin-3-yl) propiolamide,
N- (5-bromo-2-methoxyphenyl) -N-methyl-3- (pyridin-3-yl) propiolamide,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
5-fluoro-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
5-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-Methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) -5- (trifluoromethyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-amine,
7-Fluoro-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-bromo-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-Methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4- (methylthio) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-((tert-butyldimethylsilyl) oxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-ol,
7-((tert-butyldimethylsilyl) oxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
2- (Pyridin-3-ylethynyl) benzo [d] oxazol-7-ol,
4-morpholino-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tertiary butyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxylate,
Methyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxylate,
(2- (Pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) methanol,
Tertiary butyl ((2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) methyl) carbamate,
7-bromo-4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert.-butyl 2- (pyridin-3-ylethynyl) benzo [d] oxazole-4-carboxylate,
(2- (Pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) methanol,
4-methoxy-7-morpholino-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carboxylate,
4-methoxy-7- (4- (2-methoxyethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate,
4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) thiomorpholine 1,1-dioxide,
Tert-butyl (1- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-yl) carbamate
1- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-amine trifluoroacetate salt,
Tert-butyl 4- (2-((2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate,
7- (2- (Piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate,
7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7- (4-morpholinopiperidin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
1- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-one,
4-bromo-7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 4- (7-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazine-1-carboxylate,
4-methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) -1,4-diazepane-1-carboxylate,
4-Methoxy-7- (piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
7- (1,4-diazepan-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole trifluoroacetate,
2- (4- (7-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-yl) piperazin-1-yl) -N, N-dimethylethanamine hydrochloride,
7- (1,4-diazepan-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
1- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperidin-4-amine hydrochloride,
4-methoxy-7- (4- (2-methoxyethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
7- (2- (Piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
Tert-butyl (2- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2-oxoethyl) carbamate
2- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone hydrochloride,
2-Amino-1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) ethanone hydrochloride,
4-methoxy-7- (morpholinomethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 4- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carbonyl) piperidine-1-carboxylate,
(4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) (piperidin-4-yl) methanone,
4-Methoxy-7- (morpholinomethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
(4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) (piperidin-4-yl) methanone hydrochloride,
1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (piperidin-1-yl) ethanone,
3- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) propan-1-one,
7- (2- (4-Methylpiperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (piperidin-1-yl) ethanone hydrochloride,
3- (Dimethylamino) -1- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) propan-1-one hydrochloride,
Tert-butyl 4-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) methyl) piperazine-1-carboxylate,
4-methoxy-7- (4- (methylsulfonyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 3- (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazine-1-carbonyl) azetidine-1-carboxylate,
4-methoxy-7- (piperazin-1-ylmethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7-((4- (methylsulfonyl) piperazin-1-yl) methyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7- (piperazin-1-ylmethyl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
Azetidin-3-yl (4- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) methanone hydrochloride,
1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (pyrrolidin-1-yl) ethanone,
Tert-butyl 4- (2-((4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) ethyl) piperazine-1-carboxylate,
1- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -2- (pyrrolidin-1-yl) ethanone hydrochloride,
4-methoxy-7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-Methoxy-7- (2- (piperazin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
7- (4-((chloromethyl) sulfonyl) piperazin-1-yl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
Tert-butyl 5- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate,
4-methoxy-2- (pyridin-3-ylethynyl) -7- (4- (vinylsulfonyl) piperazin-1-yl) benzo [d] oxazole,
2- (4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) -N, N-dimethylethanamine,
2-((4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) sulfonyl) -N, N-dimethylethanamine,
2-((4- (4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) piperazin-1-yl) sulfonyl) -N, N-dimethylethanamine hydrochloride,
7-bromo-4-methoxy-2- (pyridin-4-ylethynyl) benzo [d] oxazole,
2-((4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) oxy) -N, N-dimethylethanamine,
4-methoxy-7- (2- (piperidin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4,7-Dimethoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-Bromo-4-ethoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
7-bromo-4-isopropoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-Methoxy-7- (2- (piperidin-1-yl) ethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
4-methoxy-7- (2-morpholinoethoxy) -2- (pyridin-3-ylethynyl) benzo [d] oxazole hydrochloride,
4-methoxy-7- (4- (2- (methylsulfonyl) ethyl) piperazin-1-yl) -2- (pyridin-3-ylethynyl) benzo [d] oxazole,
4-methoxy-2- (pyridin-3-ylethynyl) -7-thiomorpholinobenzo [d] oxazole,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-5,7-diamine,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-amine,
4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-5-amine,
3- (dimethylamino) -N- (4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) propanamide,
4-methoxy-N, N-dimethyl-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-amine,
4-Methoxy-N-methyl-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-amine,
7-Bromo-2- (pyridin-3-ylethynyl) benzo [d] oxazol-4-ol,
N- (2- (dimethylamino) ethyl) -4-methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazole-7-carboxamide,
(4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] oxazol-7-yl) (4-methylpiperazin-1-yl) methanone,
2- (2-methoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-bromo-2-methoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-bromo-2- (trifluoromethyl) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (Pyridin-3-ylethynyl) -5- (2- (trifluoromethoxy) phenyl) -1,3,4-oxadiazole,
2- (2-ethylphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (Pyridin-3-ylethynyl) -5- (2- (trifluoromethyl) phenyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) benzonitrile,
2- (2-((4-fluorobenzyl) oxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (Cyclohexylmethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2-Phenoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (3- (benzyloxy) pyridin-2-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) -5-chlorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) -5-fluorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) -6-fluorophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (Pyridin-2-ylmethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (Pyridin-3-ylethynyl) -5- (2- (thiophen-2-ylmethoxy) phenyl) -1,3,4-oxadiazole,
2- (3- (benzyloxy) thiophen-2-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzylsulfinyl) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (benzyloxy) pyridin-3-yl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenylbenzoate,
2- (2-bromophenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
N- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl) benzamide,
2- (2-phenethoxyphenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-bromo-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (Difluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-chloro-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (5-fluoro-2- (trifluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (3- (Difluoromethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
Tertiary butyl (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenyl) carbamate,
2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) aniline,
(5-((5- (2- (Trifluoromethoxy) phenyl) -1,3,4-oxadiazol-2-yl) ethynyl) pyridin-2-yl) methanol,
Tert-butyl (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) carbamate
4- (2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) morpholine,
2- (2- (2- (Piperidin-1-yl) ethoxy) phenyl) -5- (pyridin-3-ylethynyl) -1,3,4-oxadiazole,
2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl acetate,
Tert-butyl 4- (2- (2- (2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethyl) piperazine-1-carboxylate,
2- (2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) ethanol;
Tert-butyl 4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) benzyl carbamate,
(4-((2- (5- (Pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) phenyl) methanamine,
N, N-Dimethyl-1- (4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) phenyl) methanamine,
N-propyl-N- (4-((2- (5- (pyridin-3-ylethynyl) -1,3,4-oxadiazol-2-yl) phenoxy) methyl) benzyl) propan-1-amine;
5-methoxy-2- (pyridin-3-ylethynyl) benzo [d] thiazole,
Tert-butyl 2- (pyridin-3-ylethynyl) -1H-benzo [d] imidazole-1-carboxylate,
4-Methoxy-2- (pyridin-3-ylethynyl) benzo [d] thiazole.

A ZNF143 inhibitor comprising one or more of the compound according to any one of claims 1 to 3 or a salt thereof.

The anticancer agent which contains 1 type, or 2 or more types of the compound as described in any one of Claims 1-3, or its salt.

The pharmaceutical composition which uses 1 type, or 2 or more types of the compound as described in any one of Claims 1-3, or its salt as an active ingredient.

The pharmaceutical composition according to claim 6, which is for the treatment of cancer.