JP4929500B2 - New benzodiazepines - Google Patents

Description

  The present invention relates to novel benzodiazepines and pharmaceutical compositions thereof.

2,5-dihydrobenzodiazepines are reported in Patent Documents 1 to 6, Non-Patent Document 1, and the like.
As 2,5-dihydrobenzodiazepines having pharmaceutical activity, Patent Documents 1, 2 and Non-Patent Document 1 show that 3-carboxy-2,5-dihydrobenzodiazepines have a therapeutic effect on cardiovascular diseases. Is disclosed. However, there was no description of antitumor activity.
US Pat. No. 4,647,561 US Pat. No. 4,650,797 Russian Patent Application No. 791749 German Patent Application No. 116826 German Patent Application No. 117219 German Patent Application No. 267041 Journal of Medicinal Chemistry 1987, 30, p. 635-640

  Provided are novel benzodiazepines and a pharmaceutical composition containing the compound as an active ingredient.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は同一又は異なって、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいＣ２−Ｃ６アルキニル、置換されていてもよいＣ３−Ｃ６シクロアルキル、置換されていてもよいＣ３−Ｃ６シクロアルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、置換されていてもよいＣ２−Ｃ６アルキニルオキシ、置換されていてもよいＣ３−Ｃ６シクロアルキルオキシ、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいＣ３−Ｃ６シクロアルキルチオ、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオ、置換されていてもよいアミノ、カルボキシ、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいカルバモイル、ニトロ、又はシアノ；又は
Ｒ^１とＲ^２、Ｒ^２とＲ^３、又はＲ^３とＲ^４が一緒になって、隣接する炭素原子を含んで置換されていてもよい炭素環又は置換されていてもよい複素環を形成してもよい；
Ｒ^５及びＲ^６は同一又は異なって、水素原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいアリール、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいアリールオキシカルボニル、置換されていてもよいＣ１−Ｃ６アルキルスルホニル、置換されていてもよいアリールスルホニル、又は置換されていてもよいカルバモイル；
Ｒ^７及びR⁸は同一又は異なって、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、メルカプト、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよいアミノ；
R^９は、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、メルカプト、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよいアミノ；
Ｒ^１０は、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいＣ２−Ｃ６アルキニル、置換されていてもよいＣ３−Ｃ６シクロアルキル、又は置換されていてもよいアリール；
ただし、R^９がヒドロキシ又は置換されていてもよいＣ１−Ｃ６アルコキシ、及びＲ^７及びR⁸の一方が水素原子である場合、Ｒ^７及びR⁸の他方は水素原子、置換されていてもよいアリール、又は置換されていてもよいヘテロアリールではない）で示される化合物、その製薬上許容される塩、又はそれらの溶媒和物、
２）Ｒ^２及びＲ^３が同一又は異なって、ハロゲン原子又は置換されていてもよいＣ１−Ｃ６アルキルである１）記載の化合物、その製薬上許容される塩、又はそれらの溶媒和物、
３）Ｒ^５及びＲ^６が同一又は異なって、水素原子、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、又は置換されていてもよいＣ１−Ｃ６アルコキシカルボニルである１）又は２）記載の化合物、その製薬上許容される塩、又はそれらの溶媒和物、
４）Ｒ^９がハロゲン原子で置換されたＣ１−Ｃ６アルキルである１）〜３）のいずれかに記載の化合物、その製薬上許容される塩、又はそれらの溶媒和物。
５）Ｒ^７及びR⁸の一方がヒドロキシ、他方がハロゲン原子で置換されたＣ１−Ｃ６アルキルである１）〜４）のいずれかに記載の化合物、その製薬上許容される塩、又はそれらの溶媒和物。
６）Ｒ^２及びＲ^３が同一又は異なって、ハロゲン原子又は置換されていてもよいＣ１−Ｃ６アルキル；Ｒ^５及びＲ^６が同一又は異なって、水素原子、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、又は置換されていてもよいＣ１−Ｃ６アルコキシカルボニル；Ｒ^７及びR⁸の一方がヒドロキシ、他方がハロゲン原子で置換されたＣ１−Ｃ６アルキル；Ｒ^９がハロゲン原子で置換されたＣ１−Ｃ６アルキル；Ｒ^１０が水素原子である１）記載の化合物、その製薬上許容される塩、又はそれらの溶媒和物、
７）一般式（Ｉ−Ａ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は同一又は異なって、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいＣ２−Ｃ６アルキニル、置換されていてもよいＣ３−Ｃ６シクロアルキル、置換されていてもよいＣ３−Ｃ６シクロアルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、置換されていてもよいＣ２−Ｃ６アルキニルオキシ、置換されていてもよいＣ３−Ｃ６シクロアルキルオキシ、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいＣ３−Ｃ６シクロアルキルチオ、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオ、置換されていてもよいアミノ、カルボキシ、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいカルバモイル、ニトロ、又はシアノ；又は
Ｒ^１とＲ^２、Ｒ^２とＲ^３、Ｒ^３とＲ^４が一緒になって、隣接する炭素原子を含んで置換されていてもよい炭素環又は置換されていてもよい複素環を形成してもよい；
Ｒ^５及びＲ^６は同一又は異なって、水素原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいアリール、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ１−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいアリールオキシカルボニル、置換されていてもよいＣ１−Ｃ６アルキルスルホニル、置換されていてもよいアリールスルホニル、又は置換されていてもよいカルバモイル；
Ｒ^７及びR⁸は同一又は異なって、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、メルカプト、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよいアミノ）で示される化合物、その製薬上許容される塩、又はそれらの溶媒和物、
８）Ｒ^５及びＲ^６が同一又は異なって、水素原子、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、又は置換されていてもよいＣ１−Ｃ６アルコキシカルボニルである７）記載の化合物、その製薬上許容される塩、又はそれらの溶媒和物、
９）Ｒ^９がハロゲン原子で置換されたＣ１−Ｃ６アルキルである７）記載の化合物、その製薬上許容される塩、又はそれらの溶媒和物、
１０）Ｒ^７及びＲ^８の一方がヒドロキシ、他方がハロゲン原子で置換されたＣ１−Ｃ６アルキルである７）〜９）のいずれかに記載の化合物、その製薬上許容される塩、又はそれらの溶媒和物、
１１）Ｒ^２及びＲ^３が同一又は異なって、ハロゲン原子又は置換されていてもよいＣ１−Ｃ６アルキル；Ｒ^５及びＲ^６が同一又は異なって、水素原子、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、又は置換されていてもよいＣ１−Ｃ６アルコキシカルボニル；Ｒ^７及びＲ^８の一方がヒドロキシ、他方がハロゲン原子で置換されたＣ１−Ｃ６アルキル；Ｒ^９がハロゲン原子で置換されたＣ１−Ｃ６アルキル；Ｒ^１０が水素原子である７）記載の化合物、又はその製薬上許容される塩、それらの溶媒和物、
１２）１）〜１１）のいずれかに記載の化合物を有効成分として含有する医薬組成物、
１３）抗腫瘍剤である１２）記載の医薬組成物、
１４）一般式（ＩＩ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は１）と同意義）
で示される化合物と一般式（ＩＩＩ）：

（式中、Ｒ^１１及びＲ^１２は同一又は異なって、ＣＦ_３、ＣＦ_２Ｃｌ、ＣＣｌ_３、又はＣＦ_２ＣＦ_３；Ｒ^１３は水素原子、Ｃ１−Ｃ６アルキル、トリフルオロメチル、Ｃ２−Ｃ６アルケニル、Ｃ２−Ｃ６アルキニル、置換されていてもよいアリール；Ｒ^１４はＣ１−Ｃ６アルキル）
で示される化合物を反応させることを特徴とする、一般式（ＩＶ）：

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は１）と同意義；Ｒ^１１及びＲ^１２は同一又は異なって、ＣＦ_３、ＣＦ_２Ｃｌ、ＣＣｌ_３、又はＣＦ_２ＣＦ_３；Ｒ^１３は水素原子、Ｃ１−Ｃ６アルキル、トリフルオロメチル、Ｃ２−Ｃ６アルケニル、Ｃ２−Ｃ６アルキニル、又は置換されていてもよいアリール）
で示される化合物の製造方法、に関する。 The present inventors have found the following novel benzodiazepines having antitumor activity and a pharmaceutical composition containing the compound as an active ingredient.
That is, the present invention relates to 1) general formula (I):

(Wherein R ¹ , R ² , R ³ , and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, hydroxy, optionally substituted C1-C6 alkoxy, substituted Optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted C3-C6 cycloalkyloxy, optionally substituted C1-C6 alkylthio, substituted C2-C6 alkenylthio, which may be substituted, C3-C6 cycloalkylthio, which may be substituted, , Optionally substituted aryloxy, optionally substituted arylthio, optionally substituted amino, carboxy, optionally substituted C1-C6 alkylcarbonyl, optionally substituted C2- C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted carbamoyl, nitro, or cyano Or R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ together, an optionally substituted carbocycle containing an adjacent carbon atom, or an optionally substituted heterocycle May be formed;
R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, or an optionally substituted. C1-C6 alkylcarbonyl, optionally substituted C2-C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted aryl Carbonyl, optionally substituted aryloxycarbonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted arylsulfonyl, or optionally substituted carbamoyl;
R ⁷ and R ⁸ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, hydroxy, an optionally substituted C1-C6. Alkoxy, optionally substituted C2-C6 alkenyloxy, mercapto, optionally substituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio, optionally substituted aryl, substituted Optionally heteroaryl, or optionally substituted amino;
R ⁹ is a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, a hydroxy, an optionally substituted C1-C6 alkoxy, an optionally substituted Good C2-C6 alkenyloxy, mercapto, optionally substituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio, optionally substituted aryl, optionally substituted heteroaryl, or Optionally substituted amino;
R ¹⁰ represents a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C3. -C6 cycloalkyl, or optionally substituted aryl;
However, when R ⁹ is hydroxy or C1-C6 alkoxy which may be substituted, and one of R ⁷ and R ⁸ is a hydrogen atom, the other of R ⁷ and R ⁸ may be substituted with a hydrogen atom. An aryl or an optionally substituted heteroaryl), a pharmaceutically acceptable salt thereof, or a solvate thereof,
2) The compound according to 1), wherein R ² and R ³ are the same or different and are a halogen atom or an optionally substituted C1-C6 alkyl, a pharmaceutically acceptable salt thereof, or a solvate thereof,
3) The compound according to 1) or 2), wherein R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkylcarbonyl, or an optionally substituted C1-C6 alkoxycarbonyl. , A pharmaceutically acceptable salt thereof, or a solvate thereof,
4) The compound according to any one of 1) to 3), wherein R ⁹ is C1-C6 alkyl substituted with a halogen atom, a pharmaceutically acceptable salt thereof, or a solvate thereof.
5) The compound according to any one of 1) to 4), a pharmaceutically acceptable salt thereof, or a compound thereof, wherein one of R ⁷ and R ⁸ is hydroxy and the other is C1-C6 alkyl substituted with a halogen atom Solvate.
6) R ² and R ³ are the same or different and are a halogen atom or an optionally substituted C1-C6 alkyl; R ⁵ and R ⁶ are the same or different and are a hydrogen atom or an optionally substituted C1-C6 Alkylcarbonyl, or optionally substituted C1-C6 alkoxycarbonyl; one of R ⁷ and R ⁸ is hydroxy, the other is C1-C6 alkyl substituted with a halogen atom; and R ⁹ is C1-substituted with a halogen atom. C6 alkyl; the compound according to 1), wherein R ¹⁰ is a hydrogen atom, a pharmaceutically acceptable salt thereof, or a solvate thereof,
7) General formula (IA):

(Wherein R ¹ , R ² , R ³ , and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, hydroxy, optionally substituted C1-C6 alkoxy, substituted Optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted C3-C6 cycloalkyloxy, optionally substituted C1-C6 alkylthio, substituted C2-C6 alkenylthio, which may be substituted, C3-C6 cycloalkylthio, which may be substituted, , Optionally substituted aryloxy, optionally substituted arylthio, optionally substituted amino, carboxy, optionally substituted C1-C6 alkylcarbonyl, optionally substituted C2- C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted carbamoyl, nitro, or cyano Or R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ are taken together to form an optionally substituted carbocycle or an optionally substituted heterocycle including an adjacent carbon atom. May form;
R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, or an optionally substituted. C1-C6 alkylcarbonyl, optionally substituted C2-C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C1-C6 alkenyloxycarbonyl, optionally substituted aryl Carbonyl, optionally substituted aryloxycarbonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted arylsulfonyl, or optionally substituted carbamoyl;
R ⁷ and R ⁸ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, hydroxy, an optionally substituted C1-C6. Alkoxy, optionally substituted C2-C6 alkenyloxy, mercapto, optionally substituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio, optionally substituted aryl, substituted An optionally substituted heteroaryl, or an optionally substituted amino), a pharmaceutically acceptable salt thereof, or a solvate thereof,
8) The compound according to 7), wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, an optionally substituted C1-C6 alkylcarbonyl, or an optionally substituted C1-C6 alkoxycarbonyl, a pharmaceutical thereof Top acceptable salts, or solvates thereof,
9) The compound according to 7), wherein R ⁹ is C1-C6 alkyl substituted with a halogen atom, a pharmaceutically acceptable salt thereof, or a solvate thereof,
10) The compound according to any one of 7) to 9), wherein one of R ⁷ and R ⁸ is hydroxy, and the other is C1-C6 alkyl substituted with a halogen atom, or a pharmaceutically acceptable salt thereof, or Solvates,
11) R ² and R ³ are the same or different and are a halogen atom or an optionally substituted C1-C6 alkyl; R ⁵ and R ⁶ are the same or different and are a hydrogen atom or an optionally substituted C1-C6 Alkylcarbonyl, or optionally substituted C1-C6 alkoxycarbonyl; one of R ⁷ and R ⁸ is hydroxy, the other is C1-C6 alkyl substituted with a halogen atom; and R ⁹ is C1-substituted with a halogen atom. C6 alkyl; the compound according to 7), wherein R ¹⁰ is a hydrogen atom, or a pharmaceutically acceptable salt thereof, a solvate thereof,
12) A pharmaceutical composition comprising the compound according to any one of 1) to 11) as an active ingredient,
13) The pharmaceutical composition according to 12), which is an antitumor agent,
14) General formula (II):

(Wherein R ¹ , R ² , R ³ , and R ⁴ are the same as 1))
And a compound of the general formula (III):

(Wherein R ¹¹ and R ¹² are the same or different and are CF ₃ , CF ₂ Cl, CCl ₃ , or CF ₂ CF ₃ ; R ¹³ is a hydrogen atom, C1-C6 alkyl, trifluoromethyl, C2-C6 alkenyl. , C2-C6 alkynyl, optionally substituted aryl; R ¹⁴ is C1-C6 alkyl)
A compound represented by the general formula (IV):

(Wherein R ¹ , R ² , R ³ , and R ⁴ are 1); R ¹¹ and R ¹² are the same or different and are CF ₃ , CF ₂ Cl, CCl ₃ , or CF ₂ CF ₃ ; R ¹³ is a hydrogen atom, C1-C6 alkyl, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, or optionally substituted aryl)
The manufacturing method of the compound shown by these.

The meaning of each term is explained below. In the present specification, each term is used in a unified meaning, and is used in the same meaning when used alone or in combination with other terms.
“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
“Alkyl” includes linear or branched monovalent aliphatic hydrocarbon groups having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Examples include sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, 2-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. C1-C6 linear or branched alkyl is preferable, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, Examples include isopentyl, neo-pentyl, 2-methyl-2-butyl, and n-hexyl. Furthermore, linear or branched alkyl having 1 to 4 carbon atoms is more preferable, and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. It is done. In particular, when a carbon number is specified, it means “alkyl” having a carbon number within the range.
“Alkenyl” includes a C 2-10 linear or branched monovalent aliphatic hydrocarbon group having 1 to 3 double bonds, such as vinyl, 1-propenyl, Examples include allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 2,3dimethyl-2-hexenyl and the like. A straight chain or branched alkenyl having 2 to 6 carbon atoms is preferable, and specifically, vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1 , 3-butadienyl, 3-methyl-2-butenyl. Furthermore, straight chain or branched alkenyl having 2 to 4 carbon atoms is more preferable, and specific examples include allyl, isopropenyl, and 3-butenyl. In particular, when a carbon number is specified, it means “alkenyl” having a carbon number within the range of the number.
“Alkynyl” includes a C2-C10 linear or branched monovalent aliphatic hydrocarbon group having 1 to 3 triple bonds, and examples thereof include ethynyl, propargyl and the like. . A linear or branched alkynyl having 2 to 6 carbon atoms is preferable, and specific examples include propargyl. In particular, linear or branched alkynyl having 2 to 4 carbon atoms is more preferable, and specific examples include propargyl. In particular, when a carbon number is specified, it means “alkynyl” having a carbon number within the range.
“Cycloalkyl” includes cycloalkyl having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. C3-C6 cycloalkyl is preferable, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When the number of carbons is specified, it means “cycloalkyl” having the number of carbons within the range.
The “cycloalkenyl” includes cycloalkenyl having 3 to 10 carbon atoms, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. Cycloalkenyl having 3 to 6 carbon atoms is preferable, and specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. In particular, when a carbon number is specified, it means “cycloalkenyl” having a carbon number within the range.
The alkyl part of “alkoxy” has the same meaning as the above “alkyl”. Examples of “alkoxy” include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n- Examples include octyloxy. In particular, alkoxy having 1 to 6 carbon atoms is preferable. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy Is mentioned. In particular, when a carbon number is specified, it means “alkoxy” having a carbon number within the range.
The alkenyl part of “alkenyloxy” has the same meaning as the above “alkenyl”. Examples of “alkenyloxy” include vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 2-pentenyloxy, 5-pentenyloxy, 3-methyl-2-butenyloxy, 2,3dimethyl-2-hexenyloxy and the like. Can be mentioned. Particularly, alkenyloxy having 1 to 6 carbon atoms is preferable, and specific examples include vinyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 2-pentenyloxy, 5-pentenyloxy, and 3-methyl-2-butenyloxy. In particular, when a carbon number is specified, it means “alkenyloxy” having a carbon number within the range of the number.
The alkynyl part of “alkynyloxy” has the same meaning as the above “alkynyl”. Examples of “alkynyloxy” include ethynyloxy, propynyloxy, 2-butynyloxy, 3-butynyloxy, 2-pentynyloxy, 5-pentynyloxy, 3-methyl-2-butynyloxy, 2,3-dimethyl-2 -Hexynyloxy and the like. In particular, alkoxy having 1 to 6 carbon atoms is preferable, and specifically, ethynyloxy, propynyloxy, 2-butynyloxy, 3-butynyloxy, 2-pentynyloxy, 5-pentynyloxy, and 3-methyl-2-butynyloxy are preferable. Can be mentioned. In particular, when a carbon number is specified, it means “alkynyloxy” having a carbon number within the range.
The cycloalkyl part of “cycloalkyloxy” has the same meaning as the above “cycloalkyl”. Examples of “cycloalkyloxy” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like. C3-C6 cycloalkyloxy is preferable, and specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. In particular, when a carbon number is specified, it means “cycloalkyloxy” having a carbon number within the range of the number.
The alkyl part of “alkylthio” has the same meaning as the above “alkyl”. Examples of the “alkylthio” include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, n-octylthio and the like. Is mentioned. In particular, a linear or branched alkylthio having 1 to 6 carbon atoms is preferable, and specifically, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n -Pentylthio, n-hexylthio are mentioned. In particular, when a carbon number is specified, it means “alkylthio” having a carbon number within the range of the number.
The alkenyl part of “alkenylthio” has the same meaning as the above “alkenyl”. Examples of “alkenylthio” include vinylthio, allylthio, 2-butenylthio, 3-butenylthio, 2-pentenylthio, 5-pentenylthio, 3-methyl-2-butenylthio, 2,3-dimethyl-2-hexenylthio and the like. Is mentioned. In particular, a linear or branched alkenylthio having 2 to 6 carbon atoms is preferable. Specifically, vinylthio, allylthio, 2-butenylthio, 3-butenylthio, 2-pentenylthio, 5-pentenylthio, 3-methyl 2-butenylthio is mentioned. In particular, when a carbon number is specified, it means “alkenylthio” having a carbon number within that range.
The cycloalkyl part of “cycloalkylthio” has the same meaning as the above “cycloalkyl”. Examples of “cycloalkylthio” include cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, cyclooctylthio and the like. C3-C6 cycloalkylthio is preferable, and specific examples include cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio. In particular, when a carbon number is specified, it means “cycloalkylthio” having a carbon number within the range of the number.
Substituents for “optionally substituted amino” include alkyl (eg, methyl, ethyl, n-propyl, i-propyl, etc.), aryl (eg, phenyl, naphthyl etc.), acyl (eg, formyl, acetyl, etc.) , Propionyl, benzoyl, etc.). The nitrogen atom of the amino group may be mono-substituted or di-substituted with these substituents. Specific examples of the “optionally substituted amino” include amino, methylamino, ethylamino, n-propylamino, i-propylamino, dimethylamino, diethylamino, ethylmethylamino, phenylamino, 1-naphthyl. Amino, 2-naphthylamino, acetylamino, N-acetylmethylamino and propylmethylamino are preferred.
Substituents of “optionally substituted carbamoyl” include alkyl (eg, methyl, ethyl, n-propyl, i-propyl, etc.), aryl (eg, phenyl, naphthyl etc.), acyl (eg, formyl, acetyl). , Propionyl, benzoyl, etc.). The nitrogen atom of the amino group may be mono-substituted or di-substituted with these substituents. As the “optionally substituted carbamoyl”, specifically, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl and N-ethylcarbamoyl are preferable.
“Acyl” includes the following “alkylcarbonyl”, “alkenylcarbonyl”, “arylcarbonyl” and the like. For example, formyl, acetyl, propionyl, benzoyl and the like can be mentioned.
“Alkylcarbonyl” means a group obtained by substituting the above “alkyl” with carbonyl, for example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, Examples include t-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, n-heptylcarbonyl, n-octylcarbonyl and the like. In particular, methylcarbonyl, ethylcarbonyl and the like are preferable. In particular, when the number of carbon atoms of “alkyl” is designated, it means “alkylcarbonyl” having “alkyl” in the number range of carbon atoms.
“Alkenylcarbonyl” means a group in which the above “alkenyl” is substituted on carbonyl, for example, vinylcarbonyl, allylcarbonyl, 2-butenylcarbonyl, 3-butenylcarbonyl, 2-pentenylcarbonyl, 5-pentenylcarbonyl. , 3-methyl-2-butenylcarbonyl, 2,3-dimethyl-2-hexenylcarbonyl and the like. In particular, vinylcarbonyl and allylcarbonyl are preferable. In particular, when the number of carbon atoms of “alkenyl” is specified, it means “alkenylcarbonyl” having “alkenyl” in the range of the number of carbon atoms.
“Alkoxycarbonyl” means a group obtained by substituting the above “alkoxy” with carbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxy. Examples include carbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl and the like. In particular, methoxycarbonyl, ethoxycarbonyl and the like are preferable. In particular, when the number of carbon atoms of “alkoxy” is specified, it means “alkoxycarbonyl” having “alkoxy” in the number range of carbon atoms.
“Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is substituted on carbonyl, such as vinyloxycarbonyl, allyloxycarbonyl, 2-butenyloxycarbonyl, 3-butenyloxycarbonyl, 2-pentenyl. Examples include oxycarbonyl, 5-pentenyloxycarbonyl, 3-methyl-2-butenyloxycarbonyl, 2,3-dimethyl-2-hexenyloxycarbonyl, and the like. In particular, vinyloxycarbonyl and allyloxycarbonyl are preferable. In particular, when the number of carbon atoms of “alkenyloxy” is designated, it means “alkenylcarbonyl” having “alkenyloxy” in the range of the number of carbon atoms.
The alkyl part of “alkylsulfonyl” has the same meaning as the above “alkyl”. Examples of “alkylsulfonyl” include methylsulfonyl, ethylsulfonyl and the like. When the number of carbons is specified, it means “alkylsulfonyl” having the number of carbons within the range.

The “carbocycle” includes the following “cycloalkane”, the following “cycloalkene”, and the following “aromatic carbocycle”.
“Cycloalkane” includes 3- to 10-membered cycloalkane, and examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. A 5- to 8-membered cycloalkane is preferred, and specific examples include cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
“Cycloalkene” includes 3- to 10-membered cycloalkene, and examples thereof include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and the like. A 5- to 8-membered cycloalkene is preferable, and specific examples include cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
The “aromatic carbocycle” includes an aromatic carbocycle having 6 to 14 carbon atoms, and examples thereof include benzene, naphthalene, anthracene, phenanthrene and the like. In particular, benzene is preferred.
“Aryl” includes aryl having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl, anthryl, phenanthryl and the like. In particular, phenyl is preferred.
The “heterocycle” includes the following “aromatic heterocycle” and the following “non-aromatic heterocycle”.
The “aromatic heterocycle” includes an aromatic heterocycle having 1 to 9 carbon atoms containing 1 to 4 nitrogen atoms, oxygen atoms, and / or sulfur atoms, such as furan, thiophene, pyrrole, Examples include imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine, furazane, pyrazine, and oxadiazole.
The “non-aromatic heterocycle” includes a non-aromatic heterocycle having 1 to 5 carbon atoms containing 1 to 3 nitrogen atoms, oxygen atoms, and / or sulfur atoms, such as pyrroline, pyrrolidine, Examples include imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, tetrahydropyran and the like.
“Heteroaryl” includes C 1-9 heteroaryl containing 1 to 4 nitrogen, oxygen and / or sulfur atoms, for example, furyl (eg, 2-furyl, 3-furyl). , Thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl ( For example, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazole -4-yl), tetrazolyl (eg, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg, 2-oxyl). Zolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg , 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (eg 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (eg 3-furazinyl), pyrazinyl (eg 2-pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), 1, 3- Nzodioxolyl, 1,4-benzodioxanyl, benzofuryl (for example, 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl, 5-benzo [b] furyl, 6-benzo [B] furyl, 7-benzo [b] furyl), benzothienyl (eg 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl , 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzimidazolyl (for example, 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzoxazolyl, quinoxalyl ( For example, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (eg 3 -Cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8- Quinazolinyl), quinolyl (eg 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg 1-phthalazinyl, 5-phthalazinyl, 6- Phthalazinyl), isoquinolyl (for example, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (for example, 2-pteridinyl, 4-pteridinyl, 6-Pteridinyl 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (eg 1-indolyl, 2-indolyl, 3 -Indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, fanadinyl (eg 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (eg 1-phenothiazinyl, 2-phenothiazinyl) , 3-phenothiazinyl, 4-phenothiazinyl) and the like.
The aryl part of “aryloxy” has the same meaning as the above “aryl”. Examples of “aryloxy” include phenoxy, naphthoxy (eg, 1-naphthoxy, 2-naphthoxy, etc.), anthryloxy (eg, 1-anthryloxy, 2-anthryloxy, etc.), phenanthryloxy ( For example, 1-phenanthryloxy, 2-phenanthryloxy and the like). In particular, phenoxy and naphthoxy are preferable.
The aryl part of “arylthio” has the same meaning as the above “aryl”. Examples of the “arylthio” include phenylthio, naphthylthio (eg, 1-naphthylthio, 2-naphthylthio), anthrylthio (eg, 1-anthrylthio, 2-anthrylthio, etc.), phenanthryloxy (eg, 1-phenanthrylthio, 2-phenanthrylthio etc.). In particular, phenylthio and naphthylthio are preferable.
The aryl part of “arylcarbonyl” has the same meaning as the above “aryl”. Examples of the “arylcarbonyl” include phenylcarbonyl, naphthylcarbonyl (eg, 1-naphthylcarbonyl, 2-naphthylcarbonyl), anthrylcarbonyl (eg, 1-anthrylcarbonyl, 2-anthrylcarbonyl, etc.), phenane And tolylcarbonyl (for example, 1-phenanthrylcarbonyl, 2-phenanthrylcarbonyl, etc.) and the like. In particular, phenylcarbonyl and naphthylcarbonyl are preferable.
The aryl part of “aryloxycarbonyl” has the same meaning as the above “aryl”. Examples of the “aryloxycarbonyl” include phenoxycarbonyl, naphthoxycarbonyl (eg, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl), anthryloxycarbonyl (eg, 1-anthryloxycarbonyl, 2-anthryl). Oxycarbonyl, etc.), phenanthryloxy (for example, 1-phenanthryloxycarbonyl, 2-phenanthryloxycarbonyl, etc.) and the like. In particular, phenoxycarbonyl and naphthoxycarbonyl are preferable.
The aryl part of “arylsulfonyl” has the same meaning as the above “aryl”. Examples of “arylsulfonyl” include phenylsulfonyl, naphthylsulfonyl (eg, 1-, naphthylsulfonyl, 2-naphthylsulfonyl) and the like. In particular, when a carbon number is specified, it means “arylsulfonyl” having a carbon number within the range of the number.

“Optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted cycloalkyl”, “optionally substituted cycloalkenyl” ”,“ Optionally substituted alkoxy ”,“ optionally substituted alkenyloxy ”,“ optionally substituted alkynyloxy ”,“ optionally substituted cycloalkyloxy ”,“ substituted ” “Optionally substituted alkylthio”, “optionally substituted alkenylthio”, “optionally substituted cycloalkylthio”, “optionally substituted aryl”, “optionally substituted heteroaryl” , “Optionally substituted aryloxy”, “optionally substituted arylthio”, “optionally substituted alkylcarbo , “Optionally substituted alkenylcarbonyl”, “optionally substituted alkoxycarbonyl”, “optionally substituted alkenyloxycarbonyl”, “optionally substituted arylcarbonyl”, “substituted” Optionally substituted aryloxycarbonyl ”,“ optionally substituted alkylsulfonyl ”,“ optionally substituted arylsulfonyl ”,“ optionally substituted carbocycle ”,“ optionally substituted ” When the “heterocycle” has a substituent, any position may be substituted with 1 to 4 substituents which are the same or different from each other. In particular, when the number of carbons is specified, it means a group including carbon atoms within the range of the number.
Examples of the substituent include, for example, a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), halogen atom or alkyl optionally substituted with alkoxy (for example, methyl, ethyl, isopropyl, t-butyl, trifluoro). Methyl, 1-methoxyethyl etc.), alkenyl (eg vinyl etc.), alkynyl (eg ethynyl etc.), optionally substituted amino, cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl etc.), aryl (Eg, phenyl, etc.), heteroaryl (eg, 2-pyridyl, etc.), hydroxy, halogen atom or alkoxy optionally substituted with phenyl (eg, methoxy, ethoxy, propoxy, butoxy, difluoromethoxy, trifluoromethoxy, Benzyloxy), a Kenyloxy (eg, allyloxy, etc.), alkylthio (eg, methylthio, ethylthio, etc.), carboxy, alkylcarbonyl (eg, methylcarbonyl, ethylcarbonyl, etc.), alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.) , Nitro, cyano, formyl, oxo, mercapto, alkylsulfonyl (such as methylsulfonyl), arylsulfonyl (such as phenylsulfonyl) and the like.

Among the compounds represented by the formula (I), compounds having preferable substituents shown below are particularly preferable compounds.
R ¹ is preferably a hydrogen atom, a halogen atom, or C1-C6 alkyl.
R ² is preferably a hydrogen atom, a halogen atom, or C1-C6 alkyl.
R ³ is preferably a hydrogen atom, a halogen atom, or C1-C6 alkyl.
R ⁴ is preferably a hydrogen atom, a halogen atom, or C1-C6 alkyl.
R ⁵ is preferably a hydrogen atom.
R ⁶ is preferably a hydrogen atom.
R ⁷ is preferably hydroxy or C1-C6 alkoxy, and more preferably trifluoromethyl.
R ⁸ is preferably C1-C6 alkyl substituted with a halogen atom, and more preferably trifluoromethyl.
R ⁹ is preferably C1-C6 alkyl substituted with a halogen atom, and more preferably trifluoromethyl.
R ¹⁰ is preferably a hydrogen atom or C1-C6 alkyl, and more preferably a hydrogen atom.
In particular, a compound in which R ⁷ is hydroxy, R ⁸ is C1-C6 alkyl substituted with a halogen atom, and R ⁹ is the same group as R ⁸ is preferable.

Among the compounds represented by the formula (IA), compounds having the following preferred substituents are particularly preferable compounds.
R ¹ is preferably a hydrogen atom, a halogen atom, or C1-C6 alkyl.
R ² is preferably a hydrogen atom, a halogen atom, or C1-C6 alkyl.
R ³ is preferably a hydrogen atom, a halogen atom, or C1-C6 alkyl.
R ⁴ is preferably a hydrogen atom, a halogen atom, or C1-C6 alkyl.
R ⁵ is preferably a hydrogen atom.
R ⁶ is preferably a hydrogen atom.
R ⁷ is preferably hydroxy or C1-C6 alkoxy, and more preferably trifluoromethyl.
R ⁸ is preferably C1-C6 alkyl substituted with a halogen atom, and more preferably trifluoromethyl.

  The compound of the present invention has excellent antitumor activity and is useful as a pharmaceutical, particularly as an antitumor agent.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は同一又は異なって、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいＣ２−Ｃ６アルキニル、置換されていてもよいＣ３−Ｃ６シクロアルキル、置換されていてもよいＣ３−Ｃ６シクロアルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、置換されていてもよいＣ２−Ｃ６アルキニルオキシ、置換されていてもよいＣ３−Ｃ６シクロアルキルオキシ、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいＣ３−Ｃ６シクロアルキルチオ、置換されていてもよいアリール、置換されていてもよいアリールオキシ、置換されていてもよいアリールチオ、置換されていてもよいアミノ、カルボキシ、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいカルバモイル、ニトロ、又はシアノ；又は
Ｒ^１とＲ^２、Ｒ^２とＲ^３、又はＲ^３とＲ^４が一緒になって、隣接する炭素原子を含んで置換されていてもよい炭素環又は置換されていてもよい複素環を形成してもよい；
Ｒ^１１は、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、メルカプト、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよいアミノ；
R^１２は、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、メルカプト、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよいアミノ；
Ｒ^１３は、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいＣ２−Ｃ６アルキニル、置換されていてもよいＣ３−Ｃ６シクロアルキル、又は置換されていてもよいアリール；
Ｒ^１５は、Ｃ１−Ｃ６アルコキシ；
Ｒ^１６は、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいアリール、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいアリールオキシカルボニル、置換されていてもよいＣ１−Ｃ６アルキルスルホニル、置換されていてもよいアリールスルホニル、又は置換されていてもよいカルバモイル；
Ｒ^１７は、水素原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいアリール、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいアリールオキシカルボニル、置換されていてもよいＣ１−Ｃ６アルキルスルホニル、置換されていてもよいアリールスルホニル、又は置換されていてもよいカルバモイル；
Ｒ^１８及びＲ^１９は同一又は異なって、水素原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいアリール、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいアリールオキシカルボニル、置換されていてもよいＣ１−Ｃ６アルキルスルホニル、置換されていてもよいアリールスルホニル、又は置換されていてもよいカルバモイル；
Ｒ^２０は、ハロゲン原子；
Ｒ^２１は、置換されていてもよいＣ１−Ｃ６アルキル又は置換されていてもよいＣ１−Ｃ６アルケニル；
Ｍは、酸素原子、硫黄原子、またはＮＲ^２２（Ｒ^２２は、水素原子、Ｃ１−Ｃ６アルキル、又はアシル；
Ｘは、ハロゲン原子又はＯＲ^１６（Ｒ^１６は、前記と同意義）；
Ｚは、酸素原、硫黄原子、又はＮＨ）
第１工程
一般式（ＩＩ）で示される化合物と一般式（ＩＩＩａ）で示される化合物を縮合させて、一般式（ＩＶａ）で示される化合物を製造する工程である。
溶媒としては、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（トルエン、キシレン等）、ジメチルスルホキシド、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。特にニトリル類が好ましく、さらにアセトニトリルがより好ましい。
一般式（ＩＩＩａ）で示される化合物は一般式（ＩＩ）で示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましく、さらに０．７当量〜１．５当量がより好ましい。
なお、一般式（ＩＩＩａ）で示される化合物は、シンセシス（Synthesis）、１９９０年、p. ３４７−３５０に示された方法を用いて、ビニルエーテル化合物とアシル化試薬とを反応させることにより一挙に合成することができる。また、ケミストリー レターズ（Chem. Lett.）、１９７６年、p. ４９９−５０２に示された方法やシンセシス（Synthesis）、１９９１年、p. ４８３−４８６に示された方法等によって得られるアシル体（Ｚ＝Ｏ）、そのチオアシル体（Ｚ＝Ｓ）あるいはイミノ体（Ｚ＝Ｎ）を、さらに所望のアシル化剤（Ｒ^１２ＣＯ化剤）と反応させる２段階の方法によっても合成することが可能であるが、これらの方法に限定されるものではない。
化合物（ＩＩ）と（ＩＩＩａ）との環化反応は塩基非存在下で進行するが、必要であれば、塩基を使用してもよい。塩基としては、有機塩基類（例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジン等）、無機塩基（例えば、炭酸ナトリウム、炭酸カリウム等）等を用いることができる。
反応時間は、０．５時間〜４８時間、好ましくは０．５時間〜６時間で行うことができる。
反応温度は、０℃から溶媒の還流温度、好ましくは１０℃〜５０℃で行うことができる。
一般式（ＩＩ）で示される化合物としては、１，２−フェニレンジアミン、４−クロロ−１，２−フェニレンジアミン、４−メチル−１，２−フェニレンジアミン、４−メトキシ−１，２−フェニレンジアミン、３−ニトロ−１，２−フェニレンジアミン、４−ニトロ−１，２−フェニレンジアミン、４−クロロ−５−フルオロ−１，２−フェニレンジアミン、４，５−ジクロロ−１，２−フェニレンジアミン、３，５−ジブロモ−１，２−フェニレンジアミン、４，５−ジメチル−１，２−フェニレンジアミンが好ましい。
第２工程
一般式（ＩＶａ）で示される化合物と一般式（Ｖ）で示される化合物を縮合させて、一般式（ＶＩ）で示される化合物を製造する工程である。
溶媒としては、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（トルエン、キシレン等）、ジメチルスルホキシド、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。特にニトリル類が好ましく、さらにアセトニトリルがより好ましい。
一般式（Ｖ）で示される化合物は一般式（ＩＶａ）で示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましい。
一般式（Ｖ）で示される化合物としては、無水酢酸、無水トリフルオロ酢酸、無水ペンタフルオロ酢酸、無水安息香酸、塩化メタンスルホニル、ジメチル硫酸、ヨウ化メチルが好ましい。
必要であれば、塩基を使用してもよい。塩基としては、有機塩基類（例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジン等）、無機塩基（例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等）等を用いることができる。
反応時間は、０．５時間〜７２時間で行うことができる。
反応温度は、−２０℃から溶媒の還流温度で行うことができる。
第３工程
一般式（ＶＩ）で示される化合物の−Ｚ−Ｒ^１７がヒドロキシである場合、該化合物をハロゲン化剤と反応させて、一般式（ＶＩＩ）で示される化合物を製造する工程である。
溶媒としては、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（トルエン、キシレン等）、ジメチルスルホキシド、１，２−ジクロロエタン、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。
ハロゲン化剤としては、塩化チオニル、オキシ塩化リン、三臭化リン等を用いることができる。ハロゲン化剤は一般式（ＶＩ）で示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましい。
必要であれば、塩基を使用してもよい。塩基としては、有機塩基類（例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジン等）、無機塩基（例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等）を用いることができる。
反応時間は、０．５時間〜７２時間で行うことができる。
反応温度は、−２０℃から溶媒の還流温度で行うことができる。
第４工程
一般式（ＶＩＩ）で示される化合物と一般式（ＶＩＩＩ）で示される化合物を縮合させて、一般式（ＩＸ）で示される化合物を製造する工程である。
溶媒としては、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（トルエン、キシレン等）、ジメチルスルホキシド、１，２−ジクロロエタン、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。
一般式（ＶＩＩＩ）で示される化合物としては、アルコール類（例えば、メタノール、エタノール等）、メルカプタン類（例えば、メルカプタン、メチルメルカプタン等）、アミン類（例えば、メチルアミン、ジメチルアミン等）等を用いることができる。一般式（ＶＩＩＩ）示される化合物は一般式（ＶＩＩ）で示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましい。
必要であれば、塩基を使用してもよい。塩基としては、有機塩基類（例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジン等）、無機塩基（例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等）を用いることができる。
反応時間は、０．５時間〜７２時間で行うことができる。
反応温度は、−２０℃から溶媒の還流温度で行うことができる。
なお、各工程で得られた化合物は、そのまま次の工程に用いることができるが、必要であれば蒸留、再結晶、カラムクロマトグラフィー等で精製することができる。 The compound which concerns on this invention can be manufactured according to the process shown below.

(Wherein R ¹ , R ² , R ³ , and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, hydroxy, optionally substituted C1-C6 alkoxy, substituted Optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted C3-C6 cycloalkyloxy, optionally substituted C1-C6 alkylthio, substituted C2-C6 alkenylthio, which may be substituted, C3-C6 cycloalkylthio, which may be substituted, , Optionally substituted aryloxy, optionally substituted arylthio, optionally substituted amino, carboxy, optionally substituted C1-C6 alkylcarbonyl, optionally substituted C2- C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted carbamoyl, nitro, or cyano Or R ¹ and R ² , R ² and R ³ , or R ³ and R ⁴ together, an optionally substituted carbocycle containing an adjacent carbon atom, or an optionally substituted heterocycle May be formed;
R ¹¹ represents a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, hydroxy, an optionally substituted C1-C6 alkoxy, or optionally substituted. Good C2-C6 alkenyloxy, mercapto, optionally substituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio, optionally substituted aryl, optionally substituted heteroaryl, or Optionally substituted amino;
R ¹² is a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, hydroxy, an optionally substituted C1-C6 alkoxy, or optionally substituted. Good C2-C6 alkenyloxy, mercapto, optionally substituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio, optionally substituted aryl, optionally substituted heteroaryl, or Optionally substituted amino;
R ¹³ represents a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C3. -C6 cycloalkyl, or optionally substituted aryl;
R ¹⁵ is C1-C6 alkoxy;
R ¹⁶ represents an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, an optionally substituted C1-C6 alkylcarbonyl, a substituted C2-C6 alkenylcarbonyl which may be substituted, C1-C6 alkoxycarbonyl which may be substituted, C2-C6 alkenyloxycarbonyl which may be substituted, arylcarbonyl which may be substituted, aryloxy which may be substituted Carbonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted arylsulfonyl, or optionally substituted carbamoyl;
R ¹⁷ represents a hydrogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, an optionally substituted C1-C6 alkylcarbonyl, a substituted Optionally substituted C2-C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted A good aryloxycarbonyl, an optionally substituted C1-C6 alkylsulfonyl, an optionally substituted arylsulfonyl, or an optionally substituted carbamoyl;
R ¹⁸ and R ¹⁹ are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, or an optionally substituted. C1-C6 alkylcarbonyl, optionally substituted C2-C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted aryl Carbonyl, optionally substituted aryloxycarbonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted arylsulfonyl, or optionally substituted carbamoyl;
R ²⁰ represents a halogen atom;
R ²¹ represents an optionally substituted C1-C6 alkyl or an optionally substituted C1-C6 alkenyl;
M is an oxygen atom, a sulfur atom, or NR ²² (R ²² is a hydrogen atom, C1-C6 alkyl, or acyl;
X is a halogen atom or OR ¹⁶ (R ¹⁶ is as defined above);
Z is an oxygen atom, a sulfur atom, or NH)
1st process It is the process of producing the compound shown by general formula (IVa) by condensing the compound shown by general formula (II), and the compound shown by general formula (IIIa).
Solvents include nitriles (eg, acetonitrile, propionitrile, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), dimethyl sulfoxide, amides (N, N-dimethylformamide) N, N-dimethylimidazolidinone) and the like can be used. Nitriles are particularly preferable, and acetonitrile is more preferable.
The compound represented by the general formula (IIIa) can be used in an amount of 0.5 to 4 equivalents relative to the compound represented by the general formula (II). 0.5 equivalents to 2 equivalents are preferable, and 0.7 equivalents to 1.5 equivalents are more preferable.
The compound represented by the general formula (IIIa) was synthesized at once by reacting a vinyl ether compound with an acylating reagent using the method shown in Synthesis, 1990, p. 347-350. can do. In addition, an acyl compound obtained by a method shown in Chem. Lett., 1976, p. 499-502, a method shown in Synthesis, 1991, p. 483-486, or the like ( Z = O), its thioacyl form (Z = S) or imino form (Z = N) can also be synthesized by a two-step method in which it is further reacted with a desired acylating agent (R ¹² CO agent). However, it is not limited to these methods.
The cyclization reaction of compound (II) and (IIIa) proceeds in the absence of a base, but a base may be used if necessary. As the base, organic bases (for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like), inorganic bases (for example, sodium carbonate, potassium carbonate and the like) and the like can be used.
The reaction time can be 0.5 to 48 hours, preferably 0.5 to 6 hours.
The reaction temperature can be 0 ° C to the reflux temperature of the solvent, preferably 10 ° C to 50 ° C.
Examples of the compound represented by the general formula (II) include 1,2-phenylenediamine, 4-chloro-1,2-phenylenediamine, 4-methyl-1,2-phenylenediamine, and 4-methoxy-1,2-phenylene. Diamine, 3-nitro-1,2-phenylenediamine, 4-nitro-1,2-phenylenediamine, 4-chloro-5-fluoro-1,2-phenylenediamine, 4,5-dichloro-1,2-phenylene Diamine, 3,5-dibromo-1,2-phenylenediamine, and 4,5-dimethyl-1,2-phenylenediamine are preferred.
Second Step In this step, the compound represented by the general formula (IVa) and the compound represented by the general formula (V) are condensed to produce a compound represented by the general formula (VI).
Solvents include nitriles (eg, acetonitrile, propionitrile, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), dimethyl sulfoxide, amides (N, N-dimethylformamide) N, N-dimethylimidazolidinone) and the like can be used. Nitriles are particularly preferable, and acetonitrile is more preferable.
The compound represented by the general formula (V) can be used in an amount of 0.5 to 4 equivalents with respect to the compound represented by the general formula (IVa). 0.5 to 2 equivalents are preferred.
As the compound represented by the general formula (V), acetic anhydride, trifluoroacetic anhydride, pentafluoroacetic anhydride, benzoic anhydride, methanesulfonyl chloride, dimethyl sulfate, and methyl iodide are preferable.
If necessary, a base may be used. As the base, organic bases (eg, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.), inorganic bases (eg, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc.) are used. be able to.
The reaction time can be 0.5 to 72 hours.
The reaction temperature can be from −20 ° C. to the reflux temperature of the solvent.
Step 3 When -ZR ^{17 in the} compound represented by the general formula (VI) is hydroxy, the compound is reacted with a halogenating agent to produce the compound represented by the general formula (VII). .
Examples of the solvent include nitriles (for example, acetonitrile, propionitrile, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), dimethyl sulfoxide, 1,2-dichloroethane, amides ( N, N-dimethylformamide, N, N-dimethylimidazolidinone) and the like can be used.
As the halogenating agent, thionyl chloride, phosphorus oxychloride, phosphorus tribromide and the like can be used. The halogenating agent can be used in an amount of 0.5 to 4 equivalents with respect to the compound represented by the general formula (VI). 0.5 to 2 equivalents are preferred.
If necessary, a base may be used. As the base, organic bases (for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.) and inorganic bases (for example, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc.) should be used. Can do.
The reaction time can be 0.5 to 72 hours.
The reaction temperature can be from −20 ° C. to the reflux temperature of the solvent.
Fourth Step In this step, the compound represented by the general formula (VII) and the compound represented by the general formula (VIII) are condensed to produce the compound represented by the general formula (IX).
Examples of the solvent include nitriles (for example, acetonitrile, propionitrile, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), dimethyl sulfoxide, 1,2-dichloroethane, amides ( N, N-dimethylformamide, N, N-dimethylimidazolidinone) and the like can be used.
As the compound represented by the general formula (VIII), alcohols (for example, methanol, ethanol, etc.), mercaptans (for example, mercaptan, methyl mercaptan, etc.), amines (for example, methylamine, dimethylamine, etc.) are used. be able to. The compound represented by the general formula (VIII) can be used in an amount of 0.5 to 4 equivalents based on the compound represented by the general formula (VII). 0.5 to 2 equivalents are preferred.
If necessary, a base may be used. As the base, organic bases (for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.) and inorganic bases (for example, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc.) should be used. Can do.
The reaction time can be 0.5 to 72 hours.
The reaction temperature can be from −20 ° C. to the reflux temperature of the solvent.
In addition, although the compound obtained at each process can be used for the next process as it is, if necessary, it can be purified by distillation, recrystallization, column chromatography or the like.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は１）と同意義：Ｒ^１２及びＲ^１３は９）と同意義；Ｒ^１６は、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、置換されていてもよいアリール、置換されていてもよいＣ１−Ｃ６アルキルカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルカルボニル、置換されていてもよいＣ１−Ｃ６アルコキシカルボニル、置換されていてもよいＣ２−Ｃ６アルケニルオキシカルボニル、置換されていてもよいアリールカルボニル、置換されていてもよいアリールオキシカルボニル、置換されていてもよいＣ１−Ｃ６アルキルスルホニル、置換されていてもよいアリールスルホニル、又は置換されていてもよいカルバモイル；Ｒ^２３は、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、メルカプト、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよいアミノ；Ｒ^２４は、水素原子、ハロゲン原子、置換されていてもよいＣ１−Ｃ６アルキル、置換されていてもよいＣ２−Ｃ６アルケニル、ヒドロキシ、置換されていてもよいＣ１−Ｃ６アルコキシ、置換されていてもよいＣ２−Ｃ６アルケニルオキシ、メルカプト、置換されていてもよいＣ１−Ｃ６アルキルチオ、置換されていてもよいＣ２−Ｃ６アルケニルチオ、置換されていてもよいアリール、置換されていてもよいヘテロアリール、又は置換されていてもよいアミノ）
第１工程
一般式（ＩＩ）で示される化合物と一般式（Ｘ）で示される化合物を縮合させて、一般式（ＸＩ）で示される化合物を製造する工程である。
溶媒としては、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（ベンゼン、トルエン、キシレン等）、ジメチルスルホキシド、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。
一般式（Ｘ）で示される化合物は一般式（ＩＩ）で示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましい。
必要であれば、塩基を使用してもよい。塩基としては、有機塩基類（例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジン等）、無機塩基（例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等）を用いることができる。
反応時間は、０．５時間〜７２時間で行うことができる。
反応温度は、−２０℃から溶媒の還流温度で行うことができる。
第２工程
一般式（ＸＩ）で示される化合物と一般式（ＸＩＩ）で示される化合物を縮合させて、一般式（ＸＩＩＩ）で示される化合物を製造する工程である。
溶媒としては、アルコール類（例えば、メタノール、エタノール等）、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（トルエン、キシレン等）、ジメチルスルホキシド、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。
一般式（ＸＩＩ）で示される化合物は一般式（ＸＩ）で示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましい。
必要であれば、塩基を使用してもよい。塩基としては、有機塩基類（例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジン等）、無機塩基（例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等）を用いることができる。
反応時間は、０．５時間〜７２時間で行うことができる。
反応温度は、−２０℃から溶媒の還流温度で行うことができる。
第３工程
一般式（ＸＩＩＩ）で示される化合物と一般式（Ｖ）で示される化合物を縮合させて、一般式（ＸＩＶ）で示される化合物を製造する工程である。
溶媒としては、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（トルエン、キシレン等）、ジメチルスルホキシド、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。特にニトリル類が好ましく、さらにアセトニトリルがより好ましい。
一般式（Ｖ）で示される化合物は一般式（ＸＩＩＩ）示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましい。
一般式（Ｖ）で示される化合物としては、無水酢酸、無水トリフルオロ酢酸、無水ペンタフルオロ酢酸、無水安息香酸、塩化メタンスルホニル、ジメチル硫酸、ヨウ化メチルが好ましい。
必要であれば、塩基を使用してもよい。塩基としては、有機塩基類（例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジン等）、無機塩基（例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等）等を用いることができる。
反応時間は、０．５時間〜７２時間で行うことができる。
反応温度は、−２０℃から溶媒の還流温度で行うことができる。
なお、各工程で得られた化合物は、そのまま次の工程に用いることができるが、必要であれば蒸留、再結晶、カラムクロマトグラフィー等で精製することができる。 Moreover, the compound based on this invention can be manufactured also by the process shown below.

(Wherein R ¹ , R ² , R ³ , and R ⁴ are the same meanings as 1): R ¹² and R ¹³ are the same meanings as 9); R ¹⁶ is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl which may be substituted, aryl which may be substituted, C1-C6 alkylcarbonyl which may be substituted, C2-C6 alkenylcarbonyl which may be substituted, C1 which may be substituted -C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted C1-C6 alkylsulfonyl, substituted is arylsulfonyl also be, or optionally substituted carbamoyl; R ²³ represents a hydrogen atom, a halogen Child, C1-C6 alkyl which may be substituted, C2-C6 alkenyl which may be substituted, hydroxy, C1-C6 alkoxy which may be substituted, C2-C6 alkenyloxy which may be substituted, mercapto An optionally substituted C1-C6 alkylthio, an optionally substituted C2-C6 alkenylthio, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted amino; R ²⁴ represents a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, hydroxy, an optionally substituted C1-C6 alkoxy, or optionally substituted. Good C2-C6 alkenyloxy, mercapto, optionally substituted C1-C6 alkylthio, Are optionally may C2-C6 alkenylthio, aryl which may be substituted, an optionally substituted heteroaryl, or optionally substituted amino)
Step 1 In this step, the compound represented by the general formula (II) and the compound represented by the general formula (X) are condensed to produce a compound represented by the general formula (XI).
Solvents include nitriles (eg, acetonitrile, propionitrile, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), dimethyl sulfoxide, amides (N, N— (Dimethylformamide, N, N-dimethylimidazolidinone) and the like can be used.
The compound represented by the general formula (X) can be used in an amount of 0.5 to 4 equivalents relative to the compound represented by the general formula (II). 0.5 to 2 equivalents are preferred.
If necessary, a base may be used. As the base, organic bases (for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.) and inorganic bases (for example, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc.) should be used. Can do.
The reaction time can be 0.5 to 72 hours.
The reaction temperature can be from −20 ° C. to the reflux temperature of the solvent.
Second Step The second step is a step for producing a compound represented by the general formula (XIII) by condensing the compound represented by the general formula (XI) and the compound represented by the general formula (XII).
Solvents include alcohols (eg, methanol, ethanol, etc.), nitriles (eg, acetonitrile, propionitrile, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), dimethyl Sulfoxide, amides (N, N-dimethylformamide, N, N-dimethylimidazolidinone) and the like can be used.
The compound represented by the general formula (XII) can be used in an amount of 0.5 to 4 equivalents based on the compound represented by the general formula (XI). 0.5 to 2 equivalents are preferred.
If necessary, a base may be used. As the base, organic bases (for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.) and inorganic bases (for example, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc.) should be used. Can do.
The reaction time can be 0.5 to 72 hours.
The reaction temperature can be from −20 ° C. to the reflux temperature of the solvent.
Step 3 In this step, the compound represented by the general formula (XIII) is condensed with the compound represented by the general formula (V) to produce the compound represented by the general formula (XIV).
Solvents include nitriles (eg, acetonitrile, propionitrile, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), dimethyl sulfoxide, amides (N, N-dimethylformamide) N, N-dimethylimidazolidinone) and the like can be used. Nitriles are particularly preferable, and acetonitrile is more preferable.
The compound represented by the general formula (V) can be used in an amount of 0.5 to 4 equivalents with respect to the compound represented by the general formula (XIII). 0.5 to 2 equivalents are preferred.
As the compound represented by the general formula (V), acetic anhydride, trifluoroacetic anhydride, pentafluoroacetic anhydride, benzoic anhydride, methanesulfonyl chloride, dimethyl sulfate, and methyl iodide are preferable.
If necessary, a base may be used. As the base, organic bases (eg, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.), inorganic bases (eg, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc.) are used. be able to.
The reaction time can be 0.5 to 72 hours.
The reaction temperature can be from −20 ° C. to the reflux temperature of the solvent.
In addition, although the compound obtained at each process can be used for the next process as it is, if necessary, it can be purified by distillation, recrystallization, column chromatography or the like.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は１）と同意義：Ｒ^１１、Ｒ^１２、Ｒ^１３及びＲ^１４は９）と同意義）
溶媒としては、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（トルエン、キシレン等）、ジメチルスルホキシド、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。特にニトリル類が好ましく、さらにアセトニトリルがより好ましい。
一般式（ＩＩＩ）で示される化合物は一般式（ＩＩ）示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましい。
必要であれば、塩基を使用してもよい。塩基としては、有機塩基類（例えば、トリエチルアミン、ジイソプロピルエチルアミン、４−ジメチルアミノピリジン等）、無機塩基（例えば、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等）等を用いることができる。
反応時間は、０．５時間〜７２時間で行うことができる。
反応温度は、−２０℃から溶媒の還流温度で行うことができる。
なお、得られた化合物は、そのまま次の工程に用いることができるが、必要であれば蒸留、再結晶、カラムクロマトグラフィー等で精製することができる。 The compound represented by the general formula (IV) can be produced by condensing the compound represented by the general formula (II) and the compound represented by the general formula (III).

(Wherein R ¹ , R ² , R ³ , and R ⁴ are the same as 1), and R ¹¹ , R ¹² , R ^13, and R ¹⁴ are the same as 9).
Solvents include nitriles (eg, acetonitrile, propionitrile, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), dimethyl sulfoxide, amides (N, N-dimethylformamide) N, N-dimethylimidazolidinone) and the like can be used. Nitriles are particularly preferable, and acetonitrile is more preferable.
The compound represented by the general formula (III) can be used in an amount of 0.5 to 4 equivalents relative to the compound represented by the general formula (II). 0.5 to 2 equivalents are preferred.
If necessary, a base may be used. As the base, organic bases (eg, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc.), inorganic bases (eg, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc.) are used. be able to.
The reaction time can be 0.5 to 72 hours.
The reaction temperature can be from −20 ° C. to the reflux temperature of the solvent.
The obtained compound can be used in the next step as it is, but can be purified by distillation, recrystallization, column chromatography or the like if necessary.

溶媒としては、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）、ハロアルキル類（ジクロロメタン、クロロホルム等）、エーテル類（テトラヒドロフラン、ジオキサン等）、芳香族炭化水素類（トルエン、キシレン等）、ジメチルスルホキシド、アミド類（Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルイミダゾリジノン）等を使用することができる。特にニトリル類が好ましく、さらにアセトニトリルまたはクロロホルムがより好ましい。
塩化チオニルは一般式（ＩＶ）示される化合物に対して、０．５当量〜４当量用いることができる。０．５当量〜２当量が好ましい。
反応時間は、１分間〜６時間で行うことができる。
反応温度は、−２０℃から溶媒の還流温度で行うことができる。
なお、得られた化合物は、必要であれば蒸留、再結晶、カラムクロマトグラフィー等で精製することができる。 The compound represented by the general formula (IA) can be produced by treating the compound represented by the general formula (IV) with thionyl chloride.

Solvents include nitriles (eg, acetonitrile, propionitrile, etc.), haloalkyls (dichloromethane, chloroform, etc.), ethers (tetrahydrofuran, dioxane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), dimethyl sulfoxide, Amides (N, N-dimethylformamide, N, N-dimethylimidazolidinone) and the like can be used. Nitriles are particularly preferable, and acetonitrile or chloroform is more preferable.
Thionyl chloride can be used in an amount of 0.5 to 4 equivalents based on the compound represented by the general formula (IV). 0.5 to 2 equivalents are preferred.
The reaction time can be 1 minute to 6 hours.
The reaction temperature can be from −20 ° C. to the reflux temperature of the solvent.
The obtained compound can be purified by distillation, recrystallization, column chromatography or the like if necessary.

Examples of the pharmaceutically acceptable salt include basic salts such as alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt and dicyclohexyl. Aliphatic amine salts such as amine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, brocaine salts; aralkylamine salts such as N, N-dibenzylethylenediamine; pyridine salts, picoline salts, quinoline salts, isoquinoline salts, etc. Heterocyclic aromatic amine salt; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium Quaternary ammonium salts such as nium salts; basic amino acid salts such as arginine salts and lysine salts. Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate, ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.
Solvates include organic solvates that coordinate any number of organic solvent molecules and hydrates that coordinate any number of water molecules. The solvate means a solvate of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, for example, a monosolvate, a disolvate, a monohydrate, a dihydrate Thing etc. are mentioned.
The compounds of the present invention are not limited to specific isomers, but include all possible isomers and racemates.

The compound of the present invention can be used as a therapeutic agent for cancer. Specifically, treatment of brain tumor, lung cancer, colon cancer, ovarian cancer, stomach cancer, lung adenocarcinoma, pancreatic cancer, head and neck cancer, esophageal cancer, bladder cancer, kidney cancer, prostate cancer, breast cancer, uterine cancer, thyroid cancer, etc. Can be used as an agent.
In order to use the compound of the present invention for treatment, it is formulated as a usual preparation for oral or parenteral administration. The pharmaceutical composition containing the compound of the present invention can take a dosage form for oral and parenteral administration. That is, it can be an oral preparation such as a tablet, capsule, granule, powder or syrup, or a parenteral preparation such as an injection solution such as intravenous injection, intramuscular injection or subcutaneous injection.
These preparations can be produced using appropriate carriers, excipients, solvents, bases and the like known to those skilled in the art. For example, in the case of a tablet, the active ingredient and auxiliary ingredients are compressed or molded together. Auxiliary ingredients include pharmaceutically acceptable excipients such as binders (eg, corn starch), fillers (eg, lactose, microcrystalline cellulose, etc.), disintegrants (eg, sodium starch glycolate, etc.) ) Or a lubricant (for example, magnesium stearate). The tablet may be appropriately coated. In the case of liquid preparations such as syrups, solutions, and suspensions, for example, suspending agents (for example, methylcellulose), emulsifiers (for example, lecithin), preservatives, and the like are used. In the case of an injectable preparation, it may be in the form of a solution, a suspension or an oily or aqueous emulsion, and these may contain a suspension stabilizer or a dispersing agent.
The dose of the compound of the present invention varies depending on the administration form, patient's symptoms, age, body weight, sex, or concomitant drugs (if any), and ultimately depends on the judgment of a doctor. In the case of administration, 0.01-100 mg / kg body weight per day, preferably 0.01-10 mg, more preferably 0.1-10 mg, in the case of parenteral administration, 0.001-100 mg / kg body weight per day Preferably, 0.001 to 1 mg, more preferably 0.01 to 1 mg is administered. This may be divided into 1 to 4 times.

Hereinafter, the present invention will be described in detail with reference to examples. However, these are merely examples, and the present invention is not limited thereto.
Example 1 2,2,2-trifluoro-1- (2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone ( Synthesis of Compound 1) 1,1,1,5,5,5-Hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (292.0 mg, 1.0 mmol) and orthophenylenediamine (113.5 mg, 1.1 mmol) in acetonitrile (4 mL) was reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 333.0 mg of a crude solid. The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (9: 1)) and 2,2,2-trifluoro-1- (2-hydroxy-2-trifluoromethyl-2,5-dihydro -1H-benzo [b] [1,4] diazepin-3-yl) ethanone (Compound 1, 277.1 mg, 84.9%) was obtained. The physical properties are shown in Table 2.

Example 2 2,2,2-trifluoro-1- (2-hydroxy-8-methyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine-3- Yl) ethanone (compound 2a) and 2,2,2-trifluoro-1- (2-hydroxy-7-methyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4 Synthesis of diazepin-3-yl) ethanone (compound 2b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (292.2 mg, 1.0 mmol) And 4-methylbenzene-1,2-diamine (128.3 mg, 1.1 mmol) in acetonitrile (4 mL) were reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 375.8 mg of a crude solid. It was. This crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (9: 1)) to give 2,2,2-trifluoro-1- (2-hydroxy-8-methyl-2-trifluoromethyl-2). , 5-Dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 2a) and 2,2,2-trifluoro-1- (2-hydroxy-7-methyl-2- A mixture (272.9 mg, 80.2%) of trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (Compound 2b) was obtained.

Example 3 2,2,2-trifluoro-1- (2-hydroxy-9-methyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine-3- Yl) ethanone (compound 3a) and 2,2,2-trifluoro-1- (2-hydroxy-6-methyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4 Synthesis of diazepin-3-yl) ethanone (compound 3b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,3-dione (584.4 mg, 2.0 mmol) And 3-methylbenzene-1,2-diamine (256.7 mg, 2.1 mmol) in acetonitrile (8 mL) were reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 670.0 mg of a crude solid. It was. This crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (9: 1)) to give 2,2,2-trifluoro-1- (2-hydroxy-9-methyl-2-trifluoromethyl-2). , 5-Dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 3a) and 2,2,2-trifluoro-1- (2-hydroxy-6-methyl-2- A mixture (470.9 mg, 69.2%) of trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 3b) was obtained.

Example 4 1- (8-Chloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2,2,2- Trifluoroethanone (compound 4a) and 1- (7-chloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2 Of 1,2,2-trifluoroethanone (compound 4b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (584.4 mg, 2.0 mmol) And 4-chlorobenzene-1,2-diamine (300.0 mg, 2.1 mmol) in acetonitrile (8 mL) were reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 644.1 mg of a crude solid. . The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (4: 1)), and 1- (8-chloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [ b] [1,4] diazepin-3-yl) -2,2,2-trifluoroethanone (compound 4a) and 1- (7-chloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro A mixture (400.2 mg, 69.6%) of -1H-benzo [b] [1,4] diazepin-3-yl) -2,2,2-trifluoroethanone (Compound 4b) was obtained.

Example 5 2,2,2-trifluoro-1- (2-hydroxy-8-nitro-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine-3- Yl) ethanone (compound 5a) and 2,2,2-trifluoro-1- (2-hydroxy-7-nitro-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4 Synthesis of diazepin-3-yl) ethanone (compound 5b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (292.1 mg, 1.0 mmol) And 4-nitrobenzene-1,2-diamine (153.1 mg, 1.1 mmol) in acetonitrile (4 mL) were reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 402.6 mg of a crude solid. . The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (2.4: 1)) and 2,2,2-trifluoro-1- (2-hydroxy-8-nitro-2-trifluoromethyl). -2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 5a) and 2,2,2-trifluoro-1- (2-hydroxy-7-nitro- A mixture (319.5 mg, 76.1%) of 2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (Compound 5b) was obtained.

Example 6 4-Hydroxy-3- (2,2,2-trifluoroacetyl) -4-trifluoromethyl-4,5-dihydro-1H-benzo [b] [1,4] diazepine-7-carboxyl Acid (Compound 6a) and 2-hydroxy-3- (2,2,2-trifluoroacetyl) -2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine-7 -Synthesis of Carboxylic Acid (Compound 6b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (292.2 mg, 1.0 mmol) and 3,4 -Diaminobenzoic acid (153.0 mg, 1.1 mmol) in dimethyl sulfoxide (4 mL) was reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 331.0 mg of a crude solid. This crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (1.6: 1)) to give 4-hydroxy-3- (2,2,2-trifluoroacetyl) -4-trifluoromethyl-4. , 5-Dihydro-1H-benzo [b] [1,4] diazepine-7-carboxylic acid (compound 6a) and 2-hydroxy-3- (2,2,2-trifluoroacetyl) -2-trifluoro A mixture (250.9 mg, 67.8%) of methyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine-7-carboxylic acid (Compound 6b) was obtained.

Example 7 4-Hydroxy-3- (2,2,2-trifluoroacetyl) -4-trifluoromethyl-4,5-dihydro-1H-benzo [b] [1,4] diazepine-7-carboxyl Acid methyl ester (compound 7a) and 2-hydroxy-3- (2,2,2-trifluoroacetyl) -2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine Synthesis of -7-carboxylic acid methyl ester (compound 7b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (146.1 mg, 0.5 mmol) And 3,4-diaminobenzoic acid methyl ester (87.2 mg, 0.5 mmol) in acetonitrile (2 mL) was allowed to react at room temperature for 1 hour, and then the solvent was distilled off. 9 mg of crude solid was obtained. This crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (2: 1)) to give 4-hydroxy-3- (2,2,2-trifluoroacetyl) -4-trifluoromethyl-4,5. -Dihydro-1H-benzo [b] [1,4] diazepine-7-carboxylic acid methyl ester (compound 7a) and 2-hydroxy-3- (2,2,2-trifluoroacetyl) -2-trifluoro A mixture (157.4 mg, 81.9%) of methyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine-7-carboxylic acid methyl ester (Compound 7b) was obtained.

Example 8 4-Hydroxy-3- (2,2,2-trifluoroacetyl) -4-trifluoromethyl-4,5-dihydro-1H-benzo [b] [1,4] diazepine-7-carboxyl Acid normal butyl ester (compound 8a) and 2-hydroxy-3- (2,2,2-trifluoroacetyl) -2-trifluoromethyl-4,5-dihydro-1H-benzo [b] [1,4] Synthesis of diazepine-7-carboxyl acid normal butyl ester (compound 8b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (144.6 mg, 0.5 mmol) and 3,4-diaminobenzoic acid normal butyl ester (109.3 mg, 0.5 mmol) in acetonitrile (2 mL) were reacted at room temperature for 1 hour. Thereafter, the solvent was distilled off to obtain 217.7 mg of a crude solid. This crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (2: 1)) to give 4-hydroxy-3- (2,2,2-trifluoroacetyl) -4-trifluoromethyl-4,5. -Dihydro-1H-benzo [b] [1,4] diazepine-7-carboxyl acid normal butyl ester (compound 8a) and 2-hydroxy-3- (2,2,2-trifluoroacetyl) -4-tri A mixture (189.7 mg, 89.0%) of fluoromethyl-4,5-dihydro-1H-benzo [b] [1,4] diazepine-7-carboxyl acid normal butyl ester (Compound 8b) was obtained.

Example 9 1- (8-Benzoyl-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2,2,2- Trifluoroethanone (Compound 9a) and 1- (7-benzoyl-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2 , 2,2-Trifluoroethanone (Compound 9b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (292.1 mg, 1.0 mmol) And (3,4-diaminophenyl) phenylmethanone (212.3 mg, 1.1 mmol) in acetonitrile (4 mL) were reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 484.2 mg of a crude solid. Obtained. The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (2.1: 1)), and 1- (8-benzoyl-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H- Benzo [b] [1,4] diazepin-3-yl) -2,2,2-trifluoroethanone (compound 9a) and 1- (7-benzoyl-2-hydroxy-2-trifluoromethyl-2,5 A mixture (329.4 mg, 76.5%) of -dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2,2,2-trifluoroethanone (Compound 9b) was obtained.

Example 10 1,1,1,5,5,5-hexafluoro-3-[[4-hydroxy-3- (2,2,2-trifluoroacetyl) -4-trifluoromethyl-4,5- Dihydro-1H-benzo [b] [1,4] diazepin-7-ylamino] methylene] pentane-2,4-dione (compound 10a) and 1,1,1,5,5,5-hexafluoro-3- [[2-Hydroxy-3- (2,2,2-trifluoroacetyl) -2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-7-ylamino] methylene Synthesis of pentane-2,4-dione (compound 10b) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (286.0 mg, 1.0 mmol) And benzene-1,2,4-tria Emissions (130.0 mg, 1.0 mmol) in acetonitrile (4 mL) solution of mixture was reacted at room temperature for 1 hour, the solvent was distilled off to obtain 298.2 mg of crude solid. The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (4: 1)), and 1,1,1,5,5,5-hexafluoro-3-[[4-hydroxy-3- (2 , 2,2-trifluoroacetyl) -4-trifluoromethyl-4,5-dihydro-1H-benzo [b] [1,4] diazepin-7-ylamino] methylene] pentane-2,4-dione (compound 10a) and 1,1,1,5,5,5-hexafluoro-3-[[2-hydroxy-3- (2,2,2-trifluoroacetyl) -2-trifluoromethyl-2,5- A mixture (88.0 mg, 32.7%) of dihydro-1H-benzo [b] [1,4] diazepin-7-ylamino] methylene] pentane-2,4-dione (compound 10b) was obtained.

Example 11 2,2,2-trifluoro-1- (2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine- Synthesis of 3-yl) ethanone (compound 11) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (875.5 mg, 3.0 mmol) and 4, A solution of 5-dimethylbenzene-1,2-diamine (429.0 mg, 3.2 mmol) in acetonitrile (12 mL) was reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 1084.3 mg of a crude solid. . The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (9: 1)), and 2,2,2-trifluoro-1- (2-hydroxy-7,8-dimethyl-2-trifluoromethyl). -2,5-Dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (Compound 11, 852.8 mg, 87.1%) was obtained.

Example 12 1- (7,8-Dichloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2,2, Synthesis of 2-trifluoroethanone (Compound 12) 1,1,1,5,5,5-hexafluoro-3- (isobutoxymethylene) pentane-2,4-dione (292.2 mg, 1.0 mmol) and 4, After reacting a solution of 5-dichlorobenzene-1,2-diamine (185.9 mg, 1.1 mmol) in acetonitrile (4 mL) at room temperature for 1 hour, the solvent was distilled off to obtain 455.4 mg of a crude solid. . The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (2.4: 1)), and 1- (7,8-dichloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro- 1H-benzo [b] [1,4] diazepin-3-yl) -2,2,2-trifluoroethanone (Compound 12, 342.2 mg, 82.2%) was obtained.

Example 13 2-Chloro-1- [2- (chlorodifluoromethyl) -2-hydroxy-7,8-dimethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl ] -2,2-Difluoroethanone (Compound 13) 1,5-Dichloro-1,1,5,5-tetrafluoro-3- (isobutoxymethylene) pentane-2,4-dione (325.1 mg, 1.0 mmol) and 4,5-dimethylbenzene-1,2-diamine (143.0 mg, 1.1 mmol) in acetonitrile (4 mL) were reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 409.8 mg. A crude solid was obtained. The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (3.6: 1)) and 2-chloro-1- [2- (chlorodifluoromethyl) -2-hydroxy-7,8-dimethyl- 2,5-Dihydro-1H-benzo [b] [1,4] diazepin-3-yl] -2,2-difluoroethanone (Compound 13, 305.9 mg, 78.9%) was obtained.

Example 14 2,2,2-Trichloro-1- (2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine-3 -Yl) ethanone (compound 14a) and 2,2,2-trifluoro-1- (2-hydroxy-7,8-dimethyl-2-trichloromethyl-2,5-dihydro-1H-benzo [b] [1] , 4] diazepin-3-yl) ethanone (compound 14b) 1,1,1-trichloro-5,5,5-trifluoro-3- [1-isobutoxymethylidene] pentane-2,4-dione (341.5 mg, 1 mmol) and 4,5-dimethylbenzene-1,2-diamine (143.0 mg, 1.1 mmol) in acetonitrile (4 mL) were reacted at room temperature for 1 hour, and then the solvent was distilled off. 392.9 mg of crude solid was obtained. The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (9: 1)), and 2,2,2-trichloro-1- (2-hydroxy-7,8-dimethyl-2-trifluoromethyl- 2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 14a) and 2,2,2-trifluoro-1- (2-hydroxy-7,8-dimethyl) A mixture (299.0 mg, 74.1%) of 2-trichloromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (Compound 14b) was obtained.

Example 15 2,2,3,3,3-pentafluoro-1- (2-hydroxy-7,8-dimethyl-2-pentafluoroethyl-2,5-dihydro-1H-benzo [b] [1, 4] diazepin-3-yl) propan-1-one (compound 15) and 4-[(2-amino-4.5-dimethyl-1-phenylamino) methylene] -1,1,1,2,2, Synthesis of 6,6,7,7,7-decafluoroheptane-3,5-dione (Compound 16) 1,1,1,2,2,6,6,7,7,7-decafluoro-4- A solution of isobutoxymethyleneheptane-3,5-dione (953.0 mg, 2.4 mmol) and 4,5-dimethylbenzene-1,2-diamine (347.5 mg, 2.6 mmol) in acetonitrile (10 mL) at room temperature for 1 hour. After the reaction, the solvent was distilled off to obtain 1173.9 mg of a crude solid. The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (9: 1)), and 2,2,3,3,3-pentafluoro-1- (2-hydroxy-7,8-dimethyl-2). -Pentafluoroethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) propan-1-one (compound 15) and 4-[(2-amino-4.5- Dimethyl-1-phenylamino) methylene] -1,1,1,2,2,6,6,7,7,7-decafluoroheptane-3,5-dione (Compound 16) (1017.3 mg, 92.2 %, 15: 46.1%, 16: 46.1%).

Example 16 2,2,3,3,3-pentafluoro-1- (2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1, 4] Synthesis of diazepin-3-yl) propan-1-one (compound 17) 1,1,1,5,5,6,6,6-octafluoro-3- (isobutoxymethylene) hexane-2,4 -After reacting a solution of dione (171.1 mg, 0.5 mmol) and 4,5-dimethylbenzene-1,2-diamine (71.5 mg, 0.5 mmol) in acetonitrile (2 mL) at room temperature for 1 hour, the solvent was distilled off. To give 233.3 mg of crude solid. The crude solid was purified by silica gel column chromatography (hexane-ethyl acetate (9: 1)), and 2,2,3,3,3-pentafluoro-1- (2-hydroxy-7,8-dimethyl-2). -Trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) propan-1-one (compound 17, 199.2 mg, 73.2%) was obtained.

Example 17 2,2,2-trifluoro-1- [2-hydroxy-7,8-dimethyl-1- (2,2,2-trifluoroacetyl) -2-trifluoromethyl-2,5-dihydro Synthesis of -1H-benzo [b] [1,4] diazepin-3-yl] ethanone (Compound 18) 2,2,2-trifluoro-1- (2-hydroxy-7,8-dimethyl-2-tri A solution of fluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 11, 178.6 mg, 0.5 mmol) in trifluoroacetic anhydride (2 mL, 14.2 mmol) After reacting for 4 hours at room temperature, the solvent was distilled off to give 2,2,2-trifluoro-1- [2-hydroxy-7,8-dimethyl-1- (2,2,2-trimethyl). Fluoroacetyl) -2-trifluoromethyl-2,5-dihy B -1H- benzo [b] [1,4] diazepin-3-yl] ethanone (Compound 18,222.5 mg, 98.8%) was obtained.

Example 18 1- (1-Acetyl-2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl)- Synthesis of 2,2,2-trifluoroethanone (compound 19) 2,2,2-trifluoro-1- (2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H -A solution of benzo [b] [1,4] diazepin-3-yl) ethanone (compound 11, 175.1 mg, 0.5 mmol) and acetic anhydride (54.0 mg, 0.5 mmol) in chloroform (2 ml) at room temperature for 1 hour. After the reaction, the solvent was distilled off to give 1- (1-acetyl-2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1, 4] diazepin-3-yl) -2,2,2-trif Oroetanon (Compound 19,204.8 mg, 86.0%) was obtained.

Example 19 2,2,3,3,3-Pentafluoro-1- [2-hydroxy-7,8-dimethyl-3- (2,2,2-trifluoroacetyl) -2-trifluoromethyl-2 , 5-Dihydro-benzo [b] [1,4] diazepin-1-yl] propan-1-one (compound 20) 2,2,2-trifluoro-1- (2-hydroxy-7,8 -Dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 11, 178.0 mg, 0.5 mmol) in pentafluoropropionic anhydride ( (2 mL, 10.3 mmol) solution was reacted at room temperature for 1 hour, and then the solvent was distilled off to obtain 2,2,3,3,3-pentafluoro-1- [2-hydroxy-7,8-dimethyl. -3- (2,2,2-trifluoroacetyl) -2- Trifluoromethyl-2,5-dihydro - benzo [b] [1,4] diazepin-1-yl] propan-1-one (Compound 20,211.6 mg, 84.6%) was obtained.

Example 20 2-Hydroxy-7,8-dimethyl-3- (2,2,2-trifluoroacetyl) -2-trifluoromethyl-2,5-dihydro-benzo [b] [1,4] diazepine Synthesis of 1-carboxyl acid tertiary-butyl ester (compound 21) 2,2,2-trifluoro-1- (2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro- 1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 11, 177.2 mg, 0.5 mmol) and di-tertiary-butoxy dicarbonate (545.0 mg, 2.5 mmol) in chloroform (2 mL) After the solution was reacted at room temperature for 48 hours, the solvent was distilled off to give 2-hydroxy-7,8-dimethyl-3- (2,2,2-trifluoroacetyl) -2-trifluoromethyl. 2,5-dihydro - benzo [b] [1,4] diazepine-1-carboxylic acid tert - butyl ester (Compound 21,185.1 mg, 81.5%) was obtained.

The structural formulas and physical properties of the compounds synthesized in Examples 1 to 20 and the compounds synthesized in the same manner as in Examples 1 to 20 are shown in Tables 1 to 3.
In each of the synthesis examples 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, an isomer mixture was formed. Therefore, the physical properties of one of the isomers separated by repeating thin layer silica gel chromatography and the like were shown.

The compounds of the present invention also include compounds shown in Table 4. These compounds can be synthesized in the same manner as in the above examples.

Example 21 Compound of 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-4,5-dimethylanilin-2-yl) aminomethylene) pentane-2,4-dione 48) Synthesis 2,2,2-trifluoro-1- (2-hydroxy-7,8-dimethyl-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine- 3-yl) ethanone (compound 11, 354.2 mg, 1 mmol) and thionyl chloride (0.076 ml, 1.05 mmol) were reacted in acetonitrile (4 mL) for 5 minutes at room temperature, and the solvent was distilled off. 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-4,5-dimethylanilin-2-yl) aminomethylene) pentane-2,4-dione (compound 48, 396.0 mg, 99.0%) as yellow crystals. This reaction proceeded without any problem under the same conditions in chloroform, and the corresponding sulfinylaniline derivative (Compound 48) was quantitatively obtained.

Example 22 Synthesis of 1,1,1,5,5,5-hexafluoro-3-((N-sulfinylanilin-2-yl) aminomethylene) pentane-2,4-dione (Compound 49) , 2-Trifluoro-1- (2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (Compound 1, 326.2 mg, 1 mmol) and thionyl chloride (0.076 ml, 1.05 mmol) in acetonitrile (4 mL) for 5 minutes at room temperature, the solvent was distilled off to obtain 1,1,1,5, 5,5-Hexafluoro-3-((N-sulfinylanilin-2-yl) aminomethylene) pentane-2,4-dione (Compound 49, 363.2 mg, 97.6%) was obtained.

Example 23 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-4-nitroanilin-2-yl) aminomethylene) pentane-2,4-dione (compound 50a) Synthesis of 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-5-nitroanilin-2-yl) aminomethylene) pentane-2,4-dione (compound 50b) 2, 2,2-trifluoro-1- (2-hydroxy-8-nitro-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (compound 5a) and 2,2,2-trifluoro-1- (2-hydroxy-7-nitro-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepine-3- Yl) ethanone (compound 5b) and The mixture (186.3 mg, 0.5 mmol) and thionyl chloride (0.076 mL, 1.05 mmol) were reacted in acetonitrile (2 mL) for 30 minutes at room temperature, and then the solvent was distilled off. 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-4-nitroanilin-2-yl) aminomethylene) pentane-2,4-dione (compound 50a) and 1,1 , 1,5,5,5-hexafluoro-3-((N-sulfinyl-5-nitroanilin-2-yl) aminomethylene) pentane-2,4-dione (compound 50b) (204.5 mg, 98.0 %).

Example 24 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-4-benzoylanilin-2-yl) aminomethylene) pentane-2,4-dione (Compound 51a) Synthesis of 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-5-benzoylanilin-2-yl) aminomethylene) pentane-2,4-dione (Compound 51b) (8-Benzoyl-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2,2,2-trifluoroethanone (compound 9a) and 1- (7-benzoyl-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2,2,2- Trifluoroethanone (Mix compound 9b) (433.2 mg, 1 mmol) and thionyl chloride (0.076 mL, 1.05 mmol) were reacted in acetonitrile (4 mL) for 30 minutes at room temperature, and then the solvent was removed. After distillation, 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-4-benzoylanilin-2-yl) aminomethylene) pentane-2,4-dione (compound 51a ) And 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-5-benzoylanilin-2-yl) aminomethylene) pentane-2,4-dione (compound 51b) (449.7 mg, 94.4%) was obtained.

Example 25 3-N-sulfinylamino-4- (4,4,4-trifluoro-3-oxo-2- (2,2,2-trifluoroacetyl) -but-1-enylamino) benzoic acid (compound 52) 2,2,2-trifluoro-1- (2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) ethanone (Compound 1, 370.2 mg, 1 mmol) and thionyl chloride (0.36 mL, 5 mmol) were reacted in acetonitrile (4 mL) for 1 hour at room temperature, and then the solvent was distilled off. 3-N-sulfinylamino-4- (4,4,4-trifluoro-3-oxo-2- (2,2,2-trifluoroacetyl) -but-1-enylamino) benzoic acid (compounds 52, 291.3 mg, 70.0%).

Example 26 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-4,5-chloroanilin-2-yl) aminomethylene) pentane-2,4-dione (Compound 53) ) 1- (7,8-dichloro-2-hydroxy-2-trifluoromethyl-2,5-dihydro-1H-benzo [b] [1,4] diazepin-3-yl) -2,2, After reacting 2-trifluoroethanone (compound 12, 395.1 mg, 1 mmol) with thionyl chloride (0.076 mL, 1.05 mmol) in acetonitrile (4 mL) for 5 minutes at room temperature, the solvent was removed. Distilled to 1,1,1,5,5,5-hexafluoro-3-((N-sulfinyl-4,5-chloroanilin-2-yl) aminomethylene) pentane-2,4-dione ( Compound 53, 404.5 mg, 91.7%) was obtained.

The structural formulas and physical properties of the compounds synthesized in Examples 21 to 26 and the compounds that can be synthesized in the same manner as in Examples 21 to 26 are shown in Tables 5 to 6.
In each of the synthesis examples of 50a, 50b, 51a, and 51b, an isomer mixture was formed, and thus the physical properties of one of the isomers separated by repeating thin layer silica gel chromatography and the like were shown.

単位はｎＭ Test examples of the compounds of the present invention are shown below.
Test Example 1 Antitumor Activity Test Various human cells are seeded on a 96-well plate at 1000 cells / well, cultured for 24 hours, and a specimen (maximum concentration 100 μM) diluted 3-fold is added. After culturing for 3 days, the growth inhibition rate at each concentration was measured, and the 50% inhibitory concentration (IC ₅₀ , nM) was calculated and shown in Table 5.
The growth inhibition rate was measured by the following method. That is, 5 or 10 μL of WST-8 (Dojindo) was added to each well, and when a sufficient color reaction was obtained, OD450 / 620 was measured with a 96 well plate reader (NJ-2300, Nihon InterMed), and no drug was added. The inhibition rate was determined with the well value of 100%.

Unit is nM

Formulation Examples Formulation Examples 1 to 10 shown below are merely examples, and are not intended to limit the scope of the invention. The term “active ingredient” means a compound of the present invention, a tautomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
Formulation Example 1
Hard gelatin capsules are manufactured using the following ingredients:
dose
(Mg / capsule)
Active ingredient 250
Starch (dried) 200
Magnesium stearate 10
Total 460mg
Formulation Example 2
Tablets are manufactured using the following ingredients:
dose
(Mg / tablet)
Active ingredient 250
Cellulose (microcrystal) 400
Silicon dioxide (fume) 10
Stearic acid 5
665mg total
The ingredients are mixed and compressed into tablets each weighing 665 mg.
Formulation Example 3
An aerosol solution is prepared containing the following ingredients:
weight
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (chlorodifluoromethane) 74.00
Total 100.00
The active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.
Formulation Example 4
A tablet containing 60 mg of active ingredient is prepared as follows:
Active ingredient 60mg
45mg starch
Microcrystalline cellulose 35mg
Polyvinylpyrrolidone (10% solution in water) 4mg
Sodium carboxymethyl starch 4.5mg
Magnesium stearate 0.5mg
Talc 1mg
150mg total
The active ingredients, starch, and cellulose are no. 45 mesh U.F. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.
Formulation Example 5
Capsules containing 80 mg of active ingredient are prepared as follows:
Active ingredient 80mg
Starch 59mg
Microcrystalline cellulose 59mg
Magnesium stearate 2mg
Total 200mg
Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.F. S. Through the sieve and filled into hard gelatin capsules 200 mg each.
Formulation Example 6
A suppository containing 225 mg of active ingredient is prepared as follows:
Active ingredient 225mg
Saturated fatty acid glyceride 2000mg
Total 2225mg
The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.
Formulation Example 7
A suspension containing 50 mg of active ingredient is prepared as follows:
Active ingredient 50mg
Sodium carboxymethylcellulose 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Fragrance q. v.
Dye q. v.
5ml in total with purified water
The active ingredient is No. 45 mesh U.F. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add the benzoic acid solution and perfume diluted with a portion of the water and stir. Then add a sufficient amount of water to the required volume.
Formulation Example 8
The intravenous formulation is manufactured as follows:
Active ingredient 100mg
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.

  A novel benzodiazepine and a pharmaceutical composition containing the compound as an active ingredient have been found.

Claims (9)

Formula (I):

(Wherein R ¹ , R ² , R ³ , and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, hydroxy, optionally substituted C1-C6 alkoxy, substituted Optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted C3-C6 cycloalkyloxy, optionally substituted C1-C6 alkylthio, substituted C2-C6 alkenylthio, which may be substituted, C3-C6 cycloalkylthio, which may be substituted, , Optionally substituted aryloxy, optionally substituted arylthio, optionally substituted amino, carboxy, optionally substituted C1-C6 alkylcarbonyl, optionally substituted C2- C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted carbamoyl, nitro, or cyano Or R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ are taken together to form an optionally substituted carbocycle or an optionally substituted heterocycle including an adjacent carbon atom. May form;
R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, or an optionally substituted. C1-C6 alkylcarbonyl, optionally substituted C2-C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C1-C6 alkenyloxycarbonyl, optionally substituted aryl Carbonyl, optionally substituted aryloxycarbonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted arylsulfonyl, or optionally substituted carbamoyl;
One of R ⁷ and R ⁸ is hydroxy and the other is C1-C6 alkyl substituted with a halogen atom ;
R ⁹ is C1-C6 alkyl substituted with a halogen atom ;
R ¹⁰ is a hydrogen atom, a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3- C6 cycloalkyl, or optionally substituted aryl), a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ² and R ³ are the same or different and each is a halogen atom or an optionally substituted C1-C6 alkyl. The compound according to claim 1, wherein R ⁵ and R ⁶ are the same or different and each is a hydrogen atom, an optionally substituted C1-C6 alkylcarbonyl, or an optionally substituted C1-C6 alkoxycarbonyl. Acceptable salts or solvates thereof. R ² and R ³ are the same or different, a halogen atom or an optionally substituted C1-C6 alkyl; R ⁵ and R ⁶ are the same or different, a hydrogen atom, an optionally substituted C1-C6 alkylcarbonyl , or optionally substituted C1-C6 alkoxycarbonyl; compound of claim 1, wherein R ¹⁰ is a hydrogen atom, or a pharmaceutically acceptable salt, solvate thereof. General formula (IA):

(Wherein R ¹ , R ² , R ³ , and R ⁴ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, Optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkenyl, hydroxy, optionally substituted C1-C6 alkoxy, substituted Optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted C3-C6 cycloalkyloxy, optionally substituted C1-C6 alkylthio, substituted C2-C6 alkenylthio, which may be substituted, C3-C6 cycloalkylthio, which may be substituted, , Optionally substituted aryloxy, optionally substituted arylthio, optionally substituted amino, carboxy, optionally substituted C1-C6 alkylcarbonyl, optionally substituted C2- C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C2-C6 alkenyloxycarbonyl, optionally substituted arylcarbonyl, optionally substituted carbamoyl, nitro, or cyano Or R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ are taken together to form an optionally substituted carbocycle or an optionally substituted heterocycle including an adjacent carbon atom. May form;
R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted aryl, or an optionally substituted. C1-C6 alkylcarbonyl, optionally substituted C2-C6 alkenylcarbonyl, optionally substituted C1-C6 alkoxycarbonyl, optionally substituted C1-C6 alkenyloxycarbonyl, optionally substituted aryl Carbonyl, optionally substituted aryloxycarbonyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted arylsulfonyl, or optionally substituted carbamoyl;
R ⁷ and R ⁸ are the same or different and each is a compound represented by C1-C6 alkyl substituted with a halogen atom, a pharmaceutically acceptable salt thereof, or a solvate thereof. ^6. The compound according to claim 5 , wherein R ⁵ and R ⁶ are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkylcarbonyl, or an optionally substituted C1-C6 alkoxycarbonyl. Acceptable salts or solvates thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 as an active ingredient. The pharmaceutical composition according to claim 7 , which is an antitumor agent. General formula (II):

(Wherein R ¹ , R ² , R ³ , and R ⁴ are as defined in claim 1)
And a compound of the general formula (III):

(Wherein R ¹¹ and R ¹² are the same or different and are CF ₃ , CF ₂ Cl, CCl ₃ , or CF ₂ CF ₃ ; R ¹³ is a hydrogen atom, C1-C6 alkyl, trifluoromethyl, C2-C6 alkenyl. , C2-C6 alkynyl, or optionally substituted aryl; R ¹⁴ is C1-C6 alkyl)
A compound represented by the general formula (IV):

Wherein R ¹ , R ² , R ³ , and R ⁴ are as defined in claim 1; R ¹¹ and R ¹² are the same or different and are CF ₃ , CF ₂ Cl, CCl ₃ , or CF ₂ CF ₃ R ¹³ represents a hydrogen atom, C1-C6 alkyl, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, or optionally substituted aryl)
The manufacturing method of the compound shown by these.