JP2019038747A - Indoleacetic acid derivative - Google Patents

Abstract

To provide a compound useful as an agent for treating/or preventing a disease caused by an abnormality in a mitochondrial function.SOLUTION: A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof is useful as an agent for treating/or preventing a disease caused by an abnormality in a mitochondrial function.SELECTED DRAWING: None

Description

  The present invention relates to an indole acetic acid derivative useful as a medicine, or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a pharmaceutical composition containing an indole acetic acid derivative or a pharmaceutically acceptable salt thereof. The present invention relates to a therapeutic / prophylactic agent containing a novel indoleacetic acid derivative containing the compound or a pharmaceutically acceptable salt thereof.

  Mitochondria are the main energy supply organs in cells, and are present in many tissues (for example, brain, skeletal muscle, heart muscle, kidney, etc.) that are actively active and have high energy requirements in human body tissues.

  Decreased mitochondrial function associated with genetic background and aging causes various diseases. A typical example is known as a disease generally called mitochondrial disease. An effective treatment for a patient suffering from mitochondrial disease has not yet been found, only symptomatic treatment is given to some symptoms, and treatment satisfaction is not high. Accordingly, there is a need for new drugs that improve mitochondrial dysfunction and thereby exert efficacy.

In addition, mitochondrial dysfunction inhibits the activities of energy-requiring tissues, and thus may cause various diseases other than mitochondrial diseases (for example, neurodegenerative diseases, muscle diseases, heart diseases, kidney diseases, etc.). There are many diseases that are known and among which there is not enough treatment.
For example, amyotrophic lateral sclerosis (ALS) is a disease with a poor prognosis in which the cause of its onset is still unknown and causes significant muscle atrophy as a symptom, resulting in movement disorders, difficulty swallowing, and respiratory failure. For example, riluzole is known as an ALS therapeutic agent, but it only shows the effect of delaying the progression of symptoms for several months. In addition, there are currently no effective treatments for diseases such as Parkinson's disease, Alzheimer's disease, muscular dystrophy, sarcopenia, and disuse muscle atrophy.

  Patent Document 1 discloses indoleacetic acid derivatives and the like useful as therapeutic agents for mitochondrial diseases and the like.

International Publication No. 2014/080640

  An object of the present invention is to provide a novel compound useful as a therapeutic / prophylactic agent for diseases associated with abnormal mitochondrial function.

  The present inventors have found that a compound represented by the following formula (I) and a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “the compound of the present invention” if necessary) have an effect of improving mitochondrial function. As a result of diligent research to solve the above-mentioned problems, the compound of the present invention is a cell that is prominent against cell death induced by oxidative stress load in patient cells with diseases involving mitochondrial dysfunction It has been found that it exhibits a death-inhibiting action, and the present invention has been completed.

［式中、
Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃおよびＸ^ｄは、それぞれ独立して、
（１）水素原子、
（２）ハロゲン原子、
（３）シアノ基、
（４）Ｃ_１−６アルキル基（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（５）Ｃ_１−６アルコキシ基（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（６）Ｃ_３−７シクロアルキル基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（７）Ｃ_３−７シクロアルコキシ基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（８）Ｃ_６−１０アリール基（該基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（９）５員〜１０員のヘテロアリール基（該基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（１０）Ｃ_６−１０アリールオキシ基（該アリール基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（１１）５員〜１０員のヘテロアリールオキシ基（該ヘテロアリール基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（１２）−ＣＯＮＲ^１Ｒ^２、
（１３）−ＮＲ^１Ｒ^２、
（１４）−ＮＲ^１ＣＯＲ^２、
（１５）−ＮＲ^１ＳＯ_２Ｒ^２、
（１６）−ＳＯ_２Ｒ^１、または
（１７）−ＳＯ_２ＮＲ^１Ｒ^２
を表すか、または；
Ｘ^ａおよびＸ^ｂ、Ｘ^ｂおよびＸ^ｃ、またはＸ^ｃおよびＸ^ｄは、それらが結合する炭素原子と一緒になって５員〜８員のシクロアルカン環（該環は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）または５員〜８員の飽和ヘテロ環（該環は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）を形成してもよく；
Ｒ^１およびＲ^２は、それぞれ独立して
（１）水素原子、
（２）Ｃ_１−６アルキル基（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
または
（３）Ｃ_６−１０アリール基（該基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、または、
（４）５員〜１０員のヘテロアリール基（該基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
を表すか、または；
Ｒ^１およびＲ^２は一緒になって、それらが結合する窒素原子とともに４員〜１０員の飽和ヘテロ環（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）
を表し；
Ａは、
（ａ）下記式（II）：

（式中、
Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅは、それぞれ独立して、
（１）水素原子、
（２）ハロゲン原子、
（３）シアノ基、
（４）Ｃ_１−６アルキル基（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（５）Ｃ_１−６アルコキシ基（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（６）Ｃ_３−７シクロアルキル基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（７）Ｃ_３−７シクロアルコキシ基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜６個の基で置換されていてもよい）、
（８）−ＣＯＮＲ^１Ｒ^２，
（９）−ＮＲ^１Ｒ^２、
（１０）−ＮＲ^１ＣＯＲ^２、
（１１）−ＮＲ^１ＳＯ_２Ｒ^２、
（１２）−ＳＯ_２Ｒ^１、または
（１３）−ＳＯ_２ＮＲ^１Ｒ^２
を表すか、
または；
Ｙ^ａおよびＹ^ｂ、またはＹ^ｂおよびＹ^ｃは、それらが結合する炭素原子と一緒になって５員〜８員のシクロアルカン環（該環は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）または５員〜８員の飽和ヘテロ環（該環は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）を形成してもよく；
但し、ここにおいて、
Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅが、それぞれ独立して、水素原子、フッ素原子、塩素原子、Ｃ_１−６アルキル基、またはＣ_１−６アルコキシ基である場合は、
Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃおよびＸ^ｄのうち少なくとも１つは、
（１）臭素原子、
（２）シアノ基、
（３）１〜５個のフッ素原子で置換されたＣ_１−６アルキル基、
（４）１〜５個のフッ素原子で置換されたＣ_１−６アルコキシ基、
（５）Ｃ_３−７シクロアルキル基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（６）Ｃ_３−７シクロアルコキシ基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（７）Ｃ_６−１０アリール基（該基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（８）５員〜１０員のヘテロアリール基（該基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（９）Ｃ_６−１０アリールオキシ基（該アリール基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（１０）５員〜１０員のヘテロアリールオキシ基（該ヘテロアリール基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（１１）−ＣＯＮＲ^１Ｒ^２、
（１２）−ＮＲ^１Ｒ^２、
（１３）−ＮＲ^１ＣＯＲ^２、
（１４）−ＮＲ^１ＳＯ_２Ｒ^２、
（１５）−ＳＯ_２Ｒ^１、または
（１６）−ＳＯ_２ＮＲ^１Ｒ^２
であるか、または、
Ｘ^ａおよびＸ^ｂ、Ｘ^ｂおよびＸ^ｃ、またはＸ^ｃおよびＸ^ｄが、それらが結合する炭素原子と一緒になって５員〜８員のシクロアルカン環（該環は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）または５員〜８員の飽和ヘテロ環（該環は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）を形成している）で表される基；
（ｂ）下記式（III）：

（式中、
Ｑ^１は、
（１）Ｃ_３−７シクロアルキル基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、または、
（２）５員〜１０員のヘテロアリール基（該基は、
（ａ）ハロゲン原子、
（ｂ）シアノ基、
（ｃ）Ｃ_１−６アルキル（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｄ）Ｃ_１−６アルコキシ（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｅ）Ｃ_３−７シクロアルキル（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｆ）Ｃ_３−７シクロアルコキシ（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｇ）−ＣＯＮＲ^１Ｒ^２、
（ｈ）−ＮＲ^１Ｒ^２、
（ｉ）−ＮＲ^１ＣＯＲ^２、
（ｊ）−ＮＲ^１ＳＯ_２Ｒ^２、
（ｋ）−ＳＯ_２Ｒ^１、および
（ｌ）−ＳＯ_２ＮＲ^１Ｒ^２
からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）で表される基；
（ｃ）下記式（IV）：

（式中、
Ｗは、Ｃ_１−３アルキレンを表し；
Ｚは、単結合、または下記式（IV−ａ）：

（式中、
ｍは、１、２、３または４を表す）で表される基を表し；
Ｑ^２は、
（１）Ｃ_３−７シクロアルキル基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（２）Ｃ_６−１０アリール基（該基は、
（ａ）ハロゲン原子、
（ｂ）シアノ基、
（ｃ）Ｃ_１−６アルキル（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｄ）Ｃ_１−６アルコキシ（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｅ）Ｃ_３−７シクロアルキル（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｆ）Ｃ_３−７シクロアルコキシ（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｇ）−ＣＯＮＲ^１Ｒ^２、
（ｈ）−ＮＲ^１Ｒ^２、
（ｉ）−ＮＲ^１ＣＯＲ^２、
（ｊ）−ＮＲ^１ＳＯ_２Ｒ^２、
（ｋ）−ＳＯ_２Ｒ^１、および
（ｌ）−ＳＯ_２ＮＲ^１Ｒ^２
からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、または
（３）５員〜１０員のヘテロアリール基（該基は、前記（２）の（ａ）〜（ｌ）からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）
を表し；
但し、ここにおいて、
Ｗが、メチレンまたはエチレンであり、Ｚが単結合である場合、
Ｑ^２は、
（１）フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されているＣ_３−７シクロアルキル基、
（２）以下の群から選択される同種または異種の１〜５個の基で置換されているＣ_６−１０アリール基：
（ａ）ハロゲン原子、
（ｂ）シアノ基、
（ｃ）Ｃ_１−６アルキル（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｄ）Ｃ_１−６アルコキシ（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｅ）Ｃ_３−７シクロアルキル（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｆ）Ｃ_３−７シクロアルコキシ（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｇ）−ＣＯＮＲ^１Ｒ^２、
（ｈ）−ＮＲ^１Ｒ^２、
（ｉ）−ＮＲ^１ＣＯＲ^２、
（ｊ）−ＮＲ^１ＳＯ_２Ｒ^２、
（ｋ）−ＳＯ_２Ｒ^１、または
（ｌ）−ＳＯ_２ＮＲ^１Ｒ^２、
または、
（３）前記（２）の（ａ）〜（ｌ）からなる群から選択される同種または異種の１〜５個の基で置換されてもよい５員〜１０員のヘテロアリール基である）で表される基；
または、
（ｄ）１〜５個のフッ素原子で置換されているＣ_１−７アルキル基
（但し、ここにおいて、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃおよびＸ^ｄのうち少なくとも１つは、
（１）臭素原子、
（２）シアノ基、
（３）１〜５個のフッ素原子で置換されたＣ_１−６アルキル基、
（４）１〜５個のフッ素原子で置換されたＣ_１−６アルコキシ基、
（５）Ｃ_３−７シクロアルキル基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（６）Ｃ_３−７シクロアルコキシ基（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（７）Ｃ_６−１０アリール基（該基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（８）５員〜１０員のヘテロアリール基（該基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（９）Ｃ_６−１０アリールオキシ基（該アリール基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（１０）５員〜１０員のヘテロアリールオキシ基（該ヘテロアリール基は、ハロゲン原子、シアノ基、１〜５個のフッ素原子で置換されてもよいＣ_１−６アルキル基および１〜５個のフッ素原子で置換されてもよいＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（１１）−ＣＯＮＲ^１Ｒ^２、
（１２）−ＮＲ^１Ｒ^２、
（１３）−ＮＲ^１ＣＯＲ^２、
（１４）−ＮＲ^１ＳＯ_２Ｒ^２、
（１５）−ＳＯ_２Ｒ^１、または
（１６）−ＳＯ_２ＮＲ^１Ｒ^２である）を表すが、
但し、以下の化合物：
４−（４−ブロモフェニル）−２−（１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
２−（１Ｈ−インドール−３−イル）−４−オキソ−４−（５，６，７，８−テトラヒドロナフタレン−２−イル）ブタノイック アシッド、
４−（４−ブロモフェニル）−２−（７−エチル−１Ｈ−インドール−３−イル）−４−オキソブタノイック アシッド、
２−（１Ｈ−インドール−３−イル）−４−オキソ−４−（チオフェン−２−イル）ブタノイック アシッド、
２−（１Ｈ−インドール−３−イル）−３−（チオフェン−３−イル）プロパノイック アシッド、
２−（５−クロロ−１Ｈ−インドール−３−イル）−３−（チオフェン−３−イル）プロパノイック アシッド、
を除く]
で表される化合物またはその製薬学的に許容される塩。 That is, the present invention is as follows.
[1] The following formula (I):

[Where:
X ^a , X ^b , X ^c and X ^d are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) C _1-6 alkyl group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(5) C _1-6 alkoxy group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(6) C _3-7 cycloalkyl group (this group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(8) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(9) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(10) C _6-10 aryloxy group (the aryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of optionally substituted C _1-6 alkoxy groups),
(11) 5- to 10-membered heteroaryloxy group (the heteroaryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 groups. And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms),
(12) -CONR ¹ R ² ,
⁽¹³⁾ -NR ^{1 R} 2,
(14) -NR < ¹ > COR < ² >,
_{^{(15) -NR 1 SO 2 R}} 2,
(16) _-SO 2 ^{R 1} or ^{_{(17), -SO 2 NR 1}} R 2
Or
X ^a and X ^b , X ^b and X ^c , or X ^c and X ^d , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring (the ring is a fluorine atom, a hydroxyl group, Optionally substituted with the same or different 1 to 5 groups selected from the group consisting of a C _1-6 alkyl group and a C _1-6 alkoxy group) or a 5- to 8-membered saturated heterocycle The ring may be substituted with the same or different 1-5 groups selected from the group consisting of fluorine atom, hydroxyl group, C _1-6 alkyl group and C _1-6 alkoxy group) Well;
R ¹ and R ² are each independently (1) a hydrogen atom,
(2) C _1-6 alkyl group (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
Or (3) a C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Which may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of C _1-6 alkoxy groups, which may be
(4) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms) And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
Or
R ¹ and R ² together are a 4-membered to 10-membered saturated heterocycle with a nitrogen atom to which they are bonded (the group is a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group And may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of
Represents;
A is
(A) The following formula (II):

(Where
Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) C _1-6 alkyl group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(5) C _1-6 alkoxy group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(6) C _3-7 cycloalkyl group (this group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _3-7 cycloalkoxy group (the group is the same or different 1-6 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(8) -CONR ¹ R ² ,
(9) -NR < ¹ > R < ² >,
(10) -NR ¹ COR ² ,
_{^{(11) -NR 1 SO 2 R}} 2,
(12) -SO ₂ R ¹ or (13) -SO ₂ NR ¹ R ²
Or
Or;
Y ^a and Y ^b , or Y ^b and Y ^c , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring (the ring is a fluorine atom, a hydroxyl group, a C _1-6 alkyl group) And optionally substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups) or a 5- to 8-membered saturated heterocycle (the ring is a fluorine atom, Which may be substituted with the same or different 1 to 5 groups selected from the group consisting of a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group;
However, here
When Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,
At least one of X ^a , X ^b , X ^c and X ^d is:
(1) bromine atom,
(2) a cyano group,
(3) a C _1-6 alkyl group substituted with 1 to 5 fluorine atoms,
(4) a C _1-6 alkoxy group substituted with 1 to 5 fluorine atoms,
(5) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(6) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(8) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(9) C _6-10 aryloxy group (the aryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of optionally substituted C _1-6 alkoxy groups),
(10) 5- to 10-membered heteroaryloxy group (the heteroaryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 groups. And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms),
(11) -CONR ¹ R ² ,
(12) -NR ¹ R ² ,
(13) -NR < ¹ > COR < ² >,
_{^{(14) -NR 1 SO 2 R}} 2,
(15) -SO ₂ R ¹ or (16) -SO ₂ NR ¹ R ²
Or
X ^a and X ^b , X ^b and X ^c , or X ^c and X ^d together with the carbon atom to which they are attached are a 5- to 8-membered cycloalkane ring (the ring is a fluorine atom, a hydroxyl group, Optionally substituted with the same or different 1 to 5 groups selected from the group consisting of a C _1-6 alkyl group and a C _1-6 alkoxy group) or a 5- to 8-membered saturated heterocycle The ring may be substituted with the same or different 1-5 groups selected from the group consisting of fluorine atom, hydroxyl group, C _1-6 alkyl group and C _1-6 alkoxy group) A group represented by
(B) The following formula (III):

(Where
Q ¹ is
(1) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted), or
(2) a 5- to 10-membered heteroaryl group (the group is
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(F) C _3-7 cycloalkoxy (the group is the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(G) -CONR ¹ R ² ,
(H) -NR < ¹ > R < ² >,
(I) -NR < ¹ > COR < ² >,
_{^{(J) -NR 1 SO 2 R}} 2,
(K) —SO ₂ R ¹ , and (l) —SO ₂ NR ¹ R ²
A group represented by the same or different 1 to 5 groups selected from the group consisting of:
(C) The following formula (IV):

(Where
W represents C _1-3 alkylene;
Z is a single bond or the following formula (IV-a):

(Where
m represents a group represented by 1, 2, 3 or 4;
Q ² is
(1) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(2) C _6-10 aryl group (the group is
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(F) C _3-7 cycloalkoxy (the group is the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(G) -CONR ¹ R ² ,
(H) -NR < ¹ > R < ² >,
(I) -NR < ¹ > COR < ² >,
_{^{(J) -NR 1 SO 2 R}} 2,
(K) —SO ₂ R ¹ , and (l) —SO ₂ NR ¹ R ²
Or (3) a 5- to 10-membered heteroaryl group (which may be substituted with the same or different 1 to 5 groups selected from the group consisting of a) to (l) may be substituted with the same or different 1 to 5 groups selected from the group consisting of
Represents;
However, here
When W is methylene or ethylene and Z is a single bond,
Q ² is
(1) C _3-7 cycloalkyl group substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group ,
(2) C _6-10 aryl group substituted with 1 to 5 groups of the same or different types selected from the following group:
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(F) C _3-7 cycloalkoxy (the group is the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(G) -CONR ¹ R ² ,
(H) -NR < ¹ > R < ² >,
(I) -NR < ¹ > COR < ² >,
_{^{(J) -NR 1 SO 2 R}} 2,
(K) _-SO 2 ^{R 1} or _{^{(l) -SO 2 NR 1 R}} 2,,
Or
(3) A 5- to 10-membered heteroaryl group which may be substituted with the same or different 1 to 5 groups selected from the group consisting of (a) to (l) in (2) above) A group represented by:
Or
(D) a C _1-7 alkyl group substituted with 1 to 5 fluorine atoms (wherein at least one of X ^a , X ^b , X ^c and X ^d is
(1) bromine atom,
(2) a cyano group,
(3) a C _1-6 alkyl group substituted with 1 to 5 fluorine atoms,
(4) a C _1-6 alkoxy group substituted with 1 to 5 fluorine atoms,
(5) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(6) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(8) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(9) C _6-10 aryloxy group (the aryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of optionally substituted C _1-6 alkoxy groups),
(10) 5- to 10-membered heteroaryloxy group (the heteroaryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 groups. And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms),
(11) -CONR ¹ R ² ,
(12) -NR ¹ R ² ,
(13) -NR < ¹ > COR < ² >,
_{^{(14) -NR 1 SO 2 R}} 2,
(15) -SO ₂ R ¹ or (16) -SO ₂ NR ¹ R ² )
However, the following compounds:
4- (4-bromophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid,
4- (4-bromophenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (thiophen-2-yl) butanoic acid,
2- (1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid,
2- (5-chloro-1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid,
except for]
Or a pharmaceutically acceptable salt thereof.

[2] A is a group represented by the formula (II);
Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) C _1-6 alkyl group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(5) C _1-6 alkoxy group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(6) C _3-7 cycloalkyl group (this group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) Or a pharmaceutically acceptable salt thereof. The compound according to [1], which may be substituted with

[3] At least one of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e is
(1) bromine atom,
(2) a cyano group,
(3) a C _1-6 alkyl group substituted with 1 to 5 fluorine atoms,
(4) a C _1-6 alkoxy group substituted with 1 to 5 fluorine atoms, or (5) a C _3-7 cycloalkyl group (the group is a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and C Or a pharmaceutically acceptable compound thereof, which may be substituted with the same or different 1 to 5 groups selected from the group consisting of _1-6 alkoxy groups). Acceptable salt.

[4] A is a group represented by the formula (III);
Q ¹ is
(1) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted), or
(2) a 5- to 10-membered heteroaryl group (the group is
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
Optionally substituted with 1 to 5 groups of the same or different types selected from the group consisting of:
The compound according to [1] or a pharmaceutically acceptable salt thereof.

（式中、
ｍは、１、２、３または４を表す）で表される基であり；
Ｑ^２が、
（１）フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよいＣ_３−７シクロアルキル基、
（２）以下の群から選択される同種または異種の１〜５個の基で置換されていてもよいＣ_６−１０アリール基：
（ａ）ハロゲン原子、
（ｂ）シアノ基、
（ｃ）Ｃ_１−６アルキル（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｄ）Ｃ_１−６アルコキシ（該基は、フッ素原子、水酸基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
（ｅ）Ｃ_３−７シクロアルキル（該基は、フッ素原子、水酸基、Ｃ_１−６アルキル基およびＣ_１−６アルコキシ基からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい）、
または、
（３）前記（２）の（ａ）〜（ｅ）からなる群から選択される同種または異種の１〜５個の基で置換されていてもよい５員〜１０員のヘテロアリール基である、〔１〕に記載の化合物またはその製薬学的に許容される塩。 [5] A is a group represented by the formula (IV);
W is C _1-3 alkylene;
Z is a single bond or the following formula (IV-a)

(Where
m represents 1, 2, 3 or 4);
Q ² is
(1) C _3-7 cyclo optionally substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group An alkyl group,
(2) C _6-10 aryl group optionally substituted with 1 to 5 groups of the same or different types selected from the following group:
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
Or
(3) a 5- to 10-membered heteroaryl group which may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of (a) to (e) in (2) [1] or a pharmaceutically acceptable salt thereof.

[6] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein A is a C _1-7 alkyl group substituted with 1 to 5 fluorine atoms.

[7] X ^a , X ^b , X ^c and X ^d are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) C _1-6 alkyl group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(5) C _1-6 alkoxy group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(6) C _3-7 cycloalkyl group (this group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(8) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(9) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(10) C _6-10 aryloxy group (the aryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of optionally substituted C _1-6 alkoxy groups),
(11) 5- to 10-membered heteroaryloxy group (the heteroaryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 groups. And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms),
(12) -NR ¹ COR ² , or (13) -NR ¹ SO ₂ R ² ,
(Where:
R ¹ is a hydrogen atom or a C _1-6 alkyl group;
R ² represents a C _1-6 alkyl group or a phenyl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 Which may be substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms), or
Or;
X ^a and X ^b , X ^b and X ^c , or X ^c and X ^d , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring (the ring is a fluorine atom, a hydroxyl group, Optionally substituted with the same or different 1 to 5 groups selected from the group consisting of a C _1-6 alkyl group and a C _1-6 alkoxy group) or a 5- to 8-membered saturated heterocycle The ring may be substituted with the same or different 1-5 groups selected from the group consisting of fluorine atom, hydroxyl group, C _1-6 alkyl group and C _1-6 alkoxy group) The compound according to any one of [1] to [6], or a pharmaceutically acceptable salt thereof.

[8] At least one of X ^a , X ^b , X ^c and X ^d is
(1) bromine atom,
(2) a cyano group,
(3) a C _1-6 alkyl group substituted with 1 to 5 fluorine atoms,
(4) a C _1-6 alkoxy group substituted with 1 to 5 fluorine atoms,
(5) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(6) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(8) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(9) -NR ¹ COR ² or (10) -NR ¹ SO ₂ R ²
(put it here,
R ¹ is a hydrogen atom or a C _1-6 alkyl group;
R ² represents a C _1-6 alkyl group or a phenyl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 Of [1] to [7], which may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms) The compound according to any one of the above or a pharmaceutically acceptable salt thereof.

[9] The compound according to [1] or a pharmaceutically acceptable salt thereof selected from the following compounds:
4- (2,4-difluorophenyl) -2- (5H- [1,3] dioxolo [4,5-f] indol-7-yl) -4-oxobutanoic acid (Example 1),
4- (2,4-difluorophenyl) -4-oxo-2- (5-phenyl-1H-indol-3-yl) butanoic acid (Example 2),
4- (4-chlorophenyl) -4-oxo-2- [5- (trifluoromethyl) -1H-indol-3-yl] butanoic acid (Example 5),
4- (4-chlorophenyl) -2- (5-cyclohexyl-1H-indol-3-yl) -4-oxobutanoic acid (Example 6),
4- (4-tert-butylphenyl) -4-oxo-2- (5-phenyl-1H-indol-3-yl) butanoic acid (Example 8),
4- (4-tert-butylphenyl) -4-oxo-2- {6-[(phenylsulfonyl) amino] -1H-indol-3-yl} butanoic acid (Example 11),
2- (1H-indol-3-yl) -4-oxo-4- [2- (trifluoromethyl) phenyl] butanoic acid (Example 15),
4- (5-chlorothiophen-2-yl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (Example 20),
2- (5-bromo-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (Example 21),
2- (4-Bromo-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (Example 24),
2- (1H-Indol-3-yl) -4-oxo-4- [4- (trifluoromethoxy) phenyl] butanoic acid (Example 30).

[10] A medicament comprising as an active ingredient the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof.

[11] A therapeutic agent for a disease caused by mitochondrial dysfunction, comprising as an active ingredient the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof.

[12] A therapeutic agent for a disease caused by mitochondrial dysfunction, comprising as an active ingredient the following compound or a pharmaceutically acceptable salt thereof:
4- (4-bromophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid,
4- (4-bromophenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (thiophen-2-yl) butanoic acid,
2- (1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid,
2- (5-Chloro-1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid.

[13] The disease caused by mitochondrial dysfunction is mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, kidney disease, muscle disease, or heart disease, [11] or [12] Therapeutic agent.

[14] Mitochondrial diseases include Leigh's encephalopathy, stroke-like seizure syndrome (MELAS), chronic progressive extraocular muscle palsy syndrome (CPEO), Kearns-Sayer syndrome (KSS), myoclonic epilepsy syndrome with red rag fibers (MERRF), [13] The therapeutic agent according to [13], which is Pearson's disease, Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, or lactic acidosis.

[15] The neurodegenerative disease is atrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich ataxia, multiple system atrophy, progressive supranuclear palsy, spinocerebellar degeneration, [13] The therapeutic agent according to [13], which is spinal muscular atrophy, bulbar spinal muscular atrophy, or Charcot-Marie-Tooth disease.

[16] The therapeutic agent according to [13], wherein the immune neurological disease is Guillain-Barre syndrome, multiple sclerosis, Fischer syndrome, chronic inflammatory demyelinating polyneuritis, or myasthenia gravis.

[17] The therapeutic agent according to [13], wherein the cerebral ischemic disease is cerebral infarction.

[18] Renal disease is renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrotic syndrome, diabetic nephropathy, gout kidney, renal edema, kidney The therapeutic agent according to [13], which is a tumor, renal ischemic injury, renal ischemia reperfusion injury, or cystic kidney.

[19] Myopathy is progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscle atrophy (sarcopenia), or disuse muscle atrophy [13] The therapeutic agent according to [13].

[20] The therapeutic agent according to [13], wherein the heart disease is myocardial infarction, heart failure, ischemic heart disease, or cardiomyopathy.

  As another embodiment of the present invention, a method of treating a disease caused by mitochondrial dysfunction by administering the compound of the present invention to a patient in need of treatment of a disease caused by mitochondrial dysfunction, Production of the compound of the present invention for use as a therapeutic agent for diseases caused by dysfunction, the compound of the present invention for use in the treatment of diseases caused by mitochondrial dysfunction, and therapeutic agents for diseases caused by mitochondrial dysfunction The use of the compounds of the present invention to

  Since the compound of the present invention exhibits a remarkable cell death inhibitory action against cell death induced by oxidative stress in patient cells with diseases involving mitochondrial dysfunction, the therapeutic or preventive agent for diseases or symptoms involving mitochondrial dysfunction An agent can be provided. More specifically, it is useful as a therapeutic agent and / or preventive agent for mitochondrial diseases, or neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, and heart diseases.

The present invention is described in further detail below.
In the present specification, the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more.

In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-6 ”, for example. Specifically, the expression “C _1-6 alkyl” is synonymous with a linear or branched alkyl group having 1 to 6 carbon atoms.

  In this specification, the term “group” means a monovalent group. For example, “alkyl group” means a monovalent saturated hydrocarbon group. In addition, in the description of substituents in this specification, the term “group” may be omitted.

  Specific examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

“C _1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is a “C _1-4 alkyl group”. Specific examples of “C _1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

“C _1-7 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 7 carbon atoms. Specific examples of the “C _1-7 alkyl group” include, for example, a heptyl group in addition to the specific example of “C _1-6 alkyl group”.

The “C _1-7 alkyl group” portion of the “C _1-7 alkyl group substituted with 1 to 5 fluorine atoms” has the same _meaning as the “C _1-7 alkyl group”. Specific examples of “C _1-7 alkyl group substituted with 1 to 5 fluorine atoms” include, for example, 4,4,4-trifluorobutyl group, 3,3,4,4,4-penta Fluorobutyl group, 5,5,5-trifluoropentyl group, 4,4,5,5,5-pentafluoropentyl group, 6,6,6-trifluorohexyl group, 5,5,6,6,6 -A pentafluorohexyl group etc. are mentioned. Preferably, 5,5,5-trifluoropentyl group, 4,4,5,5,5-pentafluoropentyl group, 6,6,6-trifluorohexyl group, or 5,5,6,6,6- A pentafluorohexyl group may be mentioned.

“C _3-7 cycloalkyl group” means a 3- to 7-membered monocyclic saturated or partially unsaturated hydrocarbon group. Preferably, it is “C _3-6 cycloalkyl group”. Specific examples of “C _3-7 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and the like.

“C _6-10 aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferred is a “C ₆ aryl group” (phenyl). Specific examples of “C _6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.

The “C _6-10 aryl group” contains one or more (for example, 1 to 4) of the same or different heteroatoms selected from phenyl and 5- to 7-membered nitrogen, sulfur or oxygen atoms. A ring or a group condensed with a 5- to 7-membered saturated hydrocarbon ring (cyclopentane or cyclohexane) is also included. Specific examples of the group include groups represented by the following formulas.

但し、縮環するアリール基の場合には、芳香環のみが「基」の結合手を有する。例えば、下記式

However, in the case of an aryl group that is condensed, only the aromatic ring has a “group” bond. For example, the following formula

で表される「Ｃ_６−１０アリール基」の場合には、「基」が４−、５−、６−、または７−位で結合することを意味する。

In the case of the “C _6-10 aryl group” represented by the _formula, it means that the “group” is bonded at the 4-, 5-, 6-, or 7-position.

  Examples of the “heteroaryl group” include a 5-membered to 10-membered monocyclic or polycyclic aromatic group, and the group includes a heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom. It contains the same or different one or more (for example, 1 to 4). As the “polycyclic heteroaryl group”, a bicyclic or tricyclic group is preferable, and a bicyclic group is more preferable. The polycyclic heteroaryl group includes those in which the monocyclic heteroaryl group is condensed with an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, piperidine, etc.). Specific examples of the “heteroaryl group” include, for example, a group represented by the following formula.

  The bond across the ring in the above formula means that the “group” is bonded at a substitutable position in the ring. For example, the following formula

のヘテロアリール基の場合には、２−フリル基、または３−フリル基であることを意味する。
更に、「ヘテロアリール基」が多環式の基である場合において、例えば、下記式

In the case of the heteroaryl group, it means a 2-furyl group or a 3-furyl group.
Further, when the “heteroaryl group” is a polycyclic group, for example, the following formula

で表される場合には、２−ベンゾフリル、または３−ベンゾフリルの他に、４−、５−、６−または７−ベンゾフリルであってもよい。

In addition to 2-benzofuryl or 3-benzofuryl, 4-, 5-, 6-, or 7-benzofuryl may be used.

  However, in the case of a polycyclic heteroaryl group in which an aromatic ring and a non-aromatic ring (cyclohexane ring, piperidine ring, etc.) are condensed, only the aromatic ring has a “group” bond. For example, the following formula

で表される「多環式のヘテロアリール基」の場合には、「基」が２−、３−、または４−位で結合することを意味する。「ヘテロアリール基」は、５員〜１０員の単環式もしくは多環式の芳香族基が好ましく、５員もしくは６員の単環式の芳香族基が更に好ましい。

In the case of the “polycyclic heteroaryl group” represented by the formula, it means that the “group” is bonded at the 2-, 3-, or 4-position. The “heteroaryl group” is preferably a 5- to 10-membered monocyclic or polycyclic aromatic group, and more preferably a 5- or 6-membered monocyclic aromatic group.

_{"C 1-6} alkoxy group" is synonymous with _{"C 1-6} alkyl group", the _{"C 1-6} alkyl" moiety is the same as defined in the _{"C 1-6} alkyl". Preferably, it is a “C _1-4 alkoxy group”. Specific examples of “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

_{"C 3-7} cycloalkoxy group" is synonymous with _{"C 3-7} cycloalkyl group", the _{"C 3-7} cycloalkyl" moiety, interchangeably with the _{"C 3-7} cycloalkyl" is there. Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

The “C _6-10 aryl” part of the “C _6-10 aryloxy group” has the same _{meaning as} the above “C _6-10 aryl”. “C ₆ aryloxy” (phenoxy) is preferred. Specific examples of the “C _6-10 aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.

  The “heteroaryl” part of the “5- to 10-membered heteroaryloxy group” has the same meaning as the “heteroaryl”. Specific examples of the “5- to 10-membered monocyclic or polycyclic heteroaryloxy group” include, for example, pyridyloxy, imidazolyloxy, thiazolyloxy and the like.

Examples of the “C _1-3 alkylene group” include linear alkylene groups having 1 to 3 carbon atoms, and specific examples include methylene, ethylene, trimethylene and the like.

In the group represented by the formula (I) in the above [1], “X ^a and X ^b , X ^b and X ^c , or X ^c and X ^d together with the carbon atom to which they are bonded are 5-membered. Specific examples of the case where “an 8-membered cycloalkane ring may be formed” include groups represented by the following formulas.

In the group represented by the formula (I) in the above [1], “X ^a and X ^b , X ^b and X ^c , or X ^c and X ^d together with the carbon atom to which they are bonded are 5-membered. Specific examples of the case where “an 8-membered saturated heterocyclic ring may be formed” include, for example, a group represented by the following formula.

In the group represented by the formula (I) of the above [1], “Y ^a and Y ^b , or Y ^b and Y ^c together with the carbon atom to which they are bonded are 5-membered to 8-membered cycloalkane. Specific examples of the case where a ring may be formed include, for example, groups represented by the following formulae.

In the group represented by the formula (I) of the above [1], “Y ^a and Y ^b , or Y ^b and Y ^c together with the carbon atom to which they are bonded are 5-membered to 8-membered saturated hetero Specific examples of the case where a ring may be formed include, for example, groups represented by the following formulae.

  The compounds of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality and therefore may exist as multiple stereoisomers. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.

The present invention also includes the fact that one or more atoms in the compound of formula (I) are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Isotope-labeled compounds, and pharmaceutically acceptable salts thereof are also included in the present invention. Examples of isotopes contained in the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine, and chlorine isotopes such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ^It includes isotopes such as ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, and ³⁶ Cl. Also included in the present invention are compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts thereof.

Furthermore, replacement with deuterium, a heavy isotope such as ² H, can be expected to provide certain therapeutic benefits due to increased metabolic stability. For example, it may be preferred in some situations because it results in increased half-life in vivo or reduced dose requirements.

Pharmaceutically acceptable salts include acid addition salts and base addition salts.
Examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, hydroiodide, nitrate and phosphate; citrate, oxalate and acetic acid Salt, formate, propionate, benzoate, trifluoroacetate, fumarate, maleate, malonate, succinate, tartrate, hydrogen tartrate, lactate, malate, pyruvate Salt, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate [1,1′-methylene-bis- (2-hydroxy-3-naphthoate) ] Organic acid salt, such as].
Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt; organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt. Can be mentioned.
Furthermore, basic amino acid salts or acidic amino acid salts such as arginine salt, aspartate and glutamate can also be mentioned.
Preferred base addition salts include sodium, potassium, calcium and magnesium salts.

  The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or a pharmaceutically acceptable solvate. Also included in the compounds of the present invention are solvates such as hydrates or ethanolates. Furthermore, the compounds of the present invention include all forms of crystal forms.

[Production method]
Hereinafter, the method for producing the compound represented by the formula (I) in the present invention will be described with reference to examples, but the present invention is not limited thereto.

  The compound of the present invention represented by the formula (I) is produced by the following method using a commercially available compound, a known compound, or a commercially available compound or a compound that can be produced by combining known synthesis methods from known compounds as raw materials. be able to.

[Production Method 1]
Among the compounds represented by the formula (I), the compound represented by the formula (A1) can be produced, for example, by the following production method.

（式中、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃ、Ｘ^ｄ、Ｙ^ａ、Ｙ^ｂ、Ｙ^ｃ、Ｙ^ｄおよびＹ^ｅは、前記〔１〕に定義されるとおりであり、Ｐ^１はアルキル等のカルボン酸の保護基である。）

(Wherein, X ^a , X ^b , X ^c , X ^d , Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are as defined in the above [1], and P ¹ is alkyl or the like (Protecting group for carboxylic acid.)

  The benzenes (a1) and acetophenones (a3) can be purchased, for example, as commercial products, and the indoles (a4) can be produced by the method described in Org. Synth. 1985, 63, 214, etc. It can be purchased as a product.

[Step A-1]
This step is a step of obtaining compound (a2) by reacting maleic anhydride with compound (a1) in the presence of various acids, in the absence of a solvent, or in a suitable solvent. Examples of the acid used in this step include Lewis acids such as metal halides, Bronsted acids such as phosphoric acid, polyphosphoric acid, and trifluoromethanesulfonic acid, preferably aluminum chloride and iron (III) chloride, Titanium chloride (IV) is mentioned. Examples of the solvent used in this step include aromatic hydrocarbons such as nitrobenzene, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride, or a mixed solvent thereof. And methylene chloride is preferable. The reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. The reaction temperature is generally −78 ° C. to 150 ° C., preferably −20 ° C. to 100 ° C.

[Step A-2]
This step is a step of obtaining compound (a2) by reacting glyoxylic acid with compound (a3) in the presence of various acids, in the absence of a solvent, or in a suitable solvent. Examples of the acid used in this step include Bronsted acids such as acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid, and preferably include acetic acid and hydrochloric acid. Examples of the solvent include ethers such as 1,4-dioxane, water, or a mixed solvent thereof. The reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. The reaction temperature is generally −20 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

[Step A-3]
In this step, compound (a2) obtained in step A-1 or A-2 is reacted with indole compound (a4) in a suitable solvent in the presence or absence of various acids. This is a step of obtaining (A1). Examples of the acid used in this step include Bronsted acid such as acetic acid, Lewis acid such as aluminum chloride, iron chloride (III) and titanium chloride (IV), preferably acetic acid and chloride. Iron (III) is mentioned. Solvents used in this step are, for example, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane, halogenated compounds such as methylene chloride, chloroform and 1,2-dichloroethane. Examples thereof include hydrocarbons or a mixed solvent thereof, preferably benzene or toluene. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.

[Step A-4]
This step is a step of protecting the compound (a2) obtained in the step A-1 or A-2 with P ¹ . This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

  For example, compound (a5) can be produced as an ester by reacting compound (a2) with an alcohol in the presence of an acid, in the absence of a solvent, or in a suitable solvent. The solvent used in this step is selected depending on the type of raw material compound and the like, and examples thereof include aromatic hydrocarbons such as toluene and benzene. Examples of the acid used in this step include Bronsted acid such as hydrochloric acid, sulfuric acid, hydrofluoric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, boron fluoride etherate, and the like. Of Lewis acids. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −20 ° C. to 150 ° C., preferably 20 ° C. to 130 ° C.

  For example, the compound (a5) can be produced as an ester by reacting the compound (a2) with an alkyl halide in the presence of various bases in an appropriate solvent or without a solvent. The solvent used in this step is selected depending on the type of raw material compound, etc., for example, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, and aromatics such as toluene and benzene. Examples thereof include hydrocarbons, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, and mixed solvents of these solvents. Examples of the base used in this step include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is generally −20 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

  For example, the compound (a5) can be produced as an ester by reacting the compound (a2) with a diazo compound such as diazomethane or trimethylsilyldiazomethane in the presence of various inorganic salts in an appropriate solvent or without a solvent. . The solvent used in this step is selected depending on the type of raw material compound, etc., for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or a mixed solvent thereof. Is mentioned. The reaction time is usually 1 minute to 48 hours, preferably 10 minutes to 5 hours. The reaction temperature is usually −20 ° C. to 50 ° C., preferably 0 ° C. to 40 ° C.

[Step A-5]
This step is a step of converting the compound (a5) obtained in the step A-4 into the compound (a6) under the conditions according to the step A-3.

[Step A-6]
This step is a step for preparing the compound obtained in the above A-5 a protecting group P ¹ of (a6) is deprotected to a carboxylic acid (A1). This step is performed by reacting compound (a6) in an appropriate solvent under acidic or basic conditions. The solvent used in this step is selected depending on the type of raw material compound, etc. For example, alcohols such as methanol, ethanol and isopropanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like. Examples thereof include ethers, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, water, and a mixed solvent thereof. Examples of the acid used in this step include Bronsted acids such as hydrochloric acid and sulfuric acid. Examples of the base used in this step include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate. The reaction time is usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually 0 ° C to 150 ° C, preferably 20 ° C to 100 ° C.

（式中、Ｘ^ａ、Ｘ^ｂ、Ｘ^ｃ、Ｘ^ｄ、Ｙ、Ａは、前記〔１〕に定義されるとおりであり、Ｐ^１はカルボン酸の保護基であり、Ｐ^２はアミノ基の保護基であり、ＬＧは脱離基（例えば塩素、臭素、ヨウ素のようなハロゲン原子、メタンスルホニルオキシ基のようなアルキルスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基のようなトリハロゲノメタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、ｐ−トルエンスルホニルオキシ基のようなアリールスルホニルオキシ基など）である。） [Production Method 2]
Among the compounds represented by the formula (I), the compound represented by the formula (A2) can be produced, for example, by the following production method.

(Wherein, X ^a , X ^b , X ^c , X ^d , Y, A are as defined in [1] above, P ¹ is a protecting group for carboxylic acid, and P ² is an amino group. LG is a protecting group, and LG is a leaving group (for example, a halogen atom such as chlorine, bromine or iodine, an alkylsulfonyloxy group such as methanesulfonyloxy group, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy group, Benzenesulfonyloxy group, arylsulfonyloxy group such as p-toluenesulfonyloxy group, etc.).

  Indole acetic acid (a7) can be produced, for example, by the method described in US Patent Application Publication No. 5684034 and the like, or can be purchased as a commercial product, and compound (a9) is, for example, It can be produced by the method described in Journal of the Chemical Society-Perkin Transactions 1, 1996, 2303-2308, Journal of Organic Chemistry, 1984, 438-442, and the like, or can be purchased as a commercial product. .

[Step A-7]
This step is a step of introducing a protecting group P ² into the compound (a7). This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

  When a tert-butoxycarbonyl group is introduced, compound (a8) can be produced by reacting compound (a7) with di-tert-butyl dicarbonate in a suitable solvent in the presence of a base.

  When a benzyloxycarbonyl group is introduced, compound (a8) can be produced by reacting compound (a7) with benzyloxycarbonyl chloride in a suitable solvent in the presence of a base.

  When a p-toluenesulfonyl group is introduced, compound (a8) can be produced by reacting compound (a7) with p-toluenesulfonyl chloride in a suitable solvent in the presence of a base.

  Examples of the solvent used in this step include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide, N-methyl-2- Amides such as pyrrolidone, water or a mixed solvent thereof can be mentioned, and tetrahydrofuran, methylene chloride and N, N-dimethylformamide are preferred. Examples of the base used in this step include alkali carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, diisopropylethylamine, pyridine, and 4-dimethylamino. Organic bases such as pyridine and 1,8-diazabicyclo [5.4.0] -undec-7-ene are exemplified, and triethylamine, diisopropylethylamine and 4-dimethylaminopyridine are preferred. The reaction time is usually 5 minutes to about 48 hours, preferably 10 minutes to 10 hours. The reaction temperature is generally −78 ° C. to 100 ° C., preferably −20 ° C. to 40 ° C.

[Step A-8]
In this step, compound (a10) is reacted with compound (a9) in the presence of an additive in the presence or absence of an additive in a suitable solvent and compound (a8) obtained in step A-7. ). Examples of the solvent used in this step include ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. Preferably, tetrahydrofuran and N, N-dimethylformamide are used. Examples of the base used in this step include organometallic bases such as butyl lithium, lithium diisopropylamide, and lithium hexamethyldisilazide, preferably lithium hexamethyldisilazide and lithium diisopropylamide, and more preferably. Examples include lithium hexamethyldisilazide. Examples of the additive used when necessary in this step include hexamethyl phosphate triamide and N, N-dimethylpropylene urea, and more preferably hexamethyl phosphate triamide. The reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours. The reaction temperature is generally −78 ° C. to 100 ° C., preferably −78 ° C. to 20 ° C.

[Step A-9]
This step is the A-8 The compound obtained in step a protective group P ² of (a10), by deprotection, to produce compound (a11). This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

When the protecting group P ² is a tert-butoxycarbonyl group, the compound (a10) is subjected to Bronsted acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, or aluminum chloride, zinc bromide, trifluoride in a suitable solvent. Compound (a11) can be produced by using a Lewis acid such as boron. Solvents used in this step are, for example, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, aromatic hydrocarbons such as toluene and benzene, methylene chloride, chloroform. , Halogenated hydrocarbons such as 1,2-dichloroethane, mixed solvents thereof and the like. In the case of Bronsted acid, water can be used alone or mixed with the described solvent. The reaction time is usually 0.5 hours to 48 hours, preferably 0.5 hours to 24 hours. The reaction temperature is usually −20 ° C. to 100 ° C., preferably −20 ° C. to 40 ° C.

When the protecting group P ² is a benzyloxycarbonyl group, the compound (a10) can be used in an appropriate solvent, for example, in the presence of a metal catalyst such as palladium / carbon, palladium hydroxide, nickel, and ammonium formate if necessary. Can be added and reacted in a hydrogen gas atmosphere to produce the compound (a11). Examples of the solvent used in this step include alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as toluene and benzene, hexane and heptane. Aliphatic hydrocarbons such as, esters such as ethyl acetate and propyl acetate, organic acids such as acetic acid, and mixed solvents thereof.

[Step A-10]
This step is a step of producing compound (A2) from the compound (a11) obtained in the above step A-9 by the same method as in the above step A-6.

According to the production method shown above, for example, the following compounds can be synthesized.
4- (4-Chlorophenyl) -2- (5-cyclopentyl-1H-indol-3-yl) -4-oxobutanoic acid 4- (4-chlorophenyl) -4-oxo-2- [5- (pyridine) -3-yl) -1H-indol-3-yl] butanoic acid 4- (4-chlorophenyl) -4-oxo-2- [5- (pyridin-4-yl) -1H-indol-3-yl] butanoic Acid 4- (4-chlorophenyl) -2- (2,3-dihydro-6H- [1,4] dioxino [2,3-f] indol-8-yl) -4-oxobutanoic acid 2- ( 5-cyclohexyl-1H-indol-3-yl) -4- (4-methylphenyl) -4-oxobutanoic acid 2- (5H- [1,3] dioxolo [4,5-f] i Ndol-7-yl) -4- (4-methylphenyl) -4-oxobutanoic acid 2- (2,3-dihydro-6H- [1,4] dioxino [2,3-f] indole-8 -Yl) -4- (4-methylphenyl) -4-oxobutanoic acid 4- (4-tert-butylphenyl) -2- (5H- [1,3] dioxolo [4,5-f] indole -7-yl) -4-oxobutanoic acid 2- (2,3-dihydro-6H- [1,4] dioxino [2,3-f] indol-8-yl) -4-oxo-4- [4- (Trifluoromethyl) phenyl] butanoic acid 2- (5-fluoro-1H-indol-3-yl) -4-oxo-4- [4- (trifluoromethyl) phenyl] butanoic acid 2- (6 -Fluo -1H-Indol-3-yl) -4-oxo-4- [4- (trifluoromethyl) phenyl] butanoic acid 2- (5-methyl-1H-indol-3-yl) -4-oxo-4- [4- (Trifluoromethyl) phenyl] butanoic acid 4-oxo-2- [5- (propan-2-yl) -1H-indol-3-yl] -4- [4- (trifluoromethyl) phenyl] Butanoic acid 2- (5-methoxy-1H-indol-3-yl) -4-oxo-4- [4- (trifluoromethyl) phenyl] butanoic acid 2- (5H- [1,3] dioxolo [4 5-f] Indol-7-yl) -4-oxo-4- [4- (trifluoromethyl) phenyl] butanoic acid 2- (2,3-dihydro-6H- [1,4] Dioxino [2,3-f] indol-8-yl) -4-oxo-4- [4- (trifluoromethyl) phenyl] butanoic acid 2- (5-cyclohexyl-1H-indole-3 -Yl) -4-oxo-4- [4- (trifluoromethyl) phenyl] butanoic acid 4-oxo-2- (5-phenyl-1H-indol-3-yl) -4- [4- (trifluoro Methyl) phenyl] butanoic acid 4-oxo-2- (5-phenoxy-1H-indol-3-yl) -4- [4- (trifluoromethyl) phenyl] butanoic acid

  The compound of the present invention represented by formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. For example, extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization may be mentioned.

  Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and isopropanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like. A ketone solvent, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aprotic solvent such as N, N-dimethylformamide or acetonitrile, water, or a mixed solvent thereof can be used. As other purification methods, methods described in Experimental Chemistry Course (The Chemical Society of Japan, Maruzen) 5th edition, Volume 1 and the like can be used. Further, the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, a spectroscopic method such as nuclear magnetic resonance method, infrared absorption method, circular dichroism spectrum analysis method, and the like. Can be done by mass spectrometry.

  In addition, the intermediate or final product in the above production method is appropriately converted in its functional group, in particular, extending various side chains based on amino groups, hydroxyl groups, carbonyl groups, halogen groups, etc., and In this case, if necessary, the above-mentioned protection and deprotection can be performed to lead to another compound included in the present invention. The transformation of the functional group and the extension of the side chain can be performed by a commonly used general method (for example, see Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999)).

  The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may have asymmetry or may have a substituent having an asymmetric carbon. Has optical isomers. The compounds of the present invention include mixtures of these isomers and isolated ones. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. Alternatively, for example, an optical isomer can be obtained by performing a separation step such as a method using an optically active column or a fractional crystallization method at an appropriate stage of the production process. As the optical resolution method, for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, it is used in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, isopropanol, diethyl An ether solvent such as ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, water or a mixed solvent of two or more selected from the above solvents), optically active Acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine and lactic acid, tartaric acid, o-diisopropylidene tartaric acid, dicarboxylic acids such as malic acid, sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) And a diastereomeric method in which a salt is formed. When the compound of the present invention represented by formula (I) or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine) The optical resolution can also be carried out by forming a salt using an organic amine).

  The temperature at which the salt is formed is selected from the range from −50 ° C. to the boiling point of the solvent, preferably from 0 ° C. to the boiling point, more preferably from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is often desirable to raise the temperature to near the boiling point of the solvent once. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. If necessary, a salt in an inert solvent (for example, an alcohol solvent such as methanol, ethanol, isopropanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, a non-aqueous solvent such as acetonitrile, etc. It can also be recrystallized with a proton solvent or a mixed solvent of two or more selected from the above-mentioned solvents to obtain a highly pure optically active salt. Further, if necessary, the optically resolved salt can be treated with an acid or a base by a usual method to obtain the optically active compound of the present invention represented by formula (I) as a free form.

  Among the raw materials and intermediates in each of the production methods described above, those that do not describe the production method are commercially available compounds, or methods known to those skilled in the art from commercially available compounds, or methods equivalent thereto Can be synthesized.

  Since the compound of the present invention has an action for improving mitochondrial function, it can provide a therapeutic or prophylactic agent for diseases or symptoms involving mitochondrial dysfunction. More specifically, it is useful as a therapeutic and / or prophylactic agent for mitochondrial diseases, neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, or heart diseases.

The following compounds also have an effect of improving mitochondrial function, like the compounds of the present invention, and therefore can be used as a therapeutic or preventive agent for diseases or symptoms involving mitochondrial dysfunction.
4- (4-bromophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid;
2- (1H-indol-3-yl) -4-oxo-4- (5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid;
4- (4-bromophenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid;
2- (1H-indol-3-yl) -4-oxo-4- (thiophen-2-yl) butanoic acid;
2- (1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid;
2- (5-Chloro-1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid

  In the present invention, “prevention” is an act of administering the active ingredient of the present invention to a person who has not developed a disease. For example, the purpose is to prevent or delay the onset of the disease. Is. “Treatment” is an act of administering the active ingredient of the present invention to a person (patient) diagnosed as having developed a disease by a doctor.

  Mitochondrial disease is a disease in which a decrease in mitochondrial function such as ATP production, regulation of apoptosis, regulation of intracellular concentrations of calcium ions and iron, etc. occurs due to mutation or deletion of nuclear DNA or mitochondrial DNA.

  One of the symptoms of mitochondrial diseases that can be treated or prevented by the compound of the present invention is Leigh's encephalopathy. Leigh's encephalopathy is a serious congenital disease that begins in early childhood and is characterized by symmetric degeneration of the basal ganglia and brainstem, with intellectual disability, muscle movement disorder, and respiratory disorder as the main symptoms.

  Other symptoms of mitochondrial diseases that can be treated or prevented by the compounds of the present invention include, for example, mitochondrial encephalomyopathy, lactic acidosis, stroke-like seizure syndrome (MELAS), chronic progressive extraocular muscular palsy syndrome (CPEO), Kearns Sayre Syndrome (KSS), myoclonic epilepsy syndrome with red rag fibers (MERRF), Pearson's disease, Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, lactic acidosis and the like.

  Examples of neurodegenerative diseases that can be treated or prevented by the compounds of the present invention include amyotropic axillary lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, multiple system atrophy, progressive nuclear supra Include paralysis, spinocerebellar degeneration, spinal muscular atrophy, bulbar spinal muscular atrophy, Charcot-Marie-Tooth disease.

  Examples of immune neurological diseases that can be treated or prevented by the compounds of the present invention include Guillain-Barre syndrome, multiple sclerosis, Fischer syndrome, chronic inflammatory demyelinating polyneuritis, myasthenia gravis.

  Examples of cerebral ischemic diseases that can be treated or prevented by the compound of the present invention include cerebral infarction and the like.

  Examples of renal diseases that can be treated or prevented by the compound of the present invention include renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrotic syndrome, diabetic nephropathy, Examples include gout kidney, renal edema, renal tumor, renal ischemic injury, renal ischemia reperfusion injury, cystic kidney and the like.

  Examples of the muscular disease that can be treated or prevented by the compound of the present invention include progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscle atrophy (Sarcopenia), Examples include disuse muscle atrophy.

  Examples of the heart disease that can be treated or prevented by the compound of the present invention include myocardial infarction, heart failure, ischemic heart disease, cardiomyopathy and the like.

  The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like. For example, in the case of oral administration, about 0.01 mg to 5000 mg, more preferably about 0.1 mg to 3000 mg per kg body weight of a human or mammal can be administered in 1 to several times. In the case of parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.

The compound of the present invention can be formulated and administered by oral administration or parenteral administration, directly or using a suitable dosage form. Examples of the dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and haptics. The preparation is produced by a known method using a pharmaceutically acceptable additive.
Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, stearin Examples include magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

  Examples of other drugs that can be used in combination with the compound of the present invention include mitochondrial function improving agents, neurodegenerative disease therapeutic agents, muscle disease therapeutic agents, cardiac disease therapeutic agents, renal disease therapeutic agents and the like.

  Examples of the mitochondrial function improving agent include Bendavia and idebenone.

  Examples of therapeutic agents for neurodegenerative diseases include ALS therapeutic agents (rilzole, edaravone, etc.), Parkinson's disease therapeutic agents (levodopa, carbidopa, zonisamide, droxidopa, pramipexole, ropinirole, etc.), Alzheimer's disease therapeutic agents (donepezil, memantine, rivastigmine, galantamine). Etc.).

  Examples of the muscular disease therapeutic agent include anti-activin antibodies (such as bimaglumumab) and steroidal anti-inflammatory drugs (such as prednisolone and triamcinolone).

  Examples of therapeutic agents for heart diseases and kidney diseases include angiotensin II receptor antagonists (candesartan, valsartan, etc.), ACE inhibitors (captopril, enalapril, etc.), diuretics (furosemide, tolvaptan, etc.) and the like.

  In the combination of the compound of the present invention or a pharmaceutically acceptable salt thereof and other drugs that can be used in combination, the plurality of drugs may be administered separately or may be administered together as a single pharmaceutical composition. . Also, one active ingredient of the combination of the present invention may be administered prior to, simultaneously with, or after other active ingredients. These active ingredients may be prepared in a pharmaceutical formulation in a single dosage form or in a separate dosage form.

  Hereinafter, the present invention will be described more specifically with reference examples, examples, and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

In order to simplify the description, the following abbreviations may be used in the reference examples and examples.
Me: methyl Et: ethyl
^t Bu: tert-butyl TFA: trifluoroacetic acid THF: tetrahydrofuran DMSO: dimethyl sulfoxide DMSO-D ₆ : deuterated dimethyl sulfoxide Boc: tert-butoxycarbonyl (Boc) ₂ O: di-tert-butyl dicarbonate DMAP: 4-dimethyl Aminopyridine LHMDS: Lithium hexamethyldisilazide HMPA: Hexamethyl phosphate triamide

As symbols used in NMR, s is a single line, d is a double line, dd is a double double line, t is a triple line, q is a quadruple line, m is a multiple line, br is wide, brs is Wide single line and J mean coupling constant.

  The proton nuclear magnetic resonance spectrum was measured using a FT-NMR measuring apparatus (270 MHz, 300 MHz or 400 MHz) manufactured by JEOL. The chemical shift value was described in δ value (ppm).

High-performance liquid chromatograph / mass spectrometer; LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by [M + H] ⁺ and the retention time is represented by Rt (min). . In each actual measurement value, the measurement conditions used for measurement are indicated by A and B.

[Measurement condition A]
Detection equipment: Shimadzu LCMS-2020
Column: Phenomenex Kinex (1.7 μm C18, 50 mm × 2.10 mm)
Solvent: Liquid A: 0.05% TFA / H ₂ O, Liquid B: CH ₃ CN
Gradient Condition:
0.0-1.7 min; A / B = 90: 10 to 1:99 (liner gradient)
1.7-1.9 min; A / B = 1: 99
1.9-3.0 min; A / B = 90: 10
Flow rate: 0.5 mL / min UV: 220 nm
Column temperature: 40 ° C

[Measurement condition B]
Measuring instrument: Waters 2695
Column: Yamato Science Prima Sil C18HC (5 μm, 4.6 × 75 mm)
Solvent: A solution: 0.1% formic acid / H ₂ O, B solution: 0.1% formic acid / CH ₃ CN
Gradient Condition:
0.0-6.0 min; A / B = 90: 10 to 0: 100 (liner gradient)
6.0-8.0 min; A / B = 0: 100
Flow rate: 1.0 mL / min UV: 220, 254 nm
Column temperature: 40 ° C

化合物Ｉ（１００ｍｇ）の１，２−ジクロロエタン（２ｍＬ）溶液に化合物II（９５ｍｇ）と塩化鉄（III）６水和物（２４ｍｇ）を加え、室温にて１２時間撹拌した。溶媒を減圧留去後、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル）で精製し表題化合物III（６０ｍｇ）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 8.13 (1H, brs), 8.01-7.93 (1H, m), 7.87-7.85 (1H, m), 7.33-7.29 (2H, m), 7.18-7.18 (1H, m), 7.00-6.84 (2H, m), 4.55-4.50 (1H, m), 4.05-3.94 (1H, m), 3.71 (3H, s), 3.40-3.31 (1H, m) [Reference Example 1]
Preparation of methyl 2- (5-bromo-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoate (compound III)

Compound II (95 mg) and iron (III) chloride hexahydrate (24 mg) were added to a solution of compound I (100 mg) in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 12 hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain the title compound III (60 mg).
¹ H-NMR (300MHz, CDCl ₃ ) δ: 8.13 (1H, brs), 8.01-7.93 (1H, m), 7.87-7.85 (1H, m), 7.33-7.29 (2H, m), 7.18-7.18 ( 1H, m), 7.00-6.84 (2H, m), 4.55-4.50 (1H, m), 4.05-3.94 (1H, m), 3.71 (3H, s), 3.40-3.31 (1H, m)

[Reference Examples 2 to 9]
In the same manner as in Reference Example 1, compounds of Reference Examples 2 to 9 were obtained using the corresponding raw material compounds.

−７８℃の化合物Ｉ−１（４００ｍｇ）とＨＭＰＡ（０．４８ｍＬ）のＴＨＦ（１４ｍＬ）溶液に、ＬＨＭＤＳ／ＴＨＦ溶液（１．３ｍｏｌ／Ｌ、１．３ｍＬ）を加え、−７８℃にて１．５時間撹拌した。化合物II−１（３９１ｍｇ）のＴＨＦ溶液（５ｍＬ）を滴下して加え、室温にて１２時間撹拌した。水を加えた後、酢酸エチルで分液抽出し、有機層を２ｍｏｌ／Ｌ塩酸、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル）で精製することにより表題化合物III−１（６９ｍｇ）を得た。
¹H-NMR: (270MHz, CDCl₃) δ: 8.17-8.14 (1H, m), 8.07-8.01 (2H, m), 7.70-7.67 (1H, m), 7.60-7.56 (1H, m), 7.38-7.23 (4H, m), 4.57 (1H, dd, J = 10.2, 3.8 Hz), 4.13-4.01 (1H, m), 3.71 (3H, s), 3.33 (1H, dd, J = 18.0, 3.8 Hz), 1.67 (9H, s) [Reference Example 10]
of tert-butyl 3- {1-methoxy-1,4-dioxo-4- [4- (trifluoromethoxy) phenyl] butan-2-yl} -1H-indole-1-carboxylate (compound III-1) Manufacturing

LHMDS / THF solution (1.3 mol / L, 1.3 mL) was added to a THF (14 mL) solution of compound I-1 (400 mg) and HMPA (0.48 mL) at −78 ° C., and 1 at −78 ° C. Stir for 5 hours. A THF solution (5 mL) of compound II-1 (391 mg) was added dropwise, and the mixture was stirred at room temperature for 12 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2 mol / L hydrochloric acid and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound III-1 (69 mg).
¹ H-NMR: (270 MHz, CDCl ₃ ) δ: 8.17-8.14 (1H, m), 8.07-8.01 (2H, m), 7.70-7.67 (1H, m), 7.60-7.56 (1H, m), 7.38 -7.23 (4H, m), 4.57 (1H, dd, J = 10.2, 3.8 Hz), 4.13-4.01 (1H, m), 3.71 (3H, s), 3.33 (1H, dd, J = 18.0, 3.8 Hz ), 1.67 (9H, s)

ＬＣ−ＭＳ：測定法Ｂ、[M+H]^＋=476.3、Rt=7.50min [Reference Example 11]
Production of tert-butyl 3- {1-methoxy-1,4-dioxo-4- [3- (trifluoromethyl) phenyl] butan-2-yl} -1H-indole-1-carboxylate In the same manner as in Reference Example 10, the following compound was obtained.

LC-MS: Measurement method B, [M + H] ⁺ = 476.3, Rt = 7.50 min

−７８℃のジイソプロピルアミン（０．３５０ｍＬ）のＴＨＦ溶液（４．０ｍＬ）に、−７８℃にてｎ−ブチルリチウムのヘキサン溶液（１ｍｏｌ／Ｌ，２．４ｍＬ）を加えた後、氷冷で２０分間撹拌した。反応液を−７８℃に冷却し、化合物Ｉ−２（２００ｍｇ）を加え、３０分間撹拌した後、化合物II−２（０．６５０ｍＬ）を添加後、−７８℃で２．５時間撹拌し、氷冷で２時間撹拌した。反応溶液に水を加えた後、酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン／酢酸エチル）で精製し、表題化合物III−２（１５０ｍｇ）を得た。
ＬＣ−ＭＳ：測定法Ａ、[M+H]^＋=430.2、Rt=2.49min [Reference Example 12]
Preparation of tert-butyl 3- [5- (2,4-difluorophenyl) -1-methoxy-1-oxopentan-2-yl] -1H-indole-1-carboxylate (Compound III-2)

A hexane solution (1 mol / L, 2.4 mL) of n-butyllithium was added to a THF solution (4.0 mL) of diisopropylamine (0.350 mL) at −78 ° C. at −78 ° C., and then ice-cooled. Stir for 20 minutes. The reaction solution was cooled to −78 ° C., compound I-2 (200 mg) was added, and the mixture was stirred for 30 minutes. After addition of compound II-2 (0.650 mL), the mixture was stirred at −78 ° C. for 2.5 hours, The mixture was stirred on ice for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound III-2 (150 mg).
LC-MS: Method A, [M + H] ⁺ = 430.2, Rt = 2.49min

[Reference Examples 13 to 15]
The compounds of Reference Examples 13 to 15 were obtained in the same manner as in Reference Example 12 using the corresponding starting compounds.

[Reference Example 16]
Preparation of tert-butyl 3- [1-tert-butoxy-4- (4,4-difluorocyclohexyl) -1,4-dioxobutan-2-yl] -1H-indole-1-carboxylate (compound IV)

Step 1:
(Boc) ₂ O (3.5 g) and DMAP (209 mg) were added to a tert-butyl alcohol solution (50 mL) of compound I-3 (3.0 g), and the mixture was stirred at room temperature for 2 hours. Stir at 1 ° C. for 1 hour. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to obtain Compound II-3 (2.1 g).
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 8.14 (1H, d, J = 7.1 Hz), 7.55-7.53 (2H, m), 7.32-7.21 (2H, m), 3.62 (2H, s), 1.66 (9H, s), 1.46 (9H, s)

Step 2:
A LHMDS / THF solution (1.3 mol / L, 1.11 ml) was added to a THF solution (12 mL) of Compound II-3 (400 mg) and HMPA (0.42 mL) at −78 ° C., and the mixture was stirred for 1 hour. At −78 ° C., a THF solution (5 mL) of compound III-3 (291 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2 mol / L hydrochloric acid and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound IV (348 mg).
¹ H-NMR (270 MHz, CDCl ₃ ) δ: 8.13 (1H, d, J = 7.7 Hz), 7.66-7.21 (4H, m), 4.30-4.22 (1H, m), 3.53-3.42 (1H, m) , 2.82-2.70 (1H, m), 2.50-2.46 (1H, m), 2.13-2.01 (3H, m), 1.94-1.73 (5H, m), 1.67 (9H, s), 1.38 (9H, s)

化合物Ｉ−４（７０ｍｇ）のトルエン（０．７ｍＬ）溶液に化合物II−４（４８ｍｇ）を加えた後、２５時間加熱還流した。室温に冷却し、析出した固体をろ取し、トルエンとヘキサンで洗浄後、乾燥し、表題化合物III−４（３９ｍｇ）を得た。
¹H-NMR (400MHz, DMSO-D₆) δ: 12.21 (1H, brs), 10.80 (1H, brs), 8.01-7.95 (1H, m), 7.46-7.40 (1H, m), 7.26-7.22 (1H, m), 7.07-7.06 (2H, m), 6.88 (1H, s), 5.92 (2H, s), 4.21 (1H, dd, 10.5, 3.2 Hz), 3.85-3.77 (1H, m), 3.30-3.21 (1H, m) [Example 1]
4- (2,4-difluorophenyl) -2- (5H- [1,3] dioxolo [4,5-f] indol-7-yl) -4-oxobutanoic acid (III-4) Manufacturing

Compound II-4 (48 mg) was added to a solution of compound I-4 (70 mg) in toluene (0.7 mL), and the mixture was heated to reflux for 25 hours. After cooling to room temperature, the precipitated solid was collected by filtration, washed with toluene and hexane, and dried to give the title compound III-4 (39 mg).
¹ H-NMR (400MHz, DMSO-D ₆ ) δ: 12.21 (1H, brs), 10.80 (1H, brs), 8.01-7.95 (1H, m), 7.46-7.40 (1H, m), 7.26-7.22 ( 1H, m), 7.07-7.06 (2H, m), 6.88 (1H, s), 5.92 (2H, s), 4.21 (1H, dd, 10.5, 3.2 Hz), 3.85-3.77 (1H, m), 3.30 -3.21 (1H, m)

[Examples 2 to 20]
The compounds of Examples 2 to 20 were obtained in the same manner as in Example 1 using the corresponding starting compounds.

氷冷の化合物III（６０ｍｇ、参考例１）、ＴＨＦ（２ｍＬ）とメタノール（２ｍＬ）の混合溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２ｍＬ）を加え、室温にて６時間撹拌した。２ｍｏｌ／Ｌ塩酸を加えて溶液のｐＨを２にした後、クロロホルムで抽出し、有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール）で精製し表題化合物（２０ｍｇ）を得た。
¹H-NMR (300MHz, DMSO-D₆) δ: 12.35 (1H, brs), 11.19 (1H, brs), 8.00-7.92 (1H, m), 7.81 (1H, s), 7.45-7.17 (5H, m), 4.26-4.23 (1H, m), 3.88-3.79 (1H, m), 3.20-3.17 (1H, m) [Example 21]
Preparation of 2- (5-bromo-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid (compound of Example 21)

To a mixed solution of ice-cooled compound III (60 mg, Reference Example 1), THF (2 mL) and methanol (2 mL) was added 2 mol / L aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 6 hours. 2 mol / L hydrochloric acid was added to adjust the pH of the solution to 2, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol) to obtain the title compound (20 mg).
¹ H-NMR (300MHz, DMSO-D ₆ ) δ: 12.35 (1H, brs), 11.19 (1H, brs), 8.00-7.92 (1H, m), 7.81 (1H, s), 7.45-7.17 (5H, m), 4.26-4.23 (1H, m), 3.88-3.79 (1H, m), 3.20-3.17 (1H, m)

[Examples 22 to 29]
The compounds of Examples 22 to 29 were obtained in the same manner as in Example 21 using the corresponding starting compounds.

化合物III−１（６９ｍｇ、参考例１０）と塩化水素−１，４−ジオキサン（４ｍｏｌ／Ｌ、１．４ｍｌ）の混合物を室温にて１２時間撹拌した。次いで、６ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１．４ｍＬ）、メタノール（１．４ｍＬ）、水（１．４ｍＬ）を加え、室温で4時間撹拌した。反応溶液を減圧濃縮後、塩化メチレン、水を加えて分液抽出し、水層を塩化メチレンで洗浄し、４ｍｏｌ／Ｌ塩酸を加えてｐＨを１とした。塩化メチレンと水で分液抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン／メタノール）で精製し、表題化合物（２７ｍｇ）を得た。
¹H-NMR (270MHz, CD₃OD) δ: 8.13 (2H, d, J = 8.7 Hz), 7.70 (1H, d, J = 8.7 Hz), 7.39-7.33 (3H, m), 7.22 (1H, s), 7.14-7.00 (2H, m), 4.53-4.48 (1H, m), 4.12-4.01 (1H, m), 3.43-3.35 (1H, m) [Example 30]
Preparation of 2- (1H-indol-3-yl) -4-oxo-4- [4- (trifluoromethoxy) phenyl] butanoic acid (compound of Example 30)

A mixture of Compound III-1 (69 mg, Reference Example 10) and hydrogen chloride-1,4-dioxane (4 mol / L, 1.4 ml) was stirred at room temperature for 12 hours. Subsequently, 6 mol / L sodium hydroxide aqueous solution (1.4 mL), methanol (1.4 mL), and water (1.4 mL) were added, and it stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and methylene chloride and water were added for separation and extraction. The aqueous layer was washed with methylene chloride, and 4 mol / L hydrochloric acid was added to adjust the pH to 1. Liquid separation extraction was carried out with methylene chloride and water, and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol) to obtain the title compound (27 mg).
¹ H-NMR (270 MHz, CD ₃ OD) δ: 8.13 (2H, d, J = 8.7 Hz), 7.70 (1H, d, J = 8.7 Hz), 7.39-7.33 (3H, m), 7.22 (1H, s), 7.14-7.00 (2H, m), 4.53-4.48 (1H, m), 4.12-4.01 (1H, m), 3.43-3.35 (1H, m)

[Examples 31 to 35]
The compounds of Examples 31 to 35 were obtained in the same manner as in Example 30 using the corresponding starting compounds.

化合物IV（３４８ｍｇ、参考例１６）と塩化水素−１，４−ジオキサン溶液（４ｍｏｌ／Ｌ、１８ｍＬ）の混合物を室温にて１２時間撹拌した。反応溶液を減圧濃縮し、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒：塩化メチレン／メタノール）で精製した。得られた粗生成物を、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（５ｍＬ）に溶解し、塩化メチレンにて洗浄した。水層に４ｍｏｌ／Ｌ塩酸水溶液を加え、ｐＨを１とした後、塩化メチレンで抽出し、有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた残渣を塩化メチレンにて洗浄し、乾燥し、粗生成物（１２２ｍｇ）を得た。粗生成物（５０ｍｇ）をメタノール（２ｍL）に溶解し、５０℃にて１５時間撹拌した。反応溶液を減圧濃縮後、得られた残渣をヘキサンにて洗浄し、乾燥し、表題化合物（３０ｍｇ）を得た。
¹H-NMR (400MHz, DMSO-D₆) δ: 12.12 (1H, brs), 10.97 (1H, brs), 7.60 (1H, d, J = 7.9 Hz), 7.34 (1H, d, J = 7.9 Hz), 7.23 (1H, d, J = 1.8 Hz), 7.09-7.05 (1H, m), 6.99 (1H, t, J = 7.9 Hz), 4.16 (1H, dd, J = 10.4, 3.9 Hz), 3.50 (1H, dd, J = 17.9, 10.4 Hz), 2.82 (1H, dd, J = 17.9 Hz, 4.0 Hz), 2.67-2.60 (1H, m), 2.03-1.75 (6H, m), 1.55-1.49 (2H, m) [Example 36]
Preparation of 4- (4,4-difluorocyclohexyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid (compound of Example 36)

A mixture of Compound IV (348 mg, Reference Example 16) and hydrogen chloride-1,4-dioxane solution (4 mol / L, 18 mL) was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol). The obtained crude product was dissolved in 1 mol / L aqueous sodium hydroxide solution (5 mL) and washed with methylene chloride. A 4 mol / L aqueous hydrochloric acid solution was added to the aqueous layer to adjust the pH to 1, followed by extraction with methylene chloride. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was washed with methylene chloride and dried to obtain a crude product (122 mg). The crude product (50 mg) was dissolved in methanol (2 mL) and stirred at 50 ° C. for 15 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed with hexane and dried to give the title compound (30 mg).
¹ H-NMR (400MHz, DMSO-D ₆ ) δ: 12.12 (1H, brs), 10.97 (1H, brs), 7.60 (1H, d, J = 7.9 Hz), 7.34 (1H, d, J = 7.9 Hz ), 7.23 (1H, d, J = 1.8 Hz), 7.09-7.05 (1H, m), 6.99 (1H, t, J = 7.9 Hz), 4.16 (1H, dd, J = 10.4, 3.9 Hz), 3.50 (1H, dd, J = 17.9, 10.4 Hz), 2.82 (1H, dd, J = 17.9 Hz, 4.0 Hz), 2.67-2.60 (1H, m), 2.03-1.75 (6H, m), 1.55-1.49 ( 2H, m)

[Test example]
The pharmacological test results of the representative compounds of the present invention are shown below, but the present invention is not limited to these test examples.

[Test Example 1: Inhibitory effect on cell death due to oxidative stress in KSS patient-derived fibroblasts]
In order to examine the effect of suppressing cell death due to oxidative stress in KSS patient-derived fibroblasts with respect to the compound of the present invention, KSS patient-derived fibroblasts treated with glutathione synthesis inhibitor BSO (L-Buthionine sulphoximine) The cells were cultured in the presence and the cell viability was measured.

[Method]
1.5 × 10 ⁴ KSS patient-derived fibroblasts per well were seeded in a 48-well cell culture plate and then cultured for 24 hours. A glutathione synthesis inhibitor BSO (manufactured by Sigma-Aldrich) was added at 100 μmol / L. It mixed in the culture solution so that it might become. After culturing for 24 hours in the presence of BSO, each Example compound was mixed in the culture solution to 3 or 10 μmol / L. After culturing for 3 days in the presence of the compound, the number of viable cells was measured using Cell Count Reagent SF (Nacalai Tesque), and the cell viability was calculated. In addition, as a control for the oxidative stress load, a well to which both BSO and the compound were not added was used, and as a control for the effect of the compound, a BSO added well was used.

[result]
Table 6 shows the inhibitory effect of each compound on cell death due to oxidative stress in KSS patient-derived fibroblasts. When the compound concentration of each compound showing the inhibitory effect on cell death due to oxidative stress in KSS patient-derived fibroblasts is 3 μmol / L, it is expressed as ++, and when it is 10 μmol / L, it is expressed as +. This result shows that these compounds can suppress cell death due to oxidative stress in patients with mitochondrial diseases such as KSS, suggesting that the compounds of the present invention can treat mitochondrial diseases such as KSS.

[Test Example 2: Inhibitory effect on cell death by oxidative stress in LHON patient-derived fibroblasts]
In order to examine the effect of suppressing cell death due to oxidative stress of LHON patient-derived fibroblasts with respect to the compound of the present invention, LHON patient-derived fibroblasts treated with glutathione synthesis inhibitor BSO are cultured in the presence of the compound, Cell viability was measured.

[Method]
1.5 × 10 ⁴ LHON patient-derived fibroblasts per well were seeded in a 48-well cell culture plate and then cultured for 24 hours. A glutathione synthesis inhibitor BSO (manufactured by Sigma-Aldrich) was added at 100 μmol / L. It mixed in the culture solution so that it might become. After culturing for 24 hours in the presence of BSO, each Example compound was mixed in the culture solution to 3 or 10 μmol / L. After culturing for 3 days in the presence of the compound, the number of viable cells was measured using Cell Count Reagent SF (Nacalai Tesque), and the cell viability was calculated. In addition, as a control for the oxidative stress load, a well to which both BSO and the compound were not added was used, and as a control for the effect of the compound, a BSO added well was used.

[result]
Table 7 shows the inhibitory effect of each compound on cell death due to oxidative stress in LHON patient-derived fibroblasts. When the compound concentration at which each compound has an inhibitory effect on cell death due to oxidative stress in LHON patient-derived fibroblasts is 3 μmol / L, it is expressed as ++, and when it is 10 μmol / L, it is expressed as +. This result indicates that these compounds can suppress cell death due to oxidative stress in patients with mitochondrial diseases such as LHON, suggesting that the compounds of the present invention can treat mitochondrial diseases such as LHON.

[Test Example 3: Inhibitory effect on cell death due to oxidative stress in ALS patient-derived fibroblasts]
In order to examine the effect of suppressing cell death due to oxidative stress of ALS patient-derived fibroblasts, ALS patient-derived fibroblasts treated with BSO were cultured in the presence of Example 1 and the cell viability was measured.

[Method]
A 96-well cell culture plate was seeded with 6.4 × 10 ³ ALS patient-derived fibroblasts per well using DMEM medium containing 1% FBS. One day after cell seeding, the glutathione synthesis inhibitor BSO was mixed in the culture solution to 100 μmol / L. After culturing for 1 day in the presence of BSO, the compound of Example 1 was mixed in the culture solution so as to be 1, 3, 10 or 30 μmol / L. After further culturing for 2 days in the presence of the compound, the number of viable cells in each well was measured using Cell Counting Kit-8 (Dojindo Laboratories), and the cell viability was calculated. At this time, a well to which both BSO and the compound were not added was used as a control for oxidative stress load, and a BSO-added well was used as a control for the effect of the compound.

  The compound of Example 1 was statistically detected at 3, 10, and 30 μmol / L in Dunnett's multiple comparison test for cell death induced by 100 μmol / L BSO in the group added with BSO and DMSO. It showed a significant inhibitory effect. From these results, it was suggested that the compound of the present invention may be able to improve the pathology of ALS patients by suppressing the damage to cells caused by oxidative stress.

  In addition to KSS, LHON, and ALS, using fibroblasts derived from patients with other diseases (neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, heart diseases) The inhibitory effect of the compound of the present invention on cell death due to oxidative stress in various fibroblasts can be confirmed by the same or the same method as described above.

  The EC50 value of the cell death inhibitory effect of the compound of the present invention can be calculated using statistical analysis software Stat Preclinica (Takumi Information Technology). Specifically, the EC50 value is obtained by analyzing the data using a technique such as “Dx calculation (logistic curve fitting): response rate input” included in the dose-response data analysis.

  The compound of the present invention exhibits a remarkable cell death inhibitory effect on cell death induced in cells of a patient with a disease associated with abnormal mitochondrial function, and therefore a therapeutic or prophylactic agent for a disease or condition associated with abnormal mitochondrial function Can be provided. More specifically, it is useful as a therapeutic and / or prophylactic agent for mitochondrial diseases, neurodegenerative diseases, immune neurological diseases, cerebral ischemic diseases, renal diseases, muscle diseases, and heart diseases.

Claims (20)

The following formula (I):

[Where:
X ^a , X ^b , X ^c and X ^d are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) C _1-6 alkyl group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(5) C _1-6 alkoxy group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(6) C _3-7 cycloalkyl group (this group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(8) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(9) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(10) C _6-10 aryloxy group (the aryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of optionally substituted C _1-6 alkoxy groups),
(11) 5- to 10-membered heteroaryloxy group (the heteroaryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 groups. And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms),
(12) -CONR ¹ R ² ,
⁽¹³⁾ -NR ^{1 R} 2,
(14) -NR < ¹ > COR < ² >,
_{^{(15) -NR 1 SO 2 R}} 2,
(16) _-SO 2 ^{R 1} or ^{_{(17), -SO 2 NR 1}} R 2
Or
X ^a and X ^b , X ^b and X ^c , or X ^c and X ^d , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring (the ring is a fluorine atom, a hydroxyl group, Optionally substituted with the same or different 1 to 5 groups selected from the group consisting of a C _1-6 alkyl group and a C _1-6 alkoxy group) or a 5- to 8-membered saturated heterocycle The ring may be substituted with the same or different 1-5 groups selected from the group consisting of fluorine atom, hydroxyl group, C _1-6 alkyl group and C _1-6 alkoxy group) Well;
R ¹ and R ² are each independently (1) a hydrogen atom,
(2) C _1-6 alkyl group (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
Or (3) a C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Which may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of C _1-6 alkoxy groups, which may be
(4) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms) And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
Or
R ¹ and R ² together are a 4-membered to 10-membered saturated heterocycle with a nitrogen atom to which they are bonded (the group is a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group And may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of
Represents;
A is
(A) The following formula (II):

(Where
Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) C _1-6 alkyl group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(5) C _1-6 alkoxy group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(6) C _3-7 cycloalkyl group (this group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _3-7 cycloalkoxy group (the group is the same or different 1-6 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(8) -CONR ¹ R ² ,
(9) -NR < ¹ > R < ² >,
(10) -NR ¹ COR ² ,
_{^{(11) -NR 1 SO 2 R}} 2,
(12) -SO ₂ R ¹ or (13) -SO ₂ NR ¹ R ²
Or
Or;
Y ^a and Y ^b , or Y ^b and Y ^c , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring (the ring is a fluorine atom, a hydroxyl group, a C _1-6 alkyl group) And optionally substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups) or a 5- to 8-membered saturated heterocycle (the ring is a fluorine atom, Which may be substituted with the same or different 1 to 5 groups selected from the group consisting of a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group;
However, here
When Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,
At least one of X ^a , X ^b , X ^c and X ^d is:
(1) bromine atom,
(2) a cyano group,
(3) a C _1-6 alkyl group substituted with 1 to 5 fluorine atoms,
(4) a C _1-6 alkoxy group substituted with 1 to 5 fluorine atoms,
(5) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(6) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(8) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(9) C _6-10 aryloxy group (the aryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of optionally substituted C _1-6 alkoxy groups),
(10) 5- to 10-membered heteroaryloxy group (the heteroaryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 groups. And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms),
(11) -CONR ¹ R ² ,
(12) -NR ¹ R ² ,
(13) -NR < ¹ > COR < ² >,
_{^{(14) -NR 1 SO 2 R}} 2,
(15) -SO ₂ R ¹ or (16) -SO ₂ NR ¹ R ²
Or
X ^a and X ^b , X ^b and X ^c , or X ^c and X ^d together with the carbon atom to which they are attached are a 5- to 8-membered cycloalkane ring (the ring is a fluorine atom, a hydroxyl group, Optionally substituted with the same or different 1 to 5 groups selected from the group consisting of a C _1-6 alkyl group and a C _1-6 alkoxy group) or a 5- to 8-membered saturated heterocycle The ring may be substituted with the same or different 1-5 groups selected from the group consisting of fluorine atom, hydroxyl group, C _1-6 alkyl group and C _1-6 alkoxy group) A group represented by
(B) The following formula (III):

(Where
Q ¹ is
(1) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted), or
(2) a 5- to 10-membered heteroaryl group (the group is
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(F) C _3-7 cycloalkoxy (the group is the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(G) -CONR ¹ R ² ,
(H) -NR < ¹ > R < ² >,
(I) -NR < ¹ > COR < ² >,
_{^{(J) -NR 1 SO 2 R}} 2,
(K) —SO ₂ R ¹ , and (l) —SO ₂ NR ¹ R ²
A group represented by the same or different 1 to 5 groups selected from the group consisting of:
(C) The following formula (IV):

(Where
W represents C _1-3 alkylene;
Z is a single bond or the following formula (IV-a):

(Where
m represents a group represented by 1, 2, 3 or 4;
Q ² is
(1) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(2) C _6-10 aryl group (the group is
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(F) C _3-7 cycloalkoxy (the group is the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(G) -CONR ¹ R ² ,
(H) -NR < ¹ > R < ² >,
(I) -NR < ¹ > COR < ² >,
_{^{(J) -NR 1 SO 2 R}} 2,
(K) —SO ₂ R ¹ , and (l) —SO ₂ NR ¹ R ²
Or (3) a 5- to 10-membered heteroaryl group (which may be substituted with the same or different 1 to 5 groups selected from the group consisting of a) to (l) may be substituted with the same or different 1 to 5 groups selected from the group consisting of
Represents;
However, here
When W is methylene or ethylene and Z is a single bond,
Q ² is
(1) C _3-7 cycloalkyl group substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group ,
(2) C _6-10 aryl group substituted with 1 to 5 groups of the same or different types selected from the following group:
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(F) C _3-7 cycloalkoxy (the group is the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
(G) -CONR ¹ R ² ,
(H) -NR < ¹ > R < ² >,
(I) -NR < ¹ > COR < ² >,
_{^{(J) -NR 1 SO 2 R}} 2,
(K) _-SO 2 ^{R 1} or _{^{(l) -SO 2 NR 1 R}} 2,,
Or
(3) A 5- to 10-membered heteroaryl group which may be substituted with the same or different 1 to 5 groups selected from the group consisting of (a) to (l) in (2) above) A group represented by:
Or
(D) a C _1-7 alkyl group substituted with 1 to 5 fluorine atoms (wherein at least one of X ^a , X ^b , X ^c and X ^d is
(1) bromine atom,
(2) a cyano group,
(3) a C _1-6 alkyl group substituted with 1 to 5 fluorine atoms,
(4) a C _1-6 alkoxy group substituted with 1 to 5 fluorine atoms,
(5) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(6) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(8) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(9) C _6-10 aryloxy group (the aryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of optionally substituted C _1-6 alkoxy groups),
(10) 5- to 10-membered heteroaryloxy group (the heteroaryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 groups. And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms),
(11) -CONR ¹ R ² ,
(12) -NR ¹ R ² ,
(13) -NR < ¹ > COR < ² >,
_{^{(14) -NR 1 SO 2 R}} 2,
(15) -SO ₂ R ¹ or (16) -SO ₂ NR ¹ R ² )
However, the following compounds:
4- (4-bromophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid,
4- (4-bromophenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (thiophen-2-yl) butanoic acid,
2- (1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid,
2- (5-chloro-1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid,
except for]
Or a pharmaceutically acceptable salt thereof. A is a group represented by the formula (II);
Y ^a , Y ^b , Y ^c , Y ^d and Y ^e are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) C _1-6 alkyl group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(5) C _1-6 alkoxy group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(6) C _3-7 cycloalkyl group (this group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, which may be substituted with At least one of Y ^a , Y ^b , Y ^c , Y ^d and Y ^e is
(1) bromine atom,
(2) a cyano group,
(3) a C _1-6 alkyl group substituted with 1 to 5 fluorine atoms,
(4) a C _1-6 alkoxy group substituted with 1 to 5 fluorine atoms, or (5) a C _3-7 cycloalkyl group (the group is a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and C The compound according to claim 1 or 2, which may be substituted with the same or different 1 to 5 groups selected from the group consisting of _1-6 alkoxy groups), or a pharmaceutically acceptable salt thereof. Salt. A is a group represented by the formula (III);
Q ¹ is
(1) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted), or
(2) a 5- to 10-membered heteroaryl group (the group is
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
Optionally substituted with 1 to 5 groups of the same or different types selected from the group consisting of:
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. A is a group represented by the formula (IV);
W is C _1-3 alkylene;
Z is a single bond, or the following formula (IV-a)

(Where
m represents 1, 2, 3 or 4);
Q ² is
(1) C _3-7 cyclo optionally substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group An alkyl group,
(2) C _6-10 aryl group optionally substituted with 1 to 5 groups of the same or different types selected from the following group:
(A) a halogen atom,
(B) a cyano group,
(C) C _1-6 alkyl (the group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(D) C _1-6 alkoxy (this group may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group),
(E) C _3-7 cycloalkyl (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted),
Or
(3) a 5- to 10-membered heteroaryl group which may be substituted with 1 to 5 groups of the same or different types selected from the group consisting of (a) to (e) in (2) The compound according to claim 1 or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a C _1-7 alkyl group substituted with 1 to 5 fluorine atoms. X ^a , X ^b , X ^c and X ^d are each independently
(1) a hydrogen atom,
(2) a halogen atom,
(3) a cyano group,
(4) C _1-6 alkyl group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(5) C _1-6 alkoxy group (this group may be substituted with the same or different 1-5 groups selected from the group consisting of a fluorine atom, a hydroxyl group and a C _1-6 alkoxy group) ,
(6) C _3-7 cycloalkyl group (this group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(8) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(9) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(10) C _6-10 aryloxy group (the aryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of optionally substituted C _1-6 alkoxy groups),
(11) 5- to 10-membered heteroaryloxy group (the heteroaryl group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 groups. And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms),
(12) -NR ¹ COR ² , or (13) -NR ¹ SO ₂ R ² ,
(Where:
R ¹ is a hydrogen atom or a C _1-6 alkyl group;
R ² represents a C _1-6 alkyl group or a phenyl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 Which may be substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with fluorine atoms), or
Or;
X ^a and X ^b , X ^b and X ^c , or X ^c and X ^d , together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring (the ring is a fluorine atom, a hydroxyl group, Optionally substituted with the same or different 1 to 5 groups selected from the group consisting of a C _1-6 alkyl group and a C _1-6 alkoxy group) or a 5- to 8-membered saturated heterocycle The ring may be substituted with the same or different 1-5 groups selected from the group consisting of fluorine atom, hydroxyl group, C _1-6 alkyl group and C _1-6 alkoxy group) The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. At least one of X ^a , X ^b , X ^c and X ^d is
(1) bromine atom,
(2) a cyano group,
(3) a C _1-6 alkyl group substituted with 1 to 5 fluorine atoms,
(4) a C _1-6 alkoxy group substituted with 1 to 5 fluorine atoms,
(5) C _3-7 cycloalkyl group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(6) C _3-7 cycloalkoxy group (the group is the same or different 1 to 5 groups selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) May be substituted)
(7) C _6-10 aryl group (the group is substituted with a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms and 1 to 5 fluorine atoms) Optionally substituted with the same or different 1-5 groups selected from the group consisting of C _1-6 alkoxy groups),
(8) 5- to 10-membered heteroaryl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 fluorine atoms And may be substituted with the same or different 1 to 5 groups selected from the group consisting of C _1-6 alkoxy groups optionally substituted with
(9) -NR ¹ COR ² or (10) -NR ¹ SO ₂ R ²
(put it here,
R ¹ is a hydrogen atom or a C _1-6 alkyl group;
R ² represents a C _1-6 alkyl group or a phenyl group (the group is a halogen atom, a cyano group, a C _1-6 alkyl group which may be substituted with 1 to 5 fluorine atoms, and 1 to 5 Any one of the same or different 1 to 5 groups selected from the group consisting of a C _1-6 alkoxy group which may be substituted with a fluorine atom). The compound according to one item or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
4- (2,4-difluorophenyl) -2- (5H- [1,3] dioxolo [4,5-f] indol-7-yl) -4-oxobutanoic acid,
4- (2,4-difluorophenyl) -4-oxo-2- (5-phenyl-1H-indol-3-yl) butanoic acid,
4- (4-chlorophenyl) -4-oxo-2- [5- (trifluoromethyl) -1H-indol-3-yl] butanoic acid,
4- (4-chlorophenyl) -2- (5-cyclohexyl-1H-indol-3-yl) -4-oxobutanoic acid,
4- (4-tert-butylphenyl) -4-oxo-2- (5-phenyl-1H-indol-3-yl) butanoic acid,
4- (4-tert-butylphenyl) -4-oxo-2- {6-[(phenylsulfonyl) amino] -1H-indol-3-yl} butanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- [2- (trifluoromethyl) phenyl] butanoic acid,
4- (5-chlorothiophen-2-yl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (5-bromo-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid,
2- (4-bromo-1H-indol-3-yl) -4- (2,4-difluorophenyl) -4-oxobutanoic acid,
2- (1H-Indol-3-yl) -4-oxo-4- [4- (trifluoromethoxy) phenyl] butanoic acid.   The pharmaceutical which contains the compound as described in any one of Claims 1-9, or its pharmaceutically acceptable salt as an active ingredient.   The therapeutic agent of the disease resulting from a mitochondrial dysfunction containing the compound as described in any one of Claims 1-9, or its pharmaceutically acceptable salt as an active ingredient. A therapeutic agent for diseases caused by mitochondrial dysfunction comprising the following compound or a pharmaceutically acceptable salt thereof as an active ingredient:
4- (4-bromophenyl) -2- (1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid,
4- (4-bromophenyl) -2- (7-ethyl-1H-indol-3-yl) -4-oxobutanoic acid,
2- (1H-indol-3-yl) -4-oxo-4- (thiophen-2-yl) butanoic acid,
2- (1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid,
2- (5-Chloro-1H-indol-3-yl) -3- (thiophen-3-yl) propanoic acid.   The therapeutic agent according to claim 11 or 12, wherein the disease caused by mitochondrial dysfunction is mitochondrial disease, neurodegenerative disease, immune neurological disease, cerebral ischemic disease, renal disease, muscle disease, or heart disease.   Mitochondrial diseases include Leigh's encephalopathy, stroke-like seizure syndrome (MELAS), chronic progressive extraocular palsy syndrome (CPEO), Kearns-Sayer syndrome (KSS), myoclonic epilepsy syndrome with red rag fibers (MERRF), Pearson's disease, The therapeutic agent according to claim 13, which is Leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy, Bath syndrome, or lactic acidosis.   Neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, multiple system atrophy, progressive supranuclear palsy, spinocerebellar degeneration, spinal muscular The therapeutic agent according to claim 13, which is atrophy, bulbospinal muscular atrophy, or Charcot-Marie-Tooth disease.   The therapeutic agent according to claim 13, wherein the immune neurological disorder is Guillain-Barre syndrome, multiple sclerosis, Fisher syndrome, chronic inflammatory demyelinating polyneuritis, or myasthenia gravis.   The therapeutic agent according to claim 13, wherein the cerebral ischemic disease is cerebral infarction.   Kidney disease is renal failure, amyloid kidney, membranous nephropathy, focal glomerulosclerosis, IgA nephropathy, acute tubular necrosis, nephrotic syndrome, diabetic nephropathy, gout kidney, renal edema, renal tumor, kidney The therapeutic agent according to claim 13, which is ischemic injury, renal ischemia reperfusion injury, or cystic kidney.   The muscular disease is progressive muscular dystrophy, myotonic dystrophy, congenital myopathy, metabolic myopathy, distal myopathy, inflammatory myopathy, age-related muscle atrophy (sarcopenia), or disuse muscle atrophy 13. The therapeutic agent according to 13.   The therapeutic agent according to claim 13, wherein the heart disease is myocardial infarction, heart failure, ischemic heart disease, or cardiomyopathy.