JP7165501B2 - Pharmaceuticals comprising novel benzimidazole compounds - Google Patents

Description

The present invention is a therapeutic or prophylactic agent for diseases associated with Na channels, particularly SCN9A (Nav1.7), containing as an active ingredient a novel compound having a benzimidazole skeleton or a pharmaceutically acceptable salt thereof. Regarding. Specifically, therapeutic or prophylactic agents for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal pain, dysuria or multiple sclerosis. Regarding.

Nine types of α subunits that form the pore of voltage-gated Na channels are currently known to exist. In recent years, evidence has emerged that among these subunits, Nav1.7 in particular is widely involved in signaling in acute as well as chronic pain.

SCN9A (Nav1.7) is a tetrodotoxin (TTX)-sensitive Na channel localized in peripheral sensory or sympathetic nerves, also called NENA or PN1. Physiologically, Nav1.7 channels function to amplify pain signals (generate triggering potentials) in sensory nerve endings, and genetic studies have shown that humans with loss-of-function mutations in the SCN9A gene have congenital analgesia. It has been clarified that Conversely, gain-of-function mutations in SCN9A have been found in patients with severe and rare diseases such as erythromelalgia and paroxysmal erythromelalgia. Furthermore, it has been reported that as many as 30% of patients with small fiber neuropathy have a gene polymorphism that enhances Nav1.7 function (Non-Patent Document 1). In addition, since the expression level and activity are elevated in DRG neurons in chronic pain model animals, and neuropathic pain and inflammatory pain are attenuated in knockout experiments, it is suggested that Nav1.7 channel function may be associated with excess DRG neurons in pain pathologies. It has been suggested that it is directly involved in excitation (Non-Patent Document 2).

Patent Document 1 discloses a benzimidazole derivative represented by the following formula (A), which compound is 2-((4-cyclopropylpyridin-2-yl)amino)isonicotinonitrile is an essential structure and is different from the compounds of the present invention. Moreover, the content described in Patent Document 1 relates to a Syk tyrosine kinase inhibitor, and the content described in the present invention is not disclosed at all.

WO2012/057262

Nat Rev Neurosci. 14: 49, 2013 Nat Commun. 3: 791, 2012

The subject of the present invention is a disease associated with Nav1.7, specifically neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal exacerbation, dysuria or An object of the present invention is to provide a therapeutic or preventive drug for diseases such as multiple sclerosis.

In order to achieve the above object, the present inventors have made intensive studies, and as a result, a compound having a benzimidazole ring or a pharmaceutically acceptable salt thereof, which will be described later, can be used in cells expressing Nav1.7 gene via Na channel. In other words, it was found to be a blocker having inhibitory activity against Nav1.7. Further, the derivatives are also useful as therapeutic or prophylactic agents for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, or severe paroxysmal pain. The discovery led to the completion of the present invention. According to the present invention, a benzimidazole compound represented by the following formula (I) (hereinafter sometimes referred to as "compound represented by formula (I)" or "compound of formula (I)") or a pharmaceutical product thereof Pharmaceutically acceptable salts (hereinafter sometimes referred to as "compounds of the present invention") are provided.

［式（Ｉ）中、
Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃおよびＲ^１ｄは、各々独立して、水素、ハロゲン、シアノ、Ｃ_１－４アルキル、Ｃ_１－４アルコキシ、Ｃ_１－４アルキルアミノ（該アルキル、該アルコキシおよび該アルキルアミノにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、Ｃ_３－７シクロアルキル、Ｃ_３－７シクロアルコキシ、Ｃ_３－７シクロアルキルアミノ（該シクロアルキル、該シクロアルコキシおよび該シクロアルキルアミノにおけるシクロアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、Ｃ_６－１０アリール、Ｃ_６－１０アリールオキシ、５～１２員のヘテロアリールまたは５～１２員のヘテロアリールオキシ（該アリールおよび該アリールオキシにおけるアリール部分ならびに該ヘテロアリールおよび該ヘテロアリールオキシにおけるヘテロアリール部分は、各々独立して、ハロゲン、シアノ、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキルチオおよび置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキルスルホニルからなる群から独立して選択される１～５個の置換基で置換されていてもよい）を表し、但し、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃまたはＲ^１ｄの少なくとも１つは上記のＣ_６－１０アリール、Ｃ_６－１０アリールオキシ、５～１２員のヘテロアリールまたは５～１２員のヘテロアリールオキシを表し、
Ｒ^２およびＲ^３は、各々独立して、水素、Ｃ_１－６アルキル（該アルキルは、シアノ、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、またはＣ_３－１０シクロアルキルを表し、
Ｒ^４は、水素、Ｃ_１－６アルキル（該アルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）、またはＣ_３－７シクロアルキル（該シクロアルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
ｍは、１、２または３を表し、
Ｌは、ＣＲ^７Ｒ^８を表し（ｍが２または３を表す場合、それぞれのＣＲ^７Ｒ^８は、各々独立し、同一でも異なってもよい）、
Ｒ^７およびＲ^８は、各々独立して、水素、水酸基、Ｃ_１－４アルキル、Ｃ_１－４アルコキシ（該アルキルおよび該アルコキシにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－７シクロアルキル、またはＣ_３－７シクロアルコキシ（該シクロアルキルおよび該シクロアルコキシにおけるシクロアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、あるいは、
Ｒ^２、Ｒ^３および－ＯＲ^４において、
Ｒ^２とＲ^３が、それぞれが結合する炭素原子と一緒になって環を形成し、－ＯＲ^４と共に下記式（ＩＩ）：

［式（ＩＩ）中、
ｅおよびｆは、各々独立して、１、２または３を表し、
Ｒ^４は、上記と同義であり、
Ｖは単結合または酸素原子を表し、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄは、各々独立して、水素、ハロゲン、水酸基、Ｃ_１－４アルキル、またはＣ_１－４アルコキシ（該アルキルおよび該アルコキシにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す］で表される基を形成してもよく、あるいは、
Ｒ^２、Ｒ^３、－ＯＲ^４およびＬにおけるＣＲ^７Ｒ^８において、
Ｒ^２とＲ^７が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^３、－ＯＲ^４およびＲ^８と共に下記式（ＩＶ）：

［式（ＩＶ）中、
ｍ^１は、０または１を表し、
ｍ^１が１のとき、ｍ^２は、０または１を表し、ｊは、１、２、３または４を表し、
ｍ^１が０のとき、ｍ^２は、０、１または２を表し、ｊは、１、２、３または４を表し、
Ｒ^３、Ｒ^４、Ｒ^８およびＬは、上記と同義であり、
Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃおよびＲ^９ｄは、各々独立して、水素、ハロゲン、水酸基、Ｃ_１－４アルキル、またはＣ_１－４アルコキシ（該アルキルおよび該アルコキシにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す］で表される基を形成してもよく、または、
Ｒ^３と－ＯＲ^４が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^２と共に下記式（ＩＩＩ）：

［式（ＩＩＩ）中、
ｈは、１、２、３または４を表し、
Ｒ^２は、上記と同義であり、
Ｒ^６ａ、Ｒ^６ｂおよびＲ^６ｃは、各々独立して、水素、ハロゲン、水酸基、Ｃ_１－４アルキル、またはＣ_１－４アルコキシ（該アルキルおよび該アルコキシにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す］で表される基を形成してもよく（ただし、Ｒ^２、Ｒ^３および－ＯＲ^４が同時に一緒になって環を形成することはない）、
置換基群Ａは、ハロゲン、水酸基、Ｃ_１－４アルコキシ、Ｃ_３－７シクロアルキルおよびＣ_３－７シクロアルコキシを表し、
置換基群Ｂは、ハロゲン、水酸基、Ｃ_１－４アルキル、Ｃ_１－４アルコキシ、Ｃ_３－７シクロアルキルおよびＣ_３－７シクロアルコキシを表す］
で表される化合物またはその製薬学的に許容される塩を含有する医薬組成物、ただし、以下の化合物またはその製薬学的に許容される塩を含有する医薬組成物は除く、
６－［６－クロロ－２－（モルホリン－４－イル）ピリミジン－４－イル］－１－（２－メトキシエチル）－１Ｈ－ベンズイミダゾール、
２－［５－（３，５－ジメチル－１，２－オキサゾール－４－イル）－１Ｈ－ベンズイミダゾール－１－イル］エタノール、
２－｛５－［５－（テトラヒドロフラン－３－イル）－４Ｈ－１，２，４－トリアゾール－３－イル］－１Ｈ－ベンズイミダゾール－１－イル｝エタノール、
２－｛５－［３－（２－メトキシエチル）－１－（２，２，２－トリフルオロエチル）－１Ｈ－１，２，４－トリアゾール－５－イル］－１Ｈ－ベンズイミダゾール－１－イル｝エタノール、
２－｛５－［３－メチル－１－（１－メチルピペリジン－４－イル）－１Ｈ－１，２，４－トリアゾール－５－イル］－１Ｈ－ベンズイミダゾール－１－イル｝エタノール、
２－ブチル－６－［１－（２－ヒドロキシエチル）－１Ｈ－ベンズイミダゾール－６－イル］－３，４－ジヒドロピロロ［１，２－ａ］ピラジン－１（２H）－オン、
６－［１－（２－ヒドロキシエチル）－１Ｈ－ベンズイミダゾール－６－イル］－２－（３－メチルブチル）－３，４－ジヒドロピロロ［１，２－ａ］ピラジン－１（２H）－オン、
２－｛５－［１－（２－ヒドロキシエチル）－１Ｈ－ベンズイミダゾール－５－イル］－１Ｈ－１，２，４－トリアゾール－１－イル｝エタノール、
６－（２－クロロフェニル）－１－（２－ヒドロキシエチル）－１Ｈ－ベンズイミダゾール－７－カルボニトリル、
２－クロロ－６－｛７－フルオロ－１－［（１Ｓ，３Ｓ）－３－メトキシシクロヘキシル］－１Ｈ－ベンズイミダゾール－５－イル｝－９－（テトラヒドロ－２Ｈ－ピラン－２－イル）－９Ｈ－プリン、および
２－｛５－［２－（テトラヒドロフラン－３－イル）－１Ｈ－イミダゾール－１－イル］－１Ｈ－ベンズイミダゾール－１－イル｝エタノール。 That is, the present invention is as follows.
[Section 1]
Formula (I) below:

[in the formula (I),
R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino (the alkyl, the alkoxy and the each alkyl moiety in alkylamino is independently halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, Substituent Group C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from B, substituted with 1 to 3 substituents independently selected from Substituent Group B from the group consisting of optionally substituted C _3-7 cycloalkoxy and a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 5 independently selected substituents), C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (the cycloalkyl, the cyclo alkoxy and cycloalkyl moieties in said cycloalkylamino are each independently optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and Substituent Group A C _1-4 alkyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 3 substituents independently selected from Substituent Group B from the group consisting of C _3-7 cycloalkyl optionally substituted with a group and C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1-5 independently selected substituents), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryl oxy (the aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy are each independently selected from halogen, cyano and substituent group A 1 to 3 C _1-4 alkyl optionally substituted by substituents of, C _1-4 alkoxy optionally substituted by 1 to 3 substituents independently selected from substituent group A, substituent group C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from B, substituted with 1 to 3 substituents independently selected from Substituent Group B hand optionally C _3-7 cycloalkoxy, 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, Substituent Group A C _1-4 alkylthio optionally substituted with 1 to 3 substituents independently selected from and substituted with 1 to 3 substituents independently selected from Substituent Group A optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl), provided that R ^1a , R ^1b , R ^1c or R ^1d at least one represents C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy as described above;
R ² and R ³ are each independently hydrogen, C _1-6 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and Substituent Group A C _1-4 alkoxy optionally substituted, C _3-7 cycloalkyl optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted by 1 to 3 substituents selected by or represents C _3-10 cycloalkyl,
R ⁴ is hydrogen, C _1-6 alkyl (the alkyl is halogen, hydroxyl group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A , C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, 1 to 3 substituents independently selected from Substituent Group B C _3-7 cycloalkoxy optionally substituted with a group and 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _3-7 cycloalkyl (the cycloalkyl is independently halogen, hydroxyl, substituent group A C _1-4 alkyl optionally substituted by 1 to 3 substituents selected from C, optionally substituted by 1 to 3 substituents independently selected from substituent group A _1-4 alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 1 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 3 substituents),
m represents 1, 2 or 3,
L represents CR ⁷ R ⁸ (when m represents 2 or 3, each CR ⁷ R ⁸ may be independently the same or different);
R ⁷ and R ⁸ are each independently hydrogen, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy (the alkyl portion of said alkyl and said alkoxy are each independently halogen, hydroxyl group, substituent group C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from A, substituted with 1 to 3 substituents independently selected from substituent group B optionally substituted C _3-7 cycloalkyl, C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and independently from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of 3- to 7-membered non-aromatic heterocyclic rings optionally substituted by 1 to 3 substituents good), C _3-7 cycloalkyl, or C _3-7 cycloalkoxy (the cycloalkyl moieties in the cycloalkyl and the cycloalkoxy are each independently selected from halogen, hydroxyl group and Substituent Group A C _1-4 alkyl optionally substituted by 1 to 3 substituents, C _1-4 optionally substituted by 1 to 3 substituents independently selected from Substituent Group A alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted C _3-7 cycloalkoxy), or
at R ² , R ³ and —OR ⁴ ,
R ² and R ³ together with the carbon atoms to which they are attached form a ring, and together with —OR ⁴ the following formula (II):

[in the formula (II),
e and f each independently represent 1, 2 or 3;
^R4 is as defined above;
V represents a single bond or an oxygen atom,
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen, halogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl moieties in said alkyl and said alkoxy are each independently , halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 1 independently selected from Substituent Group B C _{3-7 cycloalkyl optionally substituted by 3 substituents, C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from the group consisting of a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with a substituent of] may form a group represented by
at R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ at L,
R ² and R ⁷ together with the carbon atoms to which they are attached form a ring, together with R ³ , —OR ⁴ and R ⁸ , the following formula (IV):

[In the formula (IV),
m ¹ represents 0 or 1,
when m1 is ¹ , ^m2 represents 0 or 1, j represents 1, 2, 3 or 4;
when m1 is 0, ^m2 represents 0, ¹ or 2, j represents 1, 2, 3 or 4;
R ³ , R ⁴ , R ⁸ and L are as defined above;
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen, halogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moieties in the alkoxy are each independently , halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 1 independently selected from Substituent Group B C _{3-7 cycloalkyl optionally substituted by 3 substituents, C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from the group consisting of a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with a substituent of] may form a group represented by
R ³ and —OR ⁴ together with the carbon atoms to which they are attached form a ring, together with R ² the following formula (III):

[in the formula (III),
h represents 1, 2, 3 or 4,
R ² is as defined above;
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moieties in the alkoxy are each independently halogen , a hydroxyl group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 3 independently selected from Substituent Group B C _{3-7 cycloalkyl optionally substituted by substituents, C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and a substituent 1 to 3 substituents independently selected from the group consisting of a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Group B optionally substituted with)] (provided that R ² , R ³ and —OR ⁴ are not combined together to form a ring),
Substituent group A represents halogen, hydroxyl group, C _1-4 alkoxy, C _3-7 cycloalkyl and C _3-7 cycloalkoxy,
Substituent Group B represents halogen, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy, C _3-7 cycloalkyl and C _3-7 cycloalkoxy]
A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof, excluding pharmaceutical compositions containing the following compounds or pharmaceutically acceptable salts thereof:
6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-methoxyethyl)-1H-benzimidazole,
2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-yl]ethanol,
2-{5-[5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl]-1H-benzimidazol-1-yl}ethanol,
2-{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazole-1 - yl}ethanol,
2-{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,
2-butyl-6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,
6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)- on,
2-{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-1,2,4-triazol-1-yl}ethanol,
6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile,
2-chloro-6-{7-fluoro-1-[(1S,3S)-3-methoxycyclohexyl]-1H-benzimidazol-5-yl}-9-(tetrahydro-2H-pyran-2-yl)- 9H-purine, and 2-{5-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]-1H-benzimidazol-1-yl}ethanol.

［式（Ｉ）中、
Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃおよびＲ^１ｄは、各々独立して、水素、ハロゲン、シアノ、Ｃ_１－４アルキル、Ｃ_１－４アルコキシ、Ｃ_１－４アルキルアミノ（該アルキル、該アルコキシおよび該アルキルアミノにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、Ｃ_３－７シクロアルキル、Ｃ_３－７シクロアルコキシ、Ｃ_３－７シクロアルキルアミノ（該シクロアルキル、該シクロアルコキシおよび該シクロアルキルアミノにおけるシクロアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、Ｃ_６－１０アリール、Ｃ_６－１０アリールオキシ、５～１２員のヘテロアリールまたは５～１２員のヘテロアリールオキシ（該アリールおよび該アリールオキシにおけるアリール部分ならびに該ヘテロアリールおよび該ヘテロアリールオキシにおけるヘテロアリール部分は、各々独立して、ハロゲン、シアノ、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキルチオおよび置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキルスルホニルからなる群から独立して選択される１～５個の置換基で置換されていてもよい）を表し、但し、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃまたはＲ^１ｄの少なくとも１つは上記のＣ_６－１０アリール、Ｃ_６－１０アリールオキシ、５～１２員のヘテロアリールまたは５～１２員のヘテロアリールオキシを表し、
Ｒ^２およびＲ^３は、各々独立して、水素、Ｃ_１－６アルキル（該アルキルは、シアノ、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、またはＣ_３－１０シクロアルキルを表し、
Ｒ^４は、水素、Ｃ_１－６アルキル（該アルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）、またはＣ_３－７シクロアルキル（該シクロアルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、
ｍは、１、２または３を表し、
Ｌは、ＣＲ^７Ｒ^８を表し（ｍが２または３を表す場合、それぞれのＣＲ^７Ｒ^８は、各々独立し、同一でも異なってもよい）、
Ｒ^７およびＲ^８は、各々独立して、水素、水酸基、Ｃ_１－４アルキル、Ｃ_１－４アルコキシ（該アルキルおよび該アルコキシにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－７シクロアルキル、またはＣ_３－７シクロアルコキシ（該シクロアルキルおよび該シクロアルコキシにおけるシクロアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表し、あるいは、
Ｒ^２、Ｒ^３および－ＯＲ^４において、
Ｒ^２とＲ^３が、それぞれが結合する炭素原子と一緒になって環を形成し、－ＯＲ^４と共に下記式（ＩＩ）：

［式（ＩＩ）中、
ｅおよびｆは、各々独立して、１、２または３を表し、
Ｒ^４は、上記と同義であり、
Ｖは単結合または酸素原子を表し、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄは、各々独立して、水素、ハロゲン、水酸基、Ｃ_１－４アルキル、またはＣ_１－４アルコキシ（該アルキルおよび該アルコキシにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す］で表される基を形成してもよく、または、
Ｒ^３と－ＯＲ^４が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^２と共に下記式（ＩＩＩ）：

［式（ＩＩＩ）中、
ｈは、１、２、３または４を表し、
Ｒ^２は、上記と同義であり、
Ｒ^６ａ、Ｒ^６ｂおよびＲ^６ｃは、各々独立して、水素、ハロゲン、水酸基、Ｃ_１－４アルキル、またはＣ_１－４アルコキシ（該アルキルおよび該アルコキシにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）を表す］で表される基を形成してもよく（ただし、Ｒ^２、Ｒ^３および－ＯＲ^４が同時に一緒になって環を形成することはない）、
置換基群Ａは、ハロゲン、水酸基、Ｃ_１－４アルコキシ、Ｃ_３－７シクロアルキルおよびＣ_３－７シクロアルコキシを表し、
置換基群Ｂは、ハロゲン、水酸基、Ｃ_１－４アルキル、Ｃ_１－４アルコキシ、Ｃ_３－７シクロアルキルおよびＣ_３－７シクロアルコキシを表す］
で表される、項１に記載の医薬組成物。 [Section 2]
The compound has the following formula (I):

[in the formula (I),
R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino (the alkyl, the alkoxy and the each alkyl moiety in alkylamino is independently halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, Substituent Group C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from B, substituted with 1 to 3 substituents independently selected from Substituent Group B from the group consisting of optionally substituted C _3-7 cycloalkoxy and a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 5 independently selected substituents), C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (the cycloalkyl, the cyclo alkoxy and cycloalkyl moieties in said cycloalkylamino are each independently optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and Substituent Group A C _1-4 alkyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 3 substituents independently selected from Substituent Group B from the group consisting of C _3-7 cycloalkyl optionally substituted with a group and C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1-5 independently selected substituents), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryl oxy (the aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy are each independently selected from halogen, cyano and substituent group A 1 to 3 C _1-4 alkyl optionally substituted by substituents of, C _1-4 alkoxy optionally substituted by 1 to 3 substituents independently selected from substituent group A, substituent group C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from B, substituted with 1 to 3 substituents independently selected from Substituent Group B hand optionally C _3-7 cycloalkoxy, 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, Substituent Group A C _1-4 alkylthio optionally substituted with 1 to 3 substituents independently selected from and substituted with 1 to 3 substituents independently selected from Substituent Group A optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl), provided that R ^1a , R ^1b , R ^1c or R ^1d at least one represents C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy as described above;
R ² and R ³ are each independently hydrogen, C _1-6 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and Substituent Group A C _1-4 alkoxy optionally substituted, C _3-7 cycloalkyl optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted by 1 to 3 substituents selected by or represents C _3-10 cycloalkyl,
R ⁴ is hydrogen, C _1-6 alkyl (the alkyl is halogen, hydroxyl group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A , C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, 1 to 3 substituents independently selected from Substituent Group B C _3-7 cycloalkoxy optionally substituted with a group and 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _3-7 cycloalkyl (the cycloalkyl is independently halogen, hydroxyl, substituent group A C _1-4 alkyl optionally substituted by 1 to 3 substituents selected from C, optionally substituted by 1 to 3 substituents independently selected from substituent group A _1-4 alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 1 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 3 substituents),
m represents 1, 2 or 3,
L represents CR ⁷ R ⁸ (when m represents 2 or 3, each CR ⁷ R ⁸ may be independently the same or different);
R ⁷ and R ⁸ are each independently hydrogen, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy (the alkyl portion of said alkyl and said alkoxy are each independently halogen, hydroxyl group, substituent group C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from A, substituted with 1 to 3 substituents independently selected from substituent group B optionally substituted C _3-7 cycloalkyl, C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and independently from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of 3- to 7-membered non-aromatic heterocyclic rings optionally substituted by 1 to 3 substituents good), C _3-7 cycloalkyl, or C _3-7 cycloalkoxy (the cycloalkyl moieties in the cycloalkyl and the cycloalkoxy are each independently selected from halogen, hydroxyl group and Substituent Group A C _1-4 alkyl optionally substituted by 1 to 3 substituents, C _1-4 optionally substituted by 1 to 3 substituents independently selected from Substituent Group A alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted C _3-7 cycloalkoxy), or
at R ² , R ³ and —OR ⁴ ,
R ² and R ³ together with the carbon atoms to which they are attached form a ring, and together with —OR ⁴ the following formula (II):

[in the formula (II),
e and f each independently represent 1, 2 or 3;
^R4 is as defined above;
V represents a single bond or an oxygen atom,
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen, halogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl moieties in said alkyl and said alkoxy are each independently , halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 1 independently selected from Substituent Group B C _{3-7 cycloalkyl optionally substituted by 3 substituents, C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from the group consisting of a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with a substituent of] may form a group represented by
R ³ and —OR ⁴ together with the carbon atoms to which they are attached form a ring, together with R ² the following formula (III):

[in the formula (III),
h represents 1, 2, 3 or 4,
R ² is as defined above;
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moieties in the alkoxy are each independently halogen , a hydroxyl group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 3 independently selected from Substituent Group B C _{3-7 cycloalkyl optionally substituted by substituents, C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and a substituent 1 to 3 substituents independently selected from the group consisting of a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Group B optionally substituted with)] (provided that R ² , R ³ and —OR ⁴ are not combined together to form a ring),
Substituent group A represents halogen, hydroxyl group, C _1-4 alkoxy, C _3-7 cycloalkyl and C _3-7 cycloalkoxy,
Substituent Group B represents halogen, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy, C _3-7 cycloalkyl and C _3-7 cycloalkoxy]
The pharmaceutical composition according to item 1, represented by

[Section 3]
R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy (the alkyl moieties in said alkyl and said alkoxy are each independently , optionally substituted with 1 to 3 identical or different halogens), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy ( The aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy each independently have 1 to 3 substituents independently selected from halogen, cyano and Substituent Group A C _1-4 alkyl optionally substituted with a group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A and from Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl optionally substituted by 1 to 3 independently selected substituents ), the pharmaceutical composition according to item 1 or 2.

[Section 4]
R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy (The aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy each independently have 1 to 3 substituents independently selected from halogen and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl optionally substituted with Pharmaceutical composition as described.

[Section 5]
5. The pharmaceutical composition according to any one of items 1 to 4, wherein R ^1a and R ^1d are hydrogen.

［式（ＩＩａ）中、
ｅおよびｆが、各々独立して、１または２であり、
Ｒ^４およびＶは、項１と同義であり、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄが、各々独立して、水素またはハロゲンである］で表される基を形成してもよい、あるいは、
Ｒ^２、Ｒ^３、－ＯＲ^４およびＬにおけるＣＲ^７Ｒ^８において、Ｒ^２とＲ^７が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^３、－ＯＲ^４およびＲ^８と共に下記式（ＩＶａ）；

［式（ＩＶａ）中、
ｍ^１が、０であり、
ｍ^２が、１または２であり、ｊが、１、２または３であり、
Ｒ^３は、上記と同義であり、
Ｒ^４、Ｒ^８およびＬは、項１と同義であり、
Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃおよびＲ^９ｄが、各々独立して、水素またはハロゲンである］
で表される基を形成してもよい、項１および項３～５のいずれか一項に記載の医薬組成物。 [Section 6]
R ² and R ³ are each independently hydrogen or C _1-6 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted) with the proviso that R ² and R ³ are not simultaneously hydrogen ,or,
R ² and R ³ together with the carbon atom to which they are attached form a ring, and together with —OR ⁴ the formula (IIa):

[In the formula (IIa),
e and f are each independently 1 or 2;
R ⁴ and V are as defined in item 1;
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen], or
In R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ in L, R ² and R ⁷ together with the carbon atom to which they are attached form a ring, and R ³ , —OR ⁴ and R ⁸ together with the following formula (IVa);

[In the formula (IVa),
m1 is ⁰ ;
m ² is 1 or 2, j is 1, 2 or 3,
R ³ is as defined above;
R ⁴ , R ⁸ and L are as defined in item 1;
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen or halogen]
The pharmaceutical composition according to any one of items 1 and 3 to 5, which may form a group represented by

［式（ＩＩｂ）中、
ｅおよびｆが、各々独立して、１または２であり、
Ｒ^４およびＶは、項１と同義であり、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄが、各々独立して、水素またはハロゲンである］
で表される基を形成してもよい、
あるいは、Ｒ^２、Ｒ^３、－ＯＲ^４およびＬにおけるＣＲ^７Ｒ^８において、Ｒ^２とＲ^７が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^３、－ＯＲ^４およびＲ^８と共に下記式（ＩＶａ）；

［式（ＩＶａ）中、
ｍ^１が、０であり、
ｍ^２が、１または２であり、ｊが、１、２または３であり、
Ｒ^４が、水素であり、
Ｒ^８およびＬは、項１と同義であり、
Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃおよびＲ^９ｄが、各々独立して、水素またはハロゲンである］
で表される基を形成してもよい、項１および項３～６のいずれか一項に記載の医薬組成物。 [Section 7]
R ² and R ³ are C _1-6 alkyl optionally substituted with 1 to 5 same or different halogens, or R ² and R ³ taken together with the carbon atom to which each is attached form a ring and together with —OR ⁴ formula (IIb):

[In the formula (IIb),
e and f are each independently 1 or 2;
R ⁴ and V are as defined in item 1;
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen]
may form a group represented by
Alternatively, in R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ in L, R ² and R ⁷ together with the carbon atom to which they are attached form a ring, and R ³ , —OR ⁴ and R ⁸ together with the following formula (IVa);

[In the formula (IVa),
m1 is ⁰ ;
m ² is 1 or 2, j is 1, 2 or 3,
R ⁴ is hydrogen,
R ⁸ and L are as defined in item 1;
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen or halogen]
The pharmaceutical composition according to any one of items 1 and 3 to 6, which may form a group represented by

［式（ＩＩａ）中、
ｅおよびｆが、各々独立して、１または２であり、
Ｒ^４およびＶは項１と同義であり、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄが、各々独立して、水素またはハロゲンである］
で表される基を形成してもよい、項１～６のいずれか一項に記載の医薬組成物。 [Item 8]
R ² and R ³ are each independently hydrogen or C _1-6 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted), or R ² and R ³ are each bound together with the carbon atoms to form a ring, together with —OR ⁴ the formula (IIa):

[In the formula (IIa),
e and f are each independently 1 or 2;
R ⁴ and V are as defined in item 1;
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen]
7. The pharmaceutical composition according to any one of items 1 to 6, which may form a group represented by

［式（ＩＩｂ）中、
ｅおよびｆが、各々独立して、１または２であり、
Ｒ^４およびＶは項１と同義であり、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄが、各々独立して、水素またはハロゲンである］
で表される基を形成してもよい、項１～６のいずれか一項に記載の医薬組成物。 [Item 9]
R ² and R ³ are each independently hydrogen or C _1-6 alkyl optionally substituted with 1 to 5 same or different halogens, or R ² and R ³ are each a bond together with the carbon atoms to form a ring, together with —OR ⁴ the formula (IIb):

[In the formula (IIb),
e and f are each independently 1 or 2;
R ⁴ and V are as defined in item 1;
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen]
7. The pharmaceutical composition according to any one of items 1 to 6, which may form a group represented by

[Item 10]
R ² and R ³ are each independently hydrogen or C _1-6 alkyl optionally substituted with 1 to 5 same or different halogens, and R ² and R ³ are each attached carbon Item 10. The pharmaceutical composition according to any one of Items 1 to 9, wherein the atoms do not form a ring together.

［式（ＩＩＩａ）中、
ｈが、１、２または３であり、
Ｒ^２は項１と同義であり、
Ｒ^６ａ、Ｒ^６ｂおよびＲ^６ｃが、各々独立して、水素、ハロゲンまたは１～３個の同一もしくは異なるハロゲンで置換されていてもよいＣ_１－４アルキルである］
で表される基を形成してもよい、項１～５および項１０のいずれか一項に記載の医薬組成物。 [Item 11]
R ⁴ is hydrogen, C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens, or C _3-7 cycloalkyl (wherein said cycloalkyl is independent of halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted by 1 to 3 substituents selected as Yes, or R ³ and —OR ⁴ together with the carbon atom to which they are attached form a ring and together with R ² form (IIIa):

[In the formula (IIIa),
h is 1, 2 or 3;
R ² is as defined in item 1;
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen or C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens]
11. The pharmaceutical composition according to any one of items 1 to 5 and 10, which may form a group represented by

[Item 12]
R ⁴ is hydrogen, C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens, or C _3-7 cycloalkyl (wherein said cycloalkyl is independent of halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted by 1 to 3 substituents selected as 12. The pharmaceutical composition according to any one of items 1 to 11, wherein R ³ and —OR ⁴ together with the carbon atoms to which they are attached do not form a ring.

[Item 13]
13. The pharmaceutical composition according to any one of items 1 to 12, wherein R ⁴ is hydrogen.

[Item 14]
R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from halogen, hydroxyl and Substituent Group A; _optionally substituted C _1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, independently selected from Substituent Group B C _3-7 cycloalkoxy optionally substituted by 1 to 3 substituents and optionally substituted by 1 to 3 substituents independently selected from Substituent Group B 3 to optionally substituted with 1 to 3 substituents independently selected from the group consisting of 7-membered non-aromatic heterocycles);
14. The pharmaceutical composition according to any one of items 1 to 13, wherein m is 1 or 2.

[Item 15]
R ⁷ and R ⁸ are hydrogen,
Item 15. The pharmaceutical composition according to any one of Items 1 to 14, wherein m is 1.

[Item 16]
R ^1b or R ^1c is C _6-10 aryl, C _6-10 aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy (the aryl moiety in said aryl and said aryloxy and said heteroaryl and the heteroaryl moieties in said heteroaryloxy are each independently halogen, cyano, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group A , C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A and 1 to 3 substituents independently selected from Substituent Group A any one of items 1 to 15, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl optionally substituted with The pharmaceutical composition according to .

[Item 17]
R ^1b is C _6-10 aryl, C _6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy (the aryl portion of said aryl and said aryloxy and said heteroaryl and said Each heteroaryl moiety in heteroaryloxy is independently halogen, cyano, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, substituted C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Group A and substituted with 1 to 3 substituents independently selected from Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl which may be optionally substituted) according to any one of items 1 to 16 pharmaceutical composition of

[Item 18]
R ^lc is C _6-10 aryl, C _6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy (the aryl portion of said aryl and said aryloxy and said heteroaryl and said Each heteroaryl moiety in heteroaryloxy is independently halogen, cyano, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, substituted C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Group A and substituted with 1 to 3 substituents independently selected from Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl which may be optionally substituted) according to any one of items 1 to 16 pharmaceutical composition of

[Item 19]
R ^1b or R ^1c is C _6-10 aryloxy or 5- to 12-membered heteroaryloxy (the aryl moiety in said aryloxy and the heteroaryl moiety in said heteroaryloxy are each independently halogen, cyano, substituted C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from group A, substituted with 1 to 3 substituents independently selected from group A independently selected from the group consisting of C _1-4 alkoxy optionally substituted and C _1-4 alkylsulfonyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group A 17. The pharmaceutical composition according to any one of Items 1 to 16, which is optionally substituted with 1 to 3 substituents.

[Section 20]
R ^1b or R ^1c is C _6-10 aryl or 5- to 12-membered heteroaryl (the aryl and the heteroaryl are each independently selected from halogen, cyano and Substituent Group A 1 C _1-4 alkyl optionally substituted by up to 3 substituents, C _1-4 alkoxy optionally substituted by 1 to 3 substituents independently selected from Substituent Group A, and substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl optionally substituted by 1 to 3 substituents independently selected from Substituent Group A Item 17. The pharmaceutical composition according to any one of Items 1 to 16, which is

[Section 21]
21. The pharmaceutical composition according to any one of items 1 to 20, wherein R ² and R ³ are C _1-6 alkyl optionally substituted with 1 to 5 same or different halogens.

［式（ＩＩｂ）中、
ｅおよびｆが、各々独立して、１または２であり、
Ｒ^４およびＶは、項１と同義であり、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄが、各々独立して、水素またはハロゲンである］
で表される基を形成してもよい、
あるいは、Ｒ^２、Ｒ^３、－ＯＲ^４およびＬにおけるＣＲ^７Ｒ^８において、Ｒ^２とＲ^７が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^３、－ＯＲ^４およびＲ^８と共に下記式（ＩＶａ）；

［式（ＩＶａ）中、
ｍ^１が０であり、
ｍ^２が１または２であり、ｊが１、２または３であり、
Ｒ^４が水素であり、
Ｒ^８およびＬは、項１と同義であり、
Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃおよびＲ^９ｄが、各々独立して、水素またはハロゲンである］
で表される基を形成してもよい、項１および項３～２０のいずれか一項に記載の医薬組成物。 [Section 22]
R ² and R ³ together with the carbon atom to which they are attached form a ring, together with —OR ⁴ the formula (IIb):

[In the formula (IIb),
e and f are each independently 1 or 2;
R ⁴ and V are as defined in item 1;
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen]
may form a group represented by
Alternatively, in R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ in L, R ² and R ⁷ together with the carbon atom to which they are attached form a ring, and R ³ , —OR ⁴ and R ⁸ together with the following formula (IVa);

[In the formula (IVa),
m1 is ⁰ ,
m ² is 1 or 2, j is 1, 2 or 3,
^R4 is hydrogen,
R ⁸ and L are as defined in item 1;
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen or halogen]
21. The pharmaceutical composition according to any one of items 1 and 3 to 20, which may form a group represented by

[Section 23]
Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound is a compound selected from the following group of compounds or a pharmaceutically acceptable salt thereof:
Example 1: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 2: 6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole,
Example 7: 1-(Tetrahydrofuran-2-ylmethyl)-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,
Example 9: 2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 10: 1-[2-(cyclopentyloxy)ethyl]-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,
Example 11: 2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 12: 1-[2-(Cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole,
Example 14: 2-methyl-1-[6-(4-methylphenoxy)-1H-benzimidazol-1-yl]propan-2-ol,
Example 15: 2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 20: 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 22: 2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 24: 2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 25: 2-methyl-1-(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 28: 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 51: 2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 52: 2-methyl-1-(5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 53: 1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,
Example 54: 1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
Example 56: 3-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]oxetan-3-ol,
Example 58: 1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]cyclobutanol,
Example 59: 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,
Example 60: 2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-2- oar,
Example 93: 3-({6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
Example 94: 3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
Example 101: 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol,
Example 110: 3-{[6-(2-chloro-4-fluorophenoxy)-1H-benzimidazol-1-yl]methyl}oxetan-3-ol,
Example 118: cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol,
Example 123: 1-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
Example 130: 1-[6-(4-chloro-2-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 148: 3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
Example 173: 4-{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylbutan-2-ol,
Example 176: 1-{5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
Example 179: 2-methyl-1-{5-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 181: 1-{5-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
Example 205: 3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol and Example 229: (3S) -2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.

[Section 24]
Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound is a compound selected from the following group of compounds or a pharmaceutically acceptable salt thereof:
Example 1: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 2: 6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole,
Example 7: 1-(Tetrahydrofuran-2-ylmethyl)-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,
Example 9: 2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 10: 1-[2-(cyclopentyloxy)ethyl]-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,
Example 11: 2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 12: 1-[2-(Cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole,
Example 14: 2-methyl-1-[6-(4-methylphenoxy)-1H-benzimidazol-1-yl]propan-2-ol,
Example 15: 2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 20: 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 22: 2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 24: 2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 25: 2-methyl-1-(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 28: 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 51: 2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 52: 2-methyl-1-(5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 53: 1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,
Example 54: 1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
Example 56: 3-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]oxetan-3-ol,
Example 58: 1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]cyclobutanol,
Example 59: 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol and Example 60 : 2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol.

[Section 25]
Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound is a compound selected from the following group of compounds or a pharmaceutically acceptable salt thereof:
Example 1: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 9: 2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 11: 2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 15: 2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 20: 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 22: 2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 24: 2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 28: 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 51: 2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 53: 1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,
Example 59: 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,
Example 60: 2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-2- oar,
Example 94: 3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
Example 101: 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol,
Example 118: cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol,
Example 123: 1-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
Example 148: 3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
Example 205: 3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol and Example 229: (3S) -2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.

[Section 26]
Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound is a compound selected from the following group of compounds or a pharmaceutically acceptable salt thereof:
Example 1: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 9: 2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 11: 2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,
Example 15: 2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 20: 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
Example 22: 2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 24: 2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,
Example 28: 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 51: 2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
Example 53: 1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,
Example 59: 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol, and Example 60 : 2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol.

[Section 27]
Item 27. A therapeutic agent for diseases associated with Nav1.7 (SCN9A), comprising the pharmaceutical composition according to any one of Items 1 to 26.
[Section 28]
27. The compound according to any one of Items 1 to 26 or a pharmaceutically acceptable salt thereof, or 6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1 -(2-methoxyethyl)-1H-benzimidazole,
2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-yl]ethanol,
2-{5-[5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl]-1H-benzimidazol-1-yl}ethanol,
2-{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazole-1 - yl}ethanol,
2-{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,
2-butyl-6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,
6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)- on,
2-{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-1,2,4-triazol-1-yl}ethanol,
6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile,
2-chloro-6-{7-fluoro-1-[(1S,3S)-3-methoxycyclohexyl]-1H-benzimidazol-5-yl}-9-(tetrahydro-2H-pyran-2-yl)- 9H-purine, and 2-{5-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]-1H-benzimidazol-1-yl}ethanol or a pharmaceutical permissible salt.
[Section 29]
Item 29. A therapeutic agent for diseases associated with Nav1.7 (SCN9A), comprising the compound of Item 28 or a pharmaceutically acceptable salt thereof as an active ingredient.

In item 28, the 11 compounds excluded by the proviso at the end of quoted item 1 are synonymous with any one of items 1 to 26 in the range of compounds not excluded.

[Item 30]
Neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal exacerbation, dysuria, containing the pharmaceutical composition according to any one of items 1 to 26 Or a drug for treating multiple sclerosis.
[Item 31]
Item 28. Neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, and severe paroxysmal pain containing the compound of Item 28 or a pharmaceutically acceptable salt thereof as an active ingredient medicine for dysuria, dysuria or multiple sclerosis.

[Item 32]
The pharmaceutical composition according to any one of Items 1 to 26 and at least one selected from antiepileptic drugs, antidepressants, narcotic analgesics, anti-inflammatory drugs, reductase inhibitors and prostaglandin derivative preparations A drug that combines more than one type of drug.
[Item 33]
Item 28 or a pharmaceutically acceptable salt thereof, and at least selected from antiepileptic drugs, antidepressants, narcotic analgesics, anti-inflammatory drugs, reductase inhibitors and prostaglandin derivative preparations A medicament in combination with one or more drugs.

[Item 34]
Items 1 to 26 for manufacturing a therapeutic agent for neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal pain, dysuria or multiple sclerosis Use of a pharmaceutical composition according to any one of claims.
[Item 35]
Item 29, for producing a therapeutic agent for neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal pain, dysuria or multiple sclerosis, according to Item 28 Use of a compound or a pharmaceutically acceptable salt thereof.

[Item 36]
Neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy in a mammal, comprising administering to the mammal an effective amount of the pharmaceutical composition according to any one of Items 1 to 26; A method of treating erythromelalgia, paroxysmal pain, dysuria or multiple sclerosis.
[Item 37]
Neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy in a mammal, comprising administering to the mammal an effective amount of the compound of Item 28 or a pharmaceutically acceptable salt thereof , erythromelalgia, paroxysmal excruciating pain, dysuria or multiple sclerosis.

The present invention provides blockers of Nav1.7 comprising novel benzimidazole compounds or pharmaceutically acceptable salts thereof. The compounds of the present invention are useful as therapeutic or prophylactic agents for diseases associated with Nav1.7 (SCN9A), specifically neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, It is applicable to patients with erythromelalgia, paroxysmal excruciating pain, and the like.

The present invention will be described in more detail below. In the present specification, the number of carbon atoms in the definition of "substituent" may be expressed as, for example, "C _1-6 ". Specifically, the notation "C _1-6 alkyl" is synonymous with alkyl having 1 to 6 carbon atoms. In addition, in the present specification, substituents for which the terms "optionally substituted" or "substituted" are not specifically defined mean "unsubstituted" substituents. For example, “C _1-6 alkyl” means “unsubstituted C _1-6 alkyl”.

In addition, in the description of substituents in this specification, the term "group" may be omitted. In the case defined as "optionally substituted", the number of substituents when substituents are present is not particularly limited as long as substitution is possible, and is one or more. That is, it indicates that the group may be substituted with substitutable carbon atoms in the relevant group, or substitutable number of substituents on the carbon and nitrogen atoms. Also, unless otherwise indicated, the description of each group also applies when that group is part or a substituent of another group.

The binding position of a substituent is any chemically possible position unless otherwise specified in this specification.

"Halogen" includes, for example, fluorine, chlorine, bromine or iodine. Fluorine or chlorine is preferred.

“C _1-2 alkyl” means a saturated hydrocarbon group having 1 to 2 carbon atoms, and “C _1-3 alkyl” means a linear or branched hydrocarbon group having 1 to 3 carbon atoms. means a chain saturated hydrocarbon group, and "C _1-4 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms, and "C _1- " ₆ alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Specific examples of "C _1-2 alkyl" include methyl and ethyl, and specific examples of "C _1-3 alkyl" include, in addition to the above, propyl and isopropyl, and "C _1-4 alkyl In addition to the above, specific examples of "C 1-6 alkyl" include butyl, isobutyl, sec-butyl, and tert-butyl. Specific examples of "C _1-6 alkyl" include, in addition to the above, pentyl, isopentyl, neopentyl, 1 - ethylpropyl, hexyl, and structural isomers thereof. The "C _1-6 alkyl" or "C _1-4 alkyl" is preferably "C _1-3 alkyl", more preferably methyl and ethyl.

“C _3-7 cycloalkyl” means a cyclic non-aromatic hydrocarbon group (saturated hydrocarbon group and partially unsaturated hydrocarbon group) having 3 to 7 carbon atoms, and “C ₃ " _-10 cycloalkyl" means a cyclic non-aromatic hydrocarbon group (saturated hydrocarbon group and partially unsaturated hydrocarbon group) having 3 to 10 carbon atoms. “C _3-7 cycloalkyl” and “C _3-10 cycloalkyl” also include bridged ones. Specific examples of “C _3-7 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl and the like. In addition to the above, specific examples of “C _3-10 cycloalkyl” include cyclooctyl, adamantyl and the like, preferably “C _3-7 cycloalkyl”.

The above “C _3-7 cycloalkyl” and “C _3-10 cycloalkyl” respectively include “C _3-7 cycloalkyl” and “C _3-10 cycloalkyl” and a benzene ring or a 5- or 6-membered or a ring containing two or more (for example, 2 to 4) identical or different heteroatoms selected from nitrogen, sulfur or oxygen (for example, a 5- or 6-membered monocyclic heteroatom described below). Also included are bicyclic groups in which "aryl" and a 5- or 6-membered ring of "3- to 7-membered non-aromatic heterocycles" described below) are condensed. Specific examples of the group include groups represented by the following formulas.

“C _6-10 aryl” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Phenyl is preferred. Specific examples of “C _6-10 aryl” include phenyl, 1-naphthyl, 2-naphthyl and the like.

The above “C _6-10 aryl” includes “phenyl” and 1, or 5 or 6 heteroatoms (for example, 2 to 4) which are the same or different and contain 1 or more heteroatoms selected from nitrogen, sulfur or oxygen. membered rings (e.g., "5- or 6-membered monocyclic heteroaryl" described below, 5- or 6-membered rings of "3- to 7-membered non-aromatic heterocycles" described below), or Groups condensed with a 5- to 7-membered cycloalkyl ring (eg, cyclopentane, cyclohexane or cycloheptane) are also included. Specific examples of the group include groups represented by the following formulas.

The term “5- to 12-membered heteroaryl” means, in addition to carbon, one heteroatom selected from nitrogen, sulfur or oxygen as ring-constituting atoms, or two or more identical or different heteroatoms (for example, 2 to 4 ) means a monocyclic or polycyclic 5- to 12-membered aromatic group containing, preferably "5- or 6-membered monocyclic heteroaryl". “5- or 6-membered monocyclic heteroaryl” means a monocyclic 5- or 6-membered aromatic group of “5- to 12-membered heteroaryl”.

The polycyclic heteroaryl in the above "5- to 12-membered heteroaryl" specifically includes a condensed monocyclic heteroaryl of two identical or different monocyclic heteroaryls, or a monocyclic heteroaryl and an aromatic ring (for example, benzene, etc.) or non-aromatic rings (eg, cyclohexane, etc.).
Specific examples of the “5- to 12-membered heteroaryl” include groups represented by the following formulas. Preferred "5- to 12-membered heteroaryl" include pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl. In another embodiment, benzofuranyl (the binding position is on the heteroaryl (furan) ring), pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl are preferred. Specific examples of the “5- or 6-membered monocyclic heteroaryl” are monocyclic groups represented by the following formulas.

The term "3- to 7-membered non-aromatic heterocyclic ring" means, in addition to carbon atoms as ring-constituting atoms, one heteroatom selected from nitrogen, oxygen and sulfur, or two or more identical or different heteroatoms ( For example, it means a 3- to 7-membered cyclic group having 2 to 4, preferably 2 to 3). The heterocycles are non-aromatic and can be either saturated or partially unsaturated. A saturated heterocyclic ring is preferred, and a 5- or 6-membered saturated heterocyclic ring is more preferred. Specific examples of the "3- to 7-membered non-aromatic heterocyclic ring" include oxetanyl, azetidinyl, pyranyl, tetrahydrofuryl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneimiminyl , oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxoxazolidinyl, dioxoxazolidinyl, dioxothiazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, etc. . Preferred are pyranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl and morpholinyl.

The "3- to 7-membered non-aromatic heterocycle" is a 3- to 7-membered non-aromatic heterocycle condensed with benzene or a 6-membered heteroaryl (such as pyridine, pyrimidine or pyridazine) to form a ring. Also includes cases. Specific examples include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrolopyridinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl. , decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like.

“C _1-2 alkoxy” means an oxy group substituted with the above “C _1-2 alkyl”, and “C _1-4 alkoxy” means an oxy group substituted with the above “C _1-4 alkyl”. means an oxy group. Specific examples of "C _1-2 alkoxy" include methoxy and ethoxy, and specific examples of "C _1-4 alkoxy" include, in addition to the above, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. “C _1-4 alkoxy” preferably includes methoxy, ethoxy and isopropoxy.

“C _3-7 cycloalkoxy” means an oxy group substituted with the above “C _3-7 cycloalkyl”. Specific examples of “C _3-7 cycloalkoxy” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like. Preferred is cyclohexyloxy. “C _5-6 cycloalkoxy” is a cycloalkoxy having 5 or 6 carbon atoms in “C _3-7 cycloalkoxy”.

“C _6-10 aryloxy” means an oxy group substituted with the above “C _6-10 aryl”. Specific examples of “C _6-10 aryloxy” include phenyloxy, naphthyloxy and the like, preferably phenyloxy.

"5- to 12-membered heteroaryloxy" means an oxy group substituted with the above "5- to 12-membered heteroaryl". Specific examples of "5- to 12-membered heteroaryloxy" include pyridyloxy, imidazolyloxy, furyloxy and the like, preferably pyridyloxy.

“C _1-4 alkylamino” means an amino group substituted with 1 or 2 of the aforementioned “C _1-4 alkyl”. Specific examples of “C _1-4 alkylamino” include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, ethylmethylamino and the like. Methylamino and dimethylamino are preferred.

“C _3-7 cycloalkylamino” means an amino group substituted with 1 or 2 of the aforementioned “C _3-7 cycloalkyl”. Specific examples of “C _3-7 cycloalkylamino” include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, dicyclopropylamino and the like. Preferred is cyclohexylamino.

“C _1-4 alkylsulfonyl” means a sulfonyl group substituted with the aforementioned “C _1-4 alkyl”. Specific examples of “C _1-4 alkylsulfonyl” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like, preferably methylsulfonyl.

“C _1-4 alkylthio” means a thio group substituted with the above “C _1-4 alkyl”. Specific examples of “C _1-4 alkylthio” include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like, preferably methylthio.

In order to more specifically disclose the compound of the present invention represented by the formula (I), various symbols used in the formula (I) will be described in more detail with preferred specific examples.

Preferred R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino (the alkyl, the alkoxy and the alkyl moieties in said alkylamino are each independently halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, substituted C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Group B, with 1 to 3 substituents independently selected from Substituent Group B consisting of an optionally substituted C _3-7 cycloalkoxy and a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted by 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group), C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (the cycloalkyl, The cycloalkyl moieties in the cycloalkoxy and the cycloalkylamino are each independently optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and Substituent Group A C _{1 -4} alkyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from substituent group A, 1 to 3 independently selected from substituent group B consisting of C _{3-7 cycloalkyl optionally substituted by substituents and C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1-3 substituents independently selected from the group), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy, (the aryl moiety in said aryl and said aryloxy and the heteroaryl moiety in said heteroaryl and said heteroaryloxy are each independently selected from halogen, cyano, Substituent Group A 1 C _1-4 alkyl optionally substituted by up to 3 substituents, C _1-4 alkoxy optionally substituted by 1 to 3 substituents independently selected from Substituent Group A, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from substituent group B, 1 to 3 substituents independently selected from substituent group B optionally substituted C _3-7 cycloalkoxy, 3- to 7-membered non-aromatic heterocyclic optionally substituted by 1 to 3 substituents independently selected from Substituent Group B ring, C _1-4 alkylthio optionally substituted with 1 to 3 substituents independently selected from Substituent Group A and 1 to 3 substituents independently selected from Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl optionally substituted with a group). provided that at least one of R ^1a , R ^1b , R ^1c or R ^1d is the above C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy; be.

More preferred R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy (the alkyl moieties in said alkyl and alkoxy are each independently optionally substituted with 1 to 3 identical or different halogens), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy , (the aryl portion in said aryl and aryloxy and the heteroaryl portion in said heteroaryl and heteroaryloxy each independently have 1 to 3 substituents independently selected from halogen, cyano, Substituent Group A C _1-4 alkyl optionally substituted with a group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A and from Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl optionally substituted by 1 to 3 independently selected substituents ). provided that at least one of R ^1a , R ^1b , R ^1c or R ^1d is the above C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy; be.

Even more preferably, R ^1a and R ^1d are hydrogen and R ^1b and R ^1c are each independently hydrogen, C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5- to 12-membered heteroaryloxy, (the aryl portion in said aryl and aryloxy and the heteroaryl portion in said heteroaryl and heteroaryloxy are each independently halogen and optionally substituted C _1-4 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl). provided that R ^1b and R ^1c are not hydrogen at the same time.

In another embodiment of R ^1a , R ^1b , R ^1c and R ^1d , R ^1a and R ^1d are hydrogen and R ^1b and R ^1c are each independently hydrogen, C _6-10 aryloxy or 5 ~12-membered heteroaryloxy (the aryl portion in said aryloxy and the heteroaryl portion in said heteroaryloxy are each independently from the group consisting of halogen and optionally substituted C _1-4 alkyl may be substituted with 1 to 3 selected substituents). provided that R ^1b and R ^1c are not hydrogen at the same time.

In another embodiment of R ^1a , R ^1b , R ^1c and R ^1d , R ^1a and R ^1d are hydrogen and R ^1b and R ^1c are each independently hydrogen, C _6-10 aryl or 5- 12-membered heteroaryl (said aryl and said heteroaryl each independently having 1 to 3 substituents independently selected from the group consisting of halogen and optionally substituted C _1-4 alkyl may be substituted with). provided that R ^1b and R ^1c are not hydrogen at the same time.

In another embodiment of R ^1a , R ^1b , R ^1c and R ^1d , R ^1a and R ^1d are hydrogen and either one of R ^1b or R ^1c is C _6-10 aryloxy or 5-12 membered heteroaryloxy (the aryl moiety in said aryloxy and the heteroaryl moiety in said heteroaryloxy are each independently selected from the group consisting of halogen and optionally substituted C _1-4 alkyl optionally substituted with 1 to 3 substituents) and the other is hydrogen.

In another embodiment of R ^1a , R ^1b , R ^1c and R ^1d , R ^1a and R ^1d are hydrogen and either one of R ^1b or R ^1c is C _6-10 aryl or 5-12 membered heteroaryl, wherein said aryl and said heteroaryl are each independently substituted with 1 to 3 substituents independently selected from the group consisting of halogen and optionally substituted C _1-4 alkyl and the other is hydrogen.

Preferred specific examples of R ^1a , R ^1b , R ^1c and R ^1d are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, phenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy , 3,5-difluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-methoxyphenoxy, 4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy, 4-(methyl sulfonyl)phenoxy, (5-methylpyridin-2-yl)oxy, (5-(trifluoromethyl)pyridin-2-yl)oxy, (5-fluoropyridin-2-yl)oxy.

More preferred specific examples of R ^1a , R ^1b , R ^1c and R ^1d are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 4-fluorophenyl. , 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, phenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy, 3,5-difluorophenoxy, 4 -chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-methoxyphenoxy, 4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy, 4-(methylsulfonyl)phenoxy, (5-methylpyridine -2-yl)oxy, (5-(trifluoromethyl)pyridin-2-yl)oxy, (5-fluoropyridin-2-yl)oxy.

More preferred specific examples of R ^1a , R ^1b , R ^1c and R ^1d are hydrogen, fluorine, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 3-fluorophenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-(trifluoromethoxy)phenoxy, (5-methylpyridin-2-yl)oxy, (5-(tri and fluoromethyl)pyridin-2-yl)oxy.

Further embodiments of R ^1a , R ^1b , R ^1c and R ^1d are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, phenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy , 3,5-difluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-methoxyphenoxy, 4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy, 4-(methyl sulfonyl)phenoxy, (5-methylpyridin-2-yl)oxy, (5-(trifluoromethyl)pyridin-2-yl)oxy, (5-fluoropyridin-2-yl)oxy, 2-methoxy-4- (trifluoromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-chloro-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, (5-chloropyridine-2- yl)oxy, 2,4-dichlorophenyl, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, 2,4-dichlorophenoxy.

Another embodiment of R ^1a , R ^1b , R ^1c and R ^1d is hydrogen, fluorine, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 3-fluorophenoxy, 4 -fluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-(trifluoromethoxy)phenoxy, (5-methylpyridin-2-yl)oxy, (5-(trifluoro methyl)pyridin-2-yl)oxy, 2-methoxy-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, (5-chloropyridin-2-yl)oxy.

Preferred R ² and R ³ are hydrogen or C _1-6 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and Substituent Group A). optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkoxy), more preferably substituted with hydrogen or 1 to 5 halogens and C _1-6 alkyl which may be substituted.

Preferred specific examples of R ² and R ³ include hydrogen, methyl, ethyl, isopropyl, isobutyl, trifluoromethyl, cyclopropyl, cyclopentyl and cyclohexyl, more preferably hydrogen, methyl and ethyl.

で表される基を形成してもよい。 In addition, R ² and R ³ together with the carbon atoms to which they are attached form a ring, and together with —OR ⁴ the following formula (II):

You may form the group represented by.

In the above formula (II),
Preferred e and f include 1 or 2 each independently.

Preferred R ^5a , R ^5b , R ^5c and R ^5d each independently include hydrogen or halogen.

で表される基を形成してもよい。 In addition, R ² and R ⁷ together with the carbon atoms to which they are attached form a ring, and together with R ³ , —OR ⁴ and R ⁸ , the following formula (IV):

You may form the group represented by.

In the above formula (IV),
Preferred m ¹ includes 0, and preferred m ² includes 1 or 2.
Preferred j includes 1, 2 or 3.

Preferred R ^9a , R ^9b , R ^9c and R ^9d each independently include hydrogen or halogen.
Preferred R ⁴ include hydrogen.

Preferred R ⁴ is hydrogen, C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens or C _3-7 cycloalkyl (the cycloalkyl is halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted by 1 to 3 substituents independently selected from ), more preferably hydrogen.

Preferred specific examples of R ⁴ include hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, more preferably hydrogen, isopropyl and cyclopentyl, still more preferably hydrogen is mentioned.

で表される基を形成してもよい。 In addition, R ³ and —OR ⁴ together with the carbon atoms to which they are attached form a ring, and together with R ² the following formula (III):

You may form the group represented by.

In the above formula (III),
Preferable h includes 1, 2 or 3, more preferably 2 or 3.

Preferred R ^6a , R ^6b and R ^6c each independently include hydrogen, halogen or C _1-4 alkyl optionally substituted with 1 to 3 identical or different halogens, more preferably Hydrogen is mentioned.

Preferred specific examples of R ^6a , R ^6b and R ^6c include hydrogen, fluorine, hydroxyl group, methyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy, more preferably hydrogen, fluorine and methyl. , and more preferably hydrogen.

Preferred m includes 1 or 2,
More preferably, 1 is mentioned.

L is CR ⁷ R ⁸ (when m represents 2 or 3, each CR ⁷ R ⁸ may be independently the same or different).

Preferred R ⁷ and R ⁸ are hydrogen or C _1-4 alkyl (each alkyl is independently substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and Substituent Group A). C _1-4 alkoxy which may be optionally substituted, C _3-7 cycloalkyl optionally substituted by 1 to 3 substituents independently selected from Substituent Group B, independently from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from C _3-7 cycloalkoxy optionally substituted by 1 to 3 substituents selected from Substituent Group B (optionally substituted with 1 to 3 substituents independently selected from the group consisting of 3- to 7-membered non-aromatic heterocycles), more preferably hydrogen.

Preferred specific examples of R ⁷ and R ⁸ include hydrogen, methyl and ethyl, more preferably hydrogen.

Preferred substituent group A includes fluorine, chlorine, hydroxyl, C _1-2 alkoxy and C _5-6 cycloalkoxy, more preferably fluorine, hydroxyl and C _1-2 alkoxy.

Preferred substituent group B includes fluorine, chlorine, hydroxyl, C _1-2 alkyl, C _1-2 alkoxy and C _5-6 cycloalkoxy, more preferably fluorine, hydroxyl, C _1-2 alkyl and and C _1-2 alkoxy.

［式（ＩＩａ）中、
ｅおよびｆは、各々独立して、１または２であり、
Ｒ^４は、水素、Ｃ_１－６アルキル（該アルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）またはＣ_３－７シクロアルキル（該シクロアルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）であり、
Ｖは単結合または酸素原子であり、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄは、各々独立して、水素またはハロゲンである］で表される基を形成してもよく、
あるいは、Ｒ^２、Ｒ^３、－OＲ^４およびＬにおけるＣＲ^７Ｒ^８において、Ｒ^２とＲ^７が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^３、－ＯＲ^４およびＲ^８と共に下記式（ＩＶａ）；

［式（ＩＶａ）中、
ｍ^１は０であり、
ｍ^２は１または２であり、ｊは１、２または３であり、
Ｒ^３は、水素または１～３個のハロゲンで置換されていてもよいＣ_１－６アルキルであり、
Ｒ^４は、水素または１～３個のハロゲンで置換されていてもよいＣ_３－７シクロアルキルであり、
Ｒ^８は、水素、水酸基、Ｃ_１－４アルキル、Ｃ_１－４アルコキシ（該アルキルおよび該アルコキシにおけるアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）、Ｃ_３－７シクロアルキルまたはＣ_３－７シクロアルコキシ（該シクロアルキルおよび該シクロアルコキシにおけるシクロアルキル部分は、各々独立して、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）であり、
ＬはＣＲ^７Ｒ^８（ｍ^２が２を表す場合、それぞれのＣＲ^７Ｒ^８は、各々独立し、同一でも異なってもよい）であり、
Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃおよびＲ^９ｄは、各々独立して、水素またはハロゲンである］
で表される基を形成してもよく、
Ｒ^４が、水素、１～３個の同一もしくは異なるハロゲンで置換されていてもよいＣ_１－４アルキルまたはＣ_３－７シクロアルキル（該シクロアルキルは、ハロゲン、水酸基および置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）であり、あるいは、Ｒ^３と－ＯＲ^４が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^２と共に式（ＩＩＩａ）：

［式（ＩＩＩａ）中、
ｈは、１、２または３であり、
Ｒ^２は、水素、Ｃ_１－６アルキル（該アルキルは、シアノ、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）またはＣ_３－１０シクロアルキルであり、
Ｒ^６ａ、Ｒ^６ｂおよびＲ^６ｃは、各々独立して、水素、ハロゲンまたは１～３個の同一もしくは異なるハロゲンで置換されていてもよいＣ_１－４アルキルである］
で表される基を形成してもよく、
ｍが、１または２であり、
Ｌが、ＣＲ^７Ｒ^８を表し（ｍが２を表す場合、それぞれのＣＲ^７Ｒ^８は、各々独立し、同一でも異なってもよい）、
Ｒ^７およびＲ^８が、各々独立して、水素またはＣ_１－４アルキル（該アルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）である化合物またはその製薬学的に許容される塩。 One embodiment of the compound of formula (I) includes the following.
R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy (The aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy each independently have 1 to 3 substituents independently selected from halogen and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl optionally substituted with , with the proviso that R ^1a , R ^1b , R ^1c or at least one of R ^1d is C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy;
R ² and R ³ are each independently hydrogen or C _1-6 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted) with the proviso that R ² and R ³ are not simultaneously hydrogen ,or,
R ² and R ³ together with the carbon atom to which they are attached form a ring, and together with —OR ⁴ the formula (IIa):

[In the formula (IIa),
e and f are each independently 1 or 2;
R ⁴ is hydrogen, C _1-6 alkyl (the alkyl is halogen, hydroxyl group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A , C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, 1 to 3 substituents independently selected from Substituent Group B C _3-7 cycloalkoxy optionally substituted with a group and 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of) or C _3-7 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, independently from Substituent Group A C _1-4 alkyl optionally substituted by 1 to 3 selected substituents, C ₁ optionally substituted by 1 to 3 substituents independently selected from Substituent Group A _-4 alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 1 substituent);
V is a single bond or an oxygen atom,
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen] may form a group represented by
Alternatively, in R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ in L, R ² and R ⁷ together with the carbon atom to which they are attached form a ring, and R ³ , —OR ⁴ and R ⁸ together with the following formula (IVa);

[In the formula (IVa),
m1 is ⁰ ,
m ² is 1 or 2, j is 1, 2 or 3,
R ³ is hydrogen or C _1-6 alkyl optionally substituted with 1 to 3 halogens;
R ⁴ is hydrogen or C _3-7 cycloalkyl optionally substituted with 1-3 halogens;
R ⁸ is hydrogen, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently selected from halogen, hydroxyl group and Substituent Group A C _1-4 alkoxy optionally substituted by 1 to 3 substituents, C _3-7 cyclo optionally substituted by 1 to 3 substituents independently selected from Substituent Group B alkyl, C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted 3- to 7-membered non-aromatic heterocyclic rings), C _3-7 cyclo alkyl or C _3-7 cycloalkoxy (the cycloalkyl portion in the cycloalkyl and the cycloalkoxy are each independently 1 to 3 substituents independently selected from halogen, hydroxyl group and Substituent Group A; C _1-4 alkyl optionally substituted, C _1-4 alkoxy optionally substituted by 1 to 3 substituents independently selected from substituent group A, independently from substituent group B optionally substituted with 1 to 3 substituents independently selected from C _3-7 cycloalkyl optionally substituted by 1 to 3 substituents selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy;
L is CR ⁷ R ⁸ (when m ² represents 2, each CR ⁷ R ⁸ may be independently the same or different);
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen or halogen]
may form a group represented by
R ⁴ is hydrogen, C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens, or C _3-7 cycloalkyl (wherein said cycloalkyl is independent of halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted by 1 to 3 substituents selected as Yes, or R ³ and —OR ⁴ together with the carbon atom to which they are attached form a ring and together with R ² form (IIIa):

[In the formula (IIIa),
h is 1, 2 or 3;
R ² is hydrogen, C _1-6 alkyl (the alkyl is C 1-6 optionally substituted with ₁ to 3 substituents independently selected from cyano, halogen, hydroxyl group, Substituent Group A) ₄ alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from Substituent Group B optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with a substituent of ) or C _3-10 cycloalkyl ,
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen or C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens]
may form a group represented by
m is 1 or 2,
L represents CR ⁷ R ⁸ (when m represents 2, each CR ⁷ R ⁸ may be independently the same or different),
R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from halogen, hydroxyl and Substituent Group A; _optionally substituted C _1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, independently selected from Substituent Group B C _3-7 cycloalkoxy optionally substituted by 1 to 3 substituents and optionally substituted by 1 to 3 substituents independently selected from Substituent Group B 3 to (optionally substituted with 1 to 3 substituents independently selected from the group consisting of 7-membered non-aromatic heterocycles) or a pharmaceutically acceptable salt thereof.

［式（ＩＩｂ）中、
ｅおよびｆは、各々独立して、１または２であり、
Ｒ^４は、水素、Ｃ_１－６アルキル（該アルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環からなる群から独立して選択される１～３個の置換基で置換されていてもよい）またはＣ_３－７シクロアルキル（該シクロアルキルは、ハロゲン、水酸基、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキルおよび置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシからなる群から独立して選択される１～３個の置換基で置換されていてもよい）であり、
Ｖは、単結合または酸素原子であり、
Ｒ^５ａ、Ｒ^５ｂ、Ｒ^５ｃおよびＲ^５ｄは、各々独立して、水素またはハロゲンである］
で表される基を形成してもよく、あるいは、
Ｒ^２、Ｒ^３、－OＲ^４およびＬにおけるＣＲ^７Ｒ^８において、Ｒ^２とＲ^７が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^３、－ＯＲ^４およびＲ^８と共に下記式（ＩＶａ）；

［式（ＩＶａ）中、
ｍ^１は０であり、
ｍ^２は１または２であり、
ｊは１または２であり、
Ｒ^３は水素またはＣ_１－４アルキルであり、
Ｒ^４は水素であり、
Ｒ^８は水素またはＣ_１－４アルキルであり、
ＬはＣＲ^７Ｒ^８（ｍ^２が２を表す場合、それぞれのＣＲ^７Ｒ^８は、各々独立し、同一でも異なってもよい）であり、
Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃおよびＲ^９ｄは、各々独立して、水素またはハロゲンである］
で表される基を形成してもよく、
Ｒ^４が、水素、１～３個の同一もしくは異なるハロゲンで置換されていてもよいＣ_１－４アルキルまたは１～３個の同一もしくは異なるハロゲンで置換されていてもよいＣ_３－７シクロアルキルであり、あるいは、
Ｒ^３と－ＯＲ^４が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^２と共に式（ＩＩＩａ）：

［式（ＩＩＩａ）中、
ｈは、１、２または３であり、
Ｒ^２は、水素または１～３個の同一もしくは異なるハロゲンで置換されていてもよいＣ_１－４アルキルであり、
Ｒ^６ａ、Ｒ^６ｂおよびＲ^６ｃは、各々独立して、水素、ハロゲンまたは１～３個の同一もしくは異なるハロゲンで置換されていてもよいＣ_１－４アルキルである］
で表される基を形成してもよく、
ｍが、１または２であり、
Ｌが、ＣＲ^７Ｒ^８を表し（ｍが２を表す場合、それぞれのＣＲ^７Ｒ^８は、各々独立し、同一でも異なってもよい）、
Ｒ^７およびＲ^８が、各々独立して、水素または１～３個の同一もしくは異なるハロゲンで置換されていてもよいＣ_１－４アルキルである化合物またはその製薬学的に許容される塩。 Further embodiments of compounds of formula (I) include the following.
R ^1a and R ^1d are hydrogen, and at least one of R ^1b or R ^1c is C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy ( The aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy are each independently 1 to 3 substituents independently selected from halogen and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted C _1-4 alkyl);
R ² and R ³ are each independently C _1-6 alkyl optionally substituted with 1 to 5 of the same or different halogens, or R ² and R ³ are the carbon to which they are attached Together the atoms form a ring and together with —OR ⁴ the formula (IIb):

[In the formula (IIb),
e and f are each independently 1 or 2;
R ⁴ is hydrogen, C _1-6 alkyl (the alkyl is halogen, hydroxyl group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A , C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, 1 to 3 substituents independently selected from Substituent Group B C _3-7 cycloalkoxy optionally substituted with a group and 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of) or C _3-7 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl, independently from Substituent Group A C _1-4 alkyl optionally substituted by 1 to 3 selected substituents, C ₁ optionally substituted by 1 to 3 substituents independently selected from Substituent Group A _-4 alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 1 substituent);
V is a single bond or an oxygen atom,
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen]
may form a group represented by, or
In R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ in L, R ² and R ⁷ together with the carbon atom to which they are attached form a ring, and R ³ , —OR ⁴ and R ⁸ together with the following formula (IVa);

[In the formula (IVa),
m1 is ⁰ ,
^m2 is 1 or 2,
j is 1 or 2;
R ³ is hydrogen or C _1-4 alkyl;
^R4 is hydrogen;
R ⁸ is hydrogen or C _1-4 alkyl;
L is CR ⁷ R ⁸ (when m ² represents 2, each CR ⁷ R ⁸ may be independently the same or different);
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen or halogen]
may form a group represented by
R ⁴ is hydrogen, C _1-4 alkyl optionally substituted by 1 to 3 same or different halogens or C _3-7 cycloalkyl optionally substituted by 1 to 3 same or different halogens or
R ³ and —OR ⁴ together with the carbon atom to which they are attached form a ring and together with R ² form formula (IIIa):

[In the formula (IIIa),
h is 1, 2 or 3;
R ² is hydrogen or C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens;
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen or C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens]
may form a group represented by
m is 1 or 2,
L represents CR ⁷ R ⁸ (when m represents 2, each CR ⁷ R ⁸ may be independently the same or different),
A compound, or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl optionally substituted with 1 to 3 of the same or different halogens.

［式（ＩＩｃ）中、ｅおよびｆは、各々独立して、１または２であり、Ｒ^４は、水素であり、Ｖは、単結合または酸素原子である］で表される基であるか、あるいは、
Ｒ^２とＲ^７が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^３、－ＯＲ^４およびＲ^８と共に下記式（ＩＶｃ）

［式（ＩＶｃ）中、Ｒ^３、Ｒ^４およびＲ^８は、水素であり、ｍ^１は、０であり、ｍ^２は、１または２であり、ｊは、１または２であり、Ｌは、ＣＲ^７Ｒ^８であり、Ｒ^７およびＲ^８は、共に水素である］で表される基であり、
Ｒ^４が、水素、イソプロピルまたはシクロペンチルであるか、あるいは、
Ｒ^３と－ＯＲ^４が、それぞれが結合する炭素原子と一緒になって環を形成し、Ｒ^２と共に式（ＩＩＩｂ）：

［式（ＩＩＩｂ）中、Ｒ^２は、水素であり、ｈは、２である］で表される基であり、
ｍが、１であり、
Ｌが、ＣＲ^７Ｒ^８であり、
Ｒ^７およびＲ^８が、各々独立して、水素またはメチルである化合物またはその製薬学的に許容される塩。 Further embodiments of compounds of formula (I) include the following.
R ^1a and R ^1d are hydrogen and one of R ^1b or R ^1c is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl, 5-(trifluorophenyl) fluoromethyl)pyridin-2-yl, phenoxy, 3-fluorophenoxy, 3,4-difluorophenoxy, 3,5-difluorophenoxy, 4-chlorophenoxy, 4-(trifluoromethyl)phenoxy, 4-(trifluoromethoxy ) phenoxy, 4-cyanophenoxy, 4-(methylsulfonyl)phenoxy, (5-methylpyridin-2-yl)oxy, (5-(trifluoromethyl)pyridin-2-yl)oxy, (5-fluoropyridine- 2-yl)oxy, 2-methoxy-4-(trifluoromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-chloro-4-(trifluoromethyl)phenyl, 4-(trifluoro methoxy)phenyl, (5-chloropyridin-2-yl)oxy, 2,4-dichlorophenyl, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy or 2,4-dichlorophenoxy; one is hydrogen,
R ² and R ³ are both methyl, or
R ² and R ³ together with the carbon atoms to which they are attached form a ring, and together with OR ⁴ the following formula (IIc)

[In formula (IIc), e and f are each independently 1 or 2, R ⁴ is hydrogen, and V is a single bond or an oxygen atom] ,or,
R ² and R ⁷ together with the carbon atoms to which they are attached form a ring, and together with R ³ , —OR ⁴ and R ⁸ the following formula (IVc)

[In formula (IVc), R ³ , R ⁴ and R ⁸ are hydrogen, m ¹ is 0, m ² is 1 or 2, j is 1 or 2, L is , CR ⁷ R ⁸ , and R ⁷ and R ⁸ are both hydrogen],
R ⁴ is hydrogen, isopropyl or cyclopentyl, or
R ³ and —OR ⁴ together with the carbon atom to which they are attached form a ring, together with R ² the formula (IIIb):

a group represented by [in formula (IIIb), R ² is hydrogen and h is 2];
m is 1;
^L is ^CR7R8 ;
A compound wherein ^R7 and ^R8 are each independently hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

Methods for producing the compounds of the present invention are described below. The compounds of the present invention represented by formula (I) can be produced, for example, by the following Production Methods 1 to 5.

（式中、Ｒ^１ａ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２、Ｒ^３、Ｒ^４、Ｌおよびｍは項１に記載の定義と同じであり、Ｒ^ａＯ－は、Ｒ^１ｂにおける置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_６－１０アリールオキシまたは置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい５～１２員のヘテロアリールオキシを表し、Ｘ^１およびＸ^２は、各々独立して、ハロゲン、トリフルオロメタンスルホニルオキシ、メタンスルホニルオキシ等の脱離基を表す。） Manufacturing method 1:
Of the compounds represented by formula (I), the compound represented by formula (S-5) wherein R ^1b is OR ^a or a pharmaceutically acceptable salt thereof can be produced, for example, by the following process. can be done.

(Wherein, R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m are the same as defined in item 1, R ^a O— is the substituent group A in R ^1b C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from, substituted with 1 to 3 substituents independently selected from Substituent Group B C _{3-7 cycloalkoxy} optionally substituted with 1 to 3 substituents independently selected from Substituent Group B or independently selected from Substituent Group B X ¹ and X ² each independently represent a 5- to 12-membered heteroaryloxy optionally substituted with 1 to 3 substituents such as halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, etc. represents a leaving group.)

Step (1-1):
This step is a step of producing a nitroaniline compound represented by formula (s-2) by reacting a nitrobenzene compound represented by formula (s-1) with an amine compound. Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and cesium carbonate; Organic bases can be mentioned. Moreover, when using an amine compound excessively, it is not necessary to use a base. Solvents include ether solvents such as THF, dimethoxyethane and 1,4-dioxane, DMF, NMP, acetonitrile and the like. The reaction time is usually about 10 minutes to 10 hours, and the reaction temperature is from 0°C to the boiling point of the solvent.

Step (1-2):
This step is a step of producing a compound represented by formula (s-3) by reacting a nitroaniline compound represented by formula (s-2) with a compound having a hydroxyl group. The base used in this reaction includes sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, sodium hydride and the like. Solvents include ether solvents such as THF, 1,2-dimethoxyethane and 1,4-dioxane, DMF, NMP, acetonitrile and the like. The reaction time is usually about 10 minutes to 10 hours, and the reaction temperature is from 0°C to the boiling point of the solvent.

Step (1-3):
This step is a step of reducing the nitro compound represented by the formula (s-3) to produce the amino compound represented by the formula (s-4). The conditions for this reaction include commonly used conditions for reducing a nitro group, such as catalytic reduction under hydrogenation conditions with palladium-carbon, etc., metal reduction with zinc, iron, etc., hydride reduction with lithium aluminum hydride, etc. is mentioned. Examples of the solvent include solvents commonly used under the respective reduction conditions. In the case of catalytic reduction, methanol, ethanol, THF, ethyl acetate, etc., in the case of metal reduction, THF, acetic acid, methanol, ethanol, etc., and in the case of hydride reduction, diethyl ether, THF, and the like. The reaction time is usually about 10 minutes to 24 hours, and the reaction temperature is from 0°C to the boiling point of the solvent.

Step (1-4):
This step is a step of reacting a phenylenediamine compound represented by formula (s-4) with formic acid or a formic acid equivalent to cyclize the compound to produce a compound represented by formula (S-5). Formic acid equivalents include orthoformic acid esters such as methyl orthoformate and ethyl orthoformate. As a catalyst for this reaction, an organic acid such as formic acid or acetic acid, or a Lewis acid such as ytterbium triflate may be added. Examples of solvents include alcohol solvents such as methanol and ethanol. The formic acid, orthoformic acid ester, and the like used as the reactant can also be used as the solvent. The reaction time is usually about 10 minutes to 24 hours, and the reaction temperature is room temperature to the boiling point of the solvent.

The compounds represented by formula (I) in which one or more of R ^1a , R ^1b , R ^1c and R ^1d are OR ^a or pharmaceutically acceptable salts thereof are also described above. It can be manufactured by a similar method.

（式中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２、Ｒ^３、Ｌおよびｍは項１に記載の定義と同じであり、Ｘ^３は前記のＸ^１と同じであり、Ｒ^４ａはＲ^４の定義から水素を除いたものを表す。） Manufacturing method 2:
Among the compounds represented by formula (I), the compound (S-7) in which R ⁴ is R ^4a (alkyl or cycloalkyl) or a pharmaceutically acceptable salt thereof can be produced, for example, by the following method. be able to.

(wherein R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ³ , L and m are the same as defined in item 1, X ³ is the same as X ¹ above, R ^4a represents the definition of ^R4 minus hydrogen.)

Step (2-1):
In this step, an alcohol compound (s-6) in formula (s-5) in which R ⁴ is hydrogen is reacted with a compound represented by, for example, R ^4a X ³ in the presence of a base to obtain the formula (S-7). It is a process for producing the represented ether compound. Bases include sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium butoxide and the like. Examples of the solvent include ether solvents such as diethyl ether and THF, DMF, NMP, dimethylsulfoxide and the like. The reaction time is usually about 10 minutes to 24 hours, and the reaction temperature is from 0°C to the boiling point of the solvent.

（式中、Ｒ^１ａ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２、Ｒ^３、Ｒ^４、Ｌおよびｍは項１に記載の定義と同じであり、Ｘ^２は前記と同じであり、Ｒ^ｂはＣ_６－１０アリールまたは５～１２員のヘテロアリール（該アリールおよび該ヘテロアリールは、各々独立して、ハロゲン、シアノ、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキル、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルキル、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよいＣ_３－７シクロアルコキシ、置換基群Ｂから独立して選択される１～３個の置換基で置換されていてもよい３～７員の非芳香族複素環、置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキルチオおよび置換基群Ａから独立して選択される１～３個の置換基で置換されていてもよいＣ_１－４アルキルスルホニルからなる群から独立して選択される１～５個の置換基で置換されていてもよい）を表す。） Manufacturing method 3:
Among the compounds represented by formula (I), compounds represented by formula (S-10) in which R ^1b is R ^b (aryl or heteroaryl) or pharmaceutically acceptable salts thereof are represented by, for example, the following It can be manufactured by the manufacturing method of.

(wherein R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m are the same as defined in item 1, X ² is the same as above, R ^b is C _6-10 aryl or 5- to 12-membered heteroaryl (the aryl and the heteroaryl are each independently substituted with 1 to 3 substituents independently selected from halogen, cyano, and Substituent Group A C _1-4 alkyl optionally substituted, C _1-4 alkoxy optionally substituted by 1 to 3 substituents independently selected from substituent group A, independently from substituent group B C _3-7 cycloalkyl optionally substituted by 1 to 3 selected substituents, C optionally substituted by 1 to 3 substituents independently selected from Substituent Group B _3-7 cycloalkoxy, 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from substituent group B, independently from substituent group A C _1-4 alkylthio optionally substituted by 1 to 3 selected substituents and C ₁ optionally substituted by 1 to 3 substituents independently selected from Substituent Group A _-4 optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkylsulfonyl).)

Step (3-1):
This step is a step of selectively reducing the nitro group of the nitrobenzene compound represented by formula (s-2) to produce an amino compound represented by formula (s-8). Examples of conditions for this reaction include catalytic reduction under hydrogenation conditions using platinum carbon poisoned with sulfur, metal reduction using zinc, iron, tin and the like, and hydride reduction using lithium aluminum hydride and the like. Examples of the solvent include solvents commonly used under the respective reaction conditions. In the case of catalytic reduction, methanol, ethanol, THF, ethyl acetate, etc., in the case of metal reduction, THF, acetic acid, methanol, ethanol, etc., and in the case of hydride reduction, diethyl ether, THF, and the like. The reaction time is usually about 10 minutes to 24 hours, and the reaction temperature is from 0°C to the boiling point of the solvent.

Step (3-2):
This step is a step of treating an amino compound represented by formula (s-8) in the same manner as in step (1-4) to produce a compound represented by formula (s-9).

Step (3-3):
In this step, a compound represented by formula (s-9) is reacted with a boronic acid or boronic acid ester compound having an R ^b group in the presence of a base and a catalyst to obtain a compound represented by formula (S-10). It is a process of manufacturing. Specifically, it is a step using a Suzuki coupling reaction. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate and the like. Examples of the catalyst include palladium acetate, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and the like. Solvents include 1,4-dioxane, toluene, 1,2-dimethoxyethane and the like. The reaction time is about 30 minutes to 24 hours, and the reaction temperature is from room temperature to the boiling point of the solvent.

The compounds represented by formula (I) in which one or more of R ^1a , R ^1b , R ^1c and R ^1d are R ^b or pharmaceutically acceptable salts thereof are also described above. It can be manufactured by a similar method.

（式中、Ｒ^１ａ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２、Ｒ^３、Ｒ^４、Ｌおよびｍは項１に記載の定義と同じであり、Ｒ^ｂおよびＸ^２は前記と同じであり、Ｒ^１０およびＲ^１１は、各々独立して、置換されていてもよいＣ_１－４アルキル、置換されていてもよいＣ_１－４アルコキシ、置換されていてもよいＣ_１－４ジアルキルアミノ、置換されていてもよいＣ_６－１０アリール、置換されていてもよいＣ_６－１０アリールオキシ、置換されていてもよい５～１２員のヘテロアリール、置換されていてもよい５～１２員のヘテロアリールオキシ又は水酸基を表す。Ｒ^１０Ｒ^１１Ｂ－として好ましくは以下に示す構造が挙げられるが、それらによって限定されるものではない。）

Manufacturing method 4:
Among the compounds represented by formula (I), the compound represented by formula (S-10) wherein R ^1b is R ^b or a pharmaceutically acceptable salt thereof can also be produced, for example, by the following process. be able to.

(wherein R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m are the same as defined in item 1, R ^b and X ² are the same as above, R ¹⁰ and R ¹¹ are each independently optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally substituted C _1-4 dialkylamino, substituted optionally substituted C _6-10 aryl, optionally substituted C _6-10 aryloxy, optionally substituted 5-12 membered heteroaryl, optionally substituted 5-12 membered heteroaryl represents an oxy or hydroxyl group, and preferred examples of R ¹⁰ R ¹¹ B- include the structures shown below, but are not limited thereto.)

Step (4-1):
In this step, a compound represented by the formula (s-9) and a diboron such as bispinacol diboron are reacted in the presence of a catalyst and a base to give a boronic acid ester compound represented by the formula (s-11). It is a manufacturing process. Examples of the catalyst include dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium and the like. Examples of the base include potassium acetate, tripotassium phosphate, potassium carbonate and the like. Solvents include 1,4-dioxane, toluene, 1,2-dimethoxyethane and the like. The reaction time is about 1 hour to 48 hours, and the reaction temperature is room temperature to the boiling point of the solvent.

Step (4-2):
In this step, a boronic acid ester compound represented by formula (s-11) and a halide compound or triflate compound having an R ^b group (R ^b -X (X: halogen atom) or CF ₃ SO ₂ OR ^b , etc. ) in the presence of a catalyst and a base to produce a compound represented by formula (S-10). Specifically, it is a step using a Suzuki coupling reaction. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate and the like. Examples of the catalyst include palladium acetate, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and the like. Solvents include 1,4-dioxane, toluene, 1,2-dimethoxyethane and the like. The reaction time is about 30 minutes to 48 hours, and the reaction temperature is from room temperature to the boiling point of the solvent.

The compounds represented by formula (I) in which one or more of R ^1a , R ^1b , R ^1c and R ^1d are R ^b or pharmaceutically acceptable salts thereof are also described above. It can be manufactured by a similar method.

（式中、Ｒ^１ａ、Ｒ^１ｃ、Ｒ^１ｄ、Ｒ^２、Ｒ^３、Ｒ^４、Ｌおよびｍは項１に記載の定義と同じであり、Ｒ^ａ、Ｘ^１およびＸ^３は前記と同じである。Ｂｎはベンジル基を意味するが、ベンジル基と同様に脱保護反応可能な、例えばProtective Groups in Organic Synthesisに記載の置換されたベンジル基でもよい。） Manufacturing method 5:
Among the compounds represented by formula (I), the compound represented by formula (S-5) wherein R ^1b is OR ^a or a pharmaceutically acceptable salt thereof can also be produced, for example, by the following process. be able to.

(wherein R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m are the same as defined in item 1, and R ^a , X ¹ and X ³ are the same as above) Although Bn means a benzyl group, it may be a substituted benzyl group that can be deprotected like a benzyl group, for example, as described in Protective Groups in Organic Synthesis.)

Step (5-1):
This step is a step of reacting the compound represented by the formula (s-12) with, for example, Bn—X ³ in the presence of a base to produce the compound represented by the formula (s-13). Bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and the like. Bn-X ³ includes benzyl chloride, benzyl bromide and the like. Further, if necessary, sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium hydrogensulfate, etc. may be added. Solvents include acetone, acetonitrile, THF, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, DMF, NMP and the like. The reaction time is usually 30 minutes to 24 hours, and the reaction temperature is from 0°C to the boiling point of the solvent. In addition, the compound represented by formula (s-13) can be produced from the compound represented by formula (s-12) by the method (conditions) described in Protective Groups in Organic Synthesis and the like.

Step (5-2):
This step is a step of producing a compound represented by formula (s-14) using a compound represented by formula (s-13) in the same manner as in step (1-1).

Step (5-3):
In this step, a compound represented by formula (s-15) is converted to a compound represented by formula (s-14) in the same manner as in step (3-1) (the nitro group can be selectively reduced method).

Step (5-4):
This step is a step of producing a compound represented by formula (s-16) using a compound represented by formula (s-15) in the same manner as in step (1-4).

Step (5-5):
In this step, the compound represented by the formula (s-16) is catalytically reduced, for example, under hydrogenation conditions to deprotect the hydroxyl-protecting group to produce the compound represented by the formula (s-17). It is a process. A heterogeneous catalyst such as palladium-carbon is used as the catalyst. "Hydrogenation conditions" means under a hydrogen atmosphere or in the presence of formic acid, ammonium formate, or the like. Solvents include methanol, ethanol, THF, ethyl acetate and the like. The reaction time is 30 minutes to 24 hours, and the reaction temperature is from 0° C. to the boiling point of the solvent. In addition, the compound represented by formula (s-17) can be produced from the compound represented by formula (s-16) by the method (conditions) described in Protective Groups in Organic Synthesis and the like.

Step (5-6):
This step is a step of producing a compound represented by formula (S-5) from a compound represented by formula (s-17), and includes, but is not limited to, the following two reaction conditions.
1) As conditions for using a base, a compound represented by formula (S-5) is combined with a compound represented by formula (s-17) and R ^a -X ⁴ (R ^a is a substituent group A in R ^1b C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from, substituted with 1 to 3 substituents independently selected from Substituent Group B C _{3-7 cycloalkyl} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B or independently selected from Substituent Group B represents a 5- to 12-membered heteroaryl optionally substituted with 1 to 3 substituents, and X ⁴ is the same as X ¹ above. A process of manufacturing by a method can be mentioned.
2) Conditions for using a catalyst and a base include a step of reacting a boronic acid compound or a halogen compound having an R ^a group. The catalyst includes copper (II) acetate, copper (I) iodide, copper (II) oxide, and the like. Examples of the base include potassium carbonate, cesium carbonate, potassium hydroxide, triethylamine and the like. Solvents include chloroform, 1,4-dioxane, DMF, dimethylsulfoxide, NMP (N-methyl-2-pyrrolidinone) and the like. The reaction time is usually 30 minutes to 24 hours, and the reaction temperature is from room temperature to the boiling point of the solvent.

The compounds represented by formula (I) in which one or more of R ^1a , R ^1b , R ^1c and R ^1d are OR ^a or pharmaceutically acceptable salts thereof are also described above. It can be manufactured by a similar method.

Reduction of the above nitro group (step (1-3), step (3-1), step (5-3)) and subsequent cyclization reaction (step (1-4), step (3-2), step ( 5-4)) can be carried out continuously by adding formic acid or a formic acid equivalent such as orthoformate during the reduction reaction of (s-3) or (s-14), for example. is possible, and cyclized (S-5), (s-9), and (s-16) can be produced in one step. The reaction time in that case is 10 minutes to 12 hours, and the reaction temperature is from room temperature to the boiling point of the solvent.

The room temperature in the above manufacturing method specifically means 10°C to 30°C.

The starting materials and intermediates in the above production method are known compounds, or can be synthesized from known compounds by known methods. Also, in the above process, if any functional groups other than the reaction point are altered under the described reaction conditions or otherwise unsuitable for carrying out the described method, then protecting the non-reactive point, After reacting, the target compound can be obtained by deprotecting. As the protecting group, for example, a usual protecting group as described in the above-mentioned Protective Groups in Organic Synthesis or the like can be used. Specifically, examples of amine-protecting groups include ethoxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl, and examples of hydroxyl-protecting groups include tri-lower alkylsilyl, acetyl, and benzyl. can be done.

Introduction and removal of protecting groups can be carried out by methods commonly used in synthetic organic chemistry (see, for example, Protective Groups in Organic Synthesis above) or methods based thereon.

Further, intermediates or final products in the above production methods can be converted to other compounds included in the present invention by appropriately converting their functional groups. Transformation of the functional group can be carried out by a commonly used general method (see, for example, Comprehensive Organic Transformations, R. C. Larock (1989), etc.).

Intermediates and target compounds in each of the above production methods can be isolated and purified by purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. can. In addition, the intermediate can be used in the next reaction without particular purification.
In addition, optical isomers can be separated by carrying out known separation steps such as a method using an optically active column and a fractional crystallization method in an appropriate step of the above production method. Moreover, an optically active substance can also be used as a starting material.
The compounds of the present invention may have optical isomers, stereoisomers, tautomers such as ketoenol forms, and/or geometric isomers, but the compounds of the present invention may have all possible Includes isomers and mixtures thereof.

In addition to the above isomers, the compounds of the present invention include compounds represented by formula (I) or prodrugs thereof, or pharmaceutically acceptable salts thereof. In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included. Furthermore, the compounds of the present invention include all aspects of crystal forms and compounds in which some or all of the atoms constituting the compound are converted to isotopes (for example, compounds in which hydrogen is converted to deuterium, ¹² C to ¹⁴ compounds converted to C) are also included.

The term "prodrug of the compound of formula (I)" as used herein refers to a compound that is converted to the compound of formula (I) by reactions with enzymes, gastric acid, etc. under physiological conditions in vivo, i.e., enzymatically oxidized , reduction, hydrolysis, or the like to convert to the compound of formula (I), or a compound to convert to the compound of formula (I) by hydrolysis with stomach acid or the like.

"Pharmaceutically acceptable salts" include, for example, base addition salts or acid addition salts. Base addition salts include, for example, alkali metal salts such as potassium salts and sodium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, and water-soluble amine addition salts such as N-methylglucamine (meglumine). , or lower alkanolammonium salts of organic amines. Acid addition salts include, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acetate, lactate, citrate, tartrate, tartaric acid Hydrogen salt, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, paratoluenesulfonate, pamoate [1, 1′-methylene-bis-(2-hydroxy-3-naphthoate)] and the like.

A salt of the compound of the present invention can be obtained by the following method or the like. For example, when the compound of the present invention is obtained in the form of a salt, it can be purified as it is. In addition, when the compound of the present invention is obtained in a free form, it is dissolved or suspended in a suitable organic solvent, and an acid or base capable of forming the above salt is added to form a salt by a conventional method. All you have to do is

The compound of formula (I) obtained by the production method shown above is isolated and purified by conventional methods such as extraction, column chromatography, recrystallization and reprecipitation. Extraction solvents include, for example, diethyl ether, ethyl acetate, chloroform, dichloromethane, and toluene. Purification by column chromatography is performed using, for example, silica gel or alumina subjected to acid, basic or various chemical treatments. Examples of elution solvents include hexane/ethyl acetate, hexane/chloroform, ethyl acetate/methanol, chloroform/methanol, acetonitrile/water, and methanol/water.

The novel compound having a benzimidazole ring or a pharmaceutically acceptable salt thereof of the present invention has the property of inhibiting Nav1.7, and is effective in treating pain, numbness, and pain associated with peripheral nerves such as C fibers and Aδ fibers. Spontaneous pain such as burning sensation, dull pain, stinging pain, electric pain, neuropathic pain accompanied by hyperalgesia or allodynia to mechanical or cold stimuli, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia , paroxysmal pain, etc., as a therapeutic or prophylactic agent. The neuropathic pain referred to herein includes, for example, diabetic neuropathy, post-herpetic neuralgia, chemotherapy-induced neuropathy, cancer pain, human immunodeficiency syndrome virus-infected sensory neuropathy, trigeminal neuralgia, complex regional pain syndrome, Reflex sympathetic dystrophy, Lumbar postoperative neuralgia, Phantom limb pain, Spinal cord injury pain, Protracted postoperative pain, Inflammatory demyelinating polyradiculopathy, Alcoholic neuropathy, Peripheral strangulation neuropathy, primary neuropathy, idiopathic sensory neuropathy, neuropathy due to malnutrition, post-irradiation neuropathy, radiculopathy, toxic peripheral neuropathy, traumatic peripheral neuropathy, brachial plexus abduction injury, lingual neuralgia, Examples include autoimmune neuropathy, chronic cauda equina disorder, and the like. Nociceptive pain or inflammatory pain includes low back pain, abdominal pain, chronic rheumatoid arthritis, pain due to osteoarthritis, muscle pain, acute postoperative pain, fracture pain, burn pain and the like. The compound of the present invention or a pharmaceutically acceptable salt thereof can also be used as a therapeutic or preventive agent for dysuria. The dysuria referred to here includes frequent urination, bladder pain due to prostatic hyperplasia, and the like. Furthermore, it can be used as a therapeutic or preventive agent for ataxia that suppresses abnormal neurofiring in the cerebellum in multiple sclerosis. Furthermore, since the compound of the present invention or a pharmaceutically acceptable salt thereof has selective inhibitory activity against Nav1.7, it is a drug that does not exhibit side effects derived from the heart and central nervous system, which are problematic in existing drugs. It is thought that it can become

The administration route of the compound of the present invention may be oral administration, parenteral administration or rectal administration, and the daily dose varies depending on the type of compound, administration method, patient's symptoms, age and the like. For example, in the case of oral administration, usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of humans or mammals can be administered in one to several divided doses. For parenteral administration such as intravenous injection, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per 1 kg body weight of humans or mammals can be administered.

The compounds of the present invention can be administered orally or parenterally, either directly or formulated using an appropriate dosage form and administered. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices and the like. Formulations are manufactured by known methods using pharmaceutically acceptable additives. Additives include excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , fragrance, etc. can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, stearin. Magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc and the like.

The compounds of the present invention and their pharmaceutically acceptable salts are used for the purpose of enhancing their action, for example, non-steroidal anti-inflammatory drugs such as celecoxib, voltaren, ibuprofen, loxoprofen, acetaminophen, diclofenac, dexamethasone, etc. , tramadol, morphine, oxycodone, and other opioid analgesics. In addition, antiepileptic drugs such as pregabalin and carbamazepine, aldose reductase inhibitors such as epalrestat, prostaglandin derivative preparations such as limaprost alfadex, antidepressants such as amitriptyline and duloxetine, anticonvulsants, anxiolytics, and dopamine receptors. It can also be used in combination with agents such as body agonists, Parkinson's disease therapeutic agents, hormone preparations, migraine therapeutic agents, adrenergic β-receptor antagonists, dementia therapeutic agents, and mood disorder therapeutic agents. Preferred drugs used in combination with the compound of the present invention and pharmaceutically acceptable salts thereof include antiepileptic drugs such as pregabalin and carbamazepine, antidepressants such as amitriptyline and duloxetine, and narcotic drugs such as morphine, oxycodone and tramadol. Examples include analgesics, anti-inflammatory drugs such as acetaminophen, diclofenac and dexamethasone, aldose reductase inhibitors such as epalrestat, and prostaglandin derivatives such as limaprost alfadex. In addition, for the purpose of suppressing the side effects, it can be used in combination with drugs such as antiemetics and sleep inducers. The timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at appropriate intervals. A combination drug of the compound of the present invention and a concomitant drug may also be used. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the subject of administration, administration route, target disease, symptom, combination, and the like. For example, when the subject of administration is a human, 0.01 to 1000 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

EXAMPLES The present invention will be described in more detail with reference to examples and pharmacological test examples below, but the technical scope of the present invention is not limited to these examples. As silica gel chromatography in the examples, silica gel column chromatography or amino silica gel column chromatography manufactured by Yamazen Co., Ltd. was used. Identification of the compound was carried out using proton nuclear magnetic resonance absorption spectrum ( ¹ H-NMR), high performance liquid chromatography mass spectrometer; LCMS and the like. ¹ H-NMR was measured using JNM-LA300 (JEOL) or JNM-AL400 (JEOL).

Powder X-ray diffraction measurement was performed under the following conditions.
Apparatus: X'pert-MPD (manufactured by Spectris)
X-ray: Cu Kα1 _/ 45 kV/40 mA
Entrance slit: 15 mm (auto) / divergence prevention slit: 15 mm (auto)
Sample plate: Non-reflective Si plate Step size: 0.017°
Scan range: 4-40° (2θ)
Cumulative time: 100 seconds/step

High-performance liquid chromatography mass spectrometer; LCMS measurement conditions are as follows, and observed mass spectrometry values [MS (m/z)] are indicated by M+H.
MS detector: ACQITY SQD
HPLC: ACQITY UPLC
Column: ACQITY BEH C18 1.7 μm 2.1×50 mm
Flow rate: 0.75mL/min
Measurement wavelength: 254 nm
Moving layer: A solution; 0.05% formic acid aqueous solution B solution; acetonitrile Time program:
Step time (min)
1 0.0-1.3 A solution: B solution = 90:10 → 1:99
2 1.3-1.5 A solution: B solution = 1:99
3 1.5-2.0 A solution: B solution = 90:10

Unless otherwise specified, starting compounds, reaction reagents, and solvents were commercially available or prepared according to known methods.

In the examples and pharmacological test examples, the following abbreviations may be used to simplify the description of the present specification. Me: methyl, Ac: acetyl, Ph: phenyl, THF: tetrahydrofuran, DMF: N,N-dimethylformamide, NMP: N-methyl-2-pyrrolidinone, DMAP: N,N-dimethyl-4-aminopyridine, HEPES: 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, EGTA: O,O'-bis(2-aminoethyl)ethylene glycol-N,N,N',N'-tetraacetic acid, AD-mix-β:hydroquinidine-1,4-phthalazinediyl diether:potassium carbonate:potassium ferricyanide:potassium osmate dihydrate=2:624:624:1 molar ratio mixed reagent, Pd/ C: palladium-carbon, Pt-S/C: sulfur-poisoned platinum-carbon, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, td: triple doublet, tt: triple triplet, m: multiplet, br: broad.

Example 1: Preparation of 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 1)

Step (i): Preparation of 1-[(5-fluoro-2-nitrophenyl)amino]-2-methylpropan-2-ol (Compound 62) Compound 61 (1.59 g), 1-amino-2-methyl A mixture of propan-2-ol (0.98 g), diisopropylethylamine (5.22 mL) and DMF (50 mL) was stirred at 60° C. for 2 hours. Water and a mixture of ethyl acetate/hexane (=1/1) were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to produce a crude product of compound 62.

Step (ii): Preparation of 1-[(5-(4-fluorophenoxy)-2-nitrophenyl]amino)-2-methylpropan-2-ol (compound 63) Compound 62 obtained in step (i) A mixture of the crude product of , 4-fluorophenol (1.68 g), cesium carbonate (6.52 g) and NMP (25 mL) was stirred at 100° C. for 2 hours. Water and a mixture of ethyl acetate/hexane (=1/1) were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 3/1) to produce compound 63 (3.10 g).

Step (iii): Preparation of 1-{[2-amino-5-(4-fluorophenoxy)phenyl]amino)-2-methylpropan-2-ol (Compound 64) Compound 63 (3.10 g), ammonium formate (2.95 g), 10% Pd/C (0.30 g) and methanol (47 mL) was stirred at 50° C. for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to the residue, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=99/1) to produce compound 64 (2.70 g).

Step (iv): Preparation of 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 1) Compound 64 (0.60 g), Orthogly A mixture of trimethylate (1.73 mL) and p-toluenesulfonic acid monohydrate (0.079 g) was stirred at 60° C. for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 1 (0.41 g).
¹ H-NMR (DMSO-d6) δ: 1.06 (6H, s), 4.08 (2H, s), 4.72 (1H, s), 6.87 (1H, m), 6.96-6.99 (2H, m), 7.17 ( 2H, m), 7.39 (1H, m), 7.62 (1H, m), 8.09 (1H, s).
XRD; 2θ = 12.1, 13.6, 15.0, 15.2, 16.8, 18.5, 19.1, 19.6, 19.9, 20.1, 20.7, 21.8, 23.5, 24.0, 24.5, 25.2, 26.0, 26.7, 30.4, 34.8

実施例１における１－アミノ－２－メチルプロパン－２－オールの代わりに対応する出発原料（テトラヒドロフラン－２－イル）メタノール（０．６０７ｇ）を用いて化合物２（０．２６ｇ）を製造した。
¹H-NMR (DMSO-d6) δ: 1.49 (1H, m), 1.75 (2H, m), 1.94 (1H, m), 3.63 (2H, m), 4.07-4.34 (3H, m), 6.87-6.90 (1H, m), 6.97-7.02 (2H, m), 7.19 (2H, m), 7.35 (1H, m), 7.62 (1H, m), 8.14 (1H, s). Example 2: Preparation of 6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole (compound 2)

Compound 2 (0.26 g) was prepared by substituting the corresponding starting material (tetrahydrofuran-2-yl)methanol (0.607 g) for 1-amino-2-methylpropan-2-ol in Example 1.
¹ H-NMR (DMSO-d6) δ: 1.49 (1H, m), 1.75 (2H, m), 1.94 (1H, m), 3.63 (2H, m), 4.07-4.34 (3H, m), 6.87- 6.90 (1H, m), 6.97-7.02 (2H, m), 7.19 (2H, m), 7.35 (1H, m), 7.62 (1H, m), 8.14 (1H, s).

対応する出発原料を用いて、実施例１と同様の方法で得られた化合物６５（０．０５０ｇ）、水素化ナトリウム（０．０１１ｇ）およびＤＭＦ（１．０ｍＬ）の混合物を０℃で３０分間攪拌した。反応液に２－ブロモプロパン（０．０４５ｇ）を加え、室温でさらに２時間攪拌した。反応混合液に飽和塩化アンモニウム水溶液および酢酸エチルを加え目的物を有機層に抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝９９／１）で精製し、化合物３（９ｍｇ）を製造した。
¹H-NMR (DMSO-d6) δ: 0.94 (6H, d, J = 6.1 Hz), 3.44 (1H, m), 3.64 (2H, t, J = 5.0 Hz), 4.30 (2H, t, J = 5.0 Hz), 6.87-7.02 (3H, m), 7.18 (2H, m), 7.32 (1H, m), 7.62 (1H, m), 8.13 (1H, s). Example 3: Preparation of 6-(4-fluorophenoxy)-1-[2-(propan-2-yloxy)ethyl]-1H-benzimidazole (compound 3)

A mixture of compound 65 (0.050 g) obtained in the same manner as in Example 1 using the corresponding starting materials, sodium hydride (0.011 g) and DMF (1.0 mL) was heated at 0°C for 30 minutes. Stirred. 2-Bromopropane (0.045 g) was added to the reaction solution, and the mixture was stirred at room temperature for additional 2 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=99/1) to produce compound 3 (9 mg).
¹ H-NMR (DMSO-d6) δ: 0.94 (6H, d, J = 6.1 Hz), 3.44 (1H, m), 3.64 (2H, t, J = 5.0 Hz), 4.30 (2H, t, J = 5.0 Hz), 6.87-7.02 (3H, m), 7.18 (2H, m), 7.32 (1H, m), 7.62 (1H, m), 8.13 (1H, s).

実施例３における２－ブロモプロパンの代わりにブロモシクロペンタン（０．０４９ｇ）を用いて、化合物４（０．００７ｇ）を製造した。
LCMS:T=0.828, m/z=341 Example 4: Preparation of 1-[2-(Cyclopentyloxy)ethyl]-6-(4-fluorophenoxy)-1H-benzimidazole (Compound 4)

Substituting bromocyclopentane (0.049 g) for 2-bromopropane in Example 3, compound 4 (0.007 g) was prepared.
LCMS: T=0.828, m/z=341

Example 5: Preparation of 1-[6-(4-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (compound 5)

Step (i): Preparation of 1-[(5-bromo-2-nitrophenyl)amino]-2-methylpropan-2-ol (compound 67) 66 (1.1 g) was used to prepare compound 67 (1.20 g).

Step (ii): Preparation of 1-[(2-amino-5-bromophenyl)amino]-2-methylpropan-2-ol (compound 68) Compound 68 (0.811 g) was prepared using 67 (1.20 g) with 3% Pt--S/C (0.24 g) instead of 10% Pd/C as catalyst.

Step (iii): Preparation of 1-(6-bromo-1H-benzimidazol-1-yl)-2-methylpropan-2-ol (compound 69) Substituting for compound 64 in step (iv) of Example 1 Compound 68 (0.259 g) was prepared using acetic acid (0.060 g) instead of p-toluenesulfonic acid monohydrate to prepare compound 69 (0.210 g).

Step (iv): Preparation of 1-[6-(4-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 5) Compound 69 (0.050 g), 4 -fluorophenylboronic acid (0.052 g), tetrakis(triphenylphosphine)palladium (0.043 g) and 1,4-dioxane (1.0 mL) was stirred at 80° C. for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=99/1) to produce compound 5 (30 mg).
¹ H-NMR (DMSO-d6) δ: 1.11 (6H, s), 4.20 (2H, s), 4.79 (1H, s), 7.29 (2H, m), 7.45 (1H, m), 7.66-7.76 ( 3H, m), 7.94 (1H, s), 8.13 (1H, s).

Examples 6 to 10: Using the corresponding starting materials, the compounds of Examples 6 to 10 shown in the table below were prepared in the same manner as in Example 5.

Example 11: Preparation of 2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol (Compound 11)

Step (i): 2-methyl-1-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-1-yl]propane- Preparation of 2-ol (Compound 70) Compound 69 (0.10 g), bis(pinacolate)diboron (0.142 g), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (0.054 g), A mixture of potassium acetate (0.146 g) and 1,4-dioxane (2.0 mL) was stirred at 90° C. for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/1) to produce compound 70 (90 mg).

Step (ii): Preparation of 2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol (compound 11) 70 (90 mg), 2-bromo-5-trifluoromethylpyridine (0.126 g), 3 mol/L sodium carbonate aqueous solution (0.372 mL), tetrakis(triphenylphosphine) palladium (86 mg) and 1,4-dioxane ( 2 mL) of the mixture was stirred at 80° C. for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: mixed solvent of chloroform and methanol) to produce compound 11 (40 mg).
¹ H-NMR (DMSO-d6) δ: 1.13 (6H, s), 4.25 (2H, s), 4.83 (1H, s), 7.74 (1H, m), 8.04 (1H, m), 8.24 (3H, m), 8.49 (1H, s), 9.02 (1H, s).

Example 12: Preparation of 1-[2-(Cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole (Compound 12)

Step (i): Preparation of 2-[(5-bromo-2-nitrophenyl)amino]ethan-1-ol (Compound 71) 1-Amino-2-methylpropane-2 in step (i) of Example 5 Compound 71 (0.698 g) was prepared using 2-aminoethanol (0.458 g) instead of -ol.

Step (ii): Preparation of 2-[(2-amino-5-bromophenyl)amino]ethan-1-ol (Compound 72) Substituting compound 67 in step (ii) of Example 5 for compound 71 (0. 698 g) was used to prepare compound 72 (0.561 g).

Step (iii): Preparation of 2-(6-bromo-1H-benzimidazol-1-yl)ethan-1-ol (compound 73) Compound 72 (0 .231 g) was used to prepare compound 73 (0.19 g).

Step (iv): Preparation of 6-bromo-1-[2-(cyclopentyloxy)ethyl]-1H-benzimidazole (compound 74) Substituting compound 73 (0.19 g) for compound 65 in Example 3 Compound 74 (0.025 g) was prepared.

Step (v): 1-[2-(cyclopentyloxy)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (compound Preparation of 75) Compound 75 was prepared using compound 74 (0.015 g) instead of compound 69 in step (i) of Example 11. This was used in the next step without purification.

Step (vi): Preparation of 1-[2-(Cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole (Compound 12) Example 11 (ii) Compound 12 (0.018 g) was prepared by substituting compound 75 for compound 70 in ).
LCMS: T=0.974, m/z=376

Example 13: Preparation of 2-methyl-1-(6-phenoxy-1H-benzimidazol-1-yl)propan-2-ol (Compound 13)

Step (i): Preparation of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (compound 77) Potassium carbonate (27.1 g) was added to a solution of compound 76 (20.5 g) in DMF (326 mL) under a nitrogen atmosphere. was added at room temperature and stirred. The reaction mixture was heated to 97° C. and benzyl bromide (27.9 g) was added dropwise over 20 minutes and stirred for an additional hour. Ethyl acetate and water were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was washed twice with water and then concentrated under reduced pressure. Toluene (162 mL) was added to the resulting residue and concentrated under reduced pressure (this extraction procedure was repeated twice). The resulting residue was slurry-washed with ethyl acetate/hexane (=1/4) mixture to produce compound 77 (28.0 g).

Step (ii): Preparation of 1-{[5-(benzyloxy)-2-nitrophenyl]amino}-2-methylpropan-2-ol (Compound 78) Compound 77 (24.5 g) was purified under a nitrogen atmosphere. Diisopropylethylamine (32 g) was added to a solution of NMP (248 mL) at room temperature. The reaction solution was heated to 88° C., 1-amino-2-methylpropan-2-ol (11.48 g) was added dropwise over 12 minutes, and the mixture was further stirred for 1 hour. Ethyl acetate and water were added to the reaction solution, and the desired product was extracted into the organic layer. The aqueous layer was extracted with ethyl acetate, combined with the first obtained organic layer, and washed with water. The organic layer was concentrated under reduced pressure, and toluene (248 mL) was added to the resulting residue and concentrated under reduced pressure (this extraction operation was repeated twice). Water (248 mL) was added dropwise to the resulting residue, and the precipitated crystals were collected by filtration and dried to produce compound 78 (32.8 g).

Step (iii): Preparation of 1-[6-(benzyloxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (compound 79) Compound 78 (0.5 g) in methanol (7 .9 ml) solution, trimethyl orthoformate (4.37 mL), formic acid (0.6 mL) and zinc (0.52 g) were added, and the mixture was heated and stirred at 70° C. for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. An aqueous Rochelle salt solution (30 mL) and ethyl acetate (30 mL) were added to the residue, and the desired product was extracted into the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to produce compound 79 (0.45 g).

Step (iv): Preparation of 1-(2-Hydroxy-2-methylpropyl)-1H-benzimidazol-6-ol (Compound 80) Then, 10% palladium-carbon (50% water content, 0.1 g) was added, and the mixture was stirred for 4 hours under a hydrogen atmosphere. After the reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. Ethyl acetate/hexane was added to the resulting residue, and the slurry was washed at room temperature, and the crystals were collected by filtration and dried to produce compound 80 (0.32 g).

Step (v): Preparation of 2-methyl-1-(6-phenoxy-1H-benzimidazol-1-yl)propan-2-ol (compound 13) Compound 80 (0.10 g), phenylboronic acid (0. 118 g), copper acetate (0.132 g), triethylamine (0.198 mL) and chloroform (2.5 mL) was stirred at 35° C. for 2 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=98/2) to produce compound 13 (0.013 g).
¹ H-NMR (DMSO-d6) δ: 1.06 (6H, s), 4.08 (2H, s), 4.73 (1H, s), 6.87-6.94 (3H, m), 7.05 (1H, m), 7.33 ( 2H, m), 7.42 (1H, m), 7.62 (1H, m), 8.09 (1H, s).

Examples 14 to 27: The compounds of Examples 14 to 27 shown in the table below were prepared in the same manner as in Example 13 using the corresponding starting materials.

化合物８０（１．３４ｇ）、２－フルオロ－５－（トリフルオロメチル）ピリジン（１．４０ｇ）、炭酸セシウム（３．１８ｇ）およびアセトニトリル（２２ｍＬ）の反応混合物を６０℃で４時間攪拌した。反応混合物に水および酢酸エチルを加え目的物を有機層に抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホルム／メタノール＝９５／５）で精製し、化合物２８（１．７８ｇ）を製造した。
¹H-NMR (DMSO-d6) δ: 1.07 (6H, s), 4.11 (2H, s), 4.73 (1H, s), 7.00 (1H, m), 7.18 (1H, m), 7.56 (1H, m), 7.66 (1H, m), 8.13 (1H, s), 8.20 (1H, m), 8.54 (1H, m).
XRD ; 2θ = 9.1, 12.9, 13.7, 17.5, 18.0, 18.1, 20.5, 20.8, 21.2, 21.8, 22.3, 23.2, 23.8, 24.6, 24.9, 26.9, 27.3, 28.2, 30.2, 32.5 Example 28: of 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol (Compound 28) manufacturing

A reaction mixture of compound 80 (1.34 g), 2-fluoro-5-(trifluoromethyl)pyridine (1.40 g), cesium carbonate (3.18 g) and acetonitrile (22 mL) was stirred at 60° C. for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the desired product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 28 (1.78 g).
¹ H-NMR (DMSO-d6) δ: 1.07 (6H, s), 4.11 (2H, s), 4.73 (1H, s), 7.00 (1H, m), 7.18 (1H, m), 7.56 (1H, m), 7.66 (1H, m), 8.13 (1H, s), 8.20 (1H, m), 8.54 (1H, m).
XRD; 2θ = 9.1, 12.9, 13.7, 17.5, 18.0, 18.1, 20.5, 20.8, 21.2, 21.8, 22.3, 23.2, 23.8, 24.6, 24.9, 26.9, 27.3, 28.2, 30.2, 32.5

Examples 29-42:
Compounds of Examples 29 to 42 shown in the table below were prepared in the same manner as in Example 28 using the corresponding starting materials.

Example 43: of 2-methyl-1-(5-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol (Compound 43) manufacturing

Step (i): Preparation of 4-(benzyloxy)-1-chloro-2-nitrobenzene (compound 82) To a solution of compound 81 (5 g) in DMF (56 mL) under a nitrogen atmosphere was added potassium carbonate (5.97 g) and benzyl. Bromide (5.91 g) was added at room temperature and stirred for 3 hours. Ethyl acetate and water were added to the reaction mixture, the desired product was extracted into the organic layer, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to produce compound 82 (7.52 g).

Step (ii): Preparation of 1-{[4-(benzyloxy)-2-nitrophenyl]amino}-2-methylpropan-2-ol (Compound 83) Compound 82 (7.52 g) was purified under a nitrogen atmosphere. Diisopropylethylamine (5.53 g) and 1-amino-2-methylpropan-2-ol (3.05 g) were added to NMP (30 mL) solution at room temperature, stirred at 100°C for 1 hour, and further stirred at 150°C for 1 hour. Stirred. After allowing the reaction mixture to cool to room temperature, diisopropylethylamine (5.53 g) and potassium fluoride (1.99 g) were added at room temperature, and the mixture was stirred at 150° C. for 1 hour and at 200° C. for 40 hours. Ethyl acetate and water were added to the reaction mixture, the desired product was extracted into the organic layer, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 60/40) to produce compound 83 (5.3 g).

Step (iii): Preparation of 1-[5-(benzyloxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 84) Compound 83 (5.3 g) in methanol (85 ml) ) solution, trimethyl orthoformate (44.4 g), formic acid (7.71 g) and zinc (5.48 g) were added and stirred at room temperature for 2 hours. After the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 84 (2.68 g).

Step (iv): Preparation of 1-(2-Hydroxy-2-methylpropyl)-1H-benzimidazol-5-ol (Compound 85) Compound 84 (2.68 g) in methanol (45 mL) was treated with 10% palladium- Carbon (50% water content, 0.53 g) was added and stirred for 4 hours under a hydrogen atmosphere. After the reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the slurry was washed at room temperature. Crystals were collected by filtration and dried to produce compound 85 (1.58 g).

Step (v): 2-methyl-1-(5-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol (compound 43) Under nitrogen atmosphere, 2-fluoro-6-(trifluoromethyl)pyridine (0.048 g) and cesium carbonate (0.118 g) were added to a solution of compound 85 (0.05 g) in NMP (1 mL) at room temperature, Stirred at 100° C. for 3 hours. The reaction mixture was directly purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 43 (0.064 g).
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, s), 1.83 (1H, br s), 4.14 (2H, s), 6.98 (1H, d, J = 8.7 Hz), 7.13 (1H, dd, J = 8.7, 2.3 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.45 (1H, d, J = 8.7 Hz), 7.56 (1H, d, J = 1.8 Hz), 7.78 (1H, t, J = 8.0Hz), 8.07 (1H, s).

Examples 44-54:
Compounds of Examples 44 to 54 shown in the table below were prepared in the same manner as in Example 43 using the corresponding starting materials.

Examples 55-58:
The compounds of Examples 55 to 58 shown in the table below were prepared in the same manner as in Example 59 using the corresponding starting materials.

Example 59: of 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol (Compound 59) manufacturing

Step (i): of 2-methyl-4-[(2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]butan-2-ol (Compound 86) Preparation To a solution of compound 76 (0.35 g) in NMP (7.5 mL) was added diisopropylethylamine (1.01 g) at room temperature. 4-Amino-2-methylbutan-2-ol hydrochloride (0.37 g) was added and the reaction was heated to 110° C. and stirred for 3.5 hours. The reaction was cooled to room temperature, cesium carbonate (0.95 g) and 2-fluoro-5-(trifluoromethyl)pyridine (0.42 g) were added and the reaction was heated to 110° C. and stirred for 4 hours. The reaction solution was cooled to room temperature, ethyl acetate and water were added, and the desired product was extracted into the organic layer. The aqueous layer was extracted with ethyl acetate, combined with the first obtained organic layer, and washed with water. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 65/35) to produce compound 86 (0.6 g).

Step (ii): 2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol (compound 59) To a solution of compound 86 (0.6 g) in methanol (7.8 ml) was added trimethyl orthoformate (4.26 mL), formic acid (0.6 mL) and zinc (0.51 g), and the mixture was heated and stirred at 70°C for 2 hours. did. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (eluent: chloroform/methanol=93/7) to produce compound 59 (0.23 g).
¹ H-NMR (CDCl3) δ: 1.31 (6H, s), 2.01-2.05 (2H, m), 4.30-4.34 (2H, m), 7.02 (1H, d, J = 8.7 Hz), 7.06 (1H, dd, J = 8.7, 2.3 Hz), 7.23 (1H, d, J = 2.3 Hz), 7.82 (1H, d, J = 8.7 Hz), 7.89 (1H, dd, J = 8.7, 2.7 Hz), 8.04 ( 1H, s), 8.42-8.42 (1H, m).

Example 60: 2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-2- Preparation of all (compound 60)

Step (i): Preparation of 1-{6-[(5-formylpyridin-2-yl)oxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-yl acetate (Compound 87) Compound 6-Chloronicotinaldehyde (85 mg) and cesium carbonate (326 mg) were added to a DMF solution (1 mL) of 80 (0.103 g) and heated at 110° C. for 1 hour. The reaction mixture was filtered, DMAP (92 mg) and acetic anhydride (0.142 mL) were added to the filtrate, and the mixture was stirred at room temperature for 3 days. Water and ethyl acetate:hexane=2:1 (v/v) were added to the reaction mixture, and the desired product was extracted into the organic layer (this extraction procedure was repeated three times). After the organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 87 (130 mg).

Step (ii): 2-methyl-1-(6-{[5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl ) Preparation of Propan-2-yl Acetate (Compound 88) Compound 87 (0.13 g) and trimethyl(trifluoromethyl)silane (0.163 mL) were dissolved in DMF (3.7 mL) with potassium carbonate (0.025 g) and fluoride. Cesium chloride (0.056 g) was added and the mixture was stirred at room temperature for 2 hours. Additional trimethyl(trifluoromethyl)silane (0.075 mL) was added to the reaction mixture and stirred for an additional hour at room temperature. Water and ethyl acetate:hexane=2:1 (v/v) were added to the reaction mixture, and the desired product was extracted into the organic layer (this extraction procedure was repeated three times). After the organic layer was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 88 (0.106 g).

Step (iii): 2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-2 Preparation of -yl Acetate (Compound 89) A solution of compound 88 (0.1 g) and thiocarbonyldiimidazole (0.051 g) in dry THF (2 mL) was heated to reflux for 2 hours. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure. Ethyl acetate and water were added to the residue to extract the desired product in the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in dry toluene (2 mL) under a nitrogen atmosphere, azobisisobutyronitrile (0.008 g) and tri-n-butyltin hydride (0.137 g) were added and the mixture was stirred at 90° C. for 1 hour. Stirred. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 89 (0.076 mg).

Step (iv): 2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-2 - Preparation of All (Compound 60) Potassium carbonate (100 mg) was added to a solution of compound 89 (0.076 mg) in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 60 (0.055 g).
¹ H-NMR (CDCl ₃ ) 1.22 (6H, s), 3.21-3.29 (2H, m), 4.01 (2H, s), 6.84 (6H, s), 6.94-6.99 (1H, m), 7.21 (2H , s), 7.56 (1H, d, J = 8.2 Hz), 7.69 (1H, dd, J = 8.7, 2.3 Hz), 7.88 (1H, s), 7.98 (1H, s).

Examples 90-115:
Using the corresponding starting materials and in the same manner as in Example 1, the compounds of Examples 90 to 115 shown in the table below were produced.

Examples 116-121:
Compounds of Examples 116 to 121 shown in the table below were prepared in the same manner as in Example 59 using the corresponding starting materials.

Examples 122-174:
Compounds of Examples 122 to 174 shown in the table below were prepared in the same manner as in Example 5 using the corresponding starting materials.

Example 175: Preparation of 1-[5-(4-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 175)

Step (i): Preparation of 1-[(4-bromo-2-nitrophenyl)amino]-2-methylpropan-2-ol (Compound 175b) 175a (5.0 g) was used to prepare compound 175b (4.81 g).

Step (ii): Preparation of 1-(5-Bromo-1H-benzimidazol-1-yl)-2-methylpropan-2-ol (Compound 175c) Substituting Compound 86 in Step (ii) of Example 59 Compound 175b (4.80 g) was used to prepare compound 175c (3.52 g).

Step (iii): Preparation of 1-[5-(4-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 175) Compound 175c (50 mg) was used in place of compound 69 to prepare compound 175 (29 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, s), 4.19 (2H, s), 7.10-7.13 (2H, m), 7.49 (2H, m), 7.54-7.57 (2H, m), 7.92 (1H, s), 8.23 (1H, s).

Examples 176 to 223: The compounds of Examples 176 to 223 shown in the table below were prepared in the same manner as in Example 175 using the corresponding starting materials.

化合物８５（５０ｍｇ）を用いて、実施例１３の工程（ｖ）と同様の方法で、化合物２２４（１３ｍｇ）を製造した。
LCMS：T=0.743, m/z=369 Example 224: Preparation of 1-{5-[2-fluoro-4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol

Compound 224 (13 mg) was prepared in a similar manner to Example 13, step (v) using compound 85 (50 mg).
LCMS: T=0.743, m/z=369

Examples 225 and 226: The compounds of Examples 225 and 226 shown in the table below were prepared in the same manner as in Example 224 using the corresponding starting materials.

Example 227: (2R)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-1,2- Manufacture of diols

Step (i): N-(2-methylprop-2-en-1-yl)-2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}aniline (Compound 227a) Preparation Compound 227a (1.64 g) was prepared in a similar manner to Example 59, step (i) using the corresponding starting materials.
Step (ii): of 1-(2-methylprop-2-en-1-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazole (Compound 227b) Preparation Compound 227b (1.25 g) was prepared in a similar manner to Example 59, step (ii) using compound 227a.
Step (iii): (2R)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-1,2 - Preparation of diol (compound 198) Under a nitrogen atmosphere, water (1 ml), AD-mix-β (200 mg) and methanesulfonamide (14 mg) were added to a solution of compound 227b (50 mg) in tert-butanol (1 ml) to react. The mixture was stirred at room temperature for 5 hours. The reaction mixture was directly purified by amino silica gel column chromatography (eluent: chloroform/methanol=95/5) to produce compound 227 (26 mg).
LCMS: T=0.537, m/z=368

Example 228: (3R)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol manufacturing

Step (i): Preparation of tert-butyl [(2R)-3-hydroxy-3-methylbutan-2-yl]carbamate (Compound 228b) Diethyl Boc-D-alanine methyl ester (1.0 g) under nitrogen atmosphere A 3 mol/L methylmagnesium bromide-diethyl ether solution (5.90 ml) was added to the ether (25 ml) solution at 0° C., and the mixture was stirred at room temperature for 3 hours. After quenching with an ammonium chloride solution, the mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by concentration was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=70/30) to produce compound 228b (0.86 g).
Step (ii): Preparation of (3R)-3-amino-2-methylbutan-2-ol monohydrochloride (Compound 228c) To a solution of Compound 228b (0.86 g) in ethyl acetate (5 ml) under nitrogen atmosphere , 4 mol/L hydrochloric acid/ethyl acetate solution was added, and the mixture was stirred at room temperature for 2 hours. After toluene azeotroping, the resulting solid was slurry washed with ethyl acetate to produce compound 228c (0.54 g).
Step (iii): (3R)-2-methyl-3-[(2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]butan-2-ol ( Preparation of Compound 228d) Compound 228d (490 mg) was prepared in the same manner as in step (i) of Example 59 using compound 76 (200 mg) and compound 228c (213 mg).
Step (iv): (3R)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol Preparation of (Compound 228) Compound 228 (102 mg) was prepared in the same manner as in step (ii) of Example 59 using compound 228d (490 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, s), 1.33 (3H, s), 1.64 (3H, d, J = 7.3 Hz), 1.73 (1H, s), 4.27 (1H, q, J = 7.1 Hz), 7.00 (1H, d, J = 9.2 Hz), 7.03 (1H, dd, J = 8.9, 2.1 Hz), 7.25 (1H, d, J = 2.4 Hz), 7.78 (1H, d, J = 8.5 Hz), 7.88 (1H, dd, J = 8.5, 2.4 Hz), 8.11 (1H, s), 8.41 (1H, d, J = 2.4 Hz).
Example 229: Using the corresponding starting materials and in a similar manner to Example 228, the compounds of Example 229 shown in the table below were prepared.

Example 28: of 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol (Compound 28) A compound can also be manufactured by the following method.

Step (i): of 2-methyl-1-[(2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]propan-2-ol (compound 28a) Preparation To a solution of compound 76 (1.00 g) in NMP (16 mL) was added diisopropylethylamine (2.06 g) at room temperature. 1-Amino-2-methylpropan-2-ol (0.74 g) was added and the reaction was heated to 100° C. and stirred for 4 hours. The reaction was cooled to room temperature, cesium carbonate (3.11 g) and 2-fluoro-5-(trifluoromethyl)pyridine (1.37 g) were added, the reaction was heated to 100° C. and stirred for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate, hexane and water were added, and the desired product was extracted into the organic layer. The organic layer was washed with water and dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was slurry-washed (eluent: hexane/ethyl acetate=9/1) to produce compound 28a (1.53 g).

Step (ii): 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol (compound 28) To a solution of compound 28a (0.50 g) in methanol (6.7 ml) was added trimethyl orthoformate (3.7 mL), formic acid (0.52 mL) and zinc (0.44 g), and the mixture was heated and stirred at 70°C for 2 hours. did. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with an aqueous Rochelle salt solution and saturated brine, and dried over anhydrous sodium sulfate. The crude crystals obtained by concentration were purified by recrystallization using hexane/ethyl acetate (=1:5) to produce compound 28 (0.33 g).

Pharmacological test example Measurement of Na ion current using voltage-gated Na channel gene-expressing cells Nav1.7 current was measured by the auto patch clamp method using cells stably expressing human SCN9A.

Human SCN9A Stably Expressing Cells Tetracycline-inducible SCN9A stably expressing cells were obtained from ChanTest. Cells were subcultured in Ham's F-12 medium containing 10% fetal bovine serum, 100 units/mL Penicillin-Streptomycin, 0.01 mg/mL Blasticidin, and 0.4 mg/mL Zeocin. The day before measurement, 1 μg / mL tetracycline, 100 μmol / L sodium butyrate, 10% fetal bovine serum, 100 units / mL Penicillin-streptomycin containing Ham's F-12 medium exchanged, the next day Na ion current by auto patch clamp method was measured.

Electrophysiological measurement of Na ion current Na ion current was measured using the following extracellular and intracellular fluids by the auto patch clamp method.

Extracellular solution (mmol/L): NaCl 130, MgCl ₂ 2, CaCl ₂ 2, CdCl ₂ 0.1, NiCl ₂ 0.1, Tetraethylammonium-Cl 18, 4-aminopyridine 1, HEPES 10, (pH 7.0 with NaOH). 4)

Intracellular fluid (mmol/L): CsF 120, EGTA 10, NaCl 15, HEPES 10, (adjusted to pH 7.2 with CsOH)

Stimulation pulse control and data acquisition were performed using EPC10 and Patch Master software (HEKA). Data were sampled at 10 kHz and denoised with a 3 kHz low-pass filter. All measurements were made at room temperature. The holding potential was the 50% inactivation potential of the Nav1.7 channel (around -60 mV), and a single 20 ms depolarizing pulse (+10 mV) was applied. The inhibition rate of the test compound was calculated from the results of cells with a peak current of 500 pA or more when a depolarizing pulse was applied and in which the whole-cell parameters did not change significantly until the end of data acquisition. The inhibition rate of the test compound against the Na ion current was determined by the following formula based on the current peak value generated by the depolarizing pulse.
Na ion current inhibition rate (%) = 100 × [(current peak value in the absence of the evaluation compound) - (current peak value in the presence of the evaluation compound)] / (current peak value in the absence of the evaluation compound)

Test results:
As a result of evaluating the inhibitory action on the Na ion current for the compounds obtained in Examples, it was observed that the compounds of the present invention exhibited an inhibitory action on Nav1.7. The inhibition rate (%) at a compound concentration of 10 μmol/L is shown in the table below.

Test example (2)
Measurement of analgesic effect in streptozotocin-induced diabetic peripheral neuropathic pain model. Confirmed by evaluation.
Pathological animal models were prepared by partially modifying the method of Fox et al. (Pain 81, 307-316, 1999). A diabetic peripheral neuropathy model was prepared by intraperitoneally administering 45 mg/kg body weight of STZ to male 9-week-old Wistar rats.
The von Frey test was adopted as an evaluation method for analgesic action. That is, the reaction threshold (50 % paw withdrawal thresholds) were calculated.
From 21 days after STZ administration, it was confirmed by a preliminary study that the response threshold of the animal's hind paws was markedly lowered. was evaluated on any day between The reaction threshold was measured on the day before and the day before the test compound was evaluated, and the average value was taken as the reaction threshold before administration of the test compound.
The animals were divided into 4-5 groups so that the difference in the mean values of the response thresholds before administration of the test compound was small between the groups and so that the variability within the groups was small.
In the test compound evaluation test, the response threshold after administration of the test compound was measured. Test compounds were administered orally at 3 mg/kg body weight 1 hour before measurement of response thresholds. The analgesic potency of the test compound is expressed as the elongation width (g) of the response threshold by the formula (response threshold after test compound administration)-(response threshold before test compound administration).

以上の結果から、本発明化合物は、病態動物モデルである糖尿病性末梢神経障害ラットにおいて、経口投与で良好な鎮痛作用を示すことが確認された。 Test results:
As shown in the table below, the compounds of the present invention showed extension of the response threshold of 1.3 to 6.5 g. The number in [ ] represents the extension width of the solvent-administered group in each test.

From the above results, it was confirmed that the compound of the present invention exhibits a good analgesic effect by oral administration in diabetic peripheral neuropathy rats, which is a pathological animal model.

The compounds of the present invention are useful in Nav1.7-mediated diseases, specifically neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal exacerbation, and dysuria. , can be used as an excellent therapeutic agent for diseases such as multiple sclerosis. Therefore, the compounds of the present invention can be very useful medicaments.

Claims (17)

Formula (I) below:

[in the formula (I),
R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino (the alkyl, the alkoxy and the each alkyl moiety in alkylamino is independently halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, Substituent Group C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from B, substituted with 1 to 3 substituents independently selected from Substituent Group B from the group consisting of optionally substituted C _3-7 cycloalkoxy and a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 5 independently selected substituents), C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (the cycloalkyl, the cyclo alkoxy and cycloalkyl moieties in said cycloalkylamino are each independently optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and Substituent Group A C _1-4 alkyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 3 substituents independently selected from Substituent Group B from the group consisting of C _3-7 cycloalkyl optionally substituted with a group and C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1-5 independently selected substituents), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryl oxy (the aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy are each independently selected from halogen, cyano and substituent group A 1 to 3 C _1-4 alkyl optionally substituted by substituents of, C _1-4 alkoxy optionally substituted by 1 to 3 substituents independently selected from substituent group A, substituent group C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from B, substituted with 1 to 3 substituents independently selected from Substituent Group B hand optionally C _3-7 cycloalkoxy, 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, Substituent Group A C _1-4 alkylthio optionally substituted with 1 to 3 substituents independently selected from and substituted with 1 to 3 substituents independently selected from Substituent Group A optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl), provided that R ^1a , R ^1b , R ^1c or R ^1d at least one represents C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy as described above;
R ² and R ³ are each independently hydrogen, C _1-6 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and Substituent Group A C _1-4 alkoxy optionally substituted, C _3-7 cycloalkyl optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted by 1 to 3 substituents selected by or represents C _3-10 cycloalkyl,
R ⁴ is hydrogen, C _1-6 alkyl (the alkyl is halogen, hydroxyl group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A , C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, 1 to 3 substituents independently selected from Substituent Group B C _3-7 cycloalkoxy optionally substituted with a group and 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of), or C _3-7 cycloalkyl (the cycloalkyl is independently halogen, hydroxyl, substituent group A C _1-4 alkyl optionally substituted by 1 to 3 substituents selected from C, optionally substituted by 1 to 3 substituents independently selected from substituent group A _1-4 alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 1 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 3 substituents),
m represents 1, 2 or 3,
L represents CR ⁷ R ⁸ (when m represents 2 or 3, each CR ⁷ R ⁸ may be independently the same or different);
R ⁷ and R ⁸ are each independently hydrogen, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy (the alkyl portion of said alkyl and said alkoxy are each independently halogen, hydroxyl group, substituent group C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from A, substituted with 1 to 3 substituents independently selected from substituent group B optionally substituted C _3-7 cycloalkyl, C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and independently from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of 3- to 7-membered non-aromatic heterocyclic rings optionally substituted by 1 to 3 substituents good), C _3-7 cycloalkyl, or C _3-7 cycloalkoxy (the cycloalkyl moieties in the cycloalkyl and the cycloalkoxy are each independently selected from halogen, hydroxyl group and Substituent Group A C _1-4 alkyl optionally substituted by 1 to 3 substituents, C _1-4 optionally substituted by 1 to 3 substituents independently selected from Substituent Group A alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from Substituent Group B optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted C _3-7 cycloalkoxy), or
at R ² , R ³ and —OR ⁴ ,
R ² and R ³ together with the carbon atoms to which they are attached form a ring, and together with —OR ⁴ the following formula (II):

[in the formula (II),
e and f each independently represent 1, 2 or 3;
^R4 is as defined above;
V represents a single bond or an oxygen atom,
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen, halogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl moieties in said alkyl and said alkoxy are each independently , halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 1 independently selected from Substituent Group B C _{3-7 cycloalkyl optionally substituted by 3 substituents, C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from the group consisting of a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with a substituent of] may form a group represented by
at R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ at L,
R ² and R ⁷ together with the carbon atoms to which they are attached form a ring, together with R ³ , —OR ⁴ and R ⁸ , the following formula (IV):

[In the formula (IV),
m ¹ represents 0 or 1,
when m1 is ¹ , ^m2 represents 0 or 1, j represents 1, 2, 3 or 4;
when m1 is 0, ^m2 represents 0, ¹ or 2, j represents 1, 2, 3 or 4;
R ³ , R ⁴ , R ⁸ and L are as defined above;
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen, halogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moieties in the alkoxy are each independently , halogen, hydroxyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 1 independently selected from Substituent Group B C _{3-7 cycloalkyl optionally substituted by 3 substituents, C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and 1 to 3 independently selected from the group consisting of a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Substituent Group B optionally substituted with a substituent of] may form a group represented by
R ³ and —OR ⁴ together with the carbon atoms to which they are attached form a ring, together with R ² the following formula (III):

[in the formula (III),
h represents 1, 2, 3 or 4,
R ² is as defined above;
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen, hydroxyl, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moieties in the alkoxy are each independently halogen , a hydroxyl group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, 1 to 3 independently selected from Substituent Group B C _{3-7 cycloalkyl optionally substituted by substituents, C 3-7 cycloalkoxy} optionally substituted by 1 to 3 substituents independently selected from Substituent Group B and a substituent 1 to 3 substituents independently selected from the group consisting of a 3- to 7-membered non-aromatic heterocyclic ring optionally substituted with 1 to 3 substituents independently selected from Group B optionally substituted with)] (provided that R ² , R ³ and —OR ⁴ are not combined together to form a ring),
Substituent group A represents halogen, hydroxyl group, C _1-4 alkoxy, C _3-7 cycloalkyl and C _3-7 cycloalkoxy,
Substituent Group B represents halogen, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy, C _3-7 cycloalkyl and C _3-7 cycloalkoxy]
A compound represented by or a pharmaceutically acceptable salt thereof (provided that the following compounds:
6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-methoxyethyl)-1H-benzimidazole,
2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-yl]ethanol,
2-{5-[5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl]-1H-benzimidazol-1-yl}ethanol,
2-{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazole-1 - yl}ethanol,
2-{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,
2-butyl-6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,
6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)- on,
2-{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-1,2,4-triazol-1-yl}ethanol,
6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile,
2-chloro-6-{7-fluoro-1-[(1S,3S)-3-methoxycyclohexyl]-1H-benzimidazol-5-yl}-9-(tetrahydro-2H-pyran-2-yl)- 9H-purine, and 2-{5-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]-1H-benzimidazol-1-yl}ethanol,
or excluding its pharmaceutically acceptable salts) , wherein
A pharmaceutical composition for treating peripheral neuropathic pain by oral administration. R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy (the alkyl moieties in said alkyl and said alkoxy are each independently , optionally substituted with 1 to 3 identical or different halogens), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy ( The aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy each independently have 1 to 3 substituents independently selected from halogen, cyano and Substituent Group A C _1-4 alkyl optionally substituted with a group, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A and from Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl optionally substituted by 1 to 3 independently selected substituents ), the pharmaceutical composition of claim 1. R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy (The aryl portion in the aryl and the aryloxy and the heteroaryl portion in the heteroaryl and the heteroaryloxy each independently have 1 to 3 substituents independently selected from halogen and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl optionally substituted with thing. The pharmaceutical composition according to any one of claims 1 to 3, wherein R ^1a and R ^1d are hydrogen. R ² and R ³ are each independently hydrogen or C _1-6 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted) with the proviso that R ² and R ³ are not simultaneously hydrogen ,or,
R ² and R ³ together with the carbon atom to which they are attached form a ring, and together with —OR ⁴ the formula (IIa):

[In the formula (IIa),
e and f are each independently 1 or 2;
R ⁴ and V are as defined in claim 1;
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen], or
In R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ in L, R ² and R ⁷ together with the carbon atom to which they are attached form a ring, and R ³ , —OR ⁴ and R ⁸ together with the following formula (IVa);

[In the formula (IVa),
m1 is ⁰ ;
m ² is 1 or 2, j is 1, 2 or 3,
R ³ is as defined above;
R ⁴ , R ⁸ and L are as defined in claim 1;
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen or halogen]
The pharmaceutical composition according to any one of claims 1 to 4, which may form a group represented by R ² and R ³ are C _1-6 alkyl optionally substituted with 1 to 5 same or different halogens, or R ² and R ³ taken together with the carbon atom to which each is attached form a ring and together with —OR ⁴ formula (IIb):

[In the formula (IIb),
e and f are each independently 1 or 2;
R ⁴ and V are as defined in claim 1;
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen]
may form a group represented by
Alternatively, in R ² , R ³ , —OR ⁴ and CR ⁷ R ⁸ in L, R ² and R ⁷ together with the carbon atom to which they are attached form a ring, and R ³ , —OR ⁴ and R ⁸ together with the following formula (IVa);

[In the formula (IVa),
m1 is ⁰ ;
m ² is 1 or 2, j is 1, 2 or 3,
R ⁴ is hydrogen,
R ⁸ and L are as defined in claim 1;
R ^9a , R ^9b , R ^9c and R ^9d are each independently hydrogen or halogen]
The pharmaceutical composition according to any one of claims 1 to 5, which may form a group represented by R ² and R ³ are each independently hydrogen or C _1-6 alkyl optionally substituted with 1 to 5 same or different halogens, and R ² and R ³ are the carbon to which they are attached A pharmaceutical composition according to any one of claims 1 to 6, wherein the atoms together do not form a ring. R ⁴ is hydrogen, C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens, or C _3-7 cycloalkyl (wherein said cycloalkyl is independent of halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted by 1 to 3 substituents selected as Yes, or R ³ and —OR ⁴ together with the carbon atom to which they are attached form a ring and together with R ² form (IIIa):

[In the formula (IIIa),
h is 1, 2 or 3;
R ² has the same meaning as in claim 1,
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen or C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens]
The pharmaceutical composition according to any one of claims 1 to 4 and 7, which may form a group represented by R ⁴ is hydrogen, C _1-4 alkyl optionally substituted with 1 to 3 same or different halogens, or C _3-7 cycloalkyl (wherein said cycloalkyl is independent of halogen, hydroxyl group and Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted by 1 to 3 substituents selected as and wherein R ³ and —OR ⁴ together with the carbon atom to which they are attached do not form a ring. The pharmaceutical composition according to any one of claims 1-9, wherein R ⁴ is hydrogen. R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl (wherein said alkyl is substituted with 1 to 3 substituents independently selected from halogen, hydroxyl and Substituent Group A; _optionally substituted C _1-4 alkoxy, optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, independently selected from Substituent Group B C _3-7 cycloalkoxy optionally substituted by 1 to 3 substituents and optionally substituted by 1 to 3 substituents independently selected from Substituent Group B 3 to optionally substituted with 1 to 3 substituents independently selected from the group consisting of 7-membered non-aromatic heterocycles);
The pharmaceutical composition according to any one of claims 1-10, wherein m is 1 or 2. R ⁷ and R ⁸ are hydrogen,
The pharmaceutical composition according to any one of claims 1-11, wherein m is 1. R ^1b or R ^1c is C _6-10 aryl, C _6-10 aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy (the aryl moiety in said aryl and said aryloxy and said heteroaryl and the heteroaryl moieties in said heteroaryloxy are each independently halogen, cyano, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group A , C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Substituent Group A and 1 to 3 substituents independently selected from Substituent Group A optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl optionally substituted with The pharmaceutical composition according to the paragraph. R ^1b is C _6-10 aryl, C _6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy (the aryl portion of said aryl and said aryloxy and said heteroaryl and said Each heteroaryl moiety in heteroaryloxy is independently halogen, cyano, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, substituted C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Group A and substituted with 1 to 3 substituents independently selected from Substituent Group A (optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl), according to any one of claims 1 to 13 Pharmaceutical composition as described. R ^lc is C _6-10 aryl, C _6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy (the aryl portion of said aryl and said aryloxy and said heteroaryl and said Each heteroaryl moiety in heteroaryloxy is independently halogen, cyano, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, substituted C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from Group A and substituted with 1 to 3 substituents independently selected from Substituent Group A (optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl), according to any one of claims 1 to 13 Pharmaceutical composition as described. The pharmaceutical composition according to Claim 1, wherein the compound is a compound selected from the following group of compounds or a pharmaceutically acceptable salt thereof:
1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole,
1-(tetrahydrofuran-2-ylmethyl)-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,
2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,
1-[2-(cyclopentyloxy)ethyl]-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,
2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,
1-[2-(cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole,
2-methyl-1-[6-(4-methylphenoxy)-1H-benzimidazol-1-yl]propan-2-ol,
2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,
2-methyl-1-(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
2-methyl-1-(5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,
1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
3-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]oxetan-3-ol,
1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]cyclobutanol,
2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,
2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
3-({6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol,
3-{[6-(2-chloro-4-fluorophenoxy)-1H-benzimidazol-1-yl]methyl}oxetan-3-ol,
cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol,
1-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
1-[6-(4-chloro-2-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
4-{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylbutan-2-ol,
1-{5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
2-methyl-1-{5-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,
1-{5-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol, and (3S)-2-methyl-3-( 6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol. The pharmaceutical composition according to Claim 1, wherein the compound is a compound selected from the following group of compounds or a pharmaceutically acceptable salt thereof:
1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,
2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,
2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,
2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,
2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,
2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,
2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,
2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,
3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol,
cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol,
1-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,
3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,
3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol, and (3S)-2-methyl-3-( 6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.