JP2018154620A - Novel medicine composed of benzimidazole compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an agent for treating or preventing a disease associated with SCN9A(Nav1.7).SOLUTION: The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [R, R, R, R: H, halogen, cyano, Calkyl, Calkoxy or the like. R, R: H, Calkyl, Ccycloalkyl or the like. R: H, Calkyl, Ccycloalkyl or the like. m: 1, 2 or 3. L: CRR(R, R: H, OH, Calkyl, Calkoxy or the like)].SELECTED DRAWING: None

Description

  The present invention relates to a therapeutic or prophylactic agent for a disease involving Na channel, particularly SCN9A (Nav1.7), which contains a novel compound having a benzimidazole skeleton or a pharmaceutically acceptable salt thereof as an active ingredient. About. Specifically, therapeutic or prophylactic agents for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, limb erythema pain, paroxysmal pain, dysuria or multiple sclerosis About.

  It is known that there are currently nine types of α subunits that form pores of voltage-gated Na channels. In recent years, there is evidence that Nav1.7, among such subunits, is widely involved in information transmission of acute and chronic pain.

  SCN9A (Nav1.7) is a tetrodotoxin (TTX) -sensitive Na channel localized in peripheral sensory or sympathetic nerves and is also called NENA or PN1. Physiologically, the Nav1.7 channel functions to amplify pain signals (generate an activation potential) at sensory nerve endings, and from genetic studies, humans with loss-of-function mutations in the SCN9A gene have congenital analgesia It has become clear that In contrast, SCN9A gain-of-function mutations have been observed in patients with severe rare diseases such as limb erythema pain or paroxysmal pain. Furthermore, it has been reported that 30% of patients with small-diameter fiber neuropathy have a genetic polymorphism that enhances Nav1.7 function (Non-patent Document 1). In addition, since the expression level and activity are increased in DRG neurons of chronic pain model animals and neuropathic pain and inflammatory pain are attenuated in knockout experiments, Nav1.7 channel function is excessive in DRG neurons in pain pathology. It has been suggested to be directly involved in excitement (Non-Patent Document 2).

Patent Document 1 discloses a benzimidazole derivative represented by the following formula (A), and the compound is 2-((4-cyclopropylpyridin-2-yl) amino) isonicotinonitrile. Is an essential structure and is different from the compound 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.

International Publication No. 2012/057262

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

  The subject of the present invention is a disease involving Nav1.7, specifically neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, limb erythema pain, paroxysmal pain, dysuria or The object is to provide a therapeutic or prophylactic agent for diseases such as multiple sclerosis.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that a compound having a benzimidazole ring or a pharmaceutically acceptable salt thereof described below is mediated by Na channels in Nav1.7 gene-expressing cells. It was found to be a blocker having an inhibitory activity against Nav1.7, ie, inhibiting the membrane potential change or Na ion current itself. Furthermore, the derivative is also useful as a therapeutic or prophylactic agent for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, limb erythema pain or paroxysmal pain. The headline and the present invention were completed. According to the present invention, a benzimidazole compound represented by the following formula (I) (hereinafter also referred to as “compound represented by formula (I)” or “compound of formula (I)”) or a pharmaceutical thereof Salts that are pharmaceutically acceptable (hereinafter sometimes referred to as “compounds of the 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.
[Claim 1]
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, alkoxy and the The alkyl moieties in alkylamino are each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, and 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 An optionally substituted C _3-7 cycloalkoxy and a group consisting of 3 to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from Substituent Group B 1 to 5 independently selected May be substituted with a substituent), C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (said cycloalkyl, the cycloalkyl moiety in the cycloalkoxy and the cycloalkyl amino Each independently, halogen, hydroxyl, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from substituent group A, independently selected from substituent group A 1-3 substituents in the optionally substituted C _1-4 alkoxy being, optionally substituted with 1-3 substituents independently selected from substituent group B C _{3- 7} cycloalkyl and 1 to 3 substituents independently selected from substituent group B may be substituted with a substituent C _3-7 1 to 5 amino independently selected from the group consisting of cycloalkoxy Substituent And may _{be), C 6-10 aryl, C 6-10} aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy (wherein the aryl and the aryl moiety in the aryloxy and the heteroaryl And the heteroaryl moiety in the heteroaryloxy is each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and substituent group A , 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 in an optionally substituted C _3-7 cycloalkyl, 1-3 is substituted with a substituent which may C _3-7 also be Shikuroaruko independently selected from substituent group B 3 to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, 1 independently selected from Substituent Group A C _1-4 alkylthio optionally substituted with 3 substituents and C _1-4 alkylsulfonyl optionally 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: wherein at least one of R ^1a , R ^1b , R ^1c or R ^1d is C ₆ Represents _-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy;
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 which may be substituted, C _3-7 cycloalkyl which may be substituted with 1 to 3 substituents independently selected from substituent group B and independently of substituent group B Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents selected by Or C _3-10 cycloalkyl,
R ⁴ represents hydrogen, C _1-6 alkyl (wherein the alkyl is C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, and 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 _3- to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from C _3-7 cycloalkoxy optionally substituted with a group and 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 independent of halogen, hydroxyl, substituent group A) C _1-4 optionally substituted with 1 to 3 substituents selected 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 one to three optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from which may C _3-7 also be cycloalkyl and substituent group B substituted by a group Which may be substituted with 1 to 3 substituents independently selected),
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 independent and 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 and the alkyl moiety in the 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 C _3-7 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, and optionally substituted with C _3-7 cycloalkoxy and Substituent Group B May be substituted with 1 to 3 substituents selected and may be substituted with 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles _{good), C 3-7} cycloalkyl or _{C 3-7} sheet, Loalkoxy (the cycloalkyl and the cycloalkyl moiety in the cycloalkoxy may each independently be substituted with 1 to 3 substituents independently selected from halogen, hydroxyl, 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 independently selected from substituent group B 3 may be substituted with a substituent C _3-7 cycloalkyl and 1-3 may be substituted with a substituent C _3-7 cycloalkoxy independently selected from substituent group B Or may be substituted with 1 to 3 substituents independently selected from the group consisting of:
In R ² , R ³ and —OR ⁴ ,
R ² and R ³ together with the carbon atom to which each is bonded form a ring and together with —OR ^{4 have the} formula (II)

[In the formula (II),
e and f each independently represent 1, 2 or 3;
R ⁴ has the same meaning as 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 group, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and substituent group A, 1 to 1 independently selected from substituent group B 3 may be substituted with a substituent C _3-7 cycloalkyl, 1-3 optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from substituent group B And 1 to 3 independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles optionally substituted with 1 to 3 substituents independently selected from Substituent Group B Which may be substituted with a substituent of ] May form a group represented by or,
In CR ⁷ R ⁸ in R ² , R ³ , —OR ⁴ and L,
R ² and R ⁷ together with the carbon atom to which each is bonded form a ring and together with R ³ , —OR ⁴ and R ^{8 have the following} formula (IV):

[In the formula (IV),
m ¹ represents 0 or 1,
when m ¹ is 1, m ² represents 0 or 1, j represents 1, 2, 3 or 4;
when m ¹ is 0, m ² 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 group, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and substituent group A, 1 to 1 independently selected from substituent group B 3 may be substituted with a substituent C _3-7 cycloalkyl, 1-3 optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from substituent group B And 1 to 3 independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles optionally substituted with 1 to 3 substituents independently selected from Substituent Group B Which may be substituted with a substituent of ] May form a group represented by or,
R ³ and —OR ⁴ together with the carbon atom to which each is bonded form a ring and together with R ^{2 have the} formula (III)

[In the formula (III),
h represents 1, 2, 3 or 4;
R ² has the same meaning as above,
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen, hydroxyl group, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently halogen , 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 optionally substituted with a substituent C _3-7 cycloalkyl, optionally substituted with 1-3 substituents independently selected from substituent group B C _3-7 cycloalkoxy and substituents 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles optionally substituted with 1 to 3 substituents independently selected from Group B Which may be substituted with That group may be formed (but not be R ^2, R ³ and -OR ⁴ to form a ring together at the same time),
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 the formula (I) or a pharmaceutically acceptable salt thereof, except for a pharmaceutical composition containing the following compound or a pharmaceutically acceptable salt 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 is represented by 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, alkoxy and the The alkyl moieties in alkylamino are each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, and 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 An optionally substituted C _3-7 cycloalkoxy and a group consisting of 3 to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from Substituent Group B 1 to 5 independently selected May be substituted with a substituent), C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (said cycloalkyl, the cycloalkyl moiety in the cycloalkoxy and the cycloalkyl amino Each independently, halogen, hydroxyl, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from substituent group A, independently selected from substituent group A 1-3 substituents in the optionally substituted C _1-4 alkoxy being, optionally substituted with 1-3 substituents independently selected from substituent group B C _{3- 7} cycloalkyl and 1 to 3 substituents independently selected from substituent group B may be substituted with a substituent C _3-7 1 to 5 amino independently selected from the group consisting of cycloalkoxy Substituent And may _{be), C 6-10 aryl, C 6-10} aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy (wherein the aryl and the aryl moiety in the aryloxy and the heteroaryl And the heteroaryl moiety in the heteroaryloxy is each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and substituent group A , 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 in an optionally substituted C _3-7 cycloalkyl, 1-3 is substituted with a substituent which may C _3-7 also be Shikuroaruko independently selected from substituent group B 3 to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, 1 independently selected from Substituent Group A C _1-4 alkylthio optionally substituted with 3 substituents and C _1-4 alkylsulfonyl optionally 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: wherein at least one of R ^1a , R ^1b , R ^1c or R ^1d is C ₆ Represents _-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy;
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 which may be substituted, C _3-7 cycloalkyl which may be substituted with 1 to 3 substituents independently selected from substituent group B and independently of substituent group B Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents selected by Or C _3-10 cycloalkyl,
R ⁴ represents hydrogen, C _1-6 alkyl (wherein the alkyl is C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, and 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 _3- to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from C _3-7 cycloalkoxy optionally substituted with a group and 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 independent of halogen, hydroxyl, substituent group A) C _1-4 optionally substituted with 1 to 3 substituents selected 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 one to three optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from which may C _3-7 also be cycloalkyl and substituent group B substituted by a group Which may be substituted with 1 to 3 substituents independently selected),
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 independent and 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 and the alkyl moiety in the 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 C _3-7 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, and optionally substituted with C _3-7 cycloalkoxy and Substituent Group B May be substituted with 1 to 3 substituents selected and may be substituted with 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles _{good), C 3-7} cycloalkyl or _{C 3-7} sheet, Loalkoxy (the cycloalkyl and the cycloalkyl moiety in the cycloalkoxy may each independently be substituted with 1 to 3 substituents independently selected from halogen, hydroxyl, 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 independently selected from substituent group B 3 may be substituted with a substituent C _3-7 cycloalkyl and 1-3 may be substituted with a substituent C _3-7 cycloalkoxy independently selected from substituent group B Or may be substituted with 1 to 3 substituents independently selected from the group consisting of:
In R ² , R ³ and —OR ⁴ ,
R ² and R ³ together with the carbon atom to which each is bonded form a ring and together with —OR ^{4 have the} formula (II)

[In the formula (II),
e and f each independently represent 1, 2 or 3;
R ⁴ has the same meaning as 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 group, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and substituent group A, 1 to 1 independently selected from substituent group B 3 may be substituted with a substituent C _3-7 cycloalkyl, 1-3 optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from substituent group B And 1 to 3 independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles optionally substituted with 1 to 3 substituents independently selected from Substituent Group B Which may be substituted with a substituent of ] May form a group represented by or,
R ³ and —OR ⁴ together with the carbon atom to which each is bonded form a ring and together with R ^{2 have the} formula (III)

[In the formula (III),
h represents 1, 2, 3 or 4;
R ² has the same meaning as above,
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen, hydroxyl group, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently halogen , 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 optionally substituted with a substituent C _3-7 cycloalkyl, optionally substituted with 1-3 substituents independently selected from substituent group B C _3-7 cycloalkoxy and substituents 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles optionally substituted with 1 to 3 substituents independently selected from Group B Which may be substituted with That group may be formed (but not be R ^2, R ³ and -OR ⁴ to form a ring together at the same time),
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 of claim | item 1 represented by these.

[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 and the alkyl moiety in the 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 moiety in the aryl and the aryloxy and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently 1 to 3 substituents independently selected from halogen, cyano, substituent group A good C _1-4 alkyl optionally substituted with groups, 1 to 3 substituents independently selected from substituent group a Independently from the group consisting of one to three optionally C _1-4 alkylsulfonyl optionally substituted with a substituent selected independently from an optionally substituted C _1-4 alkoxy and substituent group A also Item 3. The pharmaceutical composition according to Item 1 or 2, which may be substituted with 1 to 3 selected substituents.

[Claim 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 moiety in the aryl and the aryloxy and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently 1 to 3 substituents independently selected from halogen and substituent group A; Or optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl optionally substituted with The pharmaceutical composition as described.

[Section 5]
Item 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。 [Claim 6]
R ² and R ³ are each independently hydrogen or C _1-6 alkyl (wherein 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 which may be substituted), provided that R ² and R ³ are not simultaneously hydrogen Or
R ² and R ³ together with the carbon atom to which each is attached form a ring, together with —OR ⁴ for 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 a group represented by:
In CR ⁷ R ⁸ in R ² , R ³ , —OR ⁴ and L, R ² and R ⁷ together with the carbon atoms to which they are bonded form a ring, and R ³ , —OR ⁴ and R ⁸ Together with the following formula (IVa):

[In the formula (IVa),
m ¹ is 0,
m ² is 1 or 2, j is 1, 2 or 3,
R ³ has the same meaning as 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]
Claim | item 1 and the pharmaceutical composition as described in any one of claim | item 3-5 which may form group represented by these.

［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。 [Claim 7]
R ² and R ³ are C _1-6 alkyl _optionally substituted with 1-5 identical or different halogens, or R ² and R ³ are taken together with the carbon atom to which each is attached. To form a ring and together with —OR ⁴ for 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 CR ⁷ R ⁸ in R ² , R ³ , —OR ⁴ and L, R ² and R ⁷ together with the carbon atoms to which they are attached form a ring, and R ³ , —OR ⁴ and Together with R ^{8 the following} formula (IVa);

[In the formula (IVa),
m ¹ 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]
Item 7. A 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。 [Section 8]
R ² and R ³ are each independently hydrogen or C _1-6 alkyl (wherein the alkyl is substituted with 1 to 3 substituents independently selected from cyano, halogen, hydroxyl group and substituent group A) Or optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _1-4 alkoxy, which may be substituted, or R ² and R ³ are each bonded Together with the carbon atom to form a ring, together with -OR ^{4 of} 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]
Item 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。 [Claim 9]
R ² and R ³ are each independently hydrogen or C _1-6 alkyl optionally substituted with 1 to 5 identical or different halogens, or R ² and R ³ are each bonded Together with the carbon atom to form a ring, together with -OR ^{4 of} 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]
Item 7. The pharmaceutical composition according to any one of Items 1 to 6, which may form a group represented by:

[Section 10]
R ² and R ³ are each independently hydrogen or C _1-6 alkyl optionally substituted with 1 to 5 identical or different halogens, and R ² and R ³ are each a carbon to which they are bonded. Item 10. The pharmaceutical composition according to any one of Items 1 to 9, which does not form a ring with the atom.

［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。 [Section 11]
R ⁴ is hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl optionally substituted with 1 to 3 identical or different halogens (the cycloalkyl is independent of halogen, hydroxyl and substituent group A) Optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted with 1 to 3 substituents. Or R ³ and —OR ⁴ together with the carbon atoms to which they are attached form a ring, together with R ^{2 of} formula (IIIa):

[In the formula (IIIa),
h is 1, 2 or 3;
R ² has the same meaning as 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 identical or different halogens]
Item 11. The pharmaceutical composition according to any one of Items 1 to 5 and Item 10, which may form a group represented by:

[Claim 12]
R ⁴ is hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl optionally substituted with 1 to 3 identical or different halogens (the cycloalkyl is independent of halogen, hydroxyl and substituent group A) Optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted with 1 to 3 substituents. The pharmaceutical composition according to any one of Items 1 to 11, wherein R ³ and —OR ⁴ do not form a ring with the carbon atom to which each is bonded.

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

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

[Section 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.

[Section 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 and the aryl moiety in the aryloxy and the heteroaryl And the heteroaryl moiety in the heteroaryloxy is each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and 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 And optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl which may be substituted with The pharmaceutical composition as described in any one of -15.

[Section 17]
R ^1b is C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy (the aryl and the aryl moiety in the aryloxy and the heteroaryl and the Heteroaryl moieties in heteroaryloxy are each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and substituent group A 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 also may) be substituted with 1 to 3 substituents are also independently selected from the group consisting of optionally C _1-4 alkylsulfonyl optionally be, claim 1-16 Neu The pharmaceutical composition according to one or Re.

[Section 18]
R ^1c is C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy (the aryl and the aryl moiety in the aryloxy and the heteroaryl and the Heteroaryl moieties in heteroaryloxy are each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and substituent group A 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 also may) be substituted with 1 to 3 substituents are also independently selected from the group consisting of optionally C _1-4 alkylsulfonyl optionally be, claim 1-16 Neu The pharmaceutical composition according to one or Re.

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

[Claim 21]
Item 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 identical 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。 [Item 22]
R ² and R ³ together with the carbon atom to which they are attached form a ring, together with —OR ⁴ for 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 CR ⁷ R ⁸ in R ² , R ³ , —OR ⁴ and L, R ² and R ⁷ together with the carbon atoms to which they are attached form a ring, and R ³ , —OR ⁴ and Together with R ^{8 the following} formula (IVa);

[In the formula (IVa),
m ¹ 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 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 compound group 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) propan-2- All,
Example 93: 3-({6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} methyl) oxetane-3-ol,
Example 94: 3-({6- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl} methyl) oxetane-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} oxetane-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) oxetane-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) oxetane-3-ol, and Example 229: (3S) -2-Methyl-3- (6-{[5- (trifluoromethyl) pyridin-2-yl] oxy} -1H-benzimidazol-1-yl) butan-2-ol.

[Claim 24]
Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound is a compound selected from the following compound group 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.

[Claim 25]
Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound is a compound selected from the following compound group 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) propan-2- All,
Example 94: 3-({6- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl} methyl) oxetane-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) oxetane-3-ol,
Example 205: 3-({5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} methyl) oxetane-3-ol, and Example 229: (3S) -2-Methyl-3- (6-{[5- (trifluoromethyl) pyridin-2-yl] oxy} -1H-benzimidazol-1-yl) butan-2-ol.

[Claim 26]
Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound is a compound selected from the following compound group 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 a disease involving Nav1.7 (SCN9A), comprising the pharmaceutical composition according to any one of items 1 to 26.
[Claim 28]
26. 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 a compound selected from 2- {5- [2- (tetrahydrofuran-3-yl) -1H-imidazol-1-yl] -1H-benzimidazol-1-yl} ethanol or a pharmaceutical thereof Acceptable salt.
[Item 29]
Item 39. A therapeutic agent for a disease involving Nav1.7 (SCN9A), comprising the compound according to Item 28 or a pharmaceutically acceptable salt thereof as an active ingredient.

  Item 28 has the same meaning as any one of Items 1 to 26 in the range of compounds in which 11 compounds excluded in the proviso at the end of item 1 to be cited are not excluded.

[Section 30]
Item 25. A neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, limb erythema pain, paroxysmal pain, dysuria, comprising the pharmaceutical composition according to any one of Items 1 to 26. Or a treatment for multiple sclerosis.
[Claim 31]
Item 28. A neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, limb erythema pain, paroxysmal pain, comprising the compound according to Item 28 or a pharmaceutically acceptable salt thereof as an active ingredient For the treatment of infectious diseases, dysuria or multiple sclerosis.

[Section 32]
Item 27. 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 medicine formed by combining more than one kind of medicine.
[Section 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 pharmaceutical comprising a combination of one or more drugs.

[Section 34]
Item 1-26 for producing a therapeutic agent for neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, limb aches pain, paroxysmal pain, dysuria or multiple sclerosis Use of the pharmaceutical composition according to any one of the above.
[Claim 35]
Item 28. A method for producing a therapeutic agent for neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, limb aches pain, paroxysmal pain, dysuria, or multiple sclerosis. Use of a compound or a pharmaceutically acceptable salt thereof.

[Claim 36]
Item 27. A neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy in a mammal, comprising administering an effective amount of the pharmaceutical composition according to any one of Items 1 to 26 to the mammal. A method for treating limb aches, paroxysmal pain, dysuria or multiple sclerosis.
[Section 37]
Item 28. A neuropathic pain, nociceptive pain, inflammatory pain, small-diameter fiber neuropathy in a mammal, comprising administering an effective amount of the compound of Item 28 or a pharmaceutically acceptable salt thereof to the mammal. , Treatment for lumbago, paroxysmal pain, dysuria or multiple sclerosis.

  According to the present invention, a blocker of Nav1.7 comprising a novel benzimidazole compound or a pharmaceutically acceptable salt thereof is provided. The compound of the present invention is useful as a therapeutic or prophylactic agent for diseases involving Nav1.7 (SCN9A), specifically, neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, It can be applied to patients with limb redness, paroxysmal pain, etc.

The present invention is described in further detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-6 ”, for example. Specifically, the notation “C _1-6 alkyl” is synonymous with alkyl having 1 to 6 carbons. In the present specification, a substituent that does not clearly indicate the term “optionally substituted” or “substituted” means an “unsubstituted” substituent. 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 where “optionally substituted” is defined, the number of substituents when a substituent is present is not particularly limited as long as substitution is possible, and is one or more. That is, it may be substituted by a substitutable carbon atom in the corresponding group, or a substitutable number of substituents on the carbon atom and nitrogen atom. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

  The bonding position of the substituent is a chemically possible position unless otherwise specified in the present specification.

  Examples of “halogen” include fluorine, chlorine, bromine or iodine. Preferred is fluorine or chlorine.

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

“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. Specific examples of “C _3-10 cycloalkyl” include cyclooctyl, adamantyl and the like in addition to the above, preferably “C _3-7 cycloalkyl”.

Wherein the _{"C 3-7} cycloalkyl" and _{"C 3-10} cycloalkyl", respectively, as _{"C 3-7} cycloalkyl" and _{"C 3-10} cycloalkyl", a benzene ring or a 5- or 6-membered A ring containing one or more heteroatoms selected from nitrogen, sulfur or oxygen, or the same or different (for example, 2 to 4) (for example, “5- or 6-membered monocyclic heterocycle described below”) A bicyclic group condensed with “aryl” and “5- or 6-membered ring among“ 3 to 7-membered non-aromatic heterocycle ”described below is also included. 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. Preferred is phenyl. Specific examples of “C _6-10 aryl” include phenyl, 1-naphthyl, 2-naphthyl and the like.

The above “C _6-10 aryl” contains 5 or 6 containing “phenyl” and one or more of the same or different heteroatoms selected from nitrogen, sulfur or oxygen (for example, 2 to 4). A member ring (for example, a “5- or 6-membered monocyclic heteroaryl” described below, a 5- or 6-membered ring of “3 to 7-membered non-aromatic heterocycle” described below), or Also included are groups fused to 5-7 membered cycloalkyl rings (eg, cyclopentane, cyclohexane or cycloheptane). Specific examples of the group include groups represented by the following formulas.

  The term “5- to 12-membered heteroaryl” refers to one heteroatom selected from nitrogen, sulfur or oxygen in addition to carbon as a ring-constituting atom, or two or more (for example, 2-4) Means a monocyclic or polycyclic 5- to 12-membered aromatic group contained therein, preferably "5- or 6-membered monocyclic heteroaryl". The “5- or 6-membered monocyclic heteroaryl” means a monocyclic 5- or 6-membered aromatic group in the “5- to 12-membered heteroaryl”.

Specific examples of the polycyclic heteroaryl in the “5- to 12-membered heteroaryl” include those in which two monocyclic heteroaryls that are the same or different are condensed, or monocyclic heteroaryl and an aromatic ring (for example, Benzene etc.) or a non-aromatic ring (for example, cyclohexane etc.) condensed.
Specific examples of “5- to 12-membered heteroaryl” include groups represented by the following formulae. Preferred “5- to 12-membered heteroaryl” include pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl. In another embodiment, benzofuranyl (the bonding position is on the heteroaryl (furan) ring), pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl is preferable. A specific example of “5- or 6-membered monocyclic heteroaryl” is a monocyclic group among the groups represented by the following formulae.

  The “3- to 7-membered non-aromatic heterocycle” means one or more heteroatoms selected from nitrogen, oxygen and sulfur, or the same or different, in addition to carbon as atoms constituting the ring ( For example, it means a 3- to 7-membered cyclic group having 2 to 4, preferably 2 to 3. The heterocycle is non-aromatic and may be either saturated or partially unsaturated. A saturated heterocyclic ring is preferable, and a 5- or 6-membered saturated heterocyclic ring is more preferable. Specific examples of “3- to 7-membered non-aromatic heterocycle” include oxetanyl, azetidinyl, pyranyl, tetrahydrofuryl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl , Oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, etc. . Pyranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl and morpholinyl are preferred.

  The “3- to 7-membered non-aromatic heterocyclic ring” is a ring formed by condensing the 3- to 7-membered non-aromatic heterocyclic ring with benzene or a 6-membered heteroaryl (for example, pyridine, pyrimidine, pyridazine, etc.). Including 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” is substituted with the above “C _1-4 alkyl”. Means an oxy group. Specific examples of “C _1-2 alkoxy” include methoxy and ethoxy. Specific examples of “C _1-4 alkoxy” include, in addition to the above, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, Examples thereof include tert-butoxy. “C _1-4 alkoxy” is preferably methoxy, ethoxy or 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 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, for example, phenyloxy, naphthyloxy and the like, preferably phenyloxy.

  The “5- to 12-membered heteroaryloxy” means an oxy group substituted with the “5- to 12-membered heteroaryl”. Specific examples of “5- to 12-membered heteroaryloxy” include, for example, pyridyloxy, imidazolyloxy, furyloxy and the like, preferably pyridyloxy.

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

“C _3-7 cycloalkylamino” means an amino group substituted with 1 or 2 of the above “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 above “C _1-4 alkyl”. Specific examples of “C _1-4 alkylsulfonyl” include, for example, 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, for example, 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), the various symbols used in the formula (I) will be described in more detail with suitable 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, alkoxy And the alkyl moiety in the alkylamino is each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, and substituent group A C _3-7 cycloalkyl which may be substituted with 1 to 3 substituents independently selected from group B, and 1 to 3 substituents independently selected from substituent group B It consists of a C _3-7 cycloalkoxy which may be substituted and a _3- to 7-membered non-aromatic heterocyclic ring which may be substituted with 1 to 3 substituents independently selected from Substituent Group B Select independent of group Are optionally substituted with 1-3 _{substituents), C 3-7 cycloalkyl, C 3-7 cycloalkoxy, C 3-7} cycloalkylamino (said cycloalkyl, said cycloalkoxy and said cycloalkyl The cycloalkyl moiety in amino is independently C _1-4 alkyl which may be substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and substituent group A, 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 is independently selected from 1-3 of the group consisting of which may C _3-7 also be cycloalkoxy substituted with a substituent is also selected optionally C _3-7 independently cycloalkyl, and substituent group B, 1-3 May be substituted with a _{substituent), C 6-10 aryl, C 6-10} aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy, in (the aryl and the aryloxy The aryl moiety and the heteroaryl moiety in the heteroaryl and heteroaryloxy may be each independently substituted with 1 to 3 substituents independently selected from halogen, cyano, and substituent group A. Good C _1-4 alkyl, C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from substituent group A, 1 independently selected from substituent group B to three may be substituted with a substituent C _3-7 cycloalkyl, optionally substituted with 1-3 substituents independently selected from substituent group B C _{3 7} cycloalkoxy, non-aromatic heterocyclic ring having 1 to 3 substituents may 3-7 membered optionally substituted with groups independently selected from substituent group B, are independently selected from substituent group A that 1-3 substituents may be substituted with 1-3 substituents independently selected from which it may also be C _1-4 alkylthio and substituent group a substituted by a group C _1-4 And may be substituted with 1 to 3 substituents independently selected from the group consisting of alkylsulfonyl). 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. is there.

More preferable R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy (wherein the alkyl and the alkyl moiety in 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 moiety in the aryl and aryloxy and the heteroaryl moiety in the heteroaryl and heteroaryloxy are each independently 1 to 3 substituents independently selected from halogen, cyano, substituent group A is optionally C _1-4 alkyl substituted with a group, it is independently selected from substituent group A. 1 to Consists 1-3 may be substituted with a substituent C _1-4 alkylsulfonyl independently selected from which may C _1-4 alkoxy optionally and Substituent group A substituted by substituents, Optionally substituted with 1 to 3 substituents independently selected from the 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. is there.

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 moiety in the aryl and aryloxy and the heteroaryl moiety in the heteroaryl and heteroaryloxy are each independently halogen and optionally substituted C _1-4. And may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl). However, R ^1b and R ^1c are not simultaneously hydrogen.

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 (wherein the aryl moiety in the aryloxy and the heteroaryl moiety in the heteroaryloxy are each independently from the group consisting of halogen and optionally substituted _C1-4 alkyl. And optionally substituted with 1 to 3 selected substituents). However, R ^1b and R ^1c are not simultaneously hydrogen.

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, wherein the aryl and the heteroaryl are each independently 1 to 3 substituents independently selected from the group consisting of halogen and optionally substituted C _1-4 alkyl And optionally substituted). However, R ^1b and R ^1c are not simultaneously hydrogen.

In another embodiment of R ^1a , R ^1b , R ^1c and R ^1d , R ^1a and R ^1d are hydrogen, and either R ^1b or R ^1c is C _6-10 aryloxy or 5 to 12 members. Wherein the aryl moiety in the aryloxy and the heteroaryl moiety in the heteroaryloxy are each independently selected from the group consisting of halogen and optionally substituted C _1-4 alkyl. 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 R ^1b or R ^1c is C _6-10 aryl or 5-12 membered Heteroaryl (wherein the aryl and the 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 include 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-methyl-2-yl) oxy, (5- (trifluoromethyl) pyridin-2-yl) oxy, and (5-fluoropyridin-2-yl) oxy.

More preferred specific examples of R ^1a , R ^1b , R ^1c and R ^1d include 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, and (5-fluoropyridin-2-yl) oxy.

More preferred specific examples of R ^1a , R ^1b , R ^1c and R ^1d include 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 Fluoromethyl) pyridin-2-yl) oxy.

^Other embodiments of R ^1a , R ^1b , R ^1c and R ^1d include 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- (trifluoro) Methyl) phenyl, 2-fluoro-4- (trifluoromethyl) phenyl, 2-chloro-4- (trifluoromethyl) phenyl, 4- (trifluoromethoxy) phenyl, (5-chloropyridin-2-yl) oxy 2,4-dichlorophenyl, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy, and 2,4-dichlorophenoxy.

^Other embodiments of R ^1a , R ^1b , R ^1c and R ^1d include 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.

Preferable 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. And may be 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. C _1-6 alkyl which may be used is mentioned.

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

で表される基を形成してもよい。 R ² and R ³ together with the bonding carbon atom form a ring, and together with —OR ⁴ , the following formula (II):

You may form group represented by these.

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

Preferable 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。 R ² and R ⁷ together with the carbon atom to which each is bonded form a ring, and together with R ³ , —OR ⁴ and R ⁸ , the following formula (IV):

You may form group represented by these.

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

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

Preferable R ⁴ is hydrogen, C _1-4 alkyl which may be substituted with 1 to 3 identical 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 with 1 to 3 substituents independently selected from And more preferably hydrogen.

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

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

You may form group represented by these.

In the above formula (III),
Preferred h is 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.

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

Preferred examples of m include 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 is independent and may be the same or different).

R ⁷ and R ⁸ are preferably hydrogen or C _1-4 alkyl (wherein 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 substituted, C _3-7 cycloalkyl which may be substituted with 1 to 3 substituents independently selected from substituent group B, independently of substituent group B Optionally substituted with 1 to 3 substituents selected from C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from substituent group B And may be substituted with 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles, more preferably hydrogen.

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

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

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

［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 moiety in the aryl and the aryloxy and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently 1 to 3 substituents independently selected from halogen and substituent group A; And optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl which may be substituted with R ^1a , R ^1b , R ^1c. or at least one _{C 6-10 aryl, C 6-10} aryloxy of ^{R 1d,} 5-12 membered heteroaryl or 5-12 membered heteroaryl A reel oxy,
R ² and R ³ are each independently hydrogen or C _1-6 alkyl (wherein 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 which may be substituted), provided that R ² and R ³ are not simultaneously hydrogen Or
R ² and R ³ together with the carbon atom to which each is attached form a ring, together with —OR ⁴ for formula (IIa):

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

[In the formula (IVa),
m ¹ 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 to 3 halogens;
R ⁸ represents hydrogen, a 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 _1-3 alkoxy optionally substituted with 1 to 3 substituents, C _3-7 cyclo optionally substituted with 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 3 to 7 membered non-aromatic heterocycles optionally substituted with substituents), C _3-7 cyclo alkyl or _{C 3-7} cycloalkoxy (said Shikuroa Cycloalkyl moiety in kills and said cycloalkoxy, each independently, halogen, hydroxyl, 1-3 is optionally C _1-4 alkyl substituted with a substituent independently selected from substituent group A , 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 in independently from the group consisting of optionally substituted C _3-7 also be cycloalkyl and optionally substituted with 1-3 substituents independently selected from substituent group B C _3-7 cycloalkoxy Optionally substituted with 1 to 3 substituents selected from
L is CR ⁷ R ⁸ (when m ² represents 2, each CR ⁷ R ⁸ may be independent and 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 or C _3-7 cycloalkyl optionally substituted with 1 to 3 identical or different halogens (the cycloalkyl is independent of halogen, hydroxyl and substituent group A) Optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted with 1 to 3 substituents. Or R ³ and —OR ⁴ together with the carbon atoms to which they are attached form a ring, together with R ^{2 of} formula (IIIa):

[In the formula (IIIa),
h is 1, 2 or 3;
R ² is hydrogen, C _1-6 alkyl (the alkyl may be cyano, halogen, hydroxyl, optionally substituted with 1-3 substituents independently selected from substituent group A C _{1- 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 Or optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 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 identical 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 independent and may be the same or different);
R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl (wherein the alkyl is substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, substituent group A) Optionally selected from C _1-4 alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from substituent group B, independently selected from substituent group B Optionally substituted with 1 to 3 substituents selected from C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from substituent group B 3 Or a pharmaceutically acceptable salt thereof, which may be substituted with 1 to 3 substituents independently selected from the group consisting of 7-membered non-aromatic heterocycles.

［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。 The following is mentioned as another aspect of the compound of a formula (I).
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 moiety in the aryl and the aryloxy and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently 1 to 3 substituents independently selected from halogen and substituent group A. Optionally substituted by 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 identical or different halogens, or R ² and R ³ are each a carbon to which they are bonded. Together with the atoms to 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 represents hydrogen, C _1-6 alkyl (wherein the alkyl is C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, and 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 _3- to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from C _3-7 cycloalkoxy optionally substituted with a group and substituent group B Optionally substituted with 1 to 3 substituents independently selected from the group consisting of: C _3-7 cycloalkyl (wherein the cycloalkyl is independently of halogen, hydroxyl, substituent group A) C _1-4 a which may be substituted with 1 to 3 substituents selected 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 one to three optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from which may C _3-7 also be cycloalkyl and substituent group B substituted by a group Optionally substituted with 1 to 3 independently selected substituents),
V is a single bond or an oxygen atom,
R ^5a , R ^5b , R ^5c and R ^5d are each independently hydrogen or halogen]
Or a group represented by:
In CR ⁷ R ⁸ in R ² , R ³ , —OR ⁴ and L, R ² and R ⁷ together with the carbon atom to which each is bonded form a ring, and R ³ , —OR ⁴ and R ⁸ Together with the following formula (IVa):

[In the formula (IVa),
m ¹ is 0,
m ² is 1 or 2,
j is 1 or 2,
R ³ is hydrogen or C _1-4 alkyl;
R ⁴ 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 independent and 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 identical or different halogens or C _3-7 cycloalkyl optionally substituted with 1 to 3 identical or different halogens Or
R ³ and —OR ⁴ together with the carbon atoms to which they are attached form a ring, together with R ^{2 of} 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 identical 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 identical 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 independent and may be 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 identical 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。 The following is mentioned as another aspect of the compound of a formula (I).
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- (tri 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- (trifluoromethoxy) phenyl, (5-chloropyridin-2-yl) oxy, 2,4- Dichlorophenyl, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy or 2,4-dichlorophenoxy, the other is hydrogen,
R ² and R ³ are both methyl, or
R ² and R ³ together with the carbon atom to which each is bonded form a ring and together with OR ^{4 have the following} formula (IIc)

In the formula (IIc), each of e and f is 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 atom to which each is bonded form a ring and together with R ³ , —OR ⁴ and R ^{8 have the} formula (IVc)

[In the 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, and L is , CR ⁷ R ⁸ , 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 of} formula (IIIb):

[In the formula (IIIb), R ² is hydrogen and h is 2],
m is 1,
L is CR ⁷ R ⁸ ;
A compound or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ are each independently hydrogen or methyl.

  The production method of the compound of the present invention is described below. The compound of the present invention represented by the 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。） Production method 1:
Of the compounds represented by the formula (I), the compound represented by the formula (S-5) wherein R ^1b is OR ^a or a pharmaceutically acceptable salt thereof, for example, can be produced by the following production method. Can do.

(In the formula, 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 O— represents the substituent group A in R ^1b . C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from 1, substituted with 1 to 3 substituents independently selected from Substituent Group B C _3-7 cycloalkoxy, optionally selected from 1 to 3 substituents independently selected from Substituent Group B, optionally selected from C _6-10 aryloxy or Substituent Group B Represents a 5- to 12-membered heteroaryloxy optionally substituted by 1 to 3 substituents, and X ¹ and X ² are each independently halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, etc. Represents a leaving group of

Step (1-1):
This step is a step of producing a nitroaniline compound represented by the formula (s-2) by reacting a nitrobenzene compound represented by the 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, triethylamine, diisopropylethylamine, DABCO (1,4-diazabicyclo [2,2,2] octane) and the like. An organic base is mentioned. Moreover, when using an amine compound excessively, it is not necessary to use a base. Examples of the solvent include ether solvents such as THF, dimethoxyethane, 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 the formula (s-3) by reacting a nitroaniline compound represented by the formula (s-2) with a compound having a hydroxyl group. Examples of the base used in this reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, sodium hydride and the like. Examples of the solvent include ether solvents such as THF, 1,2-dimethoxyethane, 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 producing an amino compound represented by the formula (s-4) by reducing the nitro compound represented by the formula (s-3). Examples of the conditions for this reaction include commonly used nitro group reduction conditions, such as catalytic reduction under hydrogenation conditions such as palladium-carbon, metal reduction with zinc, iron, etc., hydride reduction with lithium aluminum hydride, etc. Is mentioned. Examples of the solvent include those usually used under the respective reducing 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., in the case of hydride reduction. Examples include diethyl ether and THF. 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 producing a compound represented by the formula (S-5) by reacting a phenylenediamine compound represented by the formula (s-4) with formic acid or a formic acid equivalent to carry out cyclization. Examples of the formic acid equivalent include orthoformates such as methyl orthoformate and ethyl orthoformate. In this reaction, an organic acid such as formic acid or acetic acid or a Lewis acid such as ytterbium triflate may be added as a catalyst. Examples of the solvent include alcohol solvents such as methanol and ethanol. It is also possible to use the above-mentioned formic acid, orthoformate or the like used as a reactant as a solvent. The reaction time is usually about 10 minutes to 24 hours, and the reaction temperature is from room temperature to the boiling point of the solvent.

In addition, any one of R ^1a , R ^1b , R ^1c and R ^1d , or a compound represented by the formula (I) wherein two or more are OR ^a or a pharmaceutically acceptable salt thereof is 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。） Production method 2:
Among the compounds represented by the formula (I), the compound (S-7) in which R ⁴ is R ^4a (alkyl or cycloalkyl) or a pharmaceutically acceptable salt thereof is produced, for example, by the following production 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, and R 1 ^4a represents the definition of R ⁴ excluding hydrogen.)

Step (2-1):
In this step, an alcohol compound (s-6) in which R ⁴ in formula (s-5) is hydrogen and a compound represented by, for example, R ^4a X ³ are reacted in the presence of a base to obtain a formula (S-7) It is the process of manufacturing the represented ether compound. Examples of the base include sodium hydride, potassium hydride, lithium hydride, butyl lithium, potassium butoxide and the like. Examples of the solvent include ether solvents such as diethyl ether and THF, DMF, NMP, dimethyl sulfoxide 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。） Production method 3:
Of the compounds represented by the formula (I), the compound represented by the formula (S-10) in which R ^1b is R ^b (aryl or heteroaryl) or a pharmaceutically acceptable salt thereof is, for example, It can manufacture by the manufacturing method of.

(In the formula, 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, and R ^b is C _6-10 aryl or 5-12 membered heteroaryl (the aryl and the heteroaryl are each independently substituted with 1 to 3 substituents independently selected from halogen, cyano, substituent group A C _1-4 alkyl which may be substituted, C _1-4 alkoxy which may be substituted with 1 to 3 substituents independently selected from substituent group A, independently from substituent group B C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents selected, C optionally substituted with 1 to 3 substituents independently selected from Substituent Group B 1 to 3 positions independently selected from _3-7 cycloalkoxy, substituent group B 3-7 membered non-aromatic heterocycle optionally substituted with a substituent, C _1-4 alkylthio optionally substituted with 1 to 3 substituents independently selected from Substituent Group A And 1 to 5 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl optionally substituted with 1 to 3 substituents independently selected from Substituent Group A Which may be substituted).

Step (3-1):
This step is a step for producing an amino compound represented by the formula (s-8) by selectively reducing the nitro group of the nitrobenzene compound represented by the formula (s-2). The conditions for this reaction include catalytic reduction under hydrogenation conditions such as platinum carbon poisoned with sulfur, metal reduction with zinc, iron, tin, etc., hydride reduction with lithium aluminum hydride, and the like. Examples of the solvent include solvents usually used in each reaction condition. In the case of catalytic reduction, methanol, ethanol, THF, ethyl acetate, etc. In the case of metal reduction, THF, acetic acid, methanol, ethanol, etc., in the case of hydride reduction. Examples include diethyl ether and THF. 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 the amino compound represented by the formula (s-8) in the same manner as in the step (1-4) to produce a compound represented by the formula (s-9).

Step (3-3):
In this step, the compound represented by the formula (S-10) is reacted with a boronic acid or boronic ester compound having an R ^b group in the presence of a base and a catalyst. Is a process of manufacturing. Specifically, this is a process 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. Examples of the solvent 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.

In addition, any one of R ^1a , R ^1b , R ^1c and R ^1d , or a compound represented by the formula (I) in which two or more are R ^b , or a pharmaceutically acceptable salt thereof is 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。）

Production method 4:
Of the compounds represented by the formula (I), the compound represented by the formula (S-10) in which R ^1b is R ^b or a pharmaceutically acceptable salt thereof is also produced, for example, by the following production method. be able to.

(In the formula, 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 defined 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 group or a hydroxyl group. R ¹⁰ R ¹¹ B- preferably includes the following structures, but is not limited thereto.

Step (4-1):
In this step, the boronic ester compound represented by the formula (s-11) is reacted with a compound represented by the formula (s-9) and diboron such as bispinacol diboron in the presence of a catalyst and a base. 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. Examples of the solvent 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 from room temperature to the boiling point of the solvent.

Step (4-2):
In this step, the boronic acid ester compound represented by the formula (s-11) and a halide compound or triflate compound having an R ^b group (R ^b —X (X: halogen atom), CF ₃ SO ₂ O—R ^b, etc.) ) In the presence of a catalyst and a base to produce a compound represented by formula (S-10). Specifically, this is a process 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. Examples of the solvent 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.

In addition, any one of R ^1a , R ^1b , R ^1c and R ^1d , or a compound represented by the formula (I) in which two or more are R ^b , or a pharmaceutically acceptable salt thereof is 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。） Production method 5:
Of the compounds represented by the formula (I), the compound represented by the formula (S-5) in which R ^1b is OR ^a or a pharmaceutically acceptable salt thereof is also produced, for example, by the following production method. be able to.

(In the formula, 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. (Bn means a benzyl group, but may be a debenzylation reaction similar to the benzyl group, for example, a substituted benzyl group described in Protective Groups in Organic Synthesis.)

Step (5-1):
This step is a step for preparing a formula to the compound represented by (s-12), for example, the presence Bn-X ³ of the base is reacted with the compound represented by formula (s-13). Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and the like. Examples of Bn-X ³ include benzyl chloride and benzyl bromide. Moreover, you may add sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, etc. as needed. Examples of the solvent include acetone, acetonitrile, THF, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, DMF, NMP and the like. The reaction time is usually from 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 the formula (s-13) can be produced from the compound represented by the 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 the compound represented by formula (s-14) by the same method as in step (1-1) using the compound represented by formula (s-13).

Step (5-3):
In this step, the compound represented by formula (s-15) is converted to the method 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 the compound represented by formula (s-16) by the same method as in step (1-4) using the compound represented by formula (s-15).

Step (5-5):
In this step, the compound represented by the formula (s-16) is deprotected by, for example, catalytic reduction under hydrogenation conditions to produce a compound represented by the formula (s-17). It is a process. As the catalyst, a heterogeneous catalyst such as palladium-carbon is used. The hydrogenation condition means a hydrogen atmosphere or the presence of formic acid, ammonium formate, or the like. Examples of the solvent 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 the formula (s-17) can be produced from the compound represented by the 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 the compound represented by the formula (S-5) from the compound represented by the formula (s-17), and includes the following two reaction conditions, but is not limited thereto.
1) As a condition for using a base, a compound represented by formula (S-5) is replaced with a compound represented by formula (s-17) and R ^a -X ⁴ (R ^a is substituent group A in R ^1b . C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from 1, substituted with 1 to 3 substituents independently selected from Substituent Group B C _3-7 cycloalkyl, optionally selected from C _6-10 aryl optionally substituted with 1 to 3 substituents independently selected from substituent group B or independently selected from substituent group B The same as in the step (1-2), using a 5- to 12-membered heteroaryl optionally substituted with 1 to 3 substituents, wherein X ⁴ is the same as X ¹ above. The process manufactured with a method is mentioned.
2) As a condition for using a catalyst and a base, there may be mentioned a step of reacting a boronic acid compound having ^{a Ra} group or a halogen compound. Examples of the catalyst include 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. Examples of the solvent include chloroform, 1,4-dioxane, DMF, dimethyl sulfoxide, 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.

In addition, any one of R ^1a , R ^1b , R ^1c and R ^1d , or a compound represented by the formula (I) wherein two or more are OR ^a or a pharmaceutically acceptable salt thereof is also described above. It can be manufactured by a similar method.

  Reduction of the 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 proceed continuously by adding a formic acid equivalent such as formic acid or orthoformate during the reduction reaction of (s-3) or (s-14), for example. (S-5), (s-9), and (s-16) cyclized in one step can be produced. In this case, the reaction time 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 said manufacturing method specifically means 10 to 30 degreeC.

  The starting materials and intermediates in the above production method are known compounds, or can be synthesized from known compounds by known methods. In the above production method, if any functional group other than the reactive site changes under the described reaction conditions or is inappropriate for carrying out the described method, the other than the reactive site is protected, After the reaction, the target compound can be obtained by deprotection. As the protecting group, for example, ordinary protecting groups as described in the above-mentioned Protective Groups in Organic Synthesis can be used. Specifically, examples of the protecting group for amine include ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like, and examples of the hydroxyl protecting group include tri-lower alkylsilyl, acetyl, benzyl and the like. Can do.

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

  Moreover, the intermediate body in the said manufacturing method or a final product can also be guide | induced to another compound included in this invention by changing the functional group suitably. The functional group can be converted by a commonly used general method (for example, see Comprehensive Organic Transformations, R. C. Larock (1989)).

The 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 chromatography. it can. Further, the intermediate can be used for the next reaction without any particular purification.
The optical isomers can be separated by carrying out a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method. 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 keto enols, and / or geometric isomers, but the compounds of the present invention may contain all possible It includes isomers and mixtures thereof.

The compound of the present invention includes the compound represented by the formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in addition to the above isomer. In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included. Furthermore, the compounds of the present invention, a compound in which a part or by converting all isotopes of atoms constituting those and compounds of the crystalline form any aspect (for example, a compound obtained by converting hydrogen to deuterium, the ^{12 C 14} And compounds converted to C).

  In the present specification, the term “prodrug of the compound of formula (I)” is a compound that is converted into a compound of formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized. It means a compound that undergoes reduction, hydrolysis or the like to change to a compound of formula (I), or a compound that undergoes hydrolysis by gastric acid or the like to change to a compound of formula (I).

  Examples of the “pharmaceutically acceptable salt” include base addition salts or acid addition salts. Examples of base addition salts include 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 alkanol ammonium salts of organic amines. Examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogensulfate, 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.

  The salt of the compound of the present invention can be obtained by the following method and the like. For example, when the compound of the present invention is obtained in the form of a salt, it may be purified as it is. 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 usual method. Just do it.

  The compound of the formula (I) obtained by the production method shown above is isolated and purified according to a conventional method such as extraction, column chromatography, recrystallization, and reprecipitation. Examples of the extraction solvent include diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene and the like. Purification by column chromatography is performed using, for example, silica gel or alumina that has been subjected to acidic, basic, or various chemical treatments. As the elution solvent, for example, hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, acetonitrile / water, methanol / water and the like are used.

  The novel compound having a benzimidazole ring of the present invention or a pharmaceutically acceptable salt thereof has a property of inhibiting Nav1.7, pain associated with peripheral nerves such as C fiber and Aδ fiber, numbness, Spontaneous pain such as burning, dull pain, stinging, electric shock, hyperalgesia or allodynia with mechanical or cold stimulation, nociceptive pain, inflammatory pain, small fiber neuropathy, limb redness It can be used as a therapeutic or prophylactic agent for paroxysmal acute pain and the like. Examples of neuropathic pain herein include diabetic neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathy, cancer pain, human immunodeficiency syndrome virus infectious sensory neuropathy, trigeminal neuralgia, complex regional pain syndrome, Reflex sympathetic dystrophy, lumbar postoperative neuralgia, phantom limb pain, post-spinal pain, prolonged postoperative pain, inflammatory demyelinating polyradiculopathy, alcoholic neuropathy, strangulated peripheral neuropathy, medicine Neuropathy, idiopathic sensory neuropathy, neuropathy caused by nutritional disorder, post-irradiation neuropathy, radiculopathy, toxic peripheral neuropathy, traumatic peripheral neuropathy, brachial plexus withdrawal injury, lingual neuropathy Examples include autoimmune neuropathy and chronic cauda equina disorder. Examples of nociceptive pain or inflammatory pain include low back pain, abdominal pain, 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 prophylactic agent for dysuria. Examples of dysuria include frequent urination and bladder pain due to enlarged prostate. Furthermore, it can also be used as a therapeutic or prophylactic agent for ataxia that suppresses cerebellar abnormal nerve firing in multiple sclerosis. Furthermore, since the compound of the present invention or a pharmaceutically acceptable salt thereof has a selective inhibitory activity of Nav1.7, it does not show side effects derived from the heart and central nervous system, which are problems with existing drugs. It is thought that it can become.

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

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

  The compounds of the present invention and pharmaceutically acceptable salts thereof 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, It can also be used in combination with opioid analgesics such as tramadol, morphine and oxycodone. In addition, antiepileptic drugs such as pregabalin and carbamazepine, aldose reductase inhibitors such as epalrestat, prostaglandin derivative preparations such as limaprost alphadex, antidepressants such as amitriptyline and duloxetine, anticonvulsants, anxiolytics and dopamine receptors It can also be used in combination with drugs such as body agonists, Parkinson's disease therapeutics, hormone preparations, migraine therapeutics, adrenergic β receptor antagonists, dementia therapeutics, and mood disorder therapeutics. Preferably, the drug used in combination with the compound of the present invention and a pharmaceutically acceptable salt thereof is preferably an antiepileptic drug such as pregabalin or carbamazepine, an antidepressant drug such as amitriptyline or duloxetine, or a narcotic drug such as morphine, oxycodone or 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 alphadex. Moreover, it can be used in combination with drugs such as antiemetics and sleep inducers for the purpose of suppressing the side effects. The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject or may be administered at an appropriate interval. Moreover, it is good also as a mixture of the compound of this invention and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 1000 parts by weight per 1 part by weight of the compound of the present invention.

The present invention will be described more specifically with reference to the following examples and pharmacological test examples. However, the technical scope of the present invention is not limited to these examples. For silica gel chromatography in the examples, silica gel column chromatography or amino silica gel column chromatography manufactured by Yamazen Co., Ltd. was used. The compound was identified 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).

The powder X-ray diffraction measurement was performed under the following conditions.
Apparatus: X'pert-MPD (Spectris)
_{X-ray: Cu Kα 1/45 kV /} 40 mA
Entrance slit: 15 mm (automatic) / divergence prevention slit: 15 mm (automatic)
Sample plate: Non-reflective Si plate Step size: 0.017 °
Scanning range: 4-40 ° (2θ)
Integration time: 100 seconds / step

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

  As the raw material compound, the reaction reagent and the solvent, commercially available ones or those produced according to known methods were used unless otherwise specified.

  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 mixed reagent containing Pd / C: palladium-carbon, Pt-S / C: platinum-carbon poisoned with sulfur, J: coupling constant, s: singlet, d: doublet, t: three Line, q: quartet, dd: double doublet, td: triple doublet, tt: triplet 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 ethyl acetate / hexane (= 1/1) mixture were added to the reaction mixture, and the target product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate and 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, 4-fluorophenol (1.68 g), cesium carbonate (6.52 g) and NMP (25 mL) was stirred at 100 ° C. for 2 hours. Water and ethyl acetate / hexane (= 1/1) mixture were added to the reaction mixture, and the target product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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) A mixture of 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. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the desired product was extracted into an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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), orthogi A mixture of trimethyl acid (1.73 mL) and p-toluenesulfonic acid monohydrate (0.079 g) was stirred at 60 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture to extract the desired product into the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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 using the corresponding starting material (tetrahydrofuran-2-yl) methanol (0.607 g) instead of 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), sodium hydride (0.011 g) and DMF (1.0 mL) obtained in the same manner as in Example 1 was prepared at 0 ° C. for 30 minutes using the corresponding starting materials. Stir. 2-Bromopropane (0.045 g) was added to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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)

Compound 4 (0.007 g) was prepared using bromocyclopentane (0.049 g) instead of 2-bromopropane in Example 3.
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) Compound instead of Compound 61 in Step (i) of Example 1 Compound 67 (1.20 g) was prepared using 66 (1.1 g).

Step (ii): Preparation of 1-[(2-amino-5-bromophenyl) amino] -2-methylpropan-2-ol (Compound 68) Compound instead of Compound 63 in Step (iii) of Example 1 Compound 68 (0.811 g) was prepared using 67 (1.20 g) using 3% Pt-S / C (0.24 g) instead of 10% Pd / C as the catalyst.

Step (iii): Preparation of 1- (6-Bromo-1H-benzimidazol-1-yl) -2-methylpropan-2-ol (Compound 69) Instead of Compound 64 in Step (iv) of Example 1 Compound 69 (0.210 g) was prepared using Compound 68 (0.259 g) in place of p-toluenesulfonic acid monohydrate using acetic acid (0.060 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 A mixture of 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 target product was extracted into an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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: Compounds of Examples 6 to 10 shown in the following table were produced in the same manner as in Example 5 using the corresponding starting materials.

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 (pinacolato) 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 target product was extracted into an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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) Compound 70 (90 mg), 2-bromo-5-trifluoromethylpyridine (0.126 g), 3 mol / L aqueous sodium carbonate (0.372 mL), tetrakis (triphenylphosphine) palladium (86 mg) and 1,4-dioxane ( 2 mL) was stirred at 80 ° C. for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol mixed solvent) 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] ethane-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] ethane-1-ol (Compound 72) In place of Compound 67 in Step (ii) of Example 5, Compound 71 (0. 698 g) was used to make compound 72 (0.561 g).

Step (iii): Preparation of 2- (6-Bromo-1H-benzimidazol-1-yl) ethane-1-ol (Compound 73) Compound 72 (0) instead of Compound 68 in Step (iii) of Example 5 .231 g) was used to produce compound 73 (0.19 g).

Step (iv): Preparation of 6-bromo-1- [2- (cyclopentyloxy) ethyl] -1H-benzimidazole (Compound 74) Using Compound 73 (0.19 g) instead of 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) (ii) of Example 11 Compound 12 (0.018 g) was prepared using Compound 75 instead of 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., benzyl bromide (27.9 g) was added dropwise over 20 minutes, and the mixture was further stirred for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the target product was extracted into the organic layer. The organic layer was washed twice with water and concentrated under reduced pressure. Toluene (162 mL) was added to the resulting residue and concentrated under reduced pressure (this extraction operation was repeated twice). The obtained residue was slurry-washed with an ethyl acetate / hexane (= 1/4) mixed solution to produce Compound 77 (28.0 g).

Step (ii): Preparation of 1-{[5- (benzyloxy) -2-nitrophenyl] amino} -2-methylpropan-2-ol (Compound 78) Under a nitrogen atmosphere, Compound 77 (24.5 g) To a NMP (248 mL) solution, diisopropylethylamine (32 g) was added 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 target product was extracted into an organic layer. The aqueous layer was extracted with ethyl acetate, combined with the initially 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 was added trimethyl orthoformate (4.37 mL), formic acid (0.6 mL) and zinc (0.52 g), 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 target product was extracted into an 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) To a solution of Compound 79 (0.5 g) in methanol (5.6 mL) at room temperature. Below, 10% palladium-carbon (50% water content, 0.1 g) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate / hexane was added to the obtained residue, and the slurry was washed at room temperature. 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) were stirred at 35 ° C. for 2 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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: Compounds of Examples 14 to 27 shown in the following table were produced 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: 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 target product was extracted into the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 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:
The compounds of Examples 29 to 42 shown in the following table were produced 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) Potassium carbonate (5.97 g) and benzyl were added to a solution of Compound 81 (5 g) in DMF (56 mL) under a nitrogen atmosphere. Bromide (5.91 g) was added at room temperature and stirred for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained 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) Under a nitrogen atmosphere, Compound 82 (7.52 g) To an NMP (30 mL) solution, diisopropylethylamine (5.53 g) and 1-amino-2-methylpropan-2-ol (3.05 g) were added at room temperature, stirred at 100 ° C. for 1 hour, and further at 150 ° C. for 1 hour. Stir. The reaction mixture was allowed 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 hr and at 200 ° C. for 40 hr. Ethyl acetate and water were added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained 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) ) Trimethyl orthoformate (44.4 g), formic acid (7.71 g) and zinc (5.48 g) were added to the solution, and the mixture was stirred at room temperature for 2 hours. 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) in 10% palladium- Carbon (50% water content, 0.53 g) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and after slurry washing at room temperature, the 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) In a 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, Stir 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 = 8.0 Hz), 8.07 (1H, s).

Examples 44-54:
The compounds of Examples 44 to 54 shown in the following table were produced in the same manner as in Example 43 using the corresponding starting materials.

Examples 55-58:
Using the corresponding starting materials, the compounds of Examples 55 to 58 shown in the following table were produced in the same manner as in Example 59.

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 solution was cooled to room temperature, cesium carbonate (0.95 g) and 2-fluoro-5- (trifluoromethyl) pyridine (0.42 g) were added, and the reaction solution 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 target product was extracted into an organic layer. The aqueous layer was extracted with ethyl acetate, combined with the initially obtained organic layer, and washed with water. The organic layer was concentrated under reduced pressure, and the resulting 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) Preparation Trimethyl orthoformate (4.26 mL), formic acid (0.6 mL) and zinc (0.51 g) were added to a solution of compound 86 (0.6 g) in methanol (7.8 ml), 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) propan-2- Production 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 the mixture was 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 target product was extracted into the organic layer (this extraction operation was repeated three times). The organic layer was concentrated under reduced pressure, and the obtained 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) in DMF (3.7 mL) and potassium carbonate (0.025 g) and fluorine. Cesium chloride (0.056 g) was added and stirred at room temperature for 2 hours. Trimethyl (trifluoromethyl) silane (0.075 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hour. Water and ethyl acetate: hexane = 2: 1 (v / v) were added to the reaction mixture, and the target product was extracted into the organic layer (this extraction operation was repeated three times). The organic layer was concentrated under reduced pressure, and 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) propan-2 -Production 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. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and water were added to the residue to extract the desired product into an organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained 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 heated at 90 ° C. for 1 hour. Stir. The reaction mixture was concentrated under reduced pressure, and the resulting 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 -Production of Ole (Compound 60) To a solution of Compound 89 (0.076 mg) in methanol (2 mL) was added potassium carbonate (100 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, 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:
The compounds of Examples 90 to 115 shown in the following table were produced in the same manner as in Example 1 using the corresponding starting materials.

Examples 116-121:
Using the corresponding starting materials, the compounds of Examples 116 to 121 shown in the following table were produced in the same manner as in Example 59.

Examples 122-174:
The compounds of Examples 122 to 174 shown in the following table were produced 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) Compound instead of Compound 61 in Step (i) of Example 1 Compound 175b (4.81 g) was prepared using 175a (5.0 g).

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

Step (iii): Preparation of 1- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -2-methylpropan-2-ol (Compound 175) In step (iv) of Example 5 Compound 175 (29 mg) was prepared using compound 175c (50 mg) instead of compound 69.
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 following table were produced 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 produced in the same manner as in step (v) of Example 13 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 following table were produced 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- Diol production

Step (i): N- (2-Methylprop-2-en-1-yl) -2-nitro-5-{[5- (trifluoromethyl) pyridin-2-yl] oxy} aniline (compound 227a) Production Compound 227a (1.64 g) was produced in the same manner as in step (i) of Example 59 using the corresponding starting materials.
Step (ii): 1- (2-Methylprop-2-en-1-yl) -6-{[5- (trifluoromethyl) pyridin-2-yl] oxy} -1H-benzimidazole (Compound 227b) Production Compound 227b (1.25 g) was produced in the same manner as in step (ii) of Example 59 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) and reacted. 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 at 0 ° C. to the ether (25 ml) solution, and the mixture was stirred at room temperature for 3 hours. After quenching with ammonium chloride solution, extraction was performed 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) In a nitrogen atmosphere, a solution of Compound 228b (0.86 g) in ethyl acetate (5 ml) A 4 mol / L hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred at room temperature for 2 hours. After toluene azeotropy, 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 ( Production of Compound 228d) Compound 228d (490 mg) was produced 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 Production of (Compound 228) Compound 228 (102 mg) was produced 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: The compound of Example 229 shown in the following table was produced in the same manner as in Example 228 using the corresponding starting materials.

Example 28: 2-Methyl-1- (6-{[5- (trifluoromethyl) pyridin-2-yl] oxy} -1H-benzimidazol-1-yl) propan-2-ol (Compound 28) The compound can also be produced 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 solution was cooled to room temperature, cesium carbonate (3.11 g) and 2-fluoro-5- (trifluoromethyl) pyridine (1.37 g) were added, and the reaction solution 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 target product was extracted into an organic layer. The organic layer was washed with water and dried using 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) Preparation 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 obtained 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).

Example of pharmacological test Measurement of Na ion current using voltage-dependent Na channel gene-expressing cells Nav1.7 current was measured by autopatch clamp method using human SCN9A stably expressing cells.

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

Electrophysiological measurement of Na ion current Na ion current was measured by the autopatch clamp method using the following extracellular fluid and intracellular fluid.

Extracellular fluid (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. Adjust to 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 sampling was performed at 10 kHz, and noise was removed with a 3 kHz low-pass filter. All measurements were performed at room temperature. The holding potential was 50% inactivation potential (near −60 mV) of the Nav1.7 channel, and a 20-millisecond depolarizing pulse (+10 mV) was applied once. The inhibition rate of the test compound was calculated from the results of the cells having a peak current of 500 pA or more when a depolarizing pulse was given and the cells having no significant change in the whole cell parameters until the end of data acquisition. The inhibition rate of the test compound with respect to the Na ion current was determined by the following calculation formula based on the current peak value generated by the depolarization pulse.
Na ion current inhibition rate (%) = 100 × [(current peak value in the absence of evaluation compound) − (current peak value in the presence of evaluation compound)] / (current peak value in the absence of evaluation compound)

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

Test example (2)
Measurement of analgesic activity in streptozotocin-induced diabetic peripheral neuropathic pain model Among the compounds of the present invention, the inhibitory effect of typical compounds on neuropathic pain is the analgesic activity in streptozotocin (STZ) -induced diabetic peripheral neuropathy rats. Confirmed by evaluation.
The pathological animal model was prepared by partially modifying the method of Fox et al. (Pain 81, 307-316, 1999). Male 9-week-old Wistar rats were intraperitoneally administered with 45 mg / kg body weight of STZ to create a diabetic peripheral neuropathy model.
As a method for evaluating analgesic action, von Frey test was adopted. That is, the animal's hind paw is poke with hair (von Frey hair) and applied to a mathematical formula according to the method of Chaplan et al. (Journal of Neuroscience Methods 53, 55-63, 1994), whereby the reaction threshold (50 % Paw withdrawal thresholds) was calculated.
From the 21st day after STZ administration, since it was confirmed by preliminary examination that the reaction threshold of the hind paw of the animal was significantly reduced, the analgesic action of the test compound was observed from the 21st day to the 30th day after STZ administration. Evaluation on any day during. The reaction threshold was measured the day before and two days 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 averaged reaction threshold values before administration of the test compound was reduced between the groups, and the variation within the groups was reduced.
In the test test of the test compound, the reaction threshold after administration of the test compound was measured. The test compound was orally administered at 3 mg / kg body weight 1 hour before the reaction threshold measurement. The efficacy of the analgesic action of the test compound is expressed as an extension width (g) of the reaction threshold by a formula of (response threshold after administration of test compound) − (response threshold before administration of test compound).

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 following table, the compounds of the present invention showed an extension of the reaction threshold of 1.3 to 6.5 g. In addition, the number in [] represents the extended width of the solvent administration group in each test.

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

  The compounds of the present invention can be used to treat diseases involving Nav1.7, specifically neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, limb redness, paroxysmal pain, dysuria It can be used as an excellent therapeutic agent for diseases such as multiple sclerosis. Therefore, the compound of the present invention can be a very useful medicament.

Claims (20)

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, alkoxy and the The alkyl moieties in alkylamino are each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, and 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 An optionally substituted C _3-7 cycloalkoxy and a group consisting of 3 to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from Substituent Group B 1 to 5 independently selected May be substituted with a substituent), C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (said cycloalkyl, the cycloalkyl moiety in the cycloalkoxy and the cycloalkyl amino Each independently, halogen, hydroxyl, C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from substituent group A, independently selected from substituent group A 1-3 substituents in the optionally substituted C _1-4 alkoxy being, optionally substituted with 1-3 substituents independently selected from substituent group B C _{3- 7} cycloalkyl and 1 to 3 substituents independently selected from substituent group B may be substituted with a substituent C _3-7 1 to 5 amino independently selected from the group consisting of cycloalkoxy Substituent And may _{be), C 6-10 aryl, C 6-10} aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy (wherein the aryl and the aryl moiety in the aryloxy and the heteroaryl And the heteroaryl moiety in the heteroaryloxy is each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and substituent group A , 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 in an optionally substituted C _3-7 cycloalkyl, 1-3 is substituted with a substituent which may C _3-7 also be Shikuroaruko independently selected from substituent group B 3 to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, 1 independently selected from Substituent Group A C _1-4 alkylthio optionally substituted with 3 substituents and C _1-4 alkylsulfonyl optionally 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: wherein at least one of R ^1a , R ^1b , R ^1c or R ^1d is C ₆ Represents _-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy;
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 which may be substituted, C _3-7 cycloalkyl which may be substituted with 1 to 3 substituents independently selected from substituent group B and independently of substituent group B Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents selected by Or C _3-10 cycloalkyl,
R ⁴ represents hydrogen, C _1-6 alkyl (wherein the alkyl is C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, and 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 _3- to 7-membered non-aromatic heterocycle optionally substituted with 1 to 3 substituents independently selected from C _3-7 cycloalkoxy optionally substituted with a group and 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 independent of halogen, hydroxyl, substituent group A) C _1-4 optionally substituted with 1 to 3 substituents selected 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 one to three optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from which may C _3-7 also be cycloalkyl and substituent group B substituted by a group Which may be substituted with 1 to 3 substituents independently selected),
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 independent and 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 and the alkyl moiety in the 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 C _3-7 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from Substituent Group B, and optionally substituted with C _3-7 cycloalkoxy and Substituent Group B May be substituted with 1 to 3 substituents selected and may be substituted with 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles _{good), C 3-7} cycloalkyl or _{C 3-7} sheet, Loalkoxy (the cycloalkyl and the cycloalkyl moiety in the cycloalkoxy may each independently be substituted with 1 to 3 substituents independently selected from halogen, hydroxyl, 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 independently selected from substituent group B 3 may be substituted with a substituent C _3-7 cycloalkyl and 1-3 may be substituted with a substituent C _3-7 cycloalkoxy independently selected from substituent group B Or may be substituted with 1 to 3 substituents independently selected from the group consisting of:
In R ² , R ³ and —OR ⁴ ,
R ² and R ³ together with the carbon atom to which each is bonded form a ring and together with —OR ^{4 have the} formula (II)

[In the formula (II),
e and f each independently represent 1, 2 or 3;
R ⁴ has the same meaning as 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 group, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and substituent group A, 1 to 1 independently selected from substituent group B 3 may be substituted with a substituent C _3-7 cycloalkyl, 1-3 optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from substituent group B And 1 to 3 independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles optionally substituted with 1 to 3 substituents independently selected from Substituent Group B Which may be substituted with a substituent of ] May form a group represented by or,
In CR ⁷ R ⁸ in R ² , R ³ , —OR ⁴ and L,
R ² and R ⁷ together with the carbon atom to which each is bonded form a ring and together with R ³ , —OR ⁴ and R ^{8 have the following} formula (IV):

[In the formula (IV),
m ¹ represents 0 or 1,
when m ¹ is 1, m ² represents 0 or 1, j represents 1, 2, 3 or 4;
when m ¹ is 0, m ² 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 group, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently C _1-4 alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group and substituent group A, 1 to 1 independently selected from substituent group B 3 may be substituted with a substituent C _3-7 cycloalkyl, 1-3 optionally substituted with a substituent C _3-7 cycloalkoxy independently selected from substituent group B And 1 to 3 independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles optionally substituted with 1 to 3 substituents independently selected from Substituent Group B Which may be substituted with a substituent of ] May form a group represented by or,
R ³ and —OR ⁴ together with the carbon atom to which each is bonded form a ring and together with R ^{2 have the} formula (III)

[In the formula (III),
h represents 1, 2, 3 or 4;
R ² has the same meaning as above,
R ^6a , R ^6b and R ^6c are each independently hydrogen, halogen, hydroxyl group, C _1-4 alkyl, or C _1-4 alkoxy (the alkyl and the alkyl moiety in the alkoxy are each independently halogen , 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 optionally substituted with a substituent C _3-7 cycloalkyl, optionally substituted with 1-3 substituents independently selected from substituent group B C _3-7 cycloalkoxy and substituents 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered non-aromatic heterocycles optionally substituted with 1 to 3 substituents independently selected from Group B Which may be substituted with That group may be formed (but not be R ^2, R ³ and -OR ⁴ to form a ring together at the same time),
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 the formula (I) or a pharmaceutically acceptable salt thereof, except for a pharmaceutical composition containing the following compound or a pharmaceutically acceptable salt 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. 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 and the alkyl moiety in the 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 moiety in the aryl and the aryloxy and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently 1 to 3 substituents independently selected from halogen, cyano, substituent group A good C _1-4 alkyl optionally substituted with groups, 1 to 3 substituents independently selected from substituent group a Independently from the group consisting of one to three optionally C _1-4 alkylsulfonyl optionally substituted with a substituent selected independently from an optionally substituted C _1-4 alkoxy and substituent group A also The pharmaceutical composition according to claim 1, which may be substituted with 1 to 3 selected substituents. 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 moiety in the aryl and the aryloxy and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently 1 to 3 substituents independently selected from halogen and substituent group A; The pharmaceutical composition according to claim 1 or 2, which may be substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl which may be substituted with object. 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 (wherein 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 which may be substituted), provided that R ² and R ³ are not simultaneously hydrogen Or
R ² and R ³ together with the carbon atom to which each is attached form a ring, together with —OR ⁴ for 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 a group represented by:
In CR ⁷ R ⁸ in R ² , R ³ , —OR ⁴ and L, R ² and R ⁷ together with the carbon atoms to which they are bonded form a ring, and R ³ , —OR ⁴ and R ⁸ Together with the following formula (IVa):

[In the formula (IVa),
m ¹ is 0,
m ² is 1 or 2, j is 1, 2 or 3,
R ³ has the same meaning as 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 as described in any one of Claims 1-4 which may form group represented by these. R ² and R ³ are C _1-6 alkyl _optionally substituted with 1-5 identical or different halogens, or R ² and R ³ are taken together with the carbon atom to which each is attached. To form a ring and together with —OR ⁴ for 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 CR ⁷ R ⁸ in R ² , R ³ , —OR ⁴ and L, R ² and R ⁷ together with the carbon atoms to which they are attached form a ring, and R ³ , —OR ⁴ and Together with R ^{8 the following} formula (IVa);

[In the formula (IVa),
m ¹ 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 as described in any one of Claims 1-5 which may form group represented by these. R ² and R ³ are each independently hydrogen or C _1-6 alkyl optionally substituted with 1 to 5 identical or different halogens, and R ² and R ³ are each a carbon to which they are bonded. The pharmaceutical composition according to any one of claims 1 to 6, which does not form a ring together with an atom. R ⁴ is hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl optionally substituted with 1 to 3 identical or different halogens (the cycloalkyl is independent of halogen, hydroxyl and substituent group A) Optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted with 1 to 3 substituents. Or R ³ and —OR ⁴ together with the carbon atoms to which they are attached form a ring, together with R ^{2 of} formula (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 identical or different halogens]
The pharmaceutical composition as described in any one of Claims 1-4 and Claim 7 which may form group represented by these. R ⁴ is hydrogen, C _1-4 alkyl or C _3-7 cycloalkyl optionally substituted with 1 to 3 identical or different halogens (the cycloalkyl is independent of halogen, hydroxyl and substituent group A) Optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy optionally substituted with 1 to 3 substituents. The pharmaceutical composition according to any one of claims 1 to 8, wherein R ³ and -OR ⁴ do not form a ring together with the carbon atom to which each is bonded. The pharmaceutical composition according to any one of claims 1 to 9, wherein R ⁴ is hydrogen. R ⁷ and R ⁸ are each independently hydrogen or C _1-4 alkyl (wherein the alkyl is substituted with 1 to 3 substituents independently selected from halogen, hydroxyl group, substituent group A) Optionally selected from C _1-4 alkoxy, C _3-7 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from substituent group B, independently selected from substituent group B Optionally substituted with 1 to 3 substituents selected from C _3-7 cycloalkoxy optionally substituted with 1 to 3 substituents independently selected from substituent group B 3 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 to 10, wherein m is 1 or 2. R ⁷ and R ⁸ are hydrogen,
The pharmaceutical composition according to any one of claims 1 to 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 and the aryl moiety in the aryloxy and the heteroaryl And the heteroaryl moiety in the heteroaryloxy is each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and 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 And optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl which may be substituted with Item 13. A pharmaceutical composition according to any one of Items 1 to 12. R ^1b is C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy (the aryl and the aryl moiety in the aryloxy and the heteroaryl and the Heteroaryl moieties in heteroaryloxy are each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and substituent group A 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 also may) be substituted with 1 to 3 substituents are also independently selected from the group consisting of optionally C _1-4 alkylsulfonyl optionally be, claims 1 to 13 The pharmaceutical composition according to any one. R ^1c is C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, or 5-12 membered heteroaryloxy (the aryl and the aryl moiety in the aryloxy and the heteroaryl and the Heteroaryl moieties in heteroaryloxy are each independently C _1-4 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and substituent group A 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 also may) be substituted with 1 to 3 substituents are also independently selected from the group consisting of optionally C _1-4 alkylsulfonyl optionally be, claims 1 to 13 The pharmaceutical composition according to any one. 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] oxetane-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) oxetane-3-ol,
3-({6- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl} methyl) oxetane-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} oxetane-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) oxetane-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) oxetane-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) oxetane-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) oxetane-3-ol,
3-({5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} methyl) oxetane-3-ol, and (3S) -2-methyl-3- ( 6-{[5- (trifluoromethyl) pyridin-2-yl] oxy} -1H-benzimidazol-1-yl) butan-2-ol.   The therapeutic agent of the disease in which Nav1.7 (SCN9A) is involved containing the pharmaceutical composition as described in any one of Claims 1-17.   Neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, limb erythema pain, paroxysmal pain, urination, comprising the pharmaceutical composition according to any one of claims 1 to 17. Treatment for disorders or multiple sclerosis.   18. A pharmaceutical composition according to any one of claims 1 to 17, and at least selected from antiepileptic drugs, antidepressants, narcotic analgesics, anti-inflammatory drugs, reductase inhibitors and prostaglandin derivative formulations. A pharmaceutical comprising a combination of one or more drugs.