JP2018052817A - Novel benzimidazole derivative and medical application thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for diseases to which Nav1.7 relates, especially neuropathic pain, nociceptive pain, inflammatory pain, small diameter fibrous neuropathy, erythromelalgia, paroxysmal pain, dysuria or multiple sclerosis or the like.SOLUTION: There is provided a compound represented by the formula (1), where Rto Rare H, cyano, Calkyl or the like, Rand Rare H, Calkyl, Ccycloalkyl, 3- to 7-membered heterocycle or the like, L is CRR, Rand Rare H, hydroxyl group, Calkyl or the like and m is 1 to 3.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. . 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, evidence has been obtained that SCN9A, among such subunits, is widely involved in the transmission of information on 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).

  Therefore, Nav1.7 inhibitor is a pain associated with peripheral nerves such as C fiber and Aδ fiber, numbness, burning sensation, blunt pain, spontaneous pain such as stinging and electric shock, hyperalgesia to mechanical stimulation and cold stimulation Alternatively, it may be an agent having an analgesic effect on diseases such as neuropathic pain accompanied by allodynia, nociceptive pain, inflammatory pain, small fiber neuropathy, limb erythema pain and paroxysmal pain. Furthermore, since Nav1.7 is hardly expressed in non-neural tissues and the central nervous system, a drug that selectively inhibits Nav1.7 does not exhibit the side effects derived from the heart and central nervous system, which are problems with existing drugs. It can be a drug.

  Patent Document 1 specifically discloses compounds relating to potassium channel antagonists. Specifically, the compound described in the patent document has a structural feature of having an imidazopyridine skeleton as represented by the following formula (A). On the other hand, the compound of the present invention is different in that it does not contain an imidazopyridine skeleton. Further, Patent Document 1 does not include any description suggesting the present invention.

International Publication No. 2005/002520 Pamphlet

Nat Rev Neurosci. 14: 49, 2013 Nat Commun. 3: 791, 2012 Brain Res Rev. 60: 65, 2009 Pain Med. 12: S93, 2011

  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 bicyclic compound having a benzimidazole ring, which will be described later, or a pharmaceutically acceptable salt thereof is Na channel in Nav1.7 gene-expressing cells. It was found that it is a blocker that inhibits membrane potential change or Na ion current per se, that is, it has an inhibitory activity against Nav1.7. 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 (1) (hereinafter also referred to as “compound represented by formula (1)” or “compound of formula (1)”) or a pharmaceutical thereof Acceptable salts (hereinafter also referred to as “compounds of the invention”) are provided.

[Claim 1] The following formula (1):

［式（１）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_３−７シクロアルキル、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されていてもよい３〜７員の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、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_３−７シクロアルキルおよび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）、Ｃ_６−１０アリール、Ｃ_６−１０アリールオキシ、Ｃ_６−１０アリールアミノ、５〜１２員のヘテロアリール、５〜１２員のヘテロアリールオキシ、５〜１２員のヘテロアリールアミノ、（Ｃ_６−１０アリール）Ｃ_１−４アルキル、（Ｃ_６−１０アリール）Ｃ_１−４アルコキシ（該アリール、該アリールオキシ、該アリールアミノ、該アリールアルキルおよび該アリールアルコキシにおけるアリール部分ならびに、該ヘテロアリール、該ヘテロアリールオキシおよび該ヘテロアリールアミノ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_３−７シクロアルキル、置換されていてもよいＣ_３−７シクロアルコキシ、置換されていてもよい３〜７員の複素環（ただしテトラゾールを除く）、置換されていてもよいＣ_１−４アルキルチオおよび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１〜３個の置換基で置換されていてもよい）、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル（該アルケニルおよび該アルキニルは、各々独立して、ハロゲン、シアノ、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_３−７シクロアルキル、置換されていてもよいＣ_３−７シクロアルコキシ、置換されていてもよい３〜７員の複素環、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５〜１２員のヘテロアリール、置換されていてもよいＣ_１−４アルキルチオおよび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１〜３個の置換基で置換されていてもよい）または、３〜７員の複素環（該複素環は、ハロゲン、水酸基、置換されていてもよいＣ_１−６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_３−７シクロアルキルおよび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、但し、Ｒ^１a、Ｒ^１ｂ、Ｒ^1cおよびＲ^1dのうち、少なくとも１つがＣ_６−１０アリール、Ｃ_６−１０アリールオキシ、Ｃ_６−１０アリールアミノ、５〜１２員のヘテロアリール、５〜１２員のヘテロアリールオキシ（該アリール、該アリールオキシ、該アリールアミノおよび該アリールアルコ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_３−７シクロアルキル、置換されていてもよいＣ_３−７シクロアルコキシ、置換されていてもよい３〜７員の複素環、置換されていてもよいＣ_１−４アルキルチオおよび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１〜３個の置換基で置換されていてもよい）または３〜７員の複素環（該複素環は、ハロゲン、水酸基、置換されていてもよいＣ_１−６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_３−７シクロアルキルおよび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^４Ｒ^５であり、
Ｒ^４およびＲ^５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は、各々独立して、ハロゲン、水酸基、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_３−７シクロアルキル、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されていてもよい３〜７員の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は、各々独立して、ハロゲン、水酸基、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_３−７シクロアルキルおよび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、
ｍは、１、２または３であり、ｍが２または３であるとき、複数のＬは互いに独立し、
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_３−７シクロアルキルおよび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_３−１０シクロアルキルまたは３〜７員の複素環（該シクロアルキルおよび該複素環は、各々独立して、ハロゲン、水酸基、置換されていてもよいＣ_１−６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_３−７シクロアルキルおよび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、ここにおいて、Ｒ^２およびＲ^３は、一緒になって隣接する窒素原子と共に下記式（２）：

[In Formula (1),
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 part in alkylamino is each independently a halogen, a hydroxyl group, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl, or an optionally substituted C _3- Optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₇ cycloalkoxy and optionally substituted 3-7 membered heterocycles, C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (the cycloalkyl part in the cycloalkyl, the cycloalkoxy and the cycloalkylamino is Each independently halogen, hydroxyl, substituted optionally optionally C _1-4 be alkoxy, substituted by comprising from good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted also be the group Optionally substituted with 1-3 independently selected substituents), C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamino, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, 5-12 membered heteroarylamino, (C _6-10 aryl) C _1-4 alkyl, (C _6-10 aryl) C _1-4 alkoxy (the aryl, aryloxy) The aryl moiety in the arylamino, the arylalkyl and the arylalkoxy, and the heteroaryl, the heteroaryloxy and the The heteroaryl part of the hetero arylamino are each independently halogen, cyano, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally C ₃ substituted _-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy, optionally substituted 3-7 membered heterocycle (except tetrazole), optionally substituted C _1-4 alkylthio and Optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted C _1-4 alkylsulfonyl), C _2-6 alkenyl, C _2-6 alkynyl ( the alkenyl and the alkynyl are each independently, halogen, cyano, optionally substituted C _1-4 alkyl, substituted C _1-4 optionally alkoxy C, C _3-7 cycloalkyl which may be substituted, C _3-7 cycloalkoxy which may be substituted, _{3- to} 7-membered heterocyclic ring which may be substituted, C ₆ which may be substituted Independently selected from the group consisting of _-10 aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C _1-4 alkylthio and optionally substituted C _1-4 alkylsulfonyl. Optionally substituted with 1 to 3 substituents) or a 3 to 7 membered heterocyclic ring (wherein the heterocyclic ring is halogen, hydroxyl group, optionally substituted C _1-6 alkyl, substituted which may be C _1-4 alkoxy, one to three independently selected from the group consisting of optionally substituted C _3-7 also be cycloalkyl and optionally substituted C _3-7 cycloalkoxy With substituents A conversion may be), where, ^{R 1a, R} 1b, one of R ^1c and R ^1d, at least one of _{C 6-10 aryl, C 6-10 aryloxy, C 6-10} arylamino, 5 ˜12 membered heteroaryl, 5-12 membered heteroaryloxy (the aryl moiety in the aryl, the aryloxy, the arylamino and the arylalkoxy, and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are independently, halogen, cyano, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, optionally substituted good C _3-7 cycloalkoxy, heterocyclic ring members 3-7 may be substituted, an optionally substituted C _-4 alkylthio and substituted may be substituted with 1 to 3 substituents are also independently selected from the group consisting of optionally C _1-4 alkylsulfonyl optionally) or 3-7 membered heterocyclic ring ( The heterocycle includes a halogen, a hydroxyl group, an optionally substituted C _1-6 alkyl, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl, and a substituted And may be substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy),
L is CR ⁴ R ⁵ ;
R ⁴ and R ⁵ are each independently hydrogen, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and alkoxy are each independently halogen, hydroxyl, or optionally substituted). C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, independently from the group consisting of heterocyclic ring optionally substituted C _3-7 cycloalkoxy and optionally substituted 3- to 7-membered Optionally selected from 1 to 3 substituents), C _3-7 cycloalkyl or C _3-7 cycloalkoxy (the cycloalkyl and the cycloalkoxy are each independently halogen , hydroxyl, optionally substituted C _1-4 alkoxy, the optionally substituted C _3-7 cycloalkyl and optionally substituted C _3-7 cycloalkoxy An that may be substituted with 1-3 substituents independently selected from the group),
m is 1, 2 or 3, and when m is 2 or 3, a plurality of Ls are independent of each other;
R ² and R ³ are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is cyano, halogen, hydroxyl group, optionally substituted C _1-4 alkoxy, optionally substituted C ₃ Optionally substituted with 1 to 5 substituents independently selected from the group consisting of _-7 cycloalkyl and optionally substituted C _3-7 cycloalkoxy), C _3-10 cycloalkyl or 3- to 7-membered heterocycle (the cycloalkyl and the heterocycle each independently represent a halogen, a hydroxyl group, an optionally substituted C _1-6 alkyl, an optionally substituted C _1-4 alkoxy, may be substituted with 1-3 substituents independently selected from optionally substituted C _3-7 also be cycloalkyl and optionally substituted C _3-7 group consisting cycloalkoxy) There, wherein, ^{R 2} and ^{R 3,} the following formula together with the adjacent nitrogen atom together (2):

［式（２）中、
Ｚは、単結合、−Ｏ−、−Ｓ−、−ＳＯ_２−、−ＮＲ^７−、−Ｎ（ＣＯＲ^７）−または−Ｎ（ＳＯ_２Ｒ^７）−であり、
ｄおよびｅは、Ｚが単結合であるとき、各々独立して、１、２または３であり、Ｚが−Ｏ−、−Ｓ−、−ＳＯ_２−、−ＮＲ^７−、−Ｎ（ＣＯＲ^７）−または−Ｎ（ＳＯ_２Ｒ^７）−であるとき、各々独立して、２または３であり、
ｆは、０、１、２または３であり、ｆが２または３であるとき、複数のＲ^６は、各々独立し、
Ｒ^６は、上記式（２）で表される環状基上の炭素原子に結合し、ハロゲン、シアノ、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は、各々独立して、ハロゲン、水酸基、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_３−７シクロアルキル、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されていてもよい３〜７員の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_６−１０アリールまたはＣ_６−１０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は、各々独立して、ハロゲン、シアノ、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_３−７シクロアルキル、置換されていてもよいＣ_３−７シクロアルコキシ、置換されていてもよい３〜７員の複素環、置換されていてもよいＣ_１−４アルキルチオおよび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１〜３個の置換基で置換されていてもよい）であり、ここにおいて、Ｒ^６が２個以上存在するときに、２または３個のＲ^６は、それらが結合する１個または複数の炭素原子と共に一緒になって３〜７員の炭素環または複素環を形成していてもよく、
Ｒ^７は、Ｃ_１−４アルキル（該アルキルは、ハロゲン、水酸基、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_３−７シクロアルキル、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されていてもよい３〜７員の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_３−７シクロアルキルおよび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）である］で表される環を形成していてもよい]で表される化合物またはその薬学的に許容される塩。

[In Formula (2),
Z is a single bond, —O—, —S—, —SO ₂ —, —NR ⁷ —, —N (COR ⁷ ) — or —N (SO ₂ R ⁷ ) —,
d and e are each independently 1, 2 or 3 when Z is a single bond, and Z is —O—, —S—, —SO ₂ —, —NR ⁷ —, —N (COR ⁷⁾ - or -N _(SO 2 ^{R 7)} - when they are each independently 2 or 3,
f is 0, 1, 2 or 3, when f is 2 or 3, a plurality of ^{R 6} are each independently,
R ⁶ is bonded to a carbon atom on the cyclic group represented by the above formula (2), and halogen, cyano, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and the alkoxy are each independently A halogen atom, a hydroxyl group, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl, an optionally substituted C _3-7 cycloalkoxy, and an optionally substituted Optionally substituted with 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered heterocycles, C _6-10 aryl or C _6-10 aryloxy (the aryl and aryl moiety in the aryloxy, each independently, halogen, cyano, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally substituted Which may C _3-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy, heterocycle substituted 3 to 7 may be members, also optionally C _1-4 alkylthio and substituted substituted And optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl, and when there are two or more R ⁶ 2 or 3 R ⁶ may be taken together with one or more carbon atoms to which they are attached to form a 3-7 membered carbocyclic or heterocyclic ring;
R ⁷ represents C _1-4 alkyl (wherein the alkyl is halogen, hydroxyl group, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy and optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted 3-7 membered heterocycles) or C _3-7 cyclo alkyl (wherein the cycloalkyl, halogen, hydroxyl, substituted optionally optionally C _1-4 also alkoxy, made from a good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted substituted Which may be substituted with 1 to 3 substituents independently selected from the group)], which may form a ring represented by] or a pharmaceutically acceptable salt thereof Salt.

[Claim 2] At least one of R ^1b and R ^1c is C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamino, 5-12 membered heteroaryl, 5-12 membered heteroaryl. Oxy (the aryl moiety in the aryl, the aryloxy, the arylamino and the arylalkoxy, and the heteroaryl moiety in the heteroaryl and the heteroaryloxy may each independently be substituted with halogen, cyano, C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy, optionally substituted 3-7 membered heterocycle, optionally substituted C _1-4 alkylthio and optionally substituted Or optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl, or a 3 to 7 membered heterocyclic ring (which is a halogen, hydroxyl group, optionally substituted C _1-6 alkyl, optionally substituted C _1-4 alkoxy, the optionally substituted C _3-7 cycloalkyl and optionally substituted C _3-7 cycloalkoxy And may be substituted with 1 to 3 substituents independently selected from the group consisting of:
At least one of R ² and R ³ is not hydrogen;
Item 3. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

[Item 3] C _1-4 alkyl which may be substituted on each substituent in R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ _Optionally substituted C _3-7 cycloalkyl, optionally substituted 3-7 membered heterocycle, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 The substituent in cycloalkoxy, optionally substituted C _1-4 alkylsulfonyl and optionally substituted C _1-4 alkylthio is fluorine, hydroxyl group or C _1-2 alkoxy, which may be substituted. C _6-10 substituents in aryl and substituted heteroaryl also be 5- to 12-membered optionally is fluorine, chlorine, _{cyano, C 1-2} alkyl or _{C 1-2} alkoxy, claim 1 or Compound or a pharmaceutically acceptable salt thereof according to any one of.

The [claim 4] ^{R 2} and ^{R 3,} each independently, _{hydrogen, C 1-6} alkyl (said alkyl, cyano, halogen, hydroxyl, optionally substituted by 1-3 fluorines _{C 1- 4} alkoxy, by one to three optionally substituted by fluorine _{C 3-7} cycloalkyl, 1-3 optionally substituted by fluorine _{C 3-7} cycloalkoxy and 1-3 fluorines Optionally substituted with 1 to 5 substituents independently selected from the group consisting of optionally substituted 3-7 membered heterocycles), C _3-7 cycloalkyl or 3-7 members (The cycloalkyl and the heterocycle are each independently a halogen, a hydroxyl group, a C _1-4 alkoxy optionally substituted by 1 to 3 fluorines, a C _3-7 cycloalkyl and a C _{3. -7} shea A independently from the group consisting Roarukokishi may be substituted with 1-3 substituents selected), wherein, R ² and R ³ are the together with the adjacent nitrogen atom together A ring represented by the formula (2) may be formed,
[In the formula (2), Z is a single bond, —O— or —SO ₂ —;
When f is 0, 1 or 2, and f is 2, two R ^{6 s} are independent and R ⁶ is halogen, hydroxyl group or C _1-4 alkoxy (the alkoxy is halogen, hydroxyl group, Substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkoxy and a 3-7 membered heterocyclic ring. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 5] R ² and R ³ are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is C _1-4 alkoxy optionally substituted by halogen, hydroxyl group, or 1 to 3 fluorines). And optionally substituted by 1 to 5 substituents independently selected from the group consisting of 3 to 7-membered heterocyclic rings optionally substituted by 1 to 3 fluorines) or C _{3− 7} cycloalkyl (which may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and C _1-4 alkoxy), wherein R ² and R ³ together may form a ring represented by the above formula (2) together with an adjacent nitrogen atom,
[In Formula (2), Z is a single bond or -O-,
f is 0 or 1,
R ⁶ is hydrogen, halogen, hydroxyl group or C _1-4 alkoxy (the alkoxy may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen and hydroxyl group). ] The compound or its pharmaceutically acceptable salt as described in any one of claim | item 1-4.

[Item 6] R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and alkoxy are each independently By halogen, hydroxyl group, C _1-4 alkoxy optionally substituted by 1 to 3 fluorines, C _3-7 cycloalkyl optionally substituted by 1 to 3 fluorines, 1 to 3 fluorines 1 to 3 substituents independently selected from the group consisting of optionally substituted C _3-7 cycloalkoxy and 1 to 3 fluorine optionally substituted 3 to 7 membered heterocycle in optionally substituted), C _3-7 cycloalkyl, C _3-7 cycloalkoxy (said cycloalkyl and said cycloalkoxy are each independently halogen, hydroxyl, 1-3 hydrofluoric May be substituted with 1-3 substituents independently selected from the group consisting of which may C _1-4 alkoxy optionally, C _3-7 cycloalkyl and C _3-7 cycloalkoxy substituted by ), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, (C _6-10 aryl) C _1-4 alkyl, (C _6-10 Aryl) C _1-4 alkoxy (the aryl, the aryloxy, the aryl moiety in the arylalkyl and the arylalkoxy, and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently halogen, cyano, C _1-4 alkyl, wherein the alkyl is independently from the group consisting of fluorine and C _1-2 alkoxy 1 to 3 independently selected from the group consisting of C _1-4 alkoxy optionally substituted by 1 to 3 selected substituents) and optionally substituted by 1 to 3 fluorines Or a 3 to 7-membered heterocyclic ring (which is a halogen, a hydroxyl group, an optionally substituted C _1-6 alkyl, or an optionally substituted C). _C1-4 alkoxy, substituted with 1-3 substituents independently selected from the group consisting of optionally substituted C _3-7 also be cycloalkyl and substituted C _3-7 optionally cycloalkoxy The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 5, which may be

[Section 7] R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and alkoxy are each independently Independently from the group consisting of halogen, hydroxyl, C _1-4 alkoxy optionally substituted by 1 to 3 fluorines, C _3-7 cycloalkyl, C _3-7 cycloalkoxy and 3-7 membered heterocycle Optionally selected from 1 to 3 substituents), C _3-7 cycloalkyl, C _3-7 cycloalkoxy (the cycloalkyl and the cycloalkoxy are each independently halogen, _hydroxyl, may be _{C 1-4 alkoxy, C 3-7} optionally substituted with 1-3 substituents independently selected from cycloalkyl and _{C 3-7} group consisting cycloalkoxy) C _{6-10 aryl, C 6-10} aryloxy (said aryl and said aryloxy are each independently halogen, _{cyano, C 1-4} alkyl (said alkyl, the group consisting of fluorine and _{C 1-2} alkoxy Independently selected from 1 to 3) and optionally selected from the group consisting of C _1-4 alkoxy optionally substituted by 1 to 3 fluorines. 1 to 3 substituents) or a 3 to 7-membered heterocycle (the heterocycle is halogen, hydroxyl group, optionally substituted C _1-6 alkyl, substituted 1-3 groups selected which may C _1-4 alkoxy, independently from substituted composed from a good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted also be the group Compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, a substituted may be substituted by a group).

^CLAIM | ^ITEM 8 The compound or its pharmaceutically acceptable salt as described in any one of claim | item 1 ^-7 whose R ^{< 1a} > and R ^<1d > are hydrogen.

[Item 9] R ⁴ and R ⁵ are each independently hydrogen, a hydroxyl group, or C _1-4 alkyl (wherein the alkyl is a C _1-4 alkoxy optionally substituted by a hydroxyl group and 1 to 3 fluorines). The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, which may be substituted with 1 to 3 substituents independently selected from the group consisting of .

CLAIM | ITEM 10 The compound or its pharmaceutically acceptable salt as described in any one of claim | item 1 -9 whose R < ⁴ > and R < ⁵ > is hydrogen.

[Item 11] The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 10, wherein m is 1.

[Item 12] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
Example 1: 1- (Pyrrolidin-1-yl) -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 2: N, N-dimethyl-2- (6-phenyl-1H-benzimidazol-1-yl) acetamide,
Example 3: N, N-dimethyl-2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 4: N-ethyl-N-methyl-2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 5: N-ethyl-N-methyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide
Example 6: N-ethyl-N-methyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 7: N-ethyl-2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 8: N-cyclohexyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 9: N-cyclopentyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 10: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 11: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 12: N-ethyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-methylacetamide,
Example 13: N-ethyl-N-methyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 14: N, N-dimethyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide,
Example 15: 2- (5-phenoxy-1H-benzimidazol-1-yl) -1- (pyrrolidin-1-yl) ethanone,
Example 16: 2- (5-phenoxy-1H-benzimidazol-1-yl) -1- (piperidin-1-yl) ethanone,
Example 17: N-cyclopentyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 18: 1- (pyrrolidin-1-yl) -2- {6- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 19: 1- (azetidin-1-yl) -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 20: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (3-phenoxyazetidin-1-yl) ethanone
Example 21: N, N-dimethyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 22: 2- [5- (4-Methylphenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 23: N-cyclopentyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 24: N-ethyl-N-methyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 25: N, N-dimethyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 26: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 27: N-cyclopentyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 28: N-ethyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-methylacetamide
Example 29: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 30: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 31: N-cyclopentyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 32: 2- [5- (4-Methylphenoxy) -1H-benzimidazol-1-yl] -1- (piperidin-1-yl) ethanone,
Example 33: 1- (piperidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 34: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (piperidin-1-yl) ethanone,
Example 35: N-cyclohexyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 36: N-cyclohexyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 37: N-cyclohexyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 38: N-cyclohexyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 39: N-ethyl-N-methyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 40 N, N-dimethyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide
Example 41: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 42: 1- (piperidin-1-yl) -2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 43: N-cyclopentyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 44: N-cyclohexyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 45: N, N-dimethyl-2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 46: 2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 47: 2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 48: N-ethyl-N-methyl-2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 49: N-ethyl-2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 50: N-cyclohexyl-2- (6-phenyl-1H-benzimidazol-1-yl) acetamide,
Example 51: 2- [6- (2-Chlorophenyl) -1H-benzimidazol-1-yl] -N-cyclohexylacetamide,
Example 52: N-cyclohexyl-2- [6- (2-methoxyphenyl) -1H-benzimidazol-1-yl] acetamide,
Example 53: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-cyclohexylacetamide,
Example 54: N-cyclohexyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 55: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 56: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 57: 2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 58: 2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 59: 2- [6- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 60: 4- {1- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -1H-benzimidazol-5-yl} benzonitrile,
Example 61: 2- [5- (4-cyanophenyl) -1H-benzimidazol-1-yl] -N-cyclopentylacetamide,
Example 62: N-ethyl-N-methyl-2- [6- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 63: 2- [6- (4-methylphenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 64: N-ethyl-N-methyl-2- {6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 65: 2- [5- (4-Fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 66: N-ethyl-2- [5- (4-fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-methylacetamide
Example 67: 2- [5- (4-Fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 68: N, N-dimethyl-2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 69: N-ethyl-N-methyl-2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 70: 1- (pyrrolidin-1-yl) -2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 71: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1-[(3R) -3-hydroxypiperidin-1-yl] Ethanon,
Example 72: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} Ethanon,
Example 73: 1- (pyrrolidin-1-yl) -2- {6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 74: N-ethyl-N-methyl-2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide,
Example 75: 1- (pyrrolidin-1-yl) -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 76: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone
Example 77: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 78: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-ethyl-N-methylacetamide,
Example 79: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 80 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide
Example 81: N-ethyl-2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 82: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 83: N-ethyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-methylacetamide,
Example 84: N-cyclopentyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 85: N, N-dimethyl-2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 86: N-ethyl-N-methyl-2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 87: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 88: N, N-dimethyl-2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 89: 2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 90: 1- (pyrrolidin-1-yl) -2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone,
Example 91: N-cyclopentyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 92: 1- (piperidin-1-yl) -2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone
Example 93: N-cyclohexyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 94: N-ethyl-N-methyl-2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 95: 1- (pyrrolidin-1-yl) -2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone,
Example 96: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 97: 1-[(3S) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 98: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1-[(3R) -3-hydroxypiperidin-1-yl] ethanone,
Example 99: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -1- (4-hydroxypiperidin-1-yl) ethanone,
Example 100: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide,
Example 101: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N- (trans-4-hydroxycyclohexyl) acetamide,
Example 102: N-cyclohexyl-2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide,
Example 103: N- (trans-4-hydroxycyclohexyl) -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 104: N-[(1S, 2S) -2-hydroxycyclohexyl] -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 105: 1- (4-hydroxypiperidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 106: N- (tetrahydro-2H-pyran-4-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 107: N- (trans-4-hydroxycyclohexyl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 108: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1- (morpholin-4-yl) ethanone
Example 109: 1- (3,3-difluoroazetidin-1-yl) -2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] ethanone,
Example 110: N-[(2R) -2-hydroxypropyl] -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 111: N-[(2S) -2-hydroxypropyl] -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 112: N- (2-hydroxy-2-methylpropyl) -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 113: N-cyclohexyl-2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 114: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N- (trans-4-hydroxycyclohexyl) acetamide,
Example 115: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-[(1S, 2S) -2-hydroxycyclohexyl] acetamide,
Example 116: 2- [6- (4-fluorophenoxy)-1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1.1 ^{3, 7]} dec-1-yl) acetamide,
Example 117: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (3-hydroxytricyclo [3.3.1.1 ^3,7 ] dec-1- Yl) acetamide,
Example 118: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide
Example 119: 1-[(3S) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 120: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone
Example 121: N- (4-hydroxycyclohexyl) -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 122: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N- (2-hydroxy-2-methylpropyl) acetamide,
Example 123: 1- (pyrrolidin-1-yl) -2- {5- [6- (trifluoromethyl) pyridin-3-yl] -1H-benzimidazol-1-yl} ethanone
Example 124: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-[(2S) -2-hydroxypropyl] acetamide,
Example 125: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N- (2-hydroxy-2-methylpropyl) acetamide,
Example 126: N- (cyclohexylmethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 127: N-[(1S) -1-cyclohexylethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 128: N-[(1R) -1-cyclohexylethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide
Example 129: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-2-yl) acetamide,
Example 130: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N-cyclohexylacetamide,
Example 131 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (cyclohexylmethyl) acetamide,
Example 132: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-1-yl) acetamide,
Example 133: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-2-yl) acetamide,
Example 134: 2- [5- (pyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 135: 2- [5- (3-methoxypyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 136: 2- [5- (5-Fluoro-2-methoxypyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
1- (3,3-difluoroazetidin-1-yl) -2- [5- (pyridin-4-yl) 1H-benzimidazol-1-yl] ethanone,
2- [5- (pyridin-4-yl) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide,
1- (pyrrolidin-1-yl) -2- {5- [5- (trifluoromethyl) pyridin-2-yl] -1H-benzimidazol-1-yl} ethanone,
2- [5- (5-fluoropyridin-2-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
1- (3,3-difluoroazetidin-1-yl) -2- [5- (5-fluoropyridin-2-yl) -1H-benzimidazol-1-yl] ethanone,
2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (4-hydroxycyclohexyl) acetamide,
2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (2-hydroxycyclohexyl) acetamide,
2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide,
2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N-[(2R) -2-hydroxypropyl] acetamide and 2- [6- (4-fluorophenoxy) -1H- Benzimidazol-1-yl] -N- (2-hydroxyethyl) acetamide.

CLAIM | ITEM 13 The compound of claim | item 1 selected from the following compound groups, or its pharmaceutically acceptable salt:
Example 1: 1- (Pyrrolidin-1-yl) -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 2: N, N-dimethyl-2- (6-phenyl-1H-benzimidazol-1-yl) acetamide,
Example 3: N, N-dimethyl-2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 4: N-ethyl-N-methyl-2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 5: N-ethyl-N-methyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide
Example 6: N-ethyl-N-methyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 7: N-ethyl-2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 8: N-cyclohexyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 9: N-cyclopentyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 10: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 11: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 12: N-ethyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-methylacetamide,
Example 13: N-ethyl-N-methyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 14: N, N-dimethyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide,
Example 15: 2- (5-phenoxy-1H-benzimidazol-1-yl) -1- (pyrrolidin-1-yl) ethanone,
Example 16: 2- (5-phenoxy-1H-benzimidazol-1-yl) -1- (piperidin-1-yl) ethanone,
Example 17: N-cyclopentyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 18: 1- (pyrrolidin-1-yl) -2- {6- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 19: 1- (azetidin-1-yl) -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 20: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (3-phenoxyazetidin-1-yl) ethanone
Example 21: N, N-dimethyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 22: 2- [5- (4-Methylphenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 23: N-cyclopentyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 24: N-ethyl-N-methyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 25: N, N-dimethyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 26: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 27: N-cyclopentyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 28: N-ethyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-methylacetamide
Example 29: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 30: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 31: N-cyclopentyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 32: 2- [5- (4-Methylphenoxy) -1H-benzimidazol-1-yl] -1- (piperidin-1-yl) ethanone,
Example 33: 1- (piperidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 34: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (piperidin-1-yl) ethanone,
Example 35: N-cyclohexyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 36: N-cyclohexyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 37: N-cyclohexyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 38: N-cyclohexyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 39: N-ethyl-N-methyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 40 N, N-dimethyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide
Example 41: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 42: 1- (piperidin-1-yl) -2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 43: N-cyclopentyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 44: N-cyclohexyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 45: N, N-dimethyl-2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 46: 2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 47: 2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 48: N-ethyl-N-methyl-2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 49: N-ethyl-2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 50: N-cyclohexyl-2- (6-phenyl-1H-benzimidazol-1-yl) acetamide,
Example 51: 2- [6- (2-Chlorophenyl) -1H-benzimidazol-1-yl] -N-cyclohexylacetamide,
Example 52: N-cyclohexyl-2- [6- (2-methoxyphenyl) -1H-benzimidazol-1-yl] acetamide,
Example 53: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-cyclohexylacetamide,
Example 54: N-cyclohexyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 55: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 56: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 57: 2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 58: 2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 59: 2- [6- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 60: 4- {1- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -1H-benzimidazol-5-yl} benzonitrile,
Example 61: 2- [5- (4-cyanophenyl) -1H-benzimidazol-1-yl] -N-cyclopentylacetamide,
Example 62: N-ethyl-N-methyl-2- [6- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 63: 2- [6- (4-methylphenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 64: N-ethyl-N-methyl-2- {6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 65: 2- [5- (4-Fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 66: N-ethyl-2- [5- (4-fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-methylacetamide
Example 67: 2- [5- (4-Fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 68: N, N-dimethyl-2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 69: N-ethyl-N-methyl-2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 70: 1- (pyrrolidin-1-yl) -2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 71: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1-[(3R) -3-hydroxypiperidin-1-yl] Ethanon,
Example 72: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} Ethanon,
Example 73: 1- (pyrrolidin-1-yl) -2- {6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 74: N-ethyl-N-methyl-2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide,
Example 75: 1- (pyrrolidin-1-yl) -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 76: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone
Example 77: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 78: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-ethyl-N-methylacetamide,
Example 79: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 80 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide
Example 81: N-ethyl-2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 82: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 83: N-ethyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-methylacetamide,
Example 84: N-cyclopentyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 85: N, N-dimethyl-2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 86: N-ethyl-N-methyl-2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 87: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 88: N, N-dimethyl-2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 89: 2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 90: 1- (pyrrolidin-1-yl) -2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone,
Example 91: N-cyclopentyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 92: 1- (piperidin-1-yl) -2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone
Example 93: N-cyclohexyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 94: N-ethyl-N-methyl-2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 95: 1- (pyrrolidin-1-yl) -2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone,
Example 96: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 97: 1-[(3S) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 98: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1-[(3R) -3-hydroxypiperidin-1-yl] ethanone,
Example 99: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -1- (4-hydroxypiperidin-1-yl) ethanone,
Example 100: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide,
Example 101: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N- (trans-4-hydroxycyclohexyl) acetamide,
Example 102: N-cyclohexyl-2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide,
Example 103: N- (trans-4-hydroxycyclohexyl) -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 104: N-[(1S, 2S) -2-hydroxycyclohexyl] -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 105: 1- (4-hydroxypiperidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 106: N- (tetrahydro-2H-pyran-4-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 107: N- (trans-4-hydroxycyclohexyl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 108: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1- (morpholin-4-yl) ethanone
Example 109: 1- (3,3-difluoroazetidin-1-yl) -2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] ethanone,
Example 110: N-[(2R) -2-hydroxypropyl] -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 111: N-[(2S) -2-hydroxypropyl] -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 112: N- (2-hydroxy-2-methylpropyl) -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 113: N-cyclohexyl-2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 114: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N- (trans-4-hydroxycyclohexyl) acetamide,
Example 115: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-[(1S, 2S) -2-hydroxycyclohexyl] acetamide,
Example 116: 2- [6- (4-fluorophenoxy)-1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1.1 ^{3, 7]} dec-1-yl) acetamide,
Example 117: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (3-hydroxytricyclo [3.3.1.1 ^3,7 ] dec-1- Yl) acetamide,
Example 118: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide
Example 119: 1-[(3S) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 120: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone
Example 121: N- (4-hydroxycyclohexyl) -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 122: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N- (2-hydroxy-2-methylpropyl) acetamide,
Example 123: 1- (pyrrolidin-1-yl) -2- {5- [6- (trifluoromethyl) pyridin-3-yl] -1H-benzimidazol-1-yl} ethanone
Example 124: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-[(2S) -2-hydroxypropyl] acetamide,
Example 125: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N- (2-hydroxy-2-methylpropyl) acetamide,
Example 126: N- (cyclohexylmethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 127: N-[(1S) -1-cyclohexylethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 128: N-[(1R) -1-cyclohexylethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide
Example 129: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-2-yl) acetamide,
Example 130: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N-cyclohexylacetamide,
Example 131 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (cyclohexylmethyl) acetamide,
Example 132: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-1-yl) acetamide,
Example 133: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-2-yl) acetamide,
Example 134: 2- [5- (pyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 135: 2- [5- (3-methoxypyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 136: 2- [5- (5-Fluoro-2-methoxypyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
1- (3,3-difluoroazetidin-1-yl) -2- [5- (pyridin-4-yl) 1H-benzimidazol-1-yl] ethanone,
2- [5- (pyridin-4-yl) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide,
1- (pyrrolidin-1-yl) -2- {5- [5- (trifluoromethyl) pyridin-2-yl] -1H-benzimidazol-1-yl} ethanone,
2- [5- (5-fluoropyridin-2-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
1- (3,3-difluoroazetidin-1-yl) -2- [5- (5-fluoropyridin-2-yl) -1H-benzimidazol-1-yl] ethanone,
2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (4-hydroxycyclohexyl) acetamide,
2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (2-hydroxycyclohexyl) acetamide,
2- [6- (4-Chlorophenoxy) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide and 2- [6- (4-fluorophenoxy) -1H -Benzimidazol-1-yl] -N-[(2R) -2-hydroxypropyl] acetamide.

CLAIM | ITEM 14 The compound of claim | item 1 or its pharmaceutically acceptable salt selected from the following compound groups:
Example 1: 1- (Pyrrolidin-1-yl) -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 2: N, N-dimethyl-2- (6-phenyl-1H-benzimidazol-1-yl) acetamide,
Example 3: N, N-dimethyl-2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 4: N-ethyl-N-methyl-2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 5: N-ethyl-N-methyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide
Example 6: N-ethyl-N-methyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 7: N-ethyl-2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 8: N-cyclohexyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 9: N-cyclopentyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 10: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 11: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 12: N-ethyl-2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-methylacetamide,
Example 13: N-ethyl-N-methyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 14: N, N-dimethyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide,
Example 15: 2- (5-phenoxy-1H-benzimidazol-1-yl) -1- (pyrrolidin-1-yl) ethanone,
Example 16: 2- (5-phenoxy-1H-benzimidazol-1-yl) -1- (piperidin-1-yl) ethanone,
Example 17: N-cyclopentyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 18: 1- (pyrrolidin-1-yl) -2- {6- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 19: 1- (azetidin-1-yl) -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 20: 2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (3-phenoxyazetidin-1-yl) ethanone
Example 21: N, N-dimethyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 22: 2- [5- (4-Methylphenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 23: N-cyclopentyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 24: N-ethyl-N-methyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 25: N, N-dimethyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 26: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 27: N-cyclopentyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 28: N-ethyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-methylacetamide
Example 29: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 30: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 31: N-cyclopentyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 32: 2- [5- (4-Methylphenoxy) -1H-benzimidazol-1-yl] -1- (piperidin-1-yl) ethanone,
Example 33: 1- (piperidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 34: 2- [5- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (piperidin-1-yl) ethanone,
Example 35: N-cyclohexyl-2- (5-phenoxy-1H-benzimidazol-1-yl) acetamide
Example 36: N-cyclohexyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 37: N-cyclohexyl-2- [5- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 38: N-cyclohexyl-2- {5- [4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 39: N-ethyl-N-methyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 40 N, N-dimethyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide
Example 41: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 42: 1- (piperidin-1-yl) -2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] ethanone,
Example 43: N-cyclopentyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 44: N-cyclohexyl-2- {5- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl] acetamide,
Example 45: N, N-dimethyl-2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 46: 2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 47: 2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 48: N-ethyl-N-methyl-2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 49: N-ethyl-2- [5- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 50: N-cyclohexyl-2- (6-phenyl-1H-benzimidazol-1-yl) acetamide,
Example 51: 2- [6- (2-Chlorophenyl) -1H-benzimidazol-1-yl] -N-cyclohexylacetamide,
Example 52: N-cyclohexyl-2- [6- (2-methoxyphenyl) -1H-benzimidazol-1-yl] acetamide,
Example 53: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-cyclohexylacetamide,
Example 54: N-cyclohexyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 55: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 56: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 57: 2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N, N-dimethylacetamide,
Example 58: 2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 59: 2- [6- (2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 60: 4- {1- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -1H-benzimidazol-5-yl} benzonitrile,
Example 61: 2- [5- (4-cyanophenyl) -1H-benzimidazol-1-yl] -N-cyclopentylacetamide,
Example 62: N-ethyl-N-methyl-2- [6- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 63: 2- [6- (4-methylphenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 64: N-ethyl-N-methyl-2- {6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 65: 2- [5- (4-Fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 66: N-ethyl-2- [5- (4-fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-methylacetamide
Example 67: 2- [5- (4-Fluoro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 68: N, N-dimethyl-2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 69: N-ethyl-N-methyl-2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 70: 1- (pyrrolidin-1-yl) -2- {5- [2- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 71: 2- {6- [2-chloro-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -1-[(3R) -3-hydroxypiperidin-1-yl] Ethanon,
Example 72: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} Ethanon,
Example 73: 1- (pyrrolidin-1-yl) -2- {6- [3- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 74: N-ethyl-N-methyl-2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide,
Example 75: 1- (pyrrolidin-1-yl) -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} ethanone,
Example 76: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone
Example 77: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide,
Example 78: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -N-ethyl-N-methylacetamide,
Example 79: 2- [5- (4-Chloro-2-methoxyphenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 80 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -N, N-dimethylacetamide
Example 81: N-ethyl-2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N-methylacetamide,
Example 82: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 83: N-ethyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} -N-methylacetamide,
Example 84: N-cyclopentyl-2- {6- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 85: N, N-dimethyl-2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 86: N-ethyl-N-methyl-2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 87: 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 88: N, N-dimethyl-2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 89: 2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} -1- (pyrrolidin-1-yl) ethanone,
Example 90: 1- (pyrrolidin-1-yl) -2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone,
Example 91: N-cyclopentyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 92: 1- (piperidin-1-yl) -2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone
Example 93: N-cyclohexyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide,
Example 94: N-ethyl-N-methyl-2- {5- [4- (methylsulfonyl) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 95: 1- (pyrrolidin-1-yl) -2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] ethanone,
Example 96: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 97: 1-[(3S) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 98: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1-[(3R) -3-hydroxypiperidin-1-yl] ethanone,
Example 99: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -1- (4-hydroxypiperidin-1-yl) ethanone,
Example 100: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide,
Example 101: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N- (trans-4-hydroxycyclohexyl) acetamide,
Example 102: N-cyclohexyl-2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide,
Example 103: N- (trans-4-hydroxycyclohexyl) -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 104: N-[(1S, 2S) -2-hydroxycyclohexyl] -2- {6- [4- (trifluoromethyl) phenoxy] -1H-benzimidazol-1-yl} acetamide
Example 105: 1- (4-hydroxypiperidin-1-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 106: N- (tetrahydro-2H-pyran-4-yl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 107: N- (trans-4-hydroxycyclohexyl) -2- {5- [4- (trifluoromethoxy) phenyl] -1H-benzimidazol-1-yl} acetamide
Example 108: 2- [5- (4-Fluorophenyl) -1H-benzimidazol-1-yl] -1- (morpholin-4-yl) ethanone
Example 109: 1- (3,3-difluoroazetidin-1-yl) -2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] ethanone,
Example 110: N-[(2R) -2-hydroxypropyl] -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 111: N-[(2S) -2-hydroxypropyl] -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 112: N- (2-hydroxy-2-methylpropyl) -2- {5- [2-methoxy-4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 113: N-cyclohexyl-2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 114: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N- (trans-4-hydroxycyclohexyl) acetamide,
Example 115: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-[(1S, 2S) -2-hydroxycyclohexyl] acetamide,
Example 116: 2- [6- (4-fluorophenoxy)-1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1.1 ^{3, 7]} dec-1-yl) acetamide,
Example 117: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (3-hydroxytricyclo [3.3.1.1 ^3,7 ] dec-1- Yl) acetamide,
Example 118: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (tetrahydro-2H-pyran-4-yl) acetamide
Example 119: 1-[(3S) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone,
Example 120: 1-[(3R) -3-hydroxypiperidin-1-yl] -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone
Example 121: N- (4-hydroxycyclohexyl) -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} acetamide,
Example 122: 2- [5- (4-fluorophenyl) -1H-benzimidazol-1-yl] -N- (2-hydroxy-2-methylpropyl) acetamide,
Example 123: 1- (pyrrolidin-1-yl) -2- {5- [6- (trifluoromethyl) pyridin-3-yl] -1H-benzimidazol-1-yl} ethanone
Example 124: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-[(2S) -2-hydroxypropyl] acetamide,
Example 125: 2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N- (2-hydroxy-2-methylpropyl) acetamide,
Example 126: N- (cyclohexylmethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 127: N-[(1S) -1-cyclohexylethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide,
Example 128: N-[(1R) -1-cyclohexylethyl) -2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] acetamide
Example 129: 2- [6- (4-Fluorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-2-yl) acetamide,
Example 130: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N-cyclohexylacetamide,
Example 131 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (cyclohexylmethyl) acetamide,
Example 132: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-1-yl) acetamide,
Example 133: 2- [6- (4-chlorophenoxy) -1H-benzimidazol-1-yl] -N- (tricyclo [3.3.1 ^3,7 ] dec-2-yl) acetamide,
Example 134: 2- [5- (pyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone,
Example 135: 2- [5- (3-Methoxypyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone and Example 136: 2- [5- (5-Fluoro-2-methoxypyridin-4-yl) -1H-benzimidazol-1-yl] -1- (pyrrolidin-1-yl) ethanone.

[Item 15] A pharmaceutical composition comprising the compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof.

CLAIM | ITEM 16 The therapeutic agent of the disease which contains Nav1.7 (SCN9A) containing the compound as described in any one of claim | item 1 -14, or its pharmaceutically acceptable salt as an active ingredient.

[Item 17] Neuropathic pain, nociceptive pain, inflammatory pain, small-diameter fiber neuropathy comprising the compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient , Treatment for erythema or paroxysmal pain.

CLAIM | ITEM 18 The therapeutic agent of the disease in which Nav1.7 (SCN9A) in which the compound as described in any one of claim | item 1-14 or its pharmaceutically acceptable salt is included as an active ingredient, and an antiepileptic drug , A drug comprising a combination of at least one drug selected from an antidepressant, a narcotic analgesic, an anti-inflammatory drug, a reductase inhibitor, and a prostaglandin derivative preparation.

[Item 19] Items 1 to 14 for the treatment of neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, redness of the limbs, paroxysmal pain, dysuria, or multiple sclerosis Use of the compound according to any one of the above or a pharmaceutically acceptable salt thereof.

[Item 20] A neuropathic pain in a mammal, comprising administering an effective amount of the compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof to the mammal, A method for treating nociceptive pain, inflammatory pain, small fiber neuropathy, limb erythema pain, paroxysmal pain.

  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 linear or branched saturated hydrocarbon group having 1 to 2 carbon atoms, and “C _1-3 alkyl” means 1 to 2 carbon atoms. Means three straight-chain or branched saturated hydrocarbon groups, and “C _1-4 alkyl” means a straight-chain or branched saturated hydrocarbon having 1 to 4 carbon atoms. Group means “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. Unless otherwise specified, the substituent in “optionally substituted C _1-4 alkyl” is selected from the following substituent group [A], and is independently substituted with 1 to 3 substituents at substitutable positions. May be.

“C _3-7 cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 7 carbon atoms, and “C _3-10 cycloalkyl” has 3 to 10 carbon atoms, A cyclic saturated hydrocarbon group is meant. “C _3-7 cycloalkyl” and “C _3-10 cycloalkyl” include those that are partially unsaturated. “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, etc. Specific examples of “C _3-10 cycloalkyl” include In addition to the above, cyclooctyl, adamantyl and the like can be mentioned. Preferred is “C _3-7 cycloalkyl”. The substituents in “optionally substituted C _3-7 cycloalkyl” and “optionally substituted C _3-10 cycloalkyl” are selected from the following substituent group [A], unless otherwise specified. 1 to 3 may be independently substituted at each substitutable position.

The _{"C 3-7} cycloalkyl" and the _{"C 3-10} cycloalkyl", respectively, as _{"C 3-7} cycloalkyl" and _{"C 3-10} cycloalkyl", phenyl or a 5- or 6-membered Rings 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 heteroaryl” described below) And a bicyclic group condensed with a 5- or 6-membered ring of “3 to 7-membered 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. Unless otherwise specified, the substituent in “optionally substituted C _6-10 aryl” is selected from the following substituent group [B], and is independently substituted with 1 to 3 substituents at substitutable positions. May be.

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

“(C _6-10 aryl) C _1-4 alkyl” means C _1-4 alkyl substituted with the above “C _6-10 aryl”, specifically, benzyl, 1-phenylethyl, Examples include 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl, 1,2-diphenylethyl and the like. “(C _6-10 aryl) C _1-4 alkyl” preferably includes C _1-4 alkyl substituted with phenyl, more preferably C _1-2 alkyl substituted with phenyl. .

“(C _6-10 aryl) C _1-4 alkoxy” means C _1-4 alkoxy substituted with the above “C _6-10 aryl”, specifically, benzyloxy, 1-phenylethyl Examples include oxy, 2-phenylethyloxy, 1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy, diphenylmethyloxy, 2,2-diphenylethyloxy, 1,2-diphenylethyloxy and the like. (C _6-10 aryl) C _1-4 alkoxy preferably includes C _1-4 alkoxy substituted with phenyl, more preferably C _1-2 alkoxy substituted with phenyl.

  The “5- to 12-membered heteroaryl” is one or the same or different heteroatoms selected from nitrogen, sulfur or oxygen in addition to carbon as a ring-constituting atom (for example, 2 to 4). ) Means a monocyclic or polycyclic 5- to 12-membered aromatic group. The “5- or 6-membered monocyclic heteroaryl” means a monocyclic 5- or 6-membered aromatic group in the “5- to 12-membered heteroaryl”. “5- to 12-membered heteroaryl” is preferably “5- or 6-membered monocyclic heteroaryl”. Unless otherwise specified, the substituent in the “optionally substituted 5- to 12-membered heteroaryl” is selected from the following substituent group [B], and is independently selected from 1 to 3 at each substitutable position. May be substituted.

  Among the “5- to 12-membered heteroaryl”, a polycyclic heteroaryl is a condensed monocyclic heteroaryl and an aromatic ring (eg, benzene, pyridine) or a non-aromatic ring (eg, cyclohexyl). Are also included. Specific examples of “5- to 12-membered heteroaryl” include groups represented by the following formulae. Of these, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are preferable. In another embodiment, it is preferably benzofuranyl (the bonding position is on the heteroaryl (furan) ring), pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl. Specific examples of “5- or 6-membered monocyclic heteroaryl” include monocyclic groups out of groups represented by the following formulae.

  “3- to 7-membered carbocycle” means a 3- to 7-membered cyclic group in which the ring is composed of only carbon atoms. The carbocycle is non-aromatic and may be either saturated or partially unsaturated. A saturated carbocyclic ring is preferable, and a 5- or 6-membered saturated carbocyclic ring is more preferable. Specific examples of “3 to 7-membered carbocycle” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. More preferred are cyclopentyl and cyclohexyl. Unless otherwise specified, the substituent in the “optionally substituted 3 to 7 membered carbocycle” is selected from the following substituent group [A] and independently represents 1 to 3 at each substitutable position. May be substituted.

  The “3- to 7-membered heterocycle” is one or the same or different heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon as atoms constituting the ring (for example, 2 to 2 4 or preferably 2 to 3), which means a 3 to 7 membered cyclic group. 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 heterocycle” include oxetanyl, azetidinyl, pyranyl, tetrahydrofuryl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, Examples include thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydropyranyl, tetrahydropyridinyl and the like. Of these, pyranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl and morpholinyl are preferable. Unless otherwise specified, the substituent in the “optionally substituted 3 to 7 membered heterocyclic ring” is selected from the following substituent group [A], and is independently selected from 1 to 3 at each substitutable position. May be substituted.

  The “3- to 7-membered heterocycle” is a condensation of a 3- to 7-membered heterocycle with a 6-membered aromatic hydrocarbon (for example, benzene) or 6-membered heteroaryl (for example, pyridine, pyrimidine or pyridazine). Includes rings. 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. Unless otherwise specified, the substituent in “optionally substituted C _1-4 alkoxy” is selected from the following substituent group [A], and is independently substituted with 1 to 3 at each substitutable position. May be.

“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. Of these, cyclohexyloxy is preferable. Unless otherwise specified, the substituent in “optionally substituted C _3-7 cycloalkoxy” is selected from the following substituent group [A], and is independently 1 to 3 at each substitutable position. May be substituted.

“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 by 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. Of these, methylamino and dimethylamino are preferable.

“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. Of these, cyclohexylamino is preferable.

“C _6-10 arylamino” means an amino group substituted with one or two of the above “C _6-10 aryl”. A specific example of “C _6-10 arylamino” is, for example, phenylamino.

  “5- to 12-membered heteroarylamino” means an amino group substituted with 1 or 2 of the “5- to 12-membered heteroaryl”. Specific examples of “5- to 12-membered heteroarylamino” include, for example, pyridylamino, pyrimidylamino, pyrazolylamino, etc. Among them, pyridylamino is preferable.

“C _2-6 alkenyl” means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms having one or more double bonds. “C _2-3 alkenyl” means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 3 carbon atoms having one or more double bonds. “C _2-6 alkenyl” is preferably “C _2-3 alkenyl”. Specific examples of “C _2-3 alkenyl” include ethenyl, propenyl, and structural and geometric isomers thereof. Specific examples of “C _2-6 alkenyl” include crotyl, Examples include butenyl, pentenyl, hexenyl and the like, and structural isomers and geometric isomers thereof. The bond in the “C _2-6 alkenyl” is preferably on an unsaturated carbon atom, such as 1-ethenyl or 1-propenyl.

“C _2-6 alkynyl” means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and having one or more triple bonds. “C _2-3 alkynyl” means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 3 carbon atoms and having one or more triple bonds. “C _2-6 alkynyl” is preferably “C _2-3 alkynyl”. Specific examples of “C _2-3 alkynyl” include ethynyl, propynyl, and structural isomers thereof. Specific examples of “C _2-6 alkynyl” include butynyl, pentynyl, and hexynyl. As well as structural isomers thereof. The bond in the “C _2-6 alkynyl” is preferably on an unsaturated carbon atom, and for example, 1-ethynyl or 1-propynyl is preferable.

“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. Unless otherwise specified, the substituent in “optionally substituted C _1-4 alkylsulfonyl” is selected from the following substituent group [A], and is independently 1 to 3 at each substitutable position. May be substituted.

“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. Unless otherwise specified, the substituent in “optionally substituted C _1-4 alkylthio” is selected from the following substituent group [A], and is independently substituted with 1 to 3 at each substitutable position. May be.

The above substituent groups [A] and [B] are shown below.
[A]: halogen, hydroxyl group, C _1-4 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkoxy [B]: halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _{3- 7} cycloalkyl, C _3-7 cycloalkoxy, 3-7 membered heterocycle, C _1-4 alkylthio, C _1-4 alkylsulfonyl

The above substituent group [A] is preferably fluorine, chlorine, hydroxyl group, C _1-2 alkoxy or C _5-6 cycloalkoxy, and more preferably [B] is fluorine, chlorine, cyano, C _1-2 alkyl. , C _1-2 alkoxy or C _5-6 cycloalkoxy.

More preferred as the above substituent group [A] is fluorine, hydroxyl group or C _1-2 alkoxy, and more preferred as [B] is fluorine, cyano, C _1-2 alkyl or C _1-2 alkoxy. .

  In order to more specifically disclose the compound of the present invention represented by the formula (1), the various symbols used in the formula (1) will be described in more detail with suitable specific examples.

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 part in alkylamino is each independently a halogen, a hydroxyl group, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl, or an optionally substituted C _3- Optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₇ cycloalkoxy and optionally substituted 3-7 membered heterocycles, C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (the cycloalkyl part in the cycloalkyl, the cycloalkoxy and the cycloalkylamino is Each independently halogen, hydroxyl, substituted optionally optionally C _1-4 be alkoxy, substituted by comprising from good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted also be the group Optionally substituted with 1-3 independently selected substituents), C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamino, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, 5-12 membered heteroarylamino, (C _6-10 aryl) C _1-4 alkyl, (C _6-10 aryl) C _1-4 alkoxy (the aryl, aryloxy) The aryl moiety in the arylamino, the arylalkyl and the arylalkoxy, and the heteroaryl, the heteroaryloxy and the The heteroaryl part of the hetero arylamino are each independently halogen, cyano, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally C ₃ substituted _-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy, optionally substituted 3-7 membered heterocycle (except tetrazole), optionally substituted C _1-4 alkylthio and Optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted C _1-4 alkylsulfonyl), C _2-6 alkenyl, C _2-6 alkynyl ( the alkenyl and the alkynyl are each independently, halogen, cyano, optionally substituted C _1-4 alkyl, substituted C _1-4 optionally alkoxy C, C _3-7 cycloalkyl which may be substituted, C _3-7 cycloalkoxy which may be substituted, _{3- to} 7-membered heterocyclic ring which may be substituted, C ₆ which may be substituted Independently selected from the group consisting of _-10 aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C _1-4 alkylthio and optionally substituted C _1-4 alkylsulfonyl. Optionally substituted with 1 to 3 substituents) or a 3 to 7 membered heterocyclic ring (wherein the heterocyclic ring is halogen, hydroxyl group, optionally substituted C _1-6 alkyl, substituted which may be C _1-4 alkoxy, one to three independently selected from the group consisting of optionally substituted C _3-7 also be cycloalkyl and optionally substituted C _3-7 cycloalkoxy With substituents A conversion may be), ^{where, R 1a, R 1b, R} 1c and R ^1d are at least one of _{C 6-10 aryl, C 6-10 aryloxy, C 6-10} arylamino, 5 12-membered heteroaryl, 5- to 12-membered heteroaryloxy (the aryl moiety in the aryl, the aryloxy, the arylamino and the arylalkoxy, the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently Halogen, cyano, C _1-4 alkyl which may be substituted, C _1-4 alkoxy which may be substituted, C _3-7 cycloalkyl which may be substituted, C which may be substituted _3-7 cycloalkoxy, heterocyclic ring members 3-7 may be substituted, an optionally substituted C _1-4 alkyl Thio and optionally substituted with 1-3 substituents independently selected from substituted composed from optionally C _1-4 alkylsulfonyl optionally group) or 3-7 membered heterocyclic ring (the Heterocycles are halogen, hydroxyl, optionally substituted C _1-6 alkyl, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl and optionally substituted. And optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy.

In the description of R ^1a , R ^1b , R ^1c and R ^1d , preferably at least one of R ^1b and R ^1c is C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamino, 5 -12 membered heteroaryl, 5-12 membered heteroaryloxy (the aryl moiety in the aryl, the aryloxy, the arylamino and the arylalkoxy, the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each a halogen atom, , cyano, optionally substituted _{C 1-4} alkyl, optionally substituted _{C 1-4} alkoxy, optionally substituted _{C 3-7} cycloalkyl, optionally substituted _{C 3-7} Cycloalkoxy, optionally substituted 3-7 membered heterocycle, optionally substituted _1-4 may be substituted with 1-3 substituents independently selected from alkylthio and substituted consists also optionally C _1-4 alkylsulfonyl optionally group) or 3-7 membered heterocyclic A ring (the heterocyclic ring is a halogen, a hydroxyl group, an optionally substituted C _1-6 alkyl, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl and a substituted ring; Optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy.

More preferably, at least one of R ^1b and R ^1c is C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy (the aryl, the aryl The aryl moiety in oxy, the arylalkyl and the arylalkoxy, and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are respectively the aryl and heteroaryl moieties of R ^1a , R ^1b , R ^1c and R ^1d described above. Optionally substituted with the same substituents as described above), 3-7 membered heterocyclic ring (the heterocyclic ring may be halogen, hydroxyl group, optionally substituted C _1-6 alkyl, optionally substituted). C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl and optionally substituted And optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy.

Preferred 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-cyanophenyl, 4-difluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2- Chloro-4-trifluoromethylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-ethoxy-4-trifluoromethylphenyl, 2-isopropoxy-4-trifluoromethylphenyl, 2-methyl-4-tri Fluoro Methylphenyl, 2-methoxymethyl-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-hydroxy-4-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 2- Chloro-4-trifluoromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 2-methyl-4-trifluoromethoxyphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-trifluoro Methoxyphenyl, 2-ethoxyphenyl, 4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 2-chloro-4-methoxyphenyl, 3-trifluoromethyl-4-methoxyphenyl, 2-trifluoromethyl-4- Methoxyphenyl, 2-chloro-5-meth Cyphenyl, 3-trifluoromethyl-5-methoxyphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-methoxy-4-chlorophenyl, 2-trifluoromethyl-4-chlorophenyl, 3-trifluoromethyl-4-chlorophenyl 4-fluorophenyl, 2-trifluoromethyl-4-fluorophenyl, 3-trifluoromethyl-4-fluorophenyl, 4-methylphenyl, 4-tert-butylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonyl Phenyl, phenoxy, 4-trifluoromethylphenoxy, 4-trifluoromethoxyphenoxy, 4-fluorophenoxy, 2-chloro-4-trifluoromethylphenoxy, 2-methoxy-4-trifluoromethylphenoxy, 2-methyl-4 Trifluoromethylphenoxy, 2-fluoro-4-trifluoromethylphenoxy, 2-chloro-4-trifluoromethoxyphenoxy, 2-methoxy-4-trifluoromethoxyphenoxy, 2-methyl-4-trifluoromethoxyphenoxy, 2 -Fluoro-4-trifluoromethoxyphenoxy, benzyl, 4-fluorobenzyl, benzyloxy, 4-trifluoromethylbenzyloxy, 4-fluorobenzyloxy, 4-fluorophenethyloxy, 4-trifluoromethoxyphenylamino, 6- Trifluoromethylpyridin-3-yl, 5-trifluoromethylpyridin-2-yl, 6-methoxypyridin-3-yl, 1-benzofuran-2-yl, 4-fluorophenylethynyl, tetrahydro-2H-pyran-4 -B , 3,6-dihydro-2H-pyran-4-yl,

  More preferably, hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethylphenyl 2-methoxy-4-trifluoromethylphenyl, 2-ethoxy-4-trifluoromethylphenyl, 2-isopropoxy-4-trifluoromethylphenyl, 2-methyl-4-trifluoromethylphenyl, 2-fluoro- 4-trifluoromethylphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2-methoxy-4-trifluoromethoxyphenyl, 2-methyl-4-trifluoromethoxyphenyl, 2-fluoro-4-trifluoromethoxyphenyl , 4-F Orophenyl, phenoxy, 4-trifluoromethylphenoxy, 4-trifluoromethoxyphenoxy, 2-chloro-4-trifluoromethylphenoxy, 2-methoxy-4-trifluoromethylphenoxy, 2-methyl-4-trifluoromethylphenoxy 2-fluoro-4-trifluoromethylphenoxy, 2-chloro-4-trifluoromethoxyphenoxy, 2-methoxy-4-trifluoromethoxyphenoxy, 2-methyl-4-trifluoromethoxyphenoxy, 2-fluoro-4 -Trifluoromethoxyphenoxy, benzyl, benzyloxy,

  Even more preferably, hydrogen, cyclopentyl, cyclohexyl, methoxy, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2 -Ethoxy-4-trifluoromethylphenyl, 2-methyl-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2-methoxy-4-tri Fluoromethoxyphenyl, 2-methyl-4-trifluoromethoxyphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 4-fluorophenyl, tetrahydro-2H-pyran-4-yl.

R ² and R ³ are hydrogen, C _1-6 alkyl (wherein the alkyl is cyano, halogen, hydroxyl group, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, 1 to 3 independently selected from the group consisting of optionally substituted C _3-7 cycloalkoxy, optionally substituted C _6-10 aryl and optionally substituted 3-7 membered heterocycle Optionally substituted with 5 substituents), C _3-10 cycloalkyl or 3-7 membered heterocycle (the cycloalkyl and the heterocycle are each halogen, hydroxyl, or optionally substituted C). _1-6 alkyl, substituted optionally optionally C _1-4 be alkoxy, substituted composed from a good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted also be the group Optionally substituted with 1-3 substituents selected et independently also be).

R ² and R ³ are preferably hydrogen, C _1-6 alkyl (the alkyl is cyano, halogen, hydroxyl group, C _1-4 alkoxy optionally substituted by 1 to 3 fluorines, 1 to 3 good C _3-7 optionally substituted by fluorine cycloalkyl, optionally substituted by one to three optionally substituted by fluorine C _3-7 cycloalkoxy and 1-3 fluorines 3 Optionally substituted with 1 to 5 substituents independently selected from the group consisting of ˜7 membered heterocycles, C _3-7 cycloalkyl or 3-7 membered heterocycles (the cycloalkyls) And the heterocyclic ring is C _1-4 alkoxy, C _3-7 cycloalkyl and C _3-7 cycloalkoxy, each optionally substituted by halogen, hydroxyl, 1-3 fluorines. Optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

R ² and R ³ are more preferably hydrogen, C _1-6 alkyl (wherein the alkyl is halogen, hydroxyl, C _1-4 alkoxy optionally substituted by 1 to 3 fluorines and 1 to 3 Optionally substituted by 1 to 5 substituents independently selected from the group consisting of 3 to 7 membered heterocycles optionally substituted by fluorine, or C _3-7 cycloalkyl (the cyclo Alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl, and C _1-4 alkoxy.

Preferable specific examples of R ² and R ³ include hydrogen, methyl, cyclopropylmethyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, propyl 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 3-hydroxypropyl, 2-hydroxypropyl, isopropyl, 1-cyano-1-methylethyl, butyl, Isobutyl, 2-hydroxy-2-methylpropyl, tert-butyl, 2-hydroxy-1,1-dimethylethyl, neopentyl, 1-ethylpropyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, 3- Fluorocyclopentyl, 2-hydroxycyclopentyl, 3-hydro Cycyclopentyl, 3,3-difluorocyclopentyl, 3-methoxycyclopentyl, 1-hydroxymethylcyclopentyl, cyclohexyl, 2-hydroxycyclohexyl, 3-fluorocyclohexyl, 3,3-difluorocyclohexyl, 4-hydroxycyclohexyl, 3-methoxycyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 4-methoxycyclohexyl, adamantan-1-yl, 3-methyloxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, 2, 2-dimethyltetrahydro-2H-pyran-4-yl, 1-methylpiperidin-4-yl,
Among these, hydrogen, methyl, ethyl, propyl, 2-hydroxypropyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopentyl, 3-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-methoxycyclopentyl, cyclohexyl, 3- Fluorocyclohexyl, 3,3-difluorocyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 3-methoxycyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 4-methoxycyclohexyl, tetrahydro-2H-pyran-4- Il
More preferably, hydrogen, methyl, ethyl, 2-hydroxypropyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 4,4-difluorocyclohexyl, 4-methoxycyclohexyl, tetrahydro-2H-pyran-4-yl It is.

As R ² and R ³ , it is preferable that at least one of R ² and R ³ is not hydrogen.

R ² and R ³ together with the adjacent nitrogen atom have the following formula (2):

で表される環状基を形成していてもよい。

The cyclic group represented by these may be formed.

In the above formula (2), d is 1, 2 or 3 when Z is a single bond, and Z is —O—, —S—, —SO ₂ —, —NR ⁷ —, —N (COR ⁷ )-or -N (SO ₂ R ⁷ )-is 2 or 3, and d is preferably 2 or 3.

e is 1, 2 or 3 when Z is a single bond, and Z is —O—, —S—, —SO ₂ —, —NR ⁷ —, —N (COR ⁷ ) — or —N ( When SO ₂ R ⁷ ) —, it is 2 or 3, and e is preferably 1 (including 1 only when Z is a single bond) or 2.

  f is 0, 1, 2 or 3, preferably 0, 1 or 2, and more preferably 0 or 1.

Z is a single bond, —O—, —S—, —SO ₂ —, —NR ⁷ —, —N (COR ⁷ ) — or —N (SO ₂ R ⁷ ) —, preferably a single bond, -O- or -SO ₂ - and the like, more preferably a single bond or -O-, and the like, more preferably a single bond.

R ⁶ is bonded to a carbon atom on the cyclic group represented by the above formula (2), and halogen, cyano, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and the alkoxy are each a halogen atom) , A hydroxyl group, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl, an optionally substituted C _3-7 cycloalkoxy, and an optionally substituted 3-7 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of member heterocycles, C _6-10 aryl or C _6-10 aryloxy (in the aryl and the aryloxy aryl moiety, halogen, cyano, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 Sik Alkyl, optionally substituted C _3-7 cycloalkoxy, heterocyclic ring members 3-7 may be substituted, which may be a good C _1-4 alkylthio and substituted also be substituted C _{1- And} optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₄ alkylsulfonyl).

R ⁶ is preferably halogen, hydroxyl group or C _1-4 alkoxy (wherein the alkoxy is halogen, hydroxyl group, C _1-4 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkoxy and 3-7 membered complex) Optionally substituted with 1 to 3 substituents independently selected from the group consisting of rings.

R ⁶ is more preferably halogen, hydroxyl group or C _1-4 alkoxy (the alkoxy may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen and hydroxyl group). Can be mentioned.

Preferred specific examples of R ⁶ include fluorine, hydroxyl group, methyl, hydroxymethyl, methoxymethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, and cyano.
More preferably, hydrogen, fluorine, hydroxyl group, methoxy, ethoxy, isopropoxy, trifluoromethoxy,
Even more preferred are fluorine and methoxy.

Also, when two or more R ⁶ are present, the plurality of R ⁶ are each independent, and two or three R ⁶ are bonded together with one or more carbon atoms to which they are bonded to form 3 to 3 A 7-membered carbocyclic or heterocyclic ring may be formed.

When two or more R ⁶ are present and two or three R ⁶ , together with one or more carbon atoms to which they are bonded, form a ring, preferred examples include those of formula (2 ) Include the following structures.

R ⁷ represents C _1-4 alkyl (wherein the alkyl is halogen, hydroxyl group, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy and optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted 3-7 membered heterocycles) or C _3-7 cyclo alkyl (wherein the cycloalkyl, halogen, hydroxyl, substituted optionally optionally C _1-4 also alkoxy, made from a good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted substituted Optionally substituted with 1 to 3 substituents independently selected from the group).

R ⁷ is preferably C _1-4 alkyl (the alkyl is selected from the group consisting of a halogen, a hydroxyl group, an optionally substituted C _3-7 cycloalkyl, and an _optionally substituted 3-7 membered heterocyclic ring. Optionally substituted with 1 to 3 independently selected substituents) or C _3-7 cycloalkyl (wherein the cycloalkyl is halogen, hydroxyl and optionally substituted C _3-7 cycloalkyl) Optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

  The cyclic group represented by the above formula (2) is preferably the following formula:

（式中、各記号は上記の定義と同義である。）
から選ばれる環状基である。

(In the formula, each symbol has the same definition as above.)
A cyclic group selected from

  More preferably, as the cyclic group represented by the above formula (2), the following formula:

（式中、各記号は上記の定義と同義である。）
から選ばれる環状基である。

(In the formula, each symbol has the same definition as above.)
A cyclic group selected from

  Preferable specific examples of the cyclic group represented by the above formula (2) include azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, difluoroazetidinyl, 2- or 3-methylpyrrolidinyl, 2- or 3-methoxypyrrolidinyl. , 2- or 3-hydroxypyrrolidinyl.

L is CR ⁴ R ⁵ .

R ⁴ and R ⁵ are each independently hydrogen, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and alkoxy are each halogen, hydroxyl group, optionally substituted C _1-4). alkoxy, optionally substituted C _3-7 cycloalkyl, 1-3 independently selected from the group consisting of heterocyclic ring optionally C _3-7 cycloalkoxy and 3-7 membered substituted Optionally substituted with a substituent), C _3-7 cycloalkyl or C _3-7 cycloalkoxy (the cycloalkyl and the cycloalkoxy are each a halogen, a hydroxyl group, or an optionally substituted C _1-4 alkoxy) , 1 are independently selected from the group consisting of which may C _3-7 cycloalkoxy optionally be a good C _3-7 cycloalkyl and substituted also be substituted Also it may) be substituted with substituents,.

R ⁴ and R ⁵ are preferably hydrogen, hydroxyl group or C _1-4 alkyl (wherein the alkyl is independently from the group consisting of hydroxyl group and C _1-4 alkoxy optionally substituted by 1 to 3 fluorines). Optionally substituted with 1 to 3 selected substituents).

More preferably, R ⁴ and R ⁵ are hydrogen or C _1-4 alkyl (the alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of a hydroxyl group and C _1-4 alkoxy. May be).

R ⁴ and R ⁵ are more preferably hydrogen.

Preferable specific examples of R ⁴ and R ⁵ include hydrogen, hydroxyl group, methyl, ethyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxymethyl, preferably hydrogen, methyl, methoxymethyl. is there.

  m is preferably 1 or 2, and more preferably 1.

Production method of compound (1):
Next, the manufacturing method of the compound of this invention is demonstrated below.

  The compound represented by formula (1) is produced from a known compound by appropriately combining, for example, the methods shown in the following production methods 1 to 11, methods similar to the following production methods, or synthesis methods well known to those skilled in the art. can do.

Production method 1:
Of the compounds of the present invention represented by formula (1), compound (S-7) or a pharmaceutically acceptable salt thereof is produced, for example, by the method shown below. Further, in the compound of the formula (1), when any of R ^1a , R ^1b, R ^1c or R ^1d is a halogen and conversion of a substituent is unnecessary, the following step (1-4) is not performed. To be manufactured. ^Furthermore, R ^{1a, R 1b,} is either hydrogen ^{R 1c} or ^{R 1d,} when the conversion of the substituents is not required, ^{X 2} in the starting compound with a compound of hydrogen, the following (1-4) It is manufactured without going through the process. The same applies to production methods 2 to 9.

[Wherein R ² , R ³ , L and m are as defined in the above item 1. R ^1A , R ^1B and R ^1C have the same ^{meanings as} R ^1a , R ^1b , R ^1c or R ^1d in the above-mentioned item 1, respectively, and R ^a and R ^c are hydrogen, C _1-8 alkyl (methyl, ethyl, t-butyl, n-octyl, etc.) or benzyl, X ¹ and X ² each independently represent a leaving group such as halogen, trifluoromethanesulfonyloxy, or methanesulfonyloxy, R ^1D represents cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, C _3-6 cycloalkylamino, C _6-10 aryl, C _{6- 10} aryloxy, C _6-10 arylamino, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, 5-12 membered heteroary Represents an amino group, (C _6-10 aryl) C _1-4 alkyl, (C _6-10 aryl) C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl or a 3-7 membered heterocyclic ring. R ^1D -Y ¹ represents an organic boron compound, an organic zinc compound, an alkenyl compound, an alkynyl compound, a hydroxy compound, an amine compound, a metal cyanide, or the like shown in the following step (1-4). ]

Step (1-1):
The 2-nitroaniline compound (s-2) can be produced by reacting the nitrobenzene compound (s-1) with an amino acid ester compound in the presence of a base. As a base, an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide, or triethylamine, N, N-diisopropylethylamine, tributylamine, DBN, DABCO, DBU, Organic bases such as pyridine, 4-N, N-dimethylaminopyridine, picoline and NMM can be used, and potassium carbonate or N, N-diisopropylethylamine is preferably used. Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, methylcyclopentyl ether, anisole, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl. An aprotic polar solvent such as 2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, or water, or a mixture thereof. The reaction temperature is usually from room temperature to heating under reflux, preferably from 50 ° C to 200 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Step (1-2):
A 1,2-diaminobenzene compound (s-3) can be produced by reducing the nitro group of the compound (s-2) to an amino group. As a method for reducing the nitro group, normal reduction conditions are used, and examples thereof include catalytic reduction and metal reduction.

  When using catalytic reduction, for example, an amino compound (s-3) is obtained by reacting a nitro compound (s-2) with hydrogen in the presence of a catalyst such as palladium carbon, Raney nickel, or platinum oxide. Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include alcohol solvents such as ethanol and methanol, ester solvents such as ethyl acetate and methyl acetate, ether solvents such as tetrahydrofuran and 1,4-dioxane, and aprotic such as N, N-dimethylformamide. Examples thereof include a polar solvent, a protic polar solvent such as acetic acid, water, or a mixture thereof. While the reaction temperature varies depending on the type of raw material compound to be used, etc., it is usually carried out at about 0 ° C. to about 80 ° C., preferably 20 ° C. to 50 ° C., and carried out at normal pressure or under pressure. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

  In the case of using metal reduction, the nitro compound (s-2) is converted into (1) a metal such as iron, zinc or tin, or a metal salt such as stannous chloride and an acid such as hydrochloric acid or acetic acid, or (2 ) By reacting with iron or stannous chloride alone, the amino compound (s-3) is obtained. Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include alcohol solvents such as ethanol and methanol, ether solvents such as tetrahydrofuran, protic polar solvents such as acetic acid, water, or a mixture thereof. While the reaction temperature varies depending on the kind of raw material compound to be used, etc., it is generally carried out at about 0 ° C. to about 100 ° C., preferably 20 ° C. to 80 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Step (1-3):
The 1,2-diaminobenzene compound (s-3) is reacted with an ortho ester such as methyl orthoformate, ethyl orthoformate or methyl orthoacetate, or a carboxylic acid such as formic acid or acetic acid. -4) can be manufactured. This reaction is carried out in the absence of a solvent or in a suitable solvent at normal pressure or under pressure, and any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, 1-methylpyrrolidin-2-one and the like. While the reaction temperature varies depending on the type of raw material compound to be used, etc., it is usually carried out at about 0 ° C. to about 80 ° C., preferably 20 ° C. to 80 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours. Further, an acid such as p-toluenesulfonic acid and hydrochloric acid may be added to the additive, and the reaction is preferably carried out by adding a catalytic amount.

Step (1-4):
With respect to the benzimidazole compound (s-4), in the presence of a base and a metal catalyst, an organic boron compound (eg, R ^1D —B (OH) ₂ etc.), an organic zinc compound (eg, R ^1D —ZnCl etc.), an alkenyl compound, Various coupling reactions are carried out by reacting an alkynyl compound, a hydroxy compound (eg, R ^1D —OH), an amine compound (eg, R ^1D —NH ₂ ), a metal cyanide (eg, CuCN), and the like (s The compound of -5) can be produced. Examples of the base include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium methoxide, sodium t-butoxide, sodium hydroxide, potassium hydroxide, potassium fluoride and other inorganic bases, or triethylamine, diisopropylethylamine, Organic bases such as butylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline and NMM are used. Depending on the type of coupling, a base may not be used. Examples of the metal catalyst include bis (tris tert-butylphosphine) palladium, bis (tris o-tolylphosphine) dichloropalladium, bis (tris o-tolylphosphine) palladium, tetrakistriphenylphosphine palladium, dichloropalladium (acetonitrile), bis (Tris o-tolylphosphine) dichloropalladium, (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium, PEPPSI ^™ • IPr ((1,3-bis (2,6-diisopropylphenyl) imidazolidene) ( Catalysts such as (3-chloropyridyl) palladium (II) dichloride) and copper (I) iodide can be used. For palladium acetate and palladium chloride, see Palladium reagents and catalysts, John Wiley & Sons Inc. (2004) or an appropriate ligand selected from the ligands described in (2004) can also be used. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene and xylene, ethyl acetate and acetic acid. Aprotic polar solvents such as ester solvents such as methyl, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide Or water, or a mixture thereof. While the reaction temperature varies depending on the type of raw material compound used, it is generally about 0 ° C. to about 250 ° C., preferably about 20 ° C. to about 200 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Step (1-5):
Carboxylic acid compound (s-6) can be produced by deprotecting the ester group of compound (s-5). To carry out this step, Protective Groups in Organic Synthesis, John Wiley & Sons Inc. (1981) and the like.

  For example, the carboxylic acid compound (s-6) can be led by alkaline hydrolysis or acid hydrolysis. That is, in the case of alkaline hydrolysis, in the presence of an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or magnesium hydroxide, together with water, for example, methanol, ethanol, 2- In the presence or absence of alcohol solvents such as propanol and butanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane, or aromatic hydrocarbon solvents such as benzene, toluene and xylene. Usually, the compound of the formula (s-6) can be obtained by reacting in the temperature range of 0 ° C. to heating under reflux for 30 minutes to 48 hours. The reaction temperature is preferably 20 ° C. to 60 ° C., and the reaction time is preferably 1 to 24 hours.

  In the case of acid hydrolysis, mineral acids such as hydrochloric acid and sulfuric acid, mixtures such as hydrobromic acid-acetic acid, organic acids such as trifluoroacetic acid and trifluoromethanesulfonic acid, boron trifluoride-diethyl ether complex, zinc chloride, aluminum chloride In the presence of a Lewis acid such as, for example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, dichloromethane, chloroform, carbon tetrachloride and the like The compound of the formula (s-6) can be obtained by reacting in a halogen solvent of 5 or water or a mixed solvent thereof usually at a temperature range of −20 ° C. to heating under reflux for 30 minutes to 48 hours. . The reaction temperature is preferably 0 to 60 ° C., and the reaction time is preferably 1 to 24 hours.

Step (1-6):
By condensing the carboxylic acid compound (s-6) and the amine compound, the amide compound (S-7) or a pharmaceutically acceptable salt thereof can be produced. Examples of the method for activating a carboxyl group include a method of converting a carboxyl group into an acid anhydride, mixed acid anhydride, acid halide, active ester or acid azide, or a method using a condensing agent.

  For example, when the acid halide method is used, an acid halide is prepared by reacting a carboxylic acid compound (s-6) with a halogenating reagent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. The amide compound (S-7) can be obtained by reacting with an amine compound or a salt thereof in the presence of a base. Here, the base is not particularly limited, but examples thereof include organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline, NMM, or sodium bicarbonate, hydrogen carbonate. Examples include inorganic bases such as potassium, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like. Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, Examples thereof include aromatic hydrocarbon solvents such as xylene, ester solvents such as ethyl acetate and methyl acetate, water, and mixtures thereof. The reaction temperature is −80 ° C. to heating under reflux, preferably −20 ° C. to 10 ° C. The reaction time is usually 10 minutes to 48 hours, preferably 1 hour to 24 hours.

  For example, when using the mixed acid anhydride method, the carboxylic acid compound (s-6) is converted to a mixed acid anhydride by reacting with an acid halide in the presence of a base, and then reacted with an amine compound or a salt thereof. To give an amide compound (S-7) or a pharmaceutically acceptable salt thereof. Examples of the acid halide include methoxycarbonyl chloride, ethoxycarbonyl chloride, isopropyloxycarbonyl chloride, isobutyloxycarbonyl chloride, paranitrophenoxycarbonyl chloride, t-butylcarbonyl chloride and the like. The base is not particularly limited, but for example, organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline, NMM, or sodium hydrogen carbonate, potassium hydrogen carbonate, carbonic acid Examples thereof include inorganic bases such as sodium and potassium carbonate. Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane, benzene, toluene, An aromatic hydrocarbon solvent such as xylene, an ester solvent such as ethyl acetate and methyl acetate, water, or a mixture thereof may be used. The reaction temperature is −80 ° C. to heating under reflux, preferably −20 ° C. to 10 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

  For example, when a condensing agent is used, the carboxylic acid compound (s-6) is reacted with an amine compound or a salt thereof in the presence or absence of a base using the condensing agent to give an amide compound (S-7) or a compound thereof. Pharmaceutically acceptable salts can also be prepared. Here, examples of the condensing agent include those described in Experimental Chemistry Course (Edited by Chemical Society of Japan, Maruzen) Vol. For example, phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide, carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride, dicyclohexylcarbodiimide, 2,2′-dipyridyl disulfide, etc. Combinations of disulfides and phosphines such as triphenylphosphine, phosphorus halides such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride, azodicarboxylic acid diesters such as diethyl azodicarboxylate and tri Combinations of phosphines such as phenylphosphine, 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide, 1,1′-carbonyldiimidazole, diphenylphosphoryl azide (D PA), diethylphosphoryl cyanide (DEPC), dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), O- (1H) -Benzotriazol-1-yl) -1,1,3,3-tetramethyl-uronium tetrahydroborate (TBTU), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetra Methyluronium hexafluorophosphate (HBTU), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), (benzotriazole- 1-yloxy) tris (dimethylamino) phosphonium hexaf Orohosufeto (BOP) and the like. The solvent is not particularly limited, and any solvent that does not react under the reaction conditions in this step can be used. Specifically, the same solvent as in the case of using the acid halide method, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, An aprotic polar solvent such as dimethyl sulfoxide, water, or a mixed solvent thereof is used. The base is not particularly limited, and examples thereof include organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline, and NMM. The reaction is usually carried out at −10 ° C. to heating under reflux, preferably 0 ° C. to 60 ° C. While the reaction time varies depending on the reaction temperature, the raw materials used, the solvent and the like, it is generally 30 minutes to 96 hours, preferably 1 hour to 24 hours.

Production method 2:
Compound (S-7) of the present invention described in Production Method 1 [may contain compound (S-9)] is prepared by using compound (s-4) described in Production Method 1 in the following steps ( It can also be produced according to (2-1) to (2-3).

(The symbols in the formula have the same meaning as in Production Method 1.)

Step (2-1):
This step is a step of obtaining compound (s-8) using compound (s-4) according to the conditions according to step (1-5) described in production method 1.

Step (2-2):
This step is a step of obtaining a compound (s-9) using the compound (s-8) according to the conditions according to the step (1-6) described in the production method 1.

Step (2-3):
This step is a step of obtaining compound (S-7) or a pharmaceutically acceptable salt thereof using compound (s-9) according to the conditions according to step (1-4) described in Production Method 1. It is.

Production method 3:
The intermediate compound (s-9) described in production method 2 [may be a compound of the present invention] is prepared by using compound (s-2) described in production method 1 in the following step (3-1). To (3-4).

(The symbols in the formula have the same meaning as in Production Method 1.)

Step (3-1):
This step is a step of obtaining compound (s-10) using compound (s-2) according to the conditions according to step (1-5) described in production method 1.

Step (3-2):
This step is a step of obtaining compound (s-11) using compound (s-10) according to the conditions according to step (1-6) described in Production Method 1.

Step (3-3):
This step is a step of obtaining a compound (s-12) using the compound (s-11) according to the conditions according to the step (1-2) described in the production method 1.

Step (3-4):
This step is a step of obtaining a compound (s-9) using the compound (s-12) according to the conditions according to the step (1-3) described in the production method 1.

Production method 4:
The intermediate compound (s-5) described in the production method 1 is produced according to the following steps (4-1) to (4-3) using the compound (s-2) described in the production method 1. You can also.

(The symbols in the formula have the same meaning as in Production Method 1.)

Step (4-1):
This step is a step of obtaining a compound (s-13) using the compound (s-2) according to the conditions according to the step (1-4) described in the production method 1.

Step (4-2):
This step is a step of obtaining a compound (s-14) using the compound (s-13) according to the conditions according to the step (1-2) described in the production method 1.

Step (4-3):
This step is a step of obtaining a compound (s-5) using the compound (s-14) according to the conditions according to the step (1-3) described in the production method 1.

Production method 5:
The intermediate compound (s-6) described in the production method 1 is produced according to the following steps (5-1) to (5-6) using the compound (s-1) described in the production method 1. You can also.

[Wherein, R ^1A , R ^1B , R ^1C , R ^1D , R ^1D -Y ¹ , R ^c , L, m, X ¹ and X ² are as defined in Production Method 1. R ^b is C _1-4 alkyl (methyl, ethyl, t-butyl, isobutyl, etc.), and two R ^b may be combined to form a ring. ]

Step (5-1):
This step is a step of obtaining a compound (s-15) using the compound (s-1) according to the conditions according to the step (1-1) described in the production method 1.

Step (5-2):
This step is a step of obtaining compound (s-16) using compound (s-15) according to the conditions according to step (1-2) described in Production Method 1.

Step (5-3):
This step is a step of obtaining compound (s-17) using compound (s-16) according to the conditions according to step (1-3) described in production method 1.

Step (5-4):
This step is a step of obtaining a compound (s-18) using the compound (s-17) according to the conditions according to the step (1-4) described in the production method 1.

Step (5-5):
An aldehyde compound (s-19) can be produced by deprotecting the acetal compound (s-18).
To carry out this step, Protective Groups in Organic Synthesis, John Wiley & Sons Inc. (1981) and the like.
For example, it can lead to an aldehyde compound (s-19) by acid hydrolysis as follows. Examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and toluenesulfonic acid, preferably trifluoroacetic acid, toluenesulfonic acid, and hydrochloric acid. It is done. Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, methylcyclopentyl ether, anisole and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, dichloromethane and chloroform. , Halogen solvents such as carbon tetrachloride, aprotic polar solvents such as acetone and acetonitrile, or water, or a mixture thereof. The reaction temperature is usually in the temperature range of −20 ° C. to heating under reflux, and the reaction time is 30 minutes to 48 hours, whereby the compound of formula (s-19) can be obtained. The reaction temperature is preferably 0 to 60 ° C., and the reaction time is preferably 1 to 24 hours.

Step (5-6):
A carboxylic acid compound (s-6) can be produced by oxidizing the aldehyde compound (s-19). For this oxidation reaction, normal oxidation conditions are used, and examples thereof include an oxidation reaction with sodium hypochlorite, sodium bromate, potassium bromate, or potassium permanganate. Of these, oxidation with sodium hypochlorite or potassium permanganate is preferred, and oxidation with hypochlorous acid is particularly preferred. Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran, dimethoxyethane, and 1,4-dioxane, aprotic polar solvents such as acetonitrile, or water, or a mixture thereof. It is done. The reaction temperature is usually in the temperature range of -20 ° C to 50 ° C, preferably room temperature. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Production method 6:
The intermediate compound (s-18) described in production method 5 is produced according to the following steps (6-1) to (6-3) using compound (s-15) described in production method 5. You can also.

(The symbols in the formula have the same meaning as in Production Method 5.)

Step (6-1):
This step is a step of obtaining a compound (s-20) using the compound (s-15) according to the conditions according to the step (1-4) described in the production method 1.

Step (6-2):
This step is a step of obtaining a compound (s-21) using the compound (s-20) according to the conditions according to the step (1-2) described in the production method 1.

Step (6-3):
This step is a step of obtaining a compound (s-18) using the compound (s-21) according to the conditions according to the step (1-3) described in the production method 1.

Production method 7:
The intermediate compound (s-6) described in the production method 1 is produced according to the following steps (7-1) to (7-5) using the compound (s-1) described in the production method 1. You can also.

(The symbols in the formula have the same meaning as in Production Method 1.)

Step (7-1):
This step is a step of obtaining a compound (s-22) using the compound (s-1) according to the conditions according to the step (1-1) described in the production method 1.

Step (7-2):
This step is a step of obtaining compound (s-23) using compound (s-22) according to the conditions according to step (1-2) described in Production Method 1.

Step (7-3):
This step is a step of obtaining compound (s-24) using compound (s-23) according to the conditions according to step (1-3) described in production method 1.

Step (7-4):
This step is a step of obtaining compound (s-25) using compound (s-24) according to the conditions according to step (1-4) described in Production Method 1.

Step (7-5):
This step is a step of obtaining a compound (s-6) using the compound (s-25) according to the conditions according to the step (5-6) described in the production method 5.

Production method 8:
The intermediate compound (s-25) described in the production method 7 is produced according to the following steps (8-1) to (8-3) using the compound (s-22) described in the production method 7. You can also.

(The symbols in the formula have the same meaning as in Production Method 1.)

Step (8-1):
This step is a step of obtaining compound (s-26) using compound (s-22) according to the conditions according to step (1-4) described in Production Method 1.

Step (8-2):
This step is a step of obtaining compound (s-27) using compound (s-26) according to the conditions according to step (1-2) described in Production Method 1.

Step (8-3):
This step is a step of using the compound (s-27) to obtain the compound (s-25) according to the conditions according to the step (1-3) described in the production method 1.

Production method 9:
The compound (S-7) of the present invention described in the production method 1 is produced according to the following steps (9-1) to (9-3) using the compound (s-11) described in the production method 3. You can also

(The symbols in the formula have the same meaning as in Production Method 1.)

Step (9-1):
This step is a step of obtaining a compound (s-28) using the compound (s-11) according to the conditions according to the step (1-4) described in the production method 1.

Step (9-2):
This step is a step of obtaining compound (s-29) using compound (s-28) according to the conditions according to step (1-2) described in Production Method 1.

Step (9-3):
This step is a step of obtaining compound (S-7) or a pharmaceutically acceptable salt thereof using compound (s-29) according to the conditions according to step (1-3) described in production method 1. It is.

Production method 10:
The intermediate compound (s-28) described in Production Method 9 is produced according to the following steps (10-1) to (10-2) using the compound (s-13) described in Production Method 4. You can also.

(The symbols in the formula have the same meaning as in Production Method 1.)

Step (10-1):
This step is a step of obtaining compound (s-30) using compound (s-13) according to the conditions according to step (1-5) described in production method 1.

Step (10-2):
This step is a step of obtaining compound (s-28) using compound (s-30) according to the conditions according to step (1-6) described in production method 1.

Production method 11:
The intermediate compound (s-2) described in Production Method 1 can also be produced according to the following step (11-1) using the compound (s-31).

(The symbols in the formula have the same meaning as in Production Method 1.)

Step (11-1):
This step is a step of obtaining compound (s-2) using compound (s-31) and compound (s-32) according to the conditions according to step (1-1) described in production method 1. .

  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, a usual protecting group as described in the aforementioned 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.

  The introduction and removal of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the above Protective Groups in Organic Synthesis) or a method analogous thereto.

  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, RC 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.
In addition, optical isomers can be separated by performing 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 (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in addition to the above isomer. The compound of the present invention may exist in the form of an adduct with water or various solvents, and these adducts are also included. Furthermore, the compound of the present invention includes all crystal forms and compounds in which atoms constituting the compound are converted to isotopes (for example, compounds in which hydrogen is deuterated or compounds in which ¹² C is converted to ¹⁴ C) Is also included.

  In the present specification, the term “prodrug of the compound of formula (1)” is a compound that is converted into a compound of formula (1) 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, etc. to change to a compound of formula (1), or a compound that undergoes hydrolysis by gastric acid or the like to change to a compound of compound (1).

  Examples of the “pharmaceutically acceptable salt” include base addition salts and 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. 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 formula (1) obtained by the production method shown above is isolated and purified according to conventional methods 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, alumina or the like 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 an imidazopyridine ring of the present invention or a pharmaceutically acceptable salt thereof has a property of inhibiting Nav1.7 and has neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, It can be used as a therapeutic or prophylactic agent for limb redness, paroxysmal pain, etc. 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 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 be used as a therapeutic or prophylactic agent for ataxia that suppresses cerebellar abnormal nerve firing in multiple sclerosis. As a drug having no side effect derived from non-neural tissue or central nervous system, a compound having a selective inhibitory activity of Nav1.7 is more preferable.

The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and its daily dose varies depending on the type of compound, administration method, patient symptom / age, etc. In the case of oral administration, the amount of active ingredient per adult patient can be 10 μg to 2 g, preferably 100 μg to 1 g, more preferably 1 mg to 200 mg, and can be divided into once or several times a day. Can be administered. Parenteral administration includes a dose of 0.1 to 100 mg / day, more preferably 0.3 to 50 mg / day per adult patient, and can be administered once or divided into several times a day. Sustained release preparations can also be used to reduce the number of administrations. The parenteral administration herein includes intravenous, intramuscular, subcutaneous, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, and the like.
The compound of the present invention can also be used as an animal drug.

  The administration period and interval of the compound of the present invention are changed according to various situations, and are determined at any time according to the judgment of a doctor, but divided administration, daily administration, intermittent administration, short-term large-scale administration, There are methods such as repeated administration. For example, in the case of oral administration, it is desirable to divide and administer once or several times (particularly two to three times a day). Moreover, it can be administered as a sustained-release preparation or can be administered by intravenous infusion over a long period of time.

  The compound of the present invention is usually administered in the form of a pharmaceutical composition (pharmaceutical preparation) prepared by mixing with a pharmaceutically acceptable carrier, that is, a carrier for pharmaceutical preparation, when used for the above-mentioned pharmaceutical use. The As the pharmaceutically acceptable carrier, a nontoxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.

  Examples of the dosage form include tablets, capsules, granules, powders, solutions, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. Liquid preparations may be dissolved or suspended in water or other suitable medium when used. Tablets and granules may be coated by a known method.

  The pharmaceutical composition of the present invention can be produced according to a conventional method, and the content ratio of the compound of the present invention in the preparation is usually 0.01 to 50% (w / w). Specific examples of dosage forms in the pharmaceutical composition of the present invention are shown below.

Examples of tablets, powders, granules, capsules and the like: For example, excipients, disintegrants, binders or lubricants are added to the compounds of the present invention and compression molded, and if necessary, taste masking, It can be produced by applying a coating for enteric or sustainable purposes.
For example, in the case of a tablet, it can be produced by mixing 20 mg of the compound of Example 1, 100 mg of lactose, 25 mg of crystalline cellulose and 1 mg of magnesium stearate, and tableting the resulting mixture.

  For the purpose of enhancing the action of the compound of the present invention, for example, non-steroidal anti-inflammatory drugs such as celecoxib, voltaren, ibuprofen, loxoprofen, acetaminophen, diclofenac, dexamethasone, and opioids such as tramadol, morphine, oxycodone, etc. It can also be used in combination with analgesics. 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 drugs, hormone preparations, migraine drugs, adrenergic β receptor antagonists, dementia drugs, and mood disorder drugs. As a drug used in combination with the compound of the present invention, an antiepileptic drug such as pregabalin and carbamazepine, an antidepressant drug such as amitriptyline and duloxetine, a narcotic analgesic drug such as morphine, oxycodone and tramadol, acetaminophen, diclofenac, dexamethasone Anti-inflammatory drugs such as epalrestat, 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 reference examples, examples and test examples, but the technical scope of the present invention is not limited to these examples. Amino silica gel chromatography manufactured by Yamazen Co., Ltd. was used for amino silica gel chromatography in Reference Examples and Examples. Reverse phase column chromatography used a Gilson preparative HPLC system. The mobile phase of HPLC was 0.05% trifluoroacetic acid aqueous solution and 0.035% trifluoroacetic acid acetonitrile solution. The compound was identified using proton nuclear magnetic resonance absorption spectrum ( ¹ H-NMR) or the like. ¹ H-NMR was measured using JNM-LA300 (JEOL) or JNM-AL400 (JEOL). 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: Waters ACQITY (registered trademark) SQD
HPLC: Waters ACQITY UPLC (registered trademark)
Column: ACQITY UPLC (registered trademark) 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 manufacturing methods, reference examples, and examples, the following abbreviations may be used to simplify the description of the present specification. Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, Ms: methanesulfonyl, n-: normal, i-: iso, sec-: secondary, t- or tert-: tertiary, THF: tetrahydrofuran, DMF : N, N-dimethylformamide, DBN: 1,5-diazabicyclo [4.3.0] non-5-ene, DABCO: 1,4-diazabicyclo [2.2.2] octane, DBU: 1,8- Diazabicyclo [5.4.0] undec-7-ene, NMM: N-methylmorpholine, HBTU: O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluoro Phosphate, HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa Fluorophosphate, TEMPO: 2,2,6,6-tetramethylpiperidine 1-oxyl, TBDMS: tertiary butyldimethylsilyl, WSC · HCl: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, HOBt · H ₂ O: 1-hydroxybenzotriazole monohydrate, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quadruple, dd: double double Line, td: triple double line, tt: triple triple line, m: multiple line, br: wide.

Example 1:
Preparation of 1- (pyrrolidin-1-yl) -2- {5- [4- (trifluoromethyl) phenyl] -1H-benzimidazol-1-yl} ethanone

Step (i):
Triethylamine (21.0 mL) was added dropwise at room temperature to a mixture of Compound Ia (15.0 g), glycine-tert-butyl ester hydrochloride (12.6 g) and N, N-dimethylacetamide (228 mL). After completion of dropping, the mixture was stirred at 50 ° C. for 2 hours. Water (300 mL) was added to the reaction mixture and stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure at 60 ° C. to obtain Compound II-a (19.0 g).

Step (ii):
A mixture of Compound II-a (19.0 g), 3% Pt sulfided carbon (hydrated product) (1.90 g) and methanol (190 mL) was stirred under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through celite, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100 / 0-50 / 50) to obtain Compound III-a (7.95 g).

Step (iii):
A mixture of compound III-a (7.95 g), trimethyl orthoformate (33 mL) and p-toluenesulfonic acid monohydrate (502 mg) was stirred at 50 ° C. for 10 minutes, and then ethyl acetate (60 mL) and p- Toluenesulfonic acid monohydrate (4.50 g) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure at 60 ° C. to obtain compound IV-a (12.4 g).

Step (iv)
Compound IV-a (240 mg), 4-trifluoromethylphenylboronic acid (176 mg), tetrakistriphenylphosphine palladium (89.1 mg), sodium carbonate (245 mg), N, N-dimethylformamide (4.0 mL) and water (2.0 mL) of the mixture was stirred at 110 ° C. for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with saturated brine (5.0 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 100/0 to 96/4) to obtain Compound Va (200 mg).

Step (v)
Compound Va (200 mg), 1N aqueous sodium hydroxide solution (1.1 mL) and methanol (2.0 mL) were stirred at 40 ° C. for 1 hour. The reaction mixture was neutralized by dropwise addition of 1N aqueous hydrochloric acid. The precipitate was collected by filtration and dried under reduced pressure at 60 ° C. to obtain compound VI-a (105 mg).

Step (vi)
After stirring a mixture of compound VI-a (50.0 mg), HBTU (88.8 mg), triethylamine (32.6 μL), pyrrolidine (26.1 μL) and tetrahydrofuran (2.0 mL) at room temperature for 2 hours, the reaction mixture Was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 98/2 to 91/9) to give the title compound VII-a (55.7 mg).
¹ H-NMR (DMSO-D ₆ ) δ: 1.78-1.85 (2H, m), 1.94-2.02 (2H, m), 3.33 (2H, t, J = 6.7 Hz), 3.61 (2H, t, J = 6.7 Hz), 5.22 (2H, s), 7.65-7.59 (2H, m), 7.79 (2H, d, J = 8.5 Hz), 7.94 (2H, d, J = 7.9 Hz), 8.01 (1H, s) , 8.18 (1H, s).

Example 2:
Production of N, N-dimethyl-2- (6-phenyl-1H-benzimidazol-1-yl) acetamide

Steps (i) to (iii):
Compound IV-b (9.27 g) was obtained using compound Ib (12.4 g) according to the same method as in steps (i) to (iii) of Example 1.

Step (iv):
Compound Vb (113 mg) was obtained using Compound IV-b (494 mg) according to the same method as in Step (iv) of Example 1.

Step (v):
To a mixture of compound Vb (112 mg) and cyclopentyl methyl ether (1.0 mL), 4N hydrochloric acid cyclopentyl methyl ether solution (1.0 mL) was added dropwise and stirred at 80 ° C. for 7 hours. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure at 60 ° C. to give compound VI-b (104 mg).

Step (vi):
The title compound VII-b (33.4 mg) was obtained in the same manner as in step (iv) of Example 1 using compound VI-b (50.0 mg) and dimethylamine hydrochloride (17.0 mg). .
¹ H-NMR (CDCl ₃ ) δ: 3.00 (3H, s), 3.18 (3H, s), 5.39 (2H, s), 7.39 (1H, m), 7.46 (2H, t, J = 7.3 Hz), 7.56 (2H, d, J = 7.3 Hz), 7.64 (2H, m), 7.82 (1H, d, J = 8.5 Hz), 9.34 (1H, s).

Example 3:
Preparation of N, N-dimethyl-2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide

Step (i):
Compound IV-a of Example 1 (315 mg), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (411 mg), tetrakis (triphenylphosphine) palladium (0) (75.5 mg), potassium carbonate (271 mg), a mixture of dimethoxyethane (1.8 mL) and water (0.4 mL) was stirred at 90 ° C. for 2 hours. Water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 100/0 to 90/10). To the obtained crude product, 2N aqueous sodium hydroxide solution (2.0 mL) and methanol (2.0 mL) were added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and dimethylamine hydrochloride (63.9 mg), HBTU (322 mg), diisopropylethylamine (341 μL) and N, N-dimethylformamide (2.0 mL) were added to the residue and stirred for 12 hours. Water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with a mixed solvent of chloroform / methanol = 9/1. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 100/0 to 90/10) to obtain Compound Ic (29.8 mg).

Step (ii):
A mixture of compound Ic (29.8 mg), 10% palladium on carbon (2.9 mg) and methanol (1.0 mL) was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 100/0 to 90/10) to give the title compound II-c (21.3 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.83-1.88 (3H, m), 2.11-2.13 (1H, m), 2.57-2.60 (0.25H, m), 2.85-2.88 (0.75H, m), 3.00 ( 3H, s), 3.11-3.11 (3H, m), 3.53-3.56 (1.6H, m), 3.95-3.96 (0.4H, m), 4.07-4.10 (1.6H, m), 4.33-4.34 (0.4H , m), 4.94-4.94 (2H, m), 7.17-7.19 (0.8H, m), 7.37-7.39 (0.2H, m), 7.64-7.66 (0.8H, m), 7.78-7.81 (0.2H, m), 7.93-7.96 (1H, m). For compounds having an amide bond, peaks were sometimes observed as two isomers. The same applies below.

Example 4:
Preparation of N-ethyl-N-methyl-2- [5- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide

Step (i):
A mixture of Example IV compound IV-a (512 mg) and saturated aqueous sodium hydrogen carbonate (5.3 mL) was stirred for 1.5 hours. The reaction mixture was extracted with ethyl acetate (10 mL × 2), and the organic layer was concentrated under reduced pressure. To the residue was added a 4 mol / L cyclopentyl methyl ether solution (5.3 mL), and the mixture was stirred at 90 ° C. for 9 hours. The reaction mixture was concentrated under reduced pressure to obtain Compound Id (309 mg).

Step (ii):
Compound II-d (74.1 mg) was obtained in the same manner as in step (vi) of Example 1 using Compound Id (174 mg) and ethylmethylamine (61.5 μL).

Step (iii):
Compound II-d (42.4 mg) and 2- (3,6-dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (90.3 mg) ) To give compound III-d (42.9 mg) according to the same method as in step (iv) of Example 1.

Step (iv):
The title compound IV-d (7.7 mg) was obtained using the compound III-d (42.9 mg) according to the same method as in step (ii) of Example 3.
¹ H-NMR (CDCl ₃ ) δ: 1.06-1.08 (1.5H, m), 1.18-1.20 (1.5H, m), 1.75-1.82 (4H, m), 2.80 (1H, m), 2.90-2.92 ( 1.5H, m), 2.99-3.02 (1.5H, m), 3.34-3.42 (2H, m), 3.47-3.50 (2H, m), 4.01-4.04 (2H, m), 4.83 (1H, m), 4.86 (1H, m), 7.10 (1H, m), 7.18 (1H, m), 7.59 (1H, s), 7.83 (1H, s).

Example 5:
Preparation of N-ethyl-N-methyl-2- [6- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-1-yl] acetamide

Step (i):
Compound IV-a (1.00 g) of Example 1 and 2- (3,6-dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane Compound Ie (428 mg) was obtained according to the same method as in step (iv) of Example 1 using (1.13 g).

Step (ii):
A mixture of compound Ie (359 mg), palladium hydroxide (64.0 mg) and methanol (3.3 mL) was stirred under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered, and 4 mol / L cyclopentyl methyl ether solution (1.2 mL) was added to the residue, followed by stirring at 65 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain Compound II-e (325 mg).

Step (iii):
The title compound III-e (7.2 mg) was obtained using the compound II-e (60.0 mg) and ethylmethylamine (70.5 μL) according to the same method as in step (vi) of Example 1. MS (ESI +) 302 (M ⁺ +1).

Example 6:
Preparation of N-ethyl-N-methyl-2- [5- (4-methylphenoxy) -1H-benzimidazol-1-yl] acetamide

Step (i):
A mixture of Example IV compound IV-a (512 mg) and saturated aqueous sodium hydrogen carbonate (5.3 mL) was stirred for 1.5 hours. The reaction mixture was extracted with ethyl acetate (10 mL × 2), and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 40/60) to obtain Compound If (328 mg).

Step (ii):
Compound If (502 mg), p-cresol (352 mg), copper iodide (180 mg), cesium carbonate (1.09 g), N, N-dimethylglycine (183 mg) and 1,4-dioxane (4.0 mL) The mixture was irradiated with microwave at 140 ° C. for 1 hour. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by amino column chromatography (eluent: chloroform / methanol = 100/0 to 99/1) and gel permeation chromatography to obtain Compound II-f (241 mg).

Step (iii):
To compound II-f (241 mg) was added 4 mol / L hydrochloric acid ethyl acetate solution (10 mL), and the mixture was stirred at room temperature for 15 hr. The precipitated solid was collected by filtration and dried under reduced pressure to obtain Compound III-f (198 mg).

Step (iv):
The title compound IV-f (20.8 mg) was obtained in the same manner as in step (vi) of Example 1 using compound III-f (29.8 mg) and ethylmethylamine (20.1 μL).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, dt, J = 49.1, 7.3 Hz), 2.31 (3H, s), 3.03 (3H, d, J = 39.4 Hz), 3.45 (2H, ddd, J = 16.5, 9.4, 4.8 Hz), 4.94 (2H, t, J = 5.7 Hz), 6.88 (2H, d, J = 8.7 Hz), 7.04 (1H, dd, J = 8.7, 1.8 Hz), 7.10 (2H , d, J = 8.3 Hz), 7.24 (1H, t, J = 4.4 Hz), 7.41 (1H, d, J = 1.8 Hz), 7.97 (1H, s).

Example 7:
Preparation of N-ethyl-2- [6- (4-fluorophenoxy) -1H-benzimidazol-1-yl] -N-methylacetamide

Step (i):
Triethylamine (17.5 mL) was added to a mixture of Compound Ig (10.0 g), glycine-tert-butyl ester hydrochloride (10.5 g) and N, N-dimethylformamide (0.1 L), and the mixture was stirred for 6 hours. did. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain Compound II-g (16.0 g).

Step (ii):
4-Fluorophenol (830 mg) was added to a mixture of compound II-g (1.00 g), potassium carbonate (1.50 g) and N, N-dimethylformamide (10 mL), and the mixture was stirred for 3 hours. The reaction mixture was extracted with ethyl acetate (10 mL × 2), and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 0/100) to obtain Compound III-g (210 mg).

Step (iii):
Compound IV-g (200 mg) was obtained using compound III-g (210 mg) according to the same method as in step (ii) of Example 1.

Step (iv):
P-Toluenesulfonic acid monohydrate (11.5 mg) was added to a mixture of Compound IV-g (200 mg), trimethyl orthoformate (13.3 μL) and toluene (5.0 mL), and 1.5 ° C. at 60 ° C. Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 0/100) to obtain Compound Vg (80.0 mg).

Step (v):
To a mixture of compound V-g (80.0 mg) and cyclopentyl methyl ether (0.2 mL) was added 4 mol / L cyclopentyl methyl ether solution (0.2 mL), and the mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain Compound VI-g (65.0 mg).

Step (vi):
The title compound VII-g (24.0 mg) was obtained in the same manner as in step (vi) of Example 1 using compound VI-g (32.5 mg) and ethylmethylamine (13.4 mg).
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.28 (3H, m), 2.96-3.08 (3H, m), 3.40-3.47 (2H, m), 4.95-4.97 (2H, m), 6.90-7.05 ( 6H, m), 7.66 (1H, dd, J = 8.9, 2.1 Hz), 8.14 (1H, d, J = 8.5 Hz).

Examples 8-136:
In the same manner as in Examples 1 to 7, the compounds of Examples 8 to 136 shown in Tables 1 to 18 were produced.

Pharmacological test example Measurement of Na ion current using voltage-dependent Na channel gene expressing cells

  Nav1.7 current was measured by auto patch clamp method using human SCN9A stably expressing cells.

Human SCN9A stably expressing cells

  Tetracycline-induced 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 following day, the Na ion current was obtained by the auto patch clamp method Was measured.

Electrophysiological measurement of Na ion current

The Na ion current was measured by the auto patch 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, (adjusted to pH 7.4 with NaOH)

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. Table 19 shows the inhibition rate (%) when the compound concentration was 10 μmol / L.

  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 (17)

Following formula (1):

[In Formula (1),
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 part in alkylamino is each independently a halogen, a hydroxyl group, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl, or an optionally substituted C _3- Optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₇ cycloalkoxy and optionally substituted 3-7 membered heterocycles, C _3-7 cycloalkyl, C _3-7 cycloalkoxy, C _3-7 cycloalkylamino (the cycloalkyl part in the cycloalkyl, the cycloalkoxy and the cycloalkylamino is Each independently halogen, hydroxyl, substituted optionally optionally C _1-4 be alkoxy, substituted by comprising from good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted also be the group Optionally substituted with 1-3 independently selected substituents), C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamino, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, 5-12 membered heteroarylamino, (C _6-10 aryl) C _1-4 alkyl, (C _6-10 aryl) C _1-4 alkoxy (the aryl, aryloxy) The aryl moiety in the arylamino, the arylalkyl and the arylalkoxy, and the heteroaryl, the heteroaryloxy and the The heteroaryl part of the hetero arylamino are each independently halogen, cyano, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally C ₃ substituted _-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy, optionally substituted 3-7 membered heterocycle (except tetrazole), optionally substituted C _1-4 alkylthio and Optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted C _1-4 alkylsulfonyl), C _2-6 alkenyl, C _2-6 alkynyl ( the alkenyl and the alkynyl are each independently, halogen, cyano, optionally substituted C _1-4 alkyl, substituted C _1-4 optionally alkoxy C, C _3-7 cycloalkyl which may be substituted, C _3-7 cycloalkoxy which may be substituted, _{3- to} 7-membered heterocyclic ring which may be substituted, C ₆ which may be substituted Independently selected from the group consisting of _-10 aryl, optionally substituted 5-12 membered heteroaryl, optionally substituted C _1-4 alkylthio and optionally substituted C _1-4 alkylsulfonyl. Optionally substituted with 1 to 3 substituents) or a 3 to 7 membered heterocyclic ring (wherein the heterocyclic ring is halogen, hydroxyl group, optionally substituted C _1-6 alkyl, substituted which may be C _1-4 alkoxy, one to three independently selected from the group consisting of optionally substituted C _3-7 also be cycloalkyl and optionally substituted C _3-7 cycloalkoxy With substituents A conversion may be), where, ^{R 1a, R} 1b, one of R ^1c and R ^1d, at least one of _{C 6-10 aryl, C 6-10 aryloxy, C 6-10} arylamino, 5 ˜12 membered heteroaryl, 5-12 membered heteroaryloxy (the aryl moiety in the aryl, the aryloxy, the arylamino and the arylalkoxy, and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are independently, halogen, cyano, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, optionally substituted good C _3-7 cycloalkoxy, heterocyclic ring members 3-7 may be substituted, an optionally substituted C _-4 alkylthio and substituted may be substituted with 1 to 3 substituents are also independently selected from the group consisting of optionally C _1-4 alkylsulfonyl optionally) or 3-7 membered heterocyclic ring ( The heterocycle includes a halogen, a hydroxyl group, an optionally substituted C _1-6 alkyl, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl, and a substituted And may be substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy),
L is CR ⁴ R ⁵ ;
R ⁴ and R ⁵ are each independently hydrogen, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and alkoxy are each independently halogen, hydroxyl, or optionally substituted). C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, independently from the group consisting of heterocyclic ring optionally substituted C _3-7 cycloalkoxy and optionally substituted 3- to 7-membered Optionally selected from 1 to 3 substituents), C _3-7 cycloalkyl or C _3-7 cycloalkoxy (the cycloalkyl and the cycloalkoxy are each independently halogen , hydroxyl, optionally substituted C _1-4 alkoxy, the optionally substituted C _3-7 cycloalkyl and optionally substituted C _3-7 cycloalkoxy An that may be substituted with 1-3 substituents independently selected from the group),
m is 1, 2 or 3, and when m is 2 or 3, a plurality of Ls are independent of each other;
R ² and R ³ are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is cyano, halogen, hydroxyl group, optionally substituted C _1-4 alkoxy, optionally substituted C ₃ Optionally substituted with 1 to 5 substituents independently selected from the group consisting of _-7 cycloalkyl and optionally substituted C _3-7 cycloalkoxy), C _3-10 cycloalkyl or 3- to 7-membered heterocycle (the cycloalkyl and the heterocycle each independently represent a halogen, a hydroxyl group, an optionally substituted C _1-6 alkyl, an optionally substituted C _1-4 alkoxy, may be substituted with 1-3 substituents independently selected from optionally substituted C _3-7 also be cycloalkyl and optionally substituted C _3-7 group consisting cycloalkoxy) There, wherein, ^{R 2} and ^{R 3,} the following formula together with the adjacent nitrogen atom together (2):

[In Formula (2),
Z is a single bond, —O—, —S—, —SO ₂ —, —NR ⁷ —, —N (COR ⁷ ) — or —N (SO ₂ R ⁷ ) —,
d and e are each independently 1, 2 or 3 when Z is a single bond, and Z is —O—, —S—, —SO ₂ —, —NR ⁷ —, —N (COR ⁷⁾ - or -N _(SO 2 ^{R 7)} - when they are each independently 2 or 3,
f is 0, 1, 2 or 3, and when f is 2 or 3, the plurality of R ⁶ are each independently
R ⁶ is bonded to a carbon atom on the cyclic group represented by the above formula (2), and halogen, cyano, hydroxyl group, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and the alkoxy are each independently A halogen atom, a hydroxyl group, an optionally substituted C _1-4 alkoxy, an optionally substituted C _3-7 cycloalkyl, an optionally substituted C _3-7 cycloalkoxy, and an optionally substituted Optionally substituted with 1 to 3 substituents independently selected from the group consisting of 3 to 7 membered heterocycles, C _6-10 aryl or C _6-10 aryloxy (the aryl and aryl moiety in the aryloxy, each independently, halogen, cyano, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, optionally substituted Which may C _3-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy, heterocycle substituted 3 to 7 may be members, also optionally C _1-4 alkylthio and substituted substituted And optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkylsulfonyl, and when there are two or more R ⁶ 2 or 3 R ⁶ may be taken together with one or more carbon atoms to which they are attached to form a 3-7 membered carbocyclic or heterocyclic ring;
R ⁷ represents C _1-4 alkyl (wherein the alkyl is halogen, hydroxyl group, optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkyl, optionally substituted C _3-7 cycloalkoxy and optionally substituted with 1 to 3 substituents independently selected from the group consisting of optionally substituted 3-7 membered heterocycles) or C _3-7 cyclo alkyl (wherein the cycloalkyl, halogen, hydroxyl, substituted optionally optionally C _1-4 also alkoxy, made from a good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted substituted Which may be substituted with 1 to 3 substituents independently selected from the group)], which may form a ring represented by] or a pharmaceutically acceptable salt thereof Salt. At least one of R ^1b and R ^1c is C _6-10 aryl, C _6-10 aryloxy, C _6-10 arylamino, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy (the aryl , The aryl moiety in the aryloxy, the arylamino and the arylalkoxy, and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently halogen, cyano, or optionally substituted C _1-4. alkyl, substituted optionally optionally C _1-4 also alkoxy, optionally substituted C _3-7 also be cycloalkyl, optionally substituted C _3-7 also be cycloalkoxy, 3-7 membered optionally substituted Heterocycles, optionally substituted _C1-4 alkylthio and optionally substituted _C1- Optionally substituted with 1 to 3 substituents independently selected from the group consisting of ₄ alkylsulfonyls) or 3-7 membered heterocycles (the heterocycles are substituted with halogens, hydroxyl groups, also C _1-6 alkyl, substituted optionally optionally C _1-4 also alkoxy, independently of the substituted composed from a good C _3-7 cycloalkoxy optionally be good C _3-7 cycloalkyl and substituted also be the group Optionally substituted with 1 to 3 substituents selected from
At least one of R ² and R ³ is not hydrogen;
The compound according to claim 1, wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof. ^Optionally substituted C _1-4 alkyl on each substituent in R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ , substituted which may be C _3-7 cycloalkyl, heterocycle membered 3-7 may be substituted, an optionally substituted C _1-4 alkoxy, optionally substituted C _3-7 cycloalkoxy, substituted The optionally substituted C _1-4 alkylsulfonyl and the optionally substituted C _1-4 alkylthio substituent is fluorine, hydroxyl group, or C _1-2 alkoxy, and optionally substituted C _6-10. substituents on heteroaryl of aryl and substituted 5-12 may have personnel, fluorine, chlorine, _{cyano, C 1-2} alkyl or _{C 1-2} alkoxy, according to claim 1 or 2 Compound or a pharmaceutically acceptable salt thereof according to the deviation or claim. R ² and R ³ are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is cyano, halogen, hydroxyl, C _1-4 alkoxy optionally substituted by 1 to 3 fluorines, 1 to three good C _3-7 cycloalkyl optionally substituted by fluorine, optionally substituted by one to three optionally substituted by fluorine C _3-7 cycloalkoxy and 1-3 fluorines Optionally substituted with 1 to 5 substituents independently selected from the group consisting of 3 to 7 membered heterocycles), C _3-7 cycloalkyl or 3 to 7 membered heterocycles ( The cycloalkyl and the heterocycle each independently represent a halogen, a hydroxyl group, C _1-4 alkoxy optionally substituted by 1 to 3 fluorines, C _3-7 cycloalkyl and C _3-7 cycloalkoxy. Optionally substituted with 1 to 3 substituents independently selected from the group consisting of xy, wherein R ² and R ³ together with the adjacent nitrogen atom are of the above formula A ring represented by (2) may be formed,
[In the formula (2), Z is a single bond, —O— or —SO ₂ —;
When f is 0, 1 or 2, and f is 2, two R ^{6 s} are independent and R ⁶ is halogen, hydroxyl group or C _1-4 alkoxy (the alkoxy is halogen, hydroxyl group, Substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkoxy and a 3-7 membered heterocyclic ring. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. R ² and R ³ are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is halogen, hydroxyl, C _1-4 alkoxy optionally substituted by 1 to 3 fluorines and 1 to 3). C _3-7 cycloalkyl (which may be substituted with 1 to 5 substituents independently selected from the group consisting of 3 to 7-membered heterocycles optionally substituted with fluorine) The cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, hydroxyl and C _1-4 alkoxy, wherein R ² and R ³ Together may form a ring represented by the above formula (2) together with the adjacent nitrogen atom,
[In Formula (2), Z is a single bond or -O-,
f is 0 or 1,
R ⁶ is hydrogen, halogen, hydroxyl group or C _1-4 alkoxy (the alkoxy may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen and hydroxyl group). ] The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and alkoxy are each independently halogen, hydroxyl, C _1-4 alkoxy optionally substituted by 1 to 3 fluorines, C _3-7 cycloalkyl optionally substituted by 1 to 3 fluorines, substituted by 1 to 3 fluorines Substituted with 1 to 3 substituents independently selected from the group consisting of C _3-7 cycloalkoxy and 3 to 7 membered heterocyclic ring optionally substituted by 1 to 3 fluorines may _{be), C 3-7 cycloalkyl, C 3-7} cycloalkoxy (said cycloalkyl and said cycloalkoxy, each independently, by halogen, hydroxyl, a 1-3 fluorines Optionally substituted C _1-4 alkoxy, optionally substituted with C _3-7 1 to 3 substituents independently selected from cycloalkyl and C _3-7 group consisting cycloalkoxy) , C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, (C _6-10 aryl) C _1-4 alkyl, (C _6-10 aryl) C _1-4 alkoxy (the aryl moiety in the aryl, the aryloxy, the arylalkyl and the arylalkoxy, and the heteroaryl moiety in the heteroaryl and the heteroaryloxy are each independently halogen, cyano, C _1-4 alkyl (said alkyl is independently selected from the group consisting of fluorine and _{C 1-2} alkoxy 1-3 1-3 substituents independently selected from the group consisting of optionally C _1-4 alkoxy optionally substituted by by may be) and 1 to 3 fluorines substituted by a substituent Optionally substituted with a group), or a 3- to 7-membered heterocyclic ring (the heterocyclic ring is a halogen, a hydroxyl group, an optionally substituted C _1-6 alkyl, an optionally substituted C _1-4). alkoxy, optionally substituted with 1-3 substituents independently selected from the group consisting of optionally substituted C _3-7 also be cycloalkyl and substituted C _3-7 optionally cycloalkoxy The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. R ^1a , R ^1b , R ^1c and R ^1d are each independently hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and alkoxy are each independently halogen, hydroxyl, Independently selected from the group consisting of C _1-4 alkoxy optionally substituted by _1-3 fluorines, C _3-7 cycloalkyl, C _3-7 cycloalkoxy and 3-7 membered heterocycle 1 to 3 substituents), C _3-7 cycloalkyl, C _3-7 cycloalkoxy (the cycloalkyl and the cycloalkoxy are each independently a halogen, a hydroxyl group, C _{1 -4 alkoxy,} optionally substituted with 1-3 substituents independently selected from _{C 3-7} cycloalkyl and _{C 3-7} group consisting _{cycloalkoxy), C 6- 0 aryl, C 6-10} aryloxy (said aryl and said aryloxy are each independently halogen, _{cyano, C 1-4} alkyl (said alkyl, independently from the group consisting of fluorine and _{C 1-2} alkoxy 1 to 3 independently selected from the group consisting of C _1-4 alkoxy which may be substituted by 1 to 3 substituents selected from Optionally substituted with 3 substituents) or a 3-7 membered heterocycle (wherein the heterocycle is halogen, hydroxyl, optionally substituted C _1-6 alkyl, optionally substituted C _1-4 alkoxy, with 1 to 3 substituents independently selected from the group consisting of optionally substituted C _3-7 also be cycloalkyl and substituted C _3-7 optionally cycloalkoxy The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which may be substituted. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ^1a and R ^1d are hydrogen. R ⁴ and R ⁵ are each independently hydrogen, hydroxyl group or C _1-4 alkyl (the alkyl is selected from the group consisting of hydroxyl group and C _1-4 alkoxy optionally substituted by 1 to 3 fluorines). The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, which may be substituted with 1 to 3 substituents independently selected. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ⁴ and R ⁵ are hydrogen.   The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein m is 1.   The pharmaceutical composition containing the compound as described in any one of Claims 1-11, or its pharmaceutically acceptable salt.   A therapeutic agent for a disease involving Nav1.7 (SCN9A), comprising as an active ingredient the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.   Neuropathic pain, nociceptive pain, inflammatory pain, small-diameter fiber neuropathy, limb end, containing the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient A treatment for erythema or paroxysmal pain.   A therapeutic agent for a disease involving Nav1.7 (SCN9A) comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient, an antiepileptic drug, and an antidepressant A pharmaceutical comprising a combination of at least one drug selected from drugs, narcotic analgesics, anti-inflammatory drugs, reductase inhibitors and prostaglandin derivative preparations.   12. Any of the claims 1-11 for the treatment of neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, limb erythema pain, paroxysmal pain, dysuria or multiple sclerosis Use of the compound according to one item or a pharmaceutically acceptable salt thereof.   Neuropathic pain and nociceptiveness in a mammal, comprising administering an effective amount of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof to the mammal. A method for treating pain, inflammatory pain, small-fiber neuropathy, erythroderma, and paroxysmal pain.