JP2017001991A - Novel benzoxazolone compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small diameter fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or multiple sclerosis.SOLUTION: There is provided a benzoxazolone compound represented by the formula (1) or a pharmaceutically acceptable salt. (1), where Rand Rare each independently H or Calkyl, where the alkyl may be substituted by hydroxy, Calkylsulfonyl, aminocarbonyl or 4 to 7-membered heterocycloalkyl, or the like, L is Calkylene, Ris Calkyl, Ccycloalkyl, where the cycloalkyl may be substituted by halogen or hydroxy or the like, Caryl, where the aryl may be substituted by halogen, Calkyl or Chaloalkyl or the like, Ris H, halogen or Calkyl.SELECTED DRAWING: None

Description

  The present invention relates to a pathological condition involving a Na channel, particularly SCN9A (Nav1.7) and SCN10A (Nav1.8), which contain a novel compound having a benzoxazolone skeleton or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to therapeutic or prophylactic drugs. Specifically, therapeutic or prophylactic agents for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, limb erythema pain, paroxysmal pain, dysuria or multiple sclerosis About.

It is known that there are currently nine types of α subunits that form pores of voltage-gated Na channels. In recent years, there has been evidence that such subunits, particularly SCN9A and SCN10A, are widely involved in signaling 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 became clear to exhibit. In contrast, SCN9A gain-of-function mutations have been found in patients with severe rare diseases such as limb erythema 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).
SCN10A (Nav1.8) is a tetrodotoxin (TTX) -resistant Na channel that is dominantly expressed in small-diameter neurons (C fibers) in the dorsal root ganglion and is also called SNS or PN3. Physiologically, nociceptive information is transmitted by generating action potentials in C fibers, and it is suggested from the phenotypic analysis of knockout mice that it plays an important role for cold pain. Similar to Nav1.7 in chronic pain pathology, both Nav1.8 expression level and activity increased, and administration of antisense nucleic acid or siRNA attenuated hyperalgesia and allodynia exhibited by neuropathic pain or inflammatory pain model animals It has been reported (Non-Patent Documents 3 and 4). Furthermore, also in clinical practice, Nav1.8 gain-of-function mutations have been found in some small fiber neuropathy patients, and these mutations have been confirmed to enhance excitability of DRG neurons (Non-patent Document 5). .
Therefore, an inhibitor of Nav1.7 or Nav1.8, preferably a compound that inhibits both subtypes, is pain associated with peripheral nerves such as C fiber and Aδ fiber, numbness, burning sensation, dull pain, stinging pain, electric shock For diseases such as spontaneous pain such as pain, hyperalgesia to mechanical or cold stimuli, or neuropathic pain with allodynia, nociceptive pain, inflammatory pain, small fiber neuropathy, limb redness and paroxysmal pain It was thought that it could be a drug that shows an analgesic effect. Furthermore, since Nav1.7 and Nav1.8 are hardly expressed in non-neural tissues and central nervous system, drugs that selectively inhibit Nav1.7 or Nav1.8, preferably both subtypes, are a problem with existing drugs. It is thought that it can be a drug that does not show side effects derived from the heart and central nervous system.

In dysuria, frequent urination, which is the main symptom, is caused by C fiber overactivity through Nav1.8 sensitization, that is, overactive bladder and bladder pain are found from the lower urinary tract. It is suggested that abnormalities of the cardiac sensory nerve tract are involved, and that suppression of C-fiber sensory nerves from the bladder by Na channel inhibition is effective (Non-Patent Document 6). Therefore, a drug that inhibits Nav1.8 is expected to be a therapeutic or preventive drug for dysuria having a novel action point.
On the other hand, it has been reported that Nav1.8, which is usually found only in C fibers, is ectopically expressed in cerebellar Purkinje cells of patients with multiple sclerosis and is involved in the development of abnormal cerebellar firing patterns ( Non-patent document 7). Therefore, Nav1.8 inhibitor is expected to be the first therapeutic or preventive agent for symptoms such as ataxia induced by abnormal cerebellar nerve firing associated with Nav1.8 expression in multiple sclerosis. The

Patent Document 1, compounds for benzodiazepine omega ₃ receptor ligands are specifically disclosed. Specifically, the compound described in the patent document has an alkylamide group as a substituent on the nitrogen atom in the benzoxazolone ring, as represented by the following formula (A). It differs in that it does not contain the inventive compound. Further, Patent Document 1 does not include any description suggesting the present invention.

International Publication No. 2005/080334

Nat Rev Neurosci. 14: 49, 2013 Nat Commun. 3: 791, 2012 Brain Res Rev. 60: 65, 2009 Pain Med. 12: S93, 2011 Proc Natl Acad Sci USA. 109: 19444, 2012 Neurour Urodyn. 29: 128, 2010 Ann Neurol. 71: 186, 2012

  The subject of the present invention is a pathology involving Nav1.7 or Nav1.8, specifically neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, limb erythema pain, paroxysmal pain An object of the present invention is to provide a therapeutic or preventive drug for diseases such as dysuria or 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 benzoxazolone ring, which will be described later, or a pharmaceutically acceptable salt thereof is a Nav1.7 gene-expressing cell and / or Nav1. .8 gene-expressing cells were found to inhibit membrane potential change through Na channel or Na ion current itself, that is, to inhibit one or both of Nav1.7 and Nav1.8. In addition, the derivatives may also be used as therapeutic agents for diseases such as neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, limb erythema pain, paroxysmal pain, dysuria or multiple sclerosis. It has been found that it is useful as a preventive agent, and the present invention has been completed. According to the present invention, a benzoxazolone compound represented by the following formula (1) (hereinafter referred to as “compound of the present invention”, “compound represented by formula (1)”, or “compound of formula (1)”). Or a pharmaceutically acceptable salt thereof.

[Item 1] The following formula (1);

［式（１）中、
Ｒ^１およびＲ^２は、各々独立して、水素、Ｃ_１−６アルキル（該アルキルは、ヒドロキシ、ハロゲン、Ｃ_１−４アルコキシ、Ｃ_１−４アルキルスルホニル、Ｃ_１−４アルキルチオ、アミノカルボニル（該アミノカルボニルのアミノ部分は、置換されていてもよいＣ_１−４アルキルによってモノまたはジ置換されていてもよい）、置換されていてもよい４〜7員のヘテロシクロアルキルおよび置換されていてもよい４〜7員のヘテロシクロアルキルカルボ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_３−７シクロアルキル、Ｃ_４−７シクロアルケニルまたは４〜７員のヘテロシクロアルキル（該シクロアルキル、該シクロアルケニルおよび該ヘテロシクロアルキルは、それぞれＣ_１−４アルキル、Ｃ_１−４ハロアルキル、ハロゲン、ヒドロキシおよびＣ_１−４アルコキシからなる群から独立して選択される１〜３個の置換基で置換されていてもよい）を表し、
Ｌは、Ｃ_１−６アルキレン（該アルキレンは、Ｃ_１−４アルキル、ハロゲン、ヒドロキシおよびＣ_１−４アルコキシからなる群から独立して選択される１〜３個の置換基で置換されていてもよい）を表し、ここにおいて、Ｒ^１が、Ｃ_１−６アルキルであるとき、Ｒ^１とＬ上の炭素原子が一緒になって、Ｒ^１が結合する窒素原子と共に４〜７員の飽和複素環を形成してもよく、
Ｒ^３は、ハロゲン、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル（該アルキル、該アルケニルおよび該アルキニルは、それぞれハロゲン、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４〜７員のヘテロシクロアルキル、Ｃ_１−４アルコキシ、Ｃ_１−４ハロアルコキシ、Ｃ_１−４アルキルスルホニル、Ｃ_１−４アルキルチオ、置換されていてもよいＣ_６−１０アリールおよび置換されていてもよいＣ_６−１０アリールオ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_３−７シクロアルキル、Ｃ_４−７シクロアルケニル、４〜７員のヘテロシクロアルキル（該シクロアルキル、該シクロアルケニル、該ヘテロシクロアルキルは、それぞれＣ_１−４アルキル、Ｃ_１−４ハロアルキル、ハロゲン、ヒドロキシおよびＣ_１−４アルコキシからなる群から独立して選択される１〜３個の置換基で置換されていてもよい）、Ｃ_６−１０アリール（該アリールは、ハロゲン、置換されていてもよいＣ_１−４アルキル、Ｃ_１−４ハロアルキル、置換されていてもよいＣ_１−４アルコキシ、Ｃ_１−４ハロアルコキシ、シアノおよびＣ_１−４アルコキシカルボ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_６−１０アリールオキシ（該アリールオキシのアリール部分は、ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４ハロアルキル、Ｃ_１−４アルコキシ、Ｃ_１−４ハ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）または５〜１０員のヘテロアリール（該ヘテロアリールは、ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４ハロアルキル、Ｃ_１−４アルコキシおよびＣ_１−４ハロアルコキシからなる群から独立して選択される１〜３個の置換基で置換されていてもよい）を表し、
Ｒ^４は、水素、ハロゲンまたはＣ_１−４アルキルを表す］
で表される化合物またはその薬学的に許容される塩；
［項２］
置換されていてもよいＣ_６−１０アリール、置換されていてもよいＣ_６−１０アリールオキシおよび置換されていてもよいＣ_３−７シクロアルキルにおける置換基が、ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４ハロアルキル、Ｃ_１−４アルコキシ、Ｃ_１−４ハロアルコキシからなる群から独立して選択される１〜３個の置換基であり、
置換されていてもよいＣ_１−４アルキルおよび置換されていてもよいＣ_１−４アルコキシにおける置換基が、Ｃ_１−４アルコキシ、Ｃ_１−４ハロアルコキシからなる群から独立して選択される１〜２個の置換基であり、
置換されていてもよい４〜７員のヘテロシクロアルおよび置換されていてもよい４〜７員のヘテロシクロアルキルカルボニルのヘテロシクロアルキルにおける置換基が、Ｃ_１−４アルキル、ハロゲン、オキソおよびヒドロキシからなる群から独立して選択される１〜３個の置換基である、項１に記載の化合物またはその薬学的に許容される塩；
［項３］
置換されていてもよいＣ_６−１０アリール、置換されていてもよいＣ_６−１０アリールオキシおよび置換されていてもよいＣ_３−７シクロアルキルにおける置換基が、１〜３個のハロゲンであり、
置換されていてもよいＣ_１−４アルキルおよび置換されていてもよいＣ_１−４アルコキシにおける置換基が、１〜２個のＣ_１−２アルコキシであり、
置換されていてもよい４〜７員のヘテロシクロアルおよび置換されていてもよい４〜７員のヘテロシクロアルキルカルボニルのヘテロシクロアルキルにおける置換基が、Ｃ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基である、項１に記載の化合物またはその薬学的に許容される塩；
［項４］
Ｒ^１およびＲ^２が、各々独立して、水素、Ｃ_１−６アルキル（該アルキルは、ヒドロキシ、ハロゲン、Ｃ_１−４アルコキシ、Ｃ_１−４アルキルスルホニル、アミノカルボニル（該アミノカルボニルのアミノ部分は、Ｃ_１−４アルキルによってモノまたはジ置換されていてもよい）、４〜7員のヘテロシクロアルキルおよび４〜７員のヘテロシクロアルキルカルボニル（該４〜７員のヘテロシクロアルキルおよび該４〜７員のヘテロシクロアルキルカルボニルのヘテロシクロアルキル部分は、それぞれＣ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）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４〜７員のヘテロシクロアルキル（該ヘテロシクロアルキルは、ハロゲン、およびＣ_１−４アルコキシからなる群から独立して選択される１〜３個の置換基で置換されていてもよい）である、項１〜３のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項５］
Ｒ^１およびＲ^２が、各々独立して、水素、Ｃ_１−４アルキル（該アルキルは、ヒドロキシ、Ｃ_１−２アルキルスルホニル、アミノカルボニル（該アミノカルボニルのアミノ部分は、Ｃ_１−２アルキルによってモノ置換されていてもよい）、４〜５員のヘテロシクロアルキルおよび４〜６員のヘテロシクロアルキルカルボニル（該４〜７員のヘテロシクロアルキルおよび該４〜７員のヘテロシクロアルキルカルボニルのヘテロシクロアルキルは、それぞれＣ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）からなる群から独立して選択される１〜２個の置換基で置換されていてもよい）または４〜５員のヘテロシクロアルキル（該ヘテロシクロアルキルは、１〜２個のハロゲンによって置換されていてもよい）である、項１〜３のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項６］
Ｒ^１が、水素またはＣ_１−４アルキルであり、Ｒ^２が、Ｃ_１−４アルキル（該アルキルは、ヒドロキシ、Ｃ_１−２アルキルスルホニルおよびアミノカルボニル（該アミノカルボニルのアミノ部分は、Ｃ_１−２アルキルによってモノ置換されていてもよい）からなる群から独立して選択される１〜２個の置換基で置換されていてもよい）または４〜５員のヘテロシクロアルキル（該ヘテロシクロアルキルは、Ｃ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）である、項１〜３のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項７］
Ｌが、Ｃ_１−６アルキレン（該アルキレンは、Ｃ_１−４アルキル、ハロゲン、ヒドロキシおよびＣ_１−４アルコキシからなる群から独立して選択される１〜３個の置換基で置換されていてもよい）であり、ここにおいて、Ｒ^１が、Ｃ_１−６アルキルであるとき、Ｒ^１とＬ上の炭素原子が一緒になって、Ｒ^１が結合する窒素原子と共に４〜７員の飽和複素環を形成してもよい、項１〜６のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項８］
Ｌが、Ｃ_１−４アルキレン（該アルキレンは、Ｃ_１−２アルキルおよびヒドロキシからなる群から独立して選択される１〜２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^１が、Ｃ_１−６アルキルであるとき、Ｒ^１とＬ上の炭素原子が一緒になって、Ｒ^１が結合する窒素原子と共に４〜６員の飽和複素環を形成してもよい、項７に記載の化合物またはその薬学的に許容される塩；
［項９］
Ｌが、Ｃ_１−３アルキレン（該アルキレンは、Ｃ_１−２アルキルおよびヒドロキシからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）である、項１〜６のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項１０］
Ｌが、Ｃ_１−３アルキレンであり、Ｒ^１が、Ｃ_１−６アルキルであり、Ｒ^１とＬ上の炭素原子が一緒になって、Ｒ^１が結合する窒素原子と共にアゼチジン、ピペリジン、ピロリジンを形成している、項１〜６のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項１１］
Ｒ^３が、ハロゲン、Ｃ_１−６アルキル、Ｃ_２−６アルケニル（該アルキルおよび該アルケニルは、それぞれハロゲン、Ｃ_３−７シクロアルキル（該シクロアルキルは、１〜２個のハロゲンによって置換されていてもよい）、４〜７員のヘテロシクロアルキル（該ヘテロシクロアルキルは、Ｃ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）、Ｃ_６−１０アリールおよび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は、それぞれ１〜３個のハロゲンによって置換されていてもよい）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_４−７シクロアルケニル、４〜７員のヘテロシクロアルキル（該シクロアルキル、該シクロアルケニル、該ヘテロシクロアルキルは、それぞれＣ_１−４アルキル、Ｃ_１−４ハロアルキルおよびハロゲン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（該アリールは、ハロゲン、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、それぞれ１〜２個のＣ_１−２アルコキシによって置換されていてもよい）、Ｃ_１−４ハロアルキル、Ｃ_１−４ハロアルコキシ、シアノおよびＣ_１−４アルコキシカルボ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５〜１０員のヘテロアリール（該ヘテロアリールは、ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４ハロアルキル、Ｃ_１−４アルコキシおよびＣ_１−４ハ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、項１〜１０のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項１２］
Ｒ^３が、ハロゲン、Ｃ_１−４アルキル、Ｃ_２−４アルケニル（該アルキルおよび該アルケニルは、それぞれハロゲン、Ｃ_４−６シクロアルキル（該シクロアルキルは、１〜２個のハロゲンによって置換されていてもよい）、置換されていてもよい４〜６員のヘテロシクロアルキル（該ヘテロシクロアルキルは、Ｃ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）、Ｃ_６−１０アリールおよび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は、それぞれ１〜２個のハロゲンによって置換されていてもよい）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_３−６シクロアルキル、Ｃ_４−６シクロアルケニル、４〜６員のヘテロシクロアルキル（該シクロアルキル、該シクロアルケニル、該ヘテロシクロアルキルは、１〜３個のハロゲンによって置換されていてもよい）、Ｃ_６−１０アリール（該アリールは、ハロゲン、Ｃ_１−２アルキル、Ｃ_１−２アルコキシ（該アルキルおよび該アルコキシは、それぞれ１〜２個のＣ_１−２アルコキシによって置換されていてもよい）、Ｃ_１−２ハロアルキル、Ｃ_１−２ハロアルコキシ、シアノおよびＣ_１−２アルコキシカルボ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６員のヘテロアリール（該ヘテロアリールは、ハロゲンおよびＣ_１−２ハロアルキルからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）である、項１〜１０のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項１３］
Ｒ^３が、Ｃ_３−６シクロアルキル、４〜６員のヘテロシクロアルキル（該シクロアルキルおよび該ヘテロシクロアルキルは、１〜３個のハロゲンによって置換されていてもよい）、フェニル（該フェニルは、ハロゲン、Ｃ_１−２アルキル、Ｃ_１−２ハロアルキル、Ｃ_１−２アルコキシおよびＣ_１−２ハ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）または６員のヘテロアリール（該ヘテロアリールは、１〜２個のＣ_１−２ハロアルキルによって置換されていてもよい）である、項１〜１０のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項１４］
Ｒ^４が、水素、ハロゲンまたはＣ_１−２アルキルである、項１〜１３のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項１５］
Ｒ^４が、水素である、項１〜１３のいずれか一項に記載の化合物またはその薬学的に許容される塩；
［項１６］
Ｒ^１およびＲ^２が、各々独立して、水素、Ｃ_１−６アルキル（該アルキルは、ヒドロキシ、ハロゲン、Ｃ_１−４アルコキシ、Ｃ_１−４アルキルスルホニル、アミノカルボニル（該アミノカルボニルのアミノ部分は、Ｃ_１−４アルキルによってモノまたはジ置換されていてもよい）、４〜7員のヘテロシクロアルキルおよび４〜７員のヘテロシクロアルキルカルボニル（該４〜７員のヘテロシクロアルキルおよび該４〜７員のヘテロシクロアルキルカルボニルのヘテロシクロアルキル部分は、それぞれＣ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）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４〜７員のヘテロシクロアルキル（該ヘテロシクロアルキルは、ハロゲン、およびＣ_１−４アルコキシからなる群から独立して選択される１〜３個の置換基で置換されていてもよい）であり、
Ｌが、Ｃ_１−６アルキレン（該アルキレンは、Ｃ_１−４アルキル、ハロゲン、ヒドロキシおよびＣ_１−４アルコキシからなる群から独立して選択される１〜３個の置換基で置換されていてもよい）であり、ここにおいて、Ｒ^１が、Ｃ_１−６アルキルであるとき、Ｒ^１とＬ上の炭素原子が一緒になって、Ｒ^１が結合する窒素原子と共に４〜７員の飽和複素環を形成してもよく、
Ｒ^３が、ハロゲン、Ｃ_１−６アルキル、Ｃ_２−６アルケニル（該アルキルおよび該アルケニルは、それぞれハロゲン、Ｃ_３−７シクロアルキル（該シクロアルキルは、１〜２個のハロゲンによって置換されていてもよい）、４〜７員のヘテロシクロアルキル（該ヘテロシクロアルキルは、Ｃ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）、Ｃ_６−１０アリールおよび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は、それぞれ１〜３個のハロゲンによって置換されていてもよい）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_４−７シクロアルケニル、４〜７員のヘテロシクロアルキル（該シクロアルキル、該シクロアルケニル、該ヘテロシクロアルキルは、それぞれＣ_１−４アルキル、Ｃ_１−４ハロアルキルおよびハロゲン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（該アリールは、ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４アルコキシ、シアノおよびＣ_１−４アルコキシカルボ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５〜１０員のヘテロアリール（該ヘテロアリールは、ハロゲン、Ｃ_１−４アルキル、Ｃ_１−４ハロアルキル、Ｃ_１−４アルコキシおよびＣ_１−４ハ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、
Ｒ^４が、水素、ハロゲンまたはＣ_１−２アルキルである、項１に記載の化合物またはその薬学的に許容される塩；
［項１７］
Ｒ^１およびＲ^２が、各々独立して、水素、Ｃ_１−４アルキル（該アルキルは、ヒドロキシ、Ｃ_１−２アルキルスルホニル、アミノカルボニル（該アミノカルボニルのアミノ部分は、Ｃ_１−２アルキルによってモノ置換されていてもよい）、４〜５員のヘテロシクロアルキルおよび４〜６員のヘテロシクロアルキルカルボニル（該４〜７員のヘテロシクロアルキルおよび該４〜７員のヘテロシクロアルキルカルボニルのヘテロシクロアルキルは、それぞれＣ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）からなる群から独立して選択される１〜２個の置換基で置換されていてもよい）または４〜５員のヘテロシクロアルキル（該ヘテロシクロアルキルは、１〜２個のハロゲンによって置換されていてもよい）であり、
Ｌが、Ｃ_１−４アルキレン（該アルキレンは、Ｃ_１−２アルキルおよびヒドロキシからなる群から独立して選択される１〜２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^１が、Ｃ_１−６アルキルであるとき、Ｒ^１とＬ上の炭素原子が一緒になって、Ｒ^１が結合する窒素原子と共に４〜６員の飽和複素環を形成してもよく、
Ｒ^３が、ハロゲン、Ｃ_１−４アルキル、Ｃ_２−４アルケニル（該アルキルおよび該アルケニルは、それぞれハロゲン、Ｃ_４−６シクロアルキル（該シクロアルキルは、１〜２個のハロゲンによって置換されていてもよい）、４〜６員のヘテロシクロアルキル（該ヘテロシクロアルキルは、Ｃ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）、Ｃ_６−１０アリールおよび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は、それぞれ１〜２個のハロゲンによって置換されていてもよい）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_３−６シクロアルキル、Ｃ_４−６シクロアルケニル、４〜６員のヘテロシクロアルキル（該シクロアルキル、該シクロアルケニル、該ヘテロシクロアルキルは、１〜３個のハロゲンによって置換されていてもよい）、Ｃ_６−１０アリール（該アリールは、ハロゲン、Ｃ_１−２アルキル、Ｃ_１−２アルコキシ（該アルキルおよび該アルコキシは、それぞれ１〜２個のＣ_１−２アルコキシによって置換されていてもよい）、Ｃ_１−２ハロアルキル、Ｃ_１−２ハロアルコキシ、シアノおよびＣ_１−２アルコキシカルボ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６員のヘテロアリール（該ヘテロアリールは、ハロゲンおよびＣ_１−２ハロアルキルからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）であり、
Ｒ^４が、水素、ハロゲンまたはＣ_１−２アルキルである、項１に記載の化合物またはその薬学的に許容される塩；
［項１８］
Ｒ^１が、水素であり、
Ｒ^２が、Ｃ_１−４アルキル（該アルキルは、ヒドロキシおよびＣ_１−２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１〜２個の置換基で置換されていてもよい）または４〜５員のヘテロシクロアルキル（該ヘテロシクロアルキルは、Ｃ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）であり、
Ｌが、Ｃ_１−３アルキレン（該アルキレンは、Ｃ_１−２アルキルおよびヒドロキシからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）であり、
Ｒ^３が、Ｃ_３−６シクロアルキル、４〜６員のヘテロシクロアルキル（該シクロアルキルおよび該ヘテロシクロアルキルは、１〜３個のハロゲンによって置換されていてもよい）、フェニル（該フェニルは、ハロゲン、Ｃ_１−２アルキル、Ｃ_１−２アルコキシ、Ｃ_１−２ハロアルキル、Ｃ_１−２ハロアルコキシ、シアノおよびＣ_１−２アルコキシカルボ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６員のヘテロアリール（該ヘテロアリールは、１〜２個のＣ_１−２ハロアルキルによって置換されていてもよい）であり、
Ｒ^４が、水素である、項１に記載の化合物またはその薬学的に許容される塩；
［項１９］
Ｒ^１が、Ｃ_１−４アルキルであり、
Ｒ^２が、Ｃ_１−４アルキル（該アルキルは、ヒドロキシおよびＣ_１−２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１〜２個の置換基で置換されていてもよい）または４〜５員のヘテロシクロアルキル（該ヘテロシクロアルキルは、Ｃ_１−２アルキルおよびオキソからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）であり、
Ｌが、Ｃ_１−３アルキレンであり、Ｒ^１のアルキルとＬ上の炭素原子が一緒になって、Ｒ^１が結合する窒素原子と共にアゼチジン、ピペリジンまたはピロリジンを形成しており、
Ｒ^３が、Ｃ_３−６シクロアルキル、４〜６員のヘテロシクロアルキル（該シクロアルキルおよび該ヘテロシクロアルキルは、１〜３個のハロゲンによって置換されていてもよい）、フェニル（該フェニルは、ハロゲン、Ｃ_１−２アルキル、Ｃ_１−２アルコキシ、Ｃ_１−２ハロアルキル、Ｃ_１−２ハロアルコキシ、シアノおよびＣ_１−２アルコキシカルボ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６員のヘテロアリール（該ヘテロアリールは、１〜２個のＣ_１−２ハロアルキルによって置換されていてもよい）であり、
Ｒ^４が、水素である、項１に記載の化合物またはその薬学的に許容される塩；
［項２０］
以下の化合物群から選択される、項１に記載の化合物またはその薬学的に許容される塩：
３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）−５−（４−（トリフルオロメチル）フェニル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１４）；
（Ｓ）−２−（（２−（２−オキソ−５−（４−（トリフルオロメチル）フェニル）ベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）エチル）アミノ）プロパンアミド（実施例１６）；
２−（（２−（２−オキソ−５−（４−（トリフルオロメチル）フェニル）ベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）エチル）アミノ）アセトアミド（実施例１９）；
（Ｒ）−２−（（２−（２−オキソ−５−（４−（トリフルオロメチル）フェニル）ベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）エチル）アミノ）プロパンアミド（実施例２０）；
３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）−５−（４−（トリフルオロメトキシ）フェニル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例３４）；
３−（２−（オキセタン−３−イルアミノ）エチル）−５−（４−（トリフルオロメチル）フェニル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例４２）；
５−（４−フルオロフェニル）−４−メチル−３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例４４）；
３−（２−メチル−３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）−５−（５−（トリフルオロメチル）ピリジン−２−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例６７）；
５−（４−フルオロフェニル）−３−（２−ヒドロキシ−３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例７０）；
５−（４−フルオロフェニル）−３−（３−（オキセタン−３−イルアミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例７２）；
３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）−５−フェニルベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例７５）；
５−（３−フルオロフェニル）−３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例７６）；
３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）−５−（４−（トリフルオロメトキシ）フェニル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例８４）；
５−（４−フルオロフェニル）−３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例８８）；
３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）−５−（４−（トリフルオロメチル）フェニル） ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例９２）；
３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）−５−（５−（トリフルオロメチル）ピリジン−２−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例９３）；
５−（４−フルオロフェニル）−４−メチル−３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例９９）；
５−（４，４−ジフルオロシクロヘキシル）−３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１００）；
６−フルオロ−３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）−５−（テトラヒドロ−２Ｈ−ピラン−４−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１０１）；
３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）−５−（テトラヒドロ−２Ｈ−ピラン−４−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１０２）；
５−シクロブチル−３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１１１）；
５−シクロペンチル−３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１１８）；
５−ブチル−３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１２４）；
３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）−７−（５−（トリフルオロメチル）ピリジン−２−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１４９）；
５−（４−フルオロフェニル）−３−（３−（（２−（メチルスルホニル）エチル）アミノ）ブチル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１５０）；
５−(３,３−ジフルオロシクロブチル)−３−(３−((２−(メチルスルホニル)エチル)アミノ)プロピル)ベンゾ[ｄ]オキサゾール−２(３Ｈ)−オン（実施例１５５）；
５−（３，３−ジフルオロシクロブチル）−３−（１−（２−（メチルスルホニル）エチル）アゼチジン−３−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１５６）；
５−（３，３−ジフルオロシクロブチル）−３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１５７）；
５−（３，３−ジフルオロシクロブチル）−３−（４−（（２−（メチルスルホニル）エチル）アミノ）ブチル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１５８）；
５−（３，３−ジフルオロシクロブチル）−３−（１−（２−（メチルスルホニル）エチル）ピペリジン−４−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１５９）；
２−（３−（５−（３，３−ジフルオロシクロブチル）−２−オキソベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）アゼチジン−１−イル）アセトアミド（実施例１６２）；
２−（４−（５−（３，３−ジフルオロシクロブチル）−２−オキソベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）ピペリジン−１−イル）アセトアミド（実施例１６３）；または
５−（３，３−ジフルオロシクロブチル）−３−（３−（（２−ヒドロキシ−２−メチルプロピル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１６５）；
［項２１］
以下の化合物群から選択される、請求項１に記載の化合物またはその薬学的に許容される塩：
５−（４−フルオロフェニル）−３−（２−ヒドロキシ−３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例７０）；
５−（４−フルオロフェニル）−３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例８８）；
３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）−５−（５−（トリフルオロメチル）ピリジン−２−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例９３）；
５−（４，４−ジフルオロシクロヘキシル）−３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１００）；
３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）−５−（テトラヒドロ−２Ｈ−ピラン−４−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１０２）；
５−シクロブチル−３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１１１）；
３−（３−（（２−（メチルスルホニル）エチル）アミノ）プロピル）−７−（５−（トリフルオロメチル）ピリジン−２−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１４９）；
５−(３,３−ジフルオロシクロブチル)−３−(３−((２−(メチルスルホニル)エチル)アミノ)プロピル)ベンゾ[ｄ]オキサゾール−２(３Ｈ)−オン（実施例１５５）；
５−（３，３−ジフルオロシクロブチル）−３−（２−（（２−（メチルスルホニル）エチル）アミノ）エチル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１５７）；
５−（３，３−ジフルオロシクロブチル）−３−（１−（２−（メチルスルホニル）エチル）ピペリジン−４−イル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１５９）；
２−（４−（５−（３，３−ジフルオロシクロブチル）−２−オキソベンゾ［ｄ］オキサゾール−３（２Ｈ）−イル）ピペリジン−１−イル）アセトアミド（実施例１６３）；または
５−（３，３−ジフルオロシクロブチル）−３−（３−（（２−ヒドロキシ−２−メチルプロピル）アミノ）プロピル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン（実施例１６５）；
［項２２］
下記式（２）；

[In Formula (1),
R ¹ And R ² Each independently represents hydrogen, C _1-6 Alkyl (wherein alkyl is hydroxy, halogen, C _1-4 Alkoxy, C _1-4 Alkylsulfonyl, C _1-4 Alkylthio, aminocarbonyl (the amino moiety of the aminocarbonyl is optionally substituted C _1-4 Independently from the group consisting of optionally substituted 4-7 membered heterocycloalkyl and optionally substituted 4-7 membered heterocycloalkylcarbonyl. Optionally substituted with 1 to 3 selected substituents), C _3-7 Cycloalkyl, C _4-7 Cycloalkenyl or 4- to 7-membered heterocycloalkyl (the cycloalkyl, the cycloalkenyl and the heterocycloalkyl are each C _1-4 Alkyl, C _1-4 Haloalkyl, halogen, hydroxy and C _1-4 Represented by 1 to 3 substituents independently selected from the group consisting of alkoxy),
L is C _1-6 Alkylene (the alkylene is C _1-4 Alkyl, halogen, hydroxy and C _1-4 And optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, wherein R ¹ But C _1-6 When alkyl, R ¹ And carbon atoms on L together, R ¹ A 4- to 7-membered saturated heterocyclic ring may be formed together with the nitrogen atom to which
R ³ Is halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl (the alkyl, the alkenyl, and the alkynyl are each halogen, optionally substituted C _3-7 Cycloalkyl, optionally substituted 4-7 membered heterocycloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, C _1-4 Alkylsulfonyl, C _1-4 Alkylthio, optionally substituted C _6-10 Aryl and optionally substituted C _6-10 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of aryloxy), C _3-7 Cycloalkyl, C _4-7 Cycloalkenyl, 4- to 7-membered heterocycloalkyl (the cycloalkyl, the cycloalkenyl, the heterocycloalkyl are each C _1-4 Alkyl, C _1-4 Haloalkyl, halogen, hydroxy and C _1-4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), C _6-10 Aryl (wherein the aryl is halogen, optionally substituted C _1-4 Alkyl, C _1-4 Haloalkyl, optionally substituted C _1-4 Alkoxy, C _1-4 Haloalkoxy, cyano and C _1-4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxycarbonyl), C _6-10 Aryloxy (the aryl moiety of the aryloxy is halogen, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy) or 5-10 membered heteroaryl (wherein the heteroaryl is halogen, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy and C _1-4 Which may be substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy)
R ⁴ Is hydrogen, halogen or C _1-4 Represents alkyl]
Or a pharmaceutically acceptable salt thereof;
[Section 2]
C which may be substituted _6-10 Aryl, optionally substituted C _6-10 Aryloxy and optionally substituted C _3-7 The substituent in cycloalkyl is halogen, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 1 to 3 substituents independently selected from the group consisting of haloalkoxy,
C which may be substituted _1-4 Alkyl and optionally substituted C _1-4 The substituent on alkoxy is C _1-4 Alkoxy, C _1-4 1 to 2 substituents independently selected from the group consisting of haloalkoxy,
Substituents in the optionally substituted 4-7 membered heterocycloalkyl and optionally substituted 4-7 membered heterocycloalkylcarbonyl heterocycloalkyl are C _1-4 Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, which is 1 to 3 substituents independently selected from the group consisting of alkyl, halogen, oxo and hydroxy;
[Section 3]
C which may be substituted _6-10 Aryl, optionally substituted C _6-10 Aryloxy and optionally substituted C _3-7 The substituent on cycloalkyl is 1-3 halogens;
C which may be substituted _1-4 Alkyl and optionally substituted C _1-4 The substituent in alkoxy is 1-2 C _1-2 Is alkoxy,
Substituents in the optionally substituted 4-7 membered heterocycloalkyl and optionally substituted 4-7 membered heterocycloalkylcarbonyl heterocycloalkyl are C _1-2 Item 2. The compound or a pharmaceutically acceptable salt thereof according to Item 1, wherein the compound is one or two substituents independently selected from the group consisting of alkyl and oxo;
[Claim 4]
R ¹ And R ² Are each independently hydrogen, C _1-6 Alkyl (wherein alkyl is hydroxy, halogen, C _1-4 Alkoxy, C _1-4 Alkylsulfonyl, aminocarbonyl (the amino moiety of the aminocarbonyl is C _1-4 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkylcarbonyl (the 4-7 membered heterocycloalkyl and the 4-7 membered heterocyclo) The heterocycloalkyl part of alkylcarbonyl is each C _1-2 Substituted with 1 to 3 substituents independently selected from the group consisting of 1 to 2 substituents independently selected from the group consisting of alkyl and oxo) Or 4-7 membered heterocycloalkyl, which is halogen, and C _1-4 The compound according to any one of Items 1 to 3, which may be substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, or a pharmaceutically acceptable salt thereof salt;
[Section 5]
R ¹ And R ² Are each independently hydrogen, C _1-4 Alkyl (wherein the alkyl is hydroxy, C _1-2 Alkylsulfonyl, aminocarbonyl (the amino moiety of the aminocarbonyl is C _1-2 4-5 membered heterocycloalkyl and 4-6 membered heterocycloalkylcarbonyl (optionally mono-substituted by alkyl) (the 4-7 membered heterocycloalkyl and the 4-7 membered heterocycloalkylcarbonyl) Each heterocycloalkyl is C _1-2 Substituted with 1 to 2 substituents independently selected from the group consisting of 1 to 2 substituents independently selected from the group consisting of alkyl and oxo) Or a 4- to 5-membered heterocycloalkyl, which is optionally substituted by 1 to 2 halogens, or a compound according to any one of items 1 to 3; A pharmaceutically acceptable salt thereof;
[Claim 6]
R ¹ Is hydrogen or C _1-4 Alkyl and R ² But C _1-4 Alkyl (wherein the alkyl is hydroxy, C _1-2 Alkylsulfonyl and aminocarbonyl (the amino moiety of the aminocarbonyl is C _1-2 Optionally substituted with 1 to 2 substituents independently selected from the group consisting of (optionally monosubstituted by alkyl) or 4 to 5 membered heterocycloalkyl (the heterocycloalkyl is , C _1-2 The compound according to any one of Items 1 to 3, which may be substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and oxo, or a pharmaceutically acceptable salt thereof Salt to be made;
[Claim 7]
L is C _1-6 Alkylene (the alkylene is C _1-4 Alkyl, halogen, hydroxy and C _1-4 And optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), wherein R ¹ But C _1-6 When alkyl, R ¹ And carbon atoms on L together, R ¹ The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 6, which may form a 4 to 7-membered saturated heterocyclic ring together with the nitrogen atom to which is bonded;
[Section 8]
L is C _1-4 Alkylene (the alkylene is C _1-2 Optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and hydroxy), wherein R ¹ But C _1-6 When alkyl, R ¹ And carbon atoms on L together, R ¹ Item 8. The compound according to Item 7 or a pharmaceutically acceptable salt thereof, which may form a 4- to 6-membered saturated heterocyclic ring with the nitrogen atom to which is bonded;
[Claim 9]
L is C _1-3 Alkylene (the alkylene is C _1-2 The compound according to any one of Items 1 to 6, which may be substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and hydroxy, or a pharmaceutically acceptable salt thereof Salt to be made;
[Section 10]
L is C _1-3 Alkylene and R ¹ But C _1-6 Alkyl and R ¹ And carbon atoms on L together, R ¹ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6, which forms azetidine, piperidine, pyrrolidine together with the nitrogen atom to which is bonded;
[Section 11]
R ³ Is halogen, C _1-6 Alkyl, C _2-6 Alkenyl (the alkyl and the alkenyl are each halogen, C _3-7 Cycloalkyl (the cycloalkyl may be substituted by 1 to 2 halogens), 4-7 membered heterocycloalkyl (the heterocycloalkyl is C _1-2 Optionally substituted by 1 to 2 substituents independently selected from the group consisting of alkyl and oxo), C _6-10 Aryl and C _6-10 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of aryloxy (wherein the aryl and the aryloxy may each be substituted with 1 to 3 halogens) ), C _3-7 Cycloalkyl, C _4-7 Cycloalkenyl, 4- to 7-membered heterocycloalkyl (the cycloalkyl, the cycloalkenyl, the heterocycloalkyl are each C _1-4 Alkyl, C _1-4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and halogen), C _6-10 Aryl (where aryl is halogen, C _1-4 Alkyl, C _1-4 Alkoxy (wherein the alkyl and the alkoxy are each 1-2 C _1-2 Optionally substituted by alkoxy), C _1-4 Haloalkyl, C _1-4 Haloalkoxy, cyano and C _1-4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxycarbonyl) or 5-10 membered heteroaryl (wherein the heteroaryl is halogen, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy and C _1-4 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, which may be substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy. Salt;
[Claim 12]
R ³ Is halogen, C _1-4 Alkyl, C _2-4 Alkenyl (the alkyl and the alkenyl are each halogen, C _4-6 Cycloalkyl (the cycloalkyl may be substituted by 1 to 2 halogens), optionally substituted 4-6 membered heterocycloalkyl (the heterocycloalkyl is C _1-2 Optionally substituted by 1 to 2 substituents independently selected from the group consisting of alkyl and oxo), C _6-10 Aryl and C _6-10 Optionally substituted by 1 to 3 substituents independently selected from the group consisting of aryloxy (wherein the aryl and the aryloxy may each be substituted by 1 to 2 halogens) ), C _3-6 Cycloalkyl, C _4-6 Cycloalkenyl, 4-6 membered heterocycloalkyl (the cycloalkyl, the cycloalkenyl, the heterocycloalkyl may be substituted by 1 to 3 halogens), C _6-10 Aryl (where aryl is halogen, C _1-2 Alkyl, C _1-2 Alkoxy (wherein the alkyl and the alkoxy are each 1-2 C _1-2 Optionally substituted by alkoxy), C _1-2 Haloalkyl, C _1-2 Haloalkoxy, cyano and C _1-2 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxycarbonyl) or 6-membered heteroaryl (wherein the heteroaryl is halogen and C _1-2 The compound according to any one of Items 1 to 10, which may be substituted with 1 to 2 substituents independently selected from the group consisting of haloalkyl, or a pharmaceutically acceptable salt thereof salt;
[Claim 13]
R ³ But C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl (the cycloalkyl and the heterocycloalkyl may be substituted by 1 to 3 halogens), phenyl (the phenyl is halogen, C _1-2 Alkyl, C _1-2 Haloalkyl, C _1-2 Alkoxy and C _1-2 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy) or 6-membered heteroaryl (wherein the heteroaryl is 1-2 C _1-2 The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 10, which may be substituted with haloalkyl;
[Section 14]
R ⁴ Is hydrogen, halogen or C _1-2 Item 14. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13, which is alkyl;
[Section 15]
R ⁴ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13, wherein is hydrogen.
[Section 16]
R ¹ And R ² Are each independently hydrogen, C _1-6 Alkyl (wherein alkyl is hydroxy, halogen, C _1-4 Alkoxy, C _1-4 Alkylsulfonyl, aminocarbonyl (the amino moiety of the aminocarbonyl is C _1-4 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkylcarbonyl (the 4-7 membered heterocycloalkyl and the 4-7 membered heterocyclo) The heterocycloalkyl part of alkylcarbonyl is each C _1-2 Substituted with 1 to 3 substituents independently selected from the group consisting of 1 to 2 substituents independently selected from the group consisting of alkyl and oxo) Or 4-7 membered heterocycloalkyl, which is halogen, and C _1-4 May be substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy),
L is C _1-6 Alkylene (the alkylene is C _1-4 Alkyl, halogen, hydroxy and C _1-4 And optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy), wherein R ¹ But C _1-6 When alkyl, R ¹ And carbon atoms on L together, R ¹ A 4- to 7-membered saturated heterocyclic ring may be formed together with the nitrogen atom to which
R ³ Is halogen, C _1-6 Alkyl, C _2-6 Alkenyl (the alkyl and the alkenyl are each halogen, C _3-7 Cycloalkyl (the cycloalkyl may be substituted by 1 to 2 halogens), 4-7 membered heterocycloalkyl (the heterocycloalkyl is C _1-2 Optionally substituted by 1 to 2 substituents independently selected from the group consisting of alkyl and oxo), C _6-10 Aryl and C _6-10 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of aryloxy (wherein the aryl and the aryloxy may each be substituted with 1 to 3 halogens) ), C _3-7 Cycloalkyl, C _4-7 Cycloalkenyl, 4- to 7-membered heterocycloalkyl (the cycloalkyl, the cycloalkenyl, the heterocycloalkyl are each C _1-4 Alkyl, C _1-4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and halogen), C _6-10 Aryl (where aryl is halogen, C _1-4 Alkyl, C _1-4 Alkoxy, cyano and C _1-4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxycarbonyl) or 5-10 membered heteroaryl (wherein the heteroaryl is halogen, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy and C _1-4 May be substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy),
R ⁴ Is hydrogen, halogen or C _1-2 Item 6. The compound according to Item 1, which is alkyl, or a pharmaceutically acceptable salt thereof;
[Section 17]
R ¹ And R ² Are each independently hydrogen, C _1-4 Alkyl (wherein the alkyl is hydroxy, C _1-2 Alkylsulfonyl, aminocarbonyl (the amino moiety of the aminocarbonyl is C _1-2 4-5 membered heterocycloalkyl and 4-6 membered heterocycloalkylcarbonyl (optionally mono-substituted by alkyl) (the 4-7 membered heterocycloalkyl and the 4-7 membered heterocycloalkylcarbonyl) Each heterocycloalkyl is C _1-2 Substituted with 1 to 2 substituents independently selected from the group consisting of 1 to 2 substituents independently selected from the group consisting of alkyl and oxo) Or 4 to 5 membered heterocycloalkyl, which may be substituted by 1 to 2 halogens,
L is C _1-4 Alkylene (the alkylene is C _1-2 Optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and hydroxy), wherein R ¹ But C _1-6 When alkyl, R ¹ And carbon atoms on L together, R ¹ A 4- to 6-membered saturated heterocyclic ring may be formed together with the nitrogen atom to which
R ³ Is halogen, C _1-4 Alkyl, C _2-4 Alkenyl (the alkyl and the alkenyl are each halogen, C _4-6 Cycloalkyl (the cycloalkyl may be substituted by 1 to 2 halogens), 4 to 6 membered heterocycloalkyl (the heterocycloalkyl is C _1-2 Optionally substituted by 1 to 2 substituents independently selected from the group consisting of alkyl and oxo), C _6-10 Aryl and C _6-10 Optionally substituted by 1 to 3 substituents independently selected from the group consisting of aryloxy (wherein the aryl and the aryloxy may each be substituted by 1 to 2 halogens) ), C _3-6 Cycloalkyl, C _4-6 Cycloalkenyl, 4-6 membered heterocycloalkyl (the cycloalkyl, the cycloalkenyl, the heterocycloalkyl may be substituted by 1 to 3 halogens), C _6-10 Aryl (where aryl is halogen, C _1-2 Alkyl, C _1-2 Alkoxy (wherein the alkyl and the alkoxy are each 1-2 C _1-2 Optionally substituted by alkoxy), C _1-2 Haloalkyl, C _1-2 Haloalkoxy, cyano and C _1-2 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxycarbonyl) or 6-membered heteroaryl (wherein the heteroaryl is halogen and C _1-2 May be substituted with 1 to 2 substituents independently selected from the group consisting of haloalkyl),
R ⁴ Is hydrogen, halogen or C _1-2 Item 6. The compound according to Item 1, which is alkyl, or a pharmaceutically acceptable salt thereof;
[Section 18]
R ¹ Is hydrogen,
R ² But C _1-4 Alkyl (wherein the alkyl is hydroxy and C _1-2 Optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkylsulfonyl) or 4 to 5 membered heterocycloalkyl (the heterocycloalkyl is C _1-2 Optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and oxo),
L is C _1-3 Alkylene (the alkylene is C _1-2 Optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and hydroxy),
R ³ But C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl (the cycloalkyl and the heterocycloalkyl may be substituted by 1 to 3 halogens), phenyl (the phenyl is halogen, C _1-2 Alkyl, C _1-2 Alkoxy, C _1-2 Haloalkyl, C _1-2 Haloalkoxy, cyano and C _1-2 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxycarbonyl) or 6-membered heteroaryl (wherein the heteroaryl is 1-2 C _1-2 Optionally substituted by haloalkyl),
R ⁴ Item 2. The compound according to Item 1 or pharmaceutically acceptable salt thereof, wherein is hydrogen.
[Section 19]
R ¹ But C _1-4 Alkyl,
R ² But C _1-4 Alkyl (wherein the alkyl is hydroxy and C _1-2 Optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkylsulfonyl) or 4 to 5 membered heterocycloalkyl (the heterocycloalkyl is C _1-2 Optionally substituted with 1 to 2 substituents independently selected from the group consisting of alkyl and oxo),
L is C _1-3 Alkylene and R ¹ Together with the alkyl of L and the carbon atom on L ¹ Forms azetidine, piperidine or pyrrolidine together with the nitrogen atom to which
R ³ But C _3-6 Cycloalkyl, 4-6 membered heterocycloalkyl (the cycloalkyl and the heterocycloalkyl may be substituted by 1 to 3 halogens), phenyl (the phenyl is halogen, C _1-2 Alkyl, C _1-2 Alkoxy, C _1-2 Haloalkyl, C _1-2 Haloalkoxy, cyano and C _1-2 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxycarbonyl) or 6-membered heteroaryl (wherein the heteroaryl is 1-2 C _1-2 Optionally substituted by haloalkyl),
R ⁴ Item 2. The compound according to Item 1 or pharmaceutically acceptable salt thereof, wherein is hydrogen.
[Section 20]
Item 1. The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the following compound group:
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-2 (3H) -one (Example 14);
(S) -2-((2- (2-oxo-5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-3 (2H) -yl) ethyl) amino) propanamide (Example 16 );
2-((2- (2-oxo-5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-3 (2H) -yl) ethyl) amino) acetamide (Example 19);
(R) -2-((2- (2-oxo-5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-3 (2H) -yl) ethyl) amino) propanamide (Example 20 );
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (4- (trifluoromethoxy) phenyl) benzo [d] oxazol-2 (3H) -one (Example 34);
3- (2- (oxetane-3-ylamino) ethyl) -5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-2 (3H) -one (Example 42);
5- (4-fluorophenyl) -4-methyl-3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one (Example 44);
3- (2-Methyl-3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazole-2 (3H) -On (Example 67);
5- (4-Fluorophenyl) -3- (2-hydroxy-3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 70);
5- (4-fluorophenyl) -3- (3- (oxetan-3-ylamino) propyl) benzo [d] oxazol-2 (3H) -one (Example 72);
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5-phenylbenzo [d] oxazol-2 (3H) -one (Example 75);
5- (3-fluorophenyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 76);
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (4- (trifluoromethoxy) phenyl) benzo [d] oxazol-2 (3H) -one (Example 84);
5- (4-fluorophenyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 88);
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-2 (3H) -one (Example 92);
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one Example 93);
5- (4-Fluorophenyl) -4-methyl-3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 99);
5- (4,4-difluorocyclohexyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one (Example 100);
6-Fluoro-3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (tetrahydro-2H-pyran-4-yl) benzo [d] oxazol-2 (3H) -one ( Example 101);
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (tetrahydro-2H-pyran-4-yl) benzo [d] oxazol-2 (3H) -one (Example 102) ;
5-cyclobutyl-3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 111);
5-cyclopentyl-3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one (Example 118);
5-butyl-3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 124);
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -7- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one (implemented) Example 149);
5- (4-fluorophenyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) butyl) benzo [d] oxazol-2 (3H) -one (Example 150);
5- (3,3-difluorocyclobutyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 155);
5- (3,3-difluorocyclobutyl) -3- (1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) benzo [d] oxazol-2 (3H) -one (Example 156);
5- (3,3-difluorocyclobutyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one (Example 157);
5- (3,3-difluorocyclobutyl) -3- (4-((2- (methylsulfonyl) ethyl) amino) butyl) benzo [d] oxazol-2 (3H) -one (Example 158);
5- (3,3-difluorocyclobutyl) -3- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) benzo [d] oxazol-2 (3H) -one (Example 159);
2- (3- (5- (3,3-difluorocyclobutyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) azetidin-1-yl) acetamide (Example 162);
2- (4- (5- (3,3-difluorocyclobutyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) piperidin-1-yl) acetamide (Example 163); or
5- (3,3-difluorocyclobutyl) -3- (3-((2-hydroxy-2-methylpropyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 165);
[Claim 21]
The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
5- (4-Fluorophenyl) -3- (2-hydroxy-3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 70);
5- (4-fluorophenyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 88);
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one Example 93);
5- (4,4-difluorocyclohexyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one (Example 100);
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (tetrahydro-2H-pyran-4-yl) benzo [d] oxazol-2 (3H) -one (Example 102) ;
5-cyclobutyl-3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 111);
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -7- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one (implemented) Example 149);
5- (3,3-difluorocyclobutyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 155);
5- (3,3-difluorocyclobutyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one (Example 157);
5- (3,3-difluorocyclobutyl) -3- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) benzo [d] oxazol-2 (3H) -one (Example 159);
2- (4- (5- (3,3-difluorocyclobutyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) piperidin-1-yl) acetamide (Example 163); or
5- (3,3-difluorocyclobutyl) -3- (3-((2-hydroxy-2-methylpropyl) amino) propyl) benzo [d] oxazol-2 (3H) -one (Example 165);
[Item 22]
Following formula (2);

［式（２）中、
Ｒ^５は、ニトロ、アミノ（該アミノは、Ｃ_１−４アルキルオキシカルボニル、フェニルメチル、フェニルメチルオキシカルボニル（該フェニルメチル、該フェニルメチルオキシカルボニルにおけるフェニルメチル部分は、ハロゲン、Ｃ_１−２アルキルおよびＣ_１−２アルコキシからなる群から独立して選択される１〜６個の置換基で置換されていてもよい）、フルオレニルメチルカルボニル、ベンゼンスルホニル（該ベンゼンスルホニルは、ニトロによって１〜２個置換されていてもよい）からなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）またはフタルイミド（該フタルイミドのフェニル部分は、Ｃ_１−２アルキルによって１〜３個置換されていてもよい）であり、
Ｒ^６は、水素またはＣ_１−２アルキル（該アルキルは、Ｃ_１−２アルコキシ、フェニルおよび４−メトキシフェニルからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）であり、
Ｒ^７は、水素またはＣ_１−２アルキルであり、
Ｒ^８は、ヨウ素、臭素、塩素または水素であり、ここにおいて、Ｒ^８がヨウ素、臭素または塩素であるとき、置換可能な位置に１〜２個置換していてもよく、
Ａ−Ａは、Ｃ−ＣまたはＣ＝Ｃである］
で表される化合物またはその塩；
［項２３］
下記式（３）；

[In Formula (2),
R ⁵ represents nitro, amino (the amino is C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl (the phenylmethyl moiety in the phenylmethyl, phenylmethyloxycarbonyl is halogen, C _1-2 alkyl And optionally substituted with 1 to 6 substituents independently selected from the group consisting of C _1-2 alkoxy), fluorenylmethylcarbonyl, benzenesulfonyl (wherein the benzenesulfonyl is 1- Optionally substituted by 1 to 2 substituents independently selected from the group consisting of: optionally substituted) or phthalimide (the phenyl portion of the phthalimide is substituted by C _1-2 alkyl) 1 to 3 may be substituted),
R ⁶ is hydrogen or C _1-2 alkyl, wherein the alkyl is substituted with 1-2 substituents independently selected from the group consisting of C _1-2 alkoxy, phenyl and 4-methoxyphenyl. Is good)
R ⁷ is hydrogen or C _1-2 alkyl;
R ⁸ is iodine, bromine, chlorine or hydrogen, and when R ⁸ is iodine, bromine or chlorine, 1 to 2 may be substituted at substitutable positions;
AA is CC or C = C]
Or a salt thereof;
[Section 23]
Following formula (3);

［式（３）中、
Ｒ^７は、水素またはＣ_１−２アルキルであり、
Ｒ^９は、Ｃ_１−４アルキルオキシカルボニル、フェニルメチルオキシカルボニル（該フェニルメチルオキシカルボニルのフェニルメチル部分は、Ｃ_１−２アルキルおよびＣ_１−２アルコキシからなる群から独立して選択される１〜６個の置換基で置換されていてもよい）、フルオレニルメチルカルボニルまたはベンゼンスルホニル（該ベンゼンスルホニルは、ニトロによって１〜２個置換されていてもよい）であり、
Ｒ^１０は、水素またはＣ_１−２アルキルであり、ここにおいて、Ｒ^９およびＲ^１０が一緒になって、Ｒ^９およびＲ^１０が結合する窒素原子と共にフタルイミド（該フタルイミドのフェニル部分は、Ｃ_１−２アルキルによって１〜３個置換されていてもよい）を形成してもよく、
Ｍは、Ｃ_１−４アルキレンであり、ここにおいて、Ｒ^１０がＣ_１−２アルキルであるとき、Ｒ^１０とＭ上の炭素原子が一緒になって、Ｒ^１０が結合する窒素原子と共に４〜６員の飽和複素環を形成してもよく、
Ｂは、ハロゲンである］
で表される化合物またはその塩；
［項２４］
下記式（４）；

[In Formula (3),
R ⁷ is hydrogen or C _1-2 alkyl;
R ⁹ represents C _1-4 alkyloxycarbonyl, phenylmethyloxycarbonyl (the phenylmethyl moiety of the phenylmethyloxycarbonyl is independently selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy) Up to 6 substituents), fluorenylmethylcarbonyl or benzenesulfonyl (wherein the benzenesulfonyl may be substituted with 1 to 2 by nitro),
R ¹⁰ is hydrogen or C _1-2 alkyl, where R ⁹ and R ¹⁰ are taken together with the nitrogen atom to which R ⁹ and R ¹⁰ are attached together with phthalimide (the phenyl portion of the phthalimide is C ₁ 1-3 may be substituted by _-2 alkyl),
M is C _1-4 alkylene, where when R ¹⁰ is C _1-2 alkyl, R ¹⁰ and the carbon atom on M are taken together and together with the nitrogen atom to which R ¹⁰ is attached, 4- May form a 6-membered saturated heterocycle,
B is halogen]
Or a salt thereof;
[Claim 24]
Following formula (4);

［式（４）中、
Ｒ^７は、水素、またはＣ_１−２アルキルであり、
Ｒ^１１およびＲ^１２は、それぞれ独立して、水素、Ｃ_１−４アルキル（該アルキルは、Ｃ_１−４アルコキシまたはフェニルによって置換されていてもよい）、Ｃ_１−４ハロアルキル、Ｃ_１−４ハロアルコキシ、ニトロ、アミノ（該アミノは、Ｃ_１−４アルキルオキシカルボニル、フェニルメチル、フェニルメチルオキシカルボニル（該フェニルメチルおよび該フェニルメチルオキシカルボニルにおけるフェニルメチル部分は、ハロゲン、Ｃ_１−２アルキルおよびＣ_１−２アルコキシからなる群から独立して選択される１〜６個の置換基で置換されていてもよい）、フルオレニルメチルカルボニル、ベンゼンスルホニル（該ベンゼンスルホニルは、ニトロによって１〜２個置換されていてもよい）からなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）、フタルイミド（該フタルイミドのフェニル部分は、Ｃ_１−２アルキルによって１〜３個置換されていてもよい）またはＣ_１−２アルコキシ（該アルコキシにおけるアルキル部分は、Ｃ_１−２アルコキシ、フェニルおよび４−メトキシフェニルからなる群から独立して選択される１〜２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^１１およびＲ^１２が互いにオルト位である場合は、Ｒ^１１とＲ^１２がフェニルと一緒になってベンズオキサゾロン環、インドール環またはインダゾール環を形成してもよい］
で表される化合物またはその塩の製造方法であって、下記式（５）

[In Formula (4),
R ⁷ is hydrogen or C _1-2 alkyl;
R ¹¹ and R ¹² are each independently hydrogen, C _1-4 alkyl (wherein the alkyl may be substituted by C _1-4 alkoxy or phenyl), C _1-4 haloalkyl, C _1-4. Haloalkoxy, nitro, amino (wherein the amino is C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl (the phenylmethyl moiety in the phenylmethyl and phenylmethyloxycarbonyl is halogen, C _1-2 alkyl and Optionally substituted with 1 to 6 substituents independently selected from the group consisting of C _1-2 alkoxy, fluorenylmethylcarbonyl, benzenesulfonyl (wherein the benzenesulfonyl is 1-2 with nitro) 1 may be independently selected from the group consisting of Number of which may be substituted by a substituent), phthalimide (phenyl moiety of the phthalimide may be 1-3 substituted by C _1-2 alkyl) or C _1-2 alkoxy (alkyl in the alkoxy The moiety is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkoxy, phenyl and 4-methoxyphenyl, wherein R ¹¹ and R ^{11 When 12} is ortho to each other, R ¹¹ and R ¹² may be combined with phenyl to form a benzoxazolone ring, an indole ring or an indazole ring.
Or a salt thereof, which is represented by the following formula (5):

［式（５）中、
Ｒ^７、Ｒ^１１およびＲ^１２は、上記式（４）と同じであり、
Ｂは、ハロゲンである］で表される化合物と、下記式（６）

[In Formula (5),
R ⁷ , R ¹¹ and R ¹² are the same as in the above formula (4),
B is a halogen], and the following formula (6)

［式（６）中、
Ｘは、ヨウ素、臭素または塩素である］で表される化合物を、パラジウム触媒を用いてカップリングさせる工程を含む製造方法。
［項２５］
下記式（７）；

[In Formula (6),
X is an iodine, bromine, or chlorine] manufacturing method including a step of coupling a compound represented by a palladium catalyst.
[Claim 25]
Following formula (7);

［式（７）中、
Ｒ^７は、水素またはＣ_１−２アルキルであり、
Ｒ^１３は、Ｃ_１−４アルキルオキシカルボニル、フェニルメチル、フェニルメチルオキシカルボニル（該フェニルメチルおよび該フェニルメチルオキシカルボニルにおけるフェニルメチル部分は、ハロゲン、Ｃ_１−２アルキルおよびＣ_１−２アルコキシからなる群から独立して選択される１〜６個の置換基で置換されていてもよい）、フルオレニルメチルカルボニル、ベンゼンスルホニル（該ベンゼンスルホニルは、ニトロによって１〜２個置換されていてもよい）であり、
Ｒ^１４は、水素、Ｃ_１−２アルキル、Ｃ_１−４アルキルオキシカルボニル、フェニルメチル、フェニルメチルオキシカルボニル（該フェニルメチルおよび該フェニルメチルオキシカルボニルにおけるフェニルメチル部分は、ハロゲン、Ｃ_１−２アルキルおよびＣ_１−２アルコキシからなる群から独立して選択される１〜６個の置換基で置換されていてもよい）、フルオレニルメチルカルボニルまたはベンゼンスルホニル（該ベンゼンスルホニルは、ニトロによって１〜２個置換されていてもよい）であり、ここにおいて、Ｒ^１３およびＲ^１４が一緒になって、Ｒ^１３およびＲ^１４が結合する窒素原子と共にフタルイミド（該フタルイミドのフェニル部分は、Ｃ_１−２アルキルによって１〜３個置換されていてもよい）を形成してもよく、
Ｍは、Ｃ_１−４アルキレンであり、ここにおいて、Ｒ^１４がＣ_１−２アルキルであるとき、Ｒ^１４とＭ上の炭素原子が一緒になって、Ｒ^１４が結合する窒素原子と共に４〜６員の飽和複素環を形成してもよい］
で表される化合物またはその塩の製造方法であって、下記式（８）

[In Formula (7),
R ⁷ is hydrogen or C _1-2 alkyl;
R ¹³ is C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl (the phenylmethyl and the phenylmethyl moiety in the phenylmethyloxycarbonyl are composed of halogen, C _1-2 alkyl and C _1-2 alkoxy. Optionally substituted with 1 to 6 substituents independently selected from the group), fluorenylmethylcarbonyl, benzenesulfonyl (the benzenesulfonyl may be substituted with 1 to 2 by nitro) ) And
R ¹⁴ is hydrogen, C _1-2 alkyl, C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl (the phenylmethyl moiety in the phenylmethyl and phenylmethyloxycarbonyl is halogen, C _1-2 alkyl And optionally substituted with 1 to 6 substituents independently selected from the group consisting of C _1-2 alkoxy), fluorenylmethylcarbonyl or benzenesulfonyl (wherein the benzenesulfonyl is 1- In which R ¹³ and R ¹⁴ are taken together with the nitrogen atom to which R ¹³ and R ¹⁴ are attached together with phthalimide (the phenyl moiety of the phthalimide is C _1-2 1 to 3 may be substituted with alkyl) ,
M is C _1-4 alkylene, where when R ¹⁴ is C _1-2 alkyl, R ¹⁴ and the carbon atom on M are taken together and together with the nitrogen atom to which R ¹⁴ is attached, 4 to 4 A 6-membered saturated heterocyclic ring may be formed]
Or a salt thereof, which is represented by the following formula (8):

［式（８）中、
Ｒ^７、Ｒ^１３、Ｒ^１４およびＭは、上記式（７）と同じであり、Ｂは、ハロゲンである］で表される化合物と、下記式（９）

[In Formula (8),
R ⁷ , R ¹³ , R ¹⁴ and M are the same as those in the above formula (7), B is a halogen], and the following formula (9)

［式（９）中、
Ｘは、ヨウ素、臭素または塩素である］で表される化合物を、パラジウム触媒を用いてカップリングさせる工程を含む製造方法。
［項２６］
請求項１〜２１のいずれか一項に記載の化合物またはその薬学的に許容される塩を含有する医薬組成物；
［項２７］
請求項１〜２１のいずれか一項に記載の化合物またはその薬学的に許容される塩を有効成分として含有する、Ｎａｖ１．７（ＳＣＮ９Ａ）、Ｎａｖ１．８（ＳＣＮ１０Ａ）またはＮａｖ１．７およびＮａｖ１．８の両方が関与する疾病の治療薬；
［項２８］
請求項１〜２１のいずれか一項に記載の化合物またはその薬学的に許容される塩を有効成分として含有する、Ｎａｖ１．７（ＳＣＮ９Ａ）が関与する疾病の治療薬；
［項２９］
請求項１〜２１のいずれか一項に記載の化合物またはその薬学的に許容される塩を有効成分として含有する、Ｎａｖ１．８（ＳＣＮ１０Ａ）が関与する疾病の治療薬；
［項３０］
請求項１〜２１のいずれか一項に記載の化合物またはその薬学的に許容される塩を有効成分として含有する神経障害性疼痛、侵害受容性疼痛、炎症性疼痛、小径線維ニューロパチー、肢端紅痛症、発作性激痛症、排尿障害または多発性硬化症の治療薬；
［項３１］
請求項１〜２１のいずれか一項に記載の化合物またはその薬学的に許容される塩を有効成分として含有する、Ｎａｖ１．７（ＳＣＮ９Ａ）、Ｎａｖ１．８（ＳＣＮ１０Ａ）またはＮａｖ１．７およびＮａｖ１．８の両方が関与する疾病の治療薬と、抗てんかん薬、抗うつ薬、麻薬性鎮痛薬、抗炎症薬、還元酵素阻害剤、プロスタグランジン誘導体製剤から選択される少なくとも１種以上の薬剤とを組み合わせてなる医薬；
［項３２］
神経障害性疼痛、侵害受容性疼痛、炎症性疼痛、小径線維ニューロパチー、肢端紅痛症、発作性激痛症、排尿障害または多発性硬化症の治療薬を製造するための、請求項１〜２１のいずれか一項に記載の化合物またはその薬学的に許容される塩の使用；
［項３３］
治療が必要な患者に、治療上の有効量の請求項１〜２１のいずれか一項に記載の化合物またはその薬学的に許容される塩を投与することを特徴とする、神経障害性疼痛、侵害受容性疼痛、炎症性疼痛、小径線維ニューロパチー、肢端紅痛症、発作性激痛症、排尿障害または多発性硬化症を治療するための方法。

[In Formula (9),
X is an iodine, bromine, or chlorine] manufacturing method including a step of coupling a compound represented by a palladium catalyst.
[Claim 26]
A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof;
[Section 27]
A Nav1.7 (SCN9A), Nav1.8 (SCN10A) or Nav1.7 and Nav1.2 containing the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient. 8 for the treatment of diseases involving both;
[Claim 28]
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 21 or a pharmaceutically acceptable salt thereof;
[Item 29]
A therapeutic agent for a disease involving Nav1.8 (SCN10A) comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient;
[Section 30]
Neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, limb redness containing the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient A drug for pain, paroxysmal pain, dysuria or multiple sclerosis;
[Claim 31]
A Nav1.7 (SCN9A), Nav1.8 (SCN10A) or Nav1.7 and Nav1.2 containing the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for a disease involving both of the above 8 and at least one drug selected from antiepileptic drugs, antidepressants, narcotic analgesics, anti-inflammatory drugs, reductase inhibitors, and prostaglandin derivative preparations. A pharmaceutical comprising a combination of
[Section 32]
Claims 1 to 21 for the manufacture of a therapeutic agent for neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, limb erythema, paroxysmal pain, dysuria or multiple sclerosis Use of a compound according to any one of the above or a pharmaceutically acceptable salt thereof;
[Section 33]
Neuropathic pain, characterized in that a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment, A method for treating nociceptive pain, inflammatory pain, small fiber neuropathy, erythema limb pain, paroxysmal pain, dysuria or multiple sclerosis.

  The present invention provides inhibitors of Nav1.7 and / or Nav1.8 comprising novel benzoxazolones or pharmaceutically acceptable salts thereof. The compounds of the present invention are useful as therapeutic or prophylactic agents for all pathological conditions involving Nav1.7 (SCN9A) or Nav1.8 (SCN10A), or both, specifically neuropathic pain, nociception Applicable to patients with receptive pain, inflammatory pain, small-fiber neuropathy, erythema acropasis, paroxysmal pain, dysuria or multiple sclerosis.

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.

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

“C _1-2 alkyl”, “C _1-4 alkyl” and “C _1-6 alkyl” are linear or straight chain having 1 to 2, 1 to 4 and 1 to 6 carbon atoms, respectively. It means a branched saturated hydrocarbon group. For example, “C _1-2 alkyl” includes methyl and ethyl, and “C _1-4 alkyl” includes “C _1-2 alkyl” in addition to n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl are exemplified, and “C _1-6 alkyl” includes “C _1-4 alkyl”, pentyl, isopentyl, neopentyl, n-hexyl, and structural isomers thereof. . As the “C _1-6 alkyl” or “C _1-4 alkyl”, C _1-3 alkyl is preferable, and methyl and ethyl are more preferable. As “C _1-2 alkyl”, methyl and ethyl are preferable. The substituent in “optionally substituted C _1-4 alkyl” is selected from the following substituent group [A], and may be independently substituted at 1 to 3 positions at substitutable positions.

“C _3-6 cycloalkyl”, “C _4-6 cycloalkyl”, and “C _3-7 cycloalkyl” have 3 to 6 carbon atoms, 4 to 7 carbon atoms, and 3 to 7 carbon atoms, respectively. A cyclic saturated hydrocarbon group is meant. “C _3-6 cycloalkyl” or “C _3-7 cycloalkyl” is preferably “C _3-6 cycloalkyl” having 3 to 6 carbon atoms. “C _4-6 cycloalkyl” is preferably cycloalkyl having 4 to 6 carbon atoms. Specific examples of “C _3-6 cycloalkyl” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, and “C _3-7 cycloalkyl” includes cycloheptyl and the like in addition to the above. Specific examples of “C _4-6 cycloalkyl” include, for example, cyclobutyl, cyclopentyl, and cyclohexyl. The substituent in “optionally substituted C _3-7 cycloalkyl” is selected from the following substituent group [B], and may be independently substituted at 1 to 3 positions at substitutable positions.

In the “C _3-7 cycloalkyl”, “C _3-7 cycloalkyl” and two or more heteroatoms selected from phenyl or 5-membered or 6-membered nitrogen, sulfur or oxygen are the same or different. A bicyclic group condensed with the ring contained above (for example, 2 to 4) is also included. Specific examples of the group include groups represented by the following formulas.

（式中、結合位置は、シクロアルキル環の炭素原子上であり、化学的に結合可能な任意の位置である。）

(In the formula, the bonding position is on a carbon atom of the cycloalkyl ring and is an arbitrary position capable of being chemically bonded.)

“C _6-10 aryl” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferred is phenyl. Specific examples of “C _6-10 aryl” include phenyl, 1-naphthyl, 2-naphthyl and the like. The substituent in “optionally substituted C _6-10 aryl” is selected from the following substituent group [B], and may be independently substituted at 1 to 3 positions at substitutable positions.

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). Or a group condensed with a 5- to 7-membered cycloalkyl ring (for example, cyclopentane, cyclohexane or cycloheptane). Specific examples of the group include groups represented by the following formulas.

(In the formula, the bonding position is on a carbon atom of the aromatic ring and is an arbitrary position capable of chemically bonding.)

“4-7 membered heterocycloalkyl”, “4-6 membered heterocycloalkyl” and “4-5 membered heterocycloalkyl” are nitrogen, sulfur or oxygen in addition to carbon as atoms constituting the ring. Means a 4-7 membered, 4-6 membered, 4-5 membered saturated cyclic group containing one or the same or different heteroatoms selected from 2 or more (for example, 2-4), Some are partially unsaturated. “4- to 7-membered heterocycloalkyl” and “4- to 6-membered heterocycloalkyl” are preferably pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, and tetrahydro-2H-pyranyl. “4- to 5-membered heterocycloalkyl” is preferably pyrrolidinyl or tetrahydrofuranyl. The substituent in the “optionally substituted 4 to 7-membered heterocycloalkyl” is selected from the following substituent group [C], and may be independently substituted with 1 to 3 at each substitutable position. Good.

  “4-7 membered heterocycloalkylcarbonyl” means a carbonyl group substituted with the above “4-7 membered heterocycloalkyl”, specifically, pyrrolidinylcarbonyl, piperidinylcarbonyl. And piperazinylcarbonyl. Preferably, piperazinylcarbonyl is used. The substituent in the “optionally substituted 4 to 7-membered heterocycloalkylcarbonyl” is selected from the following substituent group [C], and 1 to 3 substituents are independently substituted at substitutable positions. Also good.

“C _4-6 cycloalkenyl” and “C _4-7 cycloalkenyl” are cyclic hydrocarbon groups having 1 to 6 double bonds and 4 to 6 carbon atoms and 4 to 7 carbon atoms, respectively. Means. Specific examples of “C _4-6 cycloalkenyl” include cyclopentenyl and cyclohexenyl, and “C _4-7 cycloalkenyl” includes cycloheptenyl in addition to the above. Preferably, cyclohexenyl is used.

  The “5- to 10-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 aromatic group contained. Preferably it is a 5- or 6-membered monocyclic heteroaryl.

  Among the 5- to 10-membered heteroaryl, 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 10-membered heteroaryl” include, for example, groups represented by the following formulae. Of these, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are preferable.

(In the formula, the bonding position in monocyclic heteroaryl is any position that can be chemically bonded. In addition, the bonding position in polycyclic heteroaryl is on a heteroaryl ring and can be chemically bonded. Any position.)

  The “4- to 6-membered saturated heterocyclic ring” and “4- to 7-membered saturated heterocyclic ring” mean one hetero atom selected from nitrogen, oxygen and sulfur in addition to carbon as an atom constituting the ring, or It means the same or different 2 to 3 cyclic hydrocarbon groups having 4 to 6 members and 4 to 7 members, respectively. Specific examples of “4 to 6-membered saturated heterocycle” include pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, tetrahydrofuranyl, azetidinyl and the like, and “4 to 7-membered saturated heterocycle” In addition to the above, azepanyl and the like can be mentioned. As the “4 to 6-membered saturated heterocyclic ring” or “4 to 7-membered saturated heterocyclic ring”, piperidinyl, pyrrolidinyl and azetidinyl are preferable.

“C _1-2 alkoxy” and “C _1-4 alkoxy” mean an oxy group substituted with the above “C _1-2 alkyl” and “C _1-4 alkyl”, respectively. Specific examples of “C _1-2 alkoxy” include methoxy and ethoxy. In addition to the above, “C _1-4 alkoxy” includes propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Is mentioned. “C _1-2 alkoxy” preferably includes methoxy and ethoxy, and “C _1-4 alkoxy” preferably includes methoxy, ethoxy and isopropoxy. The substituent in “optionally substituted C _1-4 alkoxy” is selected from the following substituent group [A], and may be independently substituted at 1 to 3 positions at substitutable positions.

“C _1-2 haloalkyl” and “C _1-4 haloalkyl” mean a C _1-2 alkyl group and a C _1-4 alkyl group each substituted with a halogen. Specific examples of “C _1-2 haloalkyl” and “C _1-4 haloalkyl” include trifluoromethyl, fluoroethyl, trifluoroethyl, pentafluoroethyl and the like. Of these, trifluoromethyl is preferable.

“C _1-2 haloalkoxy” and “C _1-4 haloalkoxy” mean an oxy group substituted by the above “C _1-2 haloalkoxy” and “C _1-4 haloalkyl”, respectively. Specific examples of “C _1-2 haloalkoxy” and “C _1-4 haloalkoxy” include trifluoromethyloxy, 1,1,2,2-tetrafluoroethyloxy, difluoromethyloxy and the like. Of these, trifluoromethyl is preferable.

“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 substituent in “optionally substituted C _6-10 aryloxy” is selected from the following substituent group [B], and may be independently substituted at 1 to 3 positions at substitutable positions.

“C _1-3 alkylene”, “C _1-4 alkylene” and “C _1-6 alkylene” are linear or branched, each having _{1 to 3, 1 to 4, and 1 to 6} carbon atoms. Means carbon linker. Specific examples of “C _1-3 alkylene” include methylene, ethylene and propylene, and “C _1-4 alkylene” includes “C _1-3 alkylene”, 2-methylpropylene, butylene and the like. Examples of the “C _1-6 alkylene” include 2,2-dimethylpropylene, pentylene, hexylene and the like in addition to “C _1-4 alkylene”. Ethylene and propylene are preferred.

“C _2-4 alkenyl” and “C _2-6 alkenyl” are linear or branched, each having 2 to 4 or 2 to 6 carbon atoms having one or more double bonds. Means an unsaturated aliphatic hydrocarbon group. “C _2-3 alkenyl” is preferable. Specific examples of “C _2-4 alkenyl” include, for example, ethenyl, propenyl, crotyl, butenyl, and “C _2-6 alkenyl” includes, in addition to the above, pentenyl, hexenyl and the like, and structural isomers thereof. Body and geometric isomers. 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. Preferred is “C _2-3 alkynyl”. Specific examples of “C _2-6 alkynyl” include, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like, and structural isomers thereof. The bond in the “C _2-6 alkynyl” is preferably on an unsaturated carbon atom, and examples thereof include 1-ethynyl and 1-propynyl.

_{"C 1-2} alkylsulfonyl", the _{"C 1-4} alkylsulfonyl", respectively, the _{"C 1-2} alkyl" means a substituted sulfonyl group in the _{"C 1-4} alkyl". Specific examples of “C _1-2 alkylsulfonyl” include, for example, methylsulfonyl and ethylsulfonyl, and “ _C1-4 alkylsulfonyl” includes propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like in addition to the above. Can be mentioned. Preferred is methylsulfonyl.

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

The above substituent groups [A], [B] and [C] are shown below.
[A]: C _1-4 alkoxy, C _1-4 haloalkoxy [B]: halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy [C]: C _1-4 alkyl, halogen, oxo, hydroxy

The above substituent group [A] is preferably C _1-2 alkoxy or C _1-2 haloalkoxy, and [B] is preferably fluorine, C _1-2 alkyl, C _1-2 haloalkyl, C _{1. -2} alkoxy or C _1-4 haloalkoxy, and [C] is preferably C _1-2 alkyl, fluorine or oxo.

  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.

Preferably, R ¹ and R ² are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is hydroxy, halogen, C _1-4 alkoxy, C _1-4 alkylsulfonyl, aminocarbonyl (of the aminocarbonyl The amino moiety may be mono- or di-substituted by optionally substituted C _1-4 alkyl), optionally substituted 4-7 membered heterocycloalkyl and optionally substituted 4-4 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of 7-membered heterocycloalkylcarbonyl) or 4-7 membered heterocycloalkyl (wherein the heterocycloalkyl is halogen, and C _1-4 optionally substituted with 1-3 substituents independently selected from the group consisting of alkoxy are also be), more favorable Details, each independently, _{hydrogen, C 1-4} alkyl (said alkyl, _hydroxy, amino portion of _{C 1-2} alkylsulfonyl, aminocarbonyl (the amino _carbonyl, optionally mono- substituted by _{C 1-2} alkyl 1 to 2 independently selected from the group consisting of optionally substituted 4 to 5 membered heterocycloalkyl and optionally substituted 4 to 6 membered heterocycloalkylcarbonyl Optionally substituted with a substituent) or 4 to 5 membered heterocycloalkyl, which may be substituted with 1 to 2 halogens, more preferably each independently. selection Te, hydrogen or _{C 1-4} alkyl (the alkyl, independently from the group consisting of hydroxy and _{C 1-2} alkylsulfonyl 1-2 heterocycloalkyl (wherein heterocycloalkyl may be substituted with a substituent), or 4-5 membered to is 1 is independently selected from the group consisting of C _1-2 alkyl and oxo Optionally substituted with 2 substituents).
Preferred examples of R ¹ and R ² include hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, dimethylaminocarbonylmethyl, 2-hydroxy-2-methylpropyl, tetrahydrofuranyl, oxetanyl. 2-methylsulfonylethyl, 2-ethylsulfonylethyl, 2-oxoimidazolidinylethyl, 2-isopropylsulfonylethyl, aminocarbonylmethyl, 1-aminocarbonylethyl, 1-aminocarbonyl-1-methylethyl, 4-methyl Examples include piperazinylcarbonylmethyl, 2-methylsulfonyl-2-methylpropyl, and 3-methylsulfonylpropyl. Among them, hydrogen, dimethylaminocarbonylmethyl, 2-hydroxy-2-methylpropyl, teto are preferable. Hidorofuraniru, oxetanyl, 2-methylsulfonyl-ethyl.

L is preferably C _1-6 alkylene (the alkylene is substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, hydroxy and C _1-4 alkoxy. More preferably, C _1-4 alkylene (wherein the alkylene is substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and hydroxy). May be). In addition, when R ¹ is C _1-6 alkyl, R ¹ and the carbon atom on L are combined together with the nitrogen atom to which R ¹ is bonded, together with the following formula (10);

（式中、ａは、１、２または３であり、ｂは、１または２であり、Ｒ^２aは前記〔１〕に記載のＲ^２の定義と同義である。）で表される４〜７員の飽和複素環を形成したものも好ましい。
上記式（１０）中、ａとして、好ましくは１、２または３であり、より好ましくは１または２である。
ｂとして、好ましくは、１または２である。
Ｒ^２ａとして、好ましくは、ジメチルアミノカルボニルメチル、アミノカルボニルメチル、２−ヒドロキシ−２−メチルプロピル、テトラヒドロフラニル、オキセタニル、２−メチルスルホニルエチル、２−エチルスルホニルエチルが挙げられ、より好ましくは２−ヒドロキシ−２−メチルプロピル、テトラヒドロフラニル、オキセタニル、２−メチルスルホニルエチル、アミノカルボニルメチルであり、最も好ましくは２−メチルスルホニルエチル、アミノカルボニルメチルである。
上記式（１０）で表される４〜７員の飽和複素環の好ましい具体例としては、アゼチジニル、ピロリジニル、ピペリジルが挙げられる。
Ｌの好ましい具体例としては、エチレン、プロピレン、ブチレン、１−メチルプロピレン、２−メチルプロピレン、３−メチルプロピレン、２−ヒドロキシプロピレン、２，２−ジメチルプロピレン、１−メチルエチレン、２−メチルエチレン、１，１−ジメチルエチレンが挙げられ、中でも好ましくは、エチレン、プロピレン、アゼチジニレン、ピペリジニレンが挙げられる。
Ｌのうち、上記式（１０）を含むリンカーとして好ましい具体例としては、アゼチジニレン、アゼチジニルメチレン、ピペリジニレン、ピロリジニレンが挙げられる。

(Wherein, a is 1, 2 or 3, b is 1 or 2, and R ^2a has the same definition as R ² described in [1] above). What formed the 7-membered saturated heterocyclic ring is also preferable.
In the above formula (10), a is preferably 1, 2 or 3, more preferably 1 or 2.
b is preferably 1 or 2.
R ^2a is preferably dimethylaminocarbonylmethyl, aminocarbonylmethyl, 2-hydroxy-2-methylpropyl, tetrahydrofuranyl, oxetanyl, 2-methylsulfonylethyl, 2-ethylsulfonylethyl, more preferably 2- Hydroxy-2-methylpropyl, tetrahydrofuranyl, oxetanyl, 2-methylsulfonylethyl, aminocarbonylmethyl, most preferably 2-methylsulfonylethyl, aminocarbonylmethyl.
Preferable specific examples of the 4- to 7-membered saturated heterocyclic ring represented by the above formula (10) include azetidinyl, pyrrolidinyl, and piperidyl.
Preferable specific examples of L include ethylene, propylene, butylene, 1-methylpropylene, 2-methylpropylene, 3-methylpropylene, 2-hydroxypropylene, 2,2-dimethylpropylene, 1-methylethylene, 2-methylethylene. 1,1-dimethylethylene, among which ethylene, propylene, azetidinylene, and piperidinylene are preferable.
Specific examples of preferable linkers containing the above formula (10) among L include azetidinylene, azetidinylmethylene, piperidinylene and pyrrolidinylene.

R ³ is preferably halogen, C _1-6 alkyl, C _2-6 alkenyl (the alkyl and the alkenyl are each halogen, _optionally substituted C _3-7 cycloalkyl, _optionally substituted 4 1 to 3 substituents independently selected from the group consisting of 7-membered heterocycloalkyl, optionally substituted C _6-10 aryl and optionally substituted C _6-10 aryloxy Optionally substituted), C _3-7 cycloalkyl, C _4-7 cycloalkenyl, 4-7 membered heterocycloalkyl (the cycloalkyl, the cycloalkenyl, the heterocycloalkyl are each C _1-4). Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, C _1-4 haloalkyl and halogen), C _6-10 aryl (wherein the aryl is halogen, optionally substituted C _1-4 alkyl, C _1-4 haloalkyl, optionally substituted C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and Optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkoxycarbonyl, or 5-10 membered heteroaryl (wherein the heteroaryl is halogen, C _{1- 4} alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Preferably halogen, C _1-4 alkyl, C _2-4 alkenyl (the alkyl and the alkenyl are each halogen, optionally substituted C _4-6 cycloalkyl Independently selected from the group consisting of kill, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted C _6-10 aryl and optionally substituted C _6-10 aryloxy. 1 to 3 substituents), C _3-6 cycloalkyl, C _4-6 cycloalkenyl, _{4- to} 6-membered heterocycloalkyl (the cycloalkyl, the cycloalkenyl, the hetero Cycloalkyl may be substituted by 1 to 3 halogens), C _6-10 aryl (wherein the aryl is halogen, optionally substituted C _1-2 alkyl, C _1-2 haloalkyl, substituted) _{1 to 2} independently selected from the group consisting of optionally substituted C _1-2 alkoxy, C _1-2 haloalkoxy, cyano and C _1-2 alkoxycarbonyl Optionally substituted with 3 substituents) or 5-10 membered heteroaryl, wherein the heteroaryl is independently selected from the group consisting of halogen and C _1-2 haloalkyl More preferably C _3-6 cycloalkyl, 4-6 membered heterocycloalkyl (wherein the cycloalkyl, the heterocycloalkyl is substituted by 1 to 3 halogens). C _6-10 aryl (the aryl may be halogen, optionally substituted C _1-2 alkyl, C _1-2 haloalkyl, optionally substituted C _1-2 alkoxy, C _{1). -2} haloalkoxy, optionally substituted with 1-3 substituents independently selected from the group consisting of cyano and C _1-2 alkoxycarbonyl) or 5-1 Heteroaryl-membered (said heteroaryl, may be substituted with one to two substituents independently selected from the group consisting of halogen and C _1-2 haloalkyl) a.
Preferable specific examples of R ³ include hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, 4- Fluoro-2-methylphenyl, 2-methylphenyl, 3-methylphenyl, 2-fluorophenyl, phenoxy, 4-fluorophenoxy, 4-fluorophenyl, 2-methoxyphenyl, 4-trifluoromethoxyphenyl, 3,5- Difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 4-fluorophenyl, 4-fluoro-3-methylphenyl, phenyl, trifluoromethyl, 4-methoxyphenyl, 2-phenylethyl, 3-methoxy Phenyl, 4-diph Fluoromethoxyphenyl, 3,4,5-trifluorophenyl, 2-methoxy-4-trifluoromethylphenyl, 2-pyridyl, 5-fluoropyridin-2-yl, 2-trifluoromethylpyridin-5-yl, Phenylethenyl, 4-fluorophenylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, isobutyl, n-butyl, t-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, 3,3-difluorocyclobutyl 5-methylpyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 5-methoxypyridin-2-yl, 4-fluorophenoxymethyl, 4-methoxyethoxy, tetrahydropyranyl, tetrahydropyranylmethyl, 2-methylpropyl, 3- Examples include butyl butyl and 4,4-difluorocyclohexyl, among which 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, cyclobutyl, cyclopentyl, cyclohexyl, n-butyl, n-pentyl, n -Hexyl, 3,3-difluorocyclobutyl, 5-methylpyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 5-methoxypyridin-2-yl, tetrahydropyranyl, 4,4-difluorocyclohexyl And most preferably 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, cyclobutyl, cyclopentyl, cyclohexyl, 3,3-difluorocyclobutyl, 5-methylpyridin-2-yl, 5 -G Fluoromethyl-2-yl, 5-methoxy-2-yl, tetrahydropyranyl, 4,4-difluoro-cyclohexyl.

R ⁴ is preferably hydrogen, halogen or C _1-2 alkyl, and more preferably hydrogen.

In order to more specifically disclose the compound represented by the formula (2), the various symbols used in the formula (2) will be described in detail with suitable specific examples.

Ｒ^５として好ましくは、ニトロ、アミノ（該アミノは、Ｃ_１−４アルキルオキシカルボニル、フェニルメチル、フェニルメチルオキシカルボニル、フルオレニルメチルカルボニル、ベンゼンスルホニル（該ベンゼンスルホニルは、ニトロによって１〜２個置換されていてもよい）からなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）またはフタルイミドであり、中でも好ましくは、ニトロまたはＮＨ_２である。
Ｒ^５の好ましい具体例としては、ニトロ、ＮＨ_２、Ｃ_１−４アルキルオキシカルボニルアミノ、ベンジルアミノ、（ジベンジル）アミノ、ベンジルオキシカルボニルアミノ、フルオレニルメチルカルボニルアミノ、２−ニトロベンゼンスルホニルアミノ、４−ニトロベンゼンスルホニルアミノ、２，４−ジニトロベンゼンスルホニルアミノ、フタルイミドが挙げられ、中でも好ましくは、ニトロ、ＮＨ_２、ｔｅｒｔ−ブトキシカルボニルアミノ、ベンジルアミノ、ベンジルオキシカルボニルアミノ、２−ニトロベンゼンスルホニルアミノが挙げられる。
Ｒ^６として、好ましくは、水素、メチル、エチル、メトキシメチル、ベンジル、４−メトキシベンジルであり、中でも好ましくは、メチル、エチル、ベンジルである。
Ｒ^７として好ましくは、水素又はメチルであり、より好ましくは水素である。
Ｒ^８として好ましくは、塩素または水素である。
Ａ−Ａは、Ｃ−ＣまたはＣ＝Ｃであり、Ｒ^８が、塩素である場合、Ａ−Ａとして好ましくはＣ＝Ｃであり、Ｒ^８が、水素である場合、Ａ−Ａとして好ましくはＣ−Ｃである。

R ⁵ is preferably nitro, amino (the amino is C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl, fluorenylmethylcarbonyl, benzenesulfonyl (the benzenesulfonyl is one or two by nitro). And optionally substituted with 1 to 2 substituents independently selected from the group consisting of (optionally substituted) or phthalimide, among which nitro or NH ₂ is preferred.
Preferred specific examples of R ⁵ include nitro, NH ₂ , C _1-4 alkyloxycarbonylamino, benzylamino, (dibenzyl) amino, benzyloxycarbonylamino, fluorenylmethylcarbonylamino, 2-nitrobenzenesulfonylamino, 4 - nitrobenzenesulfonyl amino, 2,4-nitrobenzenesulfonyl amino, phthalimido, and among them preferably include _nitro, NH 2, tert-butoxycarbonylamino, benzylamino, benzyloxycarbonylamino, 2-nitrobenzenesulfonyl amino .
R ⁶ is preferably hydrogen, methyl, ethyl, methoxymethyl, benzyl or 4-methoxybenzyl, and particularly preferably methyl, ethyl or benzyl.
R ⁷ is preferably hydrogen or methyl, more preferably hydrogen.
R ⁸ is preferably chlorine or hydrogen.
AA is C—C or C═C, and when R ⁸ is chlorine, preferably A = A as C—C, and when R ⁸ is hydrogen, preferably as AA. Is CC.

  As the compound represented by the formula (2), a compound represented by the following formula (11) is preferable.

In order to more specifically disclose the compound represented by the formula (3), various symbols used in the formula (3) will be described in detail with suitable specific examples.

Ｒ^７として好ましくは、水素またはメチルであり、より好ましくは水素である。
Ｒ^９の具体例としては、ｔｅｒｔ−ブトキシカルボニル、ベンジルオキシカルボニル、フルオレニルメチルカルボニルまたは２−ニトロベンゼンスルホニルが挙げられ、好ましくは、ｔｅｒｔ−ブトキシカルボニル、ベンジルオキシカルボニルである。
Ｒ^１０の具体例としては、水素、メチルであるか、Ｒ^９およびＲ^１０が一緒になってフタルイミドが挙げられ、好ましくは水素である。
Ｍの具体例としては、メチレン、エチレン、プロピレン、ブチレン、アゼチジニレン、アゼチジニルメチレン、ピペリジニレン、ピロリジニレンが挙げられる。好ましくはエチレン、プロピレン、アゼチジニレン、ピペリジニレンであり、より好ましくはエチレンまたはプロピレンである。
Ｂの具体例としては、ヨウ素、臭素、塩素またはフッ素が挙げられ、好ましくはヨウ素、臭素、塩素である。

R ⁷ is preferably hydrogen or methyl, more preferably hydrogen.
Specific examples of R ⁹ include tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethylcarbonyl and 2-nitrobenzenesulfonyl, preferably tert-butoxycarbonyl and benzyloxycarbonyl.
Specific examples of R ¹⁰ are hydrogen and methyl, or R ⁹ and R ^{10 taken} together include phthalimide, preferably hydrogen.
Specific examples of M include methylene, ethylene, propylene, butylene, azetidinylene, azetidinylmethylene, piperidinylene and pyrrolidinylene. Preferred is ethylene, propylene, azetidinylene, piperidinylene, and more preferred is ethylene or propylene.
Specific examples of B include iodine, bromine, chlorine, and fluorine, preferably iodine, bromine, and chlorine.

In order to more specifically disclose the compound represented by the formula (4), the various symbols used in the formula (4) will be described in detail with suitable specific examples.

Ｒ^７として好ましくは、水素、またはメチルであり、より好ましくは水素である。
Ｒ^１１およびＲ^１２おける保護基のついたアミノとは、上記式（２）における定義と同じである。
Ｒ^１１およびＲ^１２として好ましくは、それぞれ独立して、水素、Ｃ_１−４アルキル、ニトロ、アミノ（該アミノは、Ｃ_１−４アルキルオキシカルボニル、フェニルメチル、フェニルメチルオキシカルボニル、フルオレニルメチルカルボニル、ベンゼンスルホニル（該ベンゼンスルホニルは、ニトロによって１〜２個置換されていてもよい）からなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）、フタルイミドまたはＣ_１−２アルコキシ（該アルコキシにおけるアルキル部分は、Ｃ_１−２アルコキシ、フェニルおよび４−メトキシフェニルからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）であるか、互いにオルト位に結合したＲ^１１およびＲ^１２がフェニルと一緒になって形成したベンズオキサゾロン環、インドール環またはインダゾール環であり、中でも好ましくはニトロ、アミノ（該アミノは、Ｃ_１−４アルキルオキシカルボニル、フェニルメチルオキシカルボニル、からなる群から独立して選択される１〜２個の置換基によって置換されていてもよい）、またはＣ_１−２アルコキシ（該アルコキシにおけるアルキル部分は、Ｃ_１−２アルコキシおよびフェニルからなる群から独立して選択される１〜２個の置換基で置換されていてもよい）であるか、互いにオルト位に結合したＲ^１１およびＲ^１２がフェニルと一緒になって形成したベンズオキサゾロン環である。
Ｒ^１１およびＲ^１２の好ましい具体例としては、それぞれ独立して、水素、メチル、エチル、メトキシ、メトキシメトキシ、トリフルオロメチル、トリフルオロメトキシ、ニトロ、ベンジルオキシ、４−メトキシベンジルオキシ、ｔeｒｔ−ブトキシカルボニルアミノ、ベンジルアミノ、ベンジルオキシカルボニルアミノであるか、互いにオルト位に結合したＲ^１１およびＲ^１２がフェニルと一緒になったベンズオキサゾロン、インドールまたはインダゾールが挙げられ中でも好ましくは、メトキシ、メトキシメトキシ、ベンジルオキシ、４−メトキシベンジルオキシ、ｔeｒｔ−ブトキシカルボニルアミノ、ベンジルオキシカルボニルアミノであるか、互いにオルト位に結合したＲ^１１およびＲ^１２がフェニルと一緒になって形成したベンズオキサゾロンであり、より好ましくは、メトキシ、ベンジルオキシ、ｔeｒｔ−ブトキシカルボニルアミノであるか、Ｒ^１１およびＲ^１２が隣接してフェニルに置換して、フェニルと一緒になって形成したベンズオキサゾロンである。

R ⁷ is preferably hydrogen or methyl, more preferably hydrogen.
The amino having a protecting group in R ¹¹ and R ¹² has the same definition as in the above formula (2).
Preferably, R ¹¹ and R ¹² are each independently hydrogen, C _1-4 alkyl, nitro, amino (wherein the amino is C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl, fluorenylmethyl). Carbonyl, benzenesulfonyl (which may be substituted with 1 to 2 substituents independently selected from the group consisting of 1 to 2 substituents by nitro), phthalimide Or C _1-2 alkoxy (the alkyl part in the alkoxy may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkoxy, phenyl and 4-methoxyphenyl) ) and either, R ¹¹ and R ¹² bonded to the ortho-position to each other together with the phenyl The formed benz oxazolone ring, indole ring or indazole ring, among them preferably a nitro, amino (said amino, C _1-4 alkyloxycarbonyl, phenylmethyl oxycarbonyl 1 which are independently selected from the group consisting of Optionally substituted by two substituents), or C _1-2 alkoxy, wherein the alkyl moiety in the alkoxy is independently selected from the group consisting of C _1-2 alkoxy and phenyl R ¹¹ and R ¹² bonded to each other in the ortho position may be a benzoxazolone ring formed together with phenyl.
Preferable specific examples of R ¹¹ and R ¹² are each independently hydrogen, methyl, ethyl, methoxy, methoxymethoxy, trifluoromethyl, trifluoromethoxy, nitro, benzyloxy, 4-methoxybenzyloxy, tert-butoxy Benzoxazolone, indole or indazole in which R ¹¹ and R ¹² bonded to each other in the ortho position with each other, such as carbonylamino, benzylamino, benzyloxycarbonylamino, and phenyl are preferred, among which methoxy, methoxymethoxy, benzyloxy, 4-methoxybenzyloxy, tert- butoxycarbonylamino, or a benzyloxycarbonylamino, Baie which R ¹¹ and R ¹² are bonded in the ortho-position to each other to form together with the phenyl A Zuokisazoron, more preferably, methoxy, benzyloxy, or a tert- butoxycarbonylamino, substituted phenyl R ¹¹ and R ¹² are adjacent, is benz oxazolone formed together with the phenyl .

In order to more specifically disclose the compound represented by the formula (5), the various symbols used in the formula (5) will be described in detail with suitable specific examples.

Ｒ^７、Ｒ^１１およびＲ^１２は、上記式（４）における定義と同じである。
Ｂは、上記式（３）における定義と同じである。

R ⁷ , R ¹¹ and R ¹² are the same as defined in the above formula (4).
B is the same as defined in the above formula (3).

In order to more specifically disclose the compound represented by the formula (6), the symbols used in the formula (6) will be described in detail by giving preferred specific examples.

Ｘとして好ましくはヨウ素または臭素であり、より好ましくは臭素である。

X is preferably iodine or bromine, more preferably bromine.

In the reaction of the compound of the above formula (5) and the compound of the above formula (6), suitable reaction conditions will be described in detail with specific examples.
Compound (4) can be produced by reacting compound (5) with compound (6) in the presence of a palladium catalyst. Examples of the palladium 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) ( 3-chloropyridyl) palladium (II) dichloride), Pd-PEPPSI ^™ -IPent ((1,3-bis (2,6-diisopentylphenyl) imidazolidene) (3-chloropyridyl) para And catalysts such as (dium (II) dichloride). Also, for palladium acetate and palladium chloride, palladium reagents and catalyst, John Wiley & Sons Inc. (2004) or an appropriate ligand selected from the ligands described in (2004) can also be used. Preferable as the palladium catalyst are PEPPSI ^™ • IPr and Pd-PEPPSI ^™ -IPent, and more preferred is Pd-PEPPSI ^™ -IPent. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene or xylene, ethyl acetate or acetic acid. Aprotic polarities such as ester solvents such as methyl, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or dimethyl sulfoxide A solvent, or a mixture thereof. Preferred solvents are diethyl ether, diisopropyl ether, tetrahydrofuran, and methylcyclopentyl ether. While the reaction temperature varies depending on the kind of raw material compound to be used, etc., it is generally about 0 ° C. to about 250 ° C., preferably about 20 ° C. to about 100 ° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 48 hours.

In order to more specifically disclose the compound represented by the formula (7), the various symbols used in the formula (7) will be described in detail with suitable specific examples.

Ｒ^７として好ましくは、水素またはメチルであり、より好ましくは水素である。
Ｒ^１３として好ましくは、Ｃ_１−４アルキルオキシカルボニル、フェニルメチルオキシカルボニル、フルオレニルメチルカルボニル、ベンゼンスルホニル（該ベンゼンスルホニルは、ニトロによって１〜２個置換されていてもよい）であり、より好ましくはＣ_１−４アルキルオキシカルボニルまたはフェニルメチルオキシカルボニルである。 Ｒ^１４として好ましくは、水素またはメチルである。
Ｍは、上記式（３）における定義と同じである。

R ⁷ is preferably hydrogen or methyl, more preferably hydrogen.
R ¹³ is preferably C _1-4 alkyloxycarbonyl, phenylmethyloxycarbonyl, fluorenylmethylcarbonyl, benzenesulfonyl (the benzenesulfonyl may be substituted by 1 or 2 by nitro), and more Preferably it is _C1-4 alkyloxycarbonyl or phenylmethyloxycarbonyl. R ¹⁴ is preferably hydrogen or methyl.
M is the same as defined in the above formula (3).

In order to more specifically disclose the compound represented by the following formula (8), the various symbols used in the formula (8) will be described in detail with suitable specific examples.

Ｒ^７、Ｒ^１３およびＲ^１４は、上記式（７）における定義と同じである。

R ⁷ , R ¹³ and R ¹⁴ are the same as defined in the above formula (7).

In order to more specifically disclose the compound represented by the formula (9), the symbols used in the formula (9) will be described in detail by giving preferred specific examples.

Ｘとして好ましくはヨウ素または臭素であり、より好ましくは臭素である。

X is preferably iodine or bromine, more preferably bromine.

In the reaction of the above formula (8) with the compound of the above formula (9), suitable reaction conditions will be described in detail with specific examples.
Compound (7) can be produced by reacting compound (8) with compound (9) in the presence of a palladium catalyst. Preferable reaction conditions are the same as those in the reaction between the compound (5) and the compound (6).

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 12, methods similar to the following production methods, or synthesis methods well known to those skilled in the art. can do.

Production method 1:
Among the compounds represented by the formula (1), the compound (S-8) or a pharmaceutically acceptable salt thereof is produced, for example, by the method shown below. However, when R ³ is halogen, it is produced by using a compound in which X ¹ is halogen and not passing through the step (1-4). The same applies to the manufacturing methods 2 to 7.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＬは、前記項１に定義されるとおりである。Ｘ^１、Ｘ^２およびＸ^３は、各々独立し、ハロゲン、トリフルオロメタンスルホニルオキシまたはメタンスルホニルオキシなどの脱離基を表し、Ｒ^aは、ベンジル、アセチル、ベンゾイル、ｔｅｒｔ−ブチルジメチルシリル、トリエチルシリル、トリイソプロピルシリルまたはｔｅｒｔ−ブチルジフェニルシリル等の保護基を表し、Ｒ^３ａは、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−７シクロアルキル、Ｃ_４−７シクロアルケニル、４〜７員のヘテロシクロアルキル、Ｃ_６−１０アリール、Ｃ_６−１０アリールオキシまたは５〜１０員のヘテロアリールを表す。Ｒ^３ａ−Ｙ^１は、下記工程（１−４）に示す有機ホウ素化合物、有機亜鉛化合物、アルケニル化合物、アルキニル化合物またはヒドロキシ化合物等を表す。］

[Wherein R ¹ , R ² , R ³ , R ⁴ , and L are as defined in the above item 1. X ¹ , X ² and X ³ each independently represent a leaving group such as halogen, trifluoromethanesulfonyloxy or methanesulfonyloxy, and R ^a is benzyl, acetyl, benzoyl, tert-butyldimethylsilyl, triethylsilyl Represents a protecting group such as triisopropylsilyl or tert-butyldiphenylsilyl, and R ^3a is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _4-7. Cycloalkenyl represents 4-7 membered heterocycloalkyl, C _6-10 aryl, C _6-10 aryloxy or 5-10 membered heteroaryl. R ^3a -Y ¹ represents an organic boron compound, an organic zinc compound, an alkenyl compound, an alkynyl compound, a hydroxy compound, or the like shown in the following step (1-4). ]

Step (1-1):
The 2-aminophenol compound (s-2) can be produced by reducing the nitro group of the 2-nitrophenol compound (s-1) 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, the amino compound (s-2) is obtained by reacting the nitro compound (s-1) 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 non-solvents such as N, N-dimethylformamide. Examples thereof include a protic polar solvent, a protic polar solvent such as acetic acid, or 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.

  When metal reduction is used, the nitro compound (s-1) is converted into (1) a metal such as iron, zinc or tin, or a combination of 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-2) 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, and mixtures 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 (1-2):
The benzoxazolone compound (s-3) can be produced by subjecting the 2-aminophenol compound (s-2) to a carbonylation reaction in an inert solvent in the presence or absence of a base. As the carbonylation reagent, for example, carbonyldiimidazole, triphosgene, phosgene and the like are 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 tetrahydrofuran, diethyl ether, dimethoxyethane, and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile, Ketones (acetone etc.) or these mixed solvents are mentioned. Examples of the base include organic bases such as N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, DBU, DBN, DABCO, and pyridine. As reaction temperature, it can select normally from the range of -78-150 degreeC, Preferably it carries out in the range of 0-100 degreeC. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Step (1-3):
Compound (s-4) can be produced by reacting a benzoxazolone compound (s-3) with a halogen compound in the presence of a base. 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 tetrahydrofuran, diethyl ether, dimethoxyethane, and 1,4-dioxane, and aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and acetonitrile. Examples of the base include alkali metal carbonates such as cesium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, Organic bases such as DBU, DBN, DABCO and the like can be mentioned, and potassium carbonate and sodium hydride are preferable. The reaction temperature is usually about 0 to 150 ° C, preferably 0 to 100 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Step (1-4):
With respect to compound (s-4), in the presence of a base and a metal catalyst, an organic boron compound (for example, R ^3a -B (OH) ₂ etc.), an organic zinc compound (for example, R ^3a -ZnBr), an alkenyl compound, an alkynyl compound Alternatively, the compound of (s-5) can be produced by performing various coupling reactions by allowing a hydroxy compound (for example, R ^3a —OH or the like) to act. Examples of the base include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium methoxide, sodium tert-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, or 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) can be used. For palladium acetate and palladium chloride, 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 or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene or xylene, ethyl acetate or acetic acid. Aprotic polarities such as ester solvents such as methyl, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or dimethyl sulfoxide A solvent or water, or a mixture thereof can be mentioned. 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):
Compound (s-6) can be produced by deprotecting the hydroxyl 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 compound (s-6) can be derived using a base or an acid. Examples of the base that can be used include fluoride ions such as tetrabutylammonium fluoride and hydrogen fluoride pyridine complex, and various alkali or alkaline earth metal alkoxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide. Of these, tetrabutylammonium fluoride is preferred. While the reaction temperature varies depending on the type of raw material compound used, it is generally about 0 ° C to about 80 ° C, preferably about 20 ° C to about 40 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Examples of the acid include carboxylic acids such as acetic acid and trifluoroacetic acid, mineral acids such as hydrochloric acid and sulfuric acid, and Lewis acids such as boron tribromide and trimethylsilyl iodide. The reaction temperature ranges from 0 ° C. to heating reflux, preferably 20 ° C. to 60 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Step (1-6):
Compound (s-7) can be produced by halogenation or sulfonyl esterification of the hydroxyl group of compound (s-6). When performing halogenation, it can manufacture by making carbon tetrachloride or carbon tetrabromide act on (s-6) in presence of triphenylphosphine. When chlorination is performed, it can also be produced using thionyl chloride or oxalyl dichloride. Examples of the solvent include aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene, and halogen solvents such as dichloromethane, chloroform, and carbon tetrachloride. The reaction temperature varies depending on the type of raw material compound used and the like, but is usually about 0 ° C to about 150 ° C, preferably about 20 ° C to about 50 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

When sulfonyl esterification is performed, it can be produced by reacting with a sulfonic acid chloride in the presence of a base. As the sulfonate compound, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be used. Examples of the base include, for example, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, sodium tert-butoxide and the like, or triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU , Organic bases such as pyridine, dimethylaminopyridine, picoline, or NMM are used. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene or xylene, ethyl acetate or acetic acid. Aprotic polarities such as ester solvents such as methyl, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or dimethyl sulfoxide Examples of the solvent include halogen solvents such as dichloromethane, chloroform, and carbon tetrachloride. While the reaction temperature varies depending on the type of raw material compound used, it is generally about −10 ° C. to about 100 ° C., preferably about 0 ° C. to about 40 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Step (1-7):
Compound (S-8) or a pharmaceutically acceptable salt thereof can be produced by reacting compound (s-7) with an amine compound in the presence of a base. 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 tetrahydrofuran, diethyl ether, dimethoxyethane, and 1,4-dioxane, and aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and acetonitrile. Examples of the base include alkali metal carbonates such as cesium carbonate and potassium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, Organic bases such as DBU, DBN, DABCO and the like can be mentioned, and potassium carbonate is preferable. The reaction temperature is usually about 0 to 150 ° C, preferably 20 to 100 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

Production method 2:
Of the compound (S-8) or a pharmaceutically acceptable salt thereof described in Production Method 1, (S-8a) or a pharmaceutically acceptable salt thereof is the compound (s- 3) can also be used according to the following steps (2-1) to (2-4).

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^３ａ−Ｙは、製造法１と同義である。Ｌ´は、Ｃ_１−５アルキレンであり、該アルキレンの置換基は請求項１に記載のＬと同義であり、Ｘ^４は製造法１におけるＸ^２と同義である。Ｒ^ｂはＣ_１−４アルキルであり、２個のＲ^ｂが、一緒になって環を形成してもよい。）

(In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ^3a -Y have the same meaning as in Production Method 1. L ′ is C _1-5 alkylene, and the alkylene substituent is claimed. has the same meaning as L according to claim 1, ^{X 4} has the same meaning as ^{X 2} in the production method 1 .R ^b is _{C 1-4} alkyl, the two ^{R b} are taken together to form a ring You may do it.)

Step (2-1):
This step is a step of obtaining compound (s-9) using compound (s-3) and an acetal compound according to the conditions according to step (1-3) described in Production Method 1.

Step (2-2):
This step is a step of obtaining compound (s-10) using compound (s-9) according to the conditions according to step (1-4) described in Production Method 1.

Step (2-3):
An aldehyde compound (s-11) can be produced by performing a deprotection reaction of the acetal compound (s-10).
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-11) by the following acid hydrolysis. 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 the formula (s-11) can be obtained. The reaction temperature is preferably 0 to 60 ° C., and the reaction time is preferably 1 to 24 hours.

Step (2-4):
Compound (S-8a) or a pharmaceutically acceptable salt thereof can be produced by reacting amine compound with compound (s-11) in the presence of a reducing agent and an acid.
As the reducing agent, for example, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride and the like can be used, and among these, sodium triacetoxyborohydride is preferable. As the acid, acetic acid is preferred.
Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether and 1,2-dimethoxyethane, and aromatics such as benzene, toluene and xylene. A group solvent, alcohol solvents such as methanol, ethanol, n-propanol, 2-propanol and the like can be used alone or as a mixture thereof. Among them, dichloromethane is preferable.

Production method 3:
Of the compound (S-8) or the pharmaceutically acceptable salt thereof described in Production Method 2, the sulfonyl compound (S-15) or the pharmaceutically acceptable salt thereof is the compound (s 3), it can also be produced according to the following steps (3-1) to (3-4).

（式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｌ、およびＲ^３ａ−Ｙは、製造法１と同義である。Ｘ^５は製造法１におけるＸ^２と同義である。Ｒ^５はＣ_１−４アルキルを表し、Ｒ^ｃはベンジルオキシカルボニル、ｔｅｒｔ−ブトキシカルボニル等の保護基を表す。）

(In the formula, R ² , R ³ , R ⁴ , L, and R ^3a -Y have the same meaning as in Production Method 1. X ⁵ has the same meaning as X ² in Production Method 1. R ⁵ is C _{1-. 4} represents alkyl, and R ^c represents a protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, etc.)

Step (3-1):
A compound (s-12) can be manufactured according to the conditions according to the process (2-1) of the manufacturing method 2 using a compound (s-3). Compound (s-12) can also be produced by reacting compound (s-3) with alkyl alcohol and diisopropyl azodicarboxylate or diethyl azodicarboxylate in the presence of triphenylphosphine. . Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include halogen solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, and 1,2-dimethoxyethane, or a mixture thereof. Of these, tetrahydrofuran is preferred. The reaction temperature is usually about 0 ° C to 100 ° C, preferably 0 to 40 ° C. The reaction time is usually 1 to 24 hours, preferably 2 to 12 hours.

Step (3-2):
This step is a step of obtaining a compound (s-13) using the compound (s-12) according to the conditions according to the step (1-4) described in the production method 1.

Step (3-3):
Compound (s-14) can be produced by deprotecting compound (s-13) in the presence of an acid or a base. Examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid, and examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.). Examples of the solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol, 1-butanol, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, water, or these. A mixed solvent is mentioned. The reaction temperature is usually selected from the range of 0 to 100 ° C., preferably 0 to 50 ° C. The reaction time is usually 1 to 24 hours, preferably 1 to 12 hours.

In addition, when R ^{c of} compound (s-13) is benzyloxycarbonyl, compound (s-14) can also be produced using the catalytic reduction method described in Step (1-1) described in Production Method 1. Can do.
Step (3-4):
This step is a step of obtaining compound (S-15) or a pharmaceutically acceptable salt thereof by reacting alkylvinylsulfone with compound (s-14) in the presence or absence of a base. It is. As the base, organic bases such as triethylamine, diisopropylethylamine, tributylamine, DBN, DABCO, DBU, pyridine, dimethylaminopyridine, picoline, or NMM are used. Any solvent that does not react under the reaction conditions in this step can be used. Examples of the solvent include halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, Alcohol solvents such as 2-propanol can be used alone or as a mixture thereof, and ethanol is particularly preferable.

Production method 4:
Compound (S-8) described in Production Method 1 or a pharmaceutically acceptable salt thereof is prepared using Compound (s-4) described in Production Method 1 from the following steps (4-1) to (4): -4).

（式中の記号は、製造法１と同義である。）

(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-16) using the compound (s-4) according to the conditions according to the step (1-5) described in the production method 1.

Step (4-2):
This step is a step of obtaining compound (s-17) using compound (s-16) according to the conditions according to step (1-6) described in Production Method 1.

Step (4-3):
This step is a step of obtaining compound (s-18) using compound (s-17) according to the conditions according to step (1-7) described in production method 1.

Step (4-4):
This step is a step of obtaining compound (S-8) or a pharmaceutically acceptable salt thereof using compound (s-18) according to the conditions according to step (1-4) described in Production Method 1. It is.

Production method 5:
Compound (S-8a) described in Production Method 2 can also be produced according to the following steps (5-1) to (5-3) using compound (s-9) described in Production Method 2. .

（式中の記号は製造法２と同義である。）

(The symbols in the formula have the same meaning as in Production Method 2.)

Step (5-1):
This step is a step of obtaining compound (s-19) using compound (s-9) according to the conditions according to step (2-3) described in production method 2.

Step (5-2):
This step is a step of obtaining compound (s-20) using compound (s-19) according to the conditions according to step (2-4) described in Production Method 2.

Step (5-3):
This step is a step of obtaining compound (S-8a) or a pharmaceutically acceptable salt thereof using compound (s-20) according to the conditions according to step (1-4) described in Production Method 1. It is.

Production method 6:
Compound (S-15) described in Production Method 3 or a pharmaceutically acceptable salt thereof is prepared by using compound (s-12) described in Production Method 3 in the following steps (6-1) to (6): -3).

（式中の記号は、製造法３と同義である。）

(The symbols in the formula have the same meaning as in Production Method 3.)

Step (6-1):
This step is a step of obtaining a compound (s-21) using the compound (s-12) according to the conditions according to the step (3-3) described in the production method 3.

Step (6-2):
This step is a step of obtaining a compound (s-22) using the compound (s-21) according to the conditions according to the step (3-4) described in the production method 3.

Step (6-3):
This step is a step of obtaining compound (S-15) or a pharmaceutically acceptable salt thereof using compound (s-22) according to the conditions according to step (1-4) described in Production Method 1. It is.

Production method 7:
Compound (s-5) described in Production Method 1 can also be produced according to the following steps (7-1) to (7-2) using compound (s-3) described in Production Method 1. .

（式中の記号は、製造法１と同義である。）

(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-23) using the compound (s-3) according to the conditions according to the step (1-4) described in the production method 1.

Step (7-2):
This step is a step of obtaining a compound (s-5) using the compound (s-23) according to the conditions according to the step (1-3) described in the production method 1.

Production method 8:
Compound (s-10) described in Production Method 2 can also be produced according to the following step (8-1) using compound (s-23) described in Production Method 7.

（式中の記号は、製造法２と同義である。）

(The symbols in the formula have the same meaning as in Production Method 2.)

Step (8-1):
This step is a step of obtaining a compound (s-10) using the compound (s-23) according to the conditions according to the step (2-1) described in the production method 2.

Production method 9:
Compound (s-13) described in Production Method 3 can also be produced according to the following step (9-1) using compound (s-23) described in Production Method 7.

（式中の記号は、製造法３と同義である。）

(The symbols in the formula have the same meaning as in Production Method 3.)

Step (9-1):
This step is a step of obtaining compound (s-13) using compound (s-23) according to the conditions according to step (3-1) described in production method 3.

Production method 10:
Among the compounds (s-4) described in the production method 1, (s-4a) is prepared by using the compound (s-2) described in the production method 1 from the following steps (10-1) to (10- It can also be produced according to 2).

（式中、Ｒ^４、Ｘ^１、およびＲ^ａは製造法１と同義であり、Ｌ´は製造法２と同義である。）

(In the formula, R ⁴ , X ¹ and R ^a have the same meaning as in Production Method 1, and L ′ has the same meaning as in Production Method 2.)

Step (10-1):
This step is a step of obtaining a compound (s-24) using the compound (s-2) according to the conditions according to the step (2-4) described in the production method 2.

Step (10-2):
This step is a step of obtaining compound (s-4a) using compound (s-24) according to the conditions according to step (1-2) described in Production Method 1.

Production method 11:
Of the compound (s-9) described in Production Method 2, (s-9a) is prepared from the following steps (11-1) to (11-) using the compound (s-2) described in Production Method 1. It can also be produced according to 2).

（式中Ｒ^４、Ｘ^１は製造法１と同義であり、Ｒ^ｂは製造法２と同義である。Ｌ´´は、Ｃ_１−４アルキレンであり、該アルキレンの置換基は請求項１に記載のＬと同義である。）

(Wherein R ⁴ and X ¹ have the same meaning as in Production Method 1, and R ^b has the same meaning as in Production Method 2. L ″ is C _1-4 alkylene, and the alkylene substituent is defined as Claim 1. It is synonymous with L of description.)

Step (11-1):
This step is a step of obtaining a compound (s-25) using the compound (s-2) according to the conditions according to the step (2-4) described in the production method 2.

Step (11-2):
This step is a step of obtaining a compound (s-9a) using the compound (s-25) according to the conditions according to the step (1-2) described in the production method 1.

Production method 12:
Among the compounds (s-12) described in Production Method 3, (s-12a) is prepared using the compound (s-2) described in Production Method 1 from the following steps (12-1) to (12- It can also be produced according to 2).

（式中Ｒ^４およびＸ^１は製造法１と同義である。Ｒ^ｃは製造法３と同義であり、Ｌ´は、製造法２と同義である。）

(Wherein R ⁴ and X ¹ are synonymous with production method 1. R ^c is synonymous with production method 3 and L ′ is synonymous with production method 2.)

Step (12-1):
This step is a step of obtaining compound (s-26) using compound (s-2) according to the conditions according to step (2-4) described in production method 2.

Step (12-2):
This step is a step of obtaining a compound (s-12a) using the compound (s-26) according to the conditions according to the step (1-2) described in the production method 1.
Production method 13:
Compound (s-5) described in Production Method 1 can also be produced according to the following steps (13-1) to (13-2) using compound (s-4) described in Production Method 1. . Similarly, in production methods 2, 3, 4, 5, 6, and 7, a coupling reaction can also be carried out by boring the leaving group on the benzoxazolone ring side.

（式中Ｒ^ａ、Ｒ^３、Ｒ^３ａ、Ｒ^４、Ｌ、およびＸ^１は製造法１と同義である。Ｒ^ｄは水素原子またはＣ_１−４アルキル基を示し、２個のＲ^ｄがアルキル基である場合は、一緒になって結合する酸素原子およびホウ素原子と共に５〜６員環を形成しても良い。Ｙ^２はハロゲン、トリフルオロメタンスルホニルオキシまたはメタンスルホニルオキシなどの脱離基を示す。）
工程（１３−１）
化合物（ｓ−４）に対して、塩基および金属触媒存在下に有機ホウ素化合物を作用させることにより（ｓ−２７）の化合物を製造することができる。塩基としては、炭酸ナトリウム、炭酸水素ナトリウム、フッ化カリウム、酢酸ナトリウム、酢酸カリウム等の無機塩基が用いられる。金属触媒としては例えば、テトラキストリフェニルホスフィンパラジウム、ジクロロパラジウム（アセトニトリル）、（１，１’−ビス（ジフェニルホスフィノ）フェロセン）ジクロロパラジウム等の触媒が使用できる。有機ホウ素化合物としては、ビスピナコレートジボラン、ビスネオペンチルグリコレートジボラン等が用いられる。溶媒としては、例えばジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、メチルシクロペンチルエーテル、アニソールまたは１，４−ジオキサン等のエーテル系溶媒、ベンゼン、トルエン、クロロベンゼンまたはキシレン等の芳香族炭化水素系溶媒、酢酸エチルまたは酢酸メチル等のエステル系溶媒、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリジノン、１，３−ジメチル−２−イミダゾリジノン、またはジメチルスルホキシド等の非プロトン性極性溶媒、またはそれらの混合物が挙げられる。反応温度は、用いる原料化合物の種類等により異なるが、通常約０℃〜約２５０℃であり、好ましくは約２０℃〜約１００℃である。反応時間は、通常３０分間から４８時間であり、好ましくは１時間から２４時間である。

(In the formula, R ^a , R ³ , R ^3a , R ⁴ , L, and X ¹ have the same meaning as in Production Method 1. R ^d represents a hydrogen atom or a C _1-4 alkyl group, and two R ^d are When it is an alkyl group, it may form a 5- to 6-membered ring together with the oxygen atom and boron atom bonded together, and Y ² represents a leaving group such as halogen, trifluoromethanesulfonyloxy or methanesulfonyloxy. Show.)
Step (13-1)
The compound (s-27) can be produced by reacting the compound (s-4) with an organic boron compound in the presence of a base and a metal catalyst. As the base, inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium fluoride, sodium acetate, potassium acetate and the like are used. As the metal catalyst, for example, a catalyst such as tetrakistriphenylphosphine palladium, dichloropalladium (acetonitrile), (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium can be used. As the organic boron compound, bispinacolate diborane, bisneopentyl glycolate diborane, or the like is used. Examples of the solvent include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene or xylene, ethyl acetate or acetic acid. Aprotic polarities such as ester solvents such as methyl, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or dimethyl sulfoxide A solvent, or a mixture thereof. While the reaction temperature varies depending on the kind of raw material compound to be used, etc., it is generally about 0 ° C. to about 250 ° C., preferably about 20 ° C. to about 100 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

  Moreover, it can also manufacture without using a metal catalyst. In that case, n-butyllithium, sec-butyllithium, or tert-butyllithium is used as the base. As the organoboron compound, trimethoxyborane, triethoxyborane, tributoxyborane, triisopropoxyborane, isopropyl pinacol borate and the like are 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, or mixtures thereof. Is mentioned. While the reaction temperature varies depending on the kind of raw material compound to be used, etc., it is generally about -78 ° C to about 100 ° C, preferably about -78 ° C to about 30 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.

The resulting alkoxyboron compound can be converted into a boronic acid compound by post-treatment under acidic conditions. As the acid, hydrochloric acid or sulfuric acid is used.

Step (13-2)
The compound (s-5) can be produced by reacting the compound (s-27) with R ^3a -Y ² in the presence of a base and a metal catalyst. Examples of the base include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium methoxide, sodium tert-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, or NMM are 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) can be used. For palladium acetate and palladium chloride, 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 or 1,4-dioxane, aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene or xylene, ethyl acetate or acetic acid. Aprotic polarities such as ester solvents such as methyl, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, or dimethyl sulfoxide A solvent or water, or a mixture thereof can be mentioned. 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.

  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.

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

  Moreover, the intermediate body in the said manufacturing method or a final product can also be guide | induced to another compound included in this invention by changing the functional group suitably. The functional group can be converted by a commonly used general method (for example, see Comprehensive Organic Transformations, 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. In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included. Further, the compound of the present invention includes all crystal forms and compounds obtained by converting some or all of the atoms constituting the compound into isotopes (for example, deuterated compounds of ¹² C and ¹⁴ C of ¹⁴ C The compound converted to).

  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 or alumina that has been subjected to acidic, basic, or various chemical treatments. As the elution solvent, for example, hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, acetonitrile / water, methanol / water and the like are used.

  The novel compound having a benzoxazolone ring of the present invention or a pharmaceutically acceptable salt thereof has a property of inhibiting one or both of Nav1.7 and Nav1.8, and is neuropathic pain, nociceptive pain, inflammation It can be used as a therapeutic or prophylactic agent for sexual pain, small-fiber neuropathy, limb erythema, paroxysmal acute pain and the like. Examples of neuropathic pain herein include diabetic neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathy, cancer pain, human immunodeficiency syndrome virus infectious sensory neuropathy, trigeminal neuralgia, complex regional pain syndrome, Reflex sympathetic dystrophy, lumbar postoperative neuralgia, phantom limb pain, post-spinal pain, prolonged postoperative pain, inflammatory demyelinating polyradiculopathy, alcoholic neuropathy, strangulated peripheral neuropathy, medicine Neuropathy, idiopathic sensory neuropathy, neuropathy caused by nutritional disorder, post-irradiation neuropathy, radiculopathy, toxic peripheral neuropathy, traumatic peripheral neuropathy, brachial plexus withdrawal injury, lingual neuropathy, Examples include autoimmune neuropathy and chronic cauda equina disorder. Examples of nociceptive pain or inflammatory pain include low back pain, abdominal pain, rheumatoid arthritis, pain due to osteoarthritis, muscle pain, acute postoperative pain, fracture pain, burn pain, and the like. The compound of the present invention or a pharmaceutically acceptable salt thereof can also be used as a therapeutic or prophylactic agent for dysuria. Examples of dysuria include frequent urination and bladder pain due to enlarged prostate. Furthermore, it can also be used as a therapeutic or prophylactic agent for ataxia that suppresses cerebellar abnormal nerve firing in multiple sclerosis. 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 or Nav1.8 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 the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like. For example, in the case of oral administration, usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses. In the case of parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.

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

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

The present invention will be described more specifically with reference to the following reference examples, examples and test examples. However, the technical scope of the present invention is not limited to these examples. For silica gel chromatography in Reference Examples and Examples, a silica gel column or amino silica gel column manufactured by Yamazen Co., Ltd. was used. The compound was identified using proton nuclear magnetic resonance absorption spectrum ( ¹ H-NMR), high performance liquid chromatography / mass spectrometer; LCMS and the like. ¹ H-NMR was measured using JNM-LA300 (JEOL) or JNM-AL400 (JEOL).

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

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

  In 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, TBS: tert-butyldimethylsilyl, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quadruple line, dd: double double line, td: triple double line, tt: triple triple line, m: multiple line, br: wide.

Reference example 1:
5-Chloro-6-methylbenzo [d] oxazol-2 (3H) -one

Step (i):
A mixture of Compound 1 (0.500 g), reduced iron (0.810 g), acetic acid (0.481 g), ethanol (10 mL) and water (3.0 mL) was stirred at 80 ° C. for 1 hour. The reaction mixture was filtered through celite, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 2 (0.270 g).

Step (ii):
A mixture of Compound 2 (0.050 g), 1,1′-carbonyldiimidazole (0.077 g), diisopropylethylamine (0.166 mL) and THF (1.5 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give the title compound 3 (0.041 g).

¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 7.12 (1H, s), 7.31 (1H, s), 11.68 (1H, s).

Reference example 2:
5-Bromo-4-methylbenzo [d] oxazol-2 (3H) -one

Step (i):
A mixture of compound 4 (1.00 g), N-bromosuccinimide (1.74 g), acetic acid (0.784 g) and DMF (33 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to give compound 5 (0.530 g).

Step (ii):
Using compound 5 (0.510 g), compound 6 (0.301 g) was obtained in the same manner as in step (i) of Reference Example 1.

Step (iii):
The title compound 7 (0.040 g) was obtained using the compound 6 (0.050 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (DMSO-d ₆ ) δ: 2.29 (3H, s), 7.08-7.10 (1H, m), 7.28-7.31 (1H, m), 11.94 (1H, s).

Reference Example 3:
5-Bromo-7-methylbenzo [d] oxazol-2 (3H) -one

Step (i):
To a mixture of compound 8 (1.00 g) and acetic acid (0.784 g), nitric acid (0.506 g) was added at 0 ° C. and stirred at the same temperature for 1 hour. Ice was added to the reaction mixture, and the precipitated solid was collected by filtration to obtain Compound 9 (1.01 g).

Step (ii):
Using Compound 9 (0.99 g), Compound 10 (0.700 g) was obtained in the same manner as in Step (i) of Reference Example 1.

Step (iii):
The title compound 11 (0.510 g) was obtained using the compound 10 (0.700 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (DMSO-d ₆ ) δ: 2.27 (3H, s), 7.07 (1H, s), 7.13 (1H, s), 11.74 (1H, brs).

Reference example 4:
5-Bromo-4-fluorobenzo [d] oxazol-2 (3H) -one

Step (i):
A mixture of compound 12 (2.60 g), benzyl bromide (8.57 g), potassium carbonate (6.92 g) and DMF (17 mL) was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1) to obtain Compound 13 (4.70 g).

Step (ii):
A mixture of Compound 13 (4.70 g), 4 mol / L aqueous sodium hydroxide solution (4.20 mL) and methanol (14 mL) was stirred at 50 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, water and 4 mol / L hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain Compound 14 (2.98 g).

Step (iii):
A mixture of compound 14 (2.96 g), diphenylphosphoryl azide (5.47 g), triethylamine (3.89 mL), tert-butyl alcohol (10 mL) and toluene (10 mL) was stirred at 90 ° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to obtain Compound 15 (2.80 g).

Step (iv):
Using compound 15 (1.20 g), compound 16 (1.12 g) was obtained in the same manner as in step (i) of Reference Example 2.

Step (v):
A mixture of compound 16 (1.10 g), 12 mol / L hydrochloric acid (3.00 mL) and 1,4-dioxane (0.5 mL) was stirred at 80 ° C. for 5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Compound 17 (0.510 g).

Step (vi):
The title compound 18 (0.420 g) was obtained using the compound 17 (0.510 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (DMSO-d ₆ ) δ: 7.14-7.16 (1H, m), 7.36-7.39 (1H, m), 12.49 (1H, s).

Reference example 5:
5-Bromo-6-fluorobenzo [d] oxazol-2 (3H) -one

Step (i):
The title compound 20 (0.168 g) was obtained using the compound 19 (0.200 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (DMSO-d ₆ ) δ: 7.36-7.38 (1H, m), 7.54-7.57 (1H, m), 11.88 (1H, brs).

Reference Example 6:
5- (Trifluoromethyl) benzo [d] oxazol-2 (3H) -one

Step (i):
A mixture of compound 21 (0.500 g), ammonium formate (0.761 g), 10% Pd / C (0.050 g) and methanol (12 mL) was stirred at 50 ° C. for 1 hour. The reaction mixture was filtered through Celite, concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Compound 22 (0.410 g).

Step (ii):
The title compound 23 (0.455 g) was obtained using the compound 22 (0.410 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (DMSO-d ₆ ) δ: 7.36 (1H, s), 7.45-7.49 (2H, m), 12.01 (1H, brs).

Reference example 7:
3-{[2- (methylsulfonyl) ethyl] amino} butan-1-ol

Step (i):
A mixture of compound 24 (0.178 g), 2- (methanesulfonyl) ethylamine (0.148 g), sodium triacetoxyborohydride (0.636 g), acetic acid (0.090 g) and chloroform (5.0 mL) was stirred at room temperature. For 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 19/1) to obtain Compound 25 (0.250 g).

Step (ii):
The title compound 26 (0.020 g) was obtained using the compound 25 (0.100 g) according to the same method as in step (i) of Reference Example 6.

¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (3H, d, J = 6.2 Hz), 1.33-1.41 (1H, m), 1.49-1.53 (1H, m), 2.66-2.68 (1H, m) , 2.88-2.96 (5H, m), 3.15-3.18 (2H, m), 3.44-3.46 (2H, m), 4.42 (1H, s).

Reference Example 8:
tert-Butyl (3-hydroxy-2-methylpropyl) carbamate

Step (i):
A mixture of compound 27 (0.700 g), isobutyl chloroformate (0.564 g), triethylamine (0.725 mL) and THF (17 mL) was stirred at 0 ° C. for 1 hour. The reaction mixture was filtered through celite and then concentrated under reduced pressure. To a solution of the residue in methanol (17 mL) was added sodium borohydride at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give the title compound 28 (0.380 g).

¹ H-NMR (DMSO-d ₆ ) δ: 0.77 (3H, d, J = 6.8 Hz), 1.36 (9H, s), 1.58-1.60 (1H, m), 2.72-2.74 (1H, m), 2.88 -2.92 (1H, m), 3.19-3.25 (2H, m), 4.37-4.38 (1H, m), 6.73 (1H, br s).

Reference Example 9:
tert-Butyl (3-hydroxy-2,2-dimethylpropyl) carbamate

Step (i):
A mixture of compound 29 (0.345 g), tert-butyl dicarbonate (0.730 g) and THF (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 95/5) to give the title compound 30 (0.658 g).

¹ H-NMR (CDCl ₃ ) δ: 0.83 (6H, s), 1.43 (9H, s), 2.94 (2H, d, J = 6.8 Hz), 3.17 (2H, d, J = 7.3 Hz), 3.64 ( 1H, t, J = 7.3 Hz), 4.81 (1H, br s).

Reference Example 10:
2-Methyl-2- (methylsulfonyl) propan-1-amine

Step (i):
A mixture of compound 31 (0.953 g), sodium hydride (0.663 g), methyl iodide (2.04 g) and THF (40 mL) was stirred at 0 ° C. for 30 minutes and then at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to obtain Compound 32 (0.730 g).

Step (ii):
A mixture of Compound 32 (0.700 g) and THF (2.0 mL) was added dropwise at 45 ° C. to 0.95 mol / L borane / THF complex (THF solution, 10 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was added dropwise to methanol (20 mL) at 0 ° C. and concentrated under reduced pressure. A 4 mol / L hydrogen chloride-1,4-dioxane solution (40 mL) was added to a methanol (20 mL) solution of the obtained residue, and the mixture was stirred at 80 ° C. for 1 hour. Chloroform (30 mL) was added to the mixture at 0 ° C., and the solid was collected by filtration. The solid was dissolved in methanol (20 mL) and sodium methoxide was added until the pH was 9. Chloroform was added to the reaction solution, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 9/1) to give the title compound 33 (0.480 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.21 (6H, s), 1.61 (2H, m), 2.78 (2H, m), 2.91 (3H, s).

Reference Example 11:
4-Iodobenzo [d] oxazol-2 (3H) -one

Step (i):
The title compound 35 (1.00 g) was obtained using the compound 34 (2.00 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (CDCl ₃ ) δ: 6.91-6.94 (1H, m), 7.16-7.19 (1H, m), 7.45-7.47 (1H, m), 8.70 (1H, s).

Reference Example 12:
7-Bromobenzo [d] oxazol-2 (3H) -one

Step (i):
The title compound 37 (1.02 g) was obtained using the compound 36 (1.59 g) according to the same method as in step (ii) of Reference Example 1.

LC / MS: m / z = 213, 215 (M + H) ⁺

Reference Example 13:
6- (4-Fluorophenoxy) benzo [d] oxazol-2 (3H) -one

Step (i):
Compound 39 (24.7 g) was obtained using compound 38 (15.9 g) according to the same method as in step (i) of Reference Example 4.

Step (ii):
A mixture of compound 39 (24.7 g), 4-fluorophenol (13.4 g), cesium carbonate (49.0 g) and DMF (40 mL) was stirred at 80 ° C. for 4 hours. Water was added to the reaction mixture, and the solid was collected by filtration to give compound 40 (33.9 g).

Step (iii):
A mixture of Compound 40 (5.40 g), 10% Pd / C (0.540 g), methanol (10 mL) and ethyl acetate (20 mL) was stirred at 50 ° C. for 12 hours in a hydrogen atmosphere. The reaction mixture was concentrated through Celite filtration and reduced pressure to obtain Compound 41 (3.49 g).

Step (iv):
The title compound 42 (0.300 g) was obtained using the compound 41 (0.300 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (CDCl ₃ ) δ: 6.80-7.07 (7H, m).

Reference Example 14:
5-Bromo-3- (4,4-dimethoxybutan-2-yl) benzo [d] oxazol-2 (3H) -one

Step (i):
A mixture of compound 43 (0.661 g), sodium borohydride (0.378 g) and methanol (25 mL) was stirred at 0 ° C. for 15 minutes and then at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain Compound 44 (0.620 g).

Step (ii):
A mixture of compound 44 (0.620 g), 5-bromobenzoxazolone (0.989 g), diisopropyl azodicarboxylate (1.12 g), triphenylphosphine (1.82 g) and THF (23 mL) at 0 ° C. After stirring for minutes, the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give the title compound 45 (0.960 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.44 (3H, d, J = 7.0 Hz), 1.93-1.96 (1H, m), 2.24-2.28 (1H, m), 3.08 (3H, s), 3.17 (3H, s), 4.29-4.31 (2H, m), 7.29-7.29 (2H, m), 7.63 (1H, s).

Reference Example 15:
3- (Methylsulfonyl) propyl methanesulfonate

Step (i):
A mixture of compound 46 (2.00 g), metachloroperbenzoic acid (9.40 g) and methylene chloride (60 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 9/1) to give Compound 47 (0.660 g).

Step (ii):
A mixture of compound 47 (0.100 g), methanesulfonyl chloride (0.067 mL), triethylamine (0.120 mL) and methylene chloride (2.0 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound 48. The whole amount was used for the next reaction as it was.

Reference Example 16:
tert-Butyl 3-{[5-bromo-2-oxobenzo [d] oxazol-3 (2H) -yl] methyl} azetidine-1-carboxylate

Step (i):
Compound 49 (1.00 g), tert-butyl 3-formylazetidine-1-carboxylate (1.00 g), sodium triacetoxyborohydride (2.30 g), tetraisopropoxytitanium (8.00 mL) and THF (25 mL) was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain Compound 50 (1.48 g).

Step (ii):
The title compound 51 (0.350 g) was obtained using the compound 50 (0.500 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.98-3.12 (1H, m), 3.75-3.78 (2H, m), 4.03-4.06 (4H, m), 7.09-7.13 (2H, m), 7.25-7.28 (1H, m).

Reference Example 17:
tert-Butyl {3- [5-bromo-2-oxobenzo [d] oxazol-3 (2H) -yl] propyl} [2- (methylsulfonyl) ethyl] carbamate

Step (i):
Methyl vinyl sulfone (2.1 mL) was added to a methanol (50 mL) solution of compound 52 (2.00 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 53. This product was used in the next step without purification.

Step (ii):
A mixture of the crude product of compound 53, tert-butyl dicarbonate (5.20 g) and 1,4-dioxane (50 ml) was stirred at room temperature for 2 hours. The reaction solution was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 ml), amino silica gel (40 g) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 54 (4.80 g).

Step (iii):
The title compound 55 (7.03 g) was obtained using the compound 54 (4.22 g) according to the same method as in step (ii) of Reference Example 14.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 2.07-1.99 (2H, m), 2.95 (3H, s), 3.38-3.31 (4H, m), 3.69 (2H, t, J = 7.1 Hz), 3.80 (2H, t, J = 7.3 Hz), 7.08 (1H, d, J = 8.3 Hz), 7.12 (1H, d, J = 2.0 Hz), 7.25 (1H, dd, J = 8.4, 1.8 Hz).

Reference Example 18:
5- (tert-Butyl) benzo [d] oxazol-2 (3H) -one

Step (i):
The title compound 57 (0.55 g) was obtained using the compound 56 (1.00 g) according to the same method as in step (ii) of Reference Example 1.

¹ H-NMR (DMSO-D ₆ ) δ: 1.27 (9H, s), 7.03 (1H, d, J = 1.8 Hz), 7.08 (1H, dd, J = 1.8, 7.9 Hz), 7.16 (1H, d , J = 7.9 Hz), 11.49 (1H, s).

Reference Example 19:
1-phenyl-5-[(tetrahydro-2H-pyran-4-yl) sulfonyl] -1H-tetrazole

Step (i):
Compound 59 (1.06 g) was obtained in the same manner as in step (ii) of Reference Example 14 using compound 58 (0.642 ml) and 1-phenyl-5-mercaptotetrazole (1.00 g).

Step (ii):
A mixture of Compound 59 (1.06 g), 30% aqueous hydrogen peroxide (4.1 mL), ammonium molybdate tetrahydrate (0.999 mg) and ethanol (40 mL) was stirred at room temperature for 4 hours. An aqueous sodium thiosulfate solution was added at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give the title compound 60 (0.970 g).

¹ H-NMR (CDCl ₃ ) δ: 1.95-2.06 (2H, m), 2.12-2.17 (2H, m), 3.49 (2H, m), 4.09-4.17 (3H, m), 7.56-7.67 (5H, m).

Reference Example 20:
5-[(Tetrahydro-2H-pyran-4-yl) methyl] benzo [d] oxazol-2 (3H) -one

Step (i):
Compound 62 (1.15 g) was obtained using Compound 61 (1.00 g) according to the same method as in step (i) of Reference Example 4.

Step (ii):
1.3 mol / L lithium hexamethyldisilazide (THF solution, 2.36 mL) was added dropwise at −78 ° C. to a mixture of Compound 60 (0.820 g) of Reference Example 19 and THF (30 mL). Stir for 10 minutes. A solution of compound 62 (0.862 g) in THF (5.0 mL) was added dropwise at −78 ° C., and the mixture was stirred for 1.5 hours while naturally warming to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1) to obtain Compound 63 (0.740 g).

Step (iii):
A mixture of Compound 63 (0.880 g), 10% Pd / C (0.094 g) and THF (3.0 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixture was filtered through Celite and concentrated under reduced pressure to obtain Compound 64 as a crude product. The whole amount was used for the next reaction.

Step (iv):
Using the crude product of compound 64, the title compound 65 (0.412 g) was obtained in the same manner as in step (ii) of Reference Example 1.

¹ H-NMR (DMSO-D ₆ ) δ: 1.11-1.22 (2H, m), 1.44 (2H, m), 1.69 (1H, br s), 2.47-2.52 (2H, m), 3.20 (2H, m ), 3.79 (2H, m), 6.83-6.88 (2H, m), 7.15 (1H, m), 11.52 (1H, br s).

Example 1 (A):
5- (4-Fluorophenyl) -3- {2-[(2-hydroxy-2-methylpropyl) amino] ethyl} benzo [d] oxazol-2 (3H) -one

Step (i):
Compound Ia (4.20 g), 2- (tert-butyldimethylsilyloxy) ethyl bromide (5.10 mL), lithium bromide (3.50 g), sodium hydride (0.960 g) and DMF (100 mL) The mixture was stirred at 80 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1) to obtain Compound II-a (3.10 g).

Step (ii):
Compound II-a (3.10 g), 4-fluorophenylboronic acid (1.70 g), tetrakistriphenylphosphine palladium (0.48 g), potassium carbonate (3.40 g), 1,4-dioxane (80 mL) and A mixture of water (10 mL) was stirred at 90 ° C. for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1) to obtain Compound III-a (3.20 g).

Step (iii):
A mixture of Compound III-a (3.20 g), 1.0 mol / L tetrabutylammonium fluoride (THF solution, 9.9 mL), acetic acid (0.566 mL) and THF (83 mL) was stirred at room temperature for 14 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain Compound IV-a (1.63 g).

Step (iv):
A mixture of compound IV-a (1.63 g), carbon tetrabromide (5.20 g), triphenylphosphine (2.00 g) and methylene chloride (60 mL) was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to obtain Compound Va (1.47 g).

Step (v):
A mixture of Compound Va (0.100 g), 3-amino-2-methyl-2-propanol (0.080 g), potassium carbonate (0.124 g) and acetonitrile (1.5 mL) was stirred at 70 ° C. for 18 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to give the title compound VI-a (0.081 g). It was.

¹ H-NMR (CDCl ₃ ) δ: 1.13 (6H, s), 2.59 (2H, s), 3.06 (2H, m), 3.97 (2H, m), 7.09-7.26 (5H, m), 7.47-7.52 (2H, m).

Examples 2 to 23:
In the same manner as in Example 1 (A), the compounds of Examples 2 to 23 shown in Tables 1 to 3 were produced.

Example 24:
6- (4-Fluorophenyl) -3- (2-((2-hydroxy-2-methylpropyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one With 6-bromobenzoxazolone, The title compound was produced in the same manner as Example 1 (A).

¹ H-NMR (CDCl ₃ ) δ: 1.16 (6H, s), 2.61 (2H, s), 3.10 (2H, t, J = 6.1 Hz), 3.97 (2H, t, J = 6.1 Hz), 7.06- 7.16 (3H, m), 7.35-7.39 (2H, m), 7.48-7.52 (2H, m).
Example 25:
6- (4-Fluorophenoxy) -3- (2-((2-hydroxy-2-methylpropyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one Using Compound 42 of Reference Example 13 The title compound was produced in the same manner as in Example 1 (A).

¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, s), 2.76 (2H, s), 3.19 (2H, t, J = 6.0 Hz), 4.04 (2H, t, J = 6.0 Hz), 6.83- 7.03 (7H, m).

Example 26 (B):
5- (4-Fluorophenoxy) -3- {2-[(2-hydroxy-2-methylpropyl) amino] ethyl} benzo [d] oxazol-2 (3H) -one

Step (i):
Compound II-a (1.10 g), bis (pinacolato) diboron (1.70 g), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (0.110 g), potassium acetate (0.883 g) And a mixture of 1,4-dioxane (15 mL) was stirred at 90 ° C. for 14 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1) to give Compound Ib (1.26 g).

Step (ii):
A mixture of compound Ib (0.420 g), 4-fluorophenol (0.224 g), copper acetate (0.272 g), triethylamine (0.697 mL) and acetonitrile (5 mL) was stirred at 40 ° C. for 16 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to obtain Compound II-b (0.189 g).

Step (iii):
Compound III-b (0.091 g) was obtained using Compound II-b (0.189 g) according to the same method as in step (iii) of Example A.

Step (iv):
Compound IV-b (0.074 g) was obtained using compound III-b (0.091 g) according to the same method as in step (iv) of Example A.

Step (v):
The title compound Vb (0.0084 g) was obtained using the compound IV-b (0.036 g) according to the same method as in step (v) of Example A.

¹ H-NMR (CDCl ₃ ) δ: 1.13 (6H, s), 2.56 (2H, s), 3.03 (2H, t, J = 6.1 Hz), 3.87 (2H, t, J = 6.1 Hz), 6.68- 6.72 (2H, m), 6.93-7.07 (4H, m), 7.13 (1H, m).

Example 27 (C):
5-cyclohexyl-3- {2-[(2-hydroxy-2-methylpropyl) amino] ethyl} benzo [d] oxazol-2 (3H) -one

Step (i):
A mixture of Compound Ic (Example 7) (0.040 g), 10% Pd / C (0.010 g) and methanol (3.0 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 19/1) to give the title compound II-c (0.029 g).

¹ H-NMR (CDCl ₃ ) δ: 1.12 (6H, s), 1.36-1.43 (5H, m), 1.77-1.83 (5H, m), 2.53 (1H, m), 2.60 (2H, s), 3.06 -3.08 (2H, m), 3.92-3.94 (2H, m), 6.85-6.86 (1H, m), 6.94-6.97 (1H, m), 7.10-7.13 (1H, m).

Example 28:
3- {2-[(2-hydroxy-2-methylpropyl) amino] ethyl} -5-phenethylbenzo [d] oxazol-2 (3H) -one Using the compound of Example 11, Example 27 (C ) To give the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.14 (6H, s), 2.59 (2H, s), 2.92-3.06 (6H, m), 3.88 (2H, m), 6.71 (1H, m), 6.89-6.93 (1H, m), 7.09-7.30 (6H, m)

Example 29 (D):
5-ethyl-3- {2-[(2-hydroxy-2-methylpropyl) amino] ethyl} benzo [d] oxazol-2 (3H) -one

Step (i):
Compound Id (Example 12) (0.033 g), 1 mol / L diethyl zinc (THF solution, 0.300 mL), bis (tri-tert-butylphosphine) palladium (0.010 g) and THF (0.5 mL) ) Was stirred at room temperature for 12 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 19/1) to give the title compound II-d (0.014 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (6H, s), 1.18 (3H, t, J = 7.6 Hz), 2.52 (2H, s), 2.59 (2H, q, J = 7.6 Hz), 2.94 (2H, m), 3.91 (2H, m), 6.92-6.95 (1H, m), 7.18-7.21 (2H, m).

Examples 30-31:
In the same manner as in Example 29 (D), the compounds of Examples 30 to 31 shown in Table 4 were produced.

Example 32 (E):
5- (2,4-Difluorophenyl) -3- (2-{[2- (methylsulfonyl) ethyl] amino} ethyl) benzo [d] oxazol-2 (3H) -one

Step (i):
Compound Ia (Example 1) (1.00 g), 1 mol / L potassium hexamethyldisilazide (THF solution, 5.00 mL), bromoacetaldehyde dimethyl acetal (0.587 mL) and DMF (5 mL) were mixed. Stir at 90 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6/1) to give Compound Ie (1.50 g).

Step (ii):
Using compound Ie (0.080 g) and 2,4-difluorophenylboronic acid (0.084 g) according to the same method as in step (ii) of Example 1 (A), compound II-e (0 .082 g) was obtained.

Step (iii):
A mixture of Compound II-e (0.082 g) and 5 mol / L hydrochloric acid (1.00 mL) was stirred at 50 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting crude product of compound III-e was used in the next reaction in its entirety.

Step (iv):
A mixture of the crude product of Compound III-e, 2- (methanesulfonyl) ethylamine (0.049 g), sodium triacetoxyborohydride (0.168 g), acetic acid (0.032 g) and chloroform (1.5 mL). Stir at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 49/1) to give the title compound IV-e (0.085 g).

¹ H-NMR (DMSO-d ₆ ) δ: 2.86-2.91 (7H, m), 3.13-3.15 (2H, m), 3.89-3.91 (2H, m), 7.22-7.24 (2H, m), 7.39- 7.41 (2H, m), 7.47 (1H, s), 7.59-7.61 (1H, m).

Examples 33-42:
In the same manner as in Example 32 (E), the compounds of Examples 33 to 42 shown in Table 5 were produced.

Examples 43-47:
Using the compounds 3, 7, 11, 18, and 20 of Reference Examples 1 to 5, the compounds of Examples 43 to 47 shown in Table 6 were produced in the same manner as in Example 32 (E).

Examples 48-49:
Using the compound 45 of Reference Example 14, the compounds of Examples 48 to 49 shown in Table 7 were produced in the same manner as in Example 32 (E).

Example 50 (F):
3- (4-{[2- (methylsulfonyl) ethyl] amino} butan-2-yl) -5- [5- (trifluoromethyl) pyridin-2-yl] benzo [d] oxazole-2 (3H) -ON

Step (i):
Compound If (0.080 g) was obtained using Compound 45 (0.200 g) of Reference Example 14 according to the same method as in Step (i) of Example 26 (B).

Step (ii):
Compound If (0.080 g), 2-bromo-5-trifluoromethylpyridine (0.072 g), dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (0.031 g), 3 mol / A mixture of L aqueous sodium carbonate (0.212 mL) and 1,4-dioxane (1.0 mL) was stirred at 80 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to obtain Compound II-f (0.090 g).

Step (iii):
Compound III-f was obtained as a crude product in the same manner as in step (iii) of Example 32 (E) using compound II-f (0.090 g). The whole amount was directly used for the next reaction.

Step (iv):
The title compound IV-f (0.073 g) was obtained in the same manner as in step (iv) of Example 32 (E) using the crude product of compound III-f.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50 (3H, d, J = 6.8 Hz), 1.91-1.94 (1H, m), 2.13-2.16 (1H, m), 2.81-2.82 (2H, m) , 2.93 (3H, s), 3.12-3.14 (2H, m), 4.51-4.54 (1H, m), 7.48-7.51 (1H, m), 7.97-7.99 (1H, m), 8.08 (1H, s) , 8.29-8.31 (2H, m), 9.04 (1H, s).

Example 51:
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one Example The title compound was prepared in the same manner as in Example 50 (F) using 32 (E) compound Ie.

¹ H-NMR (DMSO-d ₆ ) δ: 2.89-2.92 (7H, m), 3.14-3.16 (2H, m), 3.95-3.99 (2H, m), 7.46-7.49 (1H, m), 7.95- 7.99 (1H, m), 8.08 (1H, s), 8.26-8.29 (2H, m), 9.03 (1H, s).

Example 52 (G):
5- (4-Fluorophenyl) -3- (2-{[2- (methylsulfonyl) ethyl)] amino} propyl) benzo [d] oxazol-2 (3H) -one

Step (i):
Using compound Ia (0.214 g) and tert-butyl (1-hydroxypropan-2-yl) carbamate (0.210 g), following the same method as in step (ii) of Reference Example 14, compound I- g (0.275 g) was obtained.

Step (ii):
Compound II-g (0.095 g) was obtained by using Compound I-g (0.100 g) according to the same method as in Step (ii) of Example 1 (A).

Step (iii):
A mixture of Compound II-g (0.095 g), trifluoroacetic acid (2.00 mL) and chloroform (0.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting crude product of compound III-g was used in the next reaction in its entirety.

Step (iv):
The title compound IV-g (0.014 g) was obtained in the same manner as in step (i) of Reference Example 17 using the crude product of compound III-g.

¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (3H, d, J = 6.1 Hz), 3.13 (3H, s), 3.49-3.54 (4H, m), 3.82-3.86 (1H, m), 4.11 -4.23 (2H, m), 7.32-7.41 (4H, m), 7.74-7.77 (3H, m).

Examples 53-59:
The compounds of Examples 53 to 59 shown in Table 8 were prepared in the same manner using the corresponding carbamate in step (i) of the production method of Example 52 (G) and the corresponding boronic acid in step (ii). Manufactured. However, 6-trifluoromethylbenzoxazolone was used as a raw material for the production of the compound of Example 58, and Compound 57 of Reference Example 18 was used for the production of Example 60.

Examples 61-64:
In the same manner as in Example 52 (G), the compounds of Examples 61 to 64 shown in Table 9 were produced. Example 61 was prepared using ethyl vinyl sulfone. The compound of Example 63 was prepared using Compound 51 of Reference Example 16, and the compound of Example 64 was prepared using Compound 57 of Reference Example 18.

Example 65 (GG):
5- (tert-Butyl) -3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) benzo [d] oxazol-2 (3H) -one hydrochloride

Step (i):
Using Compound 57 (0.062 g) of Reference Example 18 and Compound 54 (0.110 g) of Reference Example 17 and following the same method as in Step (ii) of Reference Example 14, compound I-gg (0.079 g) Got.

Step (ii):
A mixture of Compound I-gg and 4 mol / L hydrogen chloride-ethyl acetate solution (2.00 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was stirred for 1 hr. The solid was collected by filtration to give the title compound II-gg (0.054 g).

¹ H-NMR (DMSO-D ₆ ) δ: 1.31 (9H, s), 2.02-2.10 (2H, m), 3.05 (2H, t, J = 7.6 Hz), 3.10 (3H, s), 3.32 (2H , t, J = 7.9 Hz), 3.55 (2H, t, J = 7.6 Hz), 3.94 (2H, t, J = 6.7 Hz), 7.14 (1H, dd, J = 8.5, 1.8 Hz), 7.23 (1H , d, J = 8.5 Hz), 7.41 (1H, d, J = 1.8 Hz), 9.26 (2H, br s).

Example 66 (H):
5-[(4-Fluorophenoxy) methyl] -3- (2-{[2- (methylsulfonyl) ethyl] amino} ethyl) benzo [d] oxazol-2 (3H) -one

Step (i):
Compound Ih (0.760 g) was obtained using tert-butyl (2-hydroxyethyl) carbamate (0.903 g) according to the same method as in step (ii) of Reference Example 14.
Step (ii):
Compound II-h was obtained as a crude product (0.760 g) in the same manner as in step (ii) of Example 1 (A) using compound Ih (1.00 g).

Step (iii):
The mixture of the crude product of Compound II-h (0.760 g) and methylene chloride (5.0 mL) was stirred for 1 hour while blowing ozone gas at -78 ° C. Dimethyl sulfide (1.00 g) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain Compound III-h (0.120 g).

Step (iv):
Compound IV-h (0.111 g) was obtained using Compound III-h (0.120 g) according to the same method as in step (i) of Reference Example 14.

Step (v):
A mixture of compound IV-h (0.050 g), 4-fluorophenol (0.027 g), azodicarbonyldipiperidine (0.061 g), tributylphosphine (0.060 mL) and THF (1.0 mL) was brought to room temperature. And stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1) to give Compound Vh (0.036 g).

Step (vi):
Compound VI-h was obtained as a crude product in the same manner as in step (iii) of Example 52 (G) using compound Vh (0.036 g).

Step (vii):
The title compound VII-h (0.020 g) was obtained in the same manner as in step (i) of Reference Example 17 using the crude product of compound VI-h.

¹ H-NMR (DMSO-d ₆ ) δ: 3.11 (3H, s), 3.36-3.46 (4H, m), 3.50-3.57 (2H, m), 4.18 (2H, m), 5.07 (2H, s) , 7.04 (2H, m), 7.13 (2H, m), 7.24 (1H, m), 7.38 (1H, m), 7.52 (1H, s), 9.29 (1H, br s).

Example 67 (I):
3- (2-Methyl-3-{[2- (methylsulfonyl) ethyl] amino} propyl) -5- [5- (trifluoromethyl) pyridin-2-yl] benzo [d] oxazole-2 (3H) -ON

Step (i):
Compound Ii (0.500 g) was obtained using Compound 28 (0.394 g) of Reference Example 8 according to the same method as in Step (ii) of Reference Example 14.

Step (ii):
Compound II-i was obtained as a crude product in the same manner as in step (iii) of Example 52 (G) using compound Ii (0.450 g). The whole amount was used for the next reaction.

Step (iii):
Compound III-i (0.320 g) was obtained by using the crude product of Compound II-i and following the same method as in Step (i) of Reference Example 17.

Step (iv):
Compound IV-i was obtained as a crude product according to the same method as in step (i) of Example 26 (B) using compound III-i (0.060 g). The whole amount was used for the next reaction.

Step (v):
The title compound Vi (0.013 g) was obtained using the crude product of compound IV-i according to the same method as in step (ii) of Example 50 (F).

LC / MS: m / z = 458 (M + H) ⁺

Examples 68-69:
In the same manner as in Example 67 (I), the compounds of Examples 68 to 69 shown in Table 10 were produced.

Example 70 (J):
5- (4-Fluorophenyl) -3- (2-hydroxy-3-{[2- (methylsulfonyl) ethyl] amino} propyl) benzo [d] oxazol-2 (3H) -one

Step (i):
Compound I-j (0.080 g) was obtained using glycidol (0.260 g) according to the same method as in step (ii) of Reference Example 14.

Step (ii):
Compound II-j (0.034 g) was obtained using compound I-j (0.076 g) according to the same method as in step (ii) of Example 1 (A).

Step (iii):
A mixture of compound II-j (0.028 g), 2- (methanesulfonyl) ethylamine (0.038 g) and ethanol (1.0 mL) was stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 19/1) to give the title compound III-j (0.013 g).

¹ H-NMR (DMSO-d ₆ ) δ: 2.55-2.68 (2H, m), 2.93 (2H, m), 3.00 (3H, s), 3.22 (2H, m), 3.76-3.99 (3H, m) , 5.12 (1H, d, J = 5.1Hz), 7.30 (2H, m), 7.34-7.41 (2H, m), 7.56 (1H, m), 7.69 (2H, m).

Example 71 (K):
5- (4-Fluorophenyl) -3- (2-{[3- (methylsulfonyl) propyl] amino} ethyl) benzo [d] oxazol-2 (3H) -one hydrochloride

Step (i):
Compound Ik (0.048 g) was obtained using Compound Ih (Example 66) (0.050 g) according to the same method as in Step (ii) of Example 1 (A).

Step (ii):
A mixture of Compound I-k (0.048 g), Compound 48 of Reference Example 15, cesium carbonate (0.088 g) and DMF (1.0 mL) was stirred at 90 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting crude product of compound II-k was used for the next reaction.

Step (iii):
A mixture of the crude product of Compound II-k and a 4 mol / L hydrogen chloride-1,4-dioxane solution (1.00 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the mixture was stirred for 1 hr. The solid was collected by filtration to give the title compound III-k (0.014 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.41-1.62 (2H, m), 2.56-2.68 (2H, m), 3.08 (3H, s), 3.17-3.26 (2H, m), 3.38-3.53 ( 4H, m), 7.05 (1H, m), 7.21 (1H, m), 7.30-7.45 (3H, m), 7.54 (2H, m), 8.84 (2H, br s).

Example 72 (L):
5- (4-Fluorophenyl) -3- [3- (oxetan-3-ylamino) propyl] benzo [d] oxazol-2 (3H) -one

Step (i):
Compound 1-1 (0.330 g) was obtained using tert-butyl (3-hydroxypropyl) carbamate (0.210 g) according to the same method as in step (ii) of Reference Example 14.

Step (ii):
Compound II-l (0.040 g) was obtained using Compound I-l (0.050 g) according to the same method as in step (ii) of Example 1 (A).

Step (iii):
Compound III-l was obtained as a crude product according to the same method as in step (iii) of Example 52 (G) using compound II-l (0.040 g). The whole amount was used for the next reaction.

Step (iv):
A mixture of crude compound III-l, 3-oxetanone (0.015 g), sodium triacetoxyborohydride (0.86 g), acetic acid (0.024 g) and chloroform (1.0 mL) was stirred at room temperature for 16 hours. Stir. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 49/1) to give the title compound IV-1 (0.019 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.78-1.81 (2H, m), 3.29-3.32 (2H, m), 3.75-3.79 (1H, m), 3.90-3.93 (2H, m), 4.27- 4.29 (2H, m), 4.55-4.57 (2H, m), 7.29-7.32 (2H, m), 7.37-7.40 (2H, m), 7.58-7.61 (1H, m), 7.69-7.71 (2H, m ).

Examples 73-74:
Using the compound corresponding to Compound III-g or III-g in Example 52 (G), the compounds of Examples 73 to 74 shown in Table 11 were produced with reference to the method of Example 72 (L).

Example 75 (M):
3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) -5-phenylbenzo [d] oxazol-2 (3H) -one hydrochloride

Step (i):
Using Compound I-1 (Example 72) (0.500 g) and following the same method as in Step (iii) of Example 52 (G), Compound Im was obtained as a crude product. The whole amount was used for the next reaction.

Step (ii):
Compound II-m (0.240 g) was obtained using the crude product of Compound Im according to the same method as in Step (i) of Reference Example 17.

Step (iii):
Compound II-m (0.050 g), phenylboronic acid (0.055 g), bis (tri-tert-butylphosphine) palladium (0.005 g), potassium carbonate (0.080 g), acetonitrile (1.0 mL) and A mixture of water (0.2 mL) was stirred at 80 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1). A mixture of the obtained compound, ethyl acetate (1.0 mL) and 4 mol / L hydrogen chloride-1,4-dioxane solution (1.00 mL) was stirred at room temperature for 1 hour, and then the mixed solution was concentrated under reduced pressure. The precipitated crystals were suspended and stirred in ethyl acetate and collected by filtration to give the title compound III-m (0.049 g).

¹ H-NMR (DMSO-d ₆ ) δ: 2.04-2.19 (2H, m), 3.03-3.12 (5H, m), 3.27-3.38 (2H, m), 3.51-3.60 (2H, m), 4.00 ( 2H, m), 7.33-7.51 (5H, m), 7.67-7.74 (3H, m), 9.32 (2H, br s).

Examples 76-91:
The compounds of Examples 76 to 91 shown in Tables 12 to 13 were produced in the same manner as in Example 75 (M).

実施例９２：
３−（３−{[２−（メチルスルホニル）エチル]アミノ}プロピル）−５−（４−（トリフルオロメチル）フェニル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン
実施例７５（Ｍ）と同様の方法にて、表題化合物を製造した。ただし、工程（ｉｉｉ）の塩酸塩化の操作は行わず、遊離体として得た。

Example 92:
3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) -5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-2 (3H) -one Example 75 (M) In the same manner as described above, the title compound was produced. However, the procedure of hydrochloric acid chlorination in step (iii) was not performed, and the product was obtained as a free form.

¹ H-NMR (DMSO-d ₆ ) δ: 1.83-1.86 (2H, m), 2.56-2.59 (2H, m), 2.88-2.90 (2H, m), 2.98 (3H, s), 3.15-3.18 ( 2H, m), 3.92-3.95 (2H, m), 7.47-7.48 (2H, m), 7.70 (1H, br s), 7.82-7.92 (4H, m).

Examples 93-97:
In the same manner as in Example 67 (I), compounds of Examples 93 to 97 shown in Table 14 were produced using Compound II-m of Example 75 (M).

Examples 98-99:
In the same manner as in Example 67 (I) or Example 75 (M), the compounds of Examples 98 and 99 shown in Table 15 were produced using the compound 7 of Reference Example 2. In the production of the compound of Example 99, hydrochloric acid chlorination was not performed in step (iii) of Example 75, and the compound was obtained as a free form.

Example 100 (MM):
5- (4,4-Difluorocyclohexyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one hydrochloride

Step (i):
Compound I-h (Example 66) (0.386 g) and 2- (4,4-difluorocyclohexen-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 In the same manner as in step (ii) of Example 1 (A), compound I-mm (0.720 g) was obtained.

Step (ii):
Compound II-mm (0.724 g) was obtained in the same manner as in step (i) of Example 27 (C) using compound I-mm (0.720 g).

Step (iii):
Using compound II-mm (0.724 mg), compound III-mm (0.582 g) was obtained in the same manner as in step (ii) of Example 65 (GG).

Step (iv):
Methyl vinyl sulfone (0.237 g) was added to a mixture of Compound III-mm (0.619 g), diisopropylamine (0.721 g) and ethanol (18 mL), and the mixture was stirred at room temperature for 7 hours. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 97/3) to obtain Compound IV-mm. The whole amount was used for the next reaction.

Step (v):
The title compound V-mm (0.517 g) was obtained in the same manner as in step (iii) of Example 71 (K) using compound IV-mm.

¹ H-NMR (DMSO-D ₆ ) δ: 1.67-1.80 (2H, m), 1.84-2.16 (6H, m), 2.74 (1H, t, J = 11.9 Hz), 3.11 (3H, s), 3.35 (2H, m), 3.41-3.46 (2H, m), 3.55 (2H, m), 4.17 (2H, m), 7.03 (1H, d, J = 7.9 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.36 (1H, s), 9.37 (2H, br s).

Examples 101-110:
In the same manner as in Example 100 (MM), the compounds of Examples 101 to 110 shown in Tables 16 to 17 were produced. 5-bromobenzoxazolone for Examples 102, 103, 106, and 110, 6-bromobenzoxazolone for Examples 104 and 105, compound 65 of Reference Example 20 for Examples 107 and 108, 109 was prepared using the compound of Reference Example 5 and the corresponding carbamate. Further, in the production of the compounds of Examples 104 and 106, hydrochloric acid was not used, and it was obtained as a free form.

Example 111 (N):
5-cyclobutyl-3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) benzo [d] oxazol-2 (3H) -one hydrochloride

Step (i):
Similar to step (i) of Example 29 (D) using Compound II-m (Example 75) (0.050 g) and 0.5 mol / L cyclobutyl zinc bromide (THF solution, 0.260 mL). Ethyl acetate (1.0 mL) and 4 mol / L hydrogen chloride-1,4-dioxane solution (1.0 mL) were added to the compound produced according to the method, and the mixture solution was concentrated under reduced pressure after stirring at room temperature for 1 hour. The precipitated crystals were suspended and stirred in ethyl acetate and collected by filtration to give the title compound In (0.039 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.86 (1H, m), 1.90-2.19 (5H, m), 2.25-2.35 (2H, m), 3.01-3.09 (2H, m), 3.10 ( 3H, s), 3.30-3.36 (2H, m), 3.48-3.60 (3H, m), 3.92 (2H, m), 6.98 (1H, m), 7.24 (1H, m), 7.27 (1H, s) , 9.07 (2H, br s).

Examples 112-115:
In the same manner as in Example 111 (N), the compounds of Examples 112 to 115 shown in Table 18 were produced.

Example 116 (O):
5- (Cyclohexylmethyl) -3- (2-{[2- (methylsulfonyl) ethyl] amino} ethyl) benzo [d] oxazol-2 (3H) -one hydrochloride

工程（ｉ）：
化合物Ｉ−ｈ（実施例６６）（５．７１ｇ）を用いて、実施例５２（Ｇ）の工程（ｉｉｉ）と同様の方法に従い、化合物Ｉ−ｏを粗生成物として得た。全量を次の反応に用いた。

Step (i):
Compound Io (Example 66) (5.71 g) was used in the same manner as in Step (iii) of Example 52 (G) to give Compound Io as a crude product. The whole amount was used for the next reaction.

Step (ii):
Compound II-o (0.936 g) was obtained according to the same method as in step (i) of Reference Example 17 using the crude product of compound Io.

Step (iii):
Compound III-o (1.25 g) was obtained using Compound II-o (1.16 g) according to the same method as in step (i) of Reference Example 9.

Step (iv):
Compound IV-o (0.119 g) was obtained using compound III-o (0.133 g) according to the same method as in step (i) of Example 29 (D).

Step (v):
The title compound Vo (0.050 g) was obtained using the compound IV-o (0.119 g) according to the same method as in step (iii) of Example 71 (K).

¹ H-NMR (CD ₃ OD) δ: 0.94-1.04 (2H, m), 1.16-1.22 (3H, m), 1.54-1.61 (1H, m), 1.67-1.73 (5H, m), 2.56 (2H , d, J = 7.1 Hz), 3.11 (3H, s), 3.52-3.59 (4H, m), 3.62-3.67 (2H, m), 4.26 (2H, t, J = 5.6 Hz), 6.99 (1H, dd, J = 8.3, 1.5 Hz), 7.11 (1H, d, J = 1.7 Hz) 7.19 (1H, d, J = 8.3 Hz).

Examples 117-122:
In the same manner as in Example 116 (O), the compounds of Examples 117 to 122 shown in Table 19 were produced.

Examples 123-127:
In the same manner as in Example 116 (O), the compounds of Examples 123 to 127 shown in Table 20 were produced using the compound 55 of Reference Example 17.

Examples 128 and 129 (P):
3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) -5- [5- (trifluoromethyl) pyrimidin-2-yl] benzo [d] oxazol-2 (3H) -one (128 ) And 3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) -5- [5- (trifluoromethyl) pyrimidin-4-yl] benzo [d] oxazole-2 (3H)- ON (129)

Step (i):
Compound Ip (1.30 g) was obtained according to the same method as in step (i) of Example 26 (B) using Compound I-l (Example 67) (1.40 g).

Step (ii):
Compound II-p (0.125 g) and 2,4-dichloro-5-trifluoromethylpyrimidine (0.065 g) were used in the same manner as in step (ii) of Example 50 (F) to give compound II. -P and compound III-p were obtained as a mixture. The whole amount was used for the next reaction.

Step (iii):
Using a mixture of Compound II-p and Compound III-p, Compound IV-p (0.010 g) and Compound Vp (0.028 g) were prepared in the same manner as in Step (i) of Reference Example 6, respectively. Obtained.

Step (iv):
Compound VI-p was obtained as a crude product according to the same method as in step (iii) of Example 52 (G) using compound IV-p (0.010 g). The whole amount was used for the next reaction.

Step (v):
The title compound VII-p (0.0065 g) was obtained in the same manner as in step (i) of Reference Example 17 using the crude product of compound VI-p.

¹ H-NMR (DMSO-d ₆ ) δ: 1.82-1.86 (2H, m), 2.55-2.58 (2H, m), 2.86-2.88 (2H, m), 2.98 (3H, s), 3.21-3.23 ( 2H, m), 3.95-3.97 (2H, m), 7.52-7.55 (1H, m), 8.29-8.32 (2H, m), 9.32-9.35 (2H, m).

Step (vi):
Compound VIII-p was obtained as a crude product according to the same method as in step (iii) of Example 52 (G) using compound Vp (0.028 g). The whole amount was used for the next reaction.

Step (vii):
The title compound IX-p (0.017 g) was obtained in the same manner as in step (i) of Reference Example 17 using the crude product of compound VIII-p.

¹ H-NMR (DMSO-d ₆ ) δ: 1.78-1.82 (2H, m), 2.53-2.56 (2H, m), 2.85-2.87 (2H, m), 2.96 (3H, s), 3.15-3.17 ( 2H, m), 3.87-3.91 (2H, m), 7.31-7.33 (1H, m), 7.50-7.52 (2H, m), 9.32-9.35 (1H, m), 9.50-9.54 (1H, m).

Examples 130-134:
In the same manner as in Example 75 (M), using the compound 35 of Reference Example 11, the compounds of Examples 130 to 134 shown in Table 21 were produced.

Example 135:
3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) -4- [5- (trifluoromethyl) pyridin-2-yl] benzo [d] oxazol-2 (3H) -one Example The title compound was produced using compound 35 of Reference Example 11 in the same manner as in 75 (M). However, the procedure of hydrochloric acid chlorination in step (iii) was not performed, and the product was obtained as a free form.

¹ H-NMR (DMSO-d ₆ ) δ: 1.15-1.18 (2H, m), 2.08-2.10 (2H, m), 2.66-2.74 (2H, m), 2.92 (3H, s), 3.02-3.04 ( 2H, m), 3.72-3.74 (2H, m), 7.28-7.30 (2H, m), 7.51-7.53 (1H, m), 7.95-7.98 (1H, m), 8.39-8.41 (1H, m), 9.12 (1H, br s).

Examples 136-142:
In the same manner as in Example 75 (M), compounds of Examples 136 to 142 shown in Table 22 were produced using commercially available 6-bromobenzoxazolone.

Example 143:
3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) -6- [5- (trifluoromethyl) pyridin-2-yl] benzo [d] oxazol-2 (3H) -one Example The title compound was prepared in the same manner as in 75 (M) using commercially available 6-bromobenzoxazolone. However, the procedure of hydrochloric acid chlorination in step (iii) was not performed, and the product was obtained as a free form.

¹ H-NMR (DMSO-d ₆ ) δ: 1.82-1.84 (2H, m), 2.49-2.58 (2H, m), 2.86-2.89 (2H, m), 2.98 (3H, s), 3.18-3.20 ( 2H, m), 3.90-3.92 (2H, m), 7.46-7.48 (1H, m), 8.11-8.14 (2H, m), 8.23-8.28 (2H, m), 9.01 (1H, br s).

Examples 144-148:
In the same manner as in Example 75 (M), compounds of Examples 144 to 148 shown in Table 23 were produced using compound 37 of Reference Example 12.

Example 149:
Preparation of 3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) -7- [5- (trifluoromethyl) pyridin-2-yl] benzo [d] oxazol-2 (3H) -one The title compound was produced in the same manner as in Example 75 (M) using compound 37 of Reference Example 12. However, the procedure of hydrochloric acid chlorination in step (iii) was not performed, and the product was obtained as a free form.

¹ H-NMR (DMSO-d ₆ ) δ: 1.80-1.85 (2H, m), 2.54-2.56 (2H, m), 2.87-2.89 (2H, m), 2.98 (3H, s), 3.18-3.20 ( 2H, m), 3.85-3.95 (2H, m), 7.31-7.48 (2H, m), 7.91-7.94 (1H, m), 8.25-8.28 (1H, m), 8.39-8.42 (1H, m), 9.12 (1H, br s).
Example 150 (Q):
5- (4-Fluorophenyl) -3- (3-{[2- (methylsulfonyl) ethyl] amino} butyl) benzo [d] oxazol-2 (3H) -one hydrochloride

Step (i):
Compound Iq (0.365 g) was obtained using Compound 26 (0.280 g) of Reference Example 7 according to the same method as in Step (ii) of Reference Example 14.

Step (ii):
Compound II-q (0.077 g) was obtained using compound Iq (0.120 g) according to the same method as in step (ii) of Example 1 (A).

Step (iii):
A mixture of Compound II-q (0.077 g) and 4 mol / L hydrogen chloride-ethyl acetate solution (0.40 mL) was stirred at room temperature for 1 hour. The solid was collected by filtration to give the title compound III-q (0.080 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.36 (3H, d, J = 6.1 Hz), 1.88-1.91 (1H, m), 2.25-2.28 (1H, m), 3.10 (3H, s), 3.32 -3.35 (3H, m), 3.47-3.50 (2H, m), 3.99-4.02 (2H, m), 7.30-7.33 (2H, m), 7.42-7.45 (2H, m), 7.67-7.77 (3H, m).

Examples 151-153:
In the same manner as in Example 150 (Q), the compounds of Examples 151 to 153 shown in Table 24 were produced.

実施例１５４：
３−（３−（（２−（メチルスルホニル）エチル）アミノ）ブチル）−５−（４−（トリフルオロメチル）フェニル）ベンゾ［ｄ］オキサゾール−２（３Ｈ）−オン
実施例１５０（Ｑ）と同様の方法にて、表題化合物を製造した。ただし、工程（ｉｉｉ）の塩酸塩化の操作は行わず、遊離体として得た。

Example 154:
3- (3-((2- (methylsulfonyl) ethyl) amino) butyl) -5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-2 (3H) -one Example 150 (Q) In the same manner as described above, the title compound was produced. However, the procedure of hydrochloric acid chlorination in step (iii) was not performed, and the product was obtained as a free form.

¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (3H, d, J = 6.2 Hz), 1.73-1.76 (3H, m), 2.48-2.68 (2H, m), 2.98 (3H, s), 3.14 -3.16 (2H, m), 3.93-3.96 (2H, m), 7.47-7.48 (2H, m), 7.67 (1H, br s), 7.82-7.92 (4H, m).

Example 155 (R):
5- (3,3-Difluorocyclobutyl) -3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) benzo [d] oxazol-2 (3H) -one hydrochloride

Step (i):
A mixture of Compound Ir (10.0 g), cesium carbonate (44.0 g), benzyl bromide (10.4 mL) and acetone (100 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained solid was suspended and stirred in hexane and collected by filtration to obtain Compound II-r (15.0 g).

Step (ii):
Compound II-r (12.0 g), vinylboronic acid anhydride pyridine complex (8.70 g), potassium fluoride (7.00 g), tetrakistriphenylphosphine palladium (3.50 g), water (10 mL) and 1,4 A mixture of dioxane (50 mL) was stirred at 90 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give compound III-r ( 8.70 g) was obtained.

Step (iii):
Trichloroacetyl chloride (14 ml) was added dropwise to a mixture of compound III-r (8.70 g), zinc-copper alloy (25.0 g), diethyl ether (10 mL) and dimethoxyethane (30 mL), and the mixture was stirred at room temperature for 12 hours. . The mixture was filtered through Celite, water was added to the filtrate, and the mixture was stirred at room temperature for 1 hr, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound IV-r as a crude product. The whole amount was used in the next step.

Step (iv):
A mixture of the crude product of Compound IV-r, zinc powder (16.5 g), ammonium chloride (20.0 g) and methanol (50 mL) was heated to reflux for 1 hour. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give compound Vr (5 .50 g) was obtained.

Step (v):
(Diethylamino) sulfur trifluoride (9.3 mL) was added dropwise at −78 ° C. to a solution of compound Vr (5.50 g) in dichloromethane (20 mL). The reaction was stirred at room temperature for 3 days. The reaction solution was added dropwise to a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give compound VI-r ( 2.20 g) was obtained.

Step (vi):
A mixture of compound VI-r (2.20 g), methanol (15 mL) and 2 mol / L aqueous sodium hydroxide solution (14 mL) was heated to reflux for 3 hours. The reaction solution was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was suspended and stirred in hexane, then collected by filtration and dried to obtain Compound VII-r (1.50 g).

Step (vii):
A mixture of compound VII-r (0.500 g), diphenylphosphoryl azide (0.5 mL), diisopropylethylamine (0.4 mL) and toluene (10 mL) was stirred at room temperature for 30 minutes and then heated to reflux for 1.5 hours. Ethanol (3 mL) was added to the reaction solution, and the mixture was further heated to reflux for 1 hour. The reaction solution was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to give compound VIII-r (0 .320 g) was obtained.

Step (viii):
A mixture of compound VIII-r (0.320 g) and 10% Pd / C (0.040 g) and ethanol (5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from a mixed solution of diethyl ether and hexane to obtain Compound IX-r (0.150 g).

Step (ix):
A mixture of compound IX-r (0.150 g), potassium tert-butoxide (0.120 g) and toluene (5.0 mL) was heated to reflux for 1 hour. The reaction solution was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/1) to give compound X-r ( 0.110 g) was obtained.

Step (x):
A mixture of Compound Xr (0.050 g), Compound 54 (0.080 g) of Reference Example 17, triphenylphosphine (0.075 g), diisopropyl azodicarboxylate (0.053 mL) and toluene (2.0 mL) was prepared. And stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give compound XI-r ( 0.046 g) was obtained.

Step (xi):
A mixture of compound XI-r (0.046 g) and 4 mol / L hydrogen chloride-1,4-dioxane solution (3.0 mL) was stirred at room temperature for 2 hours. The solid obtained by concentrating the reaction solution under reduced pressure was suspended in a mixture of hexane and ethyl acetate, collected by filtration and dried to give the title compound XII-r (0.031 g).

¹ H-NMR (DMSO-d ₆ ) δ: 2.00-2.05 (2H, m), 2.64-2.82 (2H, m), 2.92-3.10 (8H, m), 3.42-3.53 (4H, m), 3.91- 3.93 (2H, m), 7.06-7.08 (1H, m), 7.29-7.31 (1H, m), 7.38 (1H, br s), 9.11 (2H, br s).

Example 156 (S):
5- (3,3-Difluorocyclobutyl) -3- {1- [2- (methylsulfonyl) ethyl] azetidin-3-yl} benzo [d] oxazol-2 (3H) -one

Step (i):
Using compound Xr (Example 155) (0.300 g) and tert-butyl 3-hydroxyazetidine-1-carbamate (0.277 g), following the same method as in step (ii) of Reference Example 14, Compound Is (0.178 g) was obtained.

Step (ii):
Compound II-s (0.100 g) was obtained using Compound Is (0.178 g) according to the same method as in step (iii) of Example 52 (G).

Step (iii):
The title compound III-s (0.015 g) was obtained using the compound II-s (0.062 g) according to the same method as in step (i) of Reference Example 17.

¹ H-NMR (DMSO-D ₆ ) δ: 2.69-2.83 (2H, m), 2.94-3.03 (2H, m), 3.11 (3H, s), 3.35-3.44 (6H, m), 3.57 (2H, t, J = 7.7 Hz), 4.19 (2H, t, J = 5.6 Hz), 7.07 (1H, d, J = 8.3 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.50 (1H, s) .

Examples 157-161:
In the same manner as in Example 156 (S), the compounds of Examples 157 to 161 shown in Table 25 were produced.

Example 162 (T):
2- (3- (5- (3,3-Difluorocyclobutyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) azetidin-1-yl) acetamide

Step (i):
A mixture of Compound II-s (Example 156) (0.022 g), 2-bromoacetamide (0.014 g), diisopropylethylamine (0.036 mL) and THF (1.0 mL) was stirred at 60 ° C. for 3 hours. . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 95/5) to give the title compound It ( 0.016 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.58-2.70 (2H, m), 2.99-3.10 (2H, m), 3.33 (2H, s), 3.35-3.46 (1H, m), 3.87-3.93 (4H, m), 4.84-4.91 (1H, m), 5.75 (1H, br s), 6.68 (1H, br s), 6.98-7.00 (1H, m), 7.14-7.18 (2H, m).

Examples 163 to 164:
The compounds of Examples 163 to 164 shown in Table 26 were produced with reference to Examples 156 (S), 162 (T) and 100 (MM).

Example 165 (U):
5- (3,3-Difluorocyclobutyl) -3- {3-[(2-hydroxy-2-methylpropyl) amino] propyl} benzo [d] oxazol-2 (3H) -one

Step (i):
Using compound Xr (Example 155) (0.451 g) and 3-bromo-1,1-dimethoxypropane (0.549 g) according to the same method as in step (i) of Example 32 (E) Compound Iu (0.655 g) was obtained.

Step (ii):
Compound II-u was obtained as a crude product in the same manner as in step (iii) of Example E using Compound Iu (0.327 g). The whole amount was used for the next reaction.

Step (iii):
Using the crude product of compound II-u and 1-amino-2-methylpropan-2-ol (0.178 g), in the same manner as in step (i) of Reference Example 17, the title compound III-u ( 0.064 g) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 1.17 (6H, s), 2.06-2.16 (2H, m), 2.64-2.84 (4H, m), 2.89-3.11 (4H, m), 3.32 (2H, s), 3.39-3.54 (1H, m), 3.89-3.94 (2H, m), 5.15 (1H, s), 7.06-7.09 (1H, m), 7.29-7.31 (1H, m), 7.39 (1H, m).

Compound Xr of Example 155 (R) is also prepared by the following method.
5- (3,3-Difluorocyclobutyl) benzo [d] oxazol-2 (3H) -one (Xr)

Example 166 (V):
4- (4,4-Dichloro-3,3-difluorocyclo-1-buten-1-yl) -1-methoxy-2-nitrobenzene (III-v)
Step (i):
Compound Iv (0.93 g) and 1,1-dichloro-2,2-difluoroethene (9.35 g) were sealed in a pressure vessel and stirred at 130 ° C. for 7 hours. After cooling to room temperature, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1 to 4/1) to obtain Compound II-v (1.00 g). It was.

Step (ii):
70% nitric acid (410 mg) and concentrated sulfuric acid (331 mg) were added to a mixture of compound II-v (0.75 g), acetic acid (26.25 mL) and acetic anhydride (3.75 mL), and the mixture was stirred at room temperature for 3 hours. Ice (100 g) was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water. The solid dried under reduced pressure at 50 ° C. for 9 hours was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1 to 2/1) to obtain Compound III-v (0.70 g).

¹ H-NMR (CDCl ₃ , 400 MHz) δ4.05 (s, 3H), 6.43 (dd, J = 1.8, 1.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.98 (dd, J = 8.8, 2.2 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H)

Example 167 (V):
4- (4,4-Dichloro-3,3-difluorocyclo-1-buten-1-yl) -2-nitrophenol (IV-v)
Step (iii):
To a solution of compound III-v (0.62 g) in dichloromethane (9 mL) was added 1 mol / L boron tribromide (dichloromethane solution, 2.4 mL) under ice-cooling, and the mixture was stirred for 1.5 hours. Water was added dropwise to the reaction mixture, ethyl acetate was added, and the temperature was raised to room temperature. Hexane was added for liquid separation, and the obtained organic layer was washed with water and saturated brine. The solid obtained after drying over anhydrous sodium sulfate and concentration under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 8/1 to 2/1) to give compound IV-v (0.46 g). Got.

¹ H-NMR (CDCl ₃ , 400 MHz) δ6.46 (dd, J = 1.8, 1.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.96 (dd, J = 8.8, 2.2 Hz, 1H), 8.55 (d, J = 2.2 Hz, 1H), 10.88 (s, 1H).

Example 168 (V):
2-Amino-4- (3,3-difluorocyclobutyl) phenol (Vv)
Step (iv):
Compound Vv (0.33 g) was obtained using Compound IV-v (0.46 g) according to the same method as in step (i) of Example 27.

¹ H-NMR (CD ₃ OD, 400 MHz) δ2.52-2.69 (m, 2H), 2.91-3.06 (m, 2H), 3.28-3.42 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.4, 2.2 Hz, 1H).

Step (v):
1,1′-carbonyldiimidazole (0.377 g) was added to a mixture of compound Vv (0.33 g) and tetrahydrofuran (10 mL), and the mixture was stirred under reflux for 1.5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, and 1 mol / L hydrochloric acid was added to separate the layers. The obtained organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The solid obtained after drying over anhydrous sodium sulfate and concentration under reduced pressure was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1 to 1/1) to give the title compound Xr (0.24 g). )

1H-NMR (CDCl ₃ , 400 MHz) δ2.57-2.73 (m, 2H), 2.96-3.10 (m, 2H), 3.42 (ddddd, J = 8.8, 8.8, 8.8, 8.8, 2.4 Hz, 1H), 6.99 (ddd, J = 8.7, 1.8, 0.6 Hz, 1H), 6.99 (dd, J = 1.8, 0.6 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H).

Compound XII-r of Example 155 (R) is also prepared by the following method.
5- (3,3-difluorocyclobutyl) -3- (3-{[2- (methylsulfonyl) ethyl] amino} propyl) benzo [d] oxazol-2 (3H) -one hydrochloride (XII-r)

Example 169 (W):
Production process (i) of tert-butyl (3- (5- (3,3-difluorocyclobutyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) propyl) carbamate (Iw):
Dodecane (0.1 mL) as an internal standard solution in a mixture of 1-bromo-3,3-difluorocyclobutane (0.130 g), 5.0 g / dL Likezinc (THF solution, 1.2 mL) and THF (0.76 mL) ) And stirred at room temperature for 5 hours. Thereafter, a solution of compound I-1 (Example 72) (0.225 g) and Pd-PEPPSI-IPent (0.0146 g) in THF (1.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. Further, Pd-PEPPSI-IPent (0.0149 g) was added and stirred at room temperature for 9 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9/1 to 1/1) to obtain Compound I-w (0.0631 g).

¹ H-NMR (CDCl ₃ , 400 MHz) δ1.43 (s, 9H), 1.95 (m, 2H), 2.59-2.75 (m, 2H), 2.97-3.10 (m, 2H), 3.18 (q, J = 6.5 Hz, 2H), 3.42 (m, 1H), 3.90 (t, J = 6.5 Hz, 2H), 5.05 (brs, 1H), 6.84 (d, J = 1.0 Hz, 1H), 6.98 (dd, J = 8.0, 1.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H).

Step (ii):
Compound II-w (0.240 g) was obtained using Compound Iw (0.380 g) according to the same method as in step (iii) of Example 71 (K).

Step (iii):
A mixture of Compound II-w (0.050 g), methyl vinyl sulfone (0.021 ml) and diisopropylethylamine (0.080 ml) was stirred at room temperature for 4 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluent: chloroform / methanol = 100/0 to 95/5). A mixture of the obtained compound and 4 mol / L hydrogen chloride-ethyl acetate solution (1.0 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title compound XII-r (0.043 g).

Test example 1
Measurement of membrane potential change using voltage-dependent Na channel gene-expressing cells Using human SCN9A (tetracycline-inducible) or CHO-K1 cell line stably expressing human SCN10A gene, Nav1.7 and Nav1.8 currents, respectively. The inhibitory action of the compound of the present invention on the change in membrane potential derived from the origin was evaluated.
That is, a test compound is added to a confluent expression cell loaded with a membrane potential sensitive dye for 15 to 30 minutes (37 ° C., 5% CO ₂ ), and veratridine (Na channel opener) is added approximately 5 minutes later. The change in fluorescence intensity induced by this was measured, and the inhibitory effect on the increase in membrane potential via Nav1.7 or Nav1.8 was evaluated. FLIPR ^TETRA (Molecular Device) was used as a measuring device. Table 27 shows the test conditions for each channel.

The Na channel inhibition rate of the test compound was determined by the following calculation formula.
Nav1.7 inhibition rate (%) = 100 × [(peak value of veratridine stimulation in the absence of evaluation compound) − (peak value of veratridine stimulation in the presence of evaluation compound)] / [(in the absence of evaluation compound) Peak value of veratridine stimulation)-(peak value without stimulation)]
Nav1.8 inhibition rate (%) = 100 × [(veracridine-stimulated AUC in the absence of evaluation compound) − (veratridine-stimulated AUC in the presence of evaluation compound)] / [(veratridine in the absence of evaluation compound) Stimulus AUC)-(AUC without stimulation)]

Test results As a result of evaluating the inhibitory effect on the increase in membrane potential via the Na channel for the compounds obtained in the Examples, it was observed that the compound of the present invention shows an inhibitory action on both Nav1.7 and Nav1.8. . Each isoform inhibition rate (%) when the compound concentration is 40 μmol / L is shown in Tables 28-30. In addition, when (10 μmol / L) is described in the table, each isoform inhibition rate (%) when the compound concentration is 10 μmol / L is shown, and when − is described in the table, Indicates not measured.

Nav1.7 inhibition

Continuation of Nav1.7 inhibition

Nav1.8 inhibition

Test example 2
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-derived SCN9A stably expressing cells were obtained from ChanTest. Cells were maintained in Ham's F-12 medium containing 10% fetal bovine serum, 100 units / mL Penicillin-Streptomycin, 0.01 mg / mL Blasticidin, 0.4 mg / mL Zeocin. The day before the measurement, the medium was replaced with Ham's F-12 medium containing 1 μg / mL tetracycline, 100 μmol / L sodium butyrate, 10% fetal bovine serum, 100 units / mL penicillline-streptomycin, and the following day, the Na ion current was obtained by the autopatch clamp method. Was measured.
-Electrophysiological measurement of Na ion current Na ion current was measured by the auto patch clamp method using the following extracellular fluid and intracellular fluid.
-Extracellular fluid (mmol / L): NaCl 130, MgCl2, CaCl2, 0.1 CdCl2, 0.1, NiCl2 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 formula based on the peak current 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 effect 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 31 shows the inhibition rate (%) when the compound concentration is 10 μmol / L.

Nav1.7 inhibition

Test example 3
Measurement of Na ion current using voltage-dependent Na channel gene-expressing cells The Nav1.8-derived current was measured by a manual patch clamp method using human SCN10A transiently expressing cells.
-Human SCN10A transient expression cell ND7 / 23 cell which is a host cell was obtained from ECACC (European Collection of Cell Cultures). Cells were passaged in DMEM (Dulbeco's Modified Eagle's Medium) medium containing 10% fetal bovine serum, 100 units / mL Penicillin-Streptomycin, 2 mmol / L GlutaMAX (Invitrogen). Using ND7 / 23 cells seeded on a slide glass, a Nav1.8 expression plasmid incorporating a human SCN10A gene and a GFP expression plasmid (Promega) were added at 2 mmol / L using Plus Reagent (Invitrogen) and Lipofectamine 2000 (Invitrogen). It introduce | transduced in the DMEM culture medium containing GlutaMAX (Invitrogen). After 4 hours, the medium was replaced with the subculture medium, and the Na ion current was measured by the manual patch clamp method the next day.
Electrophysiological measurement of Na ion current Na ion current was measured by the manual 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 (4- (2- hydroxyethyl) -1-piperazine etheresufonic acid) 10, TTX 0.0005 (adjusted to pH 7.4 with NaOH)
Intracellular fluid (mmol / L): CsF 120, EGTA (ethylene tetraacetic acid) 10, NaCl 15, HEPES 10, (adjusted to pH 7.2 with CsOH)
Stimulation pulse control and data acquisition were performed using Axopatch 200B and Clampex software (Molecular Devices) or EPC10 and Patch Master software (HEKA). Data sampling was performed at 20 kHz, and noise was removed with a 2 kHz low-pass filter. All measurements were performed at room temperature. The holding potential was 20% inactivation potential (near -85 mV) of the Nav1.8 channel, and a 20 millisecond depolarizing pulse (near 10 mV) was applied 30 times at a frequency of 10 Hz. The inhibition rate of the test compound was calculated from the results of cells in which the peak current at the first stimulation pulse was 500 pA or more and the whole cell parameters did not change greatly 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 formula based on the current peak value generated by the 30th 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 effect 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 Nav1.8. Table 32 shows the inhibition rate (%) when the compound concentration was 10 μmol / L. In addition, when it describes as 5 umol / L in a table | surface, the inhibition rate (%) when a compound concentration is 5 umol / L is shown.

Nav1.8 inhibition

  The compounds of the present invention can be used in pathologies involving Nav1.7 and / or Nav1.8, specifically neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, limb erythema pain, seizures It can be used as an excellent therapeutic agent for diseases such as acute pain, dysuria, and multiple sclerosis. Therefore, the compound of the present invention can be a very useful medicament.

Claims (33)

Following formula (1);

[In Formula (1),
R ¹ and R ² are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is hydroxy, halogen, C _1-4 alkoxy, C _1-4 alkylsulfonyl, C _1-4 alkylthio, aminocarbonyl ( The amino moiety of the aminocarbonyl may be mono- or di-substituted by optionally substituted C _1-4 alkyl), optionally substituted 4-7 membered heterocycloalkyl and substituted Optionally substituted with 1 to 3 substituents independently selected from the group consisting of 4 to 7-membered heterocycloalkylcarbonyl), C _3-7 cycloalkyl, C _4-7 cycloalkenyl or 4-7 membered heterocycloalkyl (wherein cycloalkyl, the cycloalkenyl and the heterocycloalkyl, C _1-4 each represent an alkyl C _1-4 represents haloalkyl, halogen, hydroxy and C _1-4 optionally substituted with 1-3 substituents independently selected from the group consisting of alkoxy),
L is C _1-6 alkylene (the alkylene is substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, hydroxy and C _1-4 alkoxy; Where R ¹ is C _1-6 alkyl, the carbon atom on R ¹ and L together, together with the nitrogen atom to which R ¹ is attached, 4-7 membered saturation May form a heterocycle,
R ³ is halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the alkyl, the alkenyl and the alkynyl are each halogen, optionally substituted C _3-7 cycloalkyl, Optionally substituted 4-7 membered heterocycloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkylsulfonyl, C _1-4 alkylthio, optionally substituted C _{6-6. 10} aryl and optionally substituted with 1 to 3 substituents are also independently selected from the group consisting of optionally C _6-10 aryloxy substituted), C _3-7 cycloalkyl, C _{4 -7} cycloalkenyl, 4-7 membered heterocycloalkyl (wherein cycloalkyl, the cycloalkenyl, the heterocycloalkyl, _{C 1-4} respectively a _{Kill, C 1-4} haloalkyl, halogen, independently from the group consisting of hydroxy and _{C 1-4} alkoxy optionally substituted with 1-3 substituents _{selected), C 6-10} aryl (the Aryl is halogen, optionally substituted C _1-4 alkyl, C _1-4 haloalkyl, optionally substituted C _1-4 alkoxy, C _1-4 haloalkoxy, cyano and C _1-4 alkoxycarbonyl. Optionally substituted with 1 to 3 substituents independently selected from the group consisting of: C _6-10 aryloxy (the aryl moiety of the aryloxy is halogen, C _1-4 alkyl, C _{1-4 haloalkyl, C 1-4 alkoxy,} optionally substituted with 1-3 substituents independently selected from the group consisting of _{C 1-4} haloalkoxy) the 5-10 membered heteroaryl (wherein heteroaryl is 1 are selected from _{halogen, C 1-4 alkyl, C 1-4 haloalkyl,} independently from the group consisting of _{C 1-4} alkoxy and _{C 1-4} haloalkoxy ~ Optionally substituted with 3 substituents),
R ⁴ represents hydrogen, halogen or C _1-4 alkyl]
Or a pharmaceutically acceptable salt thereof. The substituent in the _optionally substituted C _6-10 aryl, the _optionally substituted C _6-10 aryloxy and the _optionally substituted C _3-7 cycloalkyl is halogen, C _1-4 alkyl, 1 to 3 substituents independently selected from the group consisting of C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy,
Substituents in optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy are independently selected from the group consisting of C _1-4 alkoxy, C _1-4 haloalkoxy. 1 to 2 substituents,
Substituents in heterocycloalkyl of optionally substituted 4-7 membered heterocycloalkyl and optionally substituted 4-7 membered heterocycloalkylcarbonyl are C _1-4 alkyl, halogen, oxo and hydroxy The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 1 to 3 substituents independently selected from the group consisting of: Optionally substituted C _6-10 aryl, substituent of the C _3-7 cycloalkyl be a good C _6-10 aryloxy and substituted also be substituted, it is a 1-3 halogens ,
The substituent in the optionally substituted C _1-4 alkyl and the optionally substituted C _1-4 alkoxy is _1-2 C _1-2 alkoxy,
The substituent in the optionally substituted 4-7 membered heterocycloalkyl and optionally substituted 4-7 membered heterocycloalkylcarbonyl heterocycloalkyl is selected from the group consisting of C _1-2 alkyl and oxo. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is 1 to 2 substituents independently selected. R ¹ and R ² are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is hydroxy, halogen, C _1-4 alkoxy, C _1-4 alkylsulfonyl, aminocarbonyl (the amino moiety of the aminocarbonyl) _May be mono or disubstituted by C _1-4 alkyl), 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkylcarbonyl (the 4-7 membered heterocycloalkyl and the 4 The heterocycloalkyl part of the -7 membered heterocycloalkylcarbonyl may each be substituted by 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo) Optionally substituted with 1 to 3 substituents independently selected from the group) or 4 to 7 membered heterocycloalkyl The heterocycloalkyl, halogen, and C _1-4 optionally substituted with 1-3 substituents independently selected from the group consisting of alkoxy), any one of claims 1 to 3 The compound according to one item or a pharmaceutically acceptable salt thereof. R ¹ and R ² are each independently hydrogen, C _1-4 alkyl (wherein the alkyl is hydroxy, C _1-2 alkylsulfonyl, aminocarbonyl (the amino moiety of the aminocarbonyl is represented by C _1-2 alkyl) Optionally substituted) 4-5 membered heterocycloalkyl and 4-6 membered heterocycloalkylcarbonyl (the 4-7 membered heterocycloalkyl and the 4-7 membered heterocycloalkylcarbonyl heterozygous) Each cycloalkyl is optionally selected from the group consisting of _1-2 optionally selected from 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo. Or optionally substituted with 4 to 5 membered heterocycloalkyl, which is substituted with 1 to 2 halo Also it may) be substituted by emissions, a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3. R ¹ is hydrogen or C _1-4 alkyl and R ² is C _1-4 alkyl (wherein the alkyl is hydroxy, C _1-2 alkylsulfonyl and aminocarbonyl (the amino moiety of the aminocarbonyl is C _{1 -2} alkyl optionally substituted with 1-2 substituents independently selected from the group consisting of 1-alkyl) or 4- to 5-membered heterocycloalkyl (the heterocyclo The alkyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo. Or a pharmaceutically acceptable salt thereof. L is C _1-6 alkylene (the alkylene is substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, hydroxy and C _1-4 alkoxy; Where R ¹ is C _1-6 alkyl, the carbon atoms on R ¹ and L are taken together to form a 4-7 membered saturation with the nitrogen atom to which R ¹ is attached. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which may form a heterocyclic ring. L is C _1-4 alkylene, which alkylene may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and hydroxy, wherein , When R ¹ is C _1-6 alkyl, R ¹ and the carbon atom on L may be taken together to form a 4-6 membered saturated heterocycle with the nitrogen atom to which R ¹ is attached. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. L is C _1-3 alkylene, wherein the alkylene may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and hydroxy. The compound as described in any one of 1-6, or its pharmaceutically acceptable salt. L is C _1-3 alkylene, R ¹ is C _1-6 alkyl, R ¹ and the carbon atom on L together, together with the nitrogen atom to which R ¹ is attached, azetidine, piperidine or pyrrolidine The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof. R ³ is halogen, C _1-6 alkyl, C _2-6 alkenyl (the alkyl and the alkenyl are each halogen, C _3-7 cycloalkyl (the cycloalkyl is substituted by 1 to 2 halogens) 4-7 membered heterocycloalkyl, which may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo. 1), independently selected from the group consisting of C _6-10 aryl and C _6-10 aryloxy, each of which may be substituted by 1 to 3 halogens to three may be substituted with a _{substituent), C 3-7 cycloalkyl, C 4-7} cycloalkenyl, 4-7 membered heterocycloalkylene (Said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, optionally substituted with 1-3 substituents selected respectively C _1-4 alkyl, from the group consisting of C _1-4 haloalkyl and halogen independently C _6-10 aryl (wherein the aryl is halogen, C _1-4 alkyl, C _1-4 alkoxy (the alkyl and the alkoxy are each substituted by _{1 to} 2 C _1-2 alkoxy) Optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 haloalkyl, C _1-4 haloalkoxy, cyano and C _1-4 alkoxycarbonyl. heteroaryl (said heteroaryl good) or 5-10 membered, _{halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4} Al Alkoxy and a C _1-4 optionally substituted with 1-3 substituents independently selected from the group consisting of haloalkoxy) A compound according to any one of claims 1 to 10 Or a pharmaceutically acceptable salt thereof. R ³ is halogen, C _1-4 alkyl, C _2-4 alkenyl (the alkyl and the alkenyl are each halogen, C _4-6 cycloalkyl (the cycloalkyl is substituted by 1 to 2 halogens) Optionally substituted 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is independently selected from the group consisting of C _1-2 alkyl and oxo. Independently from the group consisting of C _6-10 aryl and C _6-10 aryloxy, each of which may be substituted with 1 to 2 halogens and optionally substituted with 1-3 substituents _{selected), C 3-6 cycloalkyl, C 4-6} cycloalkenyl, 4-6 membered Heterocycloalkyl (said cycloalkyl, said cycloalkenyl, said heterocycloalkyl may be substituted with 1 to 3 _{halogens), C 6-10} aryl (the aryl, _{halogen, C 1-2} alkyl , C _1-2 alkoxy (wherein the alkyl and the alkoxy may each be substituted by _{1 to} 2 C _1-2 alkoxy), C _1-2 haloalkyl, C _1-2 haloalkoxy, cyano and C Optionally substituted with 1 to 3 substituents independently selected from the group consisting of _1-2 alkoxycarbonyl) or 6-membered heteroaryl (wherein the heteroaryl is from halogen and C _1-2 haloalkyl) Any one of claims 1 to 10, which may be substituted with 1 to 2 substituents independently selected from the group consisting of Or a pharmaceutically acceptable salt thereof. R ³ is C _3-6 cycloalkyl, a 4-6 membered heterocycloalkyl (the cycloalkyl and the heterocycloalkyl may be substituted by 1 to 3 halogens), phenyl (the phenyl is Substituted with 1 to 3 substituents independently selected from the group consisting of, halogen, C _1-2 alkyl, C _1-2 haloalkyl, C _1-2 alkoxy and C _1-2 haloalkoxy Or a 6-membered heteroaryl, wherein the heteroaryl may be substituted by _{1 to} 2 C _1-2 haloalkyls, or a compound according to any one of claims 1 to 10; Its pharmaceutically acceptable salt. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R ⁴ is hydrogen, halogen or C _1-2 alkyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R ⁴ is hydrogen. R ¹ and R ² are each independently hydrogen, C _1-6 alkyl (wherein the alkyl is hydroxy, halogen, C _1-4 alkoxy, C _1-4 alkylsulfonyl, aminocarbonyl (the amino moiety of the aminocarbonyl) _May be mono or disubstituted by C _1-4 alkyl), 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkylcarbonyl (the 4-7 membered heterocycloalkyl and the 4 The heterocycloalkyl part of the -7 membered heterocycloalkylcarbonyl may each be substituted by 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo) Optionally substituted with 1 to 3 substituents independently selected from the group) or 4 to 7 membered heterocycloalkyl The heterocycloalkyl, halogen, and a C _1-4 optionally substituted with 1-3 substituents independently selected from the group consisting of alkoxy),
L is C _1-6 alkylene (the alkylene is substituted with 1 to 3 substituents independently selected from the group consisting of C _1-4 alkyl, halogen, hydroxy and C _1-4 alkoxy; Where R ¹ is C _1-6 alkyl, the carbon atoms on R ¹ and L are taken together to form a 4-7 membered saturation with the nitrogen atom to which R ¹ is attached. May form a heterocycle,
R ³ is halogen, C _1-6 alkyl, C _2-6 alkenyl (the alkyl and the alkenyl are each halogen, C _3-7 cycloalkyl (the cycloalkyl is substituted by 1 to 2 halogens) 4-7 membered heterocycloalkyl, which may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo. 1), independently selected from the group consisting of C _6-10 aryl and C _6-10 aryloxy, each of which may be substituted by 1 to 3 halogens to three may be substituted with a _{substituent), C 3-7 cycloalkyl, C 4-7} cycloalkenyl, 4-7 membered heterocycloalkylene (Said cycloalkyl, said cycloalkenyl, said heterocycloalkyl, optionally substituted with 1-3 substituents selected respectively C _1-4 alkyl, from the group consisting of C _1-4 haloalkyl and halogen independently C _6-10 aryl, wherein the aryl is independently selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 alkoxy, cyano and C _1-4 alkoxycarbonyl Optionally substituted with 5 substituents or 5- to 10-membered heteroaryl, which is halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 May be substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy),
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen, halogen or C _1-2 alkyl. R ¹ and R ² are each independently hydrogen, C _1-4 alkyl (wherein the alkyl is hydroxy, C _1-2 alkylsulfonyl, aminocarbonyl (the amino moiety of the aminocarbonyl is represented by C _1-2 alkyl) Optionally substituted) 4-5 membered heterocycloalkyl and 4-6 membered heterocycloalkylcarbonyl (the 4-7 membered heterocycloalkyl and the 4-7 membered heterocycloalkylcarbonyl heterozygous) Each cycloalkyl is optionally selected from the group consisting of _1-2 optionally selected from 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo. Or optionally substituted with 4 to 5 membered heterocycloalkyl, which is substituted with 1 to 2 halo It is also may) be substituted by emissions,
L is C _1-4 alkylene, which alkylene may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and hydroxy, wherein , When R ¹ is C _1-6 alkyl, R ¹ and the carbon atom on L may be taken together to form a 4-6 membered saturated heterocycle with the nitrogen atom to which R ¹ is attached. ,
R ³ is halogen, C _1-4 alkyl, C _2-4 alkenyl (the alkyl and the alkenyl are each halogen, C _4-6 cycloalkyl (the cycloalkyl is substituted by 1 to 2 halogens) 4-6 membered heterocycloalkyl, which may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo. 1) independently selected from the group consisting of C _6-10 aryl and C _6-10 aryloxy, wherein said aryl and said aryloxy may each be substituted by 1 to 2 halogens to three may be substituted with a _{substituent), C 3-6 cycloalkyl, C 4-6} cycloalkenyl, 4-6 membered heterocycloalkylene (Said cycloalkyl, said cycloalkenyl, said heterocycloalkyl may be substituted with 1 to 3 _{halogens), C 6-10} aryl (the aryl, _{halogen, C 1-2} alkyl, _{C 1 -2} alkoxy (wherein the alkyl and the alkoxy may each be substituted by _{1 to} 2 C _1-2 alkoxy), C _1-2 haloalkyl, C _1-2 haloalkoxy, cyano and C _1-2 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxycarbonyl or 6-membered heteroaryl (wherein the heteroaryl is from the group consisting of halogen and C _1-2 haloalkyl) Optionally substituted with 1 to 2 substituents independently selected),
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen, halogen or C _1-2 alkyl. R ¹ is hydrogen;
R ² is C _1-4 alkyl (which may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy and C _1-2 alkylsulfonyl) or 4 to 5-membered heterocycloalkyl, which may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo;
L is C _1-3 alkylene (the alkylene may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and hydroxy);
R ³ is C _3-6 cycloalkyl, a 4-6 membered heterocycloalkyl (the cycloalkyl and the heterocycloalkyl may be substituted by 1 to 3 halogens), phenyl (the phenyl is 1 to 3 independently selected from the group consisting of, halogen, C _1-2 alkyl, C _1-2 alkoxy, C _1-2 haloalkyl, C _1-2 haloalkoxy, cyano and C _1-2 alkoxycarbonyl Or 6-membered heteroaryl, which may be substituted by _{1 to} 2 C _1-2 haloalkyls,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen. R ¹ is C _1-4 alkyl;
R ² is C _1-4 alkyl (which may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy and C _1-2 alkylsulfonyl) or 4 to 5-membered heterocycloalkyl, which may be substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkyl and oxo;
L is C _1-3 alkylene, the alkyl of R ¹ and the carbon atom on L are taken together to form an azetidine, piperidine or pyrrolidine with the nitrogen atom to which R ¹ is attached;
R ³ is C _3-6 cycloalkyl, a 4-6 membered heterocycloalkyl (the cycloalkyl and the heterocycloalkyl may be substituted by 1 to 3 halogens), phenyl (the phenyl is 1 to 3 independently selected from the group consisting of, halogen, C _1-2 alkyl, C _1-2 alkoxy, C _1-2 haloalkyl, C _1-2 haloalkoxy, cyano and C _1-2 alkoxycarbonyl Or 6-membered heteroaryl, which may be substituted by _{1 to} 2 C _1-2 haloalkyls,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-2 (3H) -one;
(S) -2-((2- (2-oxo-5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-3 (2H) -yl) ethyl) amino) propanamide;
2-((2- (2-oxo-5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-3 (2H) -yl) ethyl) amino) acetamide;
(R) -2-((2- (2-oxo-5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-3 (2H) -yl) ethyl) amino) propanamide;
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (4- (trifluoromethoxy) phenyl) benzo [d] oxazol-2 (3H) -one;
3- (2- (oxetane-3-ylamino) ethyl) -5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-2 (3H) -one;
5- (4-fluorophenyl) -4-methyl-3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one;
3- (2-Methyl-3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazole-2 (3H) -ON;
5- (4-fluorophenyl) -3- (2-hydroxy-3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
5- (4-fluorophenyl) -3- (3- (oxetan-3-ylamino) propyl) benzo [d] oxazol-2 (3H) -one;
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5-phenylbenzo [d] oxazol-2 (3H) -one;
5- (3-fluorophenyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (4- (trifluoromethoxy) phenyl) benzo [d] oxazol-2 (3H) -one;
5- (4-fluorophenyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-2 (3H) -one;
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one;
5- (4-fluorophenyl) -4-methyl-3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
5- (4,4-difluorocyclohexyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one;
6-fluoro-3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (tetrahydro-2H-pyran-4-yl) benzo [d] oxazol-2 (3H) -one;
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (tetrahydro-2H-pyran-4-yl) benzo [d] oxazol-2 (3H) -one;
5-cyclobutyl-3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
5-cyclopentyl-3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one;
5-butyl-3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -7- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one;
5- (4-fluorophenyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) butyl) benzo [d] oxazol-2 (3H) -one;
5- (3,3-difluorocyclobutyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
5- (3,3-difluorocyclobutyl) -3- (1- (2- (methylsulfonyl) ethyl) azetidin-3-yl) benzo [d] oxazol-2 (3H) -one;
5- (3,3-difluorocyclobutyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one;
5- (3,3-difluorocyclobutyl) -3- (4-((2- (methylsulfonyl) ethyl) amino) butyl) benzo [d] oxazol-2 (3H) -one;
5- (3,3-difluorocyclobutyl) -3- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) benzo [d] oxazol-2 (3H) -one;
2- (3- (5- (3,3-difluorocyclobutyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) azetidin-1-yl) acetamide;
2- (4- (5- (3,3-difluorocyclobutyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) piperidin-1-yl) acetamide; or 5- (3,3-difluoro Cyclobutyl) -3- (3-((2-hydroxy-2-methylpropyl) amino) propyl) benzo [d] oxazol-2 (3H) -one. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group of compounds:
5- (4-fluorophenyl) -3- (2-hydroxy-3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
5- (4-fluorophenyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -5- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one;
5- (4,4-difluorocyclohexyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one;
3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) -5- (tetrahydro-2H-pyran-4-yl) benzo [d] oxazol-2 (3H) -one;
5-cyclobutyl-3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) -7- (5- (trifluoromethyl) pyridin-2-yl) benzo [d] oxazol-2 (3H) -one;
5- (3,3-difluorocyclobutyl) -3- (3-((2- (methylsulfonyl) ethyl) amino) propyl) benzo [d] oxazol-2 (3H) -one;
5- (3,3-difluorocyclobutyl) -3- (2-((2- (methylsulfonyl) ethyl) amino) ethyl) benzo [d] oxazol-2 (3H) -one;
5- (3,3-difluorocyclobutyl) -3- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) benzo [d] oxazol-2 (3H) -one;
2- (4- (5- (3,3-difluorocyclobutyl) -2-oxobenzo [d] oxazol-3 (2H) -yl) piperidin-1-yl) acetamide; or 5- (3,3-difluoro Cyclobutyl) -3- (3-((2-hydroxy-2-methylpropyl) amino) propyl) benzo [d] oxazol-2 (3H) -one. Following formula (2);

[In Formula (2),
R ⁵ represents nitro, amino (the amino is C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl (the phenylmethyl moiety in the phenylmethyl, phenylmethyloxycarbonyl is halogen, C _1-2 alkyl And optionally substituted with 1 to 6 substituents independently selected from the group consisting of C _1-2 alkoxy), fluorenylmethylcarbonyl, benzenesulfonyl (wherein the benzenesulfonyl is 1- Optionally substituted by 1 to 2 substituents independently selected from the group consisting of: optionally substituted) or phthalimide (the phenyl portion of the phthalimide is substituted by C _1-2 alkyl) 1 to 3 may be substituted),
R ⁶ is hydrogen or C _1-2 alkyl, wherein the alkyl is substituted with 1-2 substituents independently selected from the group consisting of C _1-2 alkoxy, phenyl and 4-methoxyphenyl. Is good)
R ⁷ is hydrogen or C _1-2 alkyl;
R ⁸ is iodine, bromine, chlorine or hydrogen, and when R ⁸ is iodine, bromine or chlorine, 1 to 2 may be substituted at substitutable positions;
AA is CC or C = C]
Or a salt thereof. Following formula (3);

[In Formula (3),
R ⁷ is hydrogen or C _1-2 alkyl;
R ⁹ represents C _1-4 alkyloxycarbonyl, phenylmethyloxycarbonyl (the phenylmethyl moiety of the phenylmethyloxycarbonyl is independently selected from the group consisting of C _1-2 alkyl and C _1-2 alkoxy) Up to 6 substituents), fluorenylmethylcarbonyl or benzenesulfonyl (wherein the benzenesulfonyl may be substituted with 1 to 2 by nitro),
R ¹⁰ is hydrogen or C _1-2 alkyl, where R ⁹ and R ¹⁰ are taken together with the nitrogen atom to which R ⁹ and R ¹⁰ are attached together with phthalimide (the phenyl portion of the phthalimide is C ₁ 1-3 may be substituted by _-2 alkyl),
M is C _1-4 alkylene, where when R ¹⁰ is C _1-2 alkyl, R ¹⁰ and the carbon atom on M are taken together and together with the nitrogen atom to which R ¹⁰ is attached, 4- May form a 6-membered saturated heterocycle,
B is halogen]
Or a salt thereof. Following formula (4);

[In Formula (4),
R ⁷ is hydrogen or C _1-2 alkyl;
R ¹¹ and R ¹² are each independently hydrogen, C _1-4 alkyl (wherein the alkyl may be substituted by C _1-4 alkoxy or phenyl), C _1-4 haloalkyl, C _1-4. Haloalkoxy, nitro, amino (wherein the amino is C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl (the phenylmethyl moiety in the phenylmethyl and phenylmethyloxycarbonyl is halogen, C _1-2 alkyl and Optionally substituted with 1 to 6 substituents independently selected from the group consisting of C _1-2 alkoxy, fluorenylmethylcarbonyl, benzenesulfonyl (wherein the benzenesulfonyl is 1-2 with nitro) 1 may be independently selected from the group consisting of Number of which may be substituted by a substituent), phthalimide (phenyl moiety of the phthalimide may be 1-3 substituted by C _1-2 alkyl) or C _1-2 alkoxy (alkyl in the alkoxy The moiety is optionally substituted with 1 to 2 substituents independently selected from the group consisting of C _1-2 alkoxy, phenyl and 4-methoxyphenyl, wherein R ¹¹ and R ^{11 When 12} is ortho to each other, R ¹¹ and R ¹² may be combined with phenyl to form a benzoxazolone ring, an indole ring or an indazole ring.
Or a salt thereof, which is represented by the following formula (5):

[In Formula (5),
R ⁷ , R ¹¹ and R ¹² are the same as in the above formula (4),
B is a halogen], and the following formula (6)

[In Formula (6),
X is an iodine, bromine, or chlorine] manufacturing method including a step of coupling a compound represented by a palladium catalyst. Following formula (7);

[In Formula (7),
R ⁷ is hydrogen or C _1-2 alkyl;
R ¹³ is C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl (the phenylmethyl and the phenylmethyl moiety in the phenylmethyloxycarbonyl are composed of halogen, C _1-2 alkyl and C _1-2 alkoxy. Optionally substituted with 1 to 6 substituents independently selected from the group), fluorenylmethylcarbonyl, benzenesulfonyl (the benzenesulfonyl may be substituted with 1 to 2 by nitro) ) And
R ¹⁴ is hydrogen, C _1-2 alkyl, C _1-4 alkyloxycarbonyl, phenylmethyl, phenylmethyloxycarbonyl (the phenylmethyl moiety in the phenylmethyl and phenylmethyloxycarbonyl is halogen, C _1-2 alkyl And optionally substituted with 1 to 6 substituents independently selected from the group consisting of C _1-2 alkoxy), fluorenylmethylcarbonyl or benzenesulfonyl (wherein the benzenesulfonyl is 1- In which R ¹³ and R ¹⁴ are taken together with the nitrogen atom to which R ¹³ and R ¹⁴ are attached together with phthalimide (the phenyl moiety of the phthalimide is C _1-2 1 to 3 may be substituted with alkyl) ,
M is C _1-4 alkylene, where when R ¹⁴ is C _1-2 alkyl, R ¹⁴ and the carbon atom on M are taken together and together with the nitrogen atom to which R ¹⁴ is attached, 4 to 4 A 6-membered saturated heterocyclic ring may be formed]
Or a salt thereof, which is represented by the following formula (8):

[In Formula (8),
R ⁷ , R ¹³ , R ¹⁴ and M are the same as those in the above formula (7), B is a halogen], and the following formula (9)

[In Formula (9),
X is an iodine, bromine, or chlorine] manufacturing method including a step of coupling a compound represented by a palladium catalyst. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof. A Nav1.7 (SCN9A), Nav1.8 (SCN10A) or Nav1.7 and Nav1.2 containing the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient. Drugs for diseases involving both of the above. 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 21 or a pharmaceutically acceptable salt thereof. A therapeutic agent for a disease involving Nav1.8 (SCN10A), comprising as an active ingredient the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof. Neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, limb redness containing the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient A treatment for pain, paroxysmal pain, dysuria or multiple sclerosis. A Nav1.7 (SCN9A), Nav1.8 (SCN10A) or Nav1.7 and Nav1.2 containing the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for a disease involving both of the above 8 and at least one drug selected from antiepileptic drugs, antidepressants, narcotic analgesics, anti-inflammatory drugs, reductase inhibitors, and prostaglandin derivative preparations. A medicine comprising a combination of Claims 1-21 for the manufacture of a therapeutic agent for neuropathic pain, nociceptive pain, inflammatory pain, small-diameter neuropathy, limb erythema, paroxysmal pain, dysuria or multiple sclerosis Use of the compound according to any one of the above or a pharmaceutically acceptable salt thereof. Neuropathic pain, characterized in that a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment, A method for treating nociceptive pain, inflammatory pain, small fiber neuropathy, erythema limb pain, paroxysmal pain, dysuria or multiple sclerosis.