JP2012006837A - 2-indoleacrylamide analogue - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound that regulates functions of TRPV1 receptor, a TRV1 receptor regulating agent having a derivative of the compound as an active ingredient, and to provide a preventive and therapeutic agent for diseases with sharp pain relating to TRPV1 receptor.SOLUTION: The compound represented by formula (I) and a salt thereof, a solvate of the compound, and a pharmaceutical composition which contains the compound, salt or solvate as effective ingredients are disclosed. In the formula, n represents an integer of 0 to 2; Rrepresents a halogen atom, an optionally substituted hydrocarbon group, a heterocyclic group or the like; Rrepresents a hydrogen atom, an optionally substituted 1 to 4C alkyl group or a 1 to 4C alkoxyl group; Rand Reach independently represent a hydrogen atom, a 1 to 4C alkyl group or a phenyl group; Q represents an optionally substituted aryl group or a heterocyclic group; and Z represents =CR- or =N-.

Description

  The present invention relates to a compound that modulates the function of a pharmaceutical, particularly Transient Receptor Potential Vanilloid Type I receptor (hereinafter referred to as “TRPV1 receptor”), in particular, 2-indoleacrylamide analog, and the analog as an active ingredient. The present invention relates to a TRPV1 receptor antagonist or a preventive or therapeutic agent for a disease involving a TRPV1 receptor including pain.

  In a study on the mechanism of analgesia, a capsaicin (8-methyl-N-vanillyl-6-nonanamide) receptor (TRPV1 receptor), the main pungent component of chili pepper, was cloned in 1997 (Caterina MJ). , Schumacher MA, Tominaga M Rosen TA, Levine JD, Julius D .: Nature, 389: 816-824, 1997). The TRPV1 receptor is a receptor that recognizes capsaicin, and is highly expressed in afferent sensory fibers including primary sensory neurons involved in pain sensation and C-fiber nerve terminals, and many TRP families have been cloned thereafter.

The TRP family is similar in structure, has a 6-transmembrane domain, and has an N-terminal side and a C-terminal side in the cell. The TRPV1 receptor causes cations such as calcium ions and sodium ions to flow into cells in response to capsaicin stimulation, acid (pH 6.0 or lower), or heat (43 ° C. or higher). Therefore, the expression site and the action of capsaicin assumed a large contribution to the neural excitation of the TRPV1 receptor. Furthermore, the contribution of TRPV1 receptor to the living body has been clarified from many reports of information, and in particular, mice lacking TRPV1 receptor (TRPV1 knockout mice) have increased heat sensitivity due to neuropathic pain. Complete Freund's Adjuvant (CF
A) Suppression of edema in a model of induced inflammatory pain (Szabo A, Helyes Z, Sandor K, Bite A, Pinter E, Nemeth J, Banvolgyi A, Bolskii K, Elekso K, SzolcJ. And, Thermal Therapeutics, 314: 111-119, 2005), or TRPV1 receptor due to the desensitization effect of a previously reported TRPV1 receptor agonist showing an analgesic effect in neuropathic and inflammatory pain models It has been suggested that the body is involved in pain (Rashid MH, Inoue M, Kondo S, Kawashima T, Bakoshi S, Ueda H: Journal. of
Pharmacology And Experimental Therapeutics, 304: 940-948, 2003).

  The application of capsaicin causes transient severe pain, but then induces desensitization and exerts an analgesic effect. Based on this property, many TRPV1 receptor agonists including capsaicin cream are used as analgesics. Under development (Super JR, Klapper J, Mathew NT, Raport A, Phillips SB, Bernstein JE, Archives of Neurology, 59: 990-994, 2002).

Recently, it has been reported that dorsal root ganglion cells induced by administration of streptozotocin have increased depolarization induced by capsaicin, that is, increased sensitivity to the TRPV1 receptor. It has been suggested that the TRPV1 receptor is involved in diabetic pain (Hong S, Wiley JW: The Journal of
Biological Chemistry, 280: 618-627, 2005). In addition, it has been reported that the desensitizing action of capsaicin, a TRPV1 receptor agonist, is promising for improving bladder function, and it has been suggested that it contributes to urination (Masayuki Takeda, Takeo Araki, Journal of Japanese Pharmacology, Vol. 121). 325-330, 2003). Furthermore, there are reports of bronchoconstriction induced by capsaicin and the inhibitory effect of TRPV1 receptor antagonists on this action, suggesting involvement in respiratory organs, etc. TRPV1 receptor is involved in various diseases Has been revealed. From such information, the usefulness of a so-called TRPV1 receptor modulator that regulates the function of the TRPV1 receptor is expected.

Among TRPV1 modulators, agonists and antagonists that stimulate the TRPV1 receptor to induce desensitization are expected to be useful for various diseases. A TRPV1 receptor antagonist that does not induce excitement by such a stimulus has attracted attention because it induces pain. At present, compounds having TRPV1 receptor antagonistic activity are expected to have a wide range of usefulness such as analgesics, urinary incontinence drugs, and respiratory disease drugs.
“Pain includes unpleasant sensory and emotional experiences that occur based on substantial or potential injury to the tissue, as well as sensory and emotional experiences that are described using such expressions.” Yes. There are three major types of pain. Nociceptive pain, 2. 2. neuropathic pain; Classified as psychogenic pain.
Nociceptive pain is physiological pain caused by mechanical stimulation, temperature stimulation, and chemical stimulation, and is generally referred to as acute pain. Such pain serves as a biosensor based on an unpleasant sensory experience to protect yourself from danger. However, although pain such as rheumatism was certainly thought to be acute pain, it becomes chronic pain as the period from onset becomes longer and inflammation becomes chronic.
Hyperalgesia to thermal and mechanical stimuli occurs after tissue damage and during inflammation. Sensitization of pain-inducing substances and receptors to pain-inducing stimuli has been reported as an explanation of hyperalgesia to thermal and mechanical stimuli. Inflammatory mediators appearing locally in inflammation and sensitization of pain receptors by lowering pH, inflammation Increased reactivity to bradykinin and histamine due to local temperature rise, and further sensitization with nerve growth factor (NGF), etc. (reference: pain-basics, diagnosis,
Treatment-Kazuo Hanaoka [edit] Asakura Shoten 2004). Specific examples of diseases include rheumatoid arthritis and osteoarthritis of the knee. Non-steroidal anti-inflammatory analgesics (NSAIDs) have been used for a long time for inflammatory pain, including pain caused by chronic rheumatoid arthritis and knee osteoarthritis. There was limited use. Furthermore, in recent years, cyclooxygenase 2-selective inhibitors (COX2 inhibitors) developed to reduce the side effects of NSAIDs have developed into social problems because of concern about the side effects that cause heart failure. Accordingly, there is a need for a therapeutic agent for inflammatory pain that exhibits higher efficacy by oral administration and has fewer side effects.
Post-operative pain is basically inflammatory pain associated with tissue damage, and also includes elements of neurogenic pain resulting from nerve damage. Postoperative pain is broadly divided into somatic pain and visceral pain, and somatic pain is further divided into shallow pain and deep pain. Of these, leaving strong postoperative pain causes nerve sensitization and feels pain against non-noxious stimuli such as touch and pressure (allodynia). When such pain occurs, there are many intractable cases that cannot be controlled by administration of drugs such as nerve block therapy, NSAIDs, antiepileptic drugs and opioid agonists, and each drug used is, for example, NSAIDs If it is, side effects caused by gastrointestinal disorders / renal disorders; if it is an antiepileptic drug, if it is carbamazepine or phenytoin; Since drugs are associated with side effects such as constipation, there is a need for postoperative pain treatment agents that exhibit higher efficacy and fewer side effects.

Neuropathic pain is pain caused by primary damage to any part of the nerve transmission system from the periphery to the center or caused by dysfunction (illustration latest anesthesiology series 4, clinical clinic of pain 1 Akira, Kenjiro Dan, 1998, Medical View Inc.).
Nerve injury that causes neuropathic pain is typically trauma or injury to peripheral nerves, plexus or perineural soft tissue, but central somatosensory pathways (spinal cord, brainstem, It can also be caused by injury to the ascending somatosensory pathway at the thalamus or cortical level). For example, it can be caused by any of neurodegenerative disease, bone degenerative disease, metabolic disorder disease, cancer, infection, inflammation, surgical operation, trauma, radiation therapy, treatment with anticancer agent, and the like. However, its pathophysiology, or in particular the molecular mechanism of onset, has not been fully elucidated.
For example, allodynia is known as an abnormal skin reaction that characterizes neuropathic pain. Allodynia is a condition in which pain is felt by a stimulus that does not feel pain in normal humans. In allodynia, pain is caused by tactile stimulation, that is, there is a qualitative change in sensory response, and the threshold itself is considered to be a basic characteristic of allodynia. In postherpetic neuralgia, which is representative of neuropathic pain, allodynia has been confirmed in 87% of patients. The intensity of postherpetic neuralgia is said to be proportional to the degree of allodynia. Allodynia is attracting attention as a treatment target for postherpetic neuralgia as a symptom that significantly restricts patient freedom.

Herpes is a disease that develops when a herpes virus once infected is reactivated in the nerve, and 70% of herpes patients feel intense pain. Although this pain disappears with the healing of the disease, around 10% of patients suffer from so-called postherpetic neuralgia, with pain remaining for many years after healing. The onset mechanism is said to be that herpes virus re-growth occurs from the ganglia, and the nerve injury that occurs at this time promotes synaptic reorganization and causes allodynia, which is neuropathic pain. In clinical practice, older adults are more likely to develop postherpetic neuralgia, and more than 70% are 60 years or older. Anticonvulsants, non-steroidal anti-inflammatory drugs, steroids, etc. are used as therapeutic agents, but there is no complete cure (Reference: Pain-Basics / Diagnosis / Treatment-Kazuo Hanaoka [edit] Asakura Shoten 2004) .
Diabetic pain is broadly divided into acute pain that develops when hyperglycemia is corrected rapidly and chronic pain that develops due to factors such as demyelination and nerve regeneration. Among these diabetic pains, chronic pain is neuropathic pain in which dorsal root ganglion inflammation is caused by a decrease in blood flow due to diabetes, and subsequent nerve fiber regeneration causes spontaneous nerve firing and excitability. . Non-steroidal anti-inflammatory drugs, antidepressants, capsaicin cream, etc. are used as treatments, but there is no complete treatment for diabetic pain that can cure all diabetic pain with a single drug (reference: pharmaceuticals) Ayumi No. 211, No. 5, 2004, Special Feature “Pain Signal Control Mechanisms and Latest Treatment Evidence”).

  In neuropathic pain, treating patients whose chronic pain symptoms are painful and the pain itself hinders daily life is directly related to the quality of life (Quality of Life). ) Leads to improvement. However, central neuropathic drugs such as morphine, non-steroidal anti-inflammatory analgesics and steroids are considered to be ineffective for neuropathic pain. In actual drug therapy, prescription of antidepressants such as amitriptyline and In addition, anti-arrhythmic drugs such as gabapentin, pregabalin, carbamazepine, phenytoin, and mexiletine are diverted and prescribed. However, these drugs have side effects, such as dry mouth, drowsiness, sedation, constipation, difficulty in urinating, etc. for amitriptyline, carbamazepine, phenytoin, rash, gastrointestinal symptoms, cardiotoxicity, and somnolence for gabapentin. Vertigo, but mexiletine is known for vertigo and digestive symptoms. These drugs, which are not specific neuropathic pain treatment drugs, have a poor difference between drug efficacy and side effects, and treatment satisfaction is low. Accordingly, there is a need for a therapeutic agent for neuropathic pain that exhibits higher efficacy by oral administration and has fewer side effects.

In recent years, research on compounds having a TRPV1 receptor antagonistic action has been advanced. Examples of the heterocyclic compound having an amide bond include, for example, International Publication No. 03/049702 pamphlet (Patent Document 1), International Publication No. 04/056774 pamphlet (Patent Document 2), International Publication No. 04/069792 pamphlet (Patent Document). 3) Pamphlet of International Publication No. 04/100985 (Patent Document 4), Pamphlet of International Publication No. 04/110986 (Patent Document 5), Pamphlet of International Publication No. 05/016922 (Patent Document 6), International Publication No. 05 / 030766 pamphlet (patent document 7), WO05 / 040121 pamphlet (patent document 8), WO05 / 046683 pamphlet (patent document 9), WO05 / 070885 pamphlet (patent document 10). , International Publication No. 05/095329 Pamphlet (Patent Document 11), International Publication No. 06/006741 Pamphlet (Patent Document 12), International Publication No. 06/038871 Pamphlet (Patent Document 13), International Publication No. 06/058338 (Patent Document 14), International Publication No. 07/074916 (Patent Document 15) is known. However, these patent documents do not disclose 2-indoleacrylamide analogs as in the present invention.
Further, as a TRPV1 receptor agonist, WO 04/007495 pamphlet (Patent Document 16) is known, and the compound disclosed in this Patent Document is a pyrrolopyridine having an electron-withdrawing group at the 3-position. Is different from the compound of the present invention in that it has a main skeleton.

As a prior art disclosing a compound having 2-propenamide,
International Publication No. 00/006153 (Patent Document 17), Japanese Patent Application Laid-Open No. 2-160751 (Patent Document 18), International Publication No. 04/072025 (Patent Document 19), Journal of Medicinal Chemistry (Journal). of Medicinal Chemistry), Vol. 33, No. 10, pages 2856-64, 1990 (Non-patent Document 1).

Patent Document 17 discloses a compound example having a specific 3- (2- (bis (1-methylethyl) amino) ethoxy) -4-methoxyphenyl group on the nitrogen atom of various 2-propenamides as a CCR5 modulator. Has been.
Patent Document 18 discloses a compound example having a specific 4-hydroxy-3,5-dimethylphenyl group on the nitrogen atom of 2-propenamide as a lipoxygenase inhibitor.
Patent Document 19 discloses a compound example having a specific 4- (3-acetylmethylamino) -1-pyrrolidinyl) phenyl group at the nitrogen atom of 2-propenamide as an MCH (melanin-concentrating hormone) antagonist. Yes.

Non-Patent Document 1 discloses various 2-propenamide derivatives as PAF antagonists. Many of them have a naphthalene ring at the 3-position, but those having an indole are disclosed as examples of similar compounds.
However, the compounds having 2-propenamide disclosed in Patent Documents 17 to 19 and Non-Patent Document 1 are 2-indoleacrylamide analogs as in the present invention, for example, an amide nitrogen atom as defined in the present application. There is no disclosure of a compound to which an aryl group which may be substituted, a heterocyclic group which may be substituted, or the like is bonded, and there is no disclosure or suggestion about the antagonistic action of TRPV1 receptor.
As a paper reported to increase body temperature by administration of a TPRV1 receptor antagonist (Journal of Medicinal Chemistry, Vol. 48, No. 6, pages 1857-72, 2005 (Non-patent Document 2), Journal of Neuroscience, Vol. 27, No. 13, pages 3366-74, 2007 (Non-patent Document 3)) There is no disclosure. Recently, an example of a TRPV1 modulator that does not cause an increase in body temperature in rats has been reported (Journal of Pharmaceutical and Experimental Serapectics (Journ).
nal of Pharmacology and Experimental Therapeutics), Vol. 326, No. 1, pages 218-29, 2008 (Non-patent Document 4). However, there is no suggestion for 2-indoleacrylamide analogs like the present invention.

In drug development, it is required to satisfy strict criteria not only in the intended pharmacological activity but also in various aspects such as absorption, distribution, metabolism, and excretion. For example, drug interaction, desensitization or tolerance, digestive tract absorption after oral administration, transfer rate into the small intestine, absorption rate and first-pass effect, organ barrier, protein binding, induction of drug metabolizing enzymes, excretion route and clearance in the body Various studies are required in the application method (application site, method, purpose) and the like, and it is difficult to find one that satisfies these.
As for TRPV1 receptor antagonists, there are always comprehensive problems in the development of these drugs, and they have not yet been put on the market. More specifically, for compounds having a TRPV1 receptor antagonistic activity, for example, hERG (human ether-a-go-go related) has low metabolic stability and is difficult to be administered orally, and has a risk of causing arrhythmia. gene) There are problems of usefulness and safety, such as exhibiting channel inhibitory activity or poor pharmacokinetics such as absorption and sustainability. There are also issues that will be identified at the clinical trial stage. For example, although there is little change in body temperature associated with the administration of a TRPV1 receptor antagonist, as a conventional technique that suggests the possibility of a compound that solves this problem, there is a slight non-patent document 4 regarding a specific compound. There are considerations, but there is no general suggestion about chemical structure. There is a need for compounds that solve these problems as much as possible and that are highly active.
In addition, there is a need for compounds that have fewer side effects than the conventional drugs currently used for the treatment of pain, including neuropathic pain as described above.

International Publication No. 03/049702 Pamphlet International Publication No. 04/056774 pamphlet International Publication No. 04/069792 Pamphlet International Publication No. 04/100865 Pamphlet International Publication No. 04/110986 Pamphlet International Publication No. 05/016922 Pamphlet International Publication No. 05/030766 Pamphlet International Publication No. 05/040121 Pamphlet International Publication No. 05/046683 Pamphlet International Publication No. 05/070885 Pamphlet International Publication No. 05/095329 Pamphlet WO 06/006741 pamphlet International Publication No. 06/038871 Pamphlet International Publication No. 06/058338 Pamphlet International Publication No. 07/074916 Pamphlet WO04 / 007495 pamphlet International Publication No. 00/006153 Pamphlet JP-A-2-160751 International Publication No. 04/072025 Pamphlet Journal of Medicinal Chemistry, Vol. 33, No. 10, pages 2856-64, 1990 Journal of Medicinal Chemistry, Vol. 48, No. 6, 1857-72, 2005 Journal of Neuroscience, Vol. 27, No. 13, pages 3366-74, 2007 Journal of Pharmaceutical and Experimental Therapeutics, Vol. 326, No. 1, pp. 218-29, 2008, Journal of Pharmaceutical and Experimental Therapeutics, Journal of Pharmaceutical Therapies and Experimental Therapeutics

  Under such circumstances, TRPV1 receptor modulators that can be administered orally, have high safety and are highly effective, especially TRPV1 receptor antagonists, or preventive or therapeutic agents for diseases involving TRPV1 receptors ( In particular, there is a demand for a preventive or therapeutic agent for pain. In particular, the problems in the prior art as described above, more specifically, amitriptyline side effects such as dry mouth, drowsiness, sedation, constipation, difficulty in urination, etc .; carbamazepine, phenytoin side effects rash, digestive symptoms, Cardiotoxicity, etc .; side effects of gabapentin such as somnolence and dizziness; such as vertigo and gastrointestinal symptoms that are side effects of mexiletine; Problems such as side effects such as reduction of hERG current inhibitory effect; improvement of metabolic stability and absorbability, oral administration possibility, improvement of pharmacokinetics and solubility, and problems to be addressed There is. In addition, it overcomes at least one of these problems and can be administered orally to mammals including humans, especially clinically usable preventive or therapeutic agents for diseases involving TRPV1 receptor (especially pain Preventive or therapeutic agent) is desired.

  The present invention relates to a compound having an action of modulating the function of TRPV1 receptor, in particular, 2-indoleacrylamide analog represented by formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof. A TRPV1 receptor modulator comprising the analog as an active ingredient, especially a TRPV1 receptor antagonist, or a prophylactic or therapeutic agent for pain, particularly a prophylactic or therapeutic agent for neuropathic pain, or a prophylactic or therapeutic agent for fibromyalgia It consists of a therapeutic agent or a prophylactic or therapeutic agent for inflammatory pain.

In order to solve the above-mentioned problems, the present inventors have conducted extensive research to obtain a compound having a function of regulating the function of TRPV1 receptor, which is highly safe and excellent in effectiveness. The 2-indoleacrylamide analogs represented by the formula (1) or a pharmaceutically acceptable salt thereof, or a solvate thereof, has the effect of modulating the function of an excellent TRPV1 receptor, and the present invention Was completed. A pharmaceutical composition containing the compound as an active ingredient is expected to be a prophylactic or therapeutic agent for orally administrable pain, particularly as a prophylactic or therapeutic agent for neuropathic pain, fibromyalgia, or a prophylactic or therapeutic agent for inflammatory pain. Is done.
In addition, this compound group has at least metabolic stability, excellent oral absorbability, good solubility, or no increase in body temperature (especially little change in body temperature). It is highly useful because it also has one or more features.

The present invention relates to 2-indoleacrylamide analogues represented by the formula (I) shown in the following embodiments or salts thereof or solvates thereof, pharmaceutical compositions containing them as active ingredients, and the analogues or their analogues It is a medicinal use of salt.
Although the molecular weight of the compound represented by the formula (I) of the present invention is not particularly limited, the molecular weight is preferably 700 or less. More preferably, the molecular weight is 550 or less. Such molecular weight limitation is routinely used as another major limiting factor in addition to the basic skeleton with pharmacological characteristics when specifying the structure of a compound in recent drug designs.

（式中、ｎは、０〜２の整数を表し；
Ｒ¹ は、ハロゲン原子、置換されていてもよい炭化水素基、置換されていてもよいヘ
テロ環基、置換されていてもよいＣ₁〜₆アルコキシル基、置換されていてもよいＣ₁〜₆アルコキシカルボニル基、置換されていてもよいＣ₁〜₆アルキル基でモノ−もしくはジ−置換されていてもよいアミノ基、保護されていてもよい水酸基、保護されていてもよいカルボキシル基、置換されていてもよいＣ₁〜₆アルキル基でモノ−もしくはジ−置換されていてもよいカルバモイル基、Ｃ₁〜₆アルカノイル基、Ｃ₁〜₆アルキルチオ基、Ｃ₁〜₆アルキルスルフィニル基、Ｃ₁〜₆アルキルスルホニル基、置換されていてもよいＣ₁〜₆アルキル基でモノ−もしくはジ−置換されていてもよいスルファモイル基、シアノ基またはニトロ基から任意に選ばれる基を表し；
Ｒ²は、水素原子、Ｃ_１〜_４の直鎖もしくは分枝鎖のアルキル基またはＣ_１〜_４の直鎖
もしくは分枝鎖のアルコキシル基を表し、当該アルキル基またはアルコキシ基は、ハロゲン原子１〜５個で置換されていてもよいか、またはヒドロキシル基、ハロゲン原子１〜５個で置換されていてもよいＣ_１〜_２のアルキル基もしくはＣ_１〜_２のアルコキシル基、及びＣ_１〜_３のアルキル基もしくはヒドロキシアルキル基１〜２個で置換されていてもよいアミノ基から任意に選ばれる基１〜３個で置換されていてもよく；
Ｒ^３は、基：−Ａ_１−Ａ_２を表し、Ａ_１は単結合、メチレン基、Ｃ_２〜_６のアルキレン基、カルボニル基またはスルホニル基を表し、Ａ_２は、水素原子、Ｃ_１〜_６の直鎖もしくは分枝鎖のアルキル基、Ｃ_３〜_６のシクロアルキル基、アリール基またはヘテロ環基を表し、当該Ａ_２の炭素原子は、ハロゲン原子１〜５個で置換されていてもよいか、またはヒドロキシル基、ハロゲン原子１〜５個で置換されていてもよいＣ_１〜_２のアルキル基もしくはＣ_１〜_２のアルコキシル基、及びＣ_１〜_３のアルキル基もしくはヒドロキシアルキル基１〜２個で置換されていてもよいアミノ基から任意に選ばれる基１〜３個で置換されていてもよく；
Ｒ^４及びＲ^５は、各々独立に、水素原子、Ｃ_１〜_４の直鎖もしくは分枝鎖のアルキル基またはフェニル基を表し；
Ｑは、置換されていてもよいアリール基または置換されていてもよいヘテロ環基を表し；
Ｚは、＝ＣＲ^６−（Ｒ^６は水素原子または前記Ｒ^１と同じ意味を表す）または＝Ｎ−を表す。但し、Ｑが、４−（３−アセチルメチルアミノ）−１−ピロリジニル）フェニル基、３−（２−（ビス（１−メチルエチル）アミノ）エトキシ）−４−メトキシフェニル基、または
４−ヒドロキシ−３，５−ジメチルフェニル基である場合を除く。）で表される化合物、またはその塩またはそれらの溶媒和物である。 [Aspect of the Invention]
[1] Aspect 1 of the present invention
The first aspect of the present invention is:
Formula (I)

(In the formula, n represents an integer of 0 to 2;
R ¹ is a halogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, optionally substituted C ₁ ~ ₆ alkoxy group, an optionally substituted C ₁ ~ ₆ alkoxycarbonyl group, mono optionally substituted C ₁ ~ ₆ alkyl group - or di - optionally substituted amino group, a protected hydroxyl group which may have, optionally protected carboxyl group, substituted mono also good C ₁ ~ ₆ alkyl group optionally - or di - optionally substituted carbamoyl group, C ₁ ~ ₆ alkanoyl group, C ₁ ~ ₆ alkylthio group, C ₁ ~ ₆ alkylsulfinyl group, C ₁ ~ selected sulfamoyl group which may be substituted, cyano group or a nitro group optionally - ₆ alkylsulfonyl group, mono optionally substituted C ₁ to ₆ alkyl groups - or di It represents a group;
R ² represents a hydrogen atom, C ₁ ~ ₄ straight or branched chain alkyl group or a linear or branched alkoxyl group of C ₁ ~ ₄ of the alkyl or alkoxy group, a halogen atom 1 to five in either may be substituted, or a hydroxyl group, an alkyl group or _C 1 _{- 2} alkoxyl group halogen atom _{1-5-optionally C} 1 optionally substituted with one _2, and _C 1 _{- 3} Optionally substituted with 1 to 3 groups arbitrarily selected from amino groups optionally substituted with 1 to 2 alkyl groups or hydroxyalkyl groups of
R ³ is a group: represents _{-A 1 -A 2, A} 1 represents a single bond, a methylene _group, an alkylene group of C 2 _{~ 6,} a carbonyl group or a sulfonyl group, _{A 2} represents a hydrogen _{atom, C} 1 ~ straight or branched chain alkyl group having _6, cycloalkyl group C ₃ ~ _6, an aryl group or a heterocyclic group, a carbon atom of the a ₂ is optionally substituted with one to five halogen atoms or better, or hydroxyl group, alkyl group or _C 1 _{- 2} alkoxyl group halogen atom _{1-5-optionally C} 1 optionally substituted by _2, and _C 1 _{- 3} alkyl or hydroxyalkyl group 1 May be substituted with 1 to 3 groups arbitrarily selected from amino groups optionally substituted with 2;
R ⁴ and R ⁵ each independently represent a hydrogen atom, a linear or branched alkyl group or a phenyl group of C ₁ ~ _4;
Q represents an aryl group which may be substituted or a heterocyclic group which may be substituted;
Z ^{is, =} CR ⁶ - ^(R 6 has the same meaning as a hydrogen atom or the ^{R 1)} or = represents a N-. However, Q is 4- (3-acetylmethylamino) -1-pyrrolidinyl) phenyl group, 3- (2- (bis (1-methylethyl) amino) ethoxy) -4-methoxyphenyl group, or 4-hydroxy Except for the case of -3,5-dimethylphenyl group. Or a salt thereof or a solvate thereof.

Below, each group in the compound of the said formula (I) of the said aspect [1] is demonstrated concretely.
In description of the compounds of the present invention, for example, "C ₁ ~ _6" indicates that the number of constituent carbon atoms is 1 to 6, unless otherwise indicated, represents a linear, branched or cyclic groups. The chain group means “straight chain or branched chain having 1 to 6 carbon atoms”. For a cyclic group, it means the “number of carbon atoms constituting the ring”.
Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” include an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an aryl group.
Examples of the “aliphatic hydrocarbon group” include a linear or branched hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group.
As the "alkyl group", for example, straight-chain or branched alkyl group of C ₁ ~ ₆ (more preferably C ₁ ~ _4), for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl , Tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1 , 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1 , 1,2-Trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1 Methylpropyl, 1-ethyl-2-methylpropyl, and the like. That is, in the present invention, the expression C _{A -B} alkyl group is A, B (each an integer of 6 or less).
It is understood that the carbon number may be appropriately selected from these examples. C _A
The meaning of the expression _-B represents the same meaning also in the case other than an alkyl group.

Examples of "alkenyl" includes straight or branched chain alkenyl group of C ₂ ~ _6, such as vinyl, allyl, isopropenyl, 2-methylallyl, butenyl, pentenyl, hexenyl and the like.
Examples of "alkynyl" includes straight or branched chain alkynyl group of C ₂ ~ _6, such as ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl and the like.
Examples of the “alicyclic hydrocarbon group” include a saturated or unsaturated alicyclic hydrocarbon group, and examples thereof include a cycloalkyl group, a cycloalkenyl group, and a cycloalkanedienyl group.
Examples of "cycloalkyl group", cycloalkyl groups of C ₃ ~ _6, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Examples of the "cycloalkenyl group", a cycloalkenyl group of C ₃ ~ _6, for example, 1-cyclopropene-1-yl, 1-cyclobutene-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten - 1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl and the like can be mentioned.
Examples of "cycloalkanedienyl group", cycloalkanedienyl group of C ₄ ~ _6, for example, 2,4-cyclopentadiene-1-yl, 2,5-cyclohexadiene-1-yl and the like .

Examples of "aryl group", C ₆ ~ ₁₄ aryl group, e.g., phenyl, naphthyl, biphenylyl, 2-anthryl, phenanthryl, acenaphthyl, 5,6,7,8 tetrahydronaphthalenyl, etc., or indanyl, tetrahydro Examples include partially hydrogenated fused aryl such as naphthyl. Here, the partially hydrogenated aryl group means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated ring, and is a hydrogen atom of an aromatic moiety or a hydrogenated moiety. Either of the hydrogen atoms may be removed. For example, in the case of a tetrahydronaphthyl group, a 5,6,7,8-tetrahydronaphthalene (-1-yl, -2-yl, -3-yl, -4-yl) group or 1,2,3,4- Tetrahydronaphthalene (-1-yl, -2-yl, -3-yl, -4-yl) groups and the like are included. More specifically, for example, 7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl group, 7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl, 7-hydroxy- Examples include 1,2,3,4-tetrahydronaphthalen-1-yl group and aryl groups described in b7 to b14 described later. In the case of an indanyl group, an indan-1-yl group, an indan-2-yl group, an indan-3-yl group, an indan-4-yl group, an indan-5-yl group, an indan-6-yl group, Indan-7-yl groups and the like are included, and more specifically, for example, aryl groups described in b1 to b6 described later, and the like.

Examples of the “heterocyclic group” include a heteroaryl group and a saturated or unsaturated non-aromatic heterocyclic group. These rings are 5 to 14-membered rings, preferably 5 to 12-membered monocycles containing at least one heteroatom (preferably 1 to 4) selected from N, O and S in addition to carbon atoms, or Examples thereof include a ring having a condensed ring.
The “heteroaryl group” includes a monocyclic or condensed ring, and the monocyclic heteroaryl group preferably has 5 to 6 ring members, for example, pyrrolyl, furyl, thienyl, imidazolyl. , Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl , Furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4 -Triazinyl, 1,2,5-triazinyl, 1,3,5-triazinyl, thiadia Alkylsulfonyl and the like.
In addition, the condensed heteroaryl group preferably has 8 to 12 ring members, and this includes one to plural (preferably 1 to 2) aryl rings having the above 5 to 6 membered heterocycles. Examples thereof include monovalent groups formed by removing any hydrogen atom from a ring formed by condensation with (for example, a benzene ring).

  Specifically, indolyl, isoindolyl, 1H-indazolyl, benzofuranyl (-2-yl), isobenzofuranyl, benzothienyl (-2-yl), isobenzothienyl, benzindazolyl, benzoxazolyl (- 2-yl), 1,2-benzisoxazolyl, benzothiazolyl (-2-yl), 1,2-benzisothiazolyl, 2H-benzopyranyl (-3-yl), (1H-) benzimidazolyl (- 2-yl), 1H-benzotriazolyl, 4H-1,4-benzooxazinyl, 4H-1,4-benzothiazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, plinyl, pteridinyl, Carbazolyl, carbolinyl, acridinyl, phenoxazinyl, phen Thiazinyl, phenazinyl, fanoxatinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, (4,5,6,7-) tetrahydrothiazolo [5,4-c] pyridyl (-2-yl), (4 , 5,6,7-) tetrahydrothieno [3,2-c] pyridyl, (1,2,3,4-) tetrahydroisoquinolyl (-6-yl), thiazolo [5,4-c] pyridyl ( -2-yl), pyrrolo [1,2-b] pyridazinyl, pyrazo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1, 2-b] pyridazinyl, imidazo [1,5-a] pyrimidinyl, [1,2,4] triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl, chloro Nyl (2H-chromenyl), 1H-pyrazolo [3,4-b] pyridyl, [1,2,4] triazolo [1,5-a] pyrimidinyl and the like (the description in parentheses shows a preferred embodiment) )

Tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzoxazepinyl, tetrahydrobenzoazepinyl, tetrahydronaphthopyridinyl, tetrahydroquinoxalinyl, chromanyl, dihydrobenzoxazinyl, 3,4-dihydro -2H-1,4-benzothiazinyl, dihydrobenzothiazolyl, 3,4-dihydro-2H-1,4-benzoxazinyl, isochromanyl, indolinyl, pteridinyl, 2,3-dihydrobenzo [b] [1,4] Dioxynyl, 1,2,3,4-tetrahydro-1-methylquinolinyl, 1,3-dihydro-1-oxoisobenzofuranyl, 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridyl, etc. And a partially hydrogenated condensed heterocyclic aryl group. Here, the partially hydrogenated condensed heteroaryl group and the like are preferably those having the above-mentioned group ring number of 8 to 12, and 1 to plural (preferably 1 to 5 to 6-membered aromatic rings). A monovalent group formed by removing any hydrogen atom from a partially hydrogenated ring formed by condensation with ~ 2) aromatic rings (for example, benzene ring, etc.) Either hydrogen atoms or hydrogenated hydrogen atoms may be removed. For example, a tetrahydroquinolinyl group includes a 5,6,7,8-tetrahydroquinolyl group or a 1,2,3,4-tetrahydroquinolyl group. For these groups, depending on the position excluding any hydrogen atom, for example, a 5,6,7,8-tetrahydroquinolyl group, a 5,6,7,8-tetrahydroquinolin-7-yl group or 5 , 6,7,8-tetrahydroquinolin-3-yl group and the like, and a 1,2,3,4-tetrahydroquinolyl group includes, for example, 1,2,3,4-tetrahydroquinoline-7- Ilyl group or 1,2,3,4-tetrahydroquinolin-3-yl group is exemplified.

Examples of “non-aromatic heterocyclic groups” include 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic groups such as azetidinyl, oxiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl. , Pyrazolinyl, pyrazolidinyl, piperidyl, tetrahydropyranyl, piperazinyl, morpholinyl, oxazolinyl, thiazolinyl, thiomorpholinyl, quinuclidinyl, oxepanyl and the like.
Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The "C ₁ ~ ₆ alkoxy group", straight chain of 1 to 6 carbon atoms, represents a branched or cyclic alkoxyl group, generally to RO- (R is each C ₁ ~ listed in above ₆ alkyl group). For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 3-pentyloxy, tert-pentyloxy, neopentyloxy, 2-methylbutoxy, 1 , 2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, 1-cyclopropylethyloxy, 2-cyclopropylethyloxy, cyclobutylmethyl Examples include oxy, 2-cyclobutylethyloxy, cyclopentylmethyloxy and the like.

Examples of "C ₁ ~ ₆ alkoxycarbonyl group" includes a straight chain, branched chain or cyclic alkoxyl group, for example, main butoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl Group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, cyclopropyl Oxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, cyclopropylmethyloxycarbonyl group, 1-cyclopropylethylo Aryloxycarbonyl group, 2-cyclopropylethyl oxycarbonyl group, cyclobutylmethyl butyloxycarbonyl group, 2-cyclobutylethyl butyloxycarbonyl group, cyclopentylmethyl oxycarbonyl group and the like.

The "mono C ₁ ~ ₆ alkyl group - - or di which may be substituted amino group", one or two hydrogen atoms are "linear or branched C ₁ ~ ₆ alkyl group of the amino group An amino group which may be substituted with “ Specifically, amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, isohexylamino group, Dimethylamino group, diethylamino group, dipropylamino group, di-isopropylamino group, dibutylamino group, dipentylamino group, ethylmethylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group, butylethylamino Group, butylpropylamino group and the like.

Examples of the protecting group of the “optionally protected hydroxyl group” include alkyl protecting groups such as methyl group, tert-butyl group, benzyl group, trityl group, methoxymethyl group, trimethylsilyl group, tert-butyldimethylsilyl group, etc. Examples include silyl protecting groups, acyl protecting groups such as formyl group, acetyl group and benzoyl group, and carbonate protecting groups such as methoxycarbonyl group and benzyloxycarbonyl group.
Examples of the protecting group for the “optionally protected carboxyl group” include alkyl ester protecting groups such as methyl group, ethyl group, tert-butyl group, benzyl group, diphenylmethyl group, and trityl group, trimethylsilyl group, and tert-butyl group. Examples include silyl ester protecting groups such as dimethylsilyl group.

The "mono C ₁ ~ ₆ alkyl group - - or di also a carbamoyl group optionally substituted", C ₁ of one or two hydrogen atoms on the nitrogen atom of the carbamoyl group is "a straight or branched chain
Means a carbamoyl group optionally substituted by ~ ₆ alkyl groups. Specifically, for example, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, pentylcarbamoyl group, isopentylcarbamoyl group, hexylcarbamoyl group , Isohexylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, di-isopropylcarbamoyl group, dibutylcarbamoyl group, dipentylcarbamoyl group, ethylmethylcarbamoyl group, methylpropylcarbamoyl group, ethylpropylcarbamoyl group, butylmethyl Examples thereof include a carbamoyl group, a butylethylcarbamoyl group, and a butylpropylcarbamoyl group.
Examples of "C ₁ ~ ₆ alkanoyl group", for example a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, etc. hexanoyl group.

Examples of "C ₁ ~ ₆ alkylthio group", straight chain, have a branched chain or cyclic alkyl group, such as methylthio, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec -Butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, tert-pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group, 1-ethylpropylthio group, Hexylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cyclopropylmethylthio group, 1-cyclopropylethylthio group, 2-cyclopropylethylthio group, cyclobutylmethylthio group, 2-cyclo Butylethylthio group, cyclopentylmethyl Oh group, and the like.
Examples of "C ₁ ~ ₆ alkylsulfinyl group" includes a straight chain, branched chain or cyclic alkyl group, for example, methylsulfinyl group, ethylsulfinyl group, propyl sulfinyl group, isopropyl sulfinyl group, butyl sulfinyl group, Isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, pentylsulfinyl group, isopentylsulfinyl group, tert-pentylsulfinyl group, neopentylsulfinyl group, 2-methylbutylsulfinyl group, 1,2-dimethylpropylsulfinyl group Group, 1-ethylpropylsulfinyl group, hexylsulfinyl group, cyclopropylsulfinyl group, cyclobutylsulfinyl group, cyclopentylsulfinyl group, cyclohexylsulfinyl group, Black propyl methylsulfinyl group, 1-cyclopropylethyl sulfinyl group, 2-cyclopropylethyl sulfinyl group, cyclobutylmethyl sulfinyl group, 2-cyclobutyl-ethyl sulfinyl group, cyclopentylmethyl sulfinyl group and the like.

Examples of "C ₁ ~ ₆ alkylsulfonyl group" refers to a straight-chain, have a branched chain or cyclic alkyl group, for example methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, Isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, tert-pentylsulfonyl group, neopentylsulfonyl group, 2-methylbutylsulfonyl group, 1,2-dimethylpropylsulfonyl Group, 1-ethylpropylsulfonyl group, hexylsulfonyl group, cyclopropylsulfonyl group, cyclobutylsulfonyl group, cyclopentylsulfonyl group, cyclohexylsulfonyl group, cyclopropylmethylsulfonyl group, 1-cyclyl Propyl ethylsulfonyl group, 2-cyclopropylethyl sulfonyl group, cyclobutylmethyl methylsulfonyl group, 2-cyclobutyl-ethyl sulfonyl group, cyclopentylmethyl sulfonyl group and the like.

The "mono C ₁ ~ ₆ alkyl group - - or di also sulfamoyl group optionally substituted", C ₁ of one or two hydrogen atoms on the nitrogen atom of the sulfamoyl group "linear or branched Means a sulfamoyl group optionally substituted by ~ ₆ alkyl groups. Specifically, for example, sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, cyclopropylsulfamoyl group, butylsulfamoyl group, isobutylsulfamoyl Group, pentylsulfamoyl group, isopentylsulfamoyl group, hexylsulfamoyl group, isohexylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, dipropylsulfamoyl group, di-isopropylsulfate Famoyl group, dibutylsulfamoyl group, dipentylsulfamoyl group, ethylmethylsulfamoyl group, methylpropylsulfamoyl group, ethylpropylsulfamoyl group, butylmethylsulfamoyl group, butylethylsulfamoyl group , Butyl Pils sulfamoyl group and the like.

In the definition of R ^1, "optionally substituted hydrocarbon group", "optionally substituted heterocyclic group", "optionally substituted C ₁ ~ ₆ alkoxy group" have been "substituted mono also good C ₁ ~ ₆ alkoxycarbonyl group ", the" optionally substituted C ₁ ~ ₆ alkyl group - or di - optionally substituted amino group "," optionally substituted C ₁ ~ mono ₆ alkyl - or di - substituted carbamoyl group ", or" mono substituted C ₁ ~ ₆ alkyl group - or di - of which may be substituted sulfamoyl group "," Examples of the “substituent” include the following substituents, which may be optionally substituted with 1 to 5 substituents. For example, C ₁ ~ ₆ alkyl, C ₂ ~ ₆ alkenyl, C ₂ ~ ₆ alkynyl, halogen atom, halogenated C ₁ ~ ₆ alkyl, cyano, amino, hydroxy, carbamoyl, C ₁ ~ ₆ alkoxy, C ₂ ~ ₆ alkenyl oxy, C ₂ ~ ₆ alkynyloxy, C ₁ ~ ₆ alkylthio, C _1
1-6 alkylsulfinyl, C ₁ - ₆ alkylsulfonyl, mono / di C ₁ - ₆ alkylamino, C ₁ - ₆ alkoxycarbonyl, C ₂ - ₆ alkanoyl, C ₂ - ₆ alkanoylamino, hydroxy -C ₁ - ₆ alkyl, C ₁ ~ ₆ alkoxy -C ₁ ~ ₆ alkyl, carboxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxycarbonyl -C ₁ ~ ₆ alkyl, carbamoyl -C ₁ ~ ₆ alkyl, N-C ₁ ~ ₆ alkylcarbamoyl -C ₁ ~ ₆ alkyl, N, N-di-C ₁ ~ ₆ alkylcarbamoyl -C ₁ ~ ₆ alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, oxo, morpholinylcarbonyl, Morpholinylsulfonyl, 5-trifluoromethylpyridine-2-yloxy, quinoxa N-2-yl, (pyridin-4-yl) methyl, 1,2,3-thiadiazolo-4-yl, 1H-pyrazolo-1-yl, 4-chlorophenyl, tetrahydrofuranyl, oxiranyl, and the like. but aromatic ring further halogen atom in the substituent, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxyl, carbamoyl, C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkylamino , a group selected di -C ₁ ~ ₆ alkylcarbamoyl, C ₁ ~ ₆ alkoxycarbonyl, N-C ₁ ~ ₆ alkylcarbamoyl, N, from N- di C ₁ ~ ₆ alkylcarbamoyl and C ₂ ~ ₆ alkenoyl amino 1 May be substituted with ~ 5.

For example, when the substituent is C ₁ ~ ₆ alkyl group for hydroxyl group, a group represented as "C ₁ ~ ₆ hydroxyalkyl group" means an alkyl straight or branched chain having 1 to carbon atoms mentioned above 6 The group is a group in which one hydroxyl group is substituted, but there are many positional isomers at the substitution position. Specifically, in addition to the hydroxymethyl group, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxy-1-propyl, 2-hydroxy-1-propyl, 1-hydroxy-1-propyl, 1- Hydroxy-1-methyl-1-ethyl, 2-hydroxy-1-methyl-1-ethyl, 4-hydroxy-1-butyl, 3-hydroxy-1-butyl, 2-hydroxy-1-butyl, 1-hydroxy- 1-butyl, 3-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethyl-1-ethyl, 1-hydroxy-2-methylpropyl, 5-hydroxy-1 -Pentyl, 4-hydroxy-1-pentyl, 3-hydroxy-1-pentyl, 2-hydroxy-1-pentyl, 1-hydro Ci-1-pentyl, 4-hydroxy-3-methylbutyl, 4-hydroxy-2-methylbutyl, 4-hydroxy-1-methylbutyl, 3-hydroxy-3-methylbutyl, 3-hydroxy-2-methylbutyl, 3-hydroxy- 1-methylbutyl, 2-hydroxy-3-methylbutyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-1-methylbutyl, 3-hydroxy-2,2-dimethylpropyl, 3-hydroxy-1,1-dimethylpropyl, Examples include 6-hydroxy-1-hexyl, 4-hydroxy-1,1-dimethyl-1-butyl, 4-hydroxy-2,2-dimethyl-1-butyl and the like.

For example, when the substituent is _C 1 _{~ 6} alkyl group alkoxyl group _C 1 _{~ 2,} a group represented as _"C 1 _{~ 6} alkyl group substituted with an alkoxyl group of _C 1 _{~ 2"} are described above in each of the straight-chain or branched hydroxyalkyl group of C ₁ ~ _6, hydroxyl groups, corresponding those substituted in methoxyl group or ethoxyl group. For example, 2-methoxyethyl, 3-methoxy-1-propyl, 2-methoxy-1-propyl, 4-methoxy-1-butyl, 3-methoxy-2,2-dimethylpropyl, 3-methoxy-1,1- And dimethylpropyl.
The "C alkylene group having ₂ to _6" represents a straight or branched chain "C _2-6" divalent groups formed by hydrogen 2 atoms are lost from different carbon atoms of aliphatic hydrocarbons, For example, specific examples include ethylene, trimethylene, n-butylene, n-pentylene, n-hexylene, propylene (1-methyl-ethylene), 2-methyl-ethylene, 1 -Ethyl-ethylene, 2-ethyl-ethylene, 3-methyl-n-propylene, 2-methyl-n-propylene, 1-methyl-n-propylene, 3-ethyl-n-propylene, 2-ethyl-n-propylene 1-ethyl-n-propylene, 4-methyl-n-butylene, 3-methyl-n-butylene, 2-methyl-n-butylene, 1-ethyl-n-butylene, 4-ethyl-n-butylene, 3 -Echi Ru-n-butylene, 2-ethyl-n-butylene, 1-ethyl-n-butylene, 5-methyl-n-pentylene, 4-methyl-n-pentylene, 3-methyl-n-pentylene, 2-methyl- n-pentylene, 1-methyl-n-pentylene,
Etc.

In the definition of R ² , “the alkyl group may be substituted with 1 to 5 halogen atoms, or may be a hydroxyl group or C ₁ to C ₂ alkyl optionally substituted with 1 to 5 halogen atoms. Substituted with ₁ to ₃ groups arbitrarily selected from a group or an amino group optionally substituted with ₁ to ₂ alkoxy groups of C1 to ₂ and C1 to ₃ alkyl groups or hydroxyalkyl groups. also has a good ", a linear or C ₁ ~ alkoxyl group of the alkyl group or C ₁ ~ ₄ of ₄ branched,
i) either may be substituted with 1-5 halogen atoms, or ii) a hydroxyl group, iii) alkyl or _C 1 _{~ 2} halogen atoms which may be substituted with 1-5 _C 1 _{~ 2} alkoxyl group, and, iv) linear or branched C ₁ ~ ₃ alkyl or hydroxyalkyl group one to two optionally substituted by an amino group; 1-3 groups selected from optionally It may be substituted with.
_The alkyl group of C 1 _{~ 2,} methyl, _ethyl, and examples of the alkyl group of C 1 _{~ 3,} in addition to the above, propyl, _isopropyl, and examples of the alkyl group of C 1 _{~ 4} In addition to the above, butyl, isobutyl, sec-butyl, tert-butyl can be mentioned.
_As the alkoxyl group of C 1 _{~ 2,} methoxy, _ethoxy, and examples of the alkoxyl group of C 1 _{~ 4,} in addition to the above, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy Can be mentioned.
In the definition of R ³ , “group: —A ₁ -A ₂ ” is a group represented by a combination of A ₁ and A ₂ .

For example, if _{A 1} is a single bond, "group: _-A 1 -A _2" is the same meaning as _{A 2,} a hydrogen _atom, a linear or branched alkyl group of C 1 _{~ 6,} cycloalkyl group C ₃ ~ _6, an aryl group or a heterocyclic group, the carbon atoms of a ₂ is either optionally substituted with 1-5 halogen atoms, or a hydroxyl group, a halogen atom 1-5 pieces with optionally substituted C ₁ to ₂ alkyl or C ₁ - ₂ alkoxyl group, and C ₁ - ₃ alkyl or hydroxyalkyl group 1-2 amino group which may be substituted by It represents that it may be substituted with 1 to 3 groups selected arbitrarily.
Here, “the carbon atom of A ₂ may be substituted with 1 to 5 halogen atoms, or may be a hydroxyl group, C ₁ to C ₂ alkyl which may be substituted with 1 to 5 halogen atoms. Substituted with ₁ to ₃ groups arbitrarily selected from a group or an amino group optionally substituted with ₁ to ₂ alkoxy groups of C1 to ₂ and C1 to ₃ alkyl groups or hydroxyalkyl groups. “Well” means that the carbon atom of A ₂ is
i) either may be substituted with 1-5 halogen atoms, or ii) a hydroxyl group, iii) alkyl or _C 1 _{~ 2} halogen atoms which may be substituted with 1-5 _C 1 _{~ 2} alkoxyl group, and, iv) linear or branched C ₁ ~ ₃ alkyl or hydroxyalkyl group one to two optionally substituted by an amino group; 1-3 groups selected from optionally It may be substituted with.

For example, when A ₁ is a methylene group, it means “group: —CH ₂ -A ₂ ”,
For example, as when _{A 2} is a "linear or branched alkyl group of _C 1 _{~ 6",} ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2 , 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methyl Propyl, heptyl, 1-methyl-hexyl and the like;
For example, as when A ₂ is a "cycloalkyl group C ₃ ~ _6", cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, and cyclohexylmethyl group.
For example, when _{A 1} is an alkylene group of _{C 2-6} is: a sense of "group _-C alkylene -A _{2 2-6",} methylene where the _{A 1} is a methylene group C when substituted on _2-6 alkylene is exemplified, for example, include 2- (cyclopropyl) ethyl, 2- (cyclobutyl) ethyl, 2- (cyclopentyl) ethyl group, 2- (cyclohexyl) ethyl group and the like Raru.

For example, an alkylene group of A ₁ is a methylene group or a C ₂ ~ _6, when A ₂ is an aryl group or a heterocyclic group, C ₁ ~ of the "aryl group" is a straight or branched chain ₆ as an example of substituted alkyl group (aralkyl group (aryl -C ₁ ~ ₆ alkyl group)), a benzyl group, a 1-naphthylmethyl group, phenethyl group, 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) ethyl group and the like, wherein "heterocyclic group" is a linear or example of substituted C ₁ ~ ₆ alkyl group branched (heterocyclic -C ₁ ~ ₆ alkyl group) As, for example, pyrrolylmethyl, furylmethyl, thienylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyra Zolylmethyl, 1,2,3-triazolylmethyl, 1,2,4-triazolylmethyl, 1,2,3-oxadiazolylmethyl, 1,2,4-oxadiazolylmethyl, 1,3, 4-oxadiazolylmethyl, furazanylmethyl, 1,2,3-thiadiazolylmethyl, 1,2,4-thiadiazolylmethyl, 1,3,4-thiadiazolylmethyl, tetrazolylmethyl, (2- 3-, 4-) pyridylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, 1,2,3-triazinylmethyl, 1,2,4-triazinylmethyl, 1,2,5-tri Examples substituted by “monocyclic heteroaryl groups” such as azinylmethyl, 1,3,5-triazinylmethyl, thiadiazinylmethyl, and indolylmethyl, isoindolylmethyl, 1H- Dazolylmethyl, benzofuranyl (-2-yl) methyl, isobenzofuranylmethyl, benzothienyl (-2-yl) methyl, isobenzothienylmethyl, benzindazolylmethyl, benzoxazolyl (-2-yl) methyl, 1,2-benzisoxazolylmethyl, benzothiazolyl (-2-yl) methyl, 1,2-benzisothiazolylmethyl, 2H-benzopyranyl (-3-yl) methyl, (1H-) benzimidazolyl (-2 -Yl) methyl, 1H-benzotriazolylmethyl, 4H-1,4-benzooxazinylmethyl, 4H-1,4-benzothiazinylmethyl, quinolylmethyl, isoquinolylmethyl, cinnolinylmethyl, quinazolinyl Methyl, quinoxalinylmethyl, phthalazinylmethyl, naphthyridinylmethyl, pre Rumethyl, pteridinylmethyl, carbazolylmethyl, carbolinylmethyl, acridinylmethyl, phenoxazinylmethyl, phenothiazinylmethyl, phenazinylmethyl, fanoxatinylmethyl, thianthrenylmethyl, phenanthridine Rumethyl, phenanthrolinylmethyl, indolizinylmethyl, (4,5,6,7-) tetrahydrothiazolo [5,4-c] pyridyl (-2-yl) methyl, (4,5,6, 7-) Tetrahydrothieno [3,2-c] pyridylmethyl, (1,2,3,4-) tetrahydroisoquinolyl (-6-yl) methyl, thiazolo [5,4-c] pyridyl (-2- Yl) methyl, pyrrolo [1,2-b] pyridazinylmethyl, pyrazo [1,5-a] pyridylmethyl, imidazo [1,2-a] pyridylmethyl, imi Dazo [1,5-a] pyridylmethyl, imidazo [1,2-b] pyridazinylmethyl, imidazo [1,5-a] pyrimidinylmethyl, [1,2,4] triazolo [4,3-a ] Pyridylmethyl, 1,2,4-triazolo [4,3-b] pyridazinylmethyl, chromenyl (2H-chromenyl) methyl, 1H-pyrazolo [3,4-b] pyridylmethyl, [1,2, 4] Examples substituted by “condensed heteroaryl groups” such as triazolo [1,5-a] pyrimidinylmethyl, and azetidinylmethyl, oxiranylmethyl, oxetanylmethyl, thietanylmethyl, pyrrolidinylmethyl, tetrahydro Furylmethyl, thiolanylmethyl, pyrazolinylmethyl, pyrazolidinylmethyl, piperidylmethyl, tetrahydropyranylmethyl, piperazinylmethyl, mole "Non-aromatic heterocyclic groups (3-8 membered saturated or unsaturated non-aromatic Group heterocyclic group) ”is substituted.

For example, if A ₁ is a carbonyl group, a formyl group or a C ₁ ~ ₆ straight or branched chain alkyl group of a cycloalkyl group of C ₃ ~ _6, arylcarbonyl group or heterocyclic, Represents a carbonyl group, and the carbon atom of A ₂ may be substituted with 1 to 5 halogen atoms, or may be a hydroxyl group or C ₁ to ₂ which may be substituted with 1 to 5 halogen atoms. It is substituted with ₁ to ₃ groups arbitrarily selected from an alkyl group or a C _1-2 alkoxyl group, and an amino group which may be substituted with ₁ to ₂ C _1-3 alkyl groups or hydroxyalkyl groups. at best, also C ₁ ~ ₆ alkyl group straight or branched chain of the a ₂ is cycloalkyl group C ₃ ~ _6, an aryl group or a heterocyclic Indicating that it may be 1 optionally substituted with chosen based on the in.
Examples of "straight or branched chain alkyl group of C ₁ ~ _6", for example, include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, isovaleryl group, pivaloyl group, hexanoyl group and the like It is done.
Examples of "cycloalkyl group of C ₃ ~ _6" are cyclopropyl group, cyclobutyl group, cyclopentyl carbonyl group, and a cyclohexylcarbonyl group.
Examples of "arylcarbonyl group", groups carbonyl group wherein the aryl group is bonded, for example, a benzoyl group and a C ₆ ~ ₁₄ aryl group such as a naphthyl group.

Examples of the “heterocyclic carbonyl group” include a group in which a carbonyl group is bonded to the heterocyclic group (for example, a heteroaryl group, a saturated or unsaturated non-aromatic heterocyclic group, etc.), for example, pyrrolyl Carbonyl, furylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, 1,2,3-triazolylcarbonyl, 1,2, 4-triazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl, 1,3,4-oxadiazolylcarbonyl, furazanylcarbonyl, 1,2,3 -Thiadiazolylcarbonyl, 1,2,4-thiadiazolylcarbonyl, 1 3,4-thiadiazolylcarbonyl, tetrazolylcarbonyl, pyridylcarbonyl, pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, 1,2,3-triazinylcarbonyl, 1,2,4-triazi A group having a monocyclic heteroaryl ring such as nylcarbonyl, 1,2,5-triazinylcarbonyl, 1,3,5-triazinylcarbonyl, thiadiazinylcarbonyl and the like;
Indolylcarbonyl, isoindolylcarbonyl, 1H-indazolylcarbonyl, benzofuranyl (-2-yl) carbonyl, isobenzofuranylcarbonyl, benzothienyl (-2-yl) carbonyl, isobenzothienylcarbonyl, benzindazolyl Carbonyl, benzoxazolyl (-2-yl) carbonyl, 1,2-benzisoxazolylcarbonyl, benzothiazolyl (-2-yl) carbonyl, 1,2-benzisothiazolylcarbonyl, 2H-benzopyranyl (-3 -Yl) carbonyl, (1H-) benzimidazolyl (-2-yl) carbonyl, 1H-benzotriazolylcarbonyl, 4H-1,4-benzoxazinylcarbonyl, 4H-1,4-benzothiazinylcarbonyl, quino Rylcarbonyl, isoquino Carbonyl, cinnolinylcarbonyl, quinazolinylcarbonyl, quinoxalinylcarbonyl, phthalazinylcarbonyl, naphthyridinylcarbonyl, purinylcarbonyl, pteridinylcarbonyl, carbazolylcarbonyl, carbolinylcarbonyl, acridin Carbonyl, phenoxazinylcarbonyl, phenothiazinylcarbonyl, phenazinylcarbonyl, fanoxatinylcarbonyl, thianthrenylcarbonyl, phenanthridinylcarbonyl, phenanthrolinylcarbonyl, indolizinylcarbonyl, (4, 5, 6,7-) tetrahydrothiazolo [5,4-c] pyridyl (-2-yl) carbonyl, (4,5,6,7-) tetrahydrothieno [3,2-c] pyridylcarbonyl, (1,2 , 3,4-) tetrahydride Isoquinolyl (-6-yl) carbonyl, thiazolo [5,4-c] pyridyl (-2-yl) carbonyl, pyrrolo [1,2-b] pyridazinylcarbonyl, pyrazo [1,5-a] pyridylcarbonyl , Imidazo [1,2-a] pyridylcarbonyl, imidazo [1,5-a] pyridylcarbonyl, imidazo [1,2-b] pyridazinylcarbonyl, imidazo [1,5-a] pyrimidinylcarbonyl, [1 , 2,4] triazolo [4,3-a] pyridylcarbonyl, 1,2,4-triazolo [4,3-b] pyridazinylcarbonyl, chromenyl (2H-chromenyl) carbonyl, 1H-pyrazolo [3, Groups having a condensed heteroaryl ring such as 4-b] pyridylcarbonyl, [1,2,4] triazolo [1,5-a] pyrimidinylcarbonyl, and the like. (It shows a preferred embodiment described in parentheses).

For example, if A ₁ is a sulfonyl group, a linear or branched alkylsulfonyl group, a cycloalkyl sulfonyl group of C ₃ ~ _6, an arylsulfonyl group or a heterocyclic sulfonyl group of C ₁ ~ ₆ The carbon atom of A ₂ may be substituted with 1 to 5 halogen atoms, or may be a hydroxyl group, a C ₁ to C ₂ alkyl group which may be substituted with 1 to 5 halogen atoms, or C ₁ to ₂ alkoxyl groups, and ₁ to ₃ groups optionally selected from amino groups optionally substituted with ₁ to ₂ alkyl groups or hydroxyalkyl groups of C1-3 may be substituted, the C ₁ ~ ₆ alkyl group straight or branched chain of the a ₂ is selected arbitrarily from at C ₃ ~ ₆ cycloalkyl group, an aryl group or a heterocyclic group That indicates that may be monosubstituted with a group.
Examples of "straight or branched chain alkylsulfonyl group of C ₁ ~ _6", for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, iso-butylsulfonyl group, sec- Butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, tert-pentylsulfonyl group, neopentylsulfonyl group, 2-methylbutylsulfonyl group, 1,2-dimethylpropylsulfonyl group, 1-ethylpropyl A sulfonyl group, a hexyl sulfonyl group, etc. are mentioned.
Examples of "cycloalkyl sulfonyl group C ₃ ~ _6" includes cyclopropyl sulfonyl group, cyclobutylsulfonyl group, cyclopentylsulfonyl group, and a cyclohexyl sulfonyl group.
Examples of "arylsulfonyl group" means a group of sulfonyl group in the aryl group is bonded, for example, benzenesulfonyl group, and a C ₆ ~ ₁₄ arylsulfonyl group such as a naphthylsulfonyl group.

Examples of the “heterocyclic sulfonyl group” include a group in which a sulfonyl group is bonded to the heterocyclic group, for example, pyrrolylsulfonyl, furylsulfonyl, thienylsulfonyl, imidazolylsulfonyl, oxazolylsulfonyl, isoxazolylsulfonyl , Thiazolylsulfonyl, isothiazolylsulfonyl, pyrazolylsulfonyl, 1,2,3-triazolylsulfonyl, 1,2,4-triazolylsulfonyl, 1,2,3-oxadiazolylsulfonyl, 1,2 , 4-oxadiazolylsulfonyl, 1,3,4-oxadiazolylsulfonyl, furazanylsulfonyl, 1,2,3-thiadiazolylsulfonyl, 1,2,4-thiadiazolylsulfonyl, 1,3 4-thiadiazolylsulfonyl, tetrazolylsulfonyl, pyridylsulfur Nyl, pyridazinylsulfonyl, pyrimidinylsulfonyl, pyrazinylsulfonyl, 1,2,3-triazinylsulfonyl, 1,2,4-triazinylsulfonyl, 1,2,5-triazinylsulfonyl, 1 A group having a monocyclic heteroaryl ring, such as 1,3,5-triazinylsulfonyl, thiadiazinylsulfonyl;
Indolylsulfonyl, isoindolylsulfonyl, 1H-indazolylsulfonyl, benzofuranyl (-2-yl) sulfonyl, isobenzofuranylsulfonyl, benzothienyl (-2-yl) sulfonyl, isobenzothienylsulfonyl, benzindazolyl Sulfonyl, benzoxazolyl (-2-yl) sulfonyl, 1,2-benzisoxazolylsulfonyl, benzothiazolyl (-2-yl) sulfonyl, 1,2-benzisothiazolylsulfonyl, 2H-benzopyranyl (-3 -Yl) sulfonyl, (1H-) benzimidazolyl (-2-yl) sulfonyl, 1H-benzotriazolylsulfonyl, 4H-1,4-benzoxazinylsulfonyl, 4H-1,4-benzothiazinylsulfonyl, quino Rylsulfonyl, isoquino Sulfonyl, cinnolinyl sulfonyl, quinazolinyl sulfonyl, quinoxalinyl sulfonyl, phthalazinyl sulfonyl, naphthyridinyl sulfonyl, purinyl sulfonyl, pteridinyl sulfonyl, carbazolyl sulfonyl, carbolinyl sulfonyl, acridin Rusulfonyl, phenoxazinylsulfonyl, phenothiazinylsulfonyl, phenazinylsulfonyl, fanoxatinylsulfonyl, thianthrenylsulfonyl, phenanthridinylsulfonyl, phenanthrolinylsulfonyl, indolizinylsulfonyl, (4, 5, 6,7-) tetrahydrothiazolo [5,4-c] pyridyl (-2-yl) sulfonyl, (4,5,6,7-) tetrahydrothieno [3,2-c] pyridylsulfonyl, (1,2 , 3,4-) tetrahydride Isoquinolyl (-6-yl) sulfonyl, thiazolo [5,4-c] pyridyl (-2-yl) sulfonyl, pyrrolo [1,2-b] pyridazinylsulfonyl, pyrazo [1,5-a] pyridylsulfonyl , Imidazo [1,2-a] pyridylsulfonyl, imidazo [1,5-a] pyridylsulfonyl, imidazo [1,2-b] pyridazinylsulfonyl, imidazo [1,5-a] pyrimidinylsulfonyl, [1 , 2,4] triazolo [4,3-a] pyridylsulfonyl, 1,2,4-triazolo [4,3-b] pyridazinylsulfonyl, chromenyl (2H-chromenyl) sulfonyl, 1H-pyrazolo [3, 4-b] pyridylsulfonyl, [1,2,4] triazolo [1,5-a] pyrimidinylsulfonyl and the like (the description in parentheses indicates a preferred embodiment). Yl).

In the definition of Q, “aryl group” or “heterocyclic group” of “optionally substituted aryl group” or “optionally substituted heterocyclic group” is an example of the aforementioned “hydrocarbon group”. "aryl group" cited as, or represents the same meaning as "heterocyclic group", the Examples of the "substituent", C ₁ ~ ₆ alkyl, C ₂ ~ ₆ alkenyl, C ₂ ~ ₆ alkynyl, halogen atom , halogenated C ₁ ~ ₆ alkyl, cyano, amino, hydroxy, carbamoyl, C ₁ ~ ₆ alkoxy, C ₂ ~ ₆ alkenyloxy, C ₂ ~ ₆ alkynyloxy, C ₁ ~ ₆ alkylthio, C ₁ ~ ₆ alkylsulfinyl, C ₁ ~ ₆ alkylsulfonyl, mono / di C ₁ ~ ₆ alkyl amino, C ₁ ~ ₆ alkoxycarbonyl, C ₂ ~ ₆ alkanoyl, C ₂ ~ ₆ alkanoylamino, hydroxy -C _1-6 alkyl, C _1-6 alkoxy -C _1-6 alkyl, carboxy -C _1-6 alkyl, C _1-6 alkoxycarbonyl -C _1-6 alkyl, carbamoyl -C _1-6 alkyl, N-C _1-6 alkylcarbamoyl -C _1-6 alkyl, N, N-di-C _1-6 alkylcarbamoyl -C _1-6 alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, oxo, Morpholinylcarbonyl, morpholinylsulfonyl, 5-trifluoromethylpyridin-2-yloxy, quinoxalin-2-yl, (pyridin-4-yl) methyl, 1,2,3-thiadiazol-4-yl, 1H- Examples of the substituent include pyrazolo-1-yl and 4-chlorophenyl. The aromatic ring in the substituent is further halo. Gen atoms, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxyl, carbamoyl, C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkylamino, di -C ₁ ~ ₆ alkylcarbamoyl, C ₁ ~ ₆ alkoxycarbonyl, N-C ₁ ~ ₆ alkylcarbamoyl, N, N-di-C ₁ ~ ₆ alkylcarbamoyl and C ₂
~ ₆ Alkenoylamino optionally substituted with 1-5.

[1-1] In the compound represented by the formula (I), R ¹ is a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted C. _1-6 alkoxyl group, an optionally substituted C _1-6 alkoxycarbonyl group, mono optionally substituted C _1-6 alkyl group - or di - substituted amino group, are protected An optionally substituted hydroxyl group, an optionally protected carboxyl group, an optionally substituted C ₁
In _1-6 alkyl group mono- - or di - optionally substituted carbamoyl group, C ₁ - ₆ alkanoyl group, C ₁ - ₆ alkylthio group, C ₁ - ₆ alkylsulfinyl group, C ₁ ~ ₆ alkylsulfonyl group, a substituted by mono also a good C ₁ ~ ₆ alkyl group optionally - or di - represents the optionally substituted sulfamoyl group, optionally selected from a cyano group or a nitro group group.

[1-1-a]
In the compound of the formula (I) of the embodiment [1], R ¹ is preferably a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted group. good C ₁ ~ ₆ alkoxy group, and the like. As the “optionally substituted hydrocarbon group” or “optionally substituted heterocyclic group”, for example,
(1) C ₁ ~ ₆ alkyl group, (2) C ₂ ~ ₆ alkenyl or (3) C ₂ ~ ₆ alkynyl group, (4) C ₃ ~ ₆ cycloalkyl group, (5) a C ₃ ~ ₆ A cycloalkenyl group, (6) C _4
1-6 cycloalkanedienyl group, (7) C ₆ - ₁₄ aryl group, (8) an oxygen atom in addition to carbon atoms, where containing 1-4 heteroatoms selected from oxygen, sulfur atom or nitrogen atom (i) 5-6 membered monocyclic heteroaryl group, (ii) 8-12 membered condensed heteroaryl group, (iii) any of 3-8 membered saturated or unsaturated non-aromatic heterocyclic group ring group, or (9) a optionally substituted C ₁ to ₆ alkoxy group, each group of the above (1) to (9), substituents or shown in the following unsubstituted (wherein In the embodiment “1”, ¹ to 5 groups may be optionally substituted with the group described as the “substituent” in the definition of R ¹ . The examples of the substituent, C ₁ ~ ₆ alkyl, C ₂ ~ ₆ alkenyl, C ₂ ~ ₆ alkynyl, halogen atom, halogenated C ₁ ~ ₆ alkyl, cyano, amino, hydroxy, carbamoyl, C ₁ ~ ₆ alkoxy, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C ₁ ~ ₆ alkylthio, C ₁ ~ ₆ alkylsulfinyl, C ₁ ~ ₆ alkylsulfonyl, mono / di C ₁ ~ ₆ alkyl amino, C ₁ ~ ₆ alkoxycarbonyl, C ₂ ~ ₆ alkanoyl, C ₂ ~ ₆ alkanoylamino, hydroxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxy -C ₁ ~ ₆ alkyl, carboxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxycarbonyl -C _1-6 alkyl, carbamoyl -C _1-6 alkyl, N-C _1-6 alkylcarbamoyl -C _1-6 alkyl, N, N-di-C _1-6 alkyl Carbamoyl -C ₁ ~ ₆ alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, oxo, morpholinylcarbonyl, morpholinylsulfonyl sulfonyl, 5-trifluoromethyl-2-yloxy, quinoxaline Examples include substituents such as 2-yl, (pyridin-4-yl) methyl, 1,2,3-thiadiazolo-4-yl, 1H-pyrazolo-1-yl, 4-chlorophenyl, tetrahydrofuranyl, and oxiranyl. , the aromatic ring may further halogen atom in the substituent, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxyl, carbamoyl, C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkyl amino, di -C ₁ ~ ₆ alkylcarbamoyl, _1-6 alkoxycarbonyl, N-C _1-6 alkylcarbamoyl, N, N-di C ₁
With 1-5 groups selected from _1-6 alkylcarbamoyl and C ₂ to ₆ alkenoyl amino may be substituted.

[1-1-b] preferably, R ¹ is a halogen atom, and (1) C ₁ ~ ₆ alkyl group, a (9) C ₁ ~ ₆ alkoxy group, wherein the (1) and (9) Each group may further be optionally substituted with 1 to 5 groups described as the “substituent” in the definition of R ^{1 in} the above-described embodiment “1”.
[1-1-c] More preferably, R ¹ is a halogen atom (fluorine atom, a chlorine atom, a bromine atom, an iodine atom), and optionally C ₁ ~ optionally substituted with one to five halogen atoms ₆ alkyl group (especially an alkyl group of C ₁ ~ ₄₎ or C ₁ ~ ₆ alkoxyl group (especially C ₁ ~
₄ alkoxyl group).
[1-1-d] More preferably, R ¹ is a halogen atom (especially, fluorine atom, chlorine atom is preferred), and an alkyl group or a C ₁ ~ ₄ alkoxyl group C ₁ ~ _4), C
₁ the carbon chain of _1-4 alkoxyl group of the alkyl group or C ₁ - ₄ represents a group selected from the group that is optionally substituted with 1-5 halogen atoms; More than specifically, R ¹ is Fluorine atom, chlorine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethyl Tetrafluoroethyl, pentafluoroethyl, trifluoromethoxy, tetrafluoroethoxy, pentafluoroethoxy and the like.
[1-1-e] Particularly preferably, R ¹ represents a fluorine atom, a chlorine atom, methyl, ethyl,
Isopropyl, isobutyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, particularly preferably R ¹ is fluorine atom, chlorine atom, methyl, isopropyl, methoxy, trifluoromethoxy.

ここで、Ｚが、＝ＣＨ−である場合には、当該水素原子はＲ^１で置換されていてもよい。より好ましくは、
［１−２−ａ］
Ｒ^１の少なくとも１つが、５位であることが好ましい。
［１−２−ｂ］
従って、ｎが１のとき、好ましくは、式（Ｉ）において、Ｒ^１の置換位置が５位でありこれらにおいて、Ｒ^１は、ハロゲン原子、Ｃ_１〜_４のアルキル基、Ｃ_１〜_４のアルコキシル基、または、これらの基の炭素鎖が１〜５個のハロゲン原子で任意に置換されている基から選ばれる基を表す（より具体的には、Ｒ¹は、フッ素原子、塩素原子、メチル、エチ
ル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ−ブトキシ、ｔｅｒｔ−ブトキシ、トリフルオロメチル、テトラフルオロエチル、ペンタフルオロエチル、トリフルオロメトキシ、テトラフルオロエトキシ、ペンタフルオロエトキシである。より好ましくは、Ｒ¹は、フッ素原子、塩素原子、メチル、エチル、イソプ
ロピル、イソブチル、ｔｅｒｔ−ブチル、メトキシ、トリフルオロメチル、トリフルオロメトキシであり、特別に好ましくは、Ｒ¹はフッ素原子、塩素原子、メチル、イソプロピ
ル、メトキシ、トリフルオロメトキシである。）。 [1-2] In the compound represented by the formula (I) of the embodiment [1], the substitution position of R ^{1 is} the position shown in the following formula (I), that is, the 4-position and 5-position shown in the figure. , 6th and 7th are allowed.

Here, when Z is = CH-, the hydrogen atom may be substituted with R ¹ . More preferably,
[1-2a]
It is preferable that at least one of R ¹ is at the 5-position.
[1-2b]
Therefore, when n is 1, preferably, in formula (I), the substitution position of ^{R 1} is 5-position in these, ^{R 1} is a halogen _atom, an alkyl group of C 1 _{~ 4,} the C 1 _{~ 4} Represents an alkoxyl group or a group selected from groups in which the carbon chain of these groups is optionally substituted with 1 to 5 halogen atoms (more specifically, R ¹ represents a fluorine atom, a chlorine atom, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethyl, tetrafluoroethyl, penta Fluoroethyl, trifluoromethoxy, tetrafluoroethoxy and pentafluoroethoxy are more preferable. R ¹ is fluorine atom, chlorine atom, methyl, ethyl, isopropyl, isobutyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, and particularly preferably, R ¹ is fluorine atom, chlorine atom, Methyl, isopropyl, methoxy, trifluoromethoxy).

[1-3] In the compound represented by the formula (I) of the embodiment [1], R ² is a hydrogen atom, C ₁
A linear or branched alkyl group or a linear or branched alkoxyl group of C ₁ ~ ₄ of the _1-4, wherein the alkyl group or alkoxy group may be substituted with one to five halogen atoms or better, or hydroxyl group, alkyl group or _C 1 _{- 2} alkoxyl group halogen atom _{1-5-optionally C} 1 optionally substituted by _2, and _C 1 _{- 3} alkyl or hydroxyalkyl group 1 It may be substituted with 1 to 3 groups arbitrarily selected from an amino group which may be substituted with 2 groups.
In [1-3-a] embodiment [1] a compound represented by formula (I), preferably, R ² is a hydrogen _atom, an alkyl group or a _{C 1} linear or branched C 1 _{~ 4} To ₄ linear or branched alkoxyl groups, and more specifically, a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, Examples include isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
More preferably [1-3-b], R ² represents a hydrogen _atom, C 1 _{~ 4} straight or branched chain alkyl group or a linear or branched alkoxyl group of _C 1 _{~ 4} of More specifically, a hydrogen atom, methyl, ethyl, methoxy, ethoxy and the like can be mentioned. Particularly preferred are a hydrogen atom and methyl.

[1-4] In the compound represented by the formula (I) of embodiment [1], ^{R 3} is a group: _-A 1 represents -A _{2, A 1} is a single bond, a methylene _group, a C 2 _{~ 6} It represents an alkylene group, a carbonyl group or a sulfonyl group, a ₂ represents a hydrogen atom, a linear or branched alkyl group of C ₁ ~ _6, a cycloalkyl group of C ₃ ~ _6, an aryl group or a heterocyclic group The carbon atom of A ₂ may be substituted with 1 to 5 halogen atoms, or may be a hydroxyl group, a C ₁ to C ₂ alkyl group which may be substituted with 1 to 5 halogen atoms, or C _1-2 alkoxyl group, and C ₁ ~ ₃ alkyl or optionally substituted with 1 to 3 groups selected arbitrarily from hydroxyalkyl groups 1-2 with an optionally substituted amino group.
[1-4-a] Preferably, in R ³ , A ₁ is a single bond, a methylene group, a carbonyl group or a sulfonyl group.
[1-4-b] Preferably, in ^{R 3,} _{A 2} is a hydrogen atom, a linear or branched _C 1 _{~ 4} alkyl _group, a cycloalkyl group of C 3 _{~ 6,} an aryl group or a heterocyclic And the carbon atom of A ₂ may be substituted with 1 to 3 halogen atoms, or may be a hydroxyl group, C ₁ to C ₂ alkyl optionally substituted with 1 to 5 halogen atoms alkoxyl groups groups or C ₁ ~ _2, and C ₁ ~ may be substituted with ₃ alkyl or hydroxyalkyl group one to two substituted by an amino group optionally in group one selected arbitrarily . More specifically, a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, N, N-dimethylaminomethyl, N, N-dimethylaminoethyl, methoxymethyl, 2- Methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, Examples include morpholino (4-morpholinyl), 2-tetrahydropyranyl, 4-tetrahydropyranyl and the like.

[1-4-c] Preferably, R ³ represents a hydrogen atom, methyl, ethyl, propyl, isopropyl, tert-butyl, neopentyl, 2- (N, N-dimethylamino) as a group: -A ₁ -A ₂ ) Ethyl, 2-methoxyethyl, tert-butylcarbonyl, isopropylsulfonyl, pivaloyl, cyclopropyl, cyclopropylmethyl, cyclohexyl, cyclohexylmethyl, cyclohexylcarbonyl, cyclohexylsulfonyl, phenyl, benzyl, 3-fluorophenyl, 3-fluorobenzyl 4-fluorophenyl, 4-fluorobenzyl, 3-trifluoromethylphenyl, 3-trifluoromethylbenzyl, 4-trifluoromethylphenyl, 4-trifluoromethylbenzyl, 2- (4-morpholinyl) ethyl, 2- Te Trahydropyranyl, 2-tetrahydropyranylmethyl, 4-tetrahydropyranyl, 4-tetrahydrofuranyl and the like;
More preferably, ethyl, propyl, isopropyl, tert-butyl, neopentyl, tert-butylcarbonyl, isopropylsulfonyl, pivaloyl, cyclopropyl, cyclopropylmethyl, cyclohexyl, cyclohexylmethyl, cyclohexylcarbonyl, cyclohexylsulfonyl, phenyl, benzyl, 3 -Fluorophenyl, 3-fluorobenzyl, 4-fluorophenyl, 4-fluorobenzyl, 3-trifluoromethylphenyl, 3-trifluoromethylbenzyl, 4-trifluoromethylphenyl, 4-trifluoromethylbenzyl, 2-tetrahydro Examples include pyranyl, 2-tetrahydropyranylmethyl, 4-tetrahydropyranyl, 4-tetrahydropyranylmethyl and the like.
Particularly preferably, isopropyl, tert-butyl, neopentyl, tert-butylcarbonyl, cyclohexyl, cyclohexylmethyl, cyclohexylcarbonyl, cyclohexylsulfonyl, isopropylsulfonyl, 3-fluorophenyl, 3-fluorobenzyl, 4-fluorophenyl, 4-fluoro Examples include benzyl, 3-trifluoromethylphenyl, 3-trifluoromethylbenzyl, 4-trifluoromethylphenyl, 4-trifluoromethylbenzyl, 2-tetrahydropyranylmethyl, 2-methoxyethyl and the like.

[1-5] In embodiment [1] a compound represented by formula (I), ^{R 4} and ^{R 5} are each independently a hydrogen _atom, or an alkyl group of straight or branched chain C 1 _{~ 4} Represents a phenyl group.
[1-5-a] Preferably, R ⁴ includes a hydrogen atom, a methyl group, an ethyl group, and a phenyl group, and more preferably a hydrogen atom or a methyl group.
[1-5-b] Preferably, R ⁵ includes a hydrogen atom.

[1-6] In the compound represented by the formula (I) of the embodiment [1], Q represents an optionally substituted aryl group or an optionally substituted heterocyclic group. In the definition of Q, “aryl group” or “heterocyclic group” of “optionally substituted aryl group” or “optionally substituted heterocyclic group” has the same meaning as in the above-mentioned embodiment “1”. Preferably, Q- is a bicyclic heterocyclic group or aryl group which may be substituted, or a monocyclic aryl or heterocyclic group having a specific substituent. For example, the “bicyclic heterocyclic group” includes those having 8 to 12 ring members as the “condensed heteroaryl group” described in the embodiment [1]. A monovalent group formed by removing an arbitrary hydrogen atom from a ring formed by condensing a 6-membered heterocycle with 1 to plural (preferably 1 to 2) aryl rings (for example, a benzene ring); included. In addition, the “bicyclic aryl group” includes C ₉ to C such as naphthyl, 5,6,7,8-tetrahydronaphthalenyl or the like, or partially hydrogenated condensed aryl such as indanyl and tetrahydronaphthyl. _{And 12} aryl groups. Here, the partially hydrogenated aryl group means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated ring, and is a hydrogen atom of an aromatic moiety or a hydrogenated moiety. Either of the hydrogen atoms may be removed. For example, in the case of a tetrahydronaphthyl group, a 5,6,7,8-tetrahydronaphthalene (-1-yl, -2-yl, -3-yl, -4-yl) group or 1,2,3,4- Tetrahydronaphthalene (-1-yl, 2-yl, -3-yl, -4-yl) group, indanyl group (1-yl, 2-yl, 3-yl, 4-yl, 5-yl, 6-yl, Yl, 7-yl) and the like. Examples of these “optionally substituted” substituents include those listed as “substituents” in the definition of Q in [1] above, and may be substituted with 1 to 3 substituents. .

［１−６−ａ］ここで、Ｑ１において、各定義について説明する。
［１−６−ａ−１］式Ｑ１において、ｋは０〜２の整数を表し、ｊは０または１の整数を表す。ｊが０であることが好ましい。また、ｋが０または１であることが好ましく、ｋが０であることがより好ましい。 More specifically, the following formula (Q1), formula (Q2), and formula (Q3) may be mentioned.

[1-6-a] Here, in Q1, each definition will be described.
[1-6-a-1] In formula Q1, k represents an integer of 0 to 2, and j represents an integer of 0 or 1. j is preferably 0. Further, k is preferably 0 or 1, and k is more preferably 0.

In [1-6-a-2] Formula Q1, ^{R 7} is a hydrogen atom or a halogen atom, a halogenated C ₁ ~ ₆ alkyl, cyano, amino, hydroxy, carbamoyl, C ₁ ~ ₆ alkoxy, C ₂ ~ _6, alkenyloxy, C ₂ ~ ₆ alkynyloxy, C ₁ ~ ₆ alkylthio, C ₁ ~ ₆ alkylsulfinyl, C ₁ ~ ₆ alkylsulfonyl, mono / di C ₁ ~ ₆ alkyl amino, C ₁ ~ ₆ alkoxycarbonyl, C ₂ ~ ₆ alkanoyl, C ₂ ~ ₆ alkanoylamino, hydroxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxy -C ₁ ~ ₆ alkyl, carboxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxycarbonyl -C ₁ ~ ₆ alkyl, carbamoyl -C ₁ ~ ₆ alkyl, N-C _1
1-6 alkylcarbamoyl -C ₁ - ₆ alkyl, N, N-di-C ₁ - ₆ alkylcarbamoyl -
C ₁ - ₆ alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl benzoyl, morpholino, piperazino, oxo, oxiranyl, 1 or 2 optionally substituted C ₁ to ₆ alkyl substituents such as tetrahydrofuranyl Group or a tetrahydropyranyl group (preferably a tetrahydropyran-4-yl group).
^{R 7} in [1-6-a-2a] formula Q1 is a hydrogen atom or an amino, hydroxy, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkyl amino, morpholino, piperazino, oxo, oxiranyl, tetrahydrofuranyl, it is more preferred substituent such as 1 or 2 optionally substituted C ₁ to ₆ alkyl groups.

As "C ₁ ~ ₆ alkyl group" in [1-6-a-2b] More preferred substituents for ^{R 7,} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, Isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1 , 2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl 2-methyl-propyl, n- hexyl, and the like, methyl, ethyl, propyl, isopropyl, butyl, and is preferably isobutyl or sec- butyl.
[1-6-a-2c] formula ^{R 7} in the compounds represented by (Q1) is a hydrogen atom or an amino, hydroxy, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkyl amino, such as phenyl Particularly preferred is a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, which may be substituted by 1 or 2 substituents, and more specifically, a hydrogen atom, a methyl group, an ethyl group, Propyl, isopropyl, butyl, isobutyl, sec-butyl, aminomethyl, (2-) aminoethyl, hydroxymethyl, (2-) hydroxyethyl, (3-) hydroxypropane-1- Yl group, (4-) hydroxybutyl, 2-hydroxy-2,2-dimethylethyl group, 1,3-dihydroxy-propan-2-yl group, 1-methyl-2- Droxyethyl group, 2-hydroxy-propan-1-yl group, methoxyethyl group, (2-) ethoxyethyl group, (2-) N, N-dimethylaminoethyl group, (2-) N, N-diethylaminoethyl group , A benzyl group, a phenethyl group, an oxiranylmethyl group, (2-) tetrahydrofuranylmethyl, and the like (preferred embodiments are shown in parentheses).

The R ⁸ in [1-6-a-3] formula (Q1), a hydrogen atom, a halogen atom, an optionally substituted C ₁ ~ ₄ alkyl group, a hetero non-aromatic may be substituted A ring group,
Or di - - group selected arbitrarily from an amino group which may be substituted and the like may be substituted C ₁ ~ ₄ alkoxyl group or a mono-substituted by optionally C ₁ to ₄ alkyl groups.
Here, the non-aromatic heterocyclic group of the “optionally substituted non-aromatic heterocyclic group” has the same meaning as exemplified in the above embodiment [1]. For example, azetidinyl, morpholinyl , Piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, oxepanyl, thiomorpholinyl and the like. In "mono substituted by unprotected C ₁ ~ ₄ alkyl group - - or di is an amino group optionally substituted", mono C ₁ ~ ₄ alkyl group - or di - amino optionally substituted the group means a one or two hydrogen atoms are the "C ₁ ~ ₄ alkyl group" amino group which may be substituted by amino group, specifically,
Amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, dimethylamino group, diethylamino group, dipropylamino group, di-isopropylamino group, dibutylamino group, ethyl Examples thereof include a methylamino group, a methylpropylamino group, an ethylpropylamino group, a butylmethylamino group, a butylethylamino group, and a butylpropylamino group. Examples of these “optionally substituted” substituents include those listed as “substituents” in the definition of Q in [1] above, and may be substituted with 1 to 3 substituents. .

[1-6-a-3a] Preferably, R ^{8 in} the formula (Q1) is a hydrogen atom or a methyl group, an ethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an azetidinyl group, a morpholinyl group, a piperidinyl group. group, piperazinyl group, pyrrolidinyl group, thiazolinyl group, oxepanyl group, and group selected from thiomorpholinyl group or a substituted consists also an amino group substituted also a good C ₁ ~ ₂ alkyl optionally the group, each of these groups, wherein [1] substituents listed as "substituent" is mentioned in the definition of Q in, for example, C ₁ ~ ₆ alkyl, halogen, amino, hydroxy, C ₁ ~ ₆ alkoxy, mono / di C _{1 1-6} alkylamino, may be substituted with a substituent oxo etc., as the substituent of the "optionally substituted C ₁ - ₂ alkyl" In example, halogen, amino, hydroxy, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkyl amino, oxo, and substituted groups such as 4-Piranoiru.
[1-6-a-3b] More preferable R ⁸ is, specifically, a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group, or 3-hydroxypropoxy. 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, 1-piperidinyl group, 4-oxo-1-piperidinyl group, 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group 4,4-difluoro-1-piperidinyl group, 1-piperazinyl group, 4-methyl-piperazinyl group, pyrrolidinyl group, (3S) -fluoro-pyrrolidinyl group, (3S) -hydroxy-pyrrolidinyl group, thiazolinyl group, oxepanyl group Thiomorpholinyl group, (2S) -hydroxymethyl-pyrrolidinyl group, (2S) -methoxymethyl Ru-pyrrolidinyl group; N, N-dimethylamino group, N, N-diethylamino group, N, N-ethylmethylamino group, N, N-bis (2-methoxyethyl) amino group, N-methyl-N- (2-methoxyethyl) amino group, N-methyl-N-cyclohexylamino group, N-methyl-N- (2-dimethylaminoethyl) amino group, N-methyl-N- (2-hydroxyethyl) amino group, N-methyl-N- (2-methoxyethyl) amino group, N-methyl-N- (4-pyranoyl) amino group and the like can be mentioned. More preferable R ⁸ is a hydrogen atom.

[1-6-a-4] W in formula (Q1) represents a methylene group, a carbonyl group, or a sulfonyl group. W is preferably a carbonyl group or a sulfonyl group.
[1-6-a-5] L ₁ and L ₂ in formula (Q1) each independently represent a single bond, —CR ^9A R ^9B —, an oxygen atom, —NR ¹⁰ — or —S (O) t—. (T is an integer of 0 to 2).
[1-6-a-5a] As preferable L ₁ and L ₂ , when L ₁ and L ₂ are the same, they are a single bond or —CR ^9A R ^9B —, and L ₁ and L ₂ are different. Are either —CR ^9A R ^9B —, the other is an oxygen atom, —NR ¹⁰ — (R ¹⁰ is a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocycle. Represents a cyclic group or an optionally substituted acyl group) or -S (O) t- (t is an integer of 0 to 2). When W is a methylene group, L ₁ represents an oxygen atom and L ₂ represents —CR ^9A R ^9B —.

Ｒ^９Ｂが水素原子であることがより好ましい。また、Ｌ_１及びＬ_２の間の実線と破線が、二重結合である場合には、Ｌ_１及びＬ_２の部分は以下のような式で表すことができ、

ここで、Ｌ_１’及びＬ_２’は、−ＣＲ^９Ｂ＝もしくは−Ｎ＝である。 [1-6-a-5b] As more preferable L ₁ and L ₂ , when L ₁ is -CR ^9A R ^9B- , L ₂ is -CR ^9A R ^9B- , an oxygen atom, -NR ^10- , Or the case where it is -S (O) t- (t is an integer of 0-2) is mentioned. As more preferred L ₁ and L ₂ , when L ₂ is —CR ^9A R ^9B —, L ₁ is —CR ^9A R ^9B —, an oxygen atom, —NR ¹⁰ —, or —S (O) t— ( and t is an integer of 0 to 2). More specifically, when the solid line and the broken line between L ₁ and L ₂ are a single bond, the portions of L ₁ and L ₂ can be expressed by the following equations:

More preferably, R ^9B is a hydrogen atom. In addition, when the solid line and the broken line between L ₁ and L ₂ are double bonds, the portions of L ₁ and L ₂ can be expressed by the following equations:

Here, L ₁ ′ and L ₂ ′ are -CR ^9B = or -N =.

ここで、Ｌ_１’は、−ＣＲ^９Ｂ＝もしくは−Ｎ＝である。より好ましくは、Ｌ_２’中のＲ^９Ｂは水素原子である。 [1-6-a-5c] As more preferable L ₁ and L ₂ , when L ₂ is —CR ^9A R ^9B —, L ₁ is —CR ^9A R ^9B —, an oxygen atom, —NR ¹⁰ —, Or the case where it is -S (O) t- (t is an integer of 0-2) is mentioned.
The solid line and the broken line between L ₁ and L ₂ indicate a single bond or a double bond, but the portions of L ₁ and L ₂ can be represented by the following formulas,

Here, L ₁ ′ is -CR ^9B = or -N =. More preferably, R ^9B in L ₂ ′ is a hydrogen atom.

[1-6-a-5d] As particularly preferred L ₁ and L ₂ , when L ₁ is —CH ₂ —, L ₂ is —CR ^9A H—, or L ₁ is —CH═. In some cases, when L ₂ is —CH ₂ —, R ^9A is particularly preferably a morpholino group. For example, the solid line and the broken line between L ₁ and L ₂ are shown a single bond or a double bond, part of L ₁ and L ₂ can be represented by the following formula,

[1-6-a-5e] t in L ₁ and L ₂ represents an integer of 0 to 2, and is preferably 0 or 2.
In [1-6-a-6] formula ^(Q1), as the ^{R 9A} and ^{R 9B,} each independently, a hydrogen atom, optionally substituted C ₁ to ₄ alkyl groups, optionally substituted non-aromatic heterocyclic group, optionally substituted C ₁ ~ ₄ alkoxyl group, or an optionally substituted C ₁ ~ mono ₄ alkyl group, - or di - optionally from an amino group which may be substituted And the definitions each have the same meaning as R ⁸ .
[1-6-a-6a] R ^9A and R ^9B may be the same or different, and more preferable R ^9A and R ^9B include a hydrogen atom, a methyl group, an ethyl group, or a methoxy group. group, an ethoxy group, azetidinyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a pyrrolidinyl group, a thiazolinyl group, oxepanyl group, thiomorpholinyl group or optionally substituted C ₁ to ₂ amino group which may alkyl substituted include groups selected from the group consisting of, each of these groups, the [1] substituents listed as "substituent" is mentioned in the definition of Q in, for example, C ₁ ~ ₆ alkyl, halogen, amino, hydroxy , C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkylamino, may be substituted with a substituent oxo etc., "substituted A good C ₁ ~ ₂ alkyl "substituents, e.g., halogen,
Amino, hydroxy, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkyl amino, oxo, and substituted groups such as 4-Piranoiru.

[1-6-a-6b] More preferably, R ^9A and R ^9B are specifically hydrogen atom, methyl group, ethyl group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group; 4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, 1-piperidinyl group, 4-oxo-1-piperidinyl group, 4-hydroxy-1-piperidinyl group, 4-methoxy-1-piperidinyl group, 4, 4-difluoro-1-piperidinyl group, 1-piperazinyl group, 4-methyl-piperazinyl group, pyrrolidinyl group, (3S) -fluoro-pyrrolidinyl group, (3S) -hydroxy-pyrrolidinyl group, thiazolinyl group, oxepanyl group, thiomorpholinyl group (2S) -hydroxymethyl-pyrrolidinyl group, (2S) -methoxymethyl-pyrrolidinyl N, N-dimethylamino group, N, N-diethylamino group, N, N-ethylmethylamino group, N, N-bis (2-methoxyethyl) amino group, N-methyl-N- (2-methoxy) Ethyl) amino group, N-methyl-N-cyclohexylamino group, N-methyl-N- (2-dimethylaminoethyl) amino group, N-methyl-N- (2-hydroxyethyl) amino group, N-methyl- N- (2-methoxyethyl) amino group, N-methyl-N- (4-pyranoyl) amino group and the like can be mentioned.
[1-6-a-6c] More preferable R ^9A and R ^9B are, when identical, a hydrogen atom or a methyl group, and when different, either one is a hydrogen atom and the other is It is a group (excluding a hydrogen atom) mentioned in the above [1-6-a-6b].

[1-6-a-7] as ^{R 10} in the formula (Q1) is a hydrogen atom or a halogen atom, a halogenated C ₁ ~ ₆ alkyl, cyano, amino, hydroxy, carbamoyl, C ₁ ~ ₆ alkoxy, C _{2 1-6} alkenyloxy, C ₂ - ₆ alkynyloxy, C ₁ - ₆ alkylthio, C ₁ - ₆ alkylsulfinyl, C ₁ - ₆ alkylsulfonyl, mono / di C ₁ - ₆ alkylamino, C ₁ - ₆ alkoxycarbonyl, C _2-6 alkanoyl, C _2-6 alkanoylamino, hydroxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxy -C ₁ ~ ₆ alkyl, carboxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxycarbonyl -C _{1 1-6} alkyl, carbamoyl -C ₁ - ₆ alkyl, N-C ₁ - ₆ alkylcarbamoyl -C ₁ - ₆ alkyl, N, N-di-C ₁ - ₆ alkyl carba Moil -C ₁ ~ ₆ alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl benzoyl, morpholino, piperazino, oxo, oxiranyl, with a substituent such as tetrahydrofuranyl 1 or 2 optionally substituted C ₁ ~ _It is preferably a ₆ alkyl group or a tetrahydropyranyl group (preferably a tetrahydropyran-4-yl group).

^{[1-6-a-7a] R} 10 in formula (Q1) is a hydrogen atom or an amino, hydroxy, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkyl amino, morpholino, piperazino, oxo, oxiranyl, it is more preferably 1 or 2 substituted C ₁ optionally _1-6 alkyl group with a substituent such as tetrahydrofuranyl.
As "C ₁ ~ ₆ alkyl group" in the substituent of [1-6-a-7b] More preferred ^{R 10,} methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, Isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1 , 2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl And ru-2-methylpropyl, n-hexyl and the like, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl is preferable.

[1-6-a-7c] formula (Q1) ^{R 10} in a hydrogen atom or an amino, hydroxy, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkylamino, 1 or substituent such as phenyl It is particularly preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, which may be substituted, more specifically, a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group. Butyl group, butyl group, isobutyl group, sec-butyl group, aminomethyl group, (2-) aminoethyl group, hydroxymethyl group, (2-) hydroxyethyl group, (3-) hydroxypropyl, (4-) Hydroxybutyl, 2-hydroxy-2,2-dimethylethyl group, 1,3-dihydroxy-propan-2-yl group, 1-methyl-2-hydroxyethyl 2-hydroxy-propan-1-yl group, methoxyethyl group, (2-) ethoxyethyl group, (2-) N, N-dimethylaminoethyl group, (2-) N, N-diethylaminoethyl group, benzyl Group, phenethyl group, oxiranylmethyl group, (2-) tetrahydrofuranylmethyl and the like (preferred embodiments are shown in parentheses).
[1-6-a-7d] Most preferred R ¹⁰ includes a hydrogen atom, a methyl group, an ethyl group, a hydroxymethyl group, a hydroxyethyl group, or a methoxyethyl group.
[1-6-a-8] In the formula (Q1), a solid line and a broken line between L ₁ and L ₂ represent a single bond or a double bond, but a single bond is preferable.

（式中、ｋ、ｊ、ｔ、Ｗ、Ｒ^７、Ｒ^８、Ｒ^９Ａ、Ｒ^９Ｂ、Ｒ^１０、Ｌ_１及びＬ_２の定義は、前記態様の［１−６−ａ−１］〜［１−６−ａ−８］のいすれかの定義と同じである。）で表される。当該アリールアミン部分の好ましい例として、下記式（ａ）

（式中、ｋ、ｊ、ｔ、Ｗ、Ｒ^７、Ｒ^８、Ｒ^９Ａ、Ｒ^９Ｂ、Ｒ^１０、Ｌ_１及びＬ_２の定義は、前記態様の［１−６−ａ−１］〜［１−６−ａ―８］のいすれかの定義と同じである。）が挙げられる。式（Ａ）及び式（ａ）において、−ＮＨ−あるいはＲ^８の置換位置は、下記式中のフェニル部分のＥ_１〜Ｅ_４の位置の炭素原子で示すことができる。−ＮＨ−であれば、Ｌ_１が結合する炭素原子に近い位置から時計周りに数えて、１番目（Ｅ_４の位置）または３番目（Ｅ_２の位置）の炭素原子に結合していることが好ましい。

[1-6-a-9] Formula (Q1) is an arylamino group of the following formula (A) in formula (I):

(Wherein, k, j, t, W, R ⁷ , R ⁸ , R ^9A , R ^9B , R ¹⁰ , L _1, and L ₂ are defined in [1-6-a-1] to [ 1-6-a-8]. As a preferable example of the arylamine moiety, the following formula (a)

(Wherein, k, j, t, W, R ⁷ , R ⁸ , R ^9A , R ^9B , R ¹⁰ , L _1, and L ₂ are defined in [1-6-a-1] to [ 1-6-a-8]. In formula (A) and formula (a), the substitution position of —NH— or R ⁸ can be represented by the carbon atoms at positions E _{1 to} E ₄ of the phenyl moiety in the following formula. If it is —NH—, it is bonded to the first (E ₄ position) or the third (E ₂ position) carbon atom, counting clockwise from the position close to the carbon atom to which L ₁ is bonded. Is preferred.

Preferred examples of each substituent of the formula (a) include the above-described embodiments [1-6-a-1] to [1-6-a-8.
More specifically, formula (a) includes the following formula (a1) to formula (a141).

Each group of formula (a1) to formula (a141) according to the present embodiment [1-6-a-9] is not further substituted, or “substituent” in the definition of Q in the above [1] And may be substituted with 1 to 3 substituents. For example, C ₁ ~ ₆ alkyl, C ₂ ~ ₆ alkenyl, C ₂ ~ ₆ alkynyl, halogen atom, halogenated C ₁ ~ ₆ alkyl, cyano, amino, hydroxy, carbamoyl, C ₁ ~ ₆ alkoxy, C ₂ ~ ₆ alkenyl oxy, C ₂ ~ ₆ alkynyloxy, C ₁ ~ ₆ alkylthio, C ₁ ~ ₆ alkylsulfinyl, C ₁ ~ ₆ alkylsulfonyl, mono / di C ₁ ~ ₆ alkyl amino, C ₁ ~ ₆ alkoxycarbonyl, C ₂ ~ ₆ alkanoyl, C ₂ ~ ₆ alkanoylamino, hydroxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxy -C ₁ ~ ₆ alkyl, carboxy -C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxycarbonyl -C ₁ ~ ₆ alkyl , carbamoyl -C ₁ ~ ₆ alkyl, N-C ₁ ~ ₆ alkylcarbamoyl -C ₁ ~ ₆ alkyl, N, N-di-C ₁ ~ ₆ alkyl carbamoylthiopheno -C ₁ ~ ₆ alkyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, benzyl, benzoyl, morpholino, oxo, morpholinylcarbonyl, morpholinylsulfonyl sulfonyl, 5-trifluoromethyl-2-yloxy, quinoxaline - Examples of the substituent include 2-yl, (pyridin-4-yl) methyl, 1,2,3-thiadiazolo-4-yl, 1H-pyrazolo-1-yl, 4-chlorophenyl, and the like. Furthermore halogen atoms, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxyl, carbamoyl, C ₁ ~ ₆ alkyl, C ₁ ~ ₆ alkoxy, mono / di C ₁ ~ ₆ alkylamino, di -C ₁ ~ ₆ alkyl carbamoyl, C ₁ ~ ₆ alkoxycarbonyl, N-C ₁ ~ ₆ alkyl Cal Bamoiru, N, N-di-C ₁ ~ ₆ with 1-3 alkylcarbamoyl and C ₂ ~ ₆ alkenoyl amino may be substituted.

Ｒ^１１は、水素原子またはＣ₁〜_４アルキル基を表し、ｒは１または２の整数を表す。
［１−６−ｂ−１］Ｒ^１１は、水素原子であることが好ましい。
［１−６−ｂ−２］式（Ｑ２）は、式（Ｉ）において下記式（Ｂ）のアリールアミノ基、

（式中、Ｒ^１１は、水素原子またはＣ₁〜_４アルキル基を表し、ｒは１または２の整数を
表す。）で表され、当該アリールアミン部分の好ましい例は、以下の式（ｂ１）〜（ｂ１４）が挙げられる。 [1-6-b] In the following formula (Q2),

R ¹¹ represents a hydrogen atom or a C ₁ ~ ₄ alkyl group, r represents an integer of 1 or 2.
[1-6-b-1] R ¹¹ is preferably a hydrogen atom.
[1-6-b-2] Formula (Q2) is an arylamino group of the following formula (B) in formula (I):

(Wherein, R ¹¹ represents a hydrogen atom or a C ₁ ~ ₄ alkyl group, r represents. An integer of 1 or 2) is represented by, preferred examples of the arylamine moiety has the following formula (b1) To (b14).

[1-6-b-3] Preferably, as a tetrahydronaphthylamino group or an indanolamino group having a different configuration of —OR ¹¹ in the formula, the following formula (b1-A) to formula (b14-A, and Formula (b1-B) to formula (b14-B), formula (III-2-B), formula (III-3-A), formula (III-3-B) and formula (III-4-B) There are cases.
In the present specification, in the formula, —OR ¹¹ bonded to a carbon atom with * indicates any one configuration, for example, (S) or (R), for example, Formula (b1-A) and formula (b1-B) represent that they are enantiomers of each other.
In this specification, A and B are the production method F <Step 4>, production method H <Step 3>, production method I <Step 8>, production method J <Step 3>, and production method K < In Step 3> or Production Method L <Step 3>, the racemate is separated by a column for optical isomer separation, and the enantiomer obtained as the first fraction is represented as A, and the enantiomer obtained as the second fraction is represented as B. . Therefore, for example, in the case of the formula (b1-A), the first fraction obtained from the optical isomer separation column or in the case of the formula (b1-B) can be obtained from the optical isomer separation column. It means that it is a part of the formula (B) obtained using each of the second fractions.

Ｒ^１２は、ｉ）ハロゲン原子、好ましくはフッ素原子もしくは塩素原子、より好ましくはフッ素原子であるか、
ｉｉ）ハロゲン原子（好ましくはフッ素原子）１〜５個で置換されていてもよいＣ_１〜_６のアルキル基、好ましくはトリフルオロメチル基であるか、または
ｉｉｉ）基： −Ｚ_１−Ｚ_２−ＯＲ^１３
（ここで、Ｚ_１は単結合、酸素原子、−ＣＨ_２−Ｏ−もしくは−ＮＲ^１４−であり、
Ｒ^１４は、水素原子もしくはＣ_１〜_３のアルキル基であり、
Ｚ_２はメチレン基または直鎖もしくは分枝鎖のＣ_２〜_６のアルキレン基であり、
Ｚ_２は、また炭素鎖上もしくは炭素鎖内に３〜６員のシクロ環が形成されていてもよく、具体的には、Ｚ_２の鎖状の炭素の１つがシクプロピリデン、シクロブチリデン、シクロペンチリデンもしくはシクロヘキシリデン基を形成しているか、
或いは、鎖内に３〜６員のシクロアルカン−ジイル基、例えば、シクロプロパン−１，２−ジイル、シクロブタン−１，３−ジイル、シクロペンタン−１，３−ジイル、シクロヘキサン−１，４−ジイルを含むことができ、
或いは、二重結合もしくは３重結合を１つ有していてもよく、
或いは、Ｒ^１４はＺ_２のアルキレン鎖と一緒になって、双方が結合している窒素原子と一緒に３〜７員の含窒素ヘテロ環基を形成し、具体的には、
−ＮＲ^１４−Ｚ_２−で、１−アジリジニル基、１−アゼチジニル基、１−ピロリジニル基、１−ピペリジニル基を形成し、
更には、上述のＺ_１またはＺ_２の各基における任意の炭素原子は、ハロゲン原子もしくはハロゲン原子１〜５個で置換されていてもよいＣ_１〜_２のアルキル基１〜３個で置換されていてもよく；
−ＯＲ^１３は、かかるＺ_２上のいずれかの炭素原子の置換基であり、
Ｒ^１３は、水素原子またはハロゲン原子１〜５個で置換されていてもよいＣ_１〜_２のアルキル基であり）を表し；
従って、
−Ｚ_１−Ｚ_２−ＯＲ^１３ にて示される基は、
−ＯＲ^１３によって示されるヒドロキシル基、メトキシル基、エトキシル基、ハロゲノメチルオキシ基（例えばトリフルオロメトキシ基）、ハロゲノエチルオキシ基（例えばペンタフルオロエチルオキシ基）のいずれかの極性基もつという特徴を有する。 [1-6-c] In the following formula (Q3),

R ¹² is i) a halogen atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom,
ii) halogen atom (preferably fluorine atom) 1-5 in the optionally substituted _C 1 _{to 6} alkyl groups, or preferably a trifluoromethyl group, or iii) group: _-Z 1 -Z ₂ -OR ¹³
(Wherein Z ₁ is a single bond, an oxygen atom, —CH ₂ —O— or —NR ¹⁴ —;
R ¹⁴ is an alkyl group having a hydrogen atom or a _C 1 _{~ 3,}
Z ₂ is an alkylene group of C ₂ ~ ₆ methylene groups or a linear or branched,
Z ₂ may have a 3- to 6-membered cyclo ring formed on or in the carbon chain. Specifically, one of Z ₂ chain carbons is cyclopropylidene, cyclobutylidene, cyclo Forms a pentylidene or cyclohexylidene group,
Alternatively, a 3-6 membered cycloalkane-diyl group in the chain, such as cyclopropane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclohexane-1,4- Can contain giles,
Alternatively, it may have one double bond or triple bond,
Alternatively, R ¹⁴ together with the alkylene chain of Z ₂ forms a 3-7 membered nitrogen-containing heterocyclic group together with the nitrogen atom to which both are bonded, specifically,
-NR ¹⁴ -Z _2- forms a 1-aziridinyl group, 1-azetidinyl group, 1-pyrrolidinyl group, 1-piperidinyl group,
Furthermore, any carbon atoms in each group Z ₁ or Z ₂ described above is substituted with an alkyl group 1 to 3 halogen atoms or a halogen atom optionally C ₁ optionally substituted with 1-5 _1-2 May be;
-OR ¹³ is any substituent carbon atoms on such _{Z 2,}
R ¹³ represents a hydrogen atom or optionally substituted with one to five halogen atoms is an alkyl group which may _C 1 _{~ 2);}
Therefore,
The group represented by —Z ₁ —Z ₂ —OR ¹³ is
It has a characteristic of having any polar group of hydroxyl group, methoxyl group, ethoxyl group, halogenomethyloxy group (for example, trifluoromethoxy group) or halogenoethyloxy group (for example, pentafluoroethyloxy group) represented by -OR ¹³ .

[1-6-c-1]
Typical examples of the group represented by —Z ₁ —Z ₂ —OR ¹³ are groups exemplified below (v represents an integer of 0 or 1).
[1-6-c-1a]-Representative examples of groups represented by -Z ₁ -Z ₂ -OR ¹³ :

[1-6-c-1b] Representative examples of groups represented by -Z ₁ -Z ₂ -OR ¹³ :

[1-6-c-1c] Representative examples of groups represented by -Z ₁ -Z ₂ -OR ¹³ :

[1-6-d] G ₁ and G ₂ are each independently a nitrogen atom or C—R ^15.
(R ¹⁵ is a hydrogen atom, a halogen atom or C ₁ ~ ₃ alkyl group halogen atom 1-5 straight optionally substituted or branched, or a group:
-Z ₁ -Z ₂ -OR ¹³
(Z ₁ , Z ₂ , R ¹³ and R ¹⁴ are the same as defined above), and a preferred mode thereof is appropriately selected from [1-6-c-1].
[1-6-e] In the combination of the embodiment [1-6-c] and [1-6-d], “however, _one of R ⁷ in G ₁ or G ₂ or any one of R ¹² Only
Group:
-Z ₁ -Z ₂ -OR ¹³
(The definition of Z ₁ , Z ₂ , R ¹³ , R ¹⁴ is the same as described above).
At this time, in the following partial structure of the formula (Q3):

このとき、Ｒ^１２は、ｉ）ハロゲン原子、好ましくはフッ素原子もしくは塩素原子、より好ましくはフッ素原子であるか、ｉｉ）ハロゲン原子（好ましくはフッ素原子）１〜５個で置換されていてもよいＣ_１〜_６のアルキル基、好ましくはトリフルオロメチル基であり、
Ｒ^１５は水素原子、ハロゲン原子（好ましくはフッ素原子）、もしくはハロゲン原子１〜５個で置換されていてもよい直鎖もしくは分枝鎖のＣ_１〜_３のアルキル基（好ましくはトリフルオロメチル基）である。
［１−７］態様［１］の式（Ｉ）で表される化合物において、Ｚは、＝ＣＲ^６−（Ｒ^６は水素原子または前記Ｒ^１と同じ意味を表す）または＝Ｎ−を表す。Ｚが、＝ＣＲ^６−（Ｒ^６は水素原子または前記Ｒ^１と同じ意味を表す）であることが好ましく、Ｒ^６は水素原子であることがより好ましい。
［１−８］態様［１］の式（Ｉ）で表される化合物において、Ｗを含む環の員数は、５〜８であることが好ましく、５〜７であることがより好ましく、５または６であることが更に好ましい。Ｌ_１及びＬ_２が、ともに単結合である場合には、Ｗはフェニル環に直結する。 [1-6-e-1] The following Ar1 to Ar5 are preferable.

At this time, R ¹² is i) a halogen atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom, or ii) may be substituted with 1 to 5 halogen atoms (preferably fluorine atoms). alkyl group of C ₁ ~ _6, preferably trifluoromethyl group,
R ¹⁵ is a hydrogen atom, a halogen atom (preferably fluorine atom), or an alkyl group of C ₁ ~ ₃ good straight or branched chain optionally substituted with one to five halogen atoms (preferably trifluoromethyl group ).
[1-7] In the compound represented by the formula (I) of the embodiment [1], Z represents ═CR ⁶ — (R ⁶ represents a hydrogen atom or the same meaning as R ¹ described above) or ═N—. . Z is preferably ═CR ⁶ — (R ⁶ represents a hydrogen atom or the same meaning as R ¹ described above), and R ⁶ is more preferably a hydrogen atom.
[1-8] In the compound represented by the formula (I) of the embodiment [1], the number of rings containing W is preferably 5-8, more preferably 5-7, 5 or More preferably, it is 6. When L ₁ and L ₂ are both single bonds, W is directly connected to the phenyl ring.

As described above, the compounds represented by the formula (I) of the present invention by combining each of the embodiments [1-1] to [1-8] of the present invention and preferred embodiments thereof, and further appropriately defining the substituents. The preferred embodiments can be arbitrarily formed.
[1-9] Moreover, the following are illustrated as a preferable compound.
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-8 -Yl) acrylamide (Example 1);
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) acrylamide (Example 2);
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7- Yl) acrylamide (Example 3);
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3,4-dihydro-1-methyl-1H-quinoline-2- On-7-yl) acrylamide (Example 4);
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [ 2,1] thiazin-7-yl) acrylamide (Example 5);
(E) -3- (5-Fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-8 -Yl) acrylamide (Example 6);
(E) -3- (5-Fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) acrylamide (Example 7);
(E) -3- (5-Fluoro-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-8 -Yl) acrylamide (Example 8);
(E) -3- (5-Fluoro-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) acrylamide (Example 9);
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 10);

(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine- 7-yl) acrylamide (Example 11);
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1-methyl-1H-quinolin-2-one-7-yl) Acrylamide (Example 12);
(E) -3- (1-Cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1-methyl-1H-benzo [2, 1] thiazin-7-yl) acrylamide (Example 13);
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,3-dimethyl-1H-indoline-2-one-6-yl) acrylamide (Examples) 14);
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Examples) 15);
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine- 5-yl) acrylamide (Example 16);
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinazolin-2-one-5-yl) acrylamide (Examples) 17);
(E) -3- (1-Cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (2,3-dihydro-3-oxo-4H-1,4-benzoxazin-8-yl ) Acrylamide (Example 18);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 19);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Examples) 20);

(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1-methyl-1H-quinazolin-2-one-5-yl) Acrylamide (Example 21);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1-ethyl-1H-quinazolin-2-one-5-yl) Acrylamide (Example 22);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-5-yl) acrylamide (implementation) Example 23);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N-((2R) -2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl ) Acrylamide (Example 24);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N-((2S) -2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl ) Acrylamide (Example 25);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acrylamide (A ) (Example 26);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acrylamide (B ) (Example 27);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acrylamide (A ) (Example 28);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acrylamide (B ) (Example 29);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acrylamide (A) (Example 30);

(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acrylamide (B) (Example 31);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acrylamide (A) (Example 32);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acrylamide (B) (Example 33);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-1-hydroxy-1H-inden-4-yl) acrylamide (A) (Example 34);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-1-hydroxy-1H-inden-4-yl) acrylamide (B) (Example 35);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-2-hydroxy-1H-inden-5-yl) acrylamide (A) (Example 36);
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-2-hydroxy-1H-inden-5-yl) acrylamide (B) (Example 37);
(E) -3- (5-Chloro-1-cyclohexylmethylindol-2-yl) -N- (3,5-difluoro-4- (1,1-dimethyl-2-hydroxyethyloxy) phenyl) acrylamide ( Example 38);
(E) -3- (1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 39);
(E) -3- (1-cyclohexylmethyl-5-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 40);

(E) -3- (1-Cyclohexylmethyl-5-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Examples) 41);
(E) -3- (1-cyclohexylmethyl-5-isopropyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 42);
(E) -3- (1-cyclohexylmethyl-5-isopropyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Examples) 43);
(E) -3- (1-cyclohexylmethyl-5-methoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 44);
(E) -3- (1-Cyclohexylmethyl-5-methoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Examples) 45);
(E) -3- (1-cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide ( Example 46);
(E) -3- (1-cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide ( Example 47);
(E) -3- (1-Cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] Thiazin-5-yl) acrylamide (Example 48);
(E) -3- (1-cyclohexylmethyl-6-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 49);
(E) -3- (1-Cyclohexylmethyl-6-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Examples) 50);

(E) -3- (5-Fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 51);
(E) -3- (5-Fluoro-1-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 52) );
(E) -3- (1-Ethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 53) );
(E) -3- (5-Fluoro-1-neopentyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 54) );
(E) -3- (5-Fluoro-1- (2-methoxyethyl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Acrylamide (Example 55);
(E) -3- (5-Fluoro-1- (2-methoxyethyl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) Acrylamide (Example 56);
(E) -3- (1- (2- (N, N-dimethylamino) ethyl) -5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinoline-2 -On-7-yl) acrylamide (Example 57);
(E) -3- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinoline-2- On-7-yl) acrylamide (Example 58);
(E) -3- (5-Fluoro-1-isopropyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 59) );
(E) -3- (1-cyclohexyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 60) );

(E) -3- (1-Cyclohexyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Example 61) );
(E) -3- (1-Cyclohexyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine-5 -Yl) acrylamide (Example 62);
(E) -3- (1-Cyclopropyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 63);
(E) -3- (1-Cyclopropyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Examples) 64);
(E) -3- (1-tert-butyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (implemented) Example 65);
(E) -3- (1-tert-butyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (implemented) Example 66);
(E) -3- (5-Fluoro-1- (tetrahydro-4H-pyran-4-yl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one -5-yl) acrylamide (Example 67);
(E) -3- (5-Fluoro-1- (tetrahydro-4H-pyran-4-yl) -1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H -Benzo [2,1] thiazin-5-yl) acrylamide (Example 68);
(E) -3- (1-cyclohexylsulfonyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 69);
(E) -3- (1-cyclohexylsulfonyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Examples) 70);

(E) -3- (5-Fluoro-1-isopropylsulfonyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 71);
(E) -3- (1-Cyclohexylcarbonyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Examples) 72);
(E) -3- (5-Fluoro-1-pivaloyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 73) );
(E) -3- (5-Chloro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) acrylamide (Example 74);
(E) -3- (5-Chloro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) acrylamide (Example 75);
(E) -3- (5-Chloro-1-ethyl-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine-5 -Yl) acrylamide (Example 76);
(E) -3- (5-Chloro-1-cyclohexyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 77) );
(E) -3- (5-Chloro-1-cyclohexyl-1H-indol-2-yl) -N-((2R) -2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) Acrylamide (Example 78);
(E) -3- (5-Chloro-1-cyclohexyl-1H-indol-2-yl) -N-((2S) -2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) Acrylamide (Example 79);
(E) -3- (1-tert-butyl-5-chloro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (implementation) Example 80);

(E) -3- (5-Chloro-1-tert-butyl-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine -5-yl) acrylamide (Example 81);
(E) -3- (1- (2- (4-morpholinyl) ethyl) -1H-indol-2-yl) -N- (quinolin-7-yl) acrylamide (Example 82);
(E) -3- (1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) acrylamide (Example 83);
(E) -3- (5-Methoxy-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) acrylamide (Example 84);
(E) -3- (5-Methoxy-1- (3-trifluoromethylbenzyl) indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 85);
(E) -3- (1- (3-Fluorobenzyl) -5-methoxy-1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinolin-5-yl ) Acrylamide (Example 86);
(E) -3- (1- (3-Fluorobenzyl) -5-methoxyindol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (implemented) Example 87);
(E) -3- (5-Chloro-1- (3-trifluoromethylbenzyl) -1H-pyrrolo [2,3-c] pyridin-2-yl) -N- (2-hydroxy-1,2, 3,4-tetrahydronaphthalen-8-yl) acrylamide (Example 88);
(E) -3- (5-Chloro-1- (3-trifluoromethylbenzyl) -1H-pyrrolo [2,3-c] pyridin-2-yl) -N- (3-hydroxy-1,2, 3,4-tetrahydroquinolin-5-yl) acrylamide (Example 89);
(E) -3- (5-Chloro-1-cyclohexylmethyl-3-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Acrylamide (Example 90);

(E) -3- (5-Fluoro-1H-indol-2-yl) -3-phenyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 91) );
(E) -3- (5-Fluoro-1H-indol-2-yl) -3-methyl-N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Example 92) );
(E) -3- (5-Chloro-1-ethyl-1H-indol-2-yl) -3-methyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 93);
(E) -3- (5-Chloro-1H-indol-2-yl) -3-ethyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 94) );
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -3-ethyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Acrylamide (Example 95);
(E) -3- (5-Chloro-1-ethyl-3-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 96);
(E) -3- (5-Chloro-1-ethyl-3-methoxymethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Acrylamide (Example 97);
Alternatively, pharmaceutically acceptable salts thereof, solvates thereof, or optically active forms thereof can be mentioned.

（式中、ｎは、０〜２の整数を表し；
Ｒ^１A は、ハロゲン原子、Ｃ_１〜_４のアルキル基、Ｃ_１〜_４のアルコキシル基、Ｃ_１〜_６の直鎖もしくは分枝鎖のヒドロキシアルキル基、Ｃ_１〜_２のアルコキシル基で置換された直鎖もしくは分枝鎖のＣ_１〜_６アルキル基、または、これらの基の炭素鎖が１〜５個のハロゲン原子で任意に置換されている基から選ばれる基を表し；
Ｒ²は、水素原子、Ｃ_１〜_４のアルキル基またはＣ_１〜_４のアルコキシル基を表し、当
該アルキル基またはアルコキシル基は、ハロゲン原子１〜５個で、またはヒドロキシル基、ハロゲン原子１〜５個で置換されていてもよいＣ_１〜_２のアルキル基もしくはＣ_１〜_２のアルコキシル基、及びＣ_１〜_３のアルキル基もしくはヒドロキシアルキル基１〜２個で置換されていてもよいアミノ基から任意に選ばれる基１〜３個で置換されていてもよく；
Ｒ^３は、基：−Ａ_１−Ａ_２を表し、Ａ_１は単結合、メチレン基、Ｃ_２〜_６のアルキレン基、カルボニル基またはスルホニル基を表し、Ａ_２は、水素原子、Ｃ_１〜_６のアルキル基、Ｃ_３〜_６のシクロアルキル基、アリール基またはヘテロ環基を表し、当該Ａ_２の炭素原子は、ハロゲン原子１〜５個で、またはヒドロキシル基、ハロゲン原子１〜５個で置換されていてもよいＣ_１〜_２のアルキル基もしくはＣ_１〜_２のアルコキシル基、及びＣ_１〜_３のアルキル基もしくはヒドロキシアルキル基１〜２個で置換されていてもよいアミノ基から任意に選ばれる基１〜３個で置換されていてもよく；
Ｒ^４及びＲ^５は、各々独立に、水素原子、Ｃ_１〜_４のアルキル基またはフェニル基を表し；
Ｑ’は、置換されていてもよい二環性のヘテロ環基もしくはアリール基、或いはｐ位に置換基を有する単環のアリールもしくはヘテロ環基を表し；
Ｚは、＝ＣＲ^６−（Ｒ^６は水素原子または前記Ｒ^１と同じ意味を表す）または＝Ｎ−を表す）。 [1-10] A 1-10th aspect of the present invention is a compound described below, a salt thereof, or a solvate thereof. In the compound represented by the formula (I) of the embodiment “1”, preferred examples of the compound include a compound represented by the following formula (I ′), a salt thereof, or a solvate thereof.

(In the formula, n represents an integer of 0 to 2;
R ^1A is substituted with a halogen _atom, C 1 _{~ 4} alkyl _group, an alkoxyl group of C 1 _{~ 4,} linear or branched hydroxyalkyl group of _{C 1 ~ 6, C 1 ~} 2 alkoxyl group It represents a straight-chain or C ₁ ~ ₆ alkyl group branched or, group in which the carbon chain is selected from the group that is optionally substituted with 1-5 halogen atoms of these groups;
R ² represents a hydrogen _atom, an alkyl group, or _C 1 _{~ 4} alkoxyl group C 1 _{~ 4,} wherein the alkyl group or alkoxyl group, with 1-5 halogen atoms or a hydroxyl group, a halogen atom 1-5 pieces with optionally substituted C ₁ to ₂ alkyl or C ₁ - ₂ alkoxyl group, and C ₁ - ₃ alkyl or hydroxyalkyl group 1-2 amino group which may be substituted by Optionally substituted with 1 to 3 groups of choice;
R ³ is a group: represents _{-A 1 -A 2, A} 1 represents a single bond, a methylene _group, an alkylene group of C 2 _{~ 6,} a carbonyl group or a sulfonyl group, _{A 2} represents a hydrogen _{atom, C} 1 ~ ₆ alkyl _group, a cycloalkyl group of C 3 _{~ 6,} an aryl group or a heterocyclic group, a carbon atom of the _{a 2} is a 1-5 halogen atoms, or hydroxyl group, with 1-5 halogen atoms optionally substituted C ₁ ~ ₂ alkyl or C ₁ ~ ₂ alkoxyl group, and optionally from C ₁ ~ ₃ alkyl or hydroxyalkyl group 1-2 amino group which may be substituted by Optionally substituted with 1 to 3 groups selected;
R ⁴ and ^{R 5} each independently represent a hydrogen _atom, an alkyl group or a phenyl group of C 1 _{~ 4;}
Q ′ represents an optionally substituted bicyclic heterocyclic group or aryl group, or a monocyclic aryl group or heterocyclic group having a substituent at the p-position;
Z ^{is, =} CR ⁶ - ^(R 6 has the same meaning represents a hydrogen atom or the ^{R 1)} represents a or = N-).

ここで、Ｑ１、Ｑ２、Ｑ３における、Ｒ^７、Ｒ^８、Ｒ^９Ａ、Ｒ^９Ｂ、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｌ_１、Ｌ_２、Ｗ、Ｇ_１、Ｇ_２、Ｚ_１、Ｚ_２、ｊ、ｋ、ｔ、ｒ、ｖの定義は、前記態様の［１−６−ａ］〜［１−６−ｃ］のいずれかの定義と同じである。 Here, in the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and n represent the same meaning as the above-mentioned embodiment [1], and the preferred embodiment is [1-1]. To [1-5] and [1-7] to [1-9].
Q ′ represents an optionally substituted bicyclic heterocyclic group or aryl group, or a monocyclic aryl group or heterocyclic group having a substituent at the p-position,
More specifically, Q ′ includes the following formula (Q1), formula (Q2), and formula (Q3),

Here, Q1, Q2, in ^{Q3, R 7, R 8,} R 9A, R 9B, R 10, R 11, R 12, R 13, R 14, R 15, L 1, L 2, W, G 1 , G ₂ , Z ₁ , Z ₂ , j, k, t, r, and v are the same as defined in any one of [1-6-a] to [1-6-c] of the above aspect. .

（式中、Ｒ¹、Ｒ²、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、ｎ、Ｒ^７、Ｒ^８、Ｒ^９Ａ、Ｒ^９Ｂ、Ｒ^１０、Ｌ_１、Ｌ_２、Ｗ、ｊ、ｋ、ｔの定義は前記と同一の意味を表す。）
より具体的には、Ｒ¹、Ｒ²、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、ｎ、Ｒ^７、Ｒ^８、Ｒ^９Ａ、Ｒ^９Ｂ、Ｒ^１０、Ｌ_１、Ｌ_２、Ｗ、ｊ、ｋ、ｔの定義及び好ましい態様は、前記態様［１−１］〜［１−５］、［１−６−ａ］、及び［１−７］〜［１−９］のいずれかと同じである。 [1-11] A 1-11th aspect of the present invention is a compound described below, a salt thereof, or a solvate thereof. In the compound represented by the formula (I) of the embodiment “1”, preferred examples of the compound include a compound represented by the following formula (IA), a salt thereof, or a solvate thereof.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, R ⁷ , R ⁸ , R ^9A , R ^9B , R ¹⁰ , L ₁ , L ₂ , W, j, k , T has the same meaning as described above.)
More specifically, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, R ⁷ , R ⁸ , R ^9A , R ^9B , R ¹⁰ , L ₁ , L ₂ , W, j , K, and t are defined and preferred in the same manner as any one of the above-described embodiments [1-1] to [1-5], [1-6-a], and [1-7] to [1-9]. is there.

（式中、Ｒ¹、Ｒ²、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、ｎ、Ｒ^１１、ｒの定義は前記と同一の意味を表す。）
より具体的には、Ｒ¹、Ｒ²、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、ｎ、Ｒ^１１、ｒの定義及び好ましい態様は、前記態様［１−１］〜［１−５］、［１−６−ｂ］、及び［１−７］〜［１−９］のいずれかと同じである。 [1-12] A 1-12th aspect of the present invention is a compound described below, a salt thereof, or a solvate thereof. In the compound represented by the formula (I) of the embodiment “1”, preferred examples of the compound include a compound represented by the following formula (IB), a salt thereof, or a solvate thereof.

(In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, R ¹¹ , r represent the same meaning as described above.)
More specifically, the definitions and preferred embodiments of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, R ¹¹ , r are the above-described embodiments [1-1] to [1-5]. , [1-6-b], and [1-7] to [1-9].

（式中、Ｒ¹、Ｒ²、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、ｎ、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｇ_１、Ｇ_２、Ｚ_１、Ｚ_２、ｖの定義は前記と同一の意味を表す。）
より具体的には、Ｒ¹、Ｒ²、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、ｎ、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｇ_１、Ｇ_２、Ｚ_１、Ｚ_２、ｖの定義及び好ましい態様は、前記態様［１−１］〜［１−５］、［１−６−ｃ］、及び［１−７］〜［１−９］のいずれかと同じである。 [1-13] A first to thirteenth embodiment of the present invention is a compound described below, a salt thereof, or a solvate thereof. In the compound represented by the formula (I) of the embodiment “1”, preferred examples of the compound include a compound represented by the following formula (IC), a salt thereof, or a solvate thereof.

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , G ₁ , G ₂ , Z ₁ , Z ₂ , v The definition represents the same meaning as above.)
More specifically, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , G ₁ , G ₂ , Z ₁ , Z ₂ , The definition and preferred embodiment of v are the same as any of the above embodiments [1-1] to [1-5], [1-6-c], and [1-7] to [1-9].

[2] The second aspect of the present invention contains at least one of the compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. It is a pharmaceutical composition characterized by these.
More specifically, the following embodiments are preferable.
[2-1] The 2-1 aspect of the present invention is characterized in that it contains at least one of a compound represented by the following formula (I ′), a salt thereof or a solvate thereof as an active ingredient. And a pharmaceutical composition.
[2-2] The 2-2 aspect of the present invention contains at least one of a compound represented by the following formula (IA), a salt thereof or a solvate thereof as an active ingredient. A pharmaceutical composition characterized.
[2-3] A 2-3 aspect of the present invention contains at least one of a compound represented by the following formula (IB), a salt thereof or a solvate thereof as an active ingredient. A pharmaceutical composition characterized.
[2-4] The 2-4th aspect of the present invention contains at least one of a compound represented by the following formula (IC), a salt thereof or a solvate thereof as an active ingredient. A pharmaceutical composition characterized.
[2-5] The 2-5th aspect of the present invention contains, as an active ingredient, at least one of the compounds described as preferred compounds in the above aspect [1-9], or a salt thereof or a solvate thereof. It is a pharmaceutical composition characterized by the above-mentioned.

[3] A third aspect of the present invention contains at least one of the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. Is a TRPV1 receptor antagonist.
More specifically, the following embodiments are preferable.
[3-1] The 3-1 aspect of the present invention is characterized in that it contains at least one of a compound represented by the following formula (I ′), a salt thereof or a solvate thereof as an active ingredient. And a TRPV1 receptor antagonist.
[3-2] The 3-2 aspect of the present invention contains at least one of a compound represented by the following formula (IA), a salt thereof or a solvate thereof as an active ingredient. Characteristic TRPV1 receptor antagonist.
[3-3] The 3-3 aspect of the present invention contains at least one of a compound represented by the following formula (IB), a salt thereof or a solvate thereof as an active ingredient. Characteristic TRPV1 receptor antagonist.
[3-4] The third to fourth aspects of the present invention contain at least one of a compound represented by the following formula (IC), a salt thereof or a solvate thereof as an active ingredient. Characteristic TRPV1 receptor antagonist.
[3-5] The third to fifth aspects of the present invention contain, as an active ingredient, at least one of the compounds described as preferred compounds in the above aspect [1-9], or a salt thereof or a solvate thereof. It is a TRPV1 receptor antagonist characterized by the above-mentioned.

In the present specification, particularly in the third aspect of the present invention, the “TRPV1 receptor antagonist” is one aspect of the “TRPV1 receptor modulator”. “TRPV1 receptor modulator” means an agent containing a compound that modulates the function of TRPV1 receptor, and more specifically, an agent containing a compound that suppresses activation of TRPV1 receptor. The compound includes a compound that binds to the TRPV1 receptor and antagonizes an endogenous ligand to suppress TRPV1 receptor activation (TRPV1 receptor antagonist), and continuously activates the TRPV1 receptor, There are compounds (TRPV1 receptor agonists) that desensitize the nerve in which the receptor is present, thereby inhibiting subsequent activation of the receptor. Therefore, TRPV1 modulator is a general term for TRPV1 receptor antagonists and TRPV1 receptor agonists. Antagonists include neutral antagonists and inverse agonists, and agonists include full and partial agonists. The partial agonist acts as an antagonist depending on conditions. The TRPV1 receptor modulator of the present invention is preferably a TRPV1 receptor antagonist. The TRPV1 receptor antagonists of the present invention include neutral antagonists, inverse agonists and partial agonists. The TRPV1 antagonist of the present invention is expected to show promising preventive or therapeutic effects for the following various diseases. Specifically, acute pain, chronic pain, neuropathic pain, fibromyalgia , Postherpetic neuralgia, trigeminal neuralgia, low back pain, pain after spinal cord injury, lower limb pain, causalgia, diabetic neuralgia, pain due to edema, burns, sprains, fractures, postoperative pain, peri-arthritis, osteoarthritis, arthritis , Rheumatoid arthritis pain, inflammatory pain, cancer pain, migraine, headache, toothache, neuralgia, fibromyalgia, muscle pain, hyperalgesia, angina or menstrual pain, neuropathy, nerve damage, neurodegeneration , Chronic obstructive pulmonary disease (COPD), asthma, airway hypersensitivity, wheezing, cough, rhinitis, inflammation of mucous membranes such as eyes, neurological skin diseases, inflammatory skin diseases such as psoriasis and eczema, edema, allergic diseases, gastroduodenum Ulcer, large ulcer Inflammation, irritable colon, Crohn's disease, urinary incontinence, urge incontinence, overactive bladder, cystitis, nephritis, pancreatitis, uveitis, visceral disorder, ischemia, stroke, ataxia, obesity, sepsis, pruritus Treatment of diabetes and diabetes. In particular, promising therapeutic effects can be expected for neuropathic pain, fibromyalgia, inflammatory pain, and urinary incontinence.

[4] A fourth aspect of the present invention contains at least one of the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. A preventive and / or therapeutic agent for pain.
More specifically, the following embodiments are preferable.
[4-1] A fourteenth aspect of the present invention includes at least one of a compound represented by the following formula (I ′), a salt thereof or a solvate thereof as an active ingredient. And a preventive and / or therapeutic agent for pain.
[4-2] The 4-2th aspect of the present invention contains at least one of a compound represented by the following formula (IA), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for pain.
[4-3] The 4-3 aspect of the present invention contains at least one of a compound represented by the following formula (IB), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for pain.
[4-4] A fourth to fourth aspect of the present invention contains at least one of a compound represented by the following formula (IC), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for pain.
[4-5] The 4-5th aspect of the present invention contains, as an active ingredient, at least one of the compounds described as preferred compounds in the above aspect [1-9], or a salt thereof or a solvate thereof. This is a prophylactic and / or therapeutic agent for pain.

[5] A fifth aspect of the present invention contains at least one of the compound represented by the formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. It is a preventive and / or therapeutic agent for neuropathic pain, characterized by
More specifically, the following embodiments are preferable.
[5-1] The 5-1 aspect of the present invention is characterized in that it contains at least one of a compound represented by the following formula (I ′), a salt thereof or a solvate thereof as an active ingredient. And a preventive and / or therapeutic agent for neuropathic pain.
[5-2] A 5-2th aspect of the present invention contains at least one of a compound represented by the following formula (IA), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for neuropathic pain.
[5-3] The 5-3rd aspect of the present invention contains at least one of a compound represented by the following formula (IB), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for neuropathic pain.
[5-4] A fifth to fourth aspect of the present invention contains at least one of a compound represented by the following formula (IC), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for neuropathic pain.
[5-5] A fifth to fifth aspect of the present invention is characterized by containing the compound described in the above [1-9] as a preferred compound, or a salt thereof or a solvate thereof as an active ingredient. It is a preventive and / or therapeutic agent for neuropathic pain.

[6] A sixth aspect of the present invention contains at least one of the compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Is a prophylactic and / or therapeutic agent for inflammatory pain.
More specifically, the following embodiments are preferable.
[6-1] The 6-1 aspect of the present invention comprises at least one of a compound represented by the following formula (I ′), a salt thereof or a solvate thereof as an active ingredient. And a preventive and / or therapeutic agent for inflammatory pain.
[6-2] A 6-2 aspect of the present invention contains at least one of a compound represented by the following formula (IA), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for inflammatory pain.
[6-3] The 6-3rd aspect of the present invention contains at least one of a compound represented by the following formula (IB), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for inflammatory pain.
[6-4] A sixth to fourth aspect of the present invention contains at least one of a compound represented by the following formula (IC), a salt thereof or a solvate thereof as an active ingredient. It is a prophylactic and / or therapeutic agent for inflammatory pain.
[6-5] A sixth to fifth aspect of the present invention is characterized in that it contains, as an active ingredient, a compound described as a preferred compound in the above aspect [1-9], or a salt or solvate thereof. It is a preventive and / or therapeutic agent for inflammatory pain.

In the second to sixth aspects, and their preferred aspects, more preferred substituents or combinations thereof are described in the first aspect.
In each embodiment described in [1] to [6] of the present invention, TRPV1 receptor antagonistic activity (for example, Experimental Example (1)-(b) described later: Measurement of Ca inflow using FDSS-6000) ), It is preferable to use a compound having an IC ₅₀ value of 1 μM or less, preferably 100 nM or less, more preferably 30 nM or less, and still more preferably 10 nM or less.
In the embodiment of the present invention, the “therapeutic agent” is intended to include not only treatment of a disease or symptom but also improvement of the disease or symptom.

  In all of the above embodiments, when the term “compound” is used, “a pharmaceutically acceptable salt thereof” is also referred to. In addition, the compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various stereoisomers such as geometric isomers, tautomers, optical isomers, and isolated compounds. It is. Isolation and purification of such stereoisomers can be carried out by those skilled in the art through conventional techniques through preferential crystallization, optical resolution using column chromatography or asymmetric synthesis.

The compound represented by the formula (I) of the present invention may form an acid addition salt. Depending on the type of substituent, a salt with a base may be formed. Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid , Acetic acid, Propionic acid, Butyric acid, Valeric acid, Enanthic acid, Capric acid, Myristic acid, Palmitic acid, Stearic acid, Lactic acid, Sorbic acid, Mandelic acid and other aliphatic monocarboxylic acids, Benzoic acid, Salicylic acid and other aromatic monocarboxylic acids Organic carboxylic acids such as aliphatic dicarboxylic acids such as carboxylic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acid such as citric acid; methanesulfonic acid, ethanesulfonic acid Organic sulfonic acids such as aliphatic sulfonic acids such as 2-hydroxyethanesulfonic acid, aromatic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid Acid addition salts with acidic amino acids such as aspartic acid and glutamic acid, and salts with metals such as alkali metals or alkaline earth metals such as sodium, potassium, magnesium and calcium, methylamine, ethylamine, ethanolamine, pyridine , Salts with organic bases such as lysine, arginine, ornithine, ammonium salts and the like.
These salts can be obtained by a conventional method, for example, by mixing an equivalent amount of the compound of the present invention with a desired acid or base, and collecting the desired salt by filtration or distilling off the solvent. Moreover, this invention compound or its salt can form solvates with solvents, such as water, ethanol, and glycerol.

The salt of the compound of the present invention includes a mono salt and a di salt. Alternatively, the compound of the present invention can form both an acid addition salt and a base salt at the same time depending on the side chain substituent.
Furthermore, the present invention includes hydrates of the compounds represented by the formula (I) of the present invention, various pharmaceutically acceptable solvates, crystal polymorphs, and the like. Of course, the present invention is not limited to the compounds described in the examples below, but includes all of the compounds represented by the formula (I) or pharmaceutically acceptable salts of the present invention. It is.

[Method for producing compound of the present invention]
The compound represented by formula (I) and related compounds used in the present invention can be obtained by the production method shown below. Hereinafter, each reaction process will be described.
The reaction conditions in the production method are as follows unless otherwise specified. The reaction temperature is in the range from −78 ° C. to the temperature at which the solvent is refluxed, and the reaction time is the time for which the reaction proceeds sufficiently. Examples of the solvent inert to the reaction include aromatic hydrocarbon solvents such as toluene, xylene, and benzene, polar solvents such as alcohols such as methanol and ethanol, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and water. , Basic solvents such as triethylamine and pyridine, organic acid solvents such as acetic acid, halogen solvents such as chloroform, dichloromethane and 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, or these It is a mixed solvent and is appropriately selected depending on the reaction conditions. Base is an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium hydrogen carbonate, or triethylamine, diethylamine, pyridine, N, N-dialkylaniline, lithium diisopropylamide An organic base such as lithium bis (trimethylsilyl) amide, which is an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid. However, it is not necessarily limited to what was described above.

The compound represented by the formula (I) which is the compound of the present invention and a salt thereof can be easily produced from a commercially available compound or a commercially available compound by a method known in the literature, etc. and produced according to the production method shown below. Can do.
Further, the present invention is not limited to the manufacturing method described below.

Hereinafter, the production method will be described in detail.
Formula (I), Formula (V), Formula (Va), Formula (Va ′), Formula (Vb), Formula (Vc), Formula (Vc ′) in the following description ), Formula (Vd), formula (Vd ′), formula (Ve), formula (VI), formula (VI-a), formula (VI-a ′), formula (VI-b) , Formula (VI-b ′), formula (VI-c), (VI-c ′), formula (VI-d), (VI-d ′), formula (VI-e), (VI-e ′) , Formula (VI-f), (VI-f ′), formula (VI-g), formula (VI-h), formula (VI-i), formula (VI-j), formula (VI-k), R ¹ , R ² , R ³ in the compounds represented by formula (VI-l), formula (VI-m), formula (VI-n), formula (VI-o), formula (VI-p) , R
⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^9A , R ^9B , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , G ₁ , G ₂ , L ₁ , L ₂ , Q, W, Z, j, k, n, r, and t are the same as the previous definitions described in the formula (I) unless otherwise specified. R ^{3 'is, R} 3 excluding a hydrogen atom, X is a halogen (F, Cl, Br, I ) leaving substituent such as, X' is halogen or N- methoxy -N- methylamino group Y is a halogen, boric acid, boric acid ester, imidic acid, formyl group, and oxygen atom, M is X ⁻ Ph ₃ P ⁺ (X is halogen), Ph ₃ P, (R ^B ₂ O) ₂ P (═O), M ′ represents Li, MgX (X is halogen) or the like.

式（Ｖ）の化合物、および式（ＶＩ）の化合物を用い、文献公知の方法、例えば（実験化学講座 第４版 ２２ 有機合成ＩＶ 酸・アミノ酸・ペプチド、１９１−３０９頁、１９９２年、丸善）等に記載された方法に準じて、１，３−ジシクロヘキシルカルボジイミド（ＤＣＣ）、１−エチル−３−（３’−ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣ・ＨＣｌ）、ベンゾトリアゾール−１−イロキシトリス（ジメチルアミノ）ホスホニウムヘキサフルオロホスフェイト（ＢＯＰ試薬）、ビス（２−オキソ−３−オキサゾリジニル）ホスフィニッククロリド（ＢＯＰ−Ｃｌ）、２−クロロ−１，３−ジメチルイミダゾリニウムヘキサフルオロホスフェイト（ＣIＰ）、４−（４，６−ジメトキシ
−１，３，５−トリアジン−２−イル）−４−メチルモルホリニウムクロリド（ＤＭＴＭＭ）等の縮合剤の存在下、ジクロロメタン、クロロホルム等のハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、トルエン、ベンゼン等の芳香族炭化水素系溶媒、Ｎ，Ｎ−ジメチルホルムアミド等の極性溶媒、メタノール、エタノール、２−プロパノール等のアルコール系溶媒等の反応に関与しない溶媒中、トリエチルアミン、ピリジン等の塩基の存在下または非存在下、０℃から溶媒が還流する温度で反応させることにより、式（Ｉ）の化合物を製造することができる。また、式（Ｖ）の化合物を酸クロライドに変換した場合（実験化学講座 第４版 ２２ 有機合成ＩＶ 酸・アミノ酸・ペプチド、１４４−１４６頁、１９９２年、丸善）等に記載された方法に準じて、トリエチルアミン、ピリジン等の塩基の存在下、ジクロロメタン、クロロホルム等のハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン等のエーテル系溶媒、トルエン、ベンゼン等の芳香族炭化水素系溶媒、Ｎ，Ｎ−ジメチルホルムアミド等の極性溶媒等の反応に関与しない溶媒中、０℃から溶媒が還流する温度で反応させることにより、式（Ｉ）の化合物を同様に製造することができる。 The compound represented by the formula (I) is obtained by a condensation reaction between a carboxylic acid represented by the formula (V) and an amine represented by the formula (VI).
(Reaction formula)

A method known in the literature using the compound of formula (V) and the compound of formula (VI), for example (Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 191-309, 1992, Maruzen) 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), benzotriazole-1-yloxytris ( Dimethylamino) phosphonium hexafluorophosphate (BOP reagent), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate ( CIP), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) In the presence of a condensing agent such as 4-methylmorpholinium chloride (DMTMM), halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, N In a solvent that does not participate in the reaction, such as a polar solvent such as N, dimethylformamide, or an alcoholic solvent such as methanol, ethanol, or 2-propanol, the solvent is added from 0 ° C. in the presence or absence of a base such as triethylamine or pyridine. By reacting at a refluxing temperature, the compound of formula (I) can be produced. Further, when the compound of the formula (V) is converted to an acid chloride (Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 144-146, 1992, Maruzen), etc. In the presence of a base such as triethylamine and pyridine, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, N, N-dimethylformamide and the like The compound of the formula (I) can be produced in the same manner by reacting at a temperature at which the solvent is refluxed from 0 ° C. in a solvent that does not participate in the reaction, such as a polar solvent.

The compound of the formula (V) can be produced by the following production method.
(Production method A)
<When R ³ = R ^{3 ′} and R ⁴ = H in Formula (V)>

<Step 1>
Commercially available or publicly known methods such as (Experimental Chemistry Course 4th Edition 24 Organic Synthesis VI
Heteroelement / typical metal element compound, 471-482, 1992, Maruzen) and formulas that can be produced according to the methods described in (New edition, heterocyclic compounds, basic edition, pages 149-175, Kodansha), etc. Using compounds of (AI), methods known in the literature such as (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, pp. 234-245, 1992, Maruzen) According to the methods described, lithium aluminum hydride (LAH), diisobutylaluminum hydride (DIBAH), lithium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, borane-tetrahydrofuran (BH _3. THF), borane - dimethyl sulfide _(BH 3 · _Me 2 S) borane reagent presence of such di Using a solvent not involved in the reaction, such as an ether solvent such as tilether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, an aromatic hydrocarbon solvent such as toluene and benzene, or a mixed solvent thereof, 0 The reaction can be carried out at a temperature at which the solvent is refluxed from 0 ° C. to produce a compound of formula (A-II).

<Process 2>
A method known in the literature using a compound of the formula (A-II), such as (Experimental Chemistry Course 4th Edition)
21 Organic Synthesis III Aldehyde / Ketone / Quinone, pp. 1-48, 1992, Maruzen), dimethyl sulfoxide-oxalyl chloride, pyridinium chlorochromate (PCC), active manganese dioxide (MnO ₂ ) In the presence of an oxidizing agent such as a desmartin reagent, a solvent that does not participate in the reaction, such as a halogen solvent such as dichloromethane or chloroform, an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, or 1,4-dioxane, or Using these mixed solvents, the reaction can be carried out at a temperature at which the solvent is refluxed from −78 ° C. to produce a compound of the formula (A-III).

<Step 3>
The formula (A-III) is used, and is described in literature known methods such as (Experimental Chemistry Course 4th Edition 19, Organic Synthesis I, Hydrocarbon / Halogen Compounds, pages 53-298, 1992, Maruzen) According to the prepared method, ethoxycarbonylmethyltriphenylphosphonium chloride, ethoxycarbonylmethyltriphenylphosphonium bromide, triphenylphosphoranylideneethyl acetate, methyl (dimethylphosphono) acetate, ethyl (dimethylphosphono) acetate, ethyl (diethyl) Wittig reagents (formula (A-IV)) such as phosphono) acetate, ethyl 2- (diethylphosphono) propionate, ethyl 2- (diethylphosphono) butyrate, ethyl 2- (diethylphosphono) phenylacetate, Horner Emmons reagent (formula (A- V)) and sodium hydride, butyllithium, piperazine, morpholine, triethylamine, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, phosphazene base-P4-tert-butyl, etc. In the presence of a base, alcohol solvents such as methanol and ethanol, polar solvents such as N, N-dimethylformamide, ether solvents such as 1,4-dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene Using a solvent inert to the reaction such as a solvent or a mixed solvent thereof, the reaction can be performed at a temperature at which the solvent is refluxed from −78 ° C. to produce a compound of the formula (A-V).

<Step 4> (except when R ^{3 ′} is an aryl group or a heterocyclic group)
Using compounds of formula (A-V) and compounds of formula (A-VI), methods known in the literature, for example, Journal of Medicinal Chemistry, 31 (1), 230-243, According to the method described in 1988, in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, methanol, ethanol, acetone, N, N -Using a solvent inert to the reaction such as dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from the formula (A-VII). Compounds can be produced.

<Step 5>
<When R ^B = alkyl group such as methyl or ethyl>
A method described in literatures using a compound of the formula (A-VII), for example, a method described in (Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, page 1-33, 1992, Maruzen) In the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, water and methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1, 4 -Using a solvent inert to the reaction such as dioxane and tetrahydrofuran, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C to produce the compound of formula (Va).

<In the case of R ^B = tert-butyl group>
Using compounds of formula (A-VII), methods known in the literature, such as Greene et al., Protective Groups in Organic Synthesis, (USA), 3rd edition, In the presence of an acid reagent such as formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, alcoholic solvents such as methanol and ethanol, 1,4-dioxane, tetrahydrofuran 1 , 2-dimethoxyethane, a solvent not involved in the reaction, such as water, or a mixed solvent thereof, and the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C., and the compound of the formula (Va) Can also be manufactured.
Furthermore, the formula (Va ′) can be produced according to the following method.
<Step 6>
A compound of formula (Va ′) can be produced by reacting the compound of formula (A-V) in the same manner as in (Production Method A) <Step 5>.
Furthermore, the formula (A-VII) which is an intermediate can also be produced according to the following method. (Except when R ^{3 ′} is a carbonyl group or a sulfonyl group)

<Step 7>
<When R ³ = Aryl Group or Heterocyclic Group>
Using compounds of formula (AI) and compounds of formula (A-VI), methods known in the literature, for example, Journal of Heterocyclic Chemistry, 24 (3), 811- 815, in accordance with the method described in 1987, copper catalysts such as copper (II) acetate, copper (II) oxide, copper (I) bromide, and sodium hydride, lithium hydroxide, sodium hydroxide, A solvent inert to the reaction such as N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, dichloromethane, or a mixed solvent thereof in the presence of a base such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, pyridine Is used at room temperature to a temperature at which the solvent is refluxed, and the compound of formula (A-VIII) is formed. It is possible to manufacture things. Moreover, the compound of a formula (A-VIII) can also be manufactured by reacting on the same conditions using an aryl and heteroaryl boric acid and a boric acid ester instead of a formula (A-VI).
<When R ³ = aryl group or heterocyclic group is removed>
Using the compound of formula (AI) and the compound of formula (A-VI), the reaction is carried out in the same manner as in (Production Method A) <Step 4> to produce the compound of Formula (A-VIII). be able to.

<Step 8>
A compound of formula (A-IX) can be produced by reacting the compound of formula (A-VIII) in the same manner as in (Production Method A) <Step 1>.
<Step 9>
The compound of formula (A-IX) can be used for the reaction in the same manner as in (Production Method A) <Step 2> to produce the compound of Formula (AX).
<Step 10>
A compound of formula (A-VII) can be produced by reacting the compound of formula (A-X) in the same manner as in (Production Method A) <Step 3>.
Furthermore, the formula (AX) which is an intermediate can also be produced according to the following method.
(Except when R ^{3 ′} is an aryl group or a heterocyclic group)
<Step 11>
Using the compound of formula (A-III) and the compound of formula (A-VI), the reaction is carried out in the same manner as in (Production Method A) <Step 4> to produce the compound of Formula (AX) be able to.

(Production method B)
<In the formula (V), when Z = —C (R ⁶ ) =, R ³ = R ^{3 ′} , R ⁴ = R ⁵ = R ⁶ = H (where R ^{3 ′} is a carbonyl group and a sulfonyl group) Except for)>

<Step 1>
Carbon tetrabromide in accordance with methods known in the literature using compounds of formula (BI), for example, methods described in Organic Letters, 8 (4), 653-656, 2006 A 2-gem-dibromovinylnitroaryl derivative prepared from triphenylphosphine and a method known in the literature, for example (Experimental Chemistry Course 4th Edition 26
In accordance with the method described in Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Label Compound, pp. 234-245, 1992, Maruzen) etc., there is a reducing agent such as tin (II) chloride, iron powder, zinc powder, etc. In the presence of an acid such as acetic acid and hydrochloric acid, an alcoholic solvent such as methanol, ethanol and 2-propanol, a halogen-based solvent vinegar such as dichloromethane and dichloroethane, a solvent not involved in the reaction, or a mixed solvent thereof. Alternatively, the compound of formula (B-II) can be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. in the absence.

<Process 2>
Using a compound of formula (B-II) and a compound of formula (B-III), a method known in the literature, for example, (Experimental Chemistry Course 4th Edition 20 Organic Synthesis II Alcohol Amines, 279-318, 1992) , Maruzen), Organic Letters, 8 (19), 4203-4206, 2006, reaction of alkyl halide in the presence of a base such as potassium carbonate, alkyl imidate Reaction under Lewis acid catalyst such as boron trifluoride-diethyl ether complex, reductive alkylation reaction of alkyl and aryl aldehydes and ketones with a reducing agent such as sodium triacetoxyborohydride, and aryl halides, aryl boric acid, alkyl bismuth Reaction in the presence of a metal reagent such as copper (II) acetate The solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction such as ethylene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof. The compound of formula (B-IV) can be produced at a temperature of

<Step 3>
A method known in the literature using a compound of formula (B-IV) and a compound of formula (B-V), for example, Organic Letters, 8 (19), 4203-4206, 2006. Palladium catalyst such as palladium (II) acetate, tetrakistriphenylphosphine palladium, trisdibenzylideneacetone dipalladium, triphenylphosphine, tris (tert-butyl) phosphine, tris (o-tolyl) phosphine, etc. In the presence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, or in the presence of tetramethylammonium chloride, tetrabutylammonium chloride, etc. Using a solvent not involved in the reaction such as ene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent refluxes from 0 ° C. -VI) can be prepared.
<Step 4>
The compound of formula (Vb) can be produced by reacting the compound of formula (B-VI) in the same manner as in (Production Method A) <Step 5>.

(Production method C)
<In the above formula (V), when Z = —C (R ⁶ ) =, R ³ = R ^{3 ′} , R ⁶ = H (except when R ^{3 ′} is an aryl group or a heterocyclic group) > (In the formula, P ¹ represents a protecting group such as a phenylsulfonyl group or tert-butoxycarbonyl).

<Step 1>
Using compounds of formula (CI), methods known in the literature, such as Greene et al., Protective Groups in Organic Synthesis (Protective)
A protecting group is introduced by a method described in a group document such as “Groups in Organic Synthesis”, (USA), 3rd edition, 1999, etc., to produce a compound of the formula (C-II).
<Process 2>
Using a compound of formula (C-II) and a compound of formula (C-III) (for example, acid halide, Weinreb amide, etc.), a method known in the literature, for example, Journal of Medicinal Chemistry (Journal) of Medicinal Chemistry), 44 (26), 4535-4553, 2001, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, etc. In the presence of a base, the solvent is refluxed from −78 ° C. using an ether solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, or a mixed solvent such as a hydrocarbon solvent such as hexane or heptane. The compound of formula (C-IV) can be produced by reacting at a temperature of

<Step 3>
Using the compound of formula (C-IV) and the compound of formula (A-IV), the reaction is carried out in the same manner as in (Production Method A) <Step 3> to produce the compound of Formula (C-V). be able to.
<Step 4>
Using compounds of formula (CV), methods known in the literature, such as Greene et al., Protective Groups in Organic Synthesis (Protective)
The protecting group can be removed by the method described in the textbooks of Groups in Organic Synthesis (USA), (US), 3rd edition, 1999, etc. to produce a compound of formula (C-VI).
<Step 5>
Using the compound of formula (C-VI) and the compound of formula (A-VI), the reaction is carried out in the same manner as in (Production Method A) <Step 4> to produce the compound of Formula (C-VII). be able to.
<Step 6>
A compound of formula (Vc) can be produced by reacting the compound of formula (C-VII) in the same manner as in (Production Method A) <Step 5>.

Furthermore, the formula (Vc ′) can be produced according to the following method.
<Step 7>
A compound of formula (Vc ′) can be produced by reacting the compound of formula (C-VI) in the same manner as in (Production Method A) <Step 5>.
Further, the intermediate formula (C-VI) can also be produced according to the following method.
<Step 8>
A compound of formula (C-VIII) can be produced by reacting the compound of formula (C-IV) in the same manner as in (Production Method C) <Step 4>.
<Step 9>
The compound of formula (C-VIII) can be produced by reacting the compound of formula (C-VIII) in the same manner as in (Production Method A) <Step 3>.

Further, the intermediate formula (C-VIII) can also be produced according to the following method.
Using compounds of formula (C-IX) and compounds of formula (C-X), methods known in the literature, such as The Journal of Organic Chemistry (The Journal of Organic Chemistry)
Organic Chemistry), 62 (11), 3597-3609, 1997, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, or hydrocarbon solvents such as hexane and heptane. The compound of the formula (C-VIII) can be produced by performing the reaction at a temperature at which the solvent is refluxed from −78 ° C. using a mixed solvent with the above.

(Production Method D)
<In the above formula (V), when Z = —C (R ⁶ ) =, R ³ = R ^{3 ′} , R ⁴ = R ⁵ = R ⁶ = H (where R ^{3 ′} is an aryl group and a heterocyclic ring) Except in the case of a group)> (wherein P ¹ is
Protecting groups such as a phenylsulfonyl group and a tert-butoxycarbonyl group are represented. )

<Step 1>
Using compounds of formula (C-II) and formula (DI) (eg iodine, bromine), methods known in the literature, eg Journal of Heterocyclic Chemistry, 22 (2 ), 505-509, 1985, in the presence of a base such as n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropylamide, lithium bis (trimethylsilyl) amide, tetrahydrofuran, diethyl The reaction is carried out at a temperature at which the solvent is refluxed from −78 ° C. using an ether solvent such as ether or 1,2-dimethoxyethane, or a mixed solvent such as a hydrocarbon solvent such as hexane or heptane. -II) can be produced.
<Process 2>
A method known in the literature using the compound of the formula (D-II) and the compound of the formula (B-V), for example, (Experimental Chemistry Course 4th Edition 20 Organic Synthesis I Hydrocarbon / Halogen Compound, pp. 53-298, 1992) In accordance with the method described in Y. Maruzen), in the presence of a palladium catalyst such as palladium (II) acetate, tetrakistriphenylphosphine palladium, trisdibenzylideneacetone dipalladium, In the presence of a base such as triethylamine or tetrabutylammonium chloride, a solvent not involved in the reaction such as N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, toluene, or a mixed solvent thereof is used. The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. A compound of formula (D-III) can be prepared.

<Step 3>
A compound of formula (D-IV) can be produced by reacting the compound of formula (D-III) in the same manner as in (Production Method C) <Step 4>.
<Step 4>
A compound of formula (D-V) can be produced by reacting the compound of formula (D-IV) in the same manner as in (Production Method A) <Step 4>.
<Step 5>
The compound of the formula (Vd) can be produced by reacting the compound of the formula (D-V) in the same manner as in (Production Method A) <Step 5>.
Furthermore, the formula (Vd ′) can be produced according to the following method.
<Step 6>
A compound of formula (Vd ′) can be produced by reacting the compound of formula (D-VI) in the same manner as in (Production Method A) <Step 5>.

(Production method E)
<In the above formula (V), when Z = —C (R ⁶ ) =, R ³ = R ^{3 ′} , R ² = R ⁴ = R ⁵ = R ⁶ = H> (where R ^{3 ′} is a carbonyl group And except for sulfonyl group)

<Step 1>
It is described in literature known methods, for example, Organic Letters, 10 (6), 1159-1162, 2008, using a compound of formula (EI) and a compound of formula (B-V). In the presence of a palladium catalyst such as palladium (II) acetate, tetrakistriphenylphosphine palladium, trisdibenzylideneacetone dipalladium, a copper salt such as copper (II) acetate, or a silver salt such as silver acetate, Involved in reactions such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, toluene, xylene in the presence or absence of alkali metal salts such as lithium acetate, sodium acetate, lithium chloride, cesium carbonate The solvent is returned from 0 ° C using a solvent that is not used or a mixture of these. The compound of formula (E-II) can be produced by carrying out the reaction at a flowing temperature.
<Process 2>
The compound of formula (Ve) can be produced by reacting the compound of formula (E-II) in the same manner as in (Production Method A) <Step 5>.

Compounds of formula _{(VI) (Q-NH 2} ) is obtained by the following production method.
Q in the formula represents an aryl group which may be substituted or a heterocyclic group which may be substituted (where Q is a 4-((3-acetylmethylamino) -1-pyrrolidinyl) phenyl group, 3- (2- (bis (1-methylethyl) amino) ethoxy) -4-methoxyphenyl group, or 4-hydroxy-3,5-dimethylphenyl group), more specifically, (Q1), (Q2), and (Q3).

(Production Method F)
<When Q = Formula (Q2), r = 2, and R ¹¹ = H in Formula (VI)>

<Step 1>
A method known in the literature using a compound of the formula (FI), for example (Experimental Chemistry Course 4th Edition 20
Organic Synthesis II Alcohol / Amine, 394-405, 1992, Maruzen), etc., in accordance with the method described in nitric acid, nitric acid / sulfuric acid, nitric acid / acetic anhydride, potassium nitrate / sulfuric acid, sodium nitrate / sulfuric acid, potassium nitrate / anhydrous A compound of formula (F-II) can be produced by reacting with a nitrating agent such as acetic acid or nitric acid / trifluoromethanesulfonic acid at -40 ° C. at room temperature.
<Process 2>
A method known in the literature using a compound of formula (F-II), such as (Experimental Chemistry Course 4th Edition)
26 Organic Synthesis VIII According to the method described in Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, Maruzen), etc., in the presence of a reducing agent such as sodium borohydride and lithium borohydride. , Alcohol solvents such as methanol, ethanol, 2-propanol, etc., or mixed solvents thereof with inert solvents such as diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, benzene, toluene Can be used to react at a temperature at which the solvent refluxes from 0 ° C. to produce a compound of formula (F-III). Further, a reducing agent such as diisobutylaluminum hydride (DIBAH), lithium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, Using a solvent inert to the reaction such as tetrahydrofuran, benzene, toluene, or a mixed solvent thereof, the reaction may be performed at a temperature at which the solvent is refluxed from −78 ° C. to produce a compound of the formula (F-III). it can.

<Step 3>
A method known in the literature using a compound of the formula (F-III), for example, (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, Maruzen) In the presence of a catalyst such as palladium-carbon (Pd-C), Raney nickel (Raney-Ni), dichlorotristriphenylphosphine ruthenium, etc., in a hydrogen atmosphere, methanol, ethanol, 2-propanol Alcohol solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and other solvents, polar solvents such as ethyl acetate and methyl acetate, solvents that do not participate in the reaction, or a mixed solvent thereof Is used to produce a compound of formula (VI-a) by reacting at 0 ° C. at a temperature at which the solvent is refluxed. Rukoto can. Alternatively, the compound of the formula (VI-a) can be produced by reacting in concentrated hydrochloric acid or acetic acid at a temperature at which the solvent refluxes in the presence of iron (Fe) and tin (Sn). In addition, in the presence of Lewis acid such as nickel chloride (NiCl ₂ ) and tin chloride (SnCl ₂ ) and sodium borohydride, alcohol solvents such as methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran, 1,2-dimethoxy Using a solvent that does not participate in the reaction, such as an ether solvent such as ethane or 1,4-dioxane, or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent refluxes from 0 ° C. It can also be manufactured.

<Step 4>
Using a compound of formula (VI-a), a column for optical isomer separation was prepared according to a method known in the literature, for example, the method described in Journal of Synthetic Organic Chemistry, 54 (5), 344-353, 1996. The compound of the formula (VI-a ′) can be produced, for example, by optical resolution by preparative chromatography used.
In the formula (VI-a ′), the configuration of the hydroxyl group marked with * at the binding site represents any enantiomer. In the present specification, for any one of the amines represented by the formula (VI-a ′) obtained by separating the racemate using an optical isomer separation column, the first fraction of each obtained enantiomer is obtained. (A), let the second fraction be (B).
Furthermore, formula (VI-a) can also be produced according to the following method.
<Step 5>
Using the compound of formula (F-II), the compound of formula (F-IV) can be produced by the same method as in (Production Method F) <Step 3>.
<Step 6>
Using the compound of formula (F-IV), the compound of formula (VI-a) can be produced by the same method as in (Production Method F) <Step 2>.

Furthermore, the formula (VI-a ′) can also be produced according to the following method.
<Step 7>
A method known in the literature using a compound of the formula (F-IV), for example (Experimental Chemistry Course 4th Edition
26 Organic Synthesis VIII According to the method described in Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, page 23-68, 1992, Maruzen), for example, optically active dichloro [bis (diphenylphosphino) binaphthyl] [ In the presence of diphenylethylenediamine] ruthenium and a base reagent such as potassium hydroxide, potassium tert-butoxide, and the like in a hydrogen atmosphere, the reaction is carried out using 2-propanol solvent at a temperature at which the solvent is refluxed. The compound a ′) can be produced. Alternatively, transition metal complexes such as dichlorotristriphenylphosphine ruthenium, benzene ruthenium (II) chloride (dimer), and optically active 2-amino-1,2-diphenylethanol, 1-amino-2-indanol, etc. In the presence of a reagent and a base reagent such as potassium hydroxide and potassium tert-butoxide, the reaction is carried out using 2-propanol solvent at a temperature at which the solvent refluxes to produce a compound of formula (VI-a ′) You can also Alternatively, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4- in the presence of chlorodiisopinocinfeylborane (Ipc ₂ BCl), or optically active oxazaborolidine and borane (BH ₃ ) A compound of the formula (VI-a ′) can also be produced by performing the reaction at a temperature at which the solvent is refluxed from 0 ° C. using an ether solvent such as dioxane.

(Production method G)
<In the above formula (VI), Q = formula (Q2), r = 2, R ¹¹ = H> (wherein P ²
Represents a protecting group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, or a p-toluenesulfonyl group, and P ³ represents an alkyl group such as a methyl group or an ethyl group. )

<Step 1>
Using a compound of the formula (GI), protecting groups such as tert-butoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group and the like can be prepared by methods known in the literature such as Greene et al. The compound of the formula (G-II) can be produced by introducing by the method described in the textbook of Protective Groups in Organic Synthesis (USA), 3rd edition, 1999, etc. .
<Process 2>
Using a compound of the formula (G-II), an alkyl group such as a methyl group or an ethyl group is converted into a method known in the literature, for example, Greene et al., Protective Groups in Organic Synthesis (Protective Groups in Organic) Synthesis), (USA), 3rd edition, 1999, etc., can be introduced by the method described in the textbook to produce a compound of formula (G-III).

<Step 3>
Using the compound of formula (G-III), the introduced protecting group can be converted to methods known in the literature, such as Greene et al. Protective Groups in Organic Synthesis, ( The compound of the formula (G-IV) can be produced by the method described in the published texts of US, 3rd edition, 1999, etc.
<Step 4>
The compound of the formula (G-IV) is converted into a method known in the literature, for example (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 165-167, 1992, Maruzen) According to the described method, for example, in the presence of a reagent containing a metal such as lithium, sodium, etc., in a solvent containing liquid ammonia and an alcohol such as methanol, ethanol, isopropanol, tert-butanol, etc. The compound of the formula (G-V) can be produced by reacting at room temperature (Birch reduction).

<Step 5>
Compounds of formula (G-V) may be prepared by methods known in the literature, such as those described in The Journal of Organic Chemistry, 51 (26), 5252-5258, 1986. In the presence of acid reagents such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, alcohol solvents such as methanol, ethanol, 1,4-dioxane and tetrahydrofuran (THF) and 1
, 2-dimethoxyethane, a solvent not involved in the reaction such as ether, acetone, water, or a mixed solvent thereof, and the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. to obtain a compound of the formula (F-IV) Can be manufactured.
<Step 6>
Using the compound of formula (F-IV), the compound of formula (VI-a) can be produced by the same method as in (Production Method F) <Step 2>.

Furthermore, formula (VI-a) can also be produced according to the following method.
<Step 7>
In accordance with a method known in the literature using a compound of the formula (GI), for example, a method described in (New Experimental Chemistry Course 15 Oxidation and Reduction II, pages 426-428, 1977, Maruzen) In the presence of a catalyst such as carbon (Pd-C), Raney nickel (Raney-Ni), platinum oxide, etc., in an atmosphere of hydrogen at 3 to 5 atm, alcohol solvents such as methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran The solvent is refluxed from 0 ° C. using an ether solvent such as 1,2-dimethoxyethane and 1,4-dioxane, a polar solvent such as ethyl acetate and methyl acetate, or a mixed solvent thereof. The compound of the formula (VI-a) can also be produced by carrying out the reaction at the temperature to be used.

(Production method H)
<In the formula (VI), Q = formula ^{(Q2), r = 2,} R 11 = C 1 ~ 4 in the alkyl group>

<Step 1>
A method known in the literature using a compound of formula (F-III) and a compound of formula (HI), such as (Experimental Chemistry Course 4th Edition 20 Organic Synthesis II Alcohol / Amine, 187
243, 1992, Maruzen) and the like in the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, etc. , Tetrahydrofuran, 1,2-dimethoxyethane, ether solvents such as 1,4-dioxane, hydrocarbon solvents such as benzene and toluene, polar solvents such as acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, or a mixture thereof The compound of formula (H-II) can be produced by reacting with a solvent at a temperature at which the solvent is refluxed from room temperature.
Further, in place of the compound of formula (HI), sulfonate such as dimethyl sulfate or diethyl sulfate, or triethyloxonium tetrafluoroborate (Meerwein reagent), trimethyloxonium 2,4,6-trinitrobenzenesulfonic acid The compound of the formula (H-II) can also be produced using an onium salt such as a salt.

<Process 2>
Using the compound of formula (H-II), the compound of formula (VI-b) can be produced by the same method as in (Production Method F) <Step 3>.
<Step 3>
Using the compound of the formula (VI-b), the same method as in (Production Method F) <Step 4>
Ib ′) can be prepared.
In the formula (VI-b ′), the configuration of the alkoxyl group marked with * at the binding site represents any enantiomer. In this specification, for the amine represented by the formula (VI-b ′) obtained by separating the racemate using an optical isomer separation column, the first fraction of each obtained enantiomer is obtained. (A), let the second fraction be (B).

(Production Method I) <In the Formula (VI), Q = Formula (Q2), r = 1, R ¹¹ = H>

<Step 1>
The compound of the formula (I-II) can be produced by the same method as in (Production Method F) <Step 1> using the compound of the formula (II).
<Process 2>
Using the compound of formula (I-II), the compound of formula (I-III) can be produced by the same method as in (Production Method F) <Step 2>.
<Step 3>
In accordance with a method known in the literature using a compound of formula (I-III), for example, the method described in Journal of Medicinal Chemistry, 46 (13), 2683-2696, 2003. In the presence of an acid catalyst such as p-toluenesulfonic acid and sulfuric acid, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, an ether solvent such as tetrahydrofuran and the like, or a solvent mixture thereof. The compound of the formula (I-IV) can be produced by performing the reaction at a temperature at which the solvent is refluxed from room temperature.
<Step 4>
In accordance with a method known in the literature using a compound of formula (I-IV), for example, the method described in Journal of Medicinal Chemistry, 46 (13), 2683-2696, 2003 In the presence of a reagent such as m-chloroperbenzoic acid, a solvent inert to the reaction such as a halogen-based solvent such as dichloromethane or chloroform, an aromatic hydrocarbon-based solvent such as benzene, toluene or xylene, or a mixed solvent thereof. The compound of formula (IV) can be produced by reacting at a temperature at which the solvent is refluxed from room temperature.

<Step 5>
In the presence of a reagent such as a magnesium bromide-diethyl ether complex or zinc iodide in accordance with a method known in the literature, for example, the method described in WO 03/049702 pamphlet, using the compound of formula (IV) , Solvents such as halogen solvents such as dichloromethane and chloroform, ether solvents such as 1,4-dioxane and tetrahydrofuran, aromatic hydrocarbon solvents such as benzene, toluene and xylene, or a mixed solvent thereof. Can be used to carry out the reaction from room temperature to the temperature at which the solvent is refluxed to produce a compound of formula (I-VI).
<Step 6>
The compound of formula (I-VII) can be produced by the same method as in (Production Method F) <Step 2>, using the compound of formula (I-VI).
<Step 7>
Using the compound of formula (I-VII), the compound of formula (VI-c) can be produced by the same method as in (Production Method F) <Step 3>.
<Step 8>
Using the compound of formula (VI-c), the compound of formula (VI-c ′) can be produced by the same method as in (Production Method F) <Step 4>.
In the formula (VI-c), the hydroxyl group bonded to the carbon bond marked with * indicates any configuration. For any one of the amines represented by the formula (VI-c) obtained by separating the racemate using an optical isomer separation column, the first fraction of each enantiomer obtained is represented by (A), the second Let the fraction be (B).

Furthermore, formula (VI-c) can also be produced according to the following method.
<Step 9>
The compound of the formula (I-VIII) can be produced by the same method as in (Production Method F) <Step 3> using the compound of the formula (I-VI).
<Step 10>
Using the compound of formula (I-VIII), the compound of formula (VI-c) can be produced by the same method as in (Production Method F) <Step 2>.
Furthermore, the formula (VI-c ′) can also be produced according to the following method.
<Process 11>
A compound of the formula (VI-c ′) can be produced by using the compound of the formula (I-VIII) in the same manner as in (Production Method F) <Step 7>.
Furthermore, the intermediate formula (I-VI) can also be produced according to the following method.
<Step 12>
The compound of the formula (I-VI) can be produced by the same method as in (Production Method F) <Step 1> using the compound of the formula (I-IX).

(Production method J)
<In the formula (VI), Q = formula ^{(Q2), r = 1,} R 11 = C 1 ~ 4 in the alkyl group>

<Step 1>
Using the compound of formula (I-VII) and the compound of formula (HI), the compound of formula (JI) can be produced by the same method as in (Production Method H) <Step 1>. .
<Process 2>
The compound of formula (VI-d) can be produced by the same method as in (Production Method F) <Step 3>, using the compound of formula (J-I).
<Step 3>
Using the compound of formula (VI-d), the compound of formula (VI-d ′) can be produced by the same method as in (Production Method F) <Step 4>.
In the formula (VI-d ′), an alkoxyl group bonded to a carbon bond marked with * indicates any configuration. For any one of the amines represented by the formula (VI-d ′) obtained by separating the racemate using an optical isomer separation column, the first fraction of each obtained enantiomer is represented by (A), Let the bisection be (B).

(Production method K)
<When Q = Formula (Q2), r = 1, R ¹¹ = H in Formula (VI)>

<Step 1>
(Production Method I) Same as <Step 2>.
<Process 2>
Using the compound of formula (I-III), the compound of formula (VI-e) can be produced by the same method as in (Production Method F) <Step 3>.
<Step 3>
Using the compound of formula (VI-e), the compound of formula (VI-e ′) can be produced by the same method as in (Production Method F) <Step 4>. In the formula (VI-e ′), the hydroxyl group bonded to the carbon bond marked with * indicates any configuration. For any one of the amines represented by the formula (VI-e ′) obtained by separating the racemate using an optical isomer separation column, the first fraction of each obtained enantiomer is represented by (A), Let the bisection be (B).

Furthermore, the formula (VI-e) can also be produced according to the following method.
<Step 4>
Using the compound of formula (I-II), the compound of formula (KI) can be produced by the same method as in (Production Method F) <Step 3>.
<Step 5>
Using a compound of the formula (KI), a method similar to that in (Production Method F) <Step 2>,
-E) can be produced.
Furthermore, the formula (VI-e ′) can also be produced according to the following method.
<Step 6>
Using the compound of formula (KI), the compound of formula (VI-e ′) can be produced by the same method as in (Production Method F) <Step 7>.
In the formula (VI-e ′), the hydroxyl group bonded to the carbon bond marked with * indicates any configuration. For any one of the amines represented by the formula (VI-e ′) obtained by separating the racemate using an optical isomer separation column, the first fraction of each obtained enantiomer is represented by (A), Let the bisection be (B).

(Production method L)
<In the formula (VI), Q = formula ^{(Q2), r = 1,} R 11 = C 1 ~ 4 in the alkyl group>

<Step 1>
Using the compound of formula (I-III) and the compound of formula (HI), the compound of formula (LI) can be produced by the same method as in (Production Method H) <Step 1>. .
<Process 2>
Using the compound of formula (LI), the compound of formula (VI-f) can be produced by the same method as in (Production Method F) <Step 3>.
<Step 3>
Using the compound of formula (VI-f), the compound of formula (VI-f ′) can be produced by the same method as in (Production Method F) <Step 4>.
In the formula (VI-f ′), the hydroxyl group bonded to the carbon bond marked with * indicates any configuration. For any one of the amines represented by the formula (VI-f ′) obtained by separating the racemate using an optical isomer separation column, the first fraction of each obtained enantiomer is represented by (A), Let the bisection be (B).

(Production method M)
<In the case of Q = formula (Q3) and G ₁ = G ₂ = CR ^{15 in} the formula (VI)>

<Step 1>
The compound of formula (M-II) can be produced by the same method as in (Production Method F) <Step 1> using the compound of formula (M-I).
<Process 2>
Using the compound of formula (M-II), the compound of formula (VI-g) can be produced by the same method as in (Production Method F) <Step 3>.

(Production method N)
<In the formula (VI), Q = formula (Q3), G ₁ = G ₂ = CR ¹⁵ , R ¹² = OR ^E (that is, R ¹² is a group: —Z ₁ —Z ₂ —OR ¹³ ; Z ₁ is _O, -Z 2 ^{-OR 13} is ^{R E)} if>

<Step 1>
The compound of formula (N-II) can be produced by the same method as in (Production Method F) <Step 1>, using the compound of formula (NI).
<Process 2>
Using the compound of formula (N-II) and the compound of formula (N-III), the compound of formula (N-IV) can be produced by the same method as in (Production Method H) <Step 1>. .
<Step 3>
Using the compound of formula (N-IV), the compound of formula (VI-h) can be produced by the same method as in (Production Method F) <Step 3>.

(Production method O)
<In the formula (VI), Q = formula (Q3), G ₁ = G ₂ = CR ¹⁵ , R ¹² = NRR ′ (that is, R ¹² is a group: —Z ₁ —Z ₂ —OR ¹³ , Z _{When 1} is NR ¹⁴ (R ¹⁴ is R) and —Z ₂ —OR ¹³ is R ′)>

<Step 1>
The compound of formula (O-II) can be produced by the same method as in (Production Method F) <Step 1>, using the compound of formula (O-I).
<Process 2>
In accordance with a method known in the literature using a compound of the formula (O-II) and a compound of the formula (O-III), for example, a method described in Synlett, pages 10, 1747-1750, 2004 In the presence of a base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc. Using a ethereal solvent, a hydrocarbon solvent such as benzene and toluene, a polar solvent such as acetonitrile, dimethylsulfoxide, N, N-dimethylformamide, or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed from room temperature. Compounds of formula (O-IV) can be prepared.
<Step 3>
Using the compound of formula (O-IV), the compound of formula (VI-i) can be produced by the same method as in (Production Method F) <Step 3>.

＜工程１＞
式（Ｐ−Ｉ）の化合物を用い、（製造法Ｆ）＜工程１＞と同様の方法により、式（Ｐ−ＩＩ）の化合物を製造することができる。
＜工程２＞
式（Ｐ−ＩＩ）の化合物を用い、（製造法Ｆ）＜工程３＞と同様の方法により、式（ＶＩ−ｊ）の化合物を製造することができる。 (Production method P)
<In the above formula (VI), Q = formula (Q3), G ₁ = CR ¹⁵ , G ₂ = CH or G ₁ = CH, G ₂ = CR ¹⁵ >

<Step 1>
A compound of formula (P-II) can be produced by a method similar to (Production Method F) <Step 1> using a compound of formula (PI).
<Process 2>
Using the compound of formula (P-II), the compound of formula (VI-j) can be produced by the same method as in (Production Method F) <Step 3>.

(Production method Q)
<In the formula (VI-j), when R ¹⁵ = OR ^E or NRR ′ (the definition of OR ^E or NRR ′ is the same as that of the production method N or the production method O)>

<Step 1>
The compound of formula (Q-II) can be produced by using the compound of formula (QI) in the same manner as in (Production Method F) <Step 1>.
<Process 2>
Using the compound of formula (Q-II), the reaction is carried out using iron chloride (FeCl ₃ ) and diphenyl sulfide as a cocatalyst according to a method known in the literature, for example, the method described in the pamphlet of published patent application JP 01/088942 Thus, the compound of the formula (Q-III) can be produced.
<Step 3>
Using the compound of formula (Q-III) and the compound of formula (Q-IV), the compound of formula (QV) can be produced in the same manner as in (Production Method O) <Step 2>. .
<Step 4>
Using the compound of formula (QV), the compound of formula (VI-k) can be produced by the same method as in (Production Method F) <Step 3>.
<Step 5>
Using the compound of formula (Q-III) and the compound of formula (O-III), the compound of formula (Q-VI) can be produced by the same method as in (Production Method O) <Step 2>. .
<Step 6>
Using the compound of formula (Q-VI), the compound of formula (VI-l) can be produced by the same method as in (Production Method F) <Step 3>.

＜工程１＞
式（Ｒ−Ｉ）の化合物、および式（Ｒ−ＩＩ）の化合物を用い、文献公知の方法、例えば、ザ・ジャーナル・オブ・オルガニック・ケミストリー（Ｔｈｅ Ｊｏｕｒｎａｌ ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ）、４７（６）、１０７７−１０８０頁、１９８２年に記載された方法に準じて、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ピリジン等の塩基の存在下、メタノール、エタノール、２−プロパノール等のアルコール系溶媒を用いて、室温から溶媒が還流する温度で反応を行い、式（Ｒ−ＩＩＩ）の化合物を製造することができる。
＜工程２＞
式（Ｒ−ＩＩＩ）の化合物を用い、（製造法Ｆ）＜工程３＞と同様の方法により、式（ＶＩ−ｍ）の化合物を製造することができる。 (Production method R)
<When Q = Formula (Q3) and G ₁ = G ₂ = N in Formula (VI)>

<Step 1>
A method known in the literature using a compound of the formula (R-I) and a compound of the formula (R-II), for example, The Journal of Organic Chemistry, 47 (6) According to the method described on pages 1077 to 1080, 1982, in the presence of a base such as triethylamine, N, N-diisopropylethylamine or pyridine, an alcohol solvent such as methanol, ethanol or 2-propanol is used. The reaction can be performed from room temperature to the temperature at which the solvent is refluxed to produce the compound of formula (R-III).
<Process 2>
Using the compound of formula (R-III), the compound of formula (VI-m) can be produced by the same method as in (Production Method F) <Step 3>.

＜工程１＞
式（Ｓ−Ｉ）の化合物を用い、（製造法Ｆ）＜工程１＞と同様の方法により、式（Ｓ−ＩＩ）の化合物を製造することができる。
＜工程２＞
式（Ｓ−ＩＩ）の化合物、およびオキシ塩化リンを用い、文献公知の方法、例えばジャーナル・オブ・メディシナル・ケミストリー（Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ）、３１（７）、１３４７−１３５１頁、１９８８年に記載された方法に準じて、ジクロロメタン、クロロホルム等のハロゲン系溶媒、ジエチルエーテル、テトラヒドロフラン、１，２−ジメトキシエタン、１，４−ジオキサン等のエーテル系溶媒、ベンゼン、トルエン等の芳香族炭化水素系溶媒など反応に関与しない溶媒、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン等塩基溶媒、もしくはこれらの混合溶媒を用いて、０℃から溶媒が還流する温度で反応を行い、式（Ｓ−ＩＩＩ）の化合物を製造することができる。
＜工程３＞
式（Ｓ−ＩＩＩ）の化合物、および式（Ｑ−ＩＶ）の化合物を用い、文献公知の方法、例えば、国際公報第０５／０７７９０５号パンフレットに記載された方法に準じて、水素化ナトリウム、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸リチウム、炭酸ナトリウム、炭酸カリウム等の塩基存在下、ジエチルエーテル、テトラヒドロフラン、１，２−ジメトキシエタン、１，４−ジオキサン等のエーテル系溶媒、ベンゼン、トルエン等の炭化水素系溶媒、アセトニトリル、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド等極性溶媒、もしくはこれらの混合溶媒を用いて、室温から溶媒が還流する温度で反応を行い、式（Ｓ−ＩＶ）の化合物を製造することができる。
＜工程４＞
式（Ｓ−ＩＶ）の化合物を用い、（製造法Ｆ）＜工程３＞と同様の方法により、式（ＶＩ−ｎ）の化合物を製造することができる。 (Production Method S)
<In the formula (VI), Q = formula _(Q3), (the definition of ^{R E,} same as the process ^{N) G 1 = G 2 =} N, R 12 = OR E For>

<Step 1>
Using the compound of formula (SI), the compound of formula (S-II) can be produced by the same method as in (Production Method F) <Step 1>.
<Process 2>
A method known in the literature using a compound of the formula (S-II) and phosphorus oxychloride, for example, Journal of Medicinal Chemistry, 31 (7), pp. 1347-1351, 1988 According to the method, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane, aromatic hydrocarbon solvents such as benzene and toluene. The reaction is carried out using a solvent not involved in the reaction, a basic solvent such as N, N-dimethylaniline, N, N-diethylaniline, or a mixed solvent thereof at a temperature at which the solvent is refluxed from 0 ° C. The compound of III) can be prepared.
<Step 3>
Using a compound of formula (S-III) and a compound of formula (Q-IV), according to a method known in the literature, for example, a method described in International Publication No. 05/077905 pamphlet, sodium hydride, water In the presence of a base such as lithium oxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, ether solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, benzene, Using a hydrocarbon solvent such as toluene, a polar solvent such as acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent is refluxed, and the formula (S-IV) Can be produced.
<Step 4>
Using the compound of formula (S-IV), the compound of formula (VI-n) can be produced by the same method as in (Production Method F) <Step 3>.

＜工程１＞
式（Ｔ−Ｉ）の化合物を用い、（製造法Ｆ）＜工程１＞と同様の方法により、式（Ｔ−ＩＩ）の化合物を製造することができる。
＜工程２＞
式（Ｔ−ＩＩ）の化合物を用い、（製造法Ｆ）＜工程３＞と同様の方法により、式（ＶＩ−ｏ）の化合物を製造することができる。 (Production method T)
<In the above formula (VI), Q = formula (Q3), G ₁ = CR ¹⁵ , G ₂ = N, or G ₁ = N, G ₂ = CR ¹⁵ >

<Step 1>
Using the compound of formula (TI), the compound of formula (T-II) can be produced by the same method as in (Production Method F) <Step 1>.
<Process 2>
Using the compound of formula (T-II), the compound of formula (VI-o) can be produced by the same method as in (Production Method F) <Step 3>.

＜工程１＞
式（Ｕ−Ｉ）の化合物，および式（Ｑ−ＩＶ）の化合物を用い、（製造法Ｏ）＜工程２＞と同様の方法により、式（Ｕ−ＩＩ）の化合物を製造することができる。
＜工程２＞
式（Ｕ−ＩＩ）の化合物を用い、（製造法Ｆ）＜工程３＞と同様の方法により、式（ＶＩ−ｐ）の化合物を製造することができる。 (Production method U)
<In the formula (VI), Q = formula (Q3), G ₁ = CR ¹⁵ and G ₂ = N, or G ₁ = N and G ₂ = CR ¹⁵ and R ¹² = OR ^E (of R ^E The definition is the same as that of manufacturing method N)>

<Step 1>
Using the compound of formula (U-I) and the compound of formula (Q-IV), the compound of formula (U-II) can be produced by the same method as in (Production Method O) <Step 2>. .
<Process 2>
Using the compound of formula (U-II), the compound of formula (VI-p) can be produced by the same method as in (Production Method F) <Step 3>.

(Production method V)
<In the above formula (VI), Q = formula (Q1)>
The compound of the formula (VI) can be produced according to the production method described in WO08 / 091021 pamphlet.

  When each compound synthesized by each of the above production methods has a reactive group such as a hydroxyl group, an amino group, or a carboxyl group as a substituent, these groups are appropriately protected in each production process, and the protection is performed at an appropriate stage. It can be produced by removing the group. Such a method for introducing / removing a protecting group is appropriately carried out depending on the group to be protected or the type of protecting group. For example, Green, et al., Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis). ), (USA), 3rd edition, 1999, etc.

[Combination agent containing the compound of the present invention]
The compound and pharmaceutical composition of the present invention can be used in combination with other drugs or drugs by a general method performed in the medical field. For example, analgesics include acetaminophen, aspirin and opioid agonists (specifically morphine, fentanyl, oxycodone, methadone, codeine, cocaine, pethidine, opium, tocone, etc.), non-narcotic analgesics (pentazine, Buprenorphine, nalolphine, cyclazocine, butofanol, etc.) antidepressants (gabapentin, pregabalin, duloxetine, amitriptyline, imipramine, clomipramine, trimipramine, lofepramine, dosrepin, desipramine, amoxapine, nortriptyline, fluoxetamine, profluxamine, profluxamine, profluxamine, profluxamine , Antidepressants or anticonvulsants (carbamazepine, phenytoin, gabapentin, pregabalin, phenobarbital Primidone, mephenytoin, nilvanol, ethoin, trimethadione, ethosuximide, acetylphenetride, zonisamide, acetazolamide, diazepam, clonazepam, nitrazepam, diphenylhydantoin, valproic acid, baclofen, etc., antiarrhythmic drugs In addition to the prescribed mexiletine, quinidine, disopyramide, procainamide, ajmarin, prazimarium, cybenzoline, lidocaine, aprindine, tonicoid, phenytoin, flecainide, pyrushicainide, propaphenone, propranolol, amiodarone, verapamil, bepridil, etc. , Meloxicam, nimesulide, diclofenac sodium, mefenamic acid, zaltoprofen, loxopro Sodium, sulindac, nabumetone, diflunisal, piroxicam, ibuprofen, naproxen, fenoprofen, acetylsalicylic acid, tolmethine, indomethacin, flurbiprofen, oxaprozin, ketoprofen, mofezolac, acetaminophen, ketorolac, zomepirac, nitroaspirin, thiaprofen , Ampiroxicam, thiaramide, epilysole, etc.), anti-inflammatory agents such as COX-2 inhibitors (celecoxib, rofecoxib, cereblex, etc.), NR2B antagonists, bradykinin antagonists, antimigraine agents.

Other local anesthetics (including quinidine, disopyramide, procainamide, ajmarin, prazimarium, cibenzoline, lidocaine, mexiletine, aprindine, tonicoid, phenytoin, flecainide, pilsicainide, propaphenone, propranolol, amiodarone, verapamil, bepridil), anesthetics Specific examples include benzodiazepine, diazepam, midazolam, thiopental, thiamylal, propofol, baclofen, droperirol, sufentanil, and the like, and NMDA antagonists (specifically, ketamine, dextromethorphan, memantine, amantadine, etc.). It is done.
In addition, α2 adrenergic receptor agonists (clonidine, dexmedetomidine, tizanidine, guanfacine, guanabenz, etc.), calcium channel antagonists, potassium channel openers, etc., topical drugs (capsaicin cream), or
Antiviral agents (such as vidarabine, acyclovir, ganciclovir, zidovudine, didanosine, amantadine, idoxuridine, alpha or beta interferon).
Preferred are morphine, gabapentin or pregabalin, diclofenac, and Celebrex.

It is possible not only to be used in combination with other drugs, but also to be treated in combination with other treatment methods. For example, specific examples of stimulation and analgesia include acupuncture, percutaneous electrical acupuncture, transcutaneous electrical nerve stimulation, silver spike point (SSP) therapy, peripheral nerve stimulation, spinal cord electrical stimulation, and electroconvulsive therapy. , Laser therapy, low frequency therapy, nerve block (specifically, stellate ganglion block, epidural block, brachial plexus block, nerve root block, chest / lumbar sympathetic ganglion block, trigger point block, subarachnoid Block, trigeminal nerve block, sympathetic nerve block, local infiltration block, peripheral nerve block, etc.).
Diseases involving TRPV1 other than pain can be used in combination with drugs used in each region.
For example, NSAIDs, DMARDs and anti-TNFα antibodies, soluble TNFα receptors, steroids (specifically cortisol, cortisone, prednisolone, triamcinolone, dexamethasone, which are commonly used in chronic rheumatoid arthritis, etc. And betamethasone, parameterzone, fluocinolone acetonide, fluocinonide, beclomethasone, fludocortisone, etc.) and immunosuppressants can be used in combination. In addition, in COPD and allergic diseases, it can be used in combination with general therapeutic agents such as β2 receptor agonists and steroids. Furthermore, in the case of overactive bladder and urinary incontinence, it can be used in combination with an anticholinergic drug (in particular, an M3 receptor antagonist such as imidafenacin, solifenacin, tolterodine).

By using in combination with existing drugs for the above-mentioned diseases, it is possible to reduce the dosage of existing drugs and reduce the side effects of existing drugs. Of course, the combination method using the drug is not limited to the above diseases, and the drug used in combination is not limited to the compounds exemplified above.
When the compound of the present invention is used in combination with a drug used in combination, it may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.

[Formulation of the preventive / therapeutic agent of the present invention]
The medicament of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the present invention comprises at least a compound represented by the formula (I), the formula (I ′), the formula (IA), the formula (IB), or the formula (IC) of the present invention. It may contain one or more and is made in combination with a pharmaceutically acceptable additive. More specifically, excipients (eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose ( HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carbo Cymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), aminoalkyl methacrylate copolymer E, methacrylic acid) Copolymer LD), plasticizers (eg triethyl citrate, macrogol), masking agents (eg titanium oxide), colorants, flavoring agents, preservatives (eg benzalkonium chloride, paraoxybenzoic acid esters), isotonic Agents (eg, glycerin, sodium chloride, calcium chloride, mannitol, glucose), pH regulators (eg, buffers such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, phosphate buffer), stable Agent (eg, sugar, sugar a) (Alcohol, xanthan gum), dispersant, antioxidant (eg; ascorbic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffer, preservative (eg; paraben, benzyl alcohol, benzal chloride) Luconium), fragrance (eg, vanillin, l-menthol, rose oil), solubilizer (eg, polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol, triethanolamine), absorption enhancer (E.g., sodium glycolate, sodium edetate, sodium caprate, acylcarnitines, limonene), gelling agents, suspending agents or emulsifiers, commonly used suitable additives or solvents It can be combined with the compounds of the invention as appropriate to form various dosage forms. Come.

Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir. Oral, subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to a patient by inhalation or the like.
The dose of the compound of the present invention is usually 0.005 mg to 3.0 g, preferably 0.05 mg to 2.5 g, more preferably 0.1 mg to 1.5 g per day for an adult. Can be increased or decreased as appropriate.
The total amount can be divided into 1 or 2-6 doses and administered orally or parenterally, or can be administered continuously, such as intravenous infusion.

[Examples of pharmacological experiments]
Hereinafter, the present invention will be specifically described with reference to experimental examples, but the present invention is not limited to these examples.
(1) Measurement of capsaicin-induced Ca influx in human and rat TRPV1-transformed CHO cell lines (a) Establishment of human and rat TRPV1-transformed CHO cell lines And cloned from rat dorsal root ganglia. Cloned TRPV1 cDN
A was incorporated into the pCAGGS vector, which was transformed into a CHO-K1 cell line and transformed. Clones obtained by limiting dilution were stimulated with capsaicin, and clones with high response were selected using an increase in Ca concentration as an index. Selected clones were used for experiments.

(B) Measurement of Ca influx using FDSS-6000 Human or rat TRPV1-transformed CHO cells were seeded in a 96-well plate (black wall, transparent bottom / manufactured by Greiner) at a density of 40,000 cells per well. FLIP supplemented with 2.5 mmol / L probenecid after overnight culture at 37 ° C. and 5% CO ₂
The loading solution of R Calcium 3 assay kit (Molecular Devices) was added to each well in the same amount as the medium, and the cells were added at 37 ° C. for 6 minutes.
Incubated for 0 min. Capsaicin (10 nmol / L) Changes in intracellular Ca concentration were measured using FDSS-6000 (λex: 480 nm, λem: 540 nm, Hamamatsu Photonics) for 3 minutes after stimulation. After calculating the integrated value of the increase rate of intracellular Ca concentration in each of the compound treatment group and the vehicle group of the present invention, the concentration of the compound of the present invention (IC ₅₀₎ that suppresses the increase in intracellular Ca concentration induced by capsaicin by 50%. ) And the inhibitory effect of the test compound was compared using this value as an index. The IC ₅₀ value in human TRPV1 is shown in Table 1 as A when the value is 10 nmol / L or less and as B when the value is 100 nmol / L or less and up to 10 nmol / L. The compound of the present invention exhibits an intensity of at least 1 μmol / L or less when the IC ₅₀ value is measured by the above method.

(2) Effect of Compound on CFA-Induced Rat Inflammatory Pain Model A CFA-induced rat inflammatory pain model is prepared by a general method, for example, the method of Pomonis JD (The Journal of Pharmaceutical Therapies and Experimental Therapeutics, 306: 387- 393). Specifically, inflammation is induced by administering 50 μL of 100% CFA to the soles of rats.
Oral administration of the compound of the present invention to rats 2 days or 1 week after administration of CFA suppresses the decrease in pain threshold, that is, proves its effectiveness as a therapeutic agent for inflammatory pain.
(3) Effect of Compound on Neuropathic Pain Model Rat When the compound of the present invention is orally administered to any one of Chung model rat, Seltzer model rat and STZ-induced diabetic pain model rat, the decrease in pain threshold is suppressed. In other words, the effectiveness as a therapeutic agent for neuropathic pain is proved.
(4) Effect of Compound on Mouse PQ Rising Mouse PQ (Phenyl-p-quinone) rising is prepared by a method such as Mustafa AA (General Pharmacology, Vol. 23: 1177-1).
182). Specifically, after the administration of Phenyl-p-quinone diluted with physiological saline into the abdominal cavity of the mouse, the number of times that the mouse exhibited a behavior such as stretching, twisting, or rolling is recorded for a certain period of time.
By administering the compound of the present invention to mice prior to administration of Phenyl-p-quinone, the number of times of behavior such as stretching, twisting, and rounding after administration of Phenyl-p-quinone is reduced, thereby showing the effectiveness.

(5) Safety test The compound of the present invention is orally administered to a rat at a dose of 30 mg / Kg once, and no deaths are observed and no remarkable behavioral abnormalities are observed. Indicated. (6) hERG inhibition test by patch clamp method The effect on hERG (human ether-a-go-go related gene) channels is fully automatic patch clamp system (PatchXpress 700).
0A; molecular device). In order to confirm the hERG I _Kr current of the cells, a depolarizing pulse is periodically applied while maintaining the membrane potential at −80 mV. After the generated current has stabilized, the test substance is added to the perfusate. The effect of the test substance on the hERG channel is confirmed by changes in tail current induced by -50 mV, 0.2 s and 20 mV, 5 s depolarizing pulse followed by -50 mV, 5 s repolarizing pulse. Stimulation was performed once every 12 seconds. The measurement is performed at room temperature. The hERG channel inhibition rate is calculated as the reduction rate (suppression rate) of the tail current 5 minutes after application with respect to the maximum tail current before application of the test substance.
By calculating this inhibition rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.

(7) Pharmacokinetics For example, by using male SD rats aged 5 to 6 weeks to examine the plasma concentration transition after single oral administration of the compound of the present invention, the bioavailability is good, It is proved that the maximum plasma concentration (Cmax) and AUC both increase and keep linearity almost in proportion to the dose. In addition, by measuring the inhibitory action on human drug-metabolizing enzymes, the influence on it is proved. In addition, human, monkey, dog and rat liver microsomes are used to demonstrate whether they are less susceptible to metabolism and whether they are less susceptible to the first-pass effect of liver metabolism.

(8) Effect on rectal temperature The test compound was administered to the rat once at a dose of 1 mg / Kg, and the rectal temperature was measured after 15 minutes, 30 minutes, and 60 minutes. Observe.
A test compound is orally administered to a rat once at a dose of 10 mg / Kg, and the rectal temperature at 30 minutes, 60 minutes and 120 minutes is measured, and the rectal temperature is observed during that time.
In addition, the effect on the rectal temperature can be observed using various animals as appropriate in addition to rats. For example, rodents (eg, hamsters, mice, guinea pigs, etc.), carnivores (eg, Sunks), heavy teeth (eg, rabbits), carnivores (eg, dogs, ferrets, minks, cats, etc.) Ostracoda (for example, horses, etc.), cloven-hoofed eyes (for example, pigs, cows, goats, sheep, etc.), and primates (for example, various monkeys, chimpanzees, etc.). It is also possible to observe the effect on human body temperature.
It is possible to calculate the difference between the average values of the test compound administration group and the vehicle administration group at each measurement time of the rectal temperature, and classify the rat rectal temperature change into the following three levels from the maximum absolute value of the difference: Is possible.
-: Maximum value is less than 0.5 degree Celsius +: Maximum value is 0.5 degree Celsius or more and less than 1 degree ++: Maximum value is 1 degree Celsius or more

From the above results, it was shown that the compound of the present invention has an antagonistic action on an excellent TRPV1 receptor. Moreover, the analgesic effect in an in vivo inflammatory pain model and a neuropathic pain model is shown, no abnormality is observed in the safety test, and the low toxicity of the present invention is shown.
Furthermore, preferred compounds of the present invention have high metabolic stability and do not cause an increase in body temperature (especially, there is little change in body temperature) at doses that exhibit drug efficacy.
Therefore, the compound of the present invention is used as a TRPV1 receptor modulator, particularly as a TRPV1 receptor antagonist, as a prophylactic or therapeutic agent for pain, particularly as a prophylactic or therapeutic agent for inflammatory pain, fibromyalgia, or neuropathic pain. Be expected.

The compounds of the present invention are expected to show promising preventive or therapeutic effects for these various diseases. Specifically, acute pain, chronic pain, neuropathic pain, fibromyalgia, postherpetic neuralgia, trigeminal neuralgia, back pain, pain after spinal cord injury, lower limb pain, causalgia, diabetic neuralgia, edema, burns, sprains, Pain due to fractures, postoperative pain, periarthritis, osteoarthritis, arthritis, rheumatoid arthritis pain, inflammatory pain, cancer pain, migraine, headache, toothache, neuralgia, fibromyalgia, muscle pain , Hyperalgesia, pain due to angina and menstruation, neuropathy, nerve damage, neurodegeneration, chronic obstructive pulmonary disease (COPD), asthma, airway hypersensitivity, wheezing, cough, rhinitis, inflammation of the mucous membranes such as eyes, nervousness Skin diseases, inflammatory skin diseases such as psoriasis and eczema, edema, allergic diseases, gastroduodenal ulcer, ulcerative colitis, irritable colon, Crohn's disease, urinary incontinence, urge incontinence, overactive bladder, cystitis, Nephritis, pancreatitis, uveitis, viscera Harm, ischemia, stroke, schizophrenia, obesity, sepsis, pruritus, can be used for the treatment of diabetes. Promising therapeutic effects can be expected for neuropathic pain, fibromyalgia, inflammatory pain and urinary incontinence.

[Formulation example]
The following are examples of the pharmaceutical composition of the present invention.
Formulation Example 1 Compound of Tablet Example 1 100 g
137g of lactose
Crystalline cellulose 30g
Hydroxypropylcellulose 15g
Carboxymethyl starch sodium 15g
Magnesium stearate 3g
Weigh the above ingredients and mix evenly. This mixture is compressed into tablets having a weight of 150 mg.
Formulation Example 2 Film-coated hydroxypropylmethylcellulose 9g
Macrogol 6000 1g
Titanium oxide 2g
After weighing the above components, hydroxypropylmethylcellulose and macrogol 6000 are dissolved in water and titanium oxide is dispersed. This liquid is film-coated on 300 g of the tablet of Preparation Example 1 to obtain film-coated tablets.

Formulation Example 3 Capsule Example 2 Compound 50g
Lactose 435g
Magnesium stearate 15g
The above ingredients are weighed and mixed uniformly. The mixture is filled into an appropriate hard capsule in an amount of 300 mg in a capsule encapsulator to obtain a capsule.
Formulation Example 4 Capsule Example 3 Compound 100 g
Lactose 63g
Corn starch 25g
Hydroxypropylcellulose 10g
Talc 2g
After weighing the above components, the compound of Example 3, lactose and corn starch are uniformly mixed, an aqueous solution of hydroxypropylcellulose is added, and granules are produced by wet granulation. Talc is uniformly mixed into the granules, and 200 mg in weight is filled into an appropriate hard capsule to form a pushell.

Formulation Example 5 Compound of Powder Example 4 200 g
790 g of lactose
Magnesium stearate 10g
After weighing each of the above components, they are mixed uniformly to form a 20% powder.
Formulation Example 6 Granules, Fine Granules Compound of Example 5 100 g
Lactose 200g
Crystalline cellulose 100g
Partially pregelatinized starch 50g
Hydroxypropylcellulose 50g
After weighing the above components, the compound of Example 5, lactose, crystalline cellulose, and partially pregelatinized starch were added and mixed uniformly, an aqueous solution of hydroxypropyl cellulose (HPC) was added, and granules or fine granules were obtained by wet granulation. Manufacturing. The granules or fine granules are dried to obtain granules or fine granules.
Formulation Example 7 Cream Compound of Example 1 0.5 g
0.1 g of dl-α-tocopherol acetate
Stearyl glycyrrhetinate 0.05g
Stearic acid 3g
Higher alcohol 1g
Squalane 10g
Octyldodecyl myristate 3g
7g of trimethylglycine
Preservative Appropriate amount Saponifying agent Appropriate amount After weighing the above components, the compound of Example 1 is mixed and dissolved. An appropriate amount of purified water is added to make 50 g to obtain a cream formulation.

Next, examples are given to describe the present invention in more detail, but the present invention is not limited thereto.
For the measurement of nuclear magnetic resonance spectrum (NMR), Geol JNM-ECX300 (JEOL JNM-ECX300) FT-NMR (manufactured by JEOL Ltd.), Geol JNM-ECX400 (JEOL JNM-ECX400) FT-NMR (JEOL) (Made by Co., Ltd.) was used. LC Mass is a Waters FractionLynx MS system (W
water), SunFire column (4.6 mm × 5 cm, 5 μm) for the column, acetonitrile, 0.05% acetic acid aqueous solution for the mobile phase, acetonitrile: 0.05% acetic acid aqueous solution = Analysis was performed using gradient conditions from 1: 9 (0 min) to 9: 1 (5 min) to 9: 1 (7.5 min).

Reference Example 1 Synthesis of (Rac) -7-amino-1,2,3,4-tetrahydronaphthalen-1-ol <Step 1> (Rac) -7-nitro-1,2,3,4-tetrahydro Synthesis of Naphthalen-1-ol Sodium borohydride (2.0 g) was added to an ethanol solution (100 mL) of 7-nitro-1-tetralone (10 g) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (11 g).
<Step 2> Synthesis of (Rac) -7-amino-1,2,3,4-tetrahydronaphthalen-1-ol (Reference Example 1) Methanol (100 mL) of the compound (10 g) obtained in <Step 1> To the solution was added 10% palladium-carbon (Pd / C) (1.0 g), and the mixture was stirred under a hydrogen atmosphere for 12 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 90: 10-50: 50-20: 80). The title compound (6.5 g) was obtained as a pink solid.

(Reference Example 2) Optical resolution of (Rac) -7-amino-1,2,3,4-tetrahydronaphthalen-1-ol (Reference Example 1) The compound (5.0 g) obtained in <Step 2> Preparative chromatography (column: CHIRALPAK IC (5 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent: n-hexane: 2-propanol: methanol: diethylamine = 70: 20: 10: 0.1, flow rate: 32 mL / Min, UV: 295 nm detection) to give each enantiomer of the title compound the first fraction (2.3 g, white solid, 99.2% ee, retention time 6.7 minutes, [ α] ²⁷ _D = -76.6 ^(c0.1, ethanol) :( enantiomer A: reference example 2-(A)), and a second fraction (2.3 g, white solid, 98.9% ee, Li Emissions Deployment time 8.1 min, [α] ²⁷ _D = + 89.4 ^(c0.1, Ethanol) :( enantiomer B:.. Obtained as Reference Example 2-(B)) The optical purity was determined by chiral column (column : CHIRALPAK IC (0.46 cm × 25.0 cm), manufactured by Daicel Chemical Industries, Ltd., eluent; n-hexane: 2-propanol: methanol: diethylamine = 70: 20: 10: 0.1, flow rate: 1.0 mL / Min, UV: 295 nm detection).

Reference Example 3 Synthesis of (Rac) -7-amino-1,2,3,4-tetrahydronaphthalen-2-ol <Step 1> (Rac) -7-nitro-1,2,3,4-tetrahydro Synthesis of naphthalen-2-ol 7-nitro-2 synthesized according to the method described in Journal of the American Chemical Society, 119, 12722-12726, 1997 -Sodium borohydride (2.9 g) was added to a solution of tetralone (9.8 g) in methanol (200 mL) and tetrahydrofuran (100 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1N aqueous hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, triturated with ethyl acetate cooled to −60 ° C. and collected by filtration to obtain the title compound (7.2 g).
<Step 2> Synthesis of (Rac) -7-amino-1,2,3,4-tetrahydronaphthalen-2-ol (Reference Example 3) Methanol (7.2 g) of the compound (7.2 g) obtained in <Step 1> 120%), 10% palladium-carbon (Pd / C) (0.72 g) was added, and the mixture was stirred for 6 hours under a hydrogen gas atmosphere. The reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was triturated with diethyl ether and collected by filtration to give the title compound (5.8 g) as a pink solid.

(Reference Example 4) Optical resolution of (Rac) -7-amino-1,2,3,4-tetrahydronaphthalen-2-ol (Reference Example 3) The compound (5.0 g) obtained in <Step 2> Preparative chromatography (Column: CHIRALPAK IC (5 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent: n-hexane: ethanol: diethylamine = 80: 20: 0.1, flow rate: 47 mL / min, UV: 295 nm Detection) to give each enantiomer of the title compound the first fraction (2.3 g, white solid, 99.9% ee, retention time 7.9 minutes, [α] ^27.5 _D = +72.6 (c0.1, ethanol): (Enantiomer A: Reference Example 4- (A)) and second fraction (2.3 g, white solid, 99.9% ee, retention time 9. Min, [α] ^27.5 _D = -89.7 ^(c0.1, ethanol)..: Was obtained as a (enantiomer B Example 4-(B)) The optical purity was determined by chiral column (column: manufactured ) CHIRALPAK IC (0.46 cm × 25.0 cm) manufactured by Daicel Chemical Industries, eluent ;: n-hexane: ethanol: diethylamine = 80: 20: 0.1, flow rate: 1.0 mL / min, UV: 295 nm detection) .

Reference Example 5 Synthesis of (Rac) -6-amino-2,3-dihydro-1H-inden-1-ol <Step 1> (Rac) -2,3-dihydro-6-nitro-1H-indene- Synthesis of 1-ol The Journal of Organic Chemistry (The Journal of
(Organic Chemistry), 54, 1354-1359, 1989, synthesized according to the method described in 1989, (3-g-dihydro-6-nitro-1H-inden-1-one (10 g), According to the method of Step 1>, the title crude compound (10 g) was obtained as a reddish brown solid.
<Step 2> Synthesis of (Rac) -6-amino-2,3-dihydro-1H-inden-1-ol (Reference Example 1) According to the method of <Step 2> (Reference Example 5) in <Step 1> The title compound (6.8 g) was obtained as a white solid from the obtained compound (10 g).

(Reference Example 6) Optical resolution of (Rac) -6-amino-2,3-dihydro-1H-inden-1-ol (Reference Example 5) The compound (5.0 g) obtained in <Step 2> was separated. Optical resolution using preparative chromatography (column: CHIRALPAK IC (5 cm × 25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent; acetonitrile: diethylamine = 100: 0.1, flow rate: 47 mL / min, UV: 301 nm detection) To give each enantiomer of the title compound the first fraction (2.2 g, white solid, 99.6% ee, retention time 4.2 minutes, [α] ²⁹ _D = −49.8 (c0.1 , Ethanol): (Enantiomer A: Reference Example 6- (A)), and second fraction (2.4 g, white solid, 99.6% ee, retention time 5.7 minutes, [α] ²⁹ _D = + 4 6.8 (c0.1, ethanol): (Enantiomer B: Reference Example 6- (B)) Optical purity was determined with a chiral column (column: CHIRALPAK IC (0. 0) manufactured by Daicel Chemical Industries, Ltd.). 46 cm × 25.0 cm), eluent: acetonitrile: diethylamine = 100: 0.1, flow rate: 1.0 mL / min, UV: 301 nm detection).

Reference Example 7 Synthesis of (Rac) -4-amino-2,3-dihydro-1H-inden-2-ol <Step 1> (Rac) -2,3-dihydro-4-nitro-1H-indene- Synthesis of 1-ol The Journal of Organic Chemistry (The Journal of
Organic Chemistry), 52, 1649 to 1655, 2,3-dihydro-4-nitro-1H-inden-1-one (14 g) synthesized according to the method described in 1987, (Reference Example 1) < According to the method of Step 1>, the title crude compound (15 g) was obtained as a reddish brown solid.
<Step 2> Synthesis of 7-nitro-1H-indene (Reference Example 7) To a toluene (500 mL) solution of the compound (14 g) obtained in <Step 1> was added p-toluenesulfonic acid monohydrate (4.7 g). ) And heated to reflux for 13 hours. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude compound was triturated with n-hexane: diethyl ether = 1: 1 and collected by filtration to obtain the title compound (8.8 g) as a pale yellow solid.
<Step 3> Synthesis of 1a, 6a-dihydro-5-nitro-6H-indeno [1,2-b] oxylene (Reference Example 7) Dichloromethane (520 mL) of the compound (13.0 g) obtained in <Step 2> ) M-Chloroperbenzoic acid (48.8 g) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium thiosulfate, extracted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (14.7 g) as a white solid.
<Step 4> Synthesis of 2,3-dihydro-4-nitro-1H-inden-2-one (Reference Example 7) To a toluene (260 mL) solution of the compound (14.3 g) obtained in <Step 3> Zinc iodide (12.9 g) was added and heated to reflux for 1 hour. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate at room temperature, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was triturated with n-hexane: diethyl ether = 2: 1 and collected by filtration to obtain the title compound (12.3 g) as a pale red solid.
<Step 5> Synthesis of (Rac) -2,3-dihydro-4-nitro-1H-inden-2-ol (Reference Example 1) According to the method of <Step 1>, (Reference Example 7) <Step 4> The title crude compound (9.0 g) was obtained as an orange solid from the obtained compound (13 g).
<Step 6> Synthesis of (Rac) -4-amino-2,3-dihydro-1H-indene-2-ol (Reference Example 1) According to the method of <Step 2> (Reference Example 7) <Step 5 The title compound (2.3 g) was obtained as an orange solid from the compound (9.0 g) obtained in>.

(Reference Example 8) Optical resolution of (Rac) -4-amino-2,3-dihydro-1H-inden-2-ol (Reference Example 7) The compound (4.8 g) obtained in <Step 6> was separated. Preparative chromatography (Column: CHIRALPAK AD-H (5 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent: n-hexane: 2-propanol: methanol: diethylamine = 80: 15: 5: 0.1, flow rate: Each enantiomer of the title compound was subjected to optical resolution using 47 mL / min, UV: 237 nm detection) to obtain the first fraction (2.1 g, white solid, 99.5% ee, retention time 8.6 min) [Α] ²⁹ _D = −27.1 (c0.1, ethanol)): (Enantiomer A: Reference Example 8- (A)), and second fraction (2.2 g, white solid, 98.2% ee , Lite Deployment time 9.6 min, [α] ²⁹ _D = + 38.9 ^(c0.1, Ethanol) :( enantiomer B:.. Obtained as Reference Example 8- (B)) The optical purity was determined by chiral column (column : CHIRALPAK AD-H (0.46 cm × 25.0 cm), manufactured by Daicel Chemical Industries, Ltd., eluent; n-hexane: 2-propanol: methanol: diethylamine = 80: 15: 5: 0.1, flow rate: 1 0 mL / min, UV: 237 nm detection).

Reference Example 9 Synthesis of (Rac) -4-amino-2,3-dihydro-1H-inden-1-ol <Step 1> (Rac) -2,3-dihydro-4-nitro-1H-indene- Synthesis of 1-ol The Journal of Organic Chemistry (The Journal of
(Organic Chemistry), 52, 1649-1655, 2,3-dihydro-4-nitro-1H-inden-1-one (9.1 g) synthesized according to the method described in 1987, (Reference Example 1). ) According to the method of <Step 1>, the title compound (9.0 g) was obtained as an ocherous solid.
<Step 2> Synthesis of (Rac) -4-amino-2,3-dihydro-1H-inden-1-ol (Reference Example 1) According to the method of <Step 2>, (Reference Example 9) <Step 1> The resulting compound (9
. The title compound (5.5 g) was obtained as a white solid from 0 g).

(Reference Example 10) Optical resolution of (Rac) -4-amino-2,3-dihydro-1H-inden-1-ol (Reference Example 9) The compound (5.0 g) obtained in <Step 2> was separated. Preparative chromatography (column: CHIRALCEL OJ-H (5 cm × 25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent; n-hexane: ethanol: diethylamine = 70: 30: 0.1, flow rate: 32 mL / min, UV: The enantiomers of the title compound were subjected to optical resolution using 285 nm detection) to obtain the first fraction (2.3 g, white solid, 99.6% ee, retention time 9.5 minutes, [α] ²⁹ _D = -27.0 (c0.1, ethanol)): (Enantiomer A: Reference Example 10- (A)), and the second fraction (2.3 g, white solid, 99.0% ee, retention time 11) 3 min, [α] ²⁹ _D = + 14.9 ^(c0.1, Ethanol) :( enantiomer B:.. Obtained as Reference Example 10- (B)) The optical purity was determined by chiral column (column: manufactured) CHIRALCEL OJ-H (0.46 cm × 25.0 cm) manufactured by Daicel Chemical Industries, eluent; n-hexane: ethanol: diethylamine = 70: 30: 0.1, flow rate: 1.0 mL / min, UV: 285 nm detection) .

Reference Example 11 Synthesis of (Rac) -5-amino-2,3-dihydro-1H-inden-2-ol <Step 1> (Rac) -2,3-dihydro-5-nitro-1H-indene- Synthesis of 2-ol Journal of the American Chemical Society, 119, 127
22-12726, from 5-nitro-2-indanone (7.0 g) synthesized according to the method described in 1997, according to the method of (Reference Example 1) <Step 1>, the title crude compound (7.3 g ) Was obtained as a pale orange solid.
<Step 2> Synthesis of (Rac) -5-amino-2,3-dihydro-1H-inden-2-ol (Reference Example 1) According to the method of <Step 2> (Reference Example 11) <Step 1> The title compound (5.7 g) was obtained as an ocher solid from the obtained compound (7.3 g).

(Reference Example 12) Optical resolution of (Rac) -5-amino-2,3-dihydro-1H-inden-2-ol (Reference Example 11) The compound (5.0 g) obtained in <Step 2> was separated. Preparative chromatography (column: CHIRALCEL OJ-H (5 cm × 25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent; carbon dioxide: ethanol: diethylamine = 80: 20: 0.1, flow rate: 211 g / second, UV: 291 nm Detection) is used to resolve each enantiomer of the title compound in the first fraction (2.2 g, white solid, 99.8% ee, retention time 11.3 minutes, [α] ²⁹ _D = − 31.3 (c0.1, ethanol)): (enantiomer A: Reference Example 12- (A)), and second fraction (2.1 g, white solid, 98.8% ee, retention time 1 .2 min, [α] ²⁹ _D = + 38.6 ^(c0.1, Ethanol) :( enantiomer B:.. Obtained as Reference Example 12-(B)) The optical purity was determined by chiral column (column: manufactured ) CHIRALCEL OJ-H (0.46 cm × 25.0 cm) manufactured by Daicel Chemical Industries, eluent; n-hexane: ethanol: diethylamine = 60: 40: 0.1, flow rate: 1.0 mL / min, UV: 295 nm detection ).

Reference Example 13 Synthesis of 5-amino-3,4-dihydro-1-methyl-1H-quinazolin-2-one <Step 1> Synthesis of 2-methylamino-6-nitrobenzonitrile 2,6-dinitrobenzo Methylamine (40% aqueous solution) (17 mL) was added to a solution of nitrile (Alfa Aesar) (10 g) in N, N-dimethylformamide (50 mL), and the mixture was stirred at 50 ° C. for 40 minutes. The reaction solution was poured into ice water, the precipitate was collected by filtration, washed successively with water and n-hexane, and dried under reduced pressure to obtain the title compound (9.4 g) as a brown solid.
<Step 2> Synthesis of 2-methylamino-6-nitrobenzylamine Trifluoroacetic acid (20 mL) was added dropwise at 0 ° C to a suspension of sodium borohydride (10 g) in tetrahydrofuran (100 mL). To this solution, a tetrahydrofuran (100 mL) suspension of the compound (9.4 g) obtained in (Reference Example 13) <Step 1> was added dropwise over 20 minutes and stirred at room temperature for 3 hours. After the reaction solution was concentrated, water was added to the resulting residue, and the mixture was washed with dichloromethane. The aqueous layer was made alkaline with 1N aqueous sodium hydroxide solution, extracted with dichloromethane, washed successively with 2N aqueous sodium hydroxide solution, 1N aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (6.5 g) as a brown oil.
<Step 3> Synthesis of 3,4-dihydro-1-methyl-5-nitro-1H-quinazolin-2-one (Reference Example 13) Dichloromethane (6.5 g) of the crude compound obtained in <Step 2> 160 mL) solution was added with pyridine (8.7 mL) and 1,1′-carbonylbis-1H-imidazole (12 g) and stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the resulting residue was washed with diethyl ether and dried under reduced pressure to give the title compound (4.6 g) as an ocher solid.
<Step 4> Synthesis of 5-amino-3,4-dihydro-1-methyl-1H-quinazolin-2-one (Reference Example 13) Tetrahydrofuran (500 mL) of the compound (4.6 g) obtained in <Step 3> ) Tin (II) chloride dihydrate (30 g) was added to the solution and heated to reflux for 7.5 hours. After allowing to cool, 2N aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 10, followed by celite filtration. The filtrate was extracted with ethyl acetate, washed successively with 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; ethyl acetate: methanol = 100: 0 to 70:30) to give the title compound (1.8 g) as a pale yellow solid. Obtained.

Reference Example 14 Synthesis of 5-amino-3,4-dihydro-1-methyl-1H-quinazolin-2-one (alternative method)
<Step 1> Synthesis of 2-amino-6-nitrobenzonitrile To a solution of 2,6-dinitrobenzonitrile (26 g) in methanol (450 mL) and 1,4-dioxane (280 mL), hydrochloric acid (100 mL) was heated under reflux. ) And iron (22 g) were sequentially added, and the mixture was stirred at the same temperature for 1.5 hours. A 2N aqueous hydrochloric acid solution was added at room temperature, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (10 g) as a yellow solid.
<Step 2> Synthesis of 2-amino-6-nitrobenzylamine To a suspension of sodium borohydride (11 g) in tetrahydrofuran (70 mL) with ice cooling, trifluoroacetic acid (22 mL), (Reference Example 14) <Step A solution of the compound obtained in 1> (9.4 g) in tetrahydrofuran (140 mL) was sequentially added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 1N aqueous sodium hydroxide solution (1.0 L), ethyl acetate (500 mL) was added, and the mixture was stirred for 1.5 hr. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (9.2 g) as a dark purple solid.
<Step 3> Synthesis of N- (2-amino-6-nitrobenzyl) -2-nitrobenzenesulfonamide (Reference Example 14) Dichloromethane (50 mL) of the compound (0.5 g) obtained in <Step 2>
) 2-Nitrobenzenesulfonyl chloride (0.7 g) and triethylamine (0.6 mL) were sequentially added to the solution under ice cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was solidified with n-hexane / diethyl ether to obtain the title crude compound (0.8 g) as a yellow solid.
<Step 4> Synthesis of N- (2-amino-6-nitrobenzyl) -N- (3,4-dimethoxybenzyl) -2-nitrobenzenesulfonamide (Reference Example 14) Compound obtained in <Step 3> 2.0 g), veratryl alcohol (1.4 g) in tetrahydrofuran (100 mL) under ice-cooling, triphenylphosphine (3.0 g), diethyl azodicarboxylate (40% toluene solution) (5.3 mL) Were sequentially added and stirred at room temperature for 12 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent: n-hexane solution: ethyl acetate = 100: 0-50: 50) to give the title compound (2.6 g) as yellow. Obtained as a solid.
<Step 5> Synthesis of 2-amino-N- (3,4-dimethoxybenzyl) -6-nitrobenzylamine (Reference Example 14) N, N- of the compound (1.0 g) obtained in <Step 4> Lithium hydroxide monohydrate (0.40 g) and thioglycolic acid (0.30 mL) were sequentially added to a dimethylformamide (6.0 mL) solution, and the mixture was stirred at room temperature for 1 hour. 1N Aqueous sodium hydroxide solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (0.70 g) as a yellow solid.
<Step 6> Synthesis of 3- (3,4-dimethoxybenzyl) -3,4-dihydro-5-nitro-1H-quinazolin-2-one (Reference Example 14) Compound (1) obtained in <Step 5> 0.0 g) in 1,2-dichloroethane (30 mL) was added triethylamine (1.3 mL) and 1,1′-carbonylbis-1H-imidazole (1.0 g), and the mixture was heated to reflux for 3 hours. After allowing to cool, the precipitated solid was collected by filtration, washed with dichloromethane, and then dried under reduced pressure to obtain the title compound (0.60 g) as a pale red solid.
<Step 7> Synthesis of 5-amino-3,4-dihydro-1-methyl-1H-quinazolin-2-one (Reference Example 14) N, N of compound (0.30 g) obtained in <Step 6> -Potassium carbonate (0.80g) and methyl iodide (0.40mL) were added to the dimethylformamide (8.0mL) solution, and it stirred at 40 degreeC for 6 hours. Water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Trifluoroacetic acid (4.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 4.5 hours. 1N Aqueous sodium hydroxide solution was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (8.0 mL), 10% palladium-carbon (Pd-C) (30 mg) was added, and the mixture was stirred at room temperature for 1 hr in a hydrogen atmosphere. 10% Palladium-carbon (Pd-C) was filtered through Celite, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 90: 10). The compound (60 mg) was obtained as a pale yellow solid.

Reference Example 15 Synthesis of 5-amino-3,4-dihydro-1-ethyl-1H-quinazolin-2-one In accordance with Reference Example 13, the title was obtained from 2,6-dinitrobenzonitrile (13 g). Compound (2.7 g) was obtained as a brown solid.

Reference Example 16 Synthesis of 5-amino-3,4-dihydro-1-ethyl-1H-quinazolin-2-one (alternative method)
(Reference Example 14) By the method according to <Step 7>, the title crude compound (17 mg) was obtained as a brown solid from the compound (0.30 g) obtained in (Reference Example 14) <Step 6>.

Reference Example 17 Synthesis of 2- (4-amino-2,6-difluorophenoxy) -2-methyl-1-propanol <Step 1> Synthesis of 2,6-difluoro-4-nitrophenol 2,6-difluoro Phenol (25g) in acetic acid (40mL) with fuming nitric acid (10m
L) was added and stirred at 0 ° C. for 1 hour. The reaction mixture was concentrated, water was added to the resulting residue, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: n-hexane: dichloromethane = 100: 0 to 90:10, n-hexane: ethyl acetate = 90: 10 to 50:50). To give the title compound (13 g) as a yellow solid.
<Step 2> Synthesis of ethyl 2- (2,6-difluoro-4-nitrophenoxy) -2-methyl-propanoate (Reference Example 17) N of the compound (8.8 g) obtained in <Step 1> To a N-dimethylformamide (110 mL) solution were added potassium carbonate (8.4 g) and ethyl bromoisobutyrate (9.0 mL), and the mixture was heated to reflux for 10 hours. After allowing to cool, water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 90:10) to give the title compound (7.2 g) as a yellow oil. Got as.
<Step 3> Synthesis of 2- (2,6-difluoro-4-nitrophenoxy) -2-methyl-propanoic acid (Reference Example 17) Ethanol (80 mL) of the compound (7.2 g) obtained in <Step 2> ) 2N aqueous sodium hydroxide solution (25 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, water is added to the resulting residue, the pH is adjusted to 4 to 5 with a 1N aqueous hydrochloric acid solution, the resulting solid is collected by filtration, washed with water, and dried under reduced pressure to give the title compound. (5.8 g) was obtained as a white solid.
<Step 4> Synthesis of 2- (2,6-difluoro-4-nitrophenoxy) -2-methyl-1-propanol (Reference Example 17) Tetrahydrofuran of the compound (5.8 g) obtained in <Step 3> (200 mL) solution was added tetrahydrofuran borane (1M tetrahydrofuran solution, 25 mL), and the mixture was heated to reflux for 1 hour. After allowing to cool, 1N aqueous hydrochloric acid solution was added, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 75:25) to give the title compound (5.5 g) as a yellow oil. Got as. <Step 5> Synthesis of 2- (4-amino-2,6-difluorophenoxy) -2-methyl-1-propanol (Reference Example 17) Methanol (5.5 g) of the compound (5.5 g) obtained in <Step 4> (200 mL) solution was added 10% palladium-carbon (Pd-C) (0.55 g), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. 10% Palladium-carbon (Pd-C) was filtered through Celite, and the solvent was evaporated under reduced pressure to obtain the title compound (4.6 g) as a light brown solid.

Reference Example 18 Synthesis of 7-amino-3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine <Step 1> Synthesis of 2,4-dinitrophenethyl acetate Concentrated under ice cooling 90% nitric acid (110 g) was slowly added to sulfuric acid (84 mL), and phenethyl acetate (50 mL) was added dropwise at 0 ° C. or lower (internal temperature). After dropping, the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was poured into ice water, extracted with diethyl ether, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (74 g) as a brown oil.
<Step 2> Synthesis of 2,4-dinitrophenethyl alcohol (Reference Example 18) Concentrated hydrochloric acid (7 ml) was added to a methanol (250 mL) solution of the compound (74 g) obtained in <Step 1> and refluxed for 1 hour. did. After allowing to cool, the solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was triturated with toluene-hexane and collected by filtration to obtain the title crude compound (23 g) as a white solid. After the filtrate was concentrated, the residue was triturated with diethyl ether and collected by filtration to obtain the title crude compound (12 g) as a white solid.
<Step 3> Synthesis of 2,4-dinitrophenethyl chloride (Reference Example 18) To a toluene (160 mL) solution of the compound (35 g) obtained in <Step 2>, thionyl chloride (36 mL), pyridine ( 13 mL) was added dropwise and heated to reflux for 2 hours. After allowing to cool, the reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0-80: 20) to give the title compound (32 g) as an oil. It was.
<Step 4> Synthesis of sodium 2,4-dinitrophenethylsulfonate (Reference Example 18) To a solution of the compound (32 g) obtained in <Step 3> in acetonitrile (130 mL), sodium sulfite (20 g) in water (130 mL) The solution was added and heated to reflux for 3 hours. After allowing to cool, isopropanol (260 mL) was added to the reaction mixture, and the precipitate was collected by filtration and dried to obtain the title compound (18 g) as an ocherous solid. Further, the organic solvent in the filtrate was distilled off under reduced pressure, isopropanol (130 mL) was added, and the precipitate was collected by filtration and dried to obtain the title compound (9.2 g) as a brown solid.
<Step 5> Synthesis of 2,4-dinitrophenethylsulfonyl chloride (Reference Example 18) To a mixture of phosphorus oxychloride (170 mL) of the compound (27 g) obtained in <Step 4>, phosphorus pentachloride (23 g) was added, Heated to reflux for 2 hours. After allowing to cool, the reaction solution was slowly poured into ice water, extracted with dichloromethane, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (19 g) as a dark brown viscous oil.
<Step 6> Synthesis of 7-amino-3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine (Reference Example 18) THF of compound (19 g) obtained in <Step 5> To the (320 mL) solution, stannic chloride dihydrate (87 g) was added and heated to reflux for 2 hours. After cooling, the reaction mixture was adjusted to pH 8 by adding 1N aqueous sodium hydroxide solution under ice cooling, and then ethyl acetate was added and stirred. The insoluble material was filtered through celite, the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was triturated with diethyl ether and collected by filtration to give the title crude compound (7.6 g) as a brown solid.

Reference Example 19 Synthesis of 5-amino-3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine <Step 1> Synthesis of 2,6-dinitrophenethyl alcohol Paraformaldehyde (2.3 g) and potassium tert-butoxide (0.12 g) were added to a solution of nitrotoluene (10 g) in N, N-dimethylformamide (18 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. A 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with diethyl ether, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (11 g).
<Step 2> Synthesis of 2,6-dinitrophenethyl chloride (Reference Example 18) According to the method of <Step 3>, (Reference Example 19) From the compound (11 g) obtained in <Step 1>, the title crude compound (11 g )
<Step 3> Synthesis of 2,6-dinitrophenethylthioacetate (Reference Example 19) To a solution of the compound (0.50 g) obtained in <Step 2> in N, N-dimethylformamide (2.0 mL), potassium thioacetate (0.30 g) was added and stirred at room temperature overnight. Further, potassium thioacetate (74 mg) was added, and the mixture was stirred at room temperature for 2 hours and at 50 ° C. for 1 hour. After allowing to cool, water was added to the reaction mixture, extracted with diethyl ether, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (0.57 g).
<Step 4> Synthesis of 2,6-dinitrophenethylsulfonyl chloride (Reference Example 19) To a solution of the compound obtained in <Step 3> (0.57 g) in acetic acid (11 mL) -water (2.5 mL) was added sodium acetate ( After adding 1.2 g), chlorine gas was blown in at room temperature for 30 minutes. The reaction mixture was extracted with diethyl ether, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (0.48 g).
<Step 5> Synthesis of 5-amino-3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine (Reference Example 18) According to the method of <Step 6> (Reference Example 19) < The title compound (0.16 g) was obtained as a pale yellow solid from the compound (0.29 g) obtained in Step 4>.

Example 1
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-8 Synthesis of 5-yl) acrylamide <Step 1> Synthesis of 5-fluoro-1- (4-trifluoromethylphenyl) -1H-indole-2-carboxylic acid 5-fluoro-1H-indole-2-carboxylic acid (2. 0 g) in N, N-dimethylformamide (22 mL) was added 4-trifluoromethylphenyl bromide (2.0 mL), potassium hydroxide (1.4 g), and copper (II) oxide (0.44 g). In a nitrogen atmosphere, the mixture was heated to reflux for 2 hours. After standing to cool, Celite was added to the reaction solution, followed by filtration. Water and 1N aqueous sodium hydroxide solution are added to the filtrate to adjust the pH to about 10 and then washed with ethyl acetate. A 1N aqueous hydrochloric acid solution was added to the aqueous layer, adjusted to about pH 2, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 98: 2-83: 17) to give the title compound (2.8 g) as a light brown. Obtained as a colored solid.
<Step 2> Synthesis of (5-fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) methanol To a suspension of lithium aluminum hydride (0.82 g) in tetrahydrofuran (18 mL), A solution of the compound (2.8 g) obtained in (Example 1) <Step 1> in tetrahydrofuran (18 mL) was added dropwise over 1 hour under ice cooling. After stirring at room temperature for 30 minutes, water (0.90 mL), 1N aqueous sodium hydroxide solution (0.90 mL) and water (2.4 mL) were sequentially added, and the mixture was stirred at room temperature overnight. The insoluble material was filtered through celite and washed with ethyl acetate. The filtrate and washings were combined and concentrated to give the title compound (2.2 g) as a pale yellow solid.
<Step 3> Synthesis of (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) carboxaldehyde (Example 1) Compound obtained in <Step 2> (2.2 g ) In dichloromethane (20 mL) was added manganese dioxide (2.9 g), and the mixture was stirred at room temperature for 20 hours. Further, manganese dioxide (2.9 g) was added, and the mixture was stirred at room temperature for 3 hours. The insoluble material was filtered through celite and washed with ethyl acetate. The filtrate and washings were combined and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 50: 50-0: 100) to give the title compound (1.3 g). Was obtained as a pale yellow solid.
<Step 4> Synthesis of ethyl (E) -3- (5-fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) acrylate Sodium hydride (0.27 g) in tetrahydrofuran (0.27 g) 30 mL) To the suspension, ethyl diethylphosphonoacetate (1.3 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To this suspension was added dropwise a tetrahydrofuran (30 mL) solution of the compound (1.3 g) obtained in (Example 1) <Step 3>, and the mixture was stirred at room temperature for 30 minutes. Aqueous ammonium chloride solution (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was triturated with n-hexane and collected by filtration to obtain the title compound (1.1 g) as a pale yellow solid.
<Step 5> Synthesis of (E) -3- (5-fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) acrylic acid
Example 1 A suspension of the compound (1.0 g) obtained in <Step 4> and lithium hydroxide monohydrate (0.27 g) in tetrahydrofuran (8.0 mL) -water (4.0 mL) was added. The mixture was stirred at room temperature for 17 hours and at 40 ° C. for 6 hours. After the reaction solution was concentrated, 1N aqueous hydrochloric acid solution was added to the residue to adjust the pH to about 3, and the precipitate was collected by filtration and washed with water to obtain the title compound (0.91 g) as a pale yellow solid.
<Step 6> (E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2- Synthesis of On-7-yl) acrylamide (Example 1) Compound (0.11 g) obtained in <Step 5> and 8-amino-1,2,3
, 4-Tetrahydronaphthalen-2-ol (50 mg) in methanol (6.0 mL) was added 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium. Chloride (DMTMM) (0.11 g) was added and stirred at room temperature for 19 hours. The reaction precipitate was collected by filtration, and the filtered product was washed with ethyl acetate-methanol (10: 1) and dried to obtain the title compound (65 mg) as a colorless solid.

(Example 2)
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, (Example 1) 5 synthesized by the method described in <Step 5> and the method described in WO05 / 044802 pamphlet The title compound was obtained from -amino-1,2,3,4-tetrahydroquinolin-3-ol.

(Example 3)
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7- Yl) Synthesis of acrylamide (Example 1) Compound (50 mg) obtained in <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one (23 mg) N, N-dimethyl To a formamide (3.0 mL) solution, benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) (76 mg) and triethylamine (60 μL) were sequentially added under ice cooling, and then at room temperature for 13 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (NH-silica gel: eluent; n-hexane: ethyl acetate = 100: 0 to 50:50 to 10:90), and then diethyl After trituration with ether, the mixture was collected by filtration to give the title compound (39 mg) as a white solid.

Example 4
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3,4-dihydro-1-methyl-1H-quinoline-2- Synthesis of on-7-yl) acrylamide According to the method of (Example 3), the compound obtained in (Example 1) <Step 5> and 7-amino-3,4-dihydro-1-methyl-1H-quinoline The title compound was obtained from 2-one hydrochloride.

(Example 5)
(E) -3- (5-Fluoro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [ 2,1] Synthesis of thiazin-7-yl) acrylamide According to the method of (Example 3), the compound obtained in (Example 1) <Step 5> and (Reference Example 18) obtained in <Step 6>. The title compound was obtained from the above compound.

(Example 6)
(E) -3- (5-Fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-8 -Yl) Synthesis of acrylamide <Step 1> Synthesis of 5-fluoro-1- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid (Example 1) According to the method of <Step 1>, 5- From the fluoro-1H-indole-2-carboxylic acid (2.0 g) and 3-trifluoromethylphenyl bromide (2.0 mL), the title compound (2.7 g) was obtained as a light brown solid.
<Step 2> Synthesis of (5-fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2> (Example 6) < The title compound (2.3 g) was obtained as a brown solid from the compound (3.9 g) obtained in Step 1>.
<Step 3> Synthesis of (5-fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 6) The title compound (2.9 g) was obtained as a brown solid from the compound (2.3 g) obtained in <Step 2>.
<Step 4> Synthesis of ethyl (E) -3- (5-fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) acrylate (Example 1) Method of <Step 4> (Example 6) The title compound (2.9 g) was obtained as a pale yellow solid from the compound (2.3 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (5-fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) acrylic acid (Example 1) According to the method of <Step 5> (Example 6) The title compound (0.86 g) was obtained as a pale yellow solid from the compound (1.0 g) obtained in <Step 4>.
<Step 6> (E) -3- (5-Fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4- Synthesis of tetrahydronaphthalen-8-yl) acrylamide (Example 1) According to the method of <Step 6>, the compound obtained in (Step 6) of Example 6 and 8-amino-1,2,3,4- The title compound was obtained from tetrahydronaphthalen-2-ol.

(Example 7)
(E) -3- (5-Fluoro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, (Example 6) 5 synthesized by the method described in <Step 5> and the method described in International Publication No. 05/044802 pamphlet The title compound was obtained from -amino-1,2,3,4-tetrahydroquinolin-3-ol.

(Example 8)
(E) -3- (5-Fluoro-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-8 -Yl) Synthesis of acrylamide <Step 1> Synthesis of (5-fluoro-1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2>, 5-fluoro-1H-indole-2-carboxyl From the acid (25.8 g), the title compound (24.0 g) was obtained as a light brown solid.
<Step 2> Synthesis of (5-fluoro-1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 8) Compound (23) obtained in <Step 1> From 8 g) gave the title crude compound (17.4 g) as a light brown solid.
<Step 3> Synthesis of ethyl (E) -3- (5-fluoro-1H-indol-2-yl) acrylate
(Example 1) According to the method of <Step 4>, the title compound (12.9 g) was obtained as a pale yellow solid from the compound (17.0 g) obtained in (Example 8) <Step 2>.
<Step 4> Synthesis of ethyl (E) -3- (5-fluoro-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) acrylate (Example 8) Obtained in <Step 3> To a solution of the obtained compound (0.20 g) in N, N-dimethylformamide (3.0 mL) was added 3-trifluoromethylbenzyl bromide (0.16 mL) and potassium carbonate (0.30 g), and the mixture was stirred at room temperature for 1 hour. The mixture was stirred at 50 to 70 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 98: 2-83: 17) to give the title compound (0.28 g) as yellow. Obtained as a solid.
<Step 5> Synthesis of (E) -3- (5-fluoro-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) acrylic acid
Example 1 According to the method of <Step 5>, the title compound (0.20 g) was obtained as a yellow solid from the compound (0.28 g) obtained in (Example 8) <Step 4>.
<Step 6> (E) -3- (5-Fluoro-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4- Synthesis of tetrahydronaphthalen-8-yl) acrylamide (Example 1) According to the method of <Step 6>, the compound obtained in (Example 8) <Step 5> and 8-amino-1,2,3,4- The title compound was obtained from tetrahydronaphthalen-2-ol.

Example 9
(E) -3- (5-Fluoro-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, (Example 8) 5 synthesized by the method described in <Step 5> and the method described in International Publication No. 05/044802 pamphlet The title compound was obtained from -amino-1,2,3,4-tetrahydroquinolin-3-ol.

(Example 10)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide < Step 1> Synthesis of ethyl (E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) acrylate (Example 8) According to the method of <Step 4> (Example 8) Compound (1) obtained in <Step 3>
. The title compound (1.3 g) was obtained as a yellow solid from 0 g) and cyclohexylmethyl bromide (0.21 mL).
<Step 2> Synthesis of (E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) acrylic acid (Example 1) According to the method of <Step 5> (Example 10) The title compound (0.70 g) was obtained as a pale yellow solid from the compound (0.80 g) obtained in <Step 1>.
<Step 3> (E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Example 10) <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 11)
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine- Synthesis of 7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 10) From the compound obtained in <Step 2> and (Reference Example 18) from the compound obtained in <Step 6> To give the title compound.

(Example 12)
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1-methyl-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide According to the method of (Example 3), (Example 10) The compound obtained in <Step 2> and 7-amino-3,4-dihydro-1-methyl-1H-quinolin-2-one hydrochloride From the above, the title compound was obtained.

(Example 13)
(E) -3- (1-Cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1-methyl-1H-benzo [2, 1] Synthesis of thiazin-7-yl) acrylamide (Example 8) According to the method of <Step 4>, the title compound was obtained from the compound (0.10 g) obtained in (Example 11) and methyl iodide (26 μL). (28 mg) was obtained as a pale yellow solid.

(Example 14)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,3-dimethyl-1H-indoline-2-one-6-yl) acrylamide According to the method of Example 3), the compound obtained in (Example 10) <Step 2> and 6-amino-3,3-dimethyl-1H- synthesized according to the method described in WO08 / 091021 pamphlet The title compound was obtained from indoline-2-one.

(Example 15)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide According to the method of Example 3), the title compound was obtained from the compound obtained in <Example 2><Step2> and 5-amino-3,4-dihydro-1H-quinolin-2-one.

(Example 16)
(E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine- Synthesis of 5-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 10) From the compound obtained in <Step 2> and (Reference Example 19) <Compound obtained in <Step 5> To give the title compound.

(Example 17)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinazolin-2-one-5-yl) acrylamide According to the method of Example 3), 5-amino-3,4-dihydro-1H- synthesized according to the method described in (Example 10) <Step 2> and the method described in WO08 / 091021 pamphlet. The title compound was obtained from quinazolin-2-one.

(Example 18)
(E) -3- (1-Cyclohexylmethyl-5-fluoro-1H-indol-2-yl) -N- (2,3-dihydro-3-oxo-4H-1,4-benzoxazin-8-yl ) Synthesis of acrylamide According to the method of (Example 3), (Example 10) 8-amino-2,3 synthesized according to the method described in <Step 2> and the method described in WO08 / 091021 pamphlet The title compound was obtained from -dihydro-3-oxo-4H-1,4-benzoxazine.

(Example 19)
Synthesis of (E) -3- (5-chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide < Step 1> Synthesis of (5-chloro-1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2>, the title compound was obtained from 5-chloro-1H-indole-2-carboxylic acid (10 g). (5.9 g) was obtained as a pale pink solid.
<Step 2> Synthesis of (5-chloro-1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 19) Compound (5) obtained in <Step 1> 0.9 g) to give the title compound (5.3 g) as an ocher solid.
<Step 3> Synthesis of ethyl (E) -3- (5-chloro-1H-indol-2-yl) acrylate (Example 1) According to the method of <Step 4> (Example 19) <Step 2> The title compound (2.8 g) was obtained as a pale yellow solid from the compound (2.5 g) obtained in 1.
<Step 4> Synthesis of ethyl (E) -3- (5-chloro-1-cyclohexylmethyl-1H-indol-2-yl) acrylate (Example 10) According to the method of <Step 1> (Example 19) ) The title compound (0.45 g) was obtained as a pale orange solid from the compound (0.46 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (5-chloro-1-cyclohexylmethyl-1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (0.37 g) was obtained as a pale yellow solid from the compound (0.40 g) obtained in (Example 19) <Step 4>.
<Step 6> (E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Example 19) <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 20)
Synthesis of (E) -3- (5-chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Example 19) <Step 5> and 5-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 21)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1-methyl-1H-quinazolin-2-one-5-yl) Synthesis of acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Example 19) <Step 5> and the compound obtained in (Reference Example 13) <Step 4>.

(Example 22)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1-ethyl-1H-quinazolin-2-one-5-yl) Synthesis of Acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Example 19) <Step 5> and the compound obtained in (Reference Example 15).

(Example 23)
Synthesis of (E) -3- (5-chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-5-yl) acrylamide (Example 1) According to the method of <Step 6>, from the compound obtained in (Example 19) <Step 5> and 5-amino-1,2,3,4-tetrahydronaphthalen-1-ol, the title compound Got.

(Example 24)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N-((2R) -2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl ) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, (Example 19) The compound obtained in <Step 5> and the known (2R) -8-amino-1,2,3 , 4-tetrahydronaphthalen-2-ol (WO03 / 095420 pamphlet, pages 47-48), the title compound was obtained.

(Example 25)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N-((2S) -2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl ) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, the compound obtained in (Example 19) <Step 5> and the known (2S) -8-amino-1,2,3 , 4-tetrahydronaphthalen-2-ol (WO03 / 095420 pamphlet, pages 47-48), the title compound was obtained.

(Example 26)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acrylamide (A (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 2- (A)).

(Example 27)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (1-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acrylamide (B (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 2- (B)).

(Example 28)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acrylamide (A (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 4- (A)).

(Example 29)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-7-yl) acrylamide (B (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 4- (B)).

(Example 30)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acrylamide (A) (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 6- (A)).

(Example 31)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-1-hydroxy-1H-inden-6-yl) acrylamide (B) (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 6- (B)).

(Example 32)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acrylamide (A) (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 8- (A)).

(Example 33)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) acrylamide (B) (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 8- (B)).

(Example 34)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-1-hydroxy-1H-inden-4-yl) acrylamide (A) (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 10- (A)).

(Example 35)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-1-hydroxy-1H-inden-4-yl) acrylamide (B) (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of Example 19 <Step 5> and the compound of (Reference Example 10- (B)).

(Example 36)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-2-hydroxy-1H-inden-5-yl) acrylamide (A) (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 12- (A)).

(Example 37)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -N- (2,3-dihydro-2-hydroxy-1H-inden-5-yl) acrylamide (B) (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound of (Example 19) <Step 5> and the compound of (Reference Example 12- (B)).

(Example 38)
(E) -3- (5-Chloro-1-cyclohexylmethylindol-2-yl) -N- (3,5-difluoro-4- (1,1-dimethyl-2-hydroxyethyloxy) phenyl) acrylamide Synthesis (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Example 19) <Step 5> and the compound obtained in (Reference Example 17).

(Example 39)
Synthesis of (E) -3- (1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of 1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2>, the title compound (3.0 g) was converted to a pale yellow solid from 1H-indole-2-carboxylic acid (5.0 g). Obtained.
<Step 2> Synthesis of (1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 39) From the compound (3.0 g) obtained in <Step 1> The title compound (2.8 g) was obtained as a pale yellow solid.
<Step 3> Synthesis of (E) -3- (1H-indol-2-yl) ethyl acrylate (Example 1) According to the method of <Step 4> (Example 39) obtained in <Step 2> The title compound (3.2 g) was obtained as a pale yellow solid from the compound (3.5 g).
<Step 4> Synthesis of (E) -3- (1-cyclohexylmethyl-1H-indol-2-yl) ethyl acrylate (Example 10) According to the method of <Step 1> (Example 39) <Step 3 The title compound (0.58 g) was obtained as a yellow solid from the compound (0.50 g) obtained in>.
<Step 5> Synthesis of (E) -3- (1-cyclohexylmethyl-1H-indol-2-yl) acrylic acid
Example 1 According to the method of <Step 5>, the title compound (0.42 g) was obtained as a yellow solid from the compound (0.46 g) obtained in (Example 39) <Step 4>.
<Step 6> Synthesis of (E) -3- (1-cyclohexylmethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide Example 1) According to the method of <Step 6>, (Example 39) The title compound was obtained from the compound obtained in <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 40)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide < Step 1> Synthesis of (5-methyl-1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2>, the title compound was obtained from 5-methyl-1H-indole-2-carboxylic acid (10 g). (8.6 g) was obtained.
<Step 2> Synthesis of (5-methyl-1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 40) Compound (7) obtained in <Step 1> The title compound (4.7 g) was obtained from 0.0 g).
<Step 3> Synthesis of (E) -3- (5-methyl-1H-indol-2-yl) ethyl acrylate (Example 1) According to the method of <Step 4> (Example 40) <Step 2> The title compound (3.1 g) was obtained from the compound (3.0 g) obtained in 1.
<Step 4> Synthesis of ethyl (E) -3- (5-methyl-1-cyclohexylmethyl-1H-indol-2-yl) acrylate (Example 10) According to the method of <Step 1> (Example 40) ) The title compound (0.37 g) was obtained as a brown oil from the compound (0.45 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (5-methyl-1-cyclohexylmethyl-1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (0.24 g) was obtained as a pale yellow solid from the compound (0.30 g) obtained in (Example 40) <Step 4>.
<Step 6> (E) -3- (1-cyclohexylmethyl-5-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Example 40) <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 41)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Example 40) <Step 5> and 5-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 42)
(E) -3- (1-cyclohexylmethyl-5-isopropyl-1H-indole-2-
Yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of (5-isopropyl-1H-indol-2-yl) methanol (Examples) 1) The title compound (0.74 g) was obtained from 5-isopropyl-1H-indole-2-carboxylic acid (1.0 g) according to the method of <Step 2>.
<Step 2> Synthesis of (5-isopropyl-1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 42) Compound (0) obtained in <Step 1> The title compound (0.58 g) was obtained from .74 g).
<Step 3> Synthesis of (E) -3- (5-isopropyl-1H-indol-2-yl) ethyl acrylate (Example 1) According to the method of <Step 4> (Example 42) <Step 2> The title compound (0.18 g) was obtained from the compound (0.58 g) obtained in 1.
<Step 4> Synthesis of (E) -3- (1-cyclohexylmethyl-5-isopropyl-1H-indol-2-yl) ethyl acrylate (Example 10) According to the method of <Step 1> (Example 42) ) The title compound (98 mg) was obtained as a pale yellow oil from the compound (0.10 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (1-cyclohexylmethyl-5-isopropyl-1H-indol-2-yl) acrylic acid (Example 1) According to the method of <Step 5> (Example 42) The title compound (76 mg) was obtained as a yellow solid from the compound (98 mg) obtained in <Step 4>.
<Step 6> (E) -3- (1-cyclohexylmethyl-5-isopropyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 42) From the compound obtained in <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one, The title compound was obtained.

(Example 43)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-isopropyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Example 1) According to the method of <Step 6> (Example 42) The title compound was obtained from the compound obtained in <Step 5> and 5-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 44)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-methoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide < Step 1> Synthesis of (5-methoxy-1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2>, from 5-methoxy-1H-indole-2-carboxylic acid (5.0 g) The title compound (3.3 g) was obtained as a reddish brown oil.
<Step 2> Synthesis of (5-methoxy-1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 44) Compound (3) obtained in <Step 1> .3g) gave the title compound (2.0g) as an ocher solid.
<Step 3> Synthesis of (E) -3- (5-methoxy-1H-indol-2-yl) ethyl acrylate (Example 1) According to the method of <Step 4> (Example 44) <Step 2> The title compound (0.42 g) was obtained as a pale yellow solid from the compound obtained in (0.50 g).
<Step 4> Synthesis of ethyl (E) -3- (5-methoxy-1-cyclohexylmethyl-1H-indol-2-yl) acrylate (Example 10) According to the method of <Step 1> (Example 44) ) The title compound (0.39 g) was obtained as a pale yellow solid from the compound (0.40 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (5-methoxy-1-cyclohexylmethyl-1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (0.32 g) was obtained as a pale yellow solid from the compound (0.35 g) obtained in (Example 44) <Step 4>.
<Step 6> (E) -3- (1-cyclohexylmethyl-5-methoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 44) From the compound obtained in <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one, The title compound was obtained.

(Example 45)
Synthesis of (E) -3- (1-cyclohexylmethyl-5-methoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Example 44) <Step 5> and 5-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 46)
Of (E) -3- (1-cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide Synthesis <Step 1> Synthesis of (5-trifluoromethoxy-1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2>, 5-trifluoromethoxy-1H-indole-2-carboxylic acid (1.0 g) gave the title compound (0.86 g).
<Step 2> Synthesis of (5-trifluoromethoxy-1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 46) Compound obtained in <Step 1> The title compound (0.69 g) was obtained from (0.86 g).
<Step 3> Synthesis of (E) -3- (5-trifluoromethoxy-1H-indol-2-yl) ethyl acrylate (Example 1) According to the method of <Step 4> (Example 46) <Step The title compound (0.83 g) was obtained from the compound (0.69 g) obtained in 2>.
<Step 4> Synthesis of ethyl (E) -3- (1-cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) acrylate (Example 10) According to the method of <Step 1> Example 46) The title compound (0.23 g) was obtained as a pale yellow oil from the compound (0.20 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (1-cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (0.14 g) was obtained as a yellow solid from the compound (0.20 g) obtained in (Example 46) <Step 4><Step6>. Of (E) -3- (1-cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide Synthesis (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Step 46) <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one. Got.

(Example 47)
Of (E) -3- (1-cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Synthesis (Example 1) According to the method of <Step 6>, (Example 46) From the compound obtained in <Step 5> and 5-amino-3,4-dihydro-1H-quinolin-2-one, the title compound Got.

(Example 48)
(E) -3- (1-Cyclohexylmethyl-5-trifluoromethoxy-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] Synthesis of thiazin-5-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 46) The compound obtained in <Step 5> and (Reference Example 19) obtained in <Step 5> The title compound was obtained from the above compound.

(Example 49)
Synthesis of (E) -3- (1-cyclohexylmethyl-6-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide < Step 1> Synthesis of (6-Fluoro-1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2>, from 6-fluoro-1H-indole-2-carboxylic acid (1.0 g) The title compound (0.56 g) was obtained as a pale yellow oil.
<Step 2> Synthesis of (6-Fluoro-1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 49) Compound (0) obtained in <Step 1> The title compound (0.48 g) was obtained as a light brown solid from .56 g).
<Step 3> Synthesis of (E) -3- (6-fluoro-1H-indol-2-yl) ethyl acrylate (Example 1) According to the method of <Step 4> (Example 49) <Step 2> The title compound (0.45 g) was obtained as a pale orange solid from the compound obtained in step (0.48 g).
<Step 4> Synthesis of ethyl (E) -3- (1-cyclohexylmethyl-6-fluoro-1H-indol-2-yl) acrylate (Example 10) According to the method of <Step 1> (Example 49) ) The title compound (0.16 g) was obtained as a pale yellow solid from the compound (0.20 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (1-cyclohexylmethyl-6-fluoro-1H-indol-2-yl) acrylic acid
(Example 1) By the method according to <Step 5>, the title compound (0.12 g) was obtained as a pale yellow solid from the compound (0.13 g) obtained in (Example 49) <Step 4>.
<Step 6> (E) -3- (1-cyclohexylmethyl-6-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 49) From the compound obtained in <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one, The title compound was obtained.

(Example 50)
Synthesis of (E) -3- (1-cyclohexylmethyl-6-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Example 1) According to the method of <Step 6>, (Example 49) The title compound was obtained from the compound obtained in <Step 5> and 5-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 51)
Synthesis of (E) -3- (5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> (E ) -3- (5-Fluoro-1H-indol-2-yl) acrylic acid synthesis (Example 1) According to <Step 5>, the compound (Example 8) obtained in <Step 3> ( The title compound (0.14 g) was obtained as a brown solid from 0.20 g).
<Step 2> Synthesis of (E) -3- (5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide Example 1) According to the method of <Step 6>, the title compound was obtained from (Example 51) the compound obtained in <Step 1> and 7-amino-3,4-dihydro-1H-quinolin-2-one. .

(Example 52)
Synthesis of (E) -3- (5-Fluoro-1-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of (E) -3- (5-fluoro-1-methyl-1H-indol-2-yl) ethyl acrylate (Example 8) In a method according to <Step 4>, (Example 8) < From the compound obtained in step 3> (0.50 g) and methyl iodide (0.67 mL), the title compound (0.31 g) was obtained as a yellow solid.
<Step 2> Synthesis of (E) -3- (5-fluoro-1-methyl-1H-indol-2-yl) acrylic acid
(Example 1) By the method according to <Step 5>, the title compound (0.25 g) was obtained as a yellow solid from the compound (0.31 g) obtained in (Example 52) <Step 1>.
<Step 3> (E) -3- (5-Fluoro-1-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 52) From the compound obtained in <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 53)
Synthesis of (E) -3- (1-ethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of ethyl (E) -3- (1-ethyl-5-fluoro-1H-indol-2-yl) acrylate (Example 8) According to the method of <Step 4> (Example 8) <Step From the compound obtained in 3> (0.50 g) and ethyl iodide (0.86 mL), the title compound (0.31 g) was obtained as a yellow solid.
<Step 2> Synthesis of (E) -3- (1-ethyl-5-fluoro-1H-indol-2-yl) acrylic acid
(Example 1) By the method according to <Step 5>, the title compound (0.25 g) was obtained as a yellow solid from the compound (0.31 g) obtained in (Example 53) <Step 1>.
<Step 3> (E) -3- (1-Ethyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 53) From the compound obtained in <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 54)
Synthesis of (E) -3- (5-Fluoro-1-neopentyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of ethyl (E) -3- (5-fluoro-1-neopentyl-1H-indol-2-yl) acrylate (Example 8) According to the method of <Step 4> (Example 8) <Step 3> (0)
. 30 g) and neopentyl iodide (0.85 mL) gave the title compound (0.22 g) as a brown oil.
<Step 2> Synthesis of (E) -3- (5-fluoro-1-neopentyl-1H-indol-2-yl) acrylic acid (Example 1) In the same manner as in <Step 5>, (Example 54) The title compound (65 mg) was obtained as a pale yellow solid from the compound (0.21 g) obtained in <Step 1>.
<Step 3> (E) -3- (5-Fluoro-1-neopentyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 54) From the compound obtained in <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 55)
(E) -3- (5-Fluoro-1- (2-methoxyethyl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of acrylamide <Step 1> Synthesis of (E) -3- (5-fluoro-1- (2-methoxyethyl) -1H-indol-2-yl) ethyl acrylate (Example 8) <Step 4> According to the method, the title compound (0.23 g) was obtained as a brown oil from the compound (0.20 g) obtained in (Example 8) <Step 3> and 2-methoxyethyl bromide (0.16 mL).
<Step 2> Synthesis of (E) -3- (5-fluoro-1- (2-methoxyethyl) -1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (0.20 g) was obtained as a pale yellow solid from the compound (0.23 g) obtained in (Example 55) <Step 1>.
<Step 3> (E) -3- (5-Fluoro-1- (2-methoxyethyl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one- Synthesis of 7-yl) acrylamide According to the method of (Example 3), (Example 55) From the compound obtained in <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one, The title compound was obtained.

(Example 56)
(E) -3- (5-Fluoro-1- (2-methoxyethyl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) Synthesis of acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Example 55) <Step 2> and 5-amino-3,4-dihydro-1H-quinolin-2-one. .

(Example 57)
(E) -3- (1- (2- (N, N-dimethylamino) ethyl) -5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinoline-2 Synthesis of -on-7-yl) acrylamide <Step 1> (E) -3- (1- (2- (N, N-dimethylamino) ethyl) -5-fluoro-1H-indol-2-yl) acrylic Synthesis of ethyl acid (Example 8) According to the method of <Step 4>, (Example 8) Compound (0.10 g) obtained in <Step 3> and 2- (N, N-dimethylamino) ethyl chloride hydrochloride The title compound (35 mg) was obtained as a brown oil from the salt (0.12 g).
<Step 2> Synthesis of (E) -3- (1- (2- (N, N-dimethylamino) ethyl) -5-fluoro-1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, (Example 57) Compound obtained in <Step 1> (
35 mg) gave the title compound (20 mg) as a brown oil.
<Step 3> (E) -3- (1- (2- (N, N-dimethylamino) ethyl) -5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H Synthesis of -quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6> (Example 57) The compound obtained in <Step 2> and 7-amino-3,4- The title compound was obtained from dihydro-1H-quinolin-2-one.

(Example 58)
(E) -3- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinoline-2- Synthesis of on-7-yl) acrylamide
<Step 1> Synthesis of (E) -3- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) methyl-1H-indol-2-yl) carboxaldehyde
(Example 8) According to the method of <Step 4>, (Example 8) From the compound (0.20 g) obtained in <Step 2> and 2- (bromomethyl) tetrahydro-2H-pyran (0.44 g), The title compound (0.18 g) was obtained as a pale yellow solid.
<Step 2> Synthesis of ethyl (E) -3- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) methyl-1H-indol-2-yl) acrylate
Example 1 According to the method of <Step 4>, the title compound (0.21 g) was obtained as an orange solid from the compound (0.20 g) obtained in (Example 58) <Step 1>.
<Step 3> Synthesis of (E) -3- (5-fluoro-1- (tetrahydro-2H-pyran-2-yl) methyl-1H-indol-2-yl) acrylic acid
(Example 1) By a method according to <Step 5>, the title compound (0.15 g) was obtained as a pale orange solid from the compound (0.20 g) obtained in (Example 58) <Step 2>.
<Step 4> (E) -3- (5-Fluoro-1- (tetrahydro-2H-pyran-2-yl) methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H- Synthesis of quinolin-2-one-7-yl) acrylamide
(Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Example 58) <Step 3> and 7-amino-3,4-dihydro-1H-quinolin-2-one. Obtained.

(Example 59)
Synthesis of (E) -3- (5-Fluoro-1-isopropyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of 2- (2,2-dibromoethenyl) -4-fluoroaniline To a solution of 3-fluoro-6-nitrobenzaldehyde (5.0 g) and carbon tetrabromide (15 g) in dichloromethane (150 mL), ice Under cooling, a solution of triphenylphosphine (23 g) in dichloromethane (150 mL) was added dropwise over 20 minutes. After dropping, the mixture was stirred for 30 minutes under ice-cooling, and further stirred at room temperature for 1 hour. The reaction mixture was filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in ethanol (100 mL) was added tin (II) chloride dihydrate (33 g), and the mixture was heated to reflux for 2 hours. After allowing to cool, the solvent was distilled off under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was made alkaline (pH 10 or higher) with potassium carbonate, and then separated. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 90: 10-67: 33) to give the title compound (5.0 g) in green Obtained as an oil.
<Step 2> Synthesis of N-isopropyl-2- (2,2-dibromoethenyl) -4-fluoroaniline (Example 59) Dichloromethane of compound (0.50 g) obtained in <Step 1> (6. To the solution, acetone (0.19 mL) and sodium triacetoxyborohydride (0.47 g) were sequentially added and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 80:20) to give the title compound (0.51 g) as yellow. Obtained as an oil.
<Step 3> Synthesis of tert-butyl acrylate (E) -3- (5-fluoro-1-isopropyl-1H-indol-2-yl) (Example 59) Compound (0) obtained in <Step 2> .20 g) in toluene (6.0 mL), potassium phosphate (0.13 g), palladium (II) acetate (5.3 mg), tetramethylammonium chloride (0.13 g), triethylamine (0.17 mL), Tert-butyl acrylate (0.17 mL) was sequentially added, and the mixture was heated to reflux for 8 hours under an argon atmosphere. After returning to room temperature and stirring overnight, the mixture was further heated to reflux for 5 hours. After allowing to cool, water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound (38 mg) as a yellow oil.
<Step 4> Synthesis of (E) -3- (5-fluoro-1-isopropyl-1H-indol-2-yl) acrylic acid
(Example 59) 4N hydrogen chloride-ethyl acetate (1.0 mL) was added to a solution of the compound (55 mg) obtained in <Step 3> in ethyl acetate (1.0 mL), and the mixture was stirred at room temperature for 6.5 hours. . 4N Hydrogen chloride-ethyl acetate (1.0 mL) was added, and the mixture was further stirred at room temperature for 19.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (26 mg) as a brown solid. <Step 5> (E) -3- (5-Fluoro-1-isopropyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Step 59) <Step 4> and 7-amino-3,4-dihydro-1H-quinolin-2-one. .

(Example 60)
Synthesis of (E) -3- (1-cyclohexyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of N-cyclohexyl-2- (2,2-dibromoethenyl) -4-fluoroaniline (Example 59) According to the method of <Step 2> (Example 59) obtained in <Step 1> The title compound (1.1 g) was obtained as a yellow oil from the compound (1.0 g) and cyclohexanone (0.50 g).
<Step 2> Synthesis of (E) -3- (1-cyclohexyl-5-fluoro-1H-indol-2-yl) tert-butyl acrylate (Example 59) According to the method of <Step 3> (Examples) 60) The title compound (0.4 g) was obtained as a pale yellow solid from the compound (0.5 g) obtained in <Step 1>.
<Step 3> Synthesis of (E) -3- (1-cyclohexyl-5-fluoro-1H-indol-2-yl) acrylic acid
(Example 1) By the method according to <Step 5>, the title compound (75 mg) was obtained as a pale yellow solid from the compound (0.10 g) obtained in (Example 60) <Step 2>.
<Step 4> (E) -3- (1-cyclohexyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 60) From the compound obtained in <Step 3> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 61)
Synthesis of (E) -3- (1-cyclohexyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Example 60) <Step 3> and 5-amino-3,4-dihydro-1H-quinolin-2-one. .

(Example 62)
(E) -3- (1-Cyclohexyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine-5 -Yl) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, from (Example 60) the compound obtained in <Step 3> and (Reference Example 19) from the compound obtained in <Step 5> To give the title compound.

(Example 63)
Synthesis of (E) -3- (1-cyclopropyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide < Step 1> Synthesis of ethyl (E) -3- (1-cyclopropyl-5-fluoro-1H-indol-2-yl) acrylate
Example 8 To a solution of the compound (50 mg) obtained in <Step 3> in dichloromethane (2.0 mL) was added copper (II) acetate (58 mg), pyridine (52 μL), and Journal of the American. Tricyclopropylbismuth (0.18 g) prepared according to the method described in Chemical Society (Journal of the American Chemical Society), 129, 44-45, 2007 was sequentially added, and the mixture was stirred at 50 ° C. for 9 hours. . The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 83:17) to give the title compound (35 mg) as a yellow oil. Obtained.
<Step 2> Synthesis of (E) -3- (1-cyclopropyl-5-fluoro-1H-indol-2-yl) acrylic acid (Example 1) In the same manner as in <Step 5> (Example 63) ) The title compound (63 mg) was obtained as a pale yellow solid from the compound (70 mg) obtained in <Step 1>.
<Step 3> (E) -3- (1-cyclopropyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 63) From the compound obtained in <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one, The title compound was obtained.

(Example 64)
Synthesis of (E) -3- (1-cyclopropyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Example 1) According to the method of <Step 6>, (Example 63) The title compound was obtained from the compound obtained in <Step 2> and 5-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 65)
Synthesis of (E) -3- (1-tert-butyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of N-tert-butyl-2- (2,2-dibromoethenyl) -4-fluoroaniline (Example 59) Cyclohexane (0.50 g) of the compound (0.50 g) obtained in <Step 1> To the 6.0 mL) solution, tert-butyl 2,2,2-trichloroacetimidate (1.4 mL) and boron trifluoride-diethyl ether complex (3 drops) were sequentially added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Stir. Further tert-butyl 2,2,2-trichloroacetimidate (1.4 mL
), Boron trifluoride-diethyl ether complex (3 drops) was added, and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 80:20) to give the title compound (0.50 g) as yellow. Obtained as an oil.
<Step 2> Synthesis of tert-butyl (E) -3- (1-tert-butyl-5-fluoro-1H-indol-2-yl) acrylate (Example 59) According to the method of <Step 3>, ( Example 65) The title compound (0.40 g) was obtained as a yellow oil from the compound (0.50 g) obtained in <Step 1>.
<Step 3> Synthesis of (E) -3- (1-tert-butyl-5-fluoro-1H-indol-2-yl) acrylic acid (Example 1) In the same manner as in <Step 5>, (Example 65) The title compound (65 mg) was obtained as a pale yellow solid from the compound (80 mg) obtained in <Step 2>.
<Step 4> (E) -3- (1-tert-butyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl ) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 65) From the compound obtained in <Step 3> and 7-amino-3,4-dihydro-1H-quinolin-2-one To give the title compound.

Example 66
Synthesis of (E) -3- (1-tert-butyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Step 65) <Step 3> and 5-amino-3,4-dihydro-1H-quinolin-2-one. Obtained.

(Example 67)
(E) -3- (5-Fluoro-1- (tetrahydro-4H-pyran-4-yl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one Synthesis of -5-yl) acrylamide <Step 1> Synthesis of N- (tetrahydropyran-4-yl) -2- (2,2-dibromoethenyl) -4-fluoroaniline (Example 59) <Step 2> According to the method of Example 59, the title compound (0.59 g) was obtained from the compound (0.50 g) obtained in <Step 1> and tetrahydro-4H-pyran-4-one (0.26 g) as a colorless oil. Got as.
<Step 2> Synthesis of tert-butyl (E) -3- (5-fluoro-1- (tetrahydro-4H-pyran-4-yl) -1H-indol-2-yl) acrylate (Example 59) < According to the method of Step 3>, the title compound (0.15 g) was obtained as a white solid from the compound (0.30 g) obtained in Example 67 <Step 1>.
<Step 3> Synthesis of (E) -3- (5-fluoro-1- (tetrahydro-4H-pyran-4-yl) -1H-indol-2-yl) acrylic acid (Example 1) <Step 5> In the same manner as in Example 67, the title compound (86 mg) was obtained as a white solid from the compound (0.14 g) obtained in <Step 2> (Example 67).
<Step 4> (E) -3- (5-Fluoro-1- (tetrahydro-4H-pyran-4-yl) -1H-indol-2-yl) -N- (3,4-dihydro-1H-quinoline) Synthesis of 2-one-5-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 67) The compound obtained in <Step 3> and 5-amino-3,4-dihydro- The title compound was obtained from 1H-quinolin-2-one.

Example 68
(E) -3- (5-Fluoro-1- (tetrahydro-4H-pyran-4-yl) -1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H -Benzo [
2,1] Synthesis of thiazin-5-yl) acrylamide (Example 1) According to the method of <Step 6>, the compound obtained in (Example 67) <Step 3> and (Reference Example 19) <Step 5 The title compound was obtained from the compound obtained in>.

(Example 69)
Synthesis of (E) -3- (1-cyclohexylsulfonyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide < Step 1> Synthesis of (E) -3- (1-cyclohexylsulfonyl-5-fluoro-1H-indol-2-yl) ethyl acrylate To a suspension of sodium hydride (41 mg) in tetrahydrofuran (5.0 mL), Under ice cooling, a solution of the compound (0.20 g) obtained in (Example 8) <Step 3> in tetrahydrofuran (5.0 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, cyclohexylsulfonyl chloride (0.19 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 22 hours. Sodium hydride (34 mg) and cyclohexylsulfonyl chloride (0.19 mL) were added, and the mixture was further stirred at room temperature for 23 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 90:10) to give the title compound (0.12 g) as white. Obtained as a solid.
<Step 2> Synthesis of (E) -3- (1-cyclohexylsulfonyl-5-fluoro-1H-indol-2-yl) acrylic acid
(Example 1) By the method according to <Step 5>, the title compound (0.10 g) was obtained as a white solid from the compound (0.12 g) obtained in (Example 69) <Step 1>.
<Step 3> (E) -3- (1-cyclohexylsulfonyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 69) From the compound obtained in <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one, The title compound was obtained.

(Example 70)
Synthesis of (E) -3- (1-cyclohexylsulfonyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide Example 1) According to the method of <Step 6>, (Example 69) The title compound was obtained from the compound obtained in <Step 2> and 5-amino-3,4-dihydro-1H-quinolin-2-one. It was.

(Example 71)
Synthesis of (E) -3- (5-Fluoro-1-isopropylsulfonyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide
(Example 69) According to the method of <Step 1>, from the compound (30 mg) obtained in (Example 51) <Step 2> and isopropylsulfonyl chloride (12 μL), the title compound (49 mg) was obtained as a pale yellow solid. Obtained.

(Example 72)
Synthesis of (E) -3- (1-cyclohexylcarbonyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide < Step 1> Synthesis of tert-butyl (E) -3- (5-fluoro-1H-indol-2-yl) acrylate (Example 1) According to the method of <Step 4> (Example 8) <Step 2 > (Tert-butyl diethylphosphonoacetate (0.92 g)) to give the title compound (0.25 g) as a pale yellow solid.
<Step 2> Synthesis of tert-butyl acrylate (E) -3- (1-cyclohexylcarbonyl-5-fluoro-1H-indol-2-yl) (Example 69) According to the method of <Step 1> Example 72) The title compound (99 mg) was obtained as a colorless oil from the compound (70 mg) obtained in <Step 1> and cyclohexylcarbonyl chloride (55 μL).
<Step 3> Synthesis of (E) -3- (1-cyclohexylcarbonyl-5-fluoro-1H-indol-2-yl) acrylic acid
(Example 72) Formic acid (3.0 mL) was added to the compound (90 mg) obtained in <Step 2>, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with water, and azeotroped with ethanol to obtain the title compound (44 mg) as a white solid.
<Step 4> (E) -3- (1-cyclohexylcarbonyl-5-fluoro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 72) From the compound obtained in <Step 3> and 7-amino-3,4-dihydro-1H-quinolin-2-one, The title compound was obtained.

(Example 73)
Synthesis of (E) -3- (5-Fluoro-1-pivaloyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of tert-butyl (E) -3- (5-fluoro-1-pivaloyl-1H-indol-2-yl) acrylate (Example 69) According to the method of <Step 1> (Example 72) The title compound (35 mg) was obtained as a colorless oil from the compound (50 mg) obtained in <Step 1> and pivaloyl chloride (48 μL).
<Step 2> Synthesis of (E) -3- (1-cyclohexylsulfonyl-5-fluoro-1H-indol-2-yl) acrylic acid (Example 72) According to the method of <Step 3> (Example 73) The composition of the title compound (25 mg) was obtained from the compound (32 mg) obtained in <Step 1>.
<Step 3> (E) -3- (5-Fluoro-1-pivaloyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 73) From the compound obtained in <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 74)
(E) -3- (5-Chloro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 Synthesis of 5-yl) acrylamide <Step 1> Synthesis of 5-chloro-1- (3-trifluoromethylphenyl) -1H-indole-2-carboxylic acid
Example 6 According to the method of <Step 1>, the title compound (1.7 g) was obtained as a white solid from 5-chloro-1H-indole-2-carboxylic acid (2.0 g).
<Step 2> Synthesis of (5-chloro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2> (Example 74) < The title compound (0.62 g) was obtained as a pale yellow solid from the compound (1.7 g) obtained in Step 1>.
<Step 3> Synthesis of (5-chloro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 74) The title compound (0.52 g) was obtained as a pale yellow solid from the compound (0.60 g) obtained in <Step 2>.
<Step 4> Synthesis of ethyl (E) -3- (5-chloro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) acrylate (Example 1) Method of <Step 4> (Example 74) The title compound (0.48 g) was obtained as a pale yellow oil from the compound (0.50 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (5-chloro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (0.15 g) was obtained as a pale yellow solid from the compound (0.40 g) obtained in (Example 74) <Step 4>.
<Step 6> (E) -3- (5-Chloro-1- (3-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4- Synthesis of tetrahydroquinolin-5-yl) acrylamide (Example 1) According to the method of <Step 6> (Example 74) The compound obtained in <Step 5> and the method described in WO05 / 044802 pamphlet The title compound was obtained from 5-amino-1,2,3,4-tetrahydroquinolin-3-ol synthesized according to the above procedure.

(Example 75)
(E) -3- (5-Chloro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 -Yl) Synthesis of acrylamide <Step 1> Synthesis of 5-chloro-1- (4-trifluoromethylphenyl) -1H-indole-2-carboxylic acid (Example 1) According to the method of <Step 1>, 5- The title compound (2.5 g) was obtained as a white solid from chloro-1H-indole-2-carboxylic acid (2.0 g).
<Step 2> Synthesis of (5-chloro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) methanol (Example 1) According to the method of <Step 2> (Example 75) < The title compound (0.94 g) was obtained as a pale yellow solid from the compound (2.5 g) obtained in Step 1>.
<Step 3> Synthesis of (5-chloro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 75) The title compound (0.55 g) was obtained as a pale yellow solid from the compound (0.60 g) obtained in <Step 2>.
<Step 4> Synthesis of ethyl (E) -3- (5-chloro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) acrylate (Example 1) Method of <Step 4> (Example 75) The title compound (0.58 g) was obtained as a pale yellow oil from the compound (0.50 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (5-chloro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (0.14 g) was obtained as a white solid from the compound (0.40 g) obtained in (Example 75) <Step 4>.
<Step 6> (E) -3- (5-Chloro-1- (4-trifluoromethylphenyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4- Synthesis of tetrahydroquinolin-5-yl) acrylamide
(Example 1) According to the method of <Step 6>, (Example 75) 5-amino-3-hydroxy synthesized according to the method described in <Step 5> and the method described in International Publication No. 05/044802 pamphlet The title compound was obtained from -1,2,3,4-tetrahydroquinoline.

(Example 76)
(E) -3- (5-Chloro-1-ethyl-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine-5 -Yl) Synthesis of acrylamide <Step 1> Synthesis of ethyl (E) -3- (5-chloro-1-ethyl-1H-indol-2-yl) acrylate (Example 53) According to the method of <Step 1> (Example 19) The title compound (0.14 g) was obtained as a pale yellow oil from the compound (0.15 g) obtained in <Step 3>.
<Step 2> Synthesis of (E) -3- (5-chloro-1-ethyl-1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (92 mg) was obtained as a yellow solid from the compound (0.13 g) obtained in (Example 76) <Step 1>.
<Step 3> (E) -3- (5-Chloro-1-ethyl-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1 ] Synthesis of thiazin-5-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 76) The compound obtained in <Step 2> and (Reference Example 19) <Step 5> The title compound was obtained from the obtained compound.

(Example 77)
Synthesis of (E) -3- (5-Chloro-1-cyclohexyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of 2- (2,2-dibromoethenyl) -4-chloroaniline (Example 59) According to the method of <Step 1>, the title compound (3-0.0 g) was obtained from 3-chloro-6-nitrobenzaldehyde (10.0 g). 14.0 g) was obtained as a brown oil.
<Step 2> Synthesis of N-cyclohexyl-2- (2,2-dibromoethenyl) -4-chloroaniline (Example 60) According to the method of <Step 1> (Example 77) Obtained in <Step 1> The title compound (1.1 g) was obtained as a yellow oil from the obtained compound (1.0 g).
<Step 3> Synthesis of tert-butyl (E) -3- (5-chloro-1-cyclohexyl-1H-indol-2-yl) acrylate (Example 59) According to the method of <Step 3> (Examples) 77) The title compound (1.6 g) was obtained as a brown solid from the compound (4.0 g) obtained in <Step 2>.
<Step 4> Synthesis of (E) -3- (5-chloro-1-cyclohexyl-1H-indol-2-yl) acrylic acid
(Example 1) By the method according to <Step 5>, the title compound (0.77 g) was obtained as an ocher solid from the compound (1.6 g) obtained in (Example 77) <Step 3>.
<Step 5> (E) -3- (5-Chloro-1-cyclohexyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 77) From the compound obtained in <Step 4> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 78)
(E) -3- (5-Chloro-1-cyclohexyl-1H-indol-2-yl) -N-((2R) -2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 77) The compound obtained in <Step 4> and the known (2R) -8-amino-1,2,3 The title compound was obtained from 4-tetrahydronaphthalen-2-ol.

(Example 79)
(E) -3- (5-Chloro-1-cyclohexyl-1H-indol-2-yl) -N-((2S) -2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) Synthesis of Acrylamide (Example 1) According to the method of <Step 6>, (Example 77) The compound obtained in <Step 4> and the known (2S) -8-amino-1,2,3 The title compound was obtained from 4-tetrahydronaphthalen-2-ol.

(Example 80)
Synthesis of (E) -3- (1-tert-butyl-5-chloro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of N-tert-butyl-2- (2,2-dibromoethenyl) -4-chloroaniline (Example 65) According to the method of <Step 1> (Example 77) <Step 1> The title compound (4.0 g) was obtained as a yellow solid from the compound (4.0 g) obtained in 1.
<Step 2> Synthesis of tert-butyl (E) -3- (1-tert-butyl-5-chloro-1H-indol-2-yl) acrylate (Example 59) According to the method of <Step 3>, ( Example 80) The title compound (2.8 g) was obtained as a yellow solid from the compound (4.0 g) obtained in <Step 1>.
<Step 3> Synthesis of (E) -3- (1-tert-butyl-5-chloro-1H-indol-2-yl) acrylic acid (Example 1) In the same manner as in <Step 5>, (Example 80) The title compound (1.8 g) was obtained as a yellow solid from the compound (2.8 g) obtained in <Step 2>.
<Step 4> (E) -3- (1-tert-butyl-5-chloro-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl ) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, from the compound obtained in (Step 80) <Step 3> and 7-amino-3,4-dihydro-1H-quinolin-2-one The title compound was obtained.

(Example 81)
(E) -3- (5-Chloro-1-tert-butyl-1H-indol-2-yl) -N- (3,4-dihydro-2,2-dioxo-1H-benzo [2,1] thiazine Synthesis of -5-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 80) The compound obtained in <Step 3> and (Reference Example 19) obtained in <Step 5> The title compound was obtained from the compound.

(Example 82)
Synthesis of (E) -3- (1- (2- (4-morpholinyl) ethyl) -1H-indol-2-yl) -N- (quinolin-7-yl) acrylamide <Step 1> (E) -3 Synthesis of ethyl-(1- (2- (4-morpholinyl) ethyl) -1H-indol-2-yl) acrylate (Example 8) In the same manner as in <Step 4>, (Example 39) <Step 3 > (0.14 g) and 2- (4-morpholinyl) ethyl chloride (0.15 g) gave the title compound (0.14 g) as a pale yellow solid.
<Step 2> Synthesis of (E) -3- (1- (2- (4-morpholinyl) ethyl) -1H-indol-2-yl) acrylic acid (Example 1) According to the method of <Step 5> ( Example 82) The title compound (69 mg) was obtained as a white solid from the compound (0.14 g) obtained in <Step 1>.
<Step 3> Synthesis of (E) -3- (1- (2- (4-morpholinyl) ethyl) -1H-indol-2-yl) -N- (quinolin-7-yl) acrylamide (Example 3) (Example 82) The title compound was obtained from the compound obtained in <Step 2> and 7-aminoquinoline.

(Example 83)
(E) -3- (1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) acrylamide <Step 1> Synthesis of ethyl (E) -3- (1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) acrylate (Example 8) According to the method of <Step 4> Example 39 The title compound (0.18 g) was obtained as a pale yellow solid from the compound (0.20 g) obtained in <Step 3>.
<Step 2> Synthesis of (E) -3- (1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (85 mg) was obtained as a white solid from the compound (0.14 g) obtained in (Example 83) <Step 1>.
<Step 3> (E) -3- (1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (2-hydroxy-1,2,3,4-tetrahydronaphthalene-8 -Yl) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, the compound obtained in (Example 83) <Step 2> and 8-amino-1,2,3,4-tetrahydronaphthalene-2 The title compound was obtained from -ol.

(Example 84)
(E) -3- (5-Methoxy-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline-5 Synthesis of -yl) acrylamide <Step 1> Synthesis of (E) -3- (5-methoxy-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) ethyl acrylate (Example 8) The title compound (0.21 g) was obtained as a pale yellow solid from the compound (0.20 g) obtained in (Example 44) <Step 3> according to the method of <Step 4>.
<Step 2> Synthesis of (E) -3- (5-methoxy-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) acrylic acid
Example 1 According to the method of <Step 5>, the title compound (0.15 g) was obtained as a white solid from the compound (0.27 g) obtained in (Example 84) <Step 1>.
<Step 3> (E) -3- (5-methoxy-1- (3-trifluoromethylbenzyl) -1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4- Synthesis of tetrahydroquinolin-5-yl) acrylamide (Example 1) According to the method of <Step 6>, the compound obtained in (Example 84) <Step 2> and the method described in WO05 / 044802 pamphlet The title compound was obtained from 5-amino-1,2,3,4-tetrahydroquinolin-3-ol synthesized according to the above procedure.

(Example 85)
(E) -3- (5-Methoxy-1- (3-trifluoromethylbenzyl) indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Example 84) <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one. .

(Example 86)
(E) -3- (1- (3-Fluorobenzyl) -5-methoxy-1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinolin-5-yl ) Synthesis of Acrylamide <Step 1> Synthesis of ethyl (E) -3- (1- (3-fluorobenzyl) -5-methoxy-1H-indol-2-yl) acrylate (Example 8) <Step 4> According to the method of Example 44, the title compound (0.16 g) was obtained as a pale yellow solid from the compound (0.20 g) obtained in <Step 3> and 3-fluorobenzyl bromide (0.12 mL). .
<Step 2> Synthesis of (E) -3- (1- (3-fluorobenzyl) -5-methoxy-1H-indol-2-yl) acrylic acid (Example 1) According to the method of <Step 5>, ( Example 86) The title compound (0.11 g) was obtained as a yellow solid from the compound (0.25 g) obtained in <Step 1>.
<Step 3> (E) -3- (1- (3-Fluorobenzyl) -5-methoxy-1H-indol-2-yl) -N- (3-hydroxy-1,2,3,4-tetrahydroquinoline Synthesis of -5-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 86) The compound obtained in <Step 2> and the method described in International Publication No. 05/044802 pamphlet The title compound was obtained from 5-amino-1,2,3,4-tetrahydroquinolin-3-ol.

(Example 87)
Synthesis of (E) -3- (1- (3-fluorobenzyl) -5-methoxyindol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide According to the method of (Example 3), the title compound was obtained from the compound obtained in (Example 86) <Step 2> and 7-amino-3,4-dihydro-1-methyl-1H-quinolin-2-one. Obtained.

(Example 88)
(E) -3- (5-Chloro-1- (3-trifluoromethylbenzyl) -1H-pyrrolo [2,3-c] pyridin-2-yl) -N- (2-hydroxy-1,2, Synthesis of 3,4-tetrahydronaphthalen-8-yl) acrylamide <Step 1> Synthesis of ethyl 3- (2-chloro-5-nitropyridin-4-yl) -2-oxopropanoate 2-Chloro-4-methyl To a mixture of -5-nitropyridine (4.4 g) and diethyl oxalate (17 mL), 1,8-diazabicyclo [5.4.0] undec-7-ene (2.3
mL) was added and stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate (200 mL), water (150 mL) and acetic acid (5.0 mL) were added, and the layers were separated. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and washed with n-hexane. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 97: 3 to 50:50) to give the title compound (3.0 g) as a pink solid. It was.
<Step 2> Synthesis of ethyl 5-chloro-pyrrolo [2,3-c] pyridine-2-carboxylate (Example 88) Tetrahydrofuran (110 mL) of the compound (6.8 g) obtained in <Step 1> Iron powder (8.4 g) and saturated aqueous ammonium chloride solution (110 mL) were added to an ethanol (220 mL) solution, and the mixture was heated to reflux for 1.5 hours. After allowing to cool, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was washed with ethyl acetate to obtain the title compound (4.1 g) as a brown solid.
<Step 3> Synthesis of (5-chloro-1H-pyrrolo [2,3-c] pyridin-2-yl) methanol (Example 1) According to the method of <Step 2> (Example 88) <Step 2> The title compound (1.2 g) was obtained as a pale yellow solid from the compound (3.1 g) obtained in 1.
<Step 4> Synthesis of (5-chloro-1H-pyrrolo [2,3-c] pyridin-2-yl) carboxaldehyde (Example 1) According to the method of <Step 3> (Example 88) <Step 3 The title compound (0.91 g) was obtained as a brown solid from the compound (1.2 g) obtained in>.
<Step 5> Synthesis of (E) -3- (5-chloro-1- (3-trifluoromethylbenzyl) -1H-pyrrolo [2,3-c] pyridin-2-yl) carboxaldehyde Example 8 ) According to the method of <Step 1>, the title compound (0.28 g) was obtained as a white solid from the compound (0.24 g) obtained in (Example 88) <Step 4>.
<Step 6> Synthesis of ethyl (E) -3- (5-chloro-1- (3-trifluoromethylbenzyl) -1H-pyrrolo [2,3-c] pyridin-2-yl) acrylate (Examples) 1) According to the method of <Step 4>, the title compound (0.33 g) was obtained as a pale yellow solid from the compound (0.32 g) obtained in (Example 88) <Step 5>.
<Step 7> Synthesis of (E) -3- (5-chloro-1- (3-trifluoromethylbenzyl) -1H-pyrrolo [2,3-c] pyridin-2-yl) acrylic acid
(Example 1) According to the method of <Step 5>, the title compound (0.24 g) was obtained as a pale yellow solid from the compound (0.33 g) obtained in (Example 88) <Step 6>.
<Step 8>
(Example 1) According to the method of <Step 6>, the title compound was obtained from the compound obtained in (Step 88) <Step 7> and 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol. Got.

Example 89
(E) -3- (5-Chloro-1- (3-trifluoromethylbenzyl) -1H-pyrrolo [2,3-c] pyridin-2-yl) -N- (3-hydroxy-1,2, Synthesis of 3,4-tetrahydroquinolin-5-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 88) The compound obtained in <Step 7>, and International Publication No. 05/044802 The title compound was obtained from 5-amino-1,2,3,4-tetrahydroquinolin-3-ol synthesized according to the method described in the pamphlet.

(Example 90)
(E) -3- (5-Chloro-1-cyclohexylmethyl-3-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of Acrylamide <Step 1> Synthesis of ethyl (E) -3- (5-chloro-1-cyclohexylmethyl-3-formyl-1H-indol-2-yl) acrylate N, N-dimethylformamide under ice cooling (0.87 mL) was added phosphorus oxychloride (0.16 mL), and the mixture was stirred for 30 minutes under ice cooling. A solution of the compound (0.30 g) obtained in (Example 19) <Step 4> in tetrahydrofuran (5.0 mL) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, extracted with diethyl ether, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 90:10) to give the title compound (0.24 g) Obtained as a yellow solid.
<Step 2> Synthesis of ethyl (E) -3- (5-chloro-1-cyclohexylmethyl-3-methyl-1H-indol-2-yl) acrylate (Example 90) obtained in <Step 1> To a solution of the compound (0.24 g) in dichloromethane (5.0 mL), zinc iodide (0.31 g) and sodium cyanoborohydride (0.28 g) were sequentially added, and the mixture was stirred at room temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 90:10) to give the title compound (0.20 g) Obtained as a yellow solid.
<Step 3> (E) -3- (5-Chloro-1-cyclohexylmethyl-3-methyl-1H-
Synthesis of indol-2-yl) acrylic acid
(Example 1) By the method according to <Step 5>, the title compound (0.19 g) was obtained as a pale yellow solid from the compound (0.20 g) obtained in (Example 90) <Step 2>.
<Step 4> (E) -3- (5-Chloro-1-cyclohexylmethyl-3-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one- Synthesis of 7-yl) acrylamide (Example 1) In accordance with the method of <Step 6>, the compound obtained in (Example 90) <Step 3> and 7-amino-3,4-dihydro-1H-quinoline-2 -The title compound was obtained from ON.

(Example 91)
Synthesis of (E) -3- (5-Fluoro-1H-indol-2-yl) -3-phenyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of 5-fluoro-1- (phenylsulfonyl) -1H-indole
Sodium hydride (3.11 g) was added to a tetrahydrofuran (100 mL) solution of 5-fluoro-1H-indole (10.0 g) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Benzenesulfonyl chloride (14.2 mL) was added dropwise to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was triturated with ethanol and collected by filtration to give the title compound (16.4 g) as colorless crystals.
<Step 2> Synthesis of 2-benzoyl-5-fluoro-1- (phenylsulfonyl) -1H-indole In a tetrahydrofuran (50 mL) solution of diisopropylamine (4.8 mL) in a dry ice-acetone bath, n-butyllithium was cooled. (1.6 M n-hexane solution; 21 mL) was added dropwise, and the mixture was stirred for 30 minutes under ice cooling. Under a dry ice-acetone bath cooling, a tetrahydrofuran (50 mL) solution of the compound (5.0 g) obtained in (Example 91) <Step 1> was added dropwise, the temperature was raised to −20 ° C., and the mixture was stirred for 30 minutes. Under cooling with a dry ice-acetone bath again, a solution of benzoyl chloride (3.2 mL) in tetrahydrofuran (50 mL) was added dropwise and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was warmed to room temperature, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 100: 0 to 80:10), and then triturated with n-hexane / ethyl acetate. The product was collected by filtration to give the title compound (2.6 g) as a white solid.
<Step 3> Synthesis of 2-benzoyl-5-fluoro-1H-indole (Example 91) To a solution of the compound (2.3 g) obtained in <Step 2> in tetrahydrofuran (50 mL) was added tetrabutylammonium fluoride ( 1.0M tetrahydrofuran solution; 31 mL) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.3 g) as a light brown solid.
<Step 4> Synthesis of (E) -3- (5-fluoro-1H-indol-2-yl) -3-phenyl acrylate (Example 1) According to the method of <Step 4> (Example 91) The title compound (0.22 g) was obtained as an orange solid from the compound (1.0 g) obtained in <Step 3>.
<Step 5> Synthesis of (E) -3- (5-fluoro-1H-indol-2-yl) -3-phenylacrylic acid (Example 1) In the same manner as in <Step 5>, (Example 91) The title compound (83 mg) was obtained as an orange solid from the compound (0.1 g) obtained in <Step 4>.
<Step 6> (E) -3- (5-Fluoro-1H-indol-2-yl) -3-phenyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 91) From the compound obtained in <Step 5> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 92)
Synthesis of (E) -3- (5-fluoro-1H-indol-2-yl) -3-methyl-N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide <Step 1> Synthesis of 2-acetyl-5-fluoro-1- (phenylsulfonyl) -1H-indole (Example 91) According to the method of <Step 2>, the compound (Example 91) obtained in <Step 1> ( 1.0 g) and N-methoxy-N-methylacetamide (0.58 mL) gave the title compound (0.25 g) as a pale yellow solid.
<Step 2> Synthesis of 2-acetyl-5-fluoro-1H-indole (Example 91) According to the method of <Step 3>, (Example 92) From the compound (0.13 g) obtained in <Step 1> The title crude compound (93 mg) was obtained.
<Step 3> Synthesis of ethyl (E) -3- (5-fluoro-1H-indol-2-yl) -3-methylacrylate
(Example 1) According to the method of <Step 4>, the title crude compound (30 mg) was obtained from the compound (82 mg) obtained in (Example 92) <Step 2>.
<Step 4> Synthesis of (E) -3- (5-fluoro-1H-indol-2-yl) -3-methylacrylic acid
(Example 1) By the method according to <Step 5>, the title crude compound (25 mg) was obtained from the compound (29 mg) obtained in (Example 92) <Step 3>.
<Step 5> (E) -3- (5-Fluoro-1H-indol-2-yl) -3-methyl-N- (3,4-dihydro-1H-quinolin-2-one-5-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 92) From the compound obtained in <Step 4> and 5-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 93)
(E) -3- (5-Chloro-1-ethyl-1H-indol-2-yl) -3-methyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of 5-chloro-1- (phenylsulfonyl) -1H-indole
Example 91 The title compound (30.4 g) was obtained as a pale yellow solid from 5-chloro-1H-indole (25.0 g) according to the method of <Step 1>.
<Step 2> Synthesis of 2-acetyl-5-chloro-1- (phenylsulfonyl) -1H-indole (Example 92) According to the method of <Step 1>, (Example 93) obtained in <Step 1> The title compound (1.5 g) was obtained as a pale yellow solid from the compound (5.0 g).
<Step 3> Synthesis of 2-acetyl-5-chloro-1H-indole (Example 91) According to the method of <Step 3> (Example 93) From the compound (1.0 g) obtained in <Step 2> The title compound (0.50 g) was obtained as a light brown solid.
<Step 4> Synthesis of 2-acetyl-5-chloro-1-ethyl-1H-indole (Example 53) According to the method of <Step 1> (Example 93) Compound (0) obtained in <Step 3> 20 g) gave the title compound (0.12 g).
<Step 5> Synthesis of ethyl (E) -3- (5-chloro-1-ethyl-1H-indol-2-yl) -3-methylacrylate
(Example 1) According to the method of <Step 4>, the title compound (93 mg) was obtained from the compound (0.11 g) obtained in (Example 93) <Step 4>.
<Step 6> Synthesis of (E) -3- (5-chloro-1-ethyl-1H-indol-2-yl) -3-methylacrylic acid
(Example 1) By the method according to <Step 5>, the title crude compound (65 mg) was obtained from the compound (70 mg) obtained in (Example 93) <Step 5>.
<Step 7> (E) -3- (5-Chloro-1-ethyl-1H-indol-2-yl) -3-methyl-N- (3,4-dihydro-1H-quinolin-2-one-7 -Yl) Synthesis of acrylamide According to the method of (Example 3), (Example 93) From the compound obtained in <Step 6> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 94)
Synthesis of (E) -3- (5-Chloro-1H-indol-2-yl) -3-ethyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of 5-chloro-1- (phenylsulfonyl) -2-propionyl-1H-indole (Example 91) According to the method of <Step 2>, (Example 93) Compound obtained in <Step 1> ( 9.0 g) and N-methoxy-N-methylpropanamide (5.4 g) gave the title compound (3.8 g) as a pale yellow solid.
<Step 2> Synthesis of ethyl (E) -3- (5-chloro-1- (phenylsulfonyl) -1H-indol-2-yl) -3-ethyl acrylate
(Example 1) According to the method of <Step 4>, the title crude compound (1.3 g) was obtained from the compound (2.0 g) obtained in (Example 94) <Step 1>.
<Step 3> Synthesis of (E) -3- (5-chloro-1H-indol-2-yl) -3-ethyl acrylate (Example 91) According to the method of <Step 3> (Example 94) The title crude compound (0.22 g) was obtained from the compound (1.3 g) obtained in <Step 2>.
<Step 4> Synthesis of (E) -3- (5-chloro-1H-indol-2-yl) -3-ethylacrylic acid
(Example 1) By the method according to <Step 5>, the title crude compound (99 mg) was obtained from the compound (0.10 g) obtained in (Example 94) <Step 3>.
<Step 5> (E) -3- (5-Chloro-1H-indol-2-yl) -3-ethyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide (Example 1) According to the method of <Step 6>, (Example 94) From the compound obtained in <Step 4> and 7-amino-3,4-dihydro-1H-quinolin-2-one, the title A compound was obtained.

(Example 95)
(E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -3-ethyl-N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of acrylamide <Step 1> Synthesis of ethyl (E) -3- (5-chloro-1-cyclohexylmethyl-1H-indol-2-yl) -3-ethyl acrylate (Example 10) <Step 1> According to the method, the title crude compound (20 mg) was obtained from the compound (40 mg) obtained in (Example 94) <Step 3>.
<Step 2> Synthesis of (E) -3- (5-chloro-1-cyclohexylmethyl-1H-indol-2-yl) -3-ethylacrylic acid (Example 1) In a method according to <Step 5> Example 95 The title crude compound (9.0 mg) was obtained from the compound (20 mg) obtained in <Step 1>.
<Step 3> (E) -3- (5-Chloro-1-cyclohexylmethyl-1H-indol-2-yl) -3-ethyl-N- (3,4-dihydro-1H-quinolin-2-one) 7-yl) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, the compound obtained in (Example 95) <Step 2> and 7-amino-3,4-dihydro-1H-quinoline-2 -The title compound was obtained from ON.

(Example 96)
(E) -3- (5-Chloro-1-ethyl-3-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) acrylamide <Step 1> Synthesis of ethyl (E) -3- (5-chloro-1-ethyl-3-formyl-1H-indol-2-yl) acrylate (Example 90) Method according to <Step 1> (Example 76) The title compound (88 mg) was obtained as a pale yellow solid from the compound (0.13 g) obtained in <Step 1>.
<Step 2> Synthesis of ethyl (E) -3- (5-chloro-1-ethyl-3-methyl-1H-indol-2-yl) acrylate
(Example 90) By the method according to <Step 2>, the title compound (87 mg) was obtained as a pale yellow solid from the compound (0.10 g) obtained in (Example 96) <Step 1>.
<Step 3> Synthesis of (E) -3- (5-chloro-1-ethyl-3-methyl-1H-indol-2-yl) acrylic acid
(Example 1) By the method according to <Step 5>, the title compound (60 mg) was obtained as a pale yellow solid from the compound (87 mg) obtained in (Example 96) <Step 2>.
<Step 4> (E) -3- (5-Chloro-1-ethyl-3-methyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7 -Yl) Synthesis of acrylamide (Example 1) According to the method of <Step 6>, the compound obtained in (Example 96) <Step 3> and 7-amino-3,4-dihydro-1H-quinoline-2- The title compound was obtained from ON.

(Example 97)
(E) -3- (5-Chloro-1-ethyl-3-methoxymethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one-7-yl) Synthesis of acrylamide <Step 1> Synthesis of ethyl (E) -3- (5-chloro-1-ethyl-3-methoxymethyl-1H-indol-2-yl) acrylate (Example 96) <Step 1> Sodium cyanoborohydride (23 mg) and 10% hydrogen chloride-methanol (1 drop) were sequentially added to a solution of the obtained compound (48 mg) in methanol (3.0 mL), and the mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 85: 15) to obtain the title compound (30 mg) as a yellow solid.
<Step 2> Synthesis of (E) -3- (5-chloro-1-ethyl-3-methoxymethyl-1H-indol-2-yl) acrylic acid (Example 1) In a method according to <Step 5> Example 97 The title compound (6.5 mg) was obtained as a red solid from the compound (27 mg) obtained in <Step 1>.
<Step 3> (E) -3- (5-Chloro-1-ethyl-3-methoxymethyl-1H-indol-2-yl) -N- (3,4-dihydro-1H-quinolin-2-one- Synthesis of 7-yl) acrylamide According to the method of (Example 3), (Example 97) From the compound obtained in <Step 2> and 7-amino-3,4-dihydro-1H-quinolin-2-one, The title compound was obtained.

The structures of the compounds synthesized in the above (Example 1) to (Example 97) are shown in [Compound List 1], main intermediates synthesized in each Example, and (Reference Example 1) to (Reference Example 19). The structure of the synthesized intermediate is shown in [Compound List 2]. Moreover, IC ₅₀ value in human TRPV1 of an Example compound is shown in Table 1, and LC Mass data is shown in Table 2.
The NMR data of Examples and Reference Examples are shown in Table 3 and Table 4. In Table 3 and Table 4, no mark and * mark indicate (300 MHz: no mark, 400 MHz: * mark).

[List of compounds 1]

[Compound List 2]

[1-6-d] G ₁ and G ₂ are each independently a nitrogen atom or C—R ^15.
(R ¹⁵ is a hydrogen atom, a halogen atom or C ₁ ~ ₃ alkyl group halogen atom 1-5 straight optionally substituted or branched, or a group:
-Z ₁ -Z ₂ -OR ¹³
(Z ₁ , Z ₂ , R ¹³ and R ¹⁴ are the same as defined above), and a preferred mode thereof is appropriately selected from [1-6-c-1].
[1-6-e] In the combination of the embodiment [1-6-c] and [1-6-d], “however, _one of R ⁷ in G ₁ or G ₂ or any one of R ¹² Only
Group:
-Z ₁ -Z ₂ -OR ¹³
(The definition of Z ₁ , Z ₂ , R ¹³ , R ¹⁴ is the same as described above).
At this time, in the following partial structure of the formula (Q3):

このとき、Ｒ^１２は、ｉ）ハロゲン原子、好ましくはフッ素原子もしくは塩素原子、より好ましくはフッ素原子であるか、ｉｉ）ハロゲン原子（好ましくはフッ素原子）１〜５個で置換されていてもよいＣ_１〜_６のアルキル基、好ましくはトリフルオロメチル基であり、
Ｒ^１５は水素原子、ハロゲン原子（好ましくはフッ素原子）、もしくはハロゲン原子１〜５個で置換されていてもよい直鎖もしくは分枝鎖のＣ_１〜_３のアルキル基（好ましくはトリフルオロメチル基）である。 ［１−７］態様［１］の式（Ｉ）で表される化合物において、Ｚは、＝ＣＲ^６−（Ｒ^６は水素原子または前記Ｒ^１と同じ意味を表す）または＝Ｎ−を表す。Ｚが、＝ＣＲ^６−（Ｒ^６は水素原子または前記Ｒ^１と同じ意味を表す）であることが好ましく、Ｒ^６は水素原子であることがより好ましい。
［１−８］態様［１］の式（Ｉ）で表される化合物において、Ｗを含む環の員数は、５〜８であることが好ましく、５〜７であることがより好ましく、５または６であることが更に好ましい。Ｌ_１及びＬ_２が、ともに単結合である場合には、Ｗはフェニル環に直結する。
[1-6-e-1] The following Ar1 to Ar5 are preferable.

At this time, R ¹² is i) a halogen atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom, or ii) may be substituted with 1 to 5 halogen atoms (preferably fluorine atoms). alkyl group of C ₁ ~ _6, preferably trifluoromethyl group,
R ¹⁵ is a hydrogen atom, a halogen atom (preferably fluorine atom), or an alkyl group of C ₁ ~ ₃ good straight or branched chain optionally substituted with one to five halogen atoms (preferably trifluoromethyl group ). [1-7] In the compound represented by the formula (I) of the embodiment [1], Z represents ═CR ⁶ — (R ⁶ represents a hydrogen atom or the same meaning as R ¹ described above) or ═N—. . Z is preferably ═CR ⁶ — (R ⁶ represents a hydrogen atom or the same meaning as R ¹ described above), and R ⁶ is more preferably a hydrogen atom.
[1-8] In the compound represented by the formula (I) of the embodiment [1], the number of rings containing W is preferably 5-8, more preferably 5-7, 5 or More preferably, it is 6. When L ₁ and L ₂ are both single bonds, W is directly connected to the phenyl ring.

＜工程１＞
式（Ｒ−Ｉ）の化合物、および式（Ｒ−ＩＩ）の化合物を用い、文献公知の方法、例えば、ザ・ジャーナル・オブ・オルガニック・ケミストリー（Ｔｈｅ Ｊｏｕｒｎａｌ ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ）、４７（６）、１０７７−１０８０頁、１９８２年に記載された方法に準じて、トリエチルアミン、Ｎ，Ｎ−ジイソプロピルエチルアミン、ピリジン等の塩基の存在下、メタノール、エタノール、２−プロパノール等のアルコール系溶媒を用いて、室温から溶媒が還流する温度で反応を行い、式（Ｒ−ＩＩＩ）の化合物を製造することができる。
＜工程２＞
式（Ｒ−ＩＩＩ）の化合物を用い、（製造法Ｆ）＜工程３＞と同様の方法により、式（ＶＩ−ｍ）の化合物を製造することができる。 (Production method R)
<When Q = Formula (Q3) and G ₁ = G ₂ = N in Formula (VI)>

<Step 1>
A method known in the literature using a compound of the formula (R-I) and a compound of the formula (R-II), for example, The Journal of Organic Chemistry, 47 (6) According to the method described on pages 1077 to 1080, 1982, in the presence of a base such as triethylamine, N, N-diisopropylethylamine or pyridine, an alcohol solvent such as methanol, ethanol or 2-propanol is used. The reaction can be performed from room temperature to the temperature at which the solvent is refluxed to produce the compound of formula (R-III).
<Process 2>
Using the compound of formula (R-III), the compound of formula (VI-m) can be produced by the same method as in (Production Method F) <Step 3>.

Claims (3)

Formula (I)

(In the formula, n represents an integer of 0 to 2;
R ¹ is a halogen atom, optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, optionally substituted C ₁ ~ ₆ alkoxy group, an optionally substituted C ₁ ~ ₆ alkoxycarbonyl group, mono optionally substituted C ₁ ~ ₆ alkyl group - or di - optionally substituted amino group, a protected hydroxyl group which may have, optionally protected carboxyl group, substituted mono also good C ₁ ~ ₆ alkyl group optionally - or di - optionally substituted carbamoyl group, C ₁ ~ ₆ alkanoyl group, C ₁ ~ ₆ alkylthio group, C ₁ ~ ₆ alkylsulfinyl group, C ₁ ~ selected sulfamoyl group which may be substituted, cyano group or a nitro group optionally - ₆ alkylsulfonyl group, mono optionally substituted C ₁ to ₆ alkyl groups - or di It represents a group;
R ² represents a hydrogen atom, C ₁ ~ ₄ straight or branched chain alkyl group or a linear or branched alkoxyl group of C ₁ ~ ₄ of the alkyl or alkoxy group, a halogen atom 1 to five in either may be substituted, or a hydroxyl group, an alkyl group or _C 1 _{- 2} alkoxyl group halogen atom _{1-5-optionally C} 1 optionally substituted with one _2, and _C 1 _{- 3} Optionally substituted with 1 to 3 groups arbitrarily selected from amino groups optionally substituted with 1 to 2 alkyl groups or hydroxyalkyl groups of
R ³ is a group: represents _{-A 1 -A 2, A} 1 represents a single bond, a methylene _group, an alkylene group of C 2 _{~ 6,} a carbonyl group or a sulfonyl group, _{A 2} represents a hydrogen _{atom, C} 1 ~ straight or branched chain alkyl group having _6, cycloalkyl group C ₃ ~ _6, an aryl group or a heterocyclic group, a carbon atom of the a ₂ is optionally substituted with one to five halogen atoms or better, or hydroxyl group, alkyl group or _C 1 _{- 2} alkoxyl group halogen atom _{1-5-optionally C} 1 optionally substituted by _2, and _C 1 _{- 3} alkyl or hydroxyalkyl group 1 May be substituted with 1 to 3 groups arbitrarily selected from amino groups optionally substituted with 2;
R ⁴ and R ⁵ each independently represent a hydrogen atom, a linear or branched alkyl group or a phenyl group of C ₁ ~ _4;
Q represents an aryl group which may be substituted or a heterocyclic group which may be substituted;
Z ^{is, =} CR ⁶ - ^(R 6 has the same meaning as a hydrogen atom or the ^{R 1)} or = represents a N-. However, Q is 4- (3-acetylmethylamino) -1-pyrrolidinyl) phenyl group, 3- (2- (bis (1-methylethyl) amino) ethoxy) -4-methoxyphenyl group, or 4-hydroxy Except for the case of -3,5-dimethylphenyl group. Or a salt thereof or a solvate thereof.   A pharmaceutical composition comprising at least one of the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. .   TRPV1 (Transient), comprising as an active ingredient at least one of the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof. Receptor Potential Vanilloid Type I) receptor antagonist.