WO2010123139A1 - Arylcarboxamide derivative having sulfamoyl group - Google Patents

Arylcarboxamide derivative having sulfamoyl group Download PDF

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WO2010123139A1
WO2010123139A1 PCT/JP2010/057397 JP2010057397W WO2010123139A1 WO 2010123139 A1 WO2010123139 A1 WO 2010123139A1 JP 2010057397 W JP2010057397 W JP 2010057397W WO 2010123139 A1 WO2010123139 A1 WO 2010123139A1
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group
alkyl
substituted
atom
amino
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French (fr)
Japanese (ja)
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智之 神野
六大 難波
利通 浅倉
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持田製薬株式会社
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    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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Definitions

  • the present invention is effective for compounds that inhibit long-chain fatty acid elongation enzymes (Elongation of long chain fatty acids-like 6: hereinafter referred to as Elovl6), in particular, arylcarboxamide derivatives having a sulfamoyl group represented by formula (I) Elovl6 inhibitor contained as a component, or diseases involving Elovl6, particularly nonalcoholic fatty liver disease (hereinafter referred to as NAFLD) / nonalcoholic steatohepatitis (hereinafter referred to as NASH)
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • the present invention relates to a preventive or therapeutic agent for diabetes, type 2 diabetes, insulin resistance, obesity / obesity.
  • Fatty acid biosynthesis is carried out using pyruvic acid, which is produced by the decomposition of glucose by a glycolytic system, as a starting material. Pyruvate is converted to citrate by mitochondria, then transported to the cytosol, and converted to acetyl-CoA by ATP citrate lyase. Acetyl-CoA is converted to malonyl-CoA by acetyl-CoA carboxylase (ACC). Furthermore, malonyl-CoA is decarboxylated and condensed by fatty acid synthase (FAS), so that the number of carbon atoms increases by 2 for each reaction cycle, and 16-carbon palmitic acid is biosynthesized.
  • FES fatty acid synthase
  • Palmitic acid (C16: 0) can be obtained by stearic acid (C18: 0) or palmitoleic acid (C16: 1) by stearoyl-CoA desaturase-1 (SCD-1) and long-chain fatty acid elongation enzyme (Elovl6). It is then converted to oleic acid (C18: 1).
  • SCD-1 is an enzyme that introduces a double bond into a saturated fatty acid, and converts palmitic acid into palmitoleic acid and stearic acid into oleic acid.
  • Elovl6 is an enzyme that elongates fatty acids by 2 carbons and converts palmitic acid to stearic acid and palmitoleic acid to oleic acid. Further, it is known that excessive enhancement of fatty acid synthesis induces accumulation of neutral fat and further progresses to the formation of obesity.
  • Elovl6 is an enzyme belonging to the ELOVL (Elongation of long chain acid acids) family of long chain fatty acid elongation enzymes, and has various aliases (Fatty acyl-CoA elongase (FAE or FACE), Long LC LC). ) Etc).
  • Elovl6 is an enzyme that catalyzes the carbon chain elongation reaction of saturated and monounsaturated fatty acids having 12 to 16 carbon atoms, and covers a very wide range of tissues (brain, intestine, liver, adipose tissue, skeletal muscle, kidney, testis, Expressed in the skin), particularly in the liver where fatty acid biosynthesis is active (J. Biol. Chem., 276 (48), 45358-45366, (2001) (Non-patent Document 1)) J. Lipid Res., 43 (6), 911-920, (2002) (non-patent document 2)).
  • the target of disease treatment of the compound of the present invention is a disease related to increased activity of Elovl6 represented by lifestyle-related diseases, but preferably NAFLD / NASH, diabetes, type 2 diabetes, insulin resistance Or obesity and obesity are mentioned.
  • the liver is regarded as important as a treatment target for lifestyle-related diseases.
  • NAFLD and NASH are not yet fully understood and arranged for pathological conditions, diagnosis, treatment, etc., and especially NASH has a poor prognosis. Therefore, establishment of an effective treatment method is eagerly desired.
  • the onset of NAFLD and NASH has been suggested to be associated with obesity, diabetes, abnormal lipid metabolism or hypertension, and NASH is considered to progress to cirrhosis and liver cancer, but the mechanism has not yet been clarified.
  • the experimental animal model of NASH was not appropriate, the STAM Mice C57BL / 6N-NASH model has recently been reported as a model mouse close to human NASH pathology (Japanese Patent Laid-Open No. 2009-178143 ( Patent Document 2)).
  • Patent Document 2 Japanese Patent Laid-Open No. 2009-178143
  • Non-alcoholic fatty liver (NAFLD) is listed as a therapeutic target of the drug of the compound possessed along with diabetes and obesity.
  • NASH Non-alcoholic fatty liver
  • JELIS which is a large-scale clinical trial of an EPA preparation (EPA-E) for hyperlipidemia, reported that EPA administration suppressed the onset of major coronary events. It has been reported to reduce acid (J. Am. Coll. Cardiol., 49 (9) Suppl. 1, 344A (1008-123) (2007) (Non-patent Document 9)).
  • Non-patent Document 2 It has been reported that the expression of Elovl6 is reduced in the liver of mice fed with EPA (Non-patent Document 2).
  • a drug that lowers oleic acid in the living body through inhibition of Elovl6 is expected to have a preventive or therapeutic effect on NAFLD, particularly NASH.
  • NAFLD is a liver disorder characterized by hepatic fat deposition similar to alcoholic liver disorder, although there is no clear drinking history, and hepatopathy from simple fatty liver to steatohepatitis, fibrosis, cirrhosis, and liver cancer It is a disease group including. NAFLD is classified into simple fatty liver, which is generally considered to have a good prognosis, and NASH, which has a poor prognosis. NASH is considered to be a severe form of NAFLD, and is a progressive disease of NAFLD with inflammation and fibrosis of hepatocytes.
  • NAFLD NAFLD
  • NASH requires active pharmacotherapy because it may cause cirrhosis and liver cancer.
  • Various treatment methods aimed at improving various pathological conditions have been tried so far, and their effectiveness has been reported, but there is no established treatment method yet (the Japan Society for Hepatology “NASH / NAFLD diagnosis guide” “Bunkodo Publishing, August 22, 2006).
  • biguanides such as biguanides (metformin), PPAR ⁇ agonist thiazolidine derivatives (pioglitazone, rosiglitazone), glinides (nateglinide) and other antidiabetic / insulin resistance improving drugs; vitamins (vitamin E, vitamin E + C), betaine ( Choline derivatives), antioxidants such as N-acetylcysteine; PPAR ⁇ agonists (fibrates (gemfibrozil), KRP-101), HMG-CoA reductase inhibitors (atorvastatin), FXR agonists (INT-747), Antilipidemic agents such as probucol; liver protective agents such as ursodeoxycholic acid (UDCA) and polyenephosphatidylcholine (EPL); antihypertensive agents such as angiotensin II receptor antagonist (losartan); PDE-4 inhibitor (ASP9831) ), T Inflammatory cytokine production inhibitors such as NF ⁇ inhibitors (pent
  • Diabetes develops due to multiple etiologies. Generally, it is a disease characterized by high plasma glucose concentration during fasting, postprandial or oral glucose tolerance test, or chronic hyperglycemia. Uncontrollable hyperglycemia directly or indirectly presents abnormal lipid metabolism and ultimately causes vascular injury. Therefore, in diabetic patients, the risk of microvascular complications such as coronary heart disease, cerebral infarction, hypertension, nephropathy, neuropathy, retinopathy such as arteriosclerosis, angina pectoris and myocardial infarction is increased. . Therefore, control of chronic hyperglycemia, dyslipidemia and hypertension is important for clinical management and treatment of diabetes.
  • Type 1 diabetes insulin-dependent diabetes mellitus: IDDM
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • Insulin resistance refers to resistance to effects on glucose and lipid metabolism in the liver, skeletal muscle, and adipose tissue that are insulin-responsive organs.
  • a useful treatment for type 2 diabetes has not yet been established, and diet / exercise therapy is the focus. Compliance with these therapies is very poor. The cause of this is the change in lifestyle due to the intake of high-calorie foods and lifestyle changes accompanying the westernization of dietary habits.
  • Examples of the therapeutic agent for diabetes include sulfonylureas (such as tolbutamide and glimepiride) and glinides (mitiglinide) that stimulate pancreatic ⁇ cells to promote insulin secretion.
  • these drugs are known to have side effects of ineffective administration, hypoglycemia-inducing action, and insulin resistance-inducing action associated with increased plasma insulin levels. Biguanide (metformin buformin) increases insulin sensitivity and improves hyperglycemia.
  • Glitazone is an agonist of the peroxisome proliferator-activated receptor (PPAR) gamma subtype that increases insulin sensitivity in adipose tissue, liver and skeletal muscle, and improves chronic hyperglycemia .
  • PPAR peroxisome proliferator-activated receptor
  • Obesity / obesity is evaluated by BMI (body mass index, kg / m 2 ).
  • BMI body mass index, kg / m 2
  • the Japanese Society of Obesity has BMI 25 or higher as “obesity”, two or more complications such as type 2 diabetes and hypertension, and visceral fat area A person who is 100 cm 2 or more is defined as “obesity”.
  • the International Obesity Countermeasures Committee defines BMI of 25 or more and less than 30 as pre-obesity and BMI of 30 or more as obesity.
  • Obesity has been pointed out as a major factor in various lifestyle-related diseases such as cardiovascular diseases, diabetes, NAFLD / NASH, and in recent years, there has been an active movement to actively diagnose and treat obesity. Guidelines and diagnostic criteria have been published worldwide, and obesity is recognized as one of the diseases. As a result of the treatment of obesity / obesity, reduction of BMI can be mentioned. As a treatment method, improvement of lifestyle habits by diet therapy or exercise therapy is first attempted, but drug therapy is taken for patients who have not been able to obtain sufficient effects by such therapy. Therefore, in recent years, development of therapeutic agents for obesity / obesity has been promoted, but there are few drugs currently approved as anti-obesity agents.
  • mazindol monoamine reuptake inhibitor
  • side effects such as pulmonary hypertension and various neuropsychiatric symptoms
  • Orlistat a lipolytic enzyme (lipase) inhibitor
  • lipase lipolytic enzyme
  • CB-1 receptor antagonists development of cannabinoid type 1 (CB-1) receptor antagonists has been vigorously advanced. Specifically, rimonabant is being developed and sold in some countries, but there are side effects such as nausea, depression, and anxiety, making it difficult to approve in each country.
  • PYY3-36 which is a peptide YY (PYY) receptor antagonist, is expected to have an appetite-suppressing effect, but does not exhibit a medicinal effect when administered orally and has been developed as a nasal spray.
  • a number of adrenergic ⁇ 3-receptor agonists have been developed, but the effectiveness varies among races, and many have been discontinued. Accordingly, there is a need for an anti-obesity drug that exhibits higher efficacy by oral administration and has fewer side effects.
  • Patent Document 1 Although there has been little research on Elovl6 so far, the relationship between inhibition of this enzyme and diabetes or obesity has been demonstrated in mice using siRNA (Patent Document 1). However, there are very few reports of specific low molecular weight compounds having inhibitory activity, and little is known about what substances strongly inhibit this enzyme with high selectivity.
  • Patent Literature 3 discloses an anti-obesity agent, for example, Patent Literature 3, Patent Literature 4, Patent Literature 5, Patent Literature 6, Patent Literature 7 and Patent Literature 8 are known.
  • Patent Documents 3 to 7 do not suggest any arylcarboxamide derivatives having a sulfamoyl group as in the present invention.
  • Patent Document 8 discloses an arylsulfonyl derivative, which is formed by condensation of a non-aromatic heterocycle with a phenyl group like the compound in the present invention, particularly the compound represented by the formula (III) -B. There is no disclosure of compounds in which the group to be bonded is bound to the nitrogen atom of the amide bond.
  • Patent Document 9 International Publication No. 2004/058709
  • Patent Document 10 International Publication No. 2001/062718
  • Patent Document 11 International Publication No. 2005/092881
  • Patent Document 12 International Publication No. 2001/047509
  • Patent Document 13 International Publication No. 2005/115374 pamphlet
  • Patent Document 15 International Publication No. 2007/002559
  • Patent Document 16 there is no disclosure of a compound having an Elovl6 inhibitory action.
  • Patent Document 9 discloses various condensed arylsulfonamide derivatives as CCR8 inhibitors. Among them, derivatives having a 4-piperidinyl group or a cyclohexyl group at the nitrogen atom of sulfonamide are disclosed, but there is no disclosure of a compound having an Elovl6 inhibitory activity as in the present invention.
  • Patent Document 10 discloses various benzamide derivatives as CRF receptor antagonists. Among them, a derivative in which a specific phenyl group is bonded to the carbonyl of the amide bond is disclosed, but there is no disclosure of a compound having an Elovl6 inhibitory action as in the present invention.
  • Patent Document 11 discloses pyrrolidine-3,4-dicarboxamide derivatives as FXa inhibitors, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
  • Patent Document 12 discloses N-haloalkylsulfonylbenzamide for the treatment of obesity and diabetes, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
  • Patent Document 13 discloses a thiazolidinedione derivative as an insulin sensitizer, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
  • Patent Document 14 discloses substituted benzamide derivatives as CRTH2 receptor ligands, but does not disclose a compound having an Elovl6 inhibitory activity as in the present invention.
  • Patent Document 15 discloses phenol and phenyl acetate derivatives as antidiabetic agents, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
  • Patent Document 16 discloses a pyrazole derivative as an LXR modulator, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
  • Elovl6 inhibitors There are few reports of Elovl6 inhibitors, and they have not yet been put on the market. For this inhibitor as well, the above overall challenges in drug development will always arise. More specifically, for example, it exhibits inhibitory activity on hERG (human ether-a-go-go related genes) channels that have low metabolic stability and are difficult to be administered orally, or that may cause arrhythmias, or There are problems of usefulness and safety such as poor pharmacokinetics such as absorbability and sustainability, and there is a demand for compounds that solve these problems and have high activity.
  • hERG human ether-a-go-go related genes
  • the Elovl6 inhibitor has fewer side effects than the above-mentioned conventional drugs used for the treatment of NAFLD / NASH, diabetes, especially type 2 diabetes or insulin resistance, obesity / obesity There is a need for compounds.
  • the fatty acid composition in the living body preferably in blood
  • palmitic acid is increased and / or oleic acid is decreased.
  • Molecular compounds were sought.
  • Elovl6 inhibitors or preventive or therapeutic agents for diseases involving Elovl6 (particularly NAFLD ⁇ NASH, diabetes, type 2 diabetes, insulin resistance, obesity / obesity preventive or therapeutic agent) are demanded.
  • a therapeutic agent for obesity / obesity such as drug dependence in appetite suppressant (Mazindol), side effects such as pulmonary hypertension and various neuropsychiatric symptoms; Gastrointestinal side effects and side effects in which various nutrients cannot be absorbed; side effects such as nausea, depression and anxiety with CB-1 receptor antagonist (Rimonabant); oral administration with PYY receptor antagonist (PYY3-36) is not possible
  • PYY receptor antagonist PYY3-36
  • an arylcarboxamide derivative having a sulfamoyl group represented by the formula (1) or a pharmaceutically acceptable salt thereof, or a solvate thereof potently inhibits Elovl6, and when administered to a living body,
  • the present invention was completed by finding out that the fatty acid composition fluctuates, in particular, that palmitic acid is increased and oleic acid is decreased.
  • the present invention relates to an arylcarboxamide derivative having a sulfamoyl group represented by formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, a pharmaceutical composition containing the derivative as an active ingredient. is there.
  • the compound according to a preferred embodiment of the present invention is a compound having an Elovl6 inhibitory activity, or a compound having a function of changing the fatty acid composition by inhibiting Elovl6, particularly raising the palmitic acid and / or lowering the oleic acid.
  • the pharmaceutical composition comprising the compound of a further preferred embodiment of the present invention as an active ingredient is an orally administrable disease involving Elovl6 (especially enhanced activity thereof), particularly NAFLD / NASH, diabetes, type 2 diabetes, insulin resistance It is expected as an agent for preventing or treating obesity / obesity.
  • Elovl6 especially enhanced activity thereof
  • NAFLD nerve growth factor
  • NASH non-alcoholic fatty acid deposition
  • diabetes particularly fibroblast growth factor
  • type 2 diabetes fibroblast growth factor
  • insulin resistance It is expected as an agent for preventing or treating obesity / obesity.
  • the compound groups of some embodiments of the present invention have high metabolic stability, excellent oral absorption, good solubility, or little hERG channel inhibitory action, etc. It is highly useful because it also has at least one feature.
  • the present invention relates to an arylcarboxamide derivative having a sulfamoyl group represented by the formula (I) represented by the following embodiment or a salt thereof or a solvate thereof, a pharmaceutical composition containing them as an active ingredient, and the derivative or a derivative thereof It is a medicinal use of salt.
  • the molecular weight of the compound represented by the formula (I) of the present invention is not particularly limited, but 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.
  • Aspect 1 of the present invention is: Formula (I) (Wherein n represents an integer of 0 to 2; m and p represent an integer of 0 to 4; R 1 , R 2 , R 3 and R 4 each independently represents a hydrogen atom or a halogen atom; represents OH, C 1 - 6 alkoxylated, halogenated C 1 - 6 one by one to five substituents which may C 1 to 6 alkyl groups of alkoxy; Y is optionally substituted hydrocarbon group, Or a group: —NR 5 R 6 (R 5 and R 6 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R 5 , R 6 May form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or
  • R 7, R 8, R 9, R 10, R 11 each independently represent a hydrogen atom or a C 1 ⁇ 6 alkyl group, R 7 is taken together with R 3 or R 4
  • each bonded nitrogen atom and carbon atom may form a 5- to 7-membered cyclo group, and the cyclo group may have a double bond in the ring.
  • one carbon atom in the ring is an oxygen atom, sulfur atom or nitrogen Atom (said nitrogen atom, C 1 ⁇ halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with one to five substituents which may be straight or branched alkoxyl represents may) be replaced by 6 may be substituted by an alkyl group);
  • Z is optionally substituted C 3 even though 1-8 cycloalkyl group, an optionally substituted aryl group, or Represents a heterocyclic group which may be substituted, provided that Ring is a piperazine or piperidine which may be substituted or may be bridged by —CH 2 — or —CH 2 CH 2 —, (CR 1 R 2) -W- ( CR 3 R 4) -Z is bonded to the 1-position of the piperidine or piperazine, and Y-SO 2 - is attached to the 4-position of the piperazine or piperidine Or a pharmaceutically acceptable salt thereof or a
  • 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”.
  • hydrocarbon group of “optionally substituted hydrocarbon group” includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an aryl group.
  • aliphatic hydrocarbon group examples include a linear or branched hydrocarbon group such as an alkyl group, an alkenyl group, and an alkynyl group.
  • 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,
  • 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.
  • 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.
  • alicyclic hydrocarbon group examples include a saturated or unsaturated alicyclic hydrocarbon group, and examples thereof include a cycloalkyl group, a cycloalkenyl group, and a cycloalkanedienyl group.
  • cycloalkyl group examples of “cycloalkyl group”, cycloalkyl groups of C 3 ⁇ 8, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • cycloalkenyl group a cycloalkenyl group of C 3 ⁇ 8, e.g., 1-cyclopropene-1-yl, 1-cyclobutene-1-yl, 1-cyclopenten-2-cyclopentene - 1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclohepten-1-yl, 2-cyclohepten-1- Yl, 3-cyclohepten-1-yl, 4-cyclohepten-1-yl, 1-cycloocten-1-yl, 2-cycloocten-1-yl, 1-cycloocten-3-yl, 1-cyclooctene- 4-yl and the like can be mentioned.
  • cycloalkanedienyl group 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 .
  • aryl group a monocyclic or condensed cyclic C 6 ⁇ 14 aryl group, e.g., phenyl, naphthyl, biphenylyl, 2-anthryl, phenanthryl, acenaphthyl and the like, or indanyl, in part, such as a tetrahydronaphthyl And a condensed aryl hydrogenated.
  • the partially hydrogenated aryl group means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring, and the hydrogen atom of the aromatic part of the condensed ring or Either hydrogen atom in the hydrogenated part may be removed.
  • 1,2,3,4-tetrahydronaphthalene (1-yl, 2-yl, 3-yl, -4-yl, -5-yl, -6-yl, -7- Yl, -8-yl) groups and the like.
  • heterocyclic group examples include a heteroaryl group and a saturated or unsaturated non-aromatic heterocyclic group. These rings are 3- to 14-membered, preferably 3- to 12-membered monocycles containing at least one heteroatom (preferably 1 to 4) selected from N, O and S in addition to carbon atoms, A monovalent group formed by removing any hydrogen atom from a ring having a condensed ring.
  • the “heteroaryl group” may be monocyclic or condensed, and the monocyclic heteroaryl group preferably has 5 to 6 ring members, such as 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, 1,3,5-triazinyl, 2H-1,
  • the condensed heteroaryl group preferably has 8 to 14 ring members, and this includes one to a plurality of (preferably 1 to 2) monocyclic 5- to 6-membered heterocycles described above.
  • the arbitrary hydrogen atom may be removed from any condensed ring.
  • partially hydrogenated condensed heteroaryl groups are preferably those having the number of ring members of 8 to 12 in the above-mentioned condensed ring heteroaryl group.
  • Any hydrogen atom is removed from a partially hydrogenated condensed ring formed by condensing with a plurality of (preferably 1 to 2) aryl rings (eg, benzene ring) or a monocyclic heteroaryl group.
  • the hydrogen atom of the aryl ring, the heterocyclic part, or the hydrogen atom of the hydrogenated part may be removed.
  • a tetrahydroquinolinyl group includes a 5,6,7,8-tetrahydroquinolyl group or a 1,2,3,4-tetrahydroquinolyl group.
  • these groups depending on the position excluding any hydrogen atom, for example, a 5,6,7,8-tetrahydroquinolyl group, a 2-yl group, a 3-yl group, a -4-yl group , -5-yl group, -6-yl group, -7-yl group, -8-yl group and the like.
  • 1,2,3,4-tetrahydroquinolyl group for example, -1- Ilyl group, 2-yl group, 3-yl group, -4-yl group, -5-yl group, -6-yl group, -7-yl group, -8-yl group and the like are exemplified.
  • non-aromatic heterocyclic groups include 3 to 8 membered saturated or partially unsaturated containing at least one heteroatom (preferably 1 to 4) selected from N, O, S Of non-aromatic heterocyclic groups.
  • heteroatom preferably 1 to 4
  • aziridinyl, azetidinyl, oxiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, pyrazolidinyl, piperidyl, tetrahydropyranyl, piperazinyl, morpholinyl, oxazolinyl, thiazolinyl, thiomorpholinyl, quinuclidinyl, oxacridinyl, oxacridinyl, oxacridinyl, oxacridinyl Means a monovalent group formed by removing any hydrogen atom from a hetero
  • these non-aromatic heterocycles include cases where the heterocycle is substituted with 1 to 2 oxo groups, such as azetidinone, pyrrolidone (eg, 2-pyrrolidone), pyrazolone, pyrazolidinone, piperidone (eg, 2-piperidone, 4-piperidone), oxazolidinone, 3-oxomorpholine and the like are also included.
  • these non-aromatic heterocycles (groups) may be substituted with an arbitrary group selected from the R A group, the R B group or the R C group.
  • cyclic group of “optionally substituted cyclic group” in the definition of Ring include “alicyclic hydrocarbon group” and “aryl group” mentioned above as “hydrocarbon group”, “ From the “heteroaryl group” or “saturated or unsaturated non-aromatic heterocyclic group” mentioned as the “heterocyclic group” of the “optionally substituted hetero ring group”, any hydrogen atom Means a divalent group formed by removing one of
  • halogen atoms -OH, C 1 - 6 alkoxylated, halogenated C 1 ⁇ 6 1 ⁇ 5 amino substituted C 1 optionally 1-6 alkyl group in either alkoxyl
  • halogen atoms -OH, C 1 - 6 alkoxylated, halogenated C 1 ⁇ 6 1 ⁇ 5 amino substituted C 1 optionally 1-6 alkyl group in either alkoxyl
  • the "optionally 1-5 substituted by a halogen atom C 1 ⁇ 6 alkyl group” a group represented as "halogenated C 1 ⁇ 6 alkyl".
  • a halogen atom with one to five substituted C 1 ⁇ 4 may optionally be alkyl groups, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, tert
  • butyl group for example, trifluoromethyl group, tetrafluoroethyl group, pentafluoroethyl group and the like can be mentioned.
  • - the term "1-5 are also good C 1 ⁇ 6 alkyl group optionally substituted by OH” is a 1-5 substituted C 1 optionally 1-6 alkyl group with a hydroxyl group, "hydroxy is a group represented by -C 1 ⁇ 6 alkyl ".
  • the alkyl group may be substituted with 1 to 5 hydroxyl groups, but there are many positional isomers at the substitution position. To do.
  • C 1 ⁇ 6 alkoxyl with 1-5 optionally substituted C 1 ⁇ 6 alkyl group is a group represented by "C 1 ⁇ 6 alkoxy -C 1 ⁇ 6 alkyl”.
  • the carbon chain is optionally substituted with 1-5 C 1 ⁇ 6 alkoxy, more preferably, a C 1-3 alkoxyl with 1-3 optionally substituted C 1 ⁇ 4 alkyl group, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl
  • sec-butyl group and tert-butyl group for example, methoxymethyl group, methoxyethyl group, methoxypropyl group and the like can be mentioned.
  • halide C 1 ⁇ 6 alkoxy which may be 1 to 5 substituents C 1 ⁇ 6 alkyl group
  • Te represents a group selected from the group which the carbon chain is optionally substituted with 1-5 halogenated C 1 ⁇ 6 alkoxy, and more preferably is 1-3 substituents halogenated C 1-3 alkoxy a good C 1 ⁇ 4 alkyl group optionally, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, in addition to the tert- butyl group, for example, Examples thereof include a trifluoromethoxymethyl group, a trifluoromethoxyethyl group, a trifluoromethoxypropyl group, and the like.
  • Examples of the 3- to 8-membered cyclic group in “R 5 and R 6 may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded” include, for example, the above-mentioned “non-aromatic heterocycle” Among the 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic groups in the “ring group”, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, oxazolinyl, thiomorpholinyl, quinuclidinyl, oxepanyl, etc. Can be mentioned.
  • the nitrogen atom is a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with one to five substituents which may be straight or branched chain alkoxyl in R 6 the cyclic group as if "substituted with an alkyl group of C 1 ⁇ 6 of, for example,
  • each group of the compound represented by the formula (I) “optionally substituted hydrocarbon group”, “optionally substituted heterocyclic group”, “optionally substituted cyclic group” , “R 5 and R 6 may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, C 1 halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with one to five substituents which may be straight or branched alkoxyl
  • the substituent may be substituted with an alkyl group of 1 to 6 ), and the cyclic group may further have a substituent.
  • substituents of the following RA group can be mentioned. That is, each of the above groups may be optionally substituted with 1 to 5 of these groups.
  • cycloalkyl group 1-8 optionally C 3 which may be substituted
  • “optionally substituted aryl” or “cycloalkyl group” of the "optionally substituted heterocyclic group” “Aryl group” or “heterocyclic group” have the same meaning as “cycloalkyl group” or “aryl group” or “heterocyclic group” mentioned as examples of the “hydrocarbon group”. , they have the following R a group substituents may be substituted with one to five arbitrarily.
  • R A group is used in the equation described above and below, R B group, for a substituent R C group is described.
  • the alkyl chain moiety in the substituent of the R A group, aryl or heteroaryl ring may further halogen atoms, halogenated C 1 ⁇ 6 alkyl, cyano, optionally protected hydroxyl, amino, nitro, be protected good carboxyl, carbamoyl, C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkoxy, C 2 ⁇ 6 alkanoylamino, C 1 ⁇ 6 alkylthio, C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, mono / di C 1 ⁇ 6 alkylamino, mono / di C 1 ⁇ 6 alkyl sulfamoylamino, C 1 ⁇ 6 alkoxycarbonyl, mono / di C 1 ⁇ 6 alkylcarbamoyl, C 2 ⁇ 7 alkanoyl, C 6 ⁇ 14
  • a respective substituents and the number of carbon atoms in the substituent R A groups linear, branched, an example of the relationship, such as an annular Examples below.
  • halogen atom examples include fluorine atom, chlorine atom, bromine atom and iodine atom.
  • R is C 1 ⁇ 6 alkyl cited in the above Group.
  • Examples include propylmethyloxy group
  • C 1 ⁇ 6 alkoxycarbonyl straight chain C 1 -C mentioned above 6, a carbonyl group branched or cyclic alkoxyl group is bonded, RO-CO- (R is listed above C 1 ⁇ 6 are represented as alkyl groups) was, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec- butoxycarbonyl group, tert- butoxy Carbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxy Carbonyl group, cyclohexyloxycarbonyl group, cyclopropyloxy
  • mono / di C 1 ⁇ 6 alkylamino refers to one or two hydrogen atoms are "linear, branched or cyclic C 1 ⁇ 6 alkyl group" substituted amino group of the amino group To do. Specifically, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, isohexylamino group, cyclopropylamino Group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dipentylamino group, ethylmethylamino group, methylpropylamin
  • C 1 ⁇ 6 alkylthio straight chain C 1 -C 6 refers to branched or cyclic alkylthio groups such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutyl Thio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, tert-pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group, 1-ethyl Propylthio group, hexylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cyclopropylmethylthio group, 1-cyclopropylethylthio group, 2-cycl
  • C 1 ⁇ 6 alkylsulfinyl straight chain C 1 -C 6 refers to branched or cyclic alkylsulfinyl group, for example, methylsulfinyl group, ethylsulfinyl group, propyl sulfinyl group, isopropyl sulfinyl group Butylsulfinyl 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, 1-ethylpropylsulfinyl group, hexyl
  • C 1 ⁇ 6 alkylsulfonyl straight chain C 1 -C 6 refers to branched or cyclic alkylsulfonyl groups such as 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, hexylsulfon
  • Examples of the protecting group of “optionally protected hydroxyl” 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 “optionally protected carboxyl” 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-butyldimethyl group.
  • Examples include silyl ester-based protecting groups such as silyl groups.
  • the protecting group in “optionally protected hydroxyl” and “optionally protected carboxyl” refers to, for example, Greene et al. Protective Groups in Organic Synthesis in Protective Groups in (Organic Synthesis), (USA), 3rd edition, 1999, and the like are included as the respective protecting groups.
  • C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl for example, a cycloalkyl group of the C 3 ⁇ 8, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, the above-described This is a group in which a linear or branched alkyl group having 1 to 6 carbon atoms is substituted.
  • cyclopropylmethyl group cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2- (cyclopropyl) ethyl group, 2- (cyclobutyl) ethyl group, 2- (cyclopentyl) ethyl group, 2- (cyclohexyl) ) And the like.
  • the "C 6 ⁇ 14 aryl -C 1 ⁇ 6 alkyl” is the “C 6 ⁇ 14 aryl group” is substituted with C 1 ⁇ 6 alkyl group straight or branched chain group (aralkyl group), Examples include benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, phenethyl group, 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) ethyl group and the like.
  • heterocycle C 1 ⁇ 6 alkyl the "heterocyclic group” (e.g., a heteroaryl group, such as a heterocyclic group of a non-aromatic saturated or unsaturated) C 1 ⁇ of a linear or branched 6 is an alkyl group have been substituted (heterocyclic -C 1 ⁇ 6 alkyl group), for example, pyrrolylmethyl, furylmethyl, thienylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazoloxy Rylmethyl, pyrazolylmethyl, 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, , , pyr
  • C 2 ⁇ 7 alkanoyl "linear C 2 ⁇ 7, branched or cyclic alkylcarbonyl group” means a such as acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl Group, pivaloyl group, hexanoyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group and the like.
  • the "C 6 ⁇ 14 aryl-carbonyl", group carbonyl group on the aryl group is bonded, for example, a benzoyl group and a C 6 ⁇ 14 aryl group such as a naphthyl group.
  • Heterocyclic carbonyl means “heterocyclic carbonyl group”, and a carbonyl group is bonded to the heterocyclic group (for example, a heteroaryl group, a saturated or unsaturated non-aromatic heterocyclic group, etc.).
  • the "C 6 ⁇ 14 arylsulfonyl" is a sulfonyl group attached, for example, benzenesulfonyl group, and a C 6 ⁇ 14 arylsulfonyl group such as a naphthylsulfonyl group.
  • Heterocyclic sulfonyl means a “heterocyclic sulfonyl group” and is a group in which a sulfonyl group is bonded to the heterocyclic group, for example, pyrrolylsulfonyl, furylsulfonyl, thienylsulfonyl, imidazolylsulfonyl, oxazolyl.
  • the substituent of the "group R B" as used in various formulas to be described later especially a substituent attached to the nitrogen atom, for example, hydrogen atom or the following C 1 ⁇ 6 alkyl,, C 2 2-6 alkenyl, C 2 - 6 alkynyl, halogenated C 1 - 6 alkyl, hydroxy -C 1 - 6 alkyl, C 1 - 6 alkoxy -C 1 - 6 alkyl, C 1 - 6 alkylthio -C 1 - 6 alkyl, C 1 ⁇ 6 alkylsulfinyl -C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkylsulfonyl -C 1 ⁇ 6 alkyl, sulfamoyl -C 1 ⁇ 6 alkyl, N-C 1 ⁇ 6 alkylsulfamoyl -C 1 ⁇ 6 alkyl , N, N-di-C 1 ⁇ 6 alkyl
  • carbon atoms (e.g., alkyl chain moiety) further halogen atoms, halogenated C 1 ⁇ 6 alkyl, cyano, optionally protected hydroxyl, amino, nitro, optionally protected carboxyl, carbamoyl, C 1 1-6 alkyl, C 1 - 6 alkoxy, C 2 - 6 alkanoylamino, C 1 - 6 alkylthio, C 1 - 6 alkylsulfinyl, C 1 - 6 alkylsulfonyl, mono / di C 1 - 6 alkyl sulfamoyl, mono / di C 1 ⁇ 6 alkylamino, mono / di C 1 ⁇ 6 alkyl Sulfamoyl amino, C 1 - 6 alkoxycarbonyl, mono / di C 1 - 6 alkylcarbamoyl, and C 2 in group one to five selected from 1-7 group consisting alkanoyl may be substituted.
  • R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or a halogen atom, —OH. It represents a C 1 - 6 alkoxylated, halogenated C 1 - 6 one by one to five substituents which may C 1 to 6 alkyl groups of alkoxy.
  • R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom or —OH. is preferably-C 1 - 6 alkoxylated, halogenated C 1 ⁇ 6 1 ⁇ 3 or optionally substituted C 1 to 4 alkyl groups or alkoxyl.
  • R 1 , R 2 , R 3 and R 4 are each a hydrogen atom.
  • Ring represents a cyclic group which may be substituted. More specifically, the following formula (I)
  • the Ring portion (the inner portion of the wavy line) of R 1 represents a cyclic group optionally substituted with 1 to 5 groups selected from the group R A , and the “cyclic group” is “ “Heteroaryl group” mentioned as “heterocyclic group” of "alicyclic hydrocarbon group” and “aryl group” mentioned as “hydrocarbon group” or “optionally substituted heterocyclic group” Or a “saturated or unsaturated non-aromatic heterocyclic group” or the like, and a divalent group formed by removing any one hydrogen atom.
  • a ring in which an imino group is bonded to the Ring (for example, the formula a212 described below) is also included in the Ring.
  • Ring portion is given below, but the present invention is not limited thereto.
  • the divalent groups represented by each of the following partial structural formulas the bond to -S (O) n- is marked with a mark.
  • the divalent groups are each incorporated into the formula (I) as a Ring moiety to individually form a sub-embodiment of formula (I).
  • — (R A ) k (wherein R A represents a group arbitrarily selected from the R A group described in the above embodiment [1], k represents an integer of 0 to 5)
  • R A represents a group arbitrarily selected from the R A group described in the above embodiment [1]
  • k represents an integer of 0 to 5
  • the substituents R A may be the same or different and may be arbitrarily selected.
  • the upper limit of the number of k is the number that can be replaced for each formula.
  • R B is an optionally substituted group selected from R B group according to the aspect [1].
  • Ring is represented by the following formula (A1): (In the formula, r represents an integer of 0 to 2, and V 1 , V 2 , V 3 , and V 4 are each independently selected from —CR A1 R A2 —, an oxygen atom, a sulfur atom, or —NR B —.
  • the bond (broken line) of the cyclic group is a single bond or a double bond, may be aromatized, a bond between V 2 and V 4 when r is 0, or r is coupled between V 3 -V 4 when the 1 or 2 aryl groups of said C 6 ⁇ 14 (or may be partially hydrogenated), a cycloalkyl group or 3 C 3 ⁇ 8
  • Any position of the resulting 14-membered heterocyclic group (which may be partially hydrogenated) may be fused at any position, and any position of the resulting fused ring may be bonded R a in, B is a carbon atom or a nitrogen atom, -S (O) combined with n- Cage, a divalent group represented by R A1 and R A2 each independently represent a hydrogen atom or R A, or together represent an oxo group); Or the following formula (A2) (Wherein two rings of Cycle1 and Cycle2 each aryl group of said C 6 ⁇ 14 (or may be partially hydrogenated), a
  • Ring is represented by the following formula (A1a): (In the formula, r represents an integer of 0 to 2, and V 1 , V 2 , V 3 , and V 4 are each independently selected from —CR A1 R A2 —, an oxygen atom, a sulfur atom, or —NR B —.
  • the bond (broken line) of the cyclic group may be a single bond or a double bond as appropriate and may be aromatized, a bond between V 2 and V 4 when r is 0, or , r is coupled between V 3 -V 4 when the 1 or 2 (which may be partially hydrogenated) aryl groups of said C 6 ⁇ 14, or a cycloalkyl group C 3 ⁇ 8 Any of the condensed ring formed may optionally be condensed with any ring of a 3 to 14-membered heterocyclic group (which may be partially hydrogenated).
  • R a, R A1 and R A2 each independently represent a hydrogen atom or R a, there Represents an oxo group together, V 4 is -CR A1 R A2 - if it is, the R A1 and R A2 may form a 3- to 8-membered cyclic group together with the carbon atoms to which they are attached even better, the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 may be replaced by either by may be substituted with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group) alkoxyl, said cyclic group is more A divalent group represented by (which may have a substituent);
  • the following formula (A1b) In the formula, r represents an integer of 0 to 2, and V 1 ,
  • the bond (broken line) of the cyclic group is a single bond or a double bond as appropriate, a bond between V 2 and V 4 when r is 0, or r is 1 or 2
  • the bond between V 3 and V 4 is a C 6 to 14 aryl group (which may be partially hydrogenated), a C 3 to 8 cycloalkyl group or a 3 to 14-membered heterocycle. It may be condensed at any position with any ring of the ring group (which may be partially hydrogenated), and R A is bonded at any position of the resulting condensed ring.
  • R A3 and R A4 each independently represent a hydrogen atom or R A, or together oxo
  • V 4 is -CR A3 R A4 - in the case of the R A3 and R A4 may form a 3-8 membered cyclic group together with the carbon atoms to which they are attached, said cyclic group , one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, one to either a halogen atom, -OH, C 1 - 6 alkoxylated, halogenated C 1 - 6 alkoxy 5 substituted may be substituted with an alkyl group of C 1 ⁇ 6 of which may linear or branched) may be replaced by, the cyclic groups further have a substituent A divalent group represented by: Or the following formula (A2a) (Wherein, i-1, i-2 each independently represent an integer of 0-2, ring Cycle2 the aryl group of said C 6,
  • Ring is any one of the following formulas (A1aa) to (A2ac), and V 1 to V 4 , R A , k, r, i-1, i-2 and R C are as defined above, and B 3 is a carbon atom or a nitrogen atom.
  • the following formula (A1aa) (Wherein, r, k, V 1 , V 2 , V 3 , R A , R C , the bond of the cyclic group (broken line) represents the same as above, and B 3 represents the carbon atom or nitrogen forming the ring A divalent group represented by:
  • the following formula (A1ba) (Wherein, r, k, V 2 , V 3 , V 4 , R A , and the bond (broken line) of the cyclic group is the same as described above);
  • the following formula (A2aa) (Wherein the ring of i-1, i-2, k, Cycle2, the ring containing a nitrogen atom bonded to —S (O) n—, and the bond of the ring represented by Cycle2 (dashed line) and R A are R A is the same as defined above, and R A may be bonded to either a ring containing a nitrogen atom bonded to —S (O) n—
  • R A is a divalent group represented by a ring containing a nitrogen atom bonded to —S (O) n— or a ring represented by Cycle 2).
  • R A represents a group arbitrarily selected from the R A group described in the above embodiment [1], k represents an integer of 0 to 5)
  • R A represents a group arbitrarily selected from the R A group described in the above embodiment [1]
  • k represents an integer of 0 to 5
  • the substituents R A may be the same or different and may be arbitrarily selected.
  • the upper limit of the number of k is the number that can be replaced for each formula.
  • R B is an optionally substituted group selected from R B group according to the aspect [1].
  • Ring moiety can be appropriately selected from (a1) to (a212) shown below, for example.
  • Ring moiety in the formula (I) include the following formula (G) or (H): (Wherein R 17 and R 18 each independently represents a hydrogen atom or a group arbitrarily selected from the group R C , R 17 and R 18 represent a carbon atom on the benzene ring to which they are bonded and 5 to 5
  • An 8-membered cyclic group may be formed, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom, or a nitrogen atom (the nitrogen atom is a halogen atom, -OH, C 1- 6 replaced by may also) be substituted with an alkyl group of C 1 ⁇ 6 of which may straight or branched chain optionally substituted 1-5 with either an alkoxylated-halogenated C 1 ⁇ 6 alkoxy at best;
  • E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 To 6 alkyl, C 1 to 6 alkoxy-C 1 to 6 alkyl, carboxy-C 1 to 6 alkyl, C 1 to 6 alkoxycarbonyl-C 1 to 6 alkyl, carbamoyl-C 1 to 6 alkyl, N—C 1 to 6 alkylcarbamoyl -C 1 ⁇ 6 alkyl, N, N-di-C 1 ⁇ 6 alkylcarbamoyl -C 1 ⁇ 6 alkyl, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alky
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom.
  • a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • Y is an optionally substituted hydrocarbon group, or a group: —NR 5 R 6 (R 5 , R 6 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R 5 and R 6 are each a 3- to 8-membered member together with the nitrogen atom to which they are bonded.
  • cyclic group may form a cyclic group, said cyclic group is one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, halogen atom, -OH, C 1 ⁇ 6 alkoxy may be replaced by may also) be substituted by a halogenated C 1 - 6 one by one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl
  • the cyclic group further has a substituent. May be present).
  • R C optionally substituted hydrocarbon group
  • R C straight-chain or min R C optionally substituted by a group selected C 1 ⁇ from group 6 alkyl Edakusari
  • straight-chain or branched alkenyl groups of R C is optionally C 2 even though - substituted with chosen groups arbitrarily from group 6, are optionally substituted with a group selected arbitrarily from R C group a straight-chain or branched alkynyl group of which may C 2 ⁇ 6, selected cycloalkyl group R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 8, the R C groups optionally substituted with the group and an aryl group optionally C 6 ⁇ 14 even.
  • [1-3-a-1] is as the "optionally substituted hydrocarbon group" defined Y, straight of R C may be substituted with a group C 1 selected arbitrarily from the group 1-6 or branched chain alkyl group, optionally substituted by a group selected cycloalkyl group R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 8, or R C groups, optionally is preferably an aryl group optionally C 6 ⁇ 14.
  • the “optionally substituted hydrocarbon group” defined by Y may be substituted with a group arbitrarily selected from the RC group. More preferably a straight or branched chain alkyl group having optionally C 3 ⁇ 6, for example, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert- pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl and the like; More preferably from R C group is a cycloalkyl group optionally C 3 ⁇ 6 optionally substituted by a group selected arbitrarily, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; Further, more preferably from R C group is an aryl group group which may C 6
  • R 5 and R 6 are each independently selected from a hydrogen atom and an RC group.
  • straight or branched chain alkyl group - optionally C 1 be substituted with group 6 to a linear or branched R C optionally substituted with a group C 2 selected in ⁇ from group 6 alkenyl group
  • straight chain or branched chain alkynyl group of R C is optionally C 2 even though - substituted with chosen groups arbitrarily from group 6, optionally substituted by a group selected arbitrarily from R C group cycloalkyl group which may C 3 ⁇ 8
  • aryl group R C may be substituted with chosen groups arbitrarily from the group C 6 ⁇ 14, optionally substituted by a group selected arbitrarily from R C group Good heterocyclic groups are mentioned.
  • R 5 and R 6 may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, C 1 halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with one to five substituents which may be straight or branched alkoxyl To 6 alkyl groups), and the cyclic group may be further substituted with a group arbitrarily selected from the RC group.
  • Y is a group: —NR 5 R 6 , R 5 and R 6 are preferably R 5A and R 6A each independently from a hydrogen atom or an RC group.
  • straight or branched chain alkyl group having optionally C 1 ⁇ 6 be substituted with a chosen group optionally linear may be substituted by a group selected arbitrarily from R C group C 2 ⁇ 6 or branched alkenyl group, linear or branched alkynyl group of R C is optionally C 2 even though - optionally substituted with a group selected arbitrarily from group 6 or chosen groups arbitrarily from R C group, substituted cycloalkyl group which may C 3-8, R 5A, R 6A may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are attached, the cyclic group, the One carbon atom in the ring is an oxygen atom, sulfur atom or nitrogen atom (the nitrogen Atoms, straight or branched chain alkyl group having
  • Y is a group: —NR 5A R 6A
  • the group is represented by the following formula (B1) and the following formula (B2) (Wherein R 5A and R 6A represent the same meaning as described above, x represents an integer of 0 to 2, y represents an integer of 0 to 3, U represents a group: —CR 5B R 6B —, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with one to five substituents which may be C 1 ⁇ alkoxyl 6 may be substituted with a linear or branched alkyl group, and each of R 5B and R 6B may independently be substituted with a hydrogen atom or a group arbitrarily selected from the R C group.
  • R 5B and R 6B may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, 2 to the oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 optionally substituted by any of halogen atom, -OH, C 1 - 6 alkoxylated, halogenated C 1 - 6 alkoxy may be replaced by may also be substituted with a straight or branched chain alkyl group having optionally C 1 ⁇ 6), is replaced in the cyclic group may have a substituent)
  • the group of the formula (B2) may be further substituted with one or two groups
  • R 5A in the formula (B1), as R 6A, preferably, R 5A or at least one constituent carbon atoms is 3 or more groups of R 6A. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari or substituted with chosen groups arbitrarily from R C group, a cycloalkyl group of C 3 ⁇ 8 may.
  • R 5A, R 6A in Y each independently, a hydrogen atom, linear R C optionally substituted by a group selected C 1 ⁇ from group 6 or it substituted alkyl group, or R C group branched with a group selected arbitrarily cycloalkyl group which may C 3 ⁇ 8 (provided that at least one constituent carbon atoms of R 5A or R 6A a is) are more preferable number 3 or more groups;
  • R 5A in Y each independently, a hydrogen atom, a linear or branched alkyl group of C 1 ⁇ 6 (e.g., methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert- pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, etc.) or a cycloalkyl group of C 3 ⁇ 6 (For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) (provided that at least one of R 5A or R 6A is a group having 3 or more carbon atoms) is more preferable; R 5A and R 6A are a 4- to 6-membered cycl
  • [1-3-c] group is a group represented by the following formulas (b1) to (b46) (wherein —S (O) n— is bonded in formula (I)) The bond is represented as-).
  • Y— is preferably a group represented by the following formula.
  • [1-3-e] group is more preferably a group represented by the following formula.
  • R 5A and R 6A are a group having 3 or more carbon atoms, Specifically, formulas (b23), (b25) to (b29), (b31) to (b36), and (b39) to (b40) may be mentioned.
  • Z is a cycloalkyl group of 1-8 optionally C 3 substituted, optionally substituted aryl Represents a group or an optionally substituted heterocyclic group.
  • the Z moiety (the right side portion of the wavy line) a cycloalkyl group of R A may be 1-5 substituted with chosen groups arbitrarily from the group C 3 ⁇ 8, with a group selected arbitrarily from R A group 1 1-5 optionally substituted C 6 - 14 aryl group (including a ring which may be partially hydrogenated), N in addition to carbon atoms, O, at least one heteroatom selected from S (preferably 1 to 4) 3- to 14-membered heteroaryl (including rings that may be partially hydrogenated), or a saturated or unsaturated non-aromatic heterocyclic group (monocyclic or condensed ring)
  • the heteroaryl and non-aromatic heterocyclic group may be substituted with 1 to 5 groups arbitrarily selected from the R A group, and have the same meaning as described in the embodiment [1].
  • Each formula described below as an example of the Z moiety can be expressed as a formula in which the Z moiety in the formula (I) is replaced.
  • the group defined by [1-4-a] Z includes a monocyclic group and a condensed cyclic group, and has the following formula (C1) or (C2) (Wherein ring of Cycle3 and Cycle4 are each independently a cycloalkyl group of said C 3 ⁇ 8, comprising a ring which may be an aryl group (partially hydrogenated in C 6 ⁇ 14), carbon atoms
  • a ring selected from a saturated or unsaturated non-aromatic heterocyclic group, and Cycle 3 and Cycle 4 are condensed at an arbitrary position, and a bond to (CR 3 R 4 ) p- is bound by Cycle 3 R A is as defined above, k is an integer of 0 to 5, and R A may be bonded to any of the rings represented by Cycle 3 or Cycle 4).
  • the Z moiety of the formula (I) is preferably the following formula (D) (Wherein R A represents a group arbitrarily selected from the substituents described in the above embodiment [1], and g represents an integer of 0 to 5); Or the following formula (E) (Wherein j represents an integer of 0 or 1, f represents an integer of 0 to 2; R 12 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or an optionally protected carboxyl group.
  • R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from groups, heterocyclic groups nonaromatic optionally substituted with chosen groups arbitrarily from R C group, R group optionally substituted C 1 to 4 alkoxy groups selected from group C optionally, R C good C 2 - optionally substituted with chosen groups arbitrarily from group 5 alkanoyl group, or R C group, optionally substituted with chosen group optionally good C 1 ⁇ 4 alkyl group mono- - or di - represents a group selected arbitrarily from an amino group which may be substituted;
  • A represents —NR 13 —, —CR 14A R 14B —, a carbonyl group or an oxygen atom;
  • G represents a single bond, a methylene group, a carbonyl group or a sulfonyl group;
  • L 1 represents a single bond, —CR 15A R 15B —, a carbonyl group, an oxygen atom, —NR 16A — or
  • the ring containing A, G, L 1 and L 2 as a component may be further substituted with a group arbitrarily selected from the R A group; It is.
  • a group in which a non-aromatic heterocycle is condensed to a phenyl group substituted by R 12 that is, in the formula (E), A, G, L 1 and L 2 are included in the configuration. Examples include groups in which the ring is not aromatized.
  • heterocyclic group of the "R C heterocyclic group which may be substituted with chosen groups arbitrarily from the group” may be 1-5 optionally substituted with a group selected arbitrarily from R C group Heteroaryl in 3 to 14 membered ring containing at least one heteroatom (preferably 1 to 4) selected from N, O and S in addition to carbon atom, or saturated or unsaturated non-aromatic heterocycle Groups (monocyclic or condensed) are mentioned and described in embodiment [1].
  • g is preferably an integer of 1 to 3.
  • substituent of the preferred R A groups C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, hydroxy -C 1-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 alkylthio -C 1-6 alkyl, C 1-6 alkylsulfonyl -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 alkylcarbamo
  • C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkoxy, C 2 ⁇ 6 alkanoylamino, Hajime Tamaki (said ring to, N in addition to carbon atoms, O, at least one heteroatom (preferably selected from S is 1 to 4) -containing 3 to 14-membered ring, preferably 3 to 12-membered ring having a monocyclic ring or condensed ring) may be substituted with 1 to 3 groups.
  • the substitution position of RA is the case where the bonding position of W- (CR 3 R 4 ) p- is the 1st position in the following formula (D ′) It can be bonded to the 2-position, 3-position, 4-position, 5-position and 6-position, and the 2-position or 4-position is preferred.
  • g is preferably 1 to 3, and at least one of the substituents is preferably 2-position or 4-position.
  • j represents an integer of 0 or 1
  • f represents an integer of 0 to 2.
  • j is preferably 0.
  • f is preferably 0 or 1, more preferably f is 0. In the combination of j and f, it is preferable that j and f are both 0.
  • R 12 is a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected carboxyl group, from the group R C.
  • R C optionally chosen optionally substituted C 1 ⁇ 4 alkyl group with a group, selected heterocyclic group non-aromatic may be substituted by a group selected arbitrarily from R C group
  • the R C groups optionally is optionally substituted C 1 to 4 alkoxy groups with a group
  • R C optionally chosen optionally substituted C 2 even though 1-5 alkanoyl group with a group from groups or chosen groups arbitrarily from R C group
  • optionally substituted C 1 ⁇ mono 4 alkyl - or di - include groups selected arbitrarily from an amino group which may be substituted.
  • R C group may be substituted with a group selected arbitrarily from R C" group, the aspect [1] listed substituents listed, 1-3 the substituent May be substituted.
  • examples of the non-aromatic heterocyclic group in the “non-aromatic heterocyclic group optionally substituted with a group arbitrarily selected from the RC group” include those exemplified in the above embodiment [1]. It represents the same meaning, and examples thereof include azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, oxepanyl, thiomorpholinyl and the like.
  • mono C 1 - 4 alkyl group - or di - the optionally substituted amino group means a one or two hydrogen atoms are the "C 1 ⁇ 4 alkyl group" in the optionally substituted amino group of the amino group, specifically Is amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, ethyl Methylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group, butylethylamino group, butylpropyl An amino group
  • R 12 in the formula (E) is substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the group R C.
  • R C optionally optionally C 1 be ⁇ 4 alkyl group, optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ⁇ 4 alkoxyl group, or R C group from R C group mono C 1 ⁇ 4 alkyl group - or di - include groups selected arbitrarily from an amino group which may be substituted.
  • the term “optionally substituted with a group arbitrarily selected from the group RC” means that the group may be substituted with the groups listed as the substituents of the group RC in [1] above.
  • C 1 1-6 alkyl, halogen atom, amino, hydroxyl, C 1 - 6 alkoxy, mono / di C 1 - 6 alkylamino may be substituted with a substituent oxo etc.
  • "optionally substituted C 1 ⁇ Examples of the substituent of alkyl for example, a halogen atom, an amino, hydroxyl, C 1 ⁇ 6 alkoxy, mono / di C 1 ⁇ 6 alkyl amino, oxo, and substituted groups such as tetrahydropyran-4-yl.
  • R 12 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.
  • R 13, R 16A, R 16B are each independently, represent a group selected arbitrarily from a hydrogen atom or R B groups.
  • R 13, R 16A and R 16B are each independently a hydrogen atom or C 1 ⁇ 6 alkyl group (said C 1 ⁇ 6 alkyl group, a halogen atom ⁇ -OH ⁇ C 1 ⁇ 6 alkoxyl ⁇ C 1 ⁇ , 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 ⁇ 6 alkylcarbamoyl - amino-mono / di C 1 ⁇ 6 alkylamino-C 2 ⁇ 7 alkanoyl,
  • R 16A and R 16B are each independently a hydrogen atom, C 1 ⁇ 6 alkyl group, a heterocyclic group, C 1 ⁇ 6 alkylsulfonyl group, C 2 ⁇ 7 alkanoyl group, more preferably a C 1 ⁇ 6 alkoxycarbonyl group or a carbamoyl group, a carbon atom in the substituent group selected from the group further consisting of a halogen atom ⁇ -OH ⁇ C 1 ⁇ 6 alkoxyl and amino It may be substituted with 1 to 5 units.
  • R 16A and R 16B substituents R 16A and R 16B, 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-
  • R 16A and R 16B are each independently a hydrogen atom, straight or branched C 1 ⁇ 4 alkyl (the C 1 ⁇ 4 alkyl may be substituted with a halogen atom, -OH or amino), heteroaryl, C 1 ⁇ 4 alkylsulfonyl, C 2 ⁇ 5 alkanoyl (the C 2 ⁇ 5 alkanoyl, halogen atom may be substituted with -OH or amino), it is, especially preferred is a C 1 ⁇ 6 alkoxycarbonyl or carbamoyl.
  • t in L 1 and L 2 represents an integer of 0 to 2, and is preferably 0 or 2.
  • R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently a hydrogen atom, a halogen atom, or a group R C. optionally substituted by a group selected C 1 ⁇ 6 alkyl group, R C optionally chosen heterocyclic group which may be substituted with a group from a group, substituted with a group selected arbitrarily from R C group or di - - optionally substituted amino group or optionally protected C 1 to 6 alkoxy group, mono optionally substituted with chosen groups which may be C 1 - 6 alkyl radical from R C group R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D together with the carbon atom to which they are bonded are preferred.
  • An ⁇ 8-membered cyclic group may be formed, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom, —OH ⁇ C 1 It is replaced by may also) be substituted with 1-6 linear or branched alkyl group of alkoxylated, halogenated C 1 - 6 or with 1-5 optionally substituted C 1 - 6 alkoxyl
  • the cyclic group may be further substituted with a group arbitrarily selected from the RC group.
  • R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D may be the same or different in each combination, but more preferable R 14A And R 14B , R 15A and R 15B , or R 15C and R 15D are C 1 to 6 which may be substituted with a group arbitrarily selected from a hydrogen atom, a halogen atom, and —OH ⁇ —NH 2 ⁇ —COOH.
  • alkyl group -OH ⁇ -NH2 ⁇ -COOH substituted with chosen groups arbitrarily from which may be a heterocyclic group, optionally substituted by a group selected C 1 ⁇ from R C group 6 alkoxyl group optionally group substituted with a chosen by mono also good C 1 ⁇ 6 alkyl group from R C group - is an optionally substituted amino group or a protected - or di Include groups also selected from the group consisting of a good hydroxyl group, the substituents of R C group, wherein are mentioned in [1], for example, C 1 ⁇ 6 alkyl, halogen atom, amino, hydroxyl, C 1-6 alkoxyl, mono / di C 1-6 alkylamino, optionally substituted with substituents oxo, and the like.
  • the substituent of the "optionally substituted C 1 ⁇ 6 alkyl group" for example, a halogen atom, an amino, hydroxy, C 1 ⁇ 6 alkoxy, mono / di C 1 ⁇ 6 alkyl amino, oxo, tetrahydropyran - Examples include substituents such as 4-yl.
  • R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group 1 carbon atoms within the oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 alkoxy may be replaced by which may be substituted by straight-chain or branched-chain alkyl group which may C 1 ⁇ 6 have) been, the cyclic substituent groups which are further optionally selected from R C group may have, but if preferred, as the cycloalkyl ring C 3 ⁇ 8, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cyclohepta Ring, and a cyclooc
  • Examples of the 3- to 8-membered saturated or unsaturated non-aromatic heterocycle include, for example, aziridine ring, azetidine ring, oxirane ring, oxetane ring, thietane ring, pyrrolidine ring, tetrahydrofuran ring, thiolane ring, piperidine ring, tetrahydro ring
  • Examples include a pyran ring, a piperazine ring, and an oxepane ring.
  • R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D are specifically a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, ethyl Group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group, trifluoromethyl 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-methoxye
  • R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded.
  • Examples include cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, aziridine ring, azetidine ring, oxirane ring, oxetane ring, thietane ring, pyrrolidine ring, tetrahydrofuran ring, thiolane ring, piperidine ring, tetrahydropyran ring, piperazine ring, etc. It is done.
  • R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D are the same when they are the same as a hydrogen atom, a methyl group, or an ethyl group. When they are different, either one is a hydrogen atom and the other is a group (excluding a hydrogen atom) listed in the above [1-4-d-5b].
  • R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, Ring, cyclobutane ring, aziridine ring, azetidine ring, oxirane ring, oxetane ring, thietane ring and the like.
  • A represents —NR 13 —, —CR 14A R 14B —, a carbonyl group or an oxygen atom.
  • A is —NR 13 —, —CR 14A R 14B — or a carbonyl group, more preferably —NR 13 —.
  • G represents a single bond, a methylene group, a carbonyl group or a sulfonyl group.
  • G is a methylene group, a carbonyl group or a sulfonyl group, more preferably a methylene group or a carbonyl group.
  • L 1 represents a single bond, —CR 15A R 15B —, a carbonyl group, an oxygen atom, —NR 16A — or —S (O) t— (t Represents an integer of 0 to 2)
  • L 2 represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), a carbonyl group, an oxygen atom, —NR 16B — or —S ( O) t- (t is an integer of 0 to 2).
  • L 1 is —CR 15A R 15B —, an oxygen atom or —NR 16A —, and more preferably, L 1 is —CR 15A R 15B — or an oxygen atom.
  • L 2 is preferably a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom, or —NR 16B —. More preferably, L 2 is a single bond, — (CR 15A R 15B ) u— (u is an integer of 1 or 2) or —NR 16B —.
  • L 1 is —CR 15A R 15B — or an oxygen atom
  • L 2 is a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B —.
  • a combination is preferred, L 1 is —CR 15A R 15B — or an oxygen atom, and L 2 is a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2) or —NR 16B A combination of-is more preferable.
  • the ring containing A, G, L 1 and L 2 in the structure is composed of a single bond and / or a double bond and is aromatic. Although it does not need to be aromatized, it is preferable that it is not aromatized.
  • R A group C 1 ⁇ 6 alkyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkoxy -C 1 ⁇ 6 alkyl, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl, C 1 1-6 alkoxyl, halogenated C 1 - 6 alkoxyl, C 1 - 6 alkylthio, mono / di C 1 - 6 alkyl sulfamoyl, mono / di C 1 - 6 alkylamino, mono / di C 1 - 6 alkylcarbamoyl, mono / di C 6 ⁇ 14 aryl-carbamoyl, C 2 ⁇ 7 alkanoyl, C 2 ⁇
  • the substitution position of W— (CR 3 R 4 ) p— or R 12 is the position of the carbon atom of the phenyl moiety in the following formula (E ′). Can show.
  • W— (CR 3 R 4 ) p— it is preferably bonded to the first or third carbon atom, counting clockwise from a position close to the carbon atom to which L 1 is bonded. More preferably, W— (CR 3 R 4 ) p— is bonded to the third carbon atom.
  • a a is preferably —NR 13 —. It is. Particularly preferably, G a is a methylene group or a carbonyl group, and L 2a is a single bond, — (CR 15A R 15B ) u— (u is an integer of 1 or 2) or —NR 16B —.
  • each group of the formula (D) or the formula (E) is preferable, and specific examples thereof include Examples thereof include groups exemplified below in (c1) to (c68) and (c93) to (c240).
  • n represents an integer of 0 to 2, and n is preferably 2.
  • m and p each represents an integer of 0 to 4, preferably m is 0 or 1, and p is 0-3. More preferably, m is 0 and p is 0 or 1.
  • W is —CONR 7 —, —NR 8 CO—, —NR 9 CONR 10 —, or —NR 11 - (R 7, R 8, R 9, R 10, R 11 each independently represent a hydrogen atom or a C 1 ⁇ 6 alkyl group, R 7 is taken together with R 3 or R 4, each of the bond May form a 5- to 7-membered cyclo ring group together with the nitrogen atom and carbon atom, and the cyclo group may have a double bond in the ring.
  • one carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom said nitrogen atom, a halogen atom, a 1 to 5 substituents in any of -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkyl of good straight or branched chain optionally And may be substituted with a thio group).
  • W is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - is preferably, -CONR 7 - is more preferable.
  • R 7 may be taken together with R 3 or R 4 to form a 5- to 7-membered cyclo group together with each of the nitrogen and carbon atoms to which it is bonded.
  • the group may have a double bond in the ring, and one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom, —OH ⁇ C 1- 6 replaced by may also) be substituted with an alkyl group of C 1 ⁇ 6 of which may straight or branched chain optionally substituted 1-5 with either an alkoxylated-halogenated C 1 ⁇ 6 alkoxy “May be” means, for example, that when p is 3 in the nitrogen atom of —CONR 7 — defined in W, R 7 , and — (CR 3 R 4 ) p—, the following The case where the group of Formula (F) is formed is represented.
  • the number of rings containing A, G, L 1 and L 2 in the structure is 5 to 8. Preferably, it is 5-7, more preferably 5 or 6.
  • Group A any group of formulas (a1) to (a212) exemplified as Ring described in the embodiment [1-2-b], or the group represented by the formula (aa1) described in the embodiment [1-2-c] ) To any group exemplified as (aa67).
  • Group B the group of any of formulas (b1) to (b46) exemplified as Y according to the embodiment [1-3-c].
  • Group C A group of any one of formulas (c1) to (c240) exemplified as Z in the embodiment [1-4-e].
  • Group D defined as W, -CONR 7 -, - NR 8 CO -, - NR 9 CONR 10 - or -NR 11 - (R 7, R 8, R 9, R 10, R 11 are each independently represents a hydrogen atom or a C 1 ⁇ 6 alkyl group, R 7 is taken together with R 3 or R 4, each of the nitrogen atom linked, a cyclic ring group having 5 to 7-membered together with the carbon atoms formed may have, the cyclic ring groups, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy, halogen may be replaced by reduction C 1 at 1-6 or with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group alkoxyl may be substituted)) Any of the groups.
  • each group of the following groups A, B, C and D is appropriately selected.
  • the compound obtained in combination can be appropriately produced and constitutes a part of the compound represented by the formula (I) of the present invention.
  • Group A Formulas (aa21) to (aa35), (aa37) to (aa39), (aa41) to (aa50), (aa52), (a) exemplified as Rings described in the above embodiment [1-2-f] any group of aa53), (aa55), (aa58) to (aa60), (aa62) to (aa66);
  • Group B The group of any one of formulas (b13), (b14), (b17), and (b23) to (b40) exemplified as Y in the embodiment [1-3-d].
  • Group C The group of any one of (c1) to (c68) and (c93) to (c240) exemplified as Z in the embodiment [1-4-f].
  • Group D defined as W, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or a C 1 ⁇ 6 Represents an alkyl group, and R 7 may be combined with R 3 or R 4 to form a 5- to 7-membered cyclo ring group together with the nitrogen atom and carbon atom to which each is bonded, cycloalkyl ring group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, one halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 alkoxy or a group of the replaced may be) in may be substituted with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group) with or.
  • each group of the following groups A, B, C and D is appropriately selected.
  • the compound obtained in combination can be appropriately produced and constitutes a part of the compound represented by the formula (I) of the present invention.
  • Group A A group of any of formulas (aa21) to (aa27) and (aa29) exemplified as Ring according to the embodiment [1-2-g].
  • Group B any one of (b23), (b25) to (b29), (b31) to (b36), and (b39) to (b40) exemplified as Y in the embodiment [1-3-f] Base of.
  • Group C (c93) to (c117), (c121) to (c123), (c144) to (c147), (c151) to (C93) to (c117) exemplified as Z in the embodiment [1-4-f-3] Any one of (c153), (c156) to (c165), (c167) to (c177), (c189) to (c194), (c200), (c201), (c208) to (c240)
  • Group D defined as W, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or a C 1 ⁇ 6 Represents an alkyl group, and R 7 may be combined with R 3 or R 4 to form a 5- to 7-membered cyclo ring group together with the nitrogen atom and carbon atom to which each is bonded, cycloalkyl ring group, one carbon atom in the ring is an oxygen atom, a sulfur
  • Examples of preferable compounds include the following. N- (2-methoxyphenyl) -3-[(4-hydroxy-1-piperidinyl) sulfonyl] benzamide (Example 1); N- (2-methoxyphenyl) -2-chloro-5-[(2-oxo-1-piperidinyl) sulfonyl] benzamide (Example 2); N- (2-methoxyphenyl) -2-chloro-5-[(2-methyl-1-piperidinyl) sulfonyl] benzamide (Example 3); N- (2-methoxyphenyl) -2-chloro-5-[(2-hydroxymethyl-1-piperidinyl) sulfonyl] benzamide (Example 4); N- (2-methoxyphenyl) -2-chloro-5-[(2-aminocarbonyl-1-piperidinyl) sulfonyl] benzamide (Example 1); N
  • examples 82 to 92, examples 94 to 99, example 101, and example 103 are more preferable compounds.
  • Example 85 to Example 92 In the compound according to the embodiment [1-1-11-b], more preferably, Example 85 to Example 92, Example 111 to Example 122, Example 125 to Example 159, Example 165, Example 183, Example 184, Example 188, Example 189, Example 234 to Example 270, or a pharmaceutically acceptable salt thereof, or a solvate thereof Or an optically active substance thereof.
  • the 1-12th aspect of the present invention is the following formula (I) -A (Wherein, R 5A and R 6A are each independently a hydrogen atom, a linear or branched alkyl group of R C optionally substituted by a group selected C 1 ⁇ from group 6, R straight or branched chain alkenyl group of C which may C 2 even though - substituted with chosen groups arbitrarily from group 6, which may be substituted by a group selected arbitrarily from R C group C 2 - 6 It represents a straight or branched alkynyl group or cycloalkyl group R C good C 3 ⁇ optionally substituted with chosen groups arbitrarily from the group 8,, R 5A and R 6A are they bind A 3- to 8-membered cyclic group may be formed together with a nitrogen atom.
  • one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom,- OH ⁇ C 1 to 6 alkoxyl and halogenated C 1 to 6 is 1-5 substituents in any of the alkoxylation may be replaced by may also) be substituted with an alkyl group of C 1 ⁇ 6 of which may straight or branched chain, said cyclic group Further, it may be substituted with a group arbitrarily selected from the group R C ; W A represents —CONR 7 —, —NR 8 CO— or —NR 9 CONR 10 —, and R 7 , R 8 , R 9 , R 10 represents the same as the above embodiment [1-7]; Ring-A is represented by the following formula (G) or (H) (Wherein R 17 and R 18 each independently represents a hydrogen atom or a group arbitrarily selected from the group R C , R 17 and R 18 represent a carbon atom on
  • Z A is the following formula (D) or the following formula (E) (In the formula, R A , R 12 , A, G, L 1 , L 2 , g, j, f, and the definition of the broken line are defined in any one of the above embodiments [1], [1-1] to [1-10]. Represents the same meaning).
  • R 17 is hydrogen
  • R 17 is a pharmaceutically acceptable salt or solvate thereof as an active ingredient. It is a chain fatty acid elongation enzyme (Elovl6) inhibitor.
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ⁇ 6 alkoxy, C 2 ⁇ 6 alkenyloxy, C 2 ⁇ 6 alkynyl, halogen atom,
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • W A is, -CONR 7 - is preferably.
  • the 1-13th aspect of the present invention is the following formula (I) -B (Wherein R 5A , R 6A , W A , R 12 , A, G, L 1 , L 2 , j, f, the broken line and the substituents defined in those definitions have the same meaning as described above.
  • Ring-A is represented by the following formula (G) or (H) (Wherein, R 17 , R 18 , R C , E, the broken line and the substituent defined in the definition represent the same meaning as described above).
  • At least one of a compound represented by the above formula except when R 17 is hydrogen), or a pharmaceutically acceptable salt thereof or a solvate thereof, It is a long chain fatty acid elongation enzyme (Elovl6) inhibitor.
  • the substituent, or the group of the formula (D) and the formula (E) and preferred embodiments thereof are described in any one of the embodiments [1], [1-1] to [1-10] and [1-12].
  • the definition is the same as
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ⁇ 6 alkoxy, C 2 ⁇ 6 alkenyloxy, C 2 ⁇ 6 alkynyl, halogen atom,
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom.
  • a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the 1-14th aspect of the present invention is the following formula (II) (Wherein, R 5A and R 6A are each independently a hydrogen atom, a linear or branched alkyl group of R C optionally substituted by a group selected C 1 ⁇ from group 6, R straight or branched chain alkenyl group of C which may C 2 even though - substituted with chosen groups arbitrarily from group 6, which may be substituted by a group selected arbitrarily from R C group C 2 - 6 It represents a straight or branched alkynyl group or cycloalkyl group R C good C 3 ⁇ optionally substituted with chosen groups arbitrarily from the group 8,, R 5A and R 6A are they bind A 3- to 8-membered cyclic group may be formed together with a nitrogen atom.
  • R 5A and R 6A are each independently a hydrogen atom, a linear or branched alkyl group of R C optionally substituted by a group selected C 1 ⁇ from group 6, R straight or branche
  • one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom,- OH ⁇ C 1 to 6 alkoxyl and halogenated C 1 to 6 is 1-5 substituents in any of the alkoxylation may be replaced by may also) be substituted with an alkyl group of C 1 ⁇ 6 of which may straight or branched chain, said cyclic group Further, it may be substituted with a group arbitrarily selected from the R C group; R 17 and R 18 each independently represents a hydrogen atom or a group arbitrarily selected from the R C group, and R 17 and R 18 are
  • a 3- to 8-membered cyclic group may be formed together with the nitrogen atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is , substituted by a halogen
  • R 7 , R 8 , R 9 , R 10 , R A , R C , and g are the same as those in the above embodiments [1], [1-1] to [1-10]. It is the same as the definition described in any one.
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl, C 1 1-6 alkoxyl, C 2 - 6 alkeny
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom.
  • a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the 1-15th aspect of the present invention is the following formula (III) (Wherein R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, and the definition of the broken line are defined in the above aspects [1], [1-1] To the same meaning as any one of [1-10] and [1-12], except that R 17 is a hydrogen atom), or a pharmaceutically acceptable compound thereof A long-chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by containing at least one of a salt or a solvate thereof as an active ingredient.
  • Elovl6 long-chain fatty acid elongation enzyme
  • R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, the definition of a broken line, and preferred embodiments are the above-described embodiments [1 ], [1-1] to [1-10] and [1-12] have the same definition as described in any one of [1-12].
  • R 5A and R 6A preferably, at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl, C 1 1-6 alkoxyl, C 2 - 6 alkenyl
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • W A is, -CONR 7 - is preferably.
  • R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
  • the ring containing A in the structure does not include an aromatic group.
  • the substituents of the group A are the same as defined in the embodiment [1]. That is, the substituent of the R A group is a halogen atom, oxo, nitro, cyano, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono
  • substituent group R B are as defined according to the aspect [1]. That is, the substituent of the group R B is, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoy
  • the substituents of the RC group are the same as defined in the embodiment [1]. That is, the substituent of the RC group includes a halogen atom, oxo, nitro, cyano, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino
  • the 1-15-a aspect of the present invention is the following formula (III) -A (Wherein R 5A , R 6A , R 12 , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above-mentioned embodiments [1], [1-1] to [1-] 10] and [1-12] have the same meanings, and R 17A represents a group arbitrarily selected from the R C group (except that R 17A is —OH or an alkoxyl group). Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, which is an inhibitor of long-chain fatty acid elongation enzyme (Elovl6) .
  • Elovl6 long-chain fatty acid elongation enzyme
  • R 5A , R 6A , R 12 , R 18 , A a , G a , L 1a , L 2a , W A the definition of a broken line and preferred embodiments are the above-described embodiments [1], [1- 1] to [1-10] and [1-12] have the same definitions as described in any one of [1-12].
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17A is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino, and, R 18 is a hydrogen atom.
  • a group R 17A is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom. More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom. W A is, -CONR 7 - is preferably.
  • R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
  • the ring containing A a does not include an aromatic group.
  • the substitution position of W A or R 12 can be indicated by the position of the carbon atom of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. W A is more preferably bonded to the third carbon atoms.
  • the embodiment 1-15-b of the present invention is a more preferred embodiment than the embodiment [1-15-a], and has the following formula (III) -B (In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to At least a compound represented by [1-10], [1-12] and [1-15], or a pharmaceutically acceptable salt or solvate thereof. It is a long chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by containing one as an active ingredient. The ring containing A a does not include those that are aromatized.
  • Elovl6 long chain fatty acid elongation enzyme
  • R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , the definition and preferred embodiments of the broken line are the above-described embodiments [1], The definition is the same as described in any one of [1-1] to [1-10] and [1-12] and [1-15].
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 5A, R 6A are each independently a hydrogen atom, a cycloalkyl group of C 1 ⁇ linear or branched alkyl group or a C 3 ⁇ 8 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ⁇ 6 have been.
  • R 5A, R 6A is preferably represented by the following formula.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17A is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino
  • a R 18 is a hydrogen atom
  • R 17A is C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the condensed ring containing A a is represented by the following formula (E1a) (Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]).
  • a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
  • R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group.
  • C 1 ⁇ 4 alkyl group optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ⁇ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
  • a a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group
  • G a represents a methylene group, a carbonyl group or a sulfonyl group
  • L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom)
  • L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
  • R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH ⁇ —NH 2.
  • R C group optionally substituted C 1 to 6 alkoxy group with a group
  • mono group substituted by C 1 may also be ⁇ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted
  • Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group, R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with 1-5 optionally substituted straight or alkoxy
  • substitution positions of W A or R 12 is, similarly to the embodiment [1-4-d-11], can be indicated by the position of the carbon atoms of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. Bonding position of W A in formula (E1a), specifically, it is preferably the following formula (E1a-1) -b and (E1a-2) -b.
  • the formula (E1a) is arbitrarily selected from the formulas shown below.
  • W A is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or C 1 ⁇ 6 alkyl represents a group); -CONR 7 - is preferably.
  • the embodiment 1-15-c of the present invention is a more preferred embodiment than the embodiment [1-15-b], and has the following formula (III) -C (Wherein, R 5A, R 6A, R 12, R 17A, R 18, A a, G a, L 1a, L 2a, the dashed defined above aspect [1], [1-1] - [1- 10], [1-12], [1-15] and any one of [1-15-b]), or a pharmaceutically acceptable salt thereof or a compound thereof
  • a long-chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by containing at least one solvate as an active ingredient.
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 5A, R 6A are each independently hydrogen atom, a linear or branched alkyl group or cycloalkyl group C 3 ⁇ 6 of C 1 ⁇ 6 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ⁇ 6 have been.
  • R 5A, R 6A is preferably represented by the following formula.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17A is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino
  • a R 18 is a hydrogen atom
  • R 17A is C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the condensed ring containing A a is represented by the following formula (E1a) (Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]).
  • a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
  • R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group.
  • C 1 ⁇ 4 alkyl group optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ⁇ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
  • a a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group
  • G a represents a methylene group, a carbonyl group or a sulfonyl group
  • L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom)
  • L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
  • R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH ⁇ —NH 2.
  • R C group optionally substituted C 1 to 6 alkoxy group with a group
  • mono group substituted by C 1 may also be ⁇ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted
  • Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group, R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with 1-5 optionally substituted straight or alkoxy
  • the substitution position of —CONR 7 — or R 12 can be represented by the position of the carbon atom of the phenyl moiety, as in the above embodiment [1-4-d-11].
  • L 1a is bonded to the first or third carbon atom, counting clockwise from a position close to the carbon atom to which L 1a is bonded.
  • the bonding position of —CONR 7 — in the formula (E1a) is preferably the following formulas (E1a-1) -c and (E1a-2) -c.
  • the formula (E1a) is arbitrarily selected from the formulas shown below.
  • the 1-16th aspect of the present invention is the following formula (IV) (Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 1 ⁇ 5 amino optionally substituted straight or
  • a long-chain fatty acid elongation comprising as an active ingredient at least one of a compound represented by (in the same meaning) and a pharmaceutically acceptable salt or solvate thereof. It is an enzyme (Elovl6) inhibitor. More specifically, definitions and preferred embodiments of R 5A , R 6A , R C , R A3 , R A4 , W A , R A , R 12 , A, G, L 1 , L 2 , g, j, f Is the same as defined in any one of Embodiments [1], [1-1] to [1-10] and [1-12].
  • the 1-17th aspect of the present invention is the following formula (IV-a) (Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 1 ⁇ 5 amino optionally substituted straight
  • a long-chain fatty acid elongation comprising as an active ingredient at least one of a compound represented by (in the same meaning) and a pharmaceutically acceptable salt or solvate thereof. It is an enzyme (Elovl6) inhibitor. More specifically, definitions and preferred embodiments of R 5A , R 6A , R C , W A , R A , R A3 , R A4 , R 12 , A, G, L 1 , L 2 , g, j, f Is the same as defined in any one of Embodiments [1], [1-1] to [1-10] and [1-12].
  • the 1-18th aspect of the present invention is the following formula (V) (In the formula, n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R B , R C and the definitions in the substituents thereof are defined in the above-mentioned embodiments [1], [1 -1] to [1-10]), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient It is a long chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by these.
  • the 1-19th aspect of the present invention is the following formula (VI) (Wherein, n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the definitions in the substituents are defined in the above-mentioned embodiments [1], [1-1].
  • a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient It is a long chain fatty acid elongation enzyme (Elovl6) inhibitor.
  • n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the substituents thereof are the above-described embodiments [1] and This is the same as the definition described in any one of [1-1] to [1-10].
  • the compound used as the inhibitor has an Elovl6 inhibitory action, and various diseases involving Elovl6, such as NAFLD / NASH, diabetes, insulin resistance, high Expected to have promising therapeutic effects as a treatment for insulinemia, impaired glucose tolerance (IGT) / fasting glycemia (IFG), fasting hyperglycemia, obesity / obesity, or various diseases caused by or related to these .
  • the Elovl6 inhibitor of the present invention is NAFLD / NASH, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT) / fasting blood glucose abnormality (IFG), fasting hyperglycemia, obesity / obesity, or It is useful for various diseases caused by or related to these.
  • NAFLD as defined here is a liver disorder characterized by mainly large-scale hepatic fat deposition, similar to alcoholic liver disorder, although there is no clear drinking history. It is a group of diseases including hepatic disorder such as hepatitis, fibrosis, cirrhosis, and liver cancer. Viral liver diseases, autoimmune disease liver diseases, metabolic liver diseases such as hemacrotosis and Wilson disease are excluded. NAFLD is also called non-alcoholic fatty liver and is a disease concept including simple fatty liver with good prognosis and progressive NASH with poor prognosis. “NASH” is considered to be a severe form of NAFLD, and is a progressive disease of NAFLD accompanied by inflammation and fibrosis of hepatocytes.
  • NASH alcoholic liver disorder
  • viral hepatitis and drug-induced liver disorder are considered to be the pathological condition of NASH.
  • the treatment of NAFLD / NASH means that a compound having an Elovl6 inhibitory action of the present invention or a pharmaceutical composition containing the compound is administered to a NAFLD / NASH patient.
  • their treatment is the first priority treatment.
  • improvement of NASH's important pathological conditions such as oxidative stress and insulin resistance can be mentioned as a result of treatment.
  • diabetes includes both type 1 diabetes (IDDM, known as insulin-dependent diabetes) and type 2 diabetes (NIDDM, known as non-insulin-dependent diabetes).
  • IDDM type 1 diabetes
  • NIDDM type 2 diabetes
  • Diabetes is characterized by a fasting blood glucose level of 126 mg / dl or higher, or an occasional blood glucose level or a 75 g oral glucose tolerance test (OGTT) 2-hour value of 200 mg / dl or higher.
  • Glucose intolerance which is a boundary type, is a fasting blood glucose abnormality (IFG) in which a fasting blood glucose level is 110 mg / dl or more and less than 126 mg / dl, or a glucose tolerance having a 75 gOGTT 2 hour value of 140 mg / dl or more and less than 200 mg / dl. Indicates an abnormality (IGT).
  • Insulin resistance refers to a pathological condition in which insulin is unable to lower blood sugar in the living body, and is clinically evaluated by quantitative glucose clamp method or HOMA-IR. It is known that insulin resistance causes hyperinsulinemia and is a risk of hypertension and coronary artery disease.
  • Treatment of diabetes refers to administration of a compound having an Elovl6 inhibitory activity of the present invention or a pharmaceutical composition containing the compound to a diabetic patient.
  • the outcome of treatment is to increase insulin sensitivity and reduce elevated blood insulin and glucose levels.
  • “Obesity” is defined by the Japanese Society of Obesity as “a medical condition that is associated with or is predicted to be associated with obesity and is a medical condition that requires medical weight loss”. . “Obesity” as defined herein is evaluated by BMI (body mass index, kg / m 2 ). Generally, a BMI of 25 or more is diagnosed as obesity. As a result of treatment, reduction of BMI can be mentioned.
  • a second aspect of the present invention is the following formula (I) -A (Wherein R 5A , R 6A , W A , Z A and the substituents defined in these definitions have the same meaning as described above, Ring-A represents the following formula (G) or (H) (Wherein R 17 , R 18 , R C , E, the broken line and the substituent defined in the definition represent the same meaning as described above).
  • R 17 is a hydrogen atom
  • W A is —NR 8 CO—
  • R 17 and R 18 form a 5- to 8-membered cyclic group with the carbon atom on the benzene ring to which they are bonded
  • Z A is the formula (D) (WO 2004/058709);
  • Ring-A is formula (G)
  • W A is -NR 8 CO-
  • a Z A is the formula (D)
  • R A is a halogen atom, a hydroxyl group, a nitro group, C 1 ⁇ 4 alkyl group, trifluoromethyl group, C 1 ⁇ 4 alkoxyl group, group: -Y-R '(wherein, Y is -O- or -NR''is a hydrogen atom or C 1 ⁇ 4 alkyl), R''(R' is an aryl group, a carboxy group and lower alkoxycarbonyl optionally substituted C 1 to 4 alkyl group with a substituent selected from
  • R 5A , R 6A , W A , Z A and substituents defined in the definitions thereof, or groups of formula (D) and formula (E), R 17 , R 18 , R C , E, a broken line and preferred embodiments thereof are the same as defined in any one of Embodiments [1], [1-1] to [1-10] and [1-12].
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ⁇ 6 alkoxy, C 2 ⁇ 6 alkenyloxy, C 2 ⁇ 6 alkynyl, halogen atom,
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • W A is, -CONR 7 - is preferably.
  • Preferred embodiments include the following embodiments.
  • the 2-1 aspect of the present invention is the following formula (I) -B (Wherein R 5A , R 6A , W A , R 12 , A, G, L 1 , L 2 , j, f, the broken line and the substituents defined in those definitions have the same meaning as described above.
  • Ring-A is represented by the following formula (G) or (H) (Wherein R 17 , R 18 , R C , E, the broken line and the substituent defined in the definition represent the same meaning as described above).
  • a compound represented by the above formula except when R 17 is hydrogen
  • a pharmaceutically acceptable salt thereof or a solvate thereof It is a pharmaceutical composition.
  • the substituent, or the group of the formula (D) and the formula (E) and preferred embodiments thereof are described in any one of the embodiments [1], [1-1] to [1-10] and [1-12].
  • the definition is the same as
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ⁇ 6 alkoxy, C 2 ⁇ 6 alkenyloxy, C 2 ⁇ 6 alkynyl, halogen atom,
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • W A is, -CONR 7 - is preferably.
  • the 2-2 aspect of the present invention is a compound represented by the above formula (II) (provided that R 17 is a hydrogen atom; W A is —NR 8 CO—, R 17 and R 18 form a 5- to 8-membered cyclic group with the carbon atom on the benzene ring to which they are bonded, and Z A is the formula (D) (WO 2004/058709); W A is -NR 8 CO-, a Z A is the formula (D), R A is a halogen atom, a hydroxyl group, a nitro group, C 1 ⁇ 4 alkyl group, trifluoromethyl group, C 1 ⁇ 4 alkoxyl group, group: -Y-R '(wherein, Y is -O- or -NR''is a hydrogen atom or C 1 ⁇ 4 alkyl), R''(R' is an aryl group, a carboxy group and lower alkoxycarbonyl optionally substituted C 1 to 4 alkyl group
  • W A is, -CONR 7 - a and a R 17 is a hydroxyl group, and when Z A is the formula (D) (WO2006 / 120178 discloses, WO2001 / 047 509 and JP WO2003 / 103,648) ; W A is —NR 8 CO—, Z A is the formula (D), and R A is a carboxyl group at the 2-position (WO 2005/115374); When W A is —NR 9 CONR 10 —, R 17 is a hydroxyl group, is the formula (D), and R A is a 1H-pyrazol-5-yl group (WO2007 / 002559) ; Or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 1-6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl, C 1-6 alkoxyl, C 2 ⁇ 6 alkeny
  • R 17 is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 alkyl, C 1 ⁇ 6 alkoxy, C 2 ⁇ 6 alkenyloxy, a C 2 ⁇ 6 alkynyloxy, halogenated C 1 ⁇ 6 alkoxy or a group selected from mono- / di-C 1 ⁇ 6 alkyl amino, and, R 18 is a hydrogen atom.
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom.
  • a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the 2-3 aspect of the present invention is the following formula (III) (Wherein R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, and the definition of the broken line are defined in the above aspects [1], [1-1] ] To [1-10] and represents the same meaning as any of [1-12]) (except when R 17 is a hydrogen atom), or pharmaceutically acceptable A pharmaceutical composition comprising at least one of a salt or a solvate thereof as an active ingredient.
  • R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, the definition of a broken line, and preferred embodiments are the above-described embodiments [1 ], [1-1] to [1-10] and [1-12] have the same definition as described in any one of [1-12].
  • R 5A and R 6A preferably, at least one of R 5A or R 6A is a group having 3 or more constituent carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl, C 1 1-6 alkoxyl, C 2 - 6 alkenyl
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • W A is, -CONR 7 - is preferably.
  • R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
  • the ring containing A in the structure does not include an aromatic group.
  • the substituents of the group A are the same as defined in the embodiment [1]. That is, the substituent of the R A group is a halogen atom, oxo, nitro, cyano, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono
  • substituent group R B are as defined according to the aspect [1]. That is, the substituent of the group R B is, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoy
  • the substituents of the RC group are the same as defined in the embodiment [1]. That is, the substituent of the RC group includes a halogen atom, oxo, nitro, cyano, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino
  • the 2-3-a aspect of the present invention is the following formula (III) -A (In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to At least a compound represented by [1-10], [1-12] and [1-15], or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition comprising one as an active ingredient.
  • R 5A , R 6A , R 12 , R 18 , A a , G a , L 1a , L 2a , W A , broken line are the above-mentioned embodiments [1], [1- 1] to [1-10], [1-12], and the same definition as described in any of [1-15].
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17 is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino
  • a R 18 is a hydrogen atom
  • R 17A is C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • W A is, -CONR 7 - is preferably.
  • R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
  • the ring containing A a does not include an aromatic group.
  • the substitution position of W A or R 12 can be indicated by the position of the carbon atom of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. W A is more preferably bonded to the third carbon atoms.
  • the embodiment 2-3b of the present invention is a more preferred embodiment than the embodiment [2-3-a], and is represented by the following formula (III) -B (In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to At least a compound represented by [1-10], [1-12] and [1-15], or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition comprising one as an active ingredient.
  • the ring containing A a does not include those that are aromatized.
  • R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , the definition and preferred embodiments of the broken line are the above-described embodiments [1], The definition is the same as described in any one of [1-1] to [1-10] and [1-12] and [1-15].
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 5A, R 6A are each independently a hydrogen atom, a cycloalkyl group of C 1 ⁇ linear or branched alkyl group or a C 3 ⁇ 8 (where, R 5A or R At least one of 6A is a group having 3 or more carbon atoms, or R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17A is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino
  • a R 18 is a hydrogen atom
  • R 17A is C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the condensed ring containing A a is represented by the following formula (E1a) (Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]).
  • a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
  • R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group.
  • C 1 ⁇ 4 alkyl group optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ⁇ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
  • a a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group
  • G a represents a methylene group, a carbonyl group or a sulfonyl group
  • L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom)
  • L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
  • R 14A , R 14B , R 15A , R 15B , R 15C , R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH ⁇ —NH 2.
  • R C group optionally substituted C 1 to 6 alkoxy group with a group
  • mono group substituted by C 1 may also be ⁇ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted
  • Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group, R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with 1-5 optionally substituted straight or alkoxy
  • substitution positions of W A or R 12 is, similarly to the embodiment [1-4-d-11], can be indicated by the position of the carbon atoms of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. Bonding position of W A in formula (E1a), specifically, it is preferably the following formula (E1a-1) -b and (E1a-2) -b.
  • the formula (E1a) is arbitrarily selected from the formulas shown below.
  • W A is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or C 1 ⁇ 6 alkyl represents a group); -CONR 7 - is preferably.
  • the embodiment 2-3-3 of the present invention is a more preferred embodiment than the embodiment [2-3-b], and is represented by the following formula (III) -C (In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , and the definition of the broken line are defined in the above aspects [1], [1-1] to [1-] 10], [1-12], [1-15] and any one of [1-15-b]), or a pharmaceutically acceptable salt thereof or a compound thereof A pharmaceutical composition comprising at least one solvate as an active ingredient.
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 5A, R 6A are each independently hydrogen atom, a linear or branched alkyl group or cycloalkyl group C 3 ⁇ 6 of C 1 ⁇ 6 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ⁇ 6 have been.
  • R 5A, R 6A is preferably represented by the following formula.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17A is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino
  • a R 18 is a hydrogen atom
  • R 17A is C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the condensed ring containing A a is represented by the following formula (E1a) (Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]).
  • a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
  • R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group.
  • C 1 ⁇ 4 alkyl group optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ⁇ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
  • a a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group
  • G a represents a methylene group, a carbonyl group or a sulfonyl group
  • L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom)
  • L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
  • R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH ⁇ —NH 2.
  • R C group optionally substituted C 1 to 6 alkoxy group with a group
  • mono group substituted by C 1 may also be ⁇ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted
  • Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group, R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with 1-5 optionally substituted straight or alkoxy
  • the substitution position of —CONR 7 — or R 12 can be represented by the position of the carbon atom of the phenyl moiety, as in the above embodiment [1-4-d-11].
  • L 1a is bonded to the first or third carbon atom, counting clockwise from a position close to the carbon atom to which L 1a is bonded.
  • the bonding position of —CONR 7 — in the formula (E1a) is preferably the following formulas (E1a-1) -c and (E1a-2) -c. More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.
  • the 2-4th aspect of the present invention is the following formula (IV) (Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 1 ⁇ 5 amino optionally substituted straight or branche
  • W A is —CONR 7 —, Z A is the above formula (D), and R A is aryl or heteroaryl (representing the same meaning)) WO 2005/092881)
  • WO 2005/092881 a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • R 5A , R 6A , R C , W A , R A , R 12 , A, G, L 1 , L 2 , g, j, f are the above-mentioned embodiments [1 ], [1-1] to [1-10] and [1-12] are the same as defined above.
  • a second to fifth aspect of the present invention is the following formula (IV-a) (Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 1 ⁇ 5 amino optionally substituted straight
  • W A is —CONR 7 —, Z A is the above formula (D), and R A is aryl or heteroaryl (representing the same meaning)) WO2005 / 092881)
  • WO2005 / 092881 a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • a second to sixth aspect of the present invention is the following formula (V) (In the formula, n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R B , R C and the definitions in the substituents thereof are defined in the above-mentioned embodiments [1], [1 -1] to [1-10] have the same meaning) Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • a second to seventh aspect of the present invention is the following formula (VI) Wherein n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the definitions in the substituents are defined in the above-mentioned embodiments [1], [1-1] Or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, wherein the compound represents the same meaning as any one of [1-10].
  • a pharmaceutical composition is the following formula (VI) Wherein n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the definitions in the substituents are defined in the above-mentioned embodiments [1], [1-1] Or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, wherein the compound represents the same meaning as any one of [1-10].
  • n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the substituents thereof are the above-described embodiments [1] and This is the same as the definition described in any one of [1-1] to [1-10].
  • a third aspect of the present invention is the following formula (I) -B (Wherein R 5A , R 6A , W A , R 12 , A, G, L 1 , L 2 , j, f, the broken line and the substituents defined in those definitions have the same meaning as described above.
  • Ring-A is represented by the following formula (G) or (H) (Wherein R 17 , R 18 , R C , E, the broken line and the substituent defined in the definition represent the same meaning as described above).
  • R 17 , R 18 , R C , E the broken line and the substituent defined in the definition represent the same meaning as described above.
  • R 17 is a group having 3 or more carbon atoms
  • R 17 is a hydrogen atom, —OH or an alkoxyl group. Exclude certain compounds and each compound listed in “Compound List A”.
  • Ring-A is the formula (H), it is a compound represented by “except for each compound described in“ Compound List B-1 ”), a
  • the substituent, or the group of the formula (D) and the formula (E) and preferred embodiments thereof are described in any one of the embodiments [1], [1-1] to [1-10] and [1-12].
  • the definition is the same as
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ⁇ 6 alkoxy, C 2 ⁇ 6 alkenyloxy, C 2 ⁇ 6 alkynyl, halogen atom,
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom.
  • a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the 3-1 aspect of the present invention is the following formula (III) (Wherein R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, and the definition of the broken line are defined in the above aspects [1], [1-1] ] To [1-10] and [1-12] represent the same meanings), provided that at least one of R 5A and R 6A is a group having 3 or more carbon atoms. And a compound in which R 17 is a hydrogen atom, —OH or an alkoxyl group, and each compound described in “Compound List A”), or a salt thereof or a solvate thereof.
  • R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, the definition of a broken line, and preferred embodiments are the above-described embodiments [1 ], [1-1] to [1-10] and [1-12] have the same definition as described in any one of [1-12].
  • R 5A and R 6A preferably, at least one of R 5A or R 6A is a group having 3 or more constituent carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl, C 1 1-6 alkoxyl, C 2 - 6 alkenyl
  • a group R 17 is selected from C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • W A is, -CONR 7 - is preferably.
  • R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
  • the ring containing A in the structure does not include an aromatic group.
  • the substituents of the group A are the same as defined in the embodiment [1]. That is, the substituent of the R A group is a halogen atom, oxo, nitro, cyano, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono
  • substituent group R B are as defined according to the aspect [1]. That is, the substituent of the group R B is, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoy
  • the substituents of the RC group are the same as defined in the embodiment [1]. That is, the substituent of the RC group includes a halogen atom, oxo, nitro, cyano, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl (said C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, -OH, C 1 ⁇ 6 alkoxy C 1 ⁇ 6 alkylthio-C 1 ⁇ 6 alkylsulfinyl, C 1 ⁇ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ⁇ 6 alkylsulfamoyl, carboxyl, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino
  • the embodiment 3-1-a of the present invention is the following formula (III) -A (Wherein R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to A compound having the same meaning as any one of [1-10], [1-12] and [1-15] (provided that at least one of R 5A and R 6A has 3 carbon atoms) Or a salt thereof or a solvate thereof, excluding each compound described in “Compound List A-1”.
  • R 5A , R 6A , R 12 , R 18 , A a , G a , L 1a , L 2a , W A , broken line are the above-mentioned embodiments [1], [1- 1] to [1-10], [1-12], and the same definition as described in any of [1-15].
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17A is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino
  • a R 18 is a hydrogen atom
  • R 17A is C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • W A is, -CONR 7 - is preferably.
  • R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
  • the ring containing A a does not include an aromatic group.
  • the substitution position of W A or R 12 can be indicated by the position of the carbon atom of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. W A is more preferably bonded to the third carbon atoms.
  • the embodiment 3-1b of the present invention is a more preferred embodiment than the embodiment [3-1-a], and is represented by the following formula (III) -B (Wherein R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to A compound having the same meaning as any one of [1-10], [1-12] and [1-15] (provided that at least one of R 5A and R 6A has 3 carbon atoms) Or a salt thereof or a solvate thereof, excluding each compound described in “Compound List A-1”.
  • the ring containing A a does not include those that are aromatized.
  • R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , the definition and preferred embodiments of the broken line are the above-described embodiments [1], The definition is the same as described in any one of [1-1] to [1-10] and [1-12] and [1-15].
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 5A, R 6A are each independently a hydrogen atom, a cycloalkyl group of C 1 ⁇ linear or branched alkyl group or a C 3 ⁇ 8 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ⁇ 6 have been.
  • R 5A, R 6A is preferably represented by the following formula.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17A is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino
  • a R 18 is a hydrogen atom
  • R 17A is C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the condensed ring containing A a is represented by the following formula (E1a) (Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]).
  • a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
  • R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group.
  • C 1 ⁇ 4 alkyl group optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ⁇ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
  • a a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group
  • G a represents a methylene group, a carbonyl group or a sulfonyl group
  • L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom)
  • L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
  • R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH ⁇ —NH 2.
  • R C group optionally substituted C 1 to 6 alkoxy group with a group
  • mono group substituted by C 1 may also be ⁇ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted
  • Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group, R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with 1-5 optionally substituted straight or alkoxy
  • substitution positions of W A or R 12 is, similarly to the embodiment [1-4-d-11], can be indicated by the position of the carbon atoms of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. Bonding position of W A in formula (E1a), specifically, it is preferably the following formula (E1a-1) -b and (E1a-2) -b. More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.
  • W A is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or C 1 ⁇ 6 alkyl represents a group); -CONR 7 - is preferably.
  • the embodiment 3-1c of the present invention is a more preferred embodiment than the embodiment [3-1-b], and is represented by the following formula (III) -C (In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , and the definition of the broken line are defined in the above aspects [1], [1-1] to [1-] 10], [1-12], [1-15] and [3-1-b] having the same meaning as described above (provided that at least one of R 5A and R 6A is a constituent) A group having 3 or more carbon atoms, excluding the compounds of compound numbers A1 to A6, A20, A127, and A128 described in “Compound List A-1”), or a salt thereof or a solvate thereof.
  • formula (III) -C In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a
  • R 5A and R 6A preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ⁇ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ⁇ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ⁇ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ⁇ 6.
  • R 5A, R 6A are each independently hydrogen atom, a linear or branched alkyl group or cycloalkyl group C 3 ⁇ 6 of C 1 ⁇ 6 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ⁇ 6 have been.
  • R 5A, R 6A is preferably represented by the following formula.
  • R 17A is preferably, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, 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, C 3 ⁇ 8 cycloalkyl -C 1 ⁇ 6 alkyl or mono / di C 1 ⁇ 6 alkyl amino, is a group selected from the group consisting of
  • R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl.
  • R 18 is preferably a hydrogen atom.
  • R 17A is C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, C 2 ⁇ 6 alkynyl, halogen atom, halogenated C 1 ⁇ 6 alkyl, hydroxy -C 1 ⁇ 6 a group selected from alkyl or mono / di C 1 ⁇ 6 alkyl amino
  • a R 18 is a hydrogen atom
  • R 17A is C 1 ⁇ 6 alkyl, halogen atom or a halogenated C 1 ⁇ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ⁇ 6 alkyl, and R 18 is a hydrogen atom.
  • the condensed ring containing A a is represented by the following formula (E1a) (Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]).
  • a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
  • R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group.
  • C 1 ⁇ 4 alkyl group optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ⁇ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
  • a a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group
  • G a represents a methylene group, a carbonyl group or a sulfonyl group
  • L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom)
  • L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
  • R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH ⁇ —NH 2.
  • R C group optionally substituted C 1 to 6 alkoxy group with a group
  • mono group substituted by C 1 may also be ⁇ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted
  • Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group, R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 or with 1-5 optionally substituted straight or alkoxy
  • the substitution position of —CONR 7 — or R 12 can be represented by the position of the carbon atom of the phenyl moiety, as in the above embodiment [1-4-d-11].
  • L 1a is bonded to the first or third carbon atom, counting clockwise from a position close to the carbon atom to which L 1a is bonded.
  • the bonding position of —CONR 7 — in the formula (E1a) is preferably the following formulas (E1a-1) -c and (E1a-2) -c. More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.
  • the third aspect of the present invention is the above-described formula (IV) (Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 1 ⁇ 5 amino optionally substituted straight or
  • W A is -CONR 7 - a and a Z A is the formula (D), and when R A is aryl or heteroaryl (WO2005 / 092881 discloses), and according to "Compound List B" Or a salt thereof, or a solvate thereof.
  • R 5A , R 6A , R C , W A , R A , R 12 , A, G, L 1 , L 2 , g, j, f are the above-mentioned embodiments [1 ], [1-1] to [1-10] and [1-12] are the same as defined above.
  • the 3-3 aspect of the present invention is the following formula (IV-a) (Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ⁇ 6 alkoxy-halogenated C 1 ⁇ 6 1 ⁇ 5 amino optionally substituted straight or
  • W A is -CONR 7 - a and a Z A is the formula (D), and when R A is aryl or heteroaryl (WO2005 / 092881 discloses), and according to "Compound List B" Or a salt thereof or a solvate thereof.
  • R 5A , R 6A , R C , W A , R A , R 12 , A, G, L 1 , L 2 , g, j, f are the above-mentioned embodiments [1 ], [1-1] to [1-10] and [1-12] are the same as defined above.
  • the 3-4th aspect of the present invention is the following formula (V) (In the formula, n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R B , R C and the definitions in the substituents thereof are defined in the above-mentioned embodiments [1], [1 -1] to [1-10] have the same meaning) Or a salt thereof or a solvate thereof.
  • the 3-5th aspect of the present invention is the following formula (VI) Wherein n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the definitions in the substituents are defined in the above-mentioned embodiments [1], [1-1] To the same meaning as any one of [1-10], or a salt thereof or a solvate thereof.
  • n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the substituents thereof are the above-described embodiments [1] and This is the same as the definition described in any one of [1-1] to [1-10].
  • a fourth aspect of the present invention is the compound represented by the formula (I) -B according to the aspect [2-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the above as an active ingredient.
  • the definition and preferred embodiment of the formula (I) -B are the same as the definition and preferred embodiment of the formula (I) -B described in the embodiment [2-1].
  • Preferred embodiments include the following embodiments.
  • the 4-1th aspect of the present invention is a compound represented by the formula (III) described in the above aspect [2-3], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiments of the formula (III) are the same as the definition and preferred embodiments of the formula (III) described in the embodiment [2-3].
  • the 4-1a embodiment of the present invention is a compound represented by the formula (III) -A according to the embodiment [2-3-a], or a pharmaceutically acceptable It is a prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, which contains at least one of its salts or solvates thereof as an active ingredient.
  • the definition and preferred embodiment of the formula (III) -A are the same as the definition and preferred embodiment of the formula (III) -A described in the embodiment [2-3-a]. .
  • the embodiment 4-1b of the present invention is a more preferred embodiment than the embodiment [4-1-a], and is represented by the formula (III ) -B, NAFLD / NASH, diabetes, insulin resistance, characterized by containing at least one of the compound represented by -B, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient Or it is a preventive and / or therapeutic agent for obesity / obesity.
  • the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
  • the embodiment 4-1c of the present invention is a more preferred embodiment than the embodiment [4-1-b], and is represented by the formula (III )-Containing a compound represented by -C, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, NAFLD / NASH, diabetes, insulin resistance Or it is a preventive and / or therapeutic agent for obesity / obesity.
  • the definition and preferred embodiments of the formula (III) -C are the same as the definitions and preferred embodiments of the formula (III) -C described in the embodiment [2-3-c]. .
  • the 4-2th aspect of the present invention is the compound represented by the formula (IV) according to the above aspect [2-4], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiment of the formula (IV) are the same as the definition and preferred embodiment of the formula (IV) described in the above embodiment [2-4].
  • a fourth embodiment of the present invention is a compound represented by the formula (IV-a) according to the above embodiment [2-5], or a pharmaceutically acceptable salt thereof or a salt thereof. It is a prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the above solvates as an active ingredient.
  • the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the embodiment [2-5].
  • the 4-4th aspect of the present invention is the compound represented by the formula (V) according to the above aspect [2-6], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the embodiment [2-6].
  • the 4-5th aspect of the present invention is the compound represented by the formula (VI) according to the above aspect [2-7], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
  • a fifth aspect of the present invention is the compound represented by the formula (I) -B according to the aspect [2-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the definition and preferred embodiments of the formula (I) -B are the same as the definitions and preferred embodiments of the formula (I) -B described in the embodiment [2-1].
  • Preferred embodiments include the following embodiments.
  • the 5-1 aspect of the present invention is the compound represented by the formula (III) according to the aspect [2-3], or a pharmaceutically acceptable salt thereof, or a solvent thereof.
  • the definition and preferred embodiment of the formula (III) are the same as the definition and preferred embodiment of the formula (III) described in the embodiment [2-3].
  • the 5-1a embodiment of the present invention is a compound represented by the formula (III) -A according to the embodiment [2-3-a], or a pharmaceutically acceptable A method for the prevention and / or treatment of NAFLD • NASH, diabetes, insulin resistance or obesity / obesity, comprising administering to a patient an effective amount of at least one of a salt thereof or a solvate thereof.
  • the definition and preferred embodiment of the formula (III) -A are the same as the definition and preferred embodiment of the formula (III) -A described in the embodiment [2-3-a]. .
  • the embodiment 5-1b of the present invention is a more preferred embodiment than the embodiment [5-1-a], and is represented by the formula (III ) -B or at least one effective amount of a pharmaceutically acceptable salt or solvate thereof, comprising administering to a patient NAFLD • NASH, diabetes, insulin resistance or This is a method for preventing and / or treating obesity and obesity.
  • the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
  • the embodiment 5-1c of the present invention is a more preferred embodiment than the embodiment [5-1-b], and is represented by the formula (III) described in the embodiment [2-3-c].
  • )-A compound represented by -C, or a pharmaceutically acceptable salt or solvate thereof comprising administering to a patient an effective amount of NAFLD / NASH, diabetes, insulin resistance or This is a method for preventing and / or treating obesity and obesity.
  • the definition and preferred embodiment of the formula (III) -C are the same as the definition and preferred embodiment of the formula (III) -C described in the embodiment [2-3-c]. .
  • the 5-2th aspect of the present invention is the compound represented by the formula (IV) according to the above aspect [2-4], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiment of the formula (IV) are the same as the definition and preferred embodiment of the formula (IV) described in the embodiment [2-4].
  • a fifth to third aspect of the present invention is a compound represented by the formula (IV-a) according to the above aspect [2-5], a pharmaceutically acceptable salt thereof, or a salt thereof
  • the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the embodiment [2-5].
  • the 5-4th aspect of the present invention is the compound represented by the formula (V) according to the above aspect [2-6], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the above embodiment [2-6].
  • a fifth to fifth aspect of the present invention is a compound represented by the formula (VI) according to the above aspect [2-7], or a pharmaceutically acceptable salt thereof or a solvent thereof
  • a method for the prophylaxis and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity which comprises administering to a patient at least one effective amount of a Japanese product.
  • the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
  • a sixth aspect of the present invention relates to the above aspect [2-1] for producing a medicament for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity.
  • the definition and preferred embodiment of the formula (I) -B are the same as the definition and preferred embodiment of the formula (I) -B described in the embodiment [2-1].
  • Preferred embodiments include the following embodiments.
  • the 6-1 aspect of the present invention is the above aspect [2] -3], or a pharmaceutically acceptable salt or solvate thereof.
  • the definition and preferred embodiment of the formula (III) are the same as the definition and preferred embodiment of the formula (III) described in the embodiment [2-3].
  • the embodiment of the 6-1-a of the present invention is for producing a medicament for the prevention and / or treatment of NAFLD • NASH, diabetes, insulin resistance or obesity / obesity, Use of the compound represented by the formula (III) -A described in the above embodiment [2-3-a], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the definition and preferred embodiment of the formula (III) -A are the same as the definition and preferred embodiment of the formula (III) -A described in the embodiment [2-3-a]. .
  • the embodiment 6-1-b of the present invention is a more preferable embodiment than the embodiment [6-1-a], and is suitable for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity.
  • the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
  • the embodiment 6-1-c of the present invention is a more preferred embodiment than the above embodiment [6-1-b], and is suitable for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity.
  • the definition and preferred embodiments of the formula (III) -C are the same as the definitions and preferred embodiments of the formula (III) -C described in the embodiment [2-3-c]. .
  • the embodiment 6-2 of the present invention is the above embodiment [2] -4], or a pharmaceutically acceptable salt or solvate thereof.
  • the definition and preferred embodiment of the formula (IV) are the same as the definition and preferred embodiment of the formula (IV) described in the embodiment [2-4].
  • the sixth aspect of the present invention is the above aspect [2] for producing a medicament for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity. ⁇ 5], or a pharmaceutically acceptable salt or solvate thereof.
  • the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the above embodiment [2-5].
  • a sixth to fourth aspect of the present invention is the above aspect [2] ⁇ 6], or a pharmaceutically acceptable salt or solvate thereof.
  • the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the above embodiment [2-6].
  • a sixth to fifth aspect of the present invention is the above aspect [2] for producing a medicament for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity. ⁇ 7], or a pharmaceutically acceptable salt or solvate thereof.
  • the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
  • a seventh aspect of the present invention is the compound represented by the formula (I) -B according to the aspect [2-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a pharmaceutical composition for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the following.
  • the definition and preferred embodiment of the formula (I) -B are the same as the definition and preferred embodiment of the formula (I) -B described in the embodiment [2-1].
  • Preferred embodiments include the following embodiments.
  • a seventh aspect of the present invention is a compound represented by the formula (III) according to the aforementioned aspect [2-3], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiments of the formula (III) are the same as the definition and preferred embodiments of the formula (III) described in the embodiment [2-3].
  • the definition and preferred embodiment of the formula (III) -A are the same as the definition and preferred embodiment of the formula (III) -A described in the embodiment [2-3-a]. .
  • the embodiment 7-1-b of the present invention is a more preferred embodiment than the embodiment [7-1-a], and is represented by the formula (III) described in the embodiment [2-3-b].
  • ) -B NAFLD / NASH, diabetes, insulin resistance, characterized by containing at least one of a compound represented by -B, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient Or it is a pharmaceutical composition for prevention and / or treatment of obesity / obesity.
  • the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
  • the embodiment 7-1-c of the present invention is a more preferred embodiment than the embodiment [7-1-b], and is represented by the formula (III) described in the embodiment [2-3-c].
  • the definition and preferred embodiment of the formula (III) -C are the same as the definition and preferred embodiment of the formula (III) -C described in the embodiment [2-3-c]. .
  • a seventh aspect of the present invention is a compound represented by the formula (IV) according to the aforementioned aspect [2-4], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiment of the formula (IV) are the same as the definition and preferred embodiment of the formula (IV) described in the embodiment [2-4].
  • a seventh aspect of the present invention is a compound represented by the formula (IV-a) according to the above aspect [2-5], or a pharmaceutically acceptable salt thereof, or a compound thereof It is a pharmaceutical composition for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, comprising at least one of the above solvates as an active ingredient.
  • the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the above embodiment [2-5].
  • a seventh to fourth aspect of the present invention is the compound represented by the formula (V) according to the above aspect [2-6], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the above embodiment [2-6].
  • a seventh to fifth aspect of the present invention is a compound represented by the formula (VI) according to the above aspect [2-7], or a pharmaceutically acceptable salt thereof or a solvent thereof.
  • the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
  • An eighth aspect of the present invention is the compound represented by the formula (I) -B according to the above aspect [2-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition that may contain an active ingredient of another drug together with at least one of the above and a pharmaceutical carrier.
  • the other drug includes a drug having a different mechanism of action or an allotrope including another drug (Elovl6 inhibitor) having the same mechanism of action.
  • the same type of synergistic drugs include various drugs such as insulin resistance improving drugs / diabetic drugs, lipid lowering drugs / dyslipidemia drugs, anti-obesity drugs, antihypertensive drugs, or therapeutic agents considered effective for NASH treatment. Examples include drugs used for treatment.
  • other drugs include drugs targeting different types of diseases.
  • the definition and preferred embodiments of the formula (I) -B are the same as the definitions and preferred embodiments of the formula (I) -B described in the embodiment [2-1].
  • Preferred embodiments include the following embodiments.
  • the eighth aspect of the present invention is a compound represented by the formula (III) according to the aforementioned aspect [2-3], or a pharmaceutically acceptable salt thereof or a solvent thereof. It is a pharmaceutical composition which may contain an active ingredient of another drug together with at least one of the Japanese products and a pharmaceutical carrier.
  • the definition and preferred aspect of the formula (III) are the same as the definition and preferred aspect of the formula (III) described in the above aspect [2-3].
  • the embodiment of 8-1-1a of the present invention is a compound represented by the formula (III) -A according to the embodiment [2-3-a], or a pharmaceutically acceptable
  • the pharmaceutical composition may contain an active ingredient of another drug together with at least one of its salts or solvates thereof and a pharmaceutical carrier.
  • the definition and preferred embodiments of the formula (III) -A are the same as the definitions and preferred embodiments of the formula (III) -A described in the embodiment [2-3-a]. .
  • the embodiment 8-1-b of the present invention is a more preferred embodiment than the embodiment [8-1-a], and is represented by the formula (III) described in the embodiment [2-3-b].
  • the ring containing A a does not include those that are aromatized.
  • the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
  • Aspect 8-1-1 of the present invention is a more preferred embodiment than the above-mentioned embodiment [8-1-b], and is represented by the formula (III) described in the embodiment [2-3-c].
  • a pharmaceutical agent which may contain an active ingredient of another drug together with at least one of a compound represented by -C, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical carrier It is a composition.
  • the definition and preferred embodiment of the formula (III) -C are the same as the definition and preferred embodiment of the formula (III) -C described in the embodiment [2-3-c]. .
  • the eighth aspect of the present invention is a compound represented by the formula (IV) according to the aforementioned aspect [2-4], or a pharmaceutically acceptable salt thereof or a solvent thereof. It is a pharmaceutical composition which may contain an active ingredient of another drug together with at least one of the Japanese products and a pharmaceutical carrier.
  • the definition and preferred embodiments of the formula (IV) are the same as the definition and preferred embodiments of the formula (IV) described in the embodiment [2-4].
  • An eighth aspect of the present invention is the compound represented by the formula (IV-a) according to the above aspect [2-5], or a pharmaceutically acceptable salt thereof, or a salt thereof.
  • the pharmaceutical composition may contain an active ingredient of another drug together with at least one of the solvates of the above and a pharmaceutical carrier.
  • the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the embodiment [2-5].
  • the 8-4th aspect of the present invention is the compound represented by the formula (V) according to the above aspect [2-6], or a pharmaceutically acceptable salt thereof or a solvent thereof. It is a pharmaceutical composition which may contain an active ingredient of another drug together with at least one of the Japanese products and a pharmaceutical carrier.
  • the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the above embodiment [2-6].
  • An eighth to fifth aspect of the present invention is the compound represented by formula (VI) according to the above aspect [2-7], or a pharmaceutically acceptable salt thereof or a solvent thereof. It is a pharmaceutical composition which may contain an active ingredient of another drug together with at least one of the Japanese products and a pharmaceutical carrier.
  • the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
  • the IC 50 value is preferably 1 ⁇ M or less, more preferably 100 nM or less, still more preferably 30 nM or less, and particularly preferably 10 nM or less.
  • the “therapeutic agent” is intended to include not only treatment of a disease or symptom but also improvement of the disease or symptom.
  • the pharmaceutically acceptable salt is also referred to.
  • 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.
  • a salt with a base may be formed.
  • Such a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • 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 ali
  • 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.
  • 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.
  • 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.
  • the present invention also includes hydrates of compounds represented by the formula (I) of the present invention, various pharmaceutically acceptable solvates, crystal polymorphs, and the like.
  • 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.
  • the reaction conditions in the production method are as follows unless otherwise specified.
  • the reaction temperature ranges 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.
  • the solvent inert to the reaction include aromatic hydrocarbon solvents such as toluene, xylene, and benzene, alcohol solvents such as methanol and ethanol, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, and the like.
  • Polar solvents basic solvents such as triethylamine, pyridine, organic acid solvents such as acetic acid, halogen solvents such as chloroform, dichloromethane, 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc. Or it is a mixed solvent of these, and it selects suitably by 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.
  • 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.
  • 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 can be easily produced from a commercially available compound or a commercially available compound by methods known in the literature, and can be produced according to the production method shown below.
  • formula (I) -A, formula (I) -B, formula (II), formula (III), formula (III) -A, formula (III) -B, formula (III) -C, formula (IV) ), Formula (IV-a), formula (V) and formula (VI) can also be produced according to the following production method.
  • the present invention is not limited to the manufacturing method described below.
  • m ′, p ′, q and r each represent an integer of 0 to 3
  • P 1 represents a protecting group such as a methyl group or a t-butoxycarbonyl group
  • X represents a halogen atom (F, Cl, Br, I)
  • L represents a detachable substituent such as a halogen atom or phosphate ester
  • M represents lithium (Li), magnesium halide (MgX, X is a halogen atom), borate ester, or the like.
  • R 23 and R 24 each independently represents a group arbitrarily selected from the functional groups defined in R A , and a 5- to 7-membered group containing a carbon atom to which R 23 is bonded together with R 24 May be formed.
  • V A represents —COOH, —NHR 8 , —NHR 9 , —CHO, —NHR 11 , —H, —CONH 2 , —CONHR 7 , —L.
  • V B is —NHR 7 , —COOH, —NHR 10 , —NCO, —NHR 11 , —CHO, —L, —CONH 2 , —CONHR 8 ,
  • V C is —NHR 7 , —NCO, —L represents, V D is a hydrogen atom, -L represents -SH, V E represents a hydrogen atom, a -L, V F is hydrogen atom, a -L, V G represents a hydrogen atom, a -L VH represents -L.
  • Ring ' is an aryl group including a substituted phenyl ring, a substituted pyridine ring, a substituted furan ring, etc., and Ring''is a nitrogen atom at the junction with (CR 1 R 2 ) m in formula (I)
  • Ring ′ ′′ represents the case where a nitrogen atom is present at the junction with S (O) n in formula (I).
  • the compound represented by Formula (I) can be produced by the method of Reaction Formula 1 using the compound represented by Formula (X) and the compound represented by Formula (XI).
  • the compound represented by the formula (I-1) can be produced by reacting in the presence or absence at a temperature at which the solvent is refluxed from 0 ° C.
  • the compound represented by the formula (X-1) is converted to acid chloride (Experimental Chemistry Course, 4th edition, 22 Organic Synthesis IV, Acid, Amino Acid, Peptide, 144-146, 1992, Maruzen)
  • a base such as triethylamine or pyridine
  • a halogen solvent such as dichloromethane or chloroform
  • an ether solvent such as diethyl ether or tetrahydrofuran
  • an aromatic hydrocarbon solvent such as toluene or benzene
  • the compound represented by the formula (I-1) can be produced by reacting in a solvent such as N-dimethylformamide that does not participate in the reaction at a temperature at which the solvent is refluxed from 0 ° C.
  • a compound represented by formula (I-2) by a method similar to (Production Method 1-1) using a compound represented by formula (X-2) and a compound represented by formula (XI-2) Can be manufactured.
  • the reaction is carried out at a temperature at which the solvent refluxes from 0 ° C.
  • a reducing agent such as sodium borohydride, an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, a polar solvent such as N, N-dimethylformamide
  • a solvent that does not participate in the reaction such as an alcohol solvent such as methanol, ethanol, 2-propanol, or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent refluxes from 0 ° C., and is represented by the formula (I-5). Can be produced.
  • a compound represented by formula (I-6) by a method similar to (Production Method 1-5) using a compound represented by formula (X-5) and a compound represented by formula (XI-6) Can be manufactured.
  • ⁇ Step 1> Using a compound represented by the formula (X-6) and a compound represented by the formula (XI-7), a method known in the literature, for example, (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element) Compound, 319-419, 1992, Maruzen) and the like, such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, etc.
  • a method known in the literature for example, (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element) Compound, 319-419, 1992, Maruzen) and the like, such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, etc.
  • a compound represented by the formula (I-7) can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C.
  • ⁇ Step 1> Using a compound represented by the formula (X-10) and a compound represented by the formula (X-11), a method known in the literature, for example, (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element) Compound, 319-419, 1992, Maruzen) and the like, such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, etc.
  • a method known in the literature for example, (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element) Compound, 319-419, 1992, Maruzen) and the like, such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, etc.
  • a metal catalyst such as copper (I) iodide, tetrakistriphenylphosphine palladium, methanol, ethanol, acetone, N, N-dimethylformamide, 1,4-dioxane , Tetrahydrofuran, water, etc., and a solvent inert from the reaction, or a mixed solvent thereof.
  • a metal catalyst such as copper (I) iodide, tetrakistriphenylphosphine palladium, methanol, ethanol, acetone, N, N-dimethylformamide, 1,4-dioxane , Tetrahydrofuran, water, etc.
  • ⁇ Step 3> A method known in the literature using a compound represented by the formula (X-13), such as (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element Compound, 319-419, 1992, Maruzen), etc.
  • an oxidizing agent such as hydrogen peroxide, sodium periodate, peracetic acid, 2-chloroperbenzoic acid, potassium permanganate, sodium perborate, chlorine, dichloromethane, chloroform, etc.
  • the compound represented by the formula (X ′) can be produced by reacting at a temperature at which the solvent is refluxed from ⁇ 78 ° C.
  • a solvent that does not participate in the reaction such as a halogen solvent such as chloroform, an ether solvent such as diethyl ether or tetrahydrofuran, or a polar solvent such as acetone
  • the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C.
  • a compound represented by ') can be produced.
  • ⁇ Step 4> Using a compound represented by the formula (X-18) and a compound represented by the formula (X-19), a method known in the literature, for example, Journal of Medicinal Chemistry, 50 (3 ) 566-584, according to the method described in 2007, in the presence or absence of a base such as triethylamine or pyridine, a halogen-based solvent such as dichloromethane or chloroform, an ether-based solvent such as diethyl ether or tetrahydrofuran, It is represented by the formula (X ′ ′′) by reacting at a temperature at which the solvent is refluxed from 0 ° C. in a solvent not involved in the reaction such as an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as acetonitrile. Can be produced.
  • a base such as triethylamine or pyridine
  • a halogen-based solvent such as dichloromethane or chloroform
  • a compound represented by the formula (X-20) and a sulfonylating agent such as sulfuric acid a method known in the literature, for example, Organic Process Research & Development, 6 (6), 767-772, in accordance with the method described in 2002, in the presence or absence of an acid such as sulfuric acid, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, toluene, benzene and the like
  • a compound represented by the formula (X-21) by reacting at a temperature at which the solvent is refluxed from ⁇ 78 ° C. in a solvent that does not participate in the reaction, such as an aromatic hydrocarbon solvent, a polar solvent such as acetone, or the like, without solvent. Can be manufactured.
  • ⁇ Process 2> A method known in the literature using a compound represented by the formula (X-21), for example, a method described in Journal of Medicinal Chemistry, 50 (3), 566-584, 2007 In the presence of dehydrating reagents such as thionyl chloride, phosphoryl chloride, N-chlorosuccinimide (NCS), etc., halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, and aromatics such as toluene and benzene
  • a compound represented by the formula (X-18) can be produced by reacting at a temperature at which the solvent is refluxed from ⁇ 78 ° C. in a solvent that does not participate in the reaction, such as a group hydrocarbon solvent.
  • a compound represented by the formula (X-20) and a sulfonylating agent such as chlorosulfonic acid a method known in the literature, for example, Journal of Medicinal Chemistry, 51 (9), 2807
  • halogen solvents such as dichloromethane and chloroform
  • ether solvents such as diethyl ether and tetrahydrofuran
  • aromatic hydrocarbon solvents such as toluene and benzene
  • polar solvents such as acetone
  • the compound represented by the formula (X-18) can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C. in a solvent that does not participate in the reaction or without solvent.
  • the compound represented by the formula (I-6) can be produced by the same method as (Production Method 2-1).
  • the compound represented by the formula (I-9) can be produced by the method of the reaction formula 18 using the compound represented by the formula (XII) and the compound represented by the formula (XIII-1). it can.
  • a compound represented by the formula (I-9 ′) using the compound represented by the formula (XII) and the compound represented by the formula (XIII-2) in the same manner as in (Production Method 1-4) Can be manufactured.
  • the compound represented by the formula (XIV-1) as a raw material of the above reaction formula 21 and its derivative can be produced according to a method known in the literature or in accordance with, for example, the following reaction formula 22 to the following reaction formula 24.
  • the compound represented by the formula (XIV-1 ′) can be produced by the same method as in (Reaction Scheme 14) ⁇ Step 3>.
  • the compound represented by the formula (XIV-4), which is a raw material of the above reaction scheme 24, can be produced according to a method known in the literature or according thereto, for example, according to the following reaction scheme 25
  • the compound represented by the formula (I-11) in the above reaction scheme 26 can also be produced by the method of the reaction scheme 27.
  • the compound represented by the formula (XVI-1), which is a raw material of the above reaction formula 29, can be produced according to a method known in the literature or according thereto, for example, according to the following reaction formula 30.
  • the compound represented by the formula (XVI-4), which is a raw material of the above reaction scheme 31, can be produced according to a method known in the literature or according thereto, for example, according to the following reaction scheme 32.
  • the compound in which Ring is a nitrogen-containing hydrocarbon ring and derivatives thereof include, for example, formula (X-22), formula (X-23), formula (X— 24), the compound represented by the formula (X-25), the formula (X-26), and the formula (X-27) can be prepared according to a method known in the literature or according to, for example, the following reaction formula 36 to reaction formula 39. Can be manufactured.
  • ⁇ Step 1> Using a compound represented by the formula (XX), protecting groups such as tert-butoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group and the like can be prepared by methods known in the literature, for example, Protective Groups in Organic Synthesis.
  • the compound represented by the formula (XX-1) can be produced in the same manner by introducing according to the method described in (Protective Groups in Organic Synthesis), (USA), 3rd edition, 1999, etc.
  • the reaction is represented by the formula (XX-2) by reacting in a solvent that does not participate in the reaction in the absence of a solvent in the presence or absence of a base such as triethylamine or pyridine at a temperature at which the solvent refluxes from 0 ° C.
  • a base such as triethylamine or pyridine
  • ⁇ Step 4> Using a compound represented by the formula (XX-3), a method known in the literature, for example, Protective Groups in Organic Synthesis, (USA), 3rd edition, 1999, etc.
  • the compound represented by the formula (XX-4) can be produced in the same manner by deprotecting according to the method described.
  • a protecting group such as a benzyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group or the like can be formed by a method known in the literature, for example, Protective Groups in. Introducing according to the method described in Organic Synthesis (Protective Groups in Organic Synthesis), (US), 3rd edition, 1999, etc., and similarly producing the compound represented by the formula (XXII-1) Can do.
  • the compound represented by the formula (XXII-2) is reacted by reacting at a temperature at which the solvent refluxes from ⁇ 78 ° C. in a solvent such as an aromatic hydrocarbon solvent, a polar solvent such as acetone. Can be manufactured.
  • a solvent such as an aromatic hydrocarbon solvent, a polar solvent such as acetone.
  • ⁇ Step 4> Using a compound represented by the formula (XXII-3) and the formula (X-9), a method known in the literature, for example, Journal of Medicinal Chemistry, 37 (13), 2043-2058, According to the method described in 1994, in the presence of a base such as lithium diisopropylamide (LDA) or bis (trimethylsilyl) amidolithium, an ether solvent such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon such as toluene or benzene.
  • a compound represented by the formula (XXII-4) can be similarly produced by reacting in a solvent such as a solvent that does not participate in the reaction at a temperature from 0 ° C. to the reflux of the solvent.
  • Step 1 Using the compound represented by the formula (XXIV) and the compound represented by the formula (XXIV-1), the compound represented by the formula (XXIV-2) was prepared in the same manner as in Step 1 of (Reaction Scheme 13). Can be manufactured.
  • a compound represented by the formula (XXIV-2) and a compound represented by the formula (X-15) a method known in the literature, for example, Journal of Medicinal Chemistry, 49 (21 ), 6371-6390, according to the method described in 2006, in the presence of a base such as butyllithium, lithium diisopropylamide (LDA), bis (trimethylsilyl) amidolithium, an ether solvent such as diethyl ether or tetrahydrofuran, toluene
  • a compound represented by the formula (XXIV-3) is produced by reacting at a temperature at which the solvent is refluxed from ⁇ 78 ° C. in a solvent such as benzene or an aromatic hydrocarbon solvent. can do.
  • Step 4 Using the compound represented by the formula (XXIV-6) and the compound represented by the formula (X-19), (Reaction Scheme 13) represented by the formula (XXIV-3 ′) by the same method as in Step 4 Can be prepared similarly.
  • 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 performed 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, and the like.
  • the functional group present in the compound represented by the formula (I) can be converted to other functional groups according to a known method or a similar method.
  • alkylation with an alkyl halide reductive alkylation with an aldehyde, acylation with a carboxylic acid derivative, sulfonamidation with a sulfonyl chloride, urea with a carbamoyl chloride Etc.
  • alkylation with an alkyl halide reductive alkylation with an aldehyde
  • acylation with a carboxylic acid derivative acylation with a carboxylic acid derivative
  • sulfonamidation with a sulfonyl chloride urea with a carbamoyl chloride Etc.
  • Bases include inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or triethylamine, pyridine, N, N-dialkylaniline, lithium depending on the type of solvent and the respective reactivity.
  • organic base such as diisopropylamide and a metal catalyst
  • copper catalysts such as copper and copper iodide
  • palladium catalysts such as palladium acetate and tetrakistriphenylphosphine palladium can be used.
  • the functional group when it has a carboxyl group, it can be converted to an amide group by a primary or secondary amine using a condensing agent.
  • a condensing agent 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC ⁇ HCl), dicyclocarbodiimide (DCC), or the like can be used.
  • Conversion to an amide group can be carried out by converting the carboxyl group to an acid halide using thionyl chloride, oxalyl chloride, etc., and then reacting with a primary or secondary amine.
  • Combination agent containing the compound of the present invention can be used in combination with other drugs or drugs by a general method performed in the medical field.
  • Use in prevention, progression, and treatment of Elovl6 inhibitor-mediated conditions, especially NASH, NAFLD, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT), fasting glucose abnormalities (IFG), fasting high It is used in at least one disease selected from the group consisting of glycemic state, obesity / obesity, or various diseases caused or related to these.
  • 1) PPAR ⁇ agonist specifically, pioglitazone, rosiglitazone, troglitazone, siglitazone, darglitazone, englitazone, netoglitazone, CLX0921, GW-0207, LG- 2) biguanides (specifically metformin, buformin, phenformin, etc.), 3) sulfonylureas (specifically, tolbutamide, chlorpropamide, glibenclamide, glipizide, glimepiride, etc.) 4) Fast-acting insulin secretagogues (specifically, nateglinide, mitiglinide, repaglinide, etc.) 5) ⁇ -glucosidase inhibitor (instrument) Physically, acarbose, voglibose, camiglybose, adiposine, emiglitate, miglitol, prazimycin-Q, sarvostatin,
  • lipid-lowering drugs include lipid-lowering drugs and dyslipidemic agents.
  • ⁇ 3 fatty acids specifically ethyl icosapentate (EPA-E preparation), docosahexaenoic acid (DHA), etc.
  • HMG-CoA reductase inhibitor specifically atorvastatin, simvastatin, Pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, etc.
  • HMG-CoA synthetase inhibitor specifically atorvastatin, simvastatin, Pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, etc.
  • cholesterol absorption inhibitor specifically, ezetimibe
  • acyl-CoA / cholesterol acyl Transferase (ACAT) inhibitor 6) CETP inhibitor, 7) squalene synthase inhibitor,
  • CB-1 receptor antagonist specifically, rimonabant, SR-147778, BAY-6-2520, etc.
  • Monoamine reuptake inhibitor specifically sibutramine, mazindol, etc.
  • Serotonin reuptake inhibitors specifically fluoxetine, paroxetine, etc.
  • Lipase inhibitors specifically, orlistat, cetiristat, etc.
  • Neuropeptide Y (NPY) receptor antagonist specifically, S-2367 etc.)
  • Peptide YY (PYY) receptor antagonist specifically, Adrenergic ⁇ 3 receptor agonist (specifically, KRP-204, TRK-380 / TAC-301 etc.) Can be mentioned.
  • antihypertensive agents include 1) diuretics (specifically, hydrochlorothiazide, furosemide, spironolactone, eplerenone, chlorthalidone, etc.), 2) calcium antagonists (specifically, cilnidipine, amlodipine, benidipine, nifedipine, Nicardipine, nilvadipine, azelnidipine, manidipine, nitrendipine, parnidipine, nisoldipine, efonidipine, felodipine, alanidipine, diltiazem, verapamil, bepridil, etc.), 3) angiotensin converting enzyme inhibitors (specifically captopril, alacepril, imidapril, enapril, enapril 4) angiotensin receptor antagonists (specifically, losartan, valsartan, cande), temocapril, de
  • Other therapeutic agents that are considered effective for NASH treatment include, for example, 1) antioxidants (specifically, vitamin E, vitamin C, betaine, N-acetylcysteine, etc.), 2) liver protective drugs (specifically, UDCA, EPL, taurine, glycyrrhizin, Sho-saiko-to, etc.) 3) Anti-inflammatory agents (specifically, cytokine production inhibitors such as ASP9831 and pentoxyphyllin, leukotriene receptor antagonists, leukotriene biosynthesis inhibitors) , NSAIDs, COX-2 selective inhibitors, M2 / M3 antagonists, corticosteroids, steroids such as prednisolone farnesylate, histamine receptor antagonists, aminosalicylic acids such as salazosulfapyridine, mesalazine, etc.), 4) immune Inhibitors (specifically, azathioprine, 6-mercaptopurine, tacrolimus, etc.) 5) The hepatitis C
  • the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced.
  • 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.
  • a drug used in combination with the compound of the present invention may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.
  • the medicament of the present invention is administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention only needs to contain at least one compound represented by the formula (I) of the present invention, and is prepared in combination with a pharmaceutically acceptable additive.
  • 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), carbox Methyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg, cellulose
  • 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 patients by inhalation and 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 entire amount can be divided into 1 or 2-6 doses, orally or parenterally, or can be administered continuously by intravenous infusion.
  • Pharmacological Experimental Example 2 Preparation of Elovl6 Enzyme Source A human kidney-derived cell line FreeStyle TM 293F cells (Invitrogen) was seeded in a 2 L culture flask. After overnight culture, the human Elovl6 expression plasmid pTK-3088 obtained in Pharmacological Experiment Example 1 was introduced using a 293F cell-specific gene introduction reagent (293fectin, Invitrogen). After culturing for 2 days, the cells were collected and placed in Buffer A (10 mM Tris-HCl, 0.25 M Sucrose, 1 mM EDTA-2Na, pH 7.4) containing 1 tablet of Complete EDTA-free (Roche) as a protease inhibitor. Suspended.
  • Buffer A (10 mM Tris-HCl, 0.25 M Sucrose, 1 mM EDTA-2Na, pH 7.4
  • Buffer A 10 mM Tris-HCl, 0.25 M Sucrose, 1 mM EDTA-2
  • Elovl6 Enzyme Inhibition Test A test compound was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 30 mM, and further diluted with DMSO to prepare a 100-fold concentrated solution of the evaluation concentration.
  • DMSO dimethyl sulfoxide
  • the scintillator of 50 ⁇ L per well (Aquazol (PerkinElmer)) Seal the plate upper and lower added, microplate scintillation counter and radioactivity of the fixed [14 C] (1450MicroBeta (R ) TRILUX (PerkinElmer)) And measured as enzyme activity, that is, oleic acid synthesis ability.
  • the enzyme inhibitory activity of human Elovl6 by the test compound was calculated using the radioactivity in wells containing 1 ⁇ L of DMSO not containing the test compound as a control.
  • Elovl6 enzyme inhibitory activity i.e. oleic acid synthesis inhibitory activity of the present compounds are represented by an IC 50 value
  • a compound of the present invention the IC 50 values less than the 100nM as A
  • an IC 50 value is the compound of less than 100nM or ⁇ 1 [mu] M B is shown in Table 1.
  • Pharmacological Experiment Example 4 Intracellular Elovl6 Enzyme Activity Inhibition Test 1 ⁇ 10 6 mouse liver-derived cell line AML12 (ATCC) was seeded in a 10 cm 2 dish. After overnight culture, using FuGENE6 (Roche), the human Elovl6 expression plasmid pTK-3088 obtained in Pharmacological Experiment Example 1 and pSV2-neo containing the neomycin resistance gene were introduced. After overnight culture, the medium was replaced with a medium containing Geneticin (Invitrogen), and further cultured for 1 week to obtain an Elovl6 stable expression AML12 cell line. Furthermore, a monoclonal cell line was prepared by the ultradilution method and named AML12-Elovl6 cell line.
  • the AML12-Elovl6 cell line was maintained in DMEM / F12 medium (GIBCO) supplemented with 10% fetal bovine serum, dexamethasone, and animal cell culture additives (ITS Liquid Media Supplement (Sigma)) under 5% CO 2 , Cultured at 37 ° C. Approximately 2 ⁇ 10 5 AML12-Elovl6 cells were seeded in a 12-well cell culture plate (Corning) and cultured overnight. The test compound prepared by the method described in Pharmacological Experiment Example 3 was added to the evaluation concentration, and after pre-culture for 15 minutes, [ 3 H] -palmitic acid (185 MBq / mL, PerkinElmer) was added to each well, The culture was further continued for 2 hours.
  • the quantity ratio between C18 and C16 was calculated and used as the intracellular Elovl6 enzyme activity, that is, the ability to synthesize stearic acid / oleic acid.
  • the intracellular Elovl6 enzyme activity inhibitory activity of the test compound was calculated using the C18 / C16 ratio of the DMSO-added well not containing the test compound as a control.
  • Inhibitory activity of the compounds of the invention expressed as an IC 50 value an IC 50 value as the compound A of the present invention of less than 100nM, also, an IC 50 value is shown in Table 2.
  • Pharmacological Experimental Example 5 Analysis of free fatty acid composition in vivo (1) Continuous administration of Elovl6 inhibitory compound to mice 7-week-old BKS. Cg-m + / + Lepr db / J mice were acclimated for 2 weeks, and the acclimated mice were orally administered the compound of Example 140 in a volume of 2.5 mL / kg (solvent: polyethylene glycol 400 (PEG 400)). . Administration was performed twice daily in the morning and evening for 28 days. The day after the last administration day, blood was collected from the orbital venous plexus of the same mouse under fasting for 4 hours, and the obtained blood was centrifuged (7000 rpm, 15 minutes, 4 ° C.) to prepare plasma.
  • PEG 400 polyethylene glycol 400
  • the fatty acid composition in each plasma was determined by determining the content ratio of fatty acids of palmitic acid (C16: 0), palmitoleic acid (C16: 1), stearic acid (C18: 0) and oleic acid (C18: 1) contained in the sample. Ratio. That is, each fatty acid molar concentration ratio was calculated by setting the total molar concentration of the above four fatty acids to 1, and was used as the plasma fatty acid composition ratio.
  • the analysis result of each fatty acid composition is shown in FIG. As shown in FIG. 1, changes in blood fatty acid composition due to administration of the Elovl6 inhibitor compound, particularly an increase in palmitic acid and a decrease in oleic acid were confirmed.
  • DMSO Precipitation Solubility (Kinetic Solubility) A 10 mM DMSO solution of the compound of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 ⁇ M. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, then filtered through a filter plate (4 ⁇ m, MultiScreen Solidity filter plate (Millipore)), and using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength.
  • the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 ⁇ M) of the test compound is added as a calibration curve standard solution, and a calibration curve is created.
  • the solubility ( ⁇ M) of the compound is calculated from the absorbance values of the filtrate and standard solution.
  • Pharmacological experiment example 8 hERG inhibition test by patch clamp method
  • the effect on hERG (human ether-a-go-related gene) channel is measured using a fully automatic patch clamp system (Patchliner (Nanion)).
  • a depolarizing pulse is periodically applied while maintaining the membrane potential at ⁇ 80 mV.
  • the test compound is added.
  • the effect of the test compound on the hERG channel is confirmed by a change in tail current induced by a 40 mV, 0.5 second depolarizing pulse followed by a -40 mV, 0.5 second repolarizing pulse. Stimulation is performed once every 10 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 2 minutes after application with respect to the maximum tail current before application of the test compound. 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.
  • Pharmacological experiment example 10 Safety test The compound of the present invention is orally administered to a mouse or rat once, and no deaths are observed, and no remarkable behavioral abnormality is observed, which shows the safety of the compound of the present invention. .
  • the compound of the present invention has an excellent Elovl6 enzyme activity inhibitory effect and a change in fatty acid composition, particularly an increase in palmitic acid and a decrease in oleic acid. Furthermore, it is confirmed that the compound of the present invention is good in one point such as solubility, metabolic stability, pharmacokinetics, and avoidance of hERG channel inhibitory effect by conducting the above test. Therefore, the compound of the present invention is expected as an agent for preventing or treating NAFLD / NASH, diabetes, type 2 diabetes, insulin resistance and obesity / obesity.
  • the compound of the present invention has an Elovl6 inhibitory action, and various diseases involving Elovl6, such as NASH, NAFLD, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT) / fasting blood glucose abnormality (IFG) ),
  • Elovl6 an Elovl6 inhibitory action
  • various diseases involving Elovl6, such as NASH, NAFLD, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT) / fasting blood glucose abnormality (IFG)
  • IGF blood glucose abnormality
  • the compounds of the present invention include NASH, NAFLD, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT) / fasting blood glucose abnormality (IFG), fasting hyperglycemia, obesity / obesity, or these It is useful for various diseases caused by or related to.
  • NAFLD as defined here is a liver disorder characterized by mainly large-scale hepatic fat deposition, similar to alcoholic liver disorder, although there is no clear drinking history. It is a group of diseases including hepatic disorder such as hepatitis, fibrosis, cirrhosis, and liver cancer. Viral liver diseases, autoimmune disease liver diseases, metabolic liver diseases such as hemacrotosis and Wilson disease are excluded. NAFLD is also called non-alcoholic fatty liver and is a disease concept including simple fatty liver with good prognosis and progressive NASH with poor prognosis. “NASH” is considered to be a severe form of NAFLD, and is a progressive disease of NAFLD accompanied by inflammation and fibrosis of hepatocytes.
  • NASH alcoholic liver disorder
  • viral hepatitis and drug-induced liver disorder are considered to be the pathological condition of NASH.
  • the treatment of NAFLD / NASH means that a compound having an Elovl6 inhibitory action of the present invention or a pharmaceutical composition containing the compound is administered to a NAFLD / NASH patient.
  • their treatment is the first priority treatment.
  • improvement of NASH's important pathological conditions such as oxidative stress and insulin resistance can be mentioned as a result of treatment.
  • diabetes includes both type 1 diabetes (IDDM, known as insulin-dependent diabetes) and type 2 diabetes (NIDDM, known as non-insulin-dependent diabetes).
  • IDDM type 1 diabetes
  • NIDDM type 2 diabetes
  • Diabetes is characterized by a fasting blood glucose level of 126 mg / dl or higher, or an occasional blood glucose level or a 75 g oral glucose tolerance test (OGTT) 2-hour value of 200 mg / dl or higher.
  • Glucose intolerance which is a boundary type, is a fasting blood glucose abnormality (IFG) in which a fasting blood glucose level is 110 mg / dl or more and less than 126 mg / dl, or a glucose tolerance having a 75 gOGTT 2 hour value of 140 mg / dl or more and less than 200 mg / dl. Indicates an abnormality (IGT).
  • Insulin resistance refers to a pathological condition in which insulin is unable to lower blood sugar in a living body, and is clinically evaluated by a quantitative glucose clamp method or HOMA-IR. It is known that insulin resistance causes hyperinsulinemia and is a risk of hypertension and coronary artery disease.
  • Treatment of diabetes refers to administration of a compound or composition according to the present invention to a diabetic patient.
  • the outcome of treatment is to increase insulin sensitivity and reduce elevated blood insulin and glucose levels.
  • “Obesity” is defined by the Japanese Society of Obesity as “a medical condition that is associated with or is predicted to be associated with obesity and is a medical condition that requires medical weight loss”. . “Obesity” as defined herein is evaluated by BMI (body mass index, kg / m 2 ). Generally, a BMI of 25 or more is determined to be obese. As a result of treatment, reduction of BMI can be mentioned.
  • Formulation Example 1 Compound of Tablet Example 23 100 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 4 Capsule Example 101 Compound 100 g Lactose 63g Corn starch 25g Hydroxypropylcellulose 10g Talc 2g After weighing the above components, the compound of Example 101, 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 with the granules, and 200 mg in weight is filled into suitable hard capsules to form capsules.
  • Formulation Example 5 Compound of Powder Example 116 200 g 790 g of lactose Magnesium stearate 10g After weighing each of the above components, they are mixed uniformly to form a 20% powder.
  • Example 6 Granules, Fine Granules Compound of Example 194 100 g Lactose 200g Crystalline cellulose 100g Partially pregelatinized starch 50g Hydroxypropylcellulose 50g After weighing the above components, the compound of Example 194, lactose, crystalline cellulose, and partially pregelatinized starch were added and mixed uniformly, an aqueous solution of hydroxypropylcellulose (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.
  • HPC hydroxypropylcellulose
  • Example 7 Cream Compound of Example 201 0.5 g 0.1 g of dl- ⁇ -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 201 is mixed and dissolved. An appropriate amount of purified water is added to make 50 g to obtain a cream formulation.
  • Example 118, Example 191, Example 192, Example 207, Example 208, Example 211, Example 212, Example 249, Example 263, and Example 264 are methanol in the mobile phase, 0.
  • ⁇ Step 2> Synthesis of N- (2-methoxyphenyl) -3-[(4-hydroxy-1-piperidinyl) sulfonyl] benzamide
  • Example 1 Methylene chloride of the compound (50.0 mg) obtained in ⁇ Step 1> To the solution (1.0 mL) were added triethylamine (26 ⁇ L) and 4-hydroxypiperidine (16.3 mg) under ice cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate, washed successively with 0.5N hydrochloric acid, 0.5N aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by fractionation using LC Mass to obtain the title compound (44.0 mg) as a white solid.
  • ⁇ Step 3> Synthesis of N- (2-methoxyphenyl) -2-chloro-5-[(2-oxo-1-piperidinyl) sulfonyl] benzamide (Example 1) In the same manner as in ⁇ Step 2>, The title compound (3.3 mg) was obtained as a white solid from the compound (100.0 mg) obtained in 2 ⁇ Step 2>.
  • Example 3 N- (2-methoxyphenyl) -2-chloro-5-[(2-methyl-1-piperidinyl) sulfonyl] benzamide (Example 1) A method according to ⁇ Step 2> (Example 2) The title compound (22.6 mg) was obtained as a white solid from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 4 N- (2-methoxyphenyl) -2-chloro-5-[(2-hydroxymethyl-1-piperidinyl) sulfonyl] benzamide (Example 1)
  • Example 2 The title compound (15.2 mg) was obtained as a colorless oil from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 5 N- (2-methoxyphenyl) -2-chloro-5-[(2-aminocarbonyl-1-piperidinyl) sulfonyl] benzamide (Example 1)
  • Example 2 The title compound (11.8 mg) was obtained as a white solid from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 6 N- (2-methoxyphenyl) -2-chloro-5-[(3-methyl-1-piperidinyl) sulfonyl] benzamide (Example 1) A method according to ⁇ Step 2> (Example 2) The title compound (42.4 mg) was obtained as a white solid from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 7 N- (2-methoxyphenyl) -2-chloro-5-[(3-hydroxy-1-piperidinyl) sulfonyl] benzamide (Example 1) According to the method of ⁇ Step 2>, (Example 2) The title compound (30.9 mg) was obtained as a white solid from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 8 N- (2-methoxyphenyl) -2-chloro-5-[(3-aminocarbonyl-1-piperidinyl) sulfonyl] benzamide (Example 1)
  • Example 2 The title compound (8.4 mg) was obtained as a white solid from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 9 N- (2-methoxyphenyl) -2-chloro-5-[(3-hydroxymethyl-1-piperidinyl) sulfonyl] benzamide (Example 1)
  • Example 2 The title compound (6.7 mg) was obtained as a white solid from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 10 N- (2-methoxyphenyl) -2-chloro-5-[(3,5-dimethyl-1-piperidinyl) sulfonyl] benzamide (Example 1) A method according to ⁇ Step 2> Example 2) The title compound (7.9 mg) was obtained as a white solid from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 11 N- (2-methoxyphenyl) -2-chloro-5-[(2- (trifluoromethyl) -1-pyrrolidinyl) sulfonyl] benzamide (Example 1)
  • Example 2 The title compound (27.0 mg) was obtained as a colorless oily substance from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 12 N- (2-methoxyphenyl) -2-chloro-5-[(hexahydro-1H-azepin-1-yl) sulfonyl] benzamide (Example 1) In a method according to ⁇ Step 2>, ( Example 2) The title compound (41.1 mg) was obtained as a white solid from the compound (50.0 mg) obtained in ⁇ Step 2>.
  • Example 13 N- (2-Hydroxyphenyl) -2-chloro-5-[(4-methyl-1-piperidinyl) sulfonyl] benzamide 2-chloro-5- (chlorosulfonyl) benzoic acid (50.0 mg) To a methylene chloride solution (2.0 mL) was added 4-methylpiperidine (19.1 ⁇ L) and triethylamine (30.1 ⁇ L) under ice cooling, and the mixture was stirred at room temperature overnight. To the reaction solution, 2-aminophenol (21.4 mg), WSC-HCl (45.0 mg) and 1-hydroxybenzotriazole (3.2 mg) were added and stirred overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by LC Mass to obtain the title compound (8.6 mg) as a white solid.
  • Example 18 N- (2-methoxyphenyl) -2-bromo-5- (1-piperidinylsulfonyl) benzamide o-anisidine (140.0 mg) in methylene chloride solution (4.0 mL) at room temperature 2-Bromo-5- (1-piperidinylsulfonyl) benzoic acid (400.0 mg) and WSC-HCl (230.0 mg) were added and stirred overnight. Water was added to the reaction solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was triturated with ether to obtain the title compound (350.0 mg) as a pale pink solid.
  • Example 19 N- (2-methoxyphenyl) -2-methoxy-5- (1-piperidinylsulfonyl) benzamide N- (2-methoxyphenyl) -2-bromo- synthesized in Example 18 To 5- (1-piperidinylsulfonyl) benzamide (100.0 mg) was added 8M ammonia-methanol solution (2.0 mL), and the mixture was stirred at 120 ° C. for 5 hours in an autoclave.
  • Example 20 N- (2-Methoxyphenyl) -2- (methylamino) -5- (1-piperidinylsulfonyl) benzamide N- (2-methoxyphenyl)-obtained in Example 18 Methylamine (40% methanol solution, 2.0 mL) was added to 2-bromo-5- (1-piperidinylsulfonyl) benzamide (50 mg), and the mixture was stirred in an autoclave at 120 ° C. for 4 hours and at room temperature overnight. did.
  • Example 21 N- (2-methoxyphenyl) -2-[(phenylmethyl) amino] -5- (1-piperidinylsulfonyl) benzamide N- (2-methoxy obtained in Example 18) Benzylamine (0.5 mL) was added to (phenyl) -2-bromo-5- (1-piperidinylsulfonyl) benzamide (100.0 mg), and the mixture was stirred at 130 ° C. for 1 hour. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid, and dried over anhydrous sodium sulfate.
  • Example 23 N- (2-Methoxyphenyl) -2-ethenyl-5- (1-piperidinylsulfonyl) benzamide N- (2-methoxyphenyl) -2-bromo-5- (1-piperidinylsulfonyl) benzamide (60.0 mg) obtained in (Example 18), potassium vinyl trifluoroborate (17.7 mg) ), Palladium acetate (4.7 mg), triphenylphosphine (13.9 mg), di-tert-butylphenol (1.0 mg) in tetrahydrofuran (4.0 mL) and 1N aqueous sodium hydroxide solution (0.7 mL). And stirred at 65 ° C. for 4 hours under an argon atmosphere.
  • Example 24 Obtained with N- (2-methoxyphenyl) -2- (3-hydroxy-1-propyn-1-yl) -5- (1-piperidinylsulfonyl) benzamide (Example 18)
  • tetrakistriphenylphosphine palladium (12.7 mg)
  • copper iodide 1.1 mg
  • triethylamine 1. mL
  • tetrahydrofuran 3.0 mL
  • propargyl alcohol 9. 6 ⁇ L
  • the reaction solution was separated and purified by LC MASS to obtain the title compound (16.5 mg) as a colorless amorphous.
  • ⁇ Step 2> Synthesis of 5-methoxycarbonyl-3- (1-piperidinylsulfonyl) benzoic acid (Example 25)
  • a methanol solution of the compound (7.0 g) obtained in ⁇ Step 1> (700. 0 mL) was added 1N aqueous sodium hydroxide solution (20.5 mL), and the mixture was stirred with heating under reflux for 3 hours. After the solvent was distilled off under reduced pressure, acetone was added and the precipitate was filtered, and the resulting solid was suspended in water. Concentrated hydrochloric acid was added to the suspension and stirred for 1 hour, and then the precipitate was filtered to obtain the title compound (6.5 g) as a white solid.
  • ⁇ Step 3> Synthesis of methyl 5- (tert-butoxycarbonylamino) -3- (1-piperidinylsulfonyl) benzoate (Example 25) Toluene of the compound (500.0 mg) obtained in ⁇ Step 2> To the solution (20.0 mL) were added diphenylphosphoryl azide (0.36 mL), tert-butyl alcohol (0.3 mL) and triethylamine (0.23 mL), and the mixture was stirred until the solid was completely dissolved. The mixture was stirred at 100 ° C. for 5 hours, and the reaction solution was washed with water.
  • ⁇ Step 4> Synthesis of methyl 5-amino-3- (1-piperidinylsulfonyl) benzoate hydrochloride (Example 25)
  • Ethyl acetate solution (10.0 mg) of the compound (120.0 mg) obtained in ⁇ Step 3> 0 mL) was added 4N hydrochloric acid-ethyl acetate solution (1.0 mL) at room temperature and stirred overnight. The precipitate was filtered and washed with ethyl acetate to give the title compound (76 mg) as a white solid.
  • ⁇ Step 5> Synthesis of methyl 3-iodo-5- (1-piperidinylsulfonyl) benzoate (Example 25) 2N hydrochloric acid (2.0 mL) of the compound (75.0 mg) obtained in ⁇ Step 4> ) An aqueous solution of sodium nitrite (15.5 mg) was added to the suspension under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was added dropwise to an aqueous solution of potassium iodide (74.4 mg) under ice cooling, and stirred at the same temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate.
  • ⁇ Step 2> Synthesis of 5-nitro-3- (1-piperidinylsulfonyl) benzoic acid (Example 25) In the same manner as in ⁇ Step 1>, the compound obtained in (Example 26) ⁇ Step 1> (70.0 mg) gave the title compound (84.0 mg) as a yellow solid.
  • ⁇ Step 4> Synthesis of N- (2-methoxyphenyl) -5-amino-3- (1-piperidinylsulfonyl) benzamide (Example 26) Compound (67.0 mg) obtained in ⁇ Step 3> To a methanol solution (2.0 mL) was added 10% palladium-carbon (Pd / C) (7.0 mg) at room temperature, and the mixture was stirred overnight under a hydrogen gas atmosphere. After removing the catalyst, the product was triturated with diethyl ether to obtain the title compound (60.0 mg) as a light brown solid.
  • Pd / C 10% palladium-carbon
  • ⁇ Step 5> Synthesis of N- (2-methoxyphenyl) -5- (dimethylamino) -3- (1-piperidinylsulfonyl) benzamide 36% formaldehyde aqueous solution (0.5 mL) in concentrated sulfuric acid (190.0 mg) Under ice cooling, a tetrahydrofuran solution (0.5 mL) of the compound (30.0 mg) obtained in ⁇ Example 4> ⁇ Step4> was added dropwise, and then sodium borohydride (29.2 mg) was added. Added and stirred.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate.
  • Example 27 N- (2-Methoxyphenyl) -5-methyl-3- (1-piperidinylsulfonyl) -benzamide ⁇ Step 1> Synthesis of 3- (chlorosulfonyl) -5-methylbenzoic acid Example 2) The title compound (4.5 g) was obtained as a brown solid from 3-methylbenzoic acid (4.0 g) by a method according to ⁇ Step 1>.
  • Example 28 N- (2-methoxyphenyl) -3- (1-piperidinylsulfonyl) -5-phenylbenzamide
  • Example 25 N- (2-methoxyphenyl) obtained in ⁇ Step 7> -3-Iodo 5- (1-piperidinylsulfonyl) benzamide (20.0 mg), phenylboronic acid (9.8 mg), sodium carbonate (30.0 mg) in toluene-ethanol (1.5 mL, 2 1) was added tetrakistriphenylphosphine palladium (3.0 mg) under an argon atmosphere, and the mixture was stirred with heating under reflux for 4 hours.
  • Example 29 N- (2-Methoxyphenyl) -5- (hydroxymethyl) -3- (1-piperidinylsulfonyl) benzamide ⁇ Step 1> 5- (Hydroxymethyl) -3- (1-piperidi Synthesis of methyl (nylsulfonyl) benzoate (Example 25)
  • a tetrahydrofuran solution (1.0 mL) of the compound (230 mg) obtained in ⁇ Step 2> was added to a tetrahydrofuran solution (3. 0 mL) was added and stirred at the same temperature for 2 hours.
  • Methanol 1.0 mL was added to the reaction solution, and the mixture was further stirred for 1 hour.
  • ⁇ Step 2> Synthesis of 5- (hydroxymethyl) -3- (1-piperidinylsulfonyl) benzoic acid (Example 25) In the same manner as ⁇ Step 2>, obtained in (Example 29) ⁇ Step 1> The title compound (100.0 mg) was obtained as a colorless viscous substance from the obtained compound (150.0 mg).
  • ⁇ Step 2> Synthesis of N- (2-methoxyphenyl) -5- (1-hydroxyethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 30)
  • Compound obtained in ⁇ Step 1> A tetrahydrofuran solution (1.0 M, 0.6 mL) of methylmagnesium bromide was added to a tetrahydrofuran solution (1.0 mL) of 100.0 mg) under ice cooling, and the mixture was stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate.
  • Example 31 N- (2-methoxyphenyl) -5-ethenyl-3- (1-piperidinylsulfonyl) benzamide
  • Example 32 N- (2-Methoxyphenyl) -5-cyano-3- (1-piperidinylsulfonyl) benzamide ⁇ Step 1> N- (2-Methoxyphenyl) -5-[(hydroxyimino) methyl Synthesis of 3- (1-piperidinylsulfonyl) benzamide (Example 30) Hydroxyamine hydrochloride (5.0 mL) was added to an ethanol solution (5.0 mL) of the compound (200.0 mg) obtained in ⁇ Step 1>. 100.0 mg) and sodium acetate (120.0 mg) were added, and the mixture was stirred with heating under reflux for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (230.0 mg) as a colorless amorphous.
  • ⁇ Step 2> Synthesis of N- (2-methoxyphenyl) -5-cyano-3- (1-piperidinylsulfonyl) benzamide (Example 32) Compound (60.0 mg) obtained in ⁇ Step 1> To a methylene chloride solution (2.0 mL) were added 2-chloro-1,3-dimethylimidazolinium chloride (29.0 mg) and triethylamine (50.0 ⁇ L) at room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate.
  • ⁇ Step 2> Synthesis of N- (2-methoxyphenyl) -5- (methoxymethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 33)
  • the compound obtained in ⁇ Step 1> 40.
  • Sodium methoxide (28% methanol solution, 0.1 mL) was added to a methanol solution (1.0 mL) of 0 mg), and the mixture was stirred at room temperature overnight and at 60 ° C. for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate.
  • ⁇ Step 2> Synthesis of N- (2-methoxyphenyl) -5-[(acetylamino) methyl)]-3- (1-piperidinylsulfonyl) benzamide (Example 34)
  • Acetic anhydride (3 drops) was added to a pyridine solution (0.5 mL) of (20.0 mg), and the mixture was stirred at room temperature for 3 hours. Then, water (5 mL) was added and further stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed successively with water and 1N hydrochloric acid, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was triturated with ether to obtain the title compound (13.0 mg) as a white solid.
  • Example 35 N- (2-methoxyphenyl) -5-[(dimethylamino) methyl] -3- (1-piperidinylsulfonyl) benzamide
  • a dimethylamine-tetrahydrofuran solution 2.0 M, 1.0 mL
  • the compound synthesized in ⁇ Step 1> (30.0 mg) was added, and the mixture was stirred at room temperature overnight.
  • Example 36 N- (4-Methoxyphenyl) -4-chloro-3- (4-morpholinylsulfonyl) benzamide
  • Example 37 N- (2-pyridinyl) -4-bromo-3- (1 -Piperidinylsulfonyl) benzamide
  • Example 38 N- (4-Ethoxyphenyl) -4-fluoro-3- (1-piperidinylsulfonyl) benzamide
  • Example 39 N- (4-methoxyphenyl)- 4-Methoxy-3- (4-morpholinylsulfonyl) benzamide
  • Example 40 N- [2-[[(4-Chlorophenyl) amino] carbonyl] phenyl] -4-methyl-3- (4-morpholine Nylsulf
  • Example 42 N- [2-Hydroxy-4- (trifluoromethyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide
  • Example 43 N- [2- (4- Morpholinyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide
  • Example 44 N- [2- (1-methylethyl) phenyl] -2-chloro-5- (1-piperidi) Nylsulfonyl) benzamide
  • Example 45 N-[(2-aminocarbonyl) phenyl] -3- (1-pyrrolidinylsulfonyl) benzamide
  • Example 46 N- [2′-methoxy [1,1′
  • Example 18 N-cyclohexyl-2-chloro-5- (1-piperidinylsulfonyl) benzamide
  • Example 59 N- (1,2,3,4-tetrahydronaphthalen-1-yl) -3- (1-Piperidinylsulfonyl) benzamide
  • Example 60 [3,6-Dihydro-4-phenyl-1 (2H) -pyridinyl]-[3- (1-piperidinylsulfonyl) phenyl] methanone
  • Example 61 N- (Benzimidazol-2-yl) -3- (1-piperidinylsulfonyl) benzamide
  • Example 62 N- [3- (1-piperidinylsulfonyl) phenyl]
  • Example 64 N- (2-methoxyphenyl) -3- (1-piperidinylsulfonyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxamide ⁇ Step 1> 3- (1-Pi Synthesis of (peridinylsulfonyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (Example 25) According to the method described in ⁇ Step 1> and synthesized according to the method described in German pamphlet No. 75/252644. The title compound (170.0 mg) was obtained as a brown viscous substance from 3- (chlorosulfonyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (140.0 mg).
  • Example 65 N- [4- (trifluoromethoxy) phenyl] -6- (1-piperidinylsulfonyl) -2,3-dihydro-3-methyl-1H-indene-4-carboxamide ⁇ Step 1 > Synthesis of 2- (2-carboxy-1-methylethenyl) benzoic acid Ethyl synthesized according to the method described in Journal of Medicinal Chemistry, 26, 1764-1766, 1996 2- (1 , 3-Dihydro-1-methyl-3-oxoisobenzofuran-1-yl) acetic acid (600.0 mg) in methanol (10.0 mL) was charged with 1N aqueous sodium hydroxide (10.0 mL) and heated to reflux. Stir for 4 hours.
  • ⁇ Step 2> Synthesis of 3- (2-carboxyphenyl) butyric acid (Example 26) In the same manner as ⁇ Step 4>, the title was obtained from the compound (300.0 mg) obtained in (Example 65) ⁇ Step 1>. The compound (280.0 mg) was obtained as a white solid.
  • ⁇ Step 3> Synthesis of 2,3-dihydro-3-methyl-1-oxo-1H-indene-4-carboxylic acid (Example 65) Compound (280.0 mg) obtained in ⁇ Step 2>, sodium chloride (90.0 mg) was added with aluminum chloride (900.0 mg) and heated at 150 ° C. for 4 hours. 1N hydrochloric acid cooled with ice was added to the mixture to precipitate a solid, which was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was triturated with diethyl ether to obtain the title compound (100.0 mg) as a light brown solid.
  • ⁇ Step 4> Synthesis of 2,3-dihydro-1-hydroxy-3-methyl-1H-indene-4-carboxylic acid (Example 65) Methanol solution of the compound (100.0 mg) obtained in ⁇ Step 3> (5.0 mL) was added sodium borohydride at room temperature and stirred overnight. The reaction solution was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (100.0 mg) as a light brown solid.
  • ⁇ Step 6> Synthesis of 6- (chlorosulfonyl) -2,3-dihydro-3-methyl-1H-indene-4-carboxylic acid (Example 65) Compound obtained in ⁇ Step 5> (90.0 mg) To the mixture, chlorosulfonic acid (1.0 mL) was added, and the mixture was stirred at 100 ° C. for 4 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (120.0 mg) as a light brown solid.
  • ⁇ Step 7> Synthesis of 6- (1-piperidinylsulfonyl) -2,3-dihydro-3-methyl-1H-indene-4-carboxylic acid (Example 25) In the same manner as in ⁇ Step 1>, ( Example 65 The title compound (54.0 mg) was obtained as a pale-brown solid from the compound (120.0 mg) obtained in ⁇ Step 6>.
  • ⁇ Step 2> Synthesis of 2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid methyl ester
  • Example 66 Compound obtained in ⁇ Step 1> (2.2 g) To a methylene chloride solution (40.0 mL) of triethylamine (6.3 mL) was added trifluoroacetic anhydride (3.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. 0.5N Hydrochloric acid was added to the reaction solution, the mixture was extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • ⁇ Step 3> Synthesis of 7- (chlorosulfonyl) -2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid
  • chlorosulfonic acid 8.3 mL
  • Example 66 The compound obtained in ⁇ Step 2> (2.4 g) was added, and the temperature was raised to 100 ° C. and stirred for 2 hours.
  • the reaction solution was poured into ice water, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (3.2 g) as a brown solid.
  • ⁇ Step 4> Synthesis of 7- (1-piperidinylsulfonyl) -2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (Example 66) In ⁇ Step 3> Using the obtained compound (1.9 g), the title compound (1.6 g) was obtained as a brown solid by a method according to (Example 25) ⁇ Step 1>.
  • Example 67 N- (2-methoxyphenyl) -2-methylsulfonyl-7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 66) Methanesulfonyl chloride was added to a methylene chloride solution (1.0 mL) of the compound synthesized in ⁇ Step 6> (50.0 mg) and diisopropylethylamine (24 ⁇ L) at room temperature and stirred for 2 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with methylene chloride and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was triturated with ethyl acetate to obtain the title compound (36.8 mg) as a white solid.
  • Example 70 N- [4- (trifluoromethoxy) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) -3-pyridinecarboxamide ⁇ Step 1> 2-hydroxy-5-sulfo- Synthesis of 3-pyridinecarboxylic acid 2-hydroxy-3-pyridinecarboxylic acid (10.0 g) was added to 60% sulfuric acid (15.0 mL) at room temperature, and the mixture was stirred at 140 ° C. for 10 hours. Water was added to the reaction solution, and the precipitated solid was filtered off. The obtained solid was stirred in acetone, then collected by filtration and dried under reduced pressure to obtain the title compound (7.0 g) as a white solid.
  • ⁇ Step 2> Synthesis of 2-chloro-5- (chlorosulfonyl) -3-pyridinecarboxylic acid (Example 70)
  • a toluene solution (5.0 mL) of the compound (1.0 g) obtained in ⁇ Step 1> Thionyl chloride (1.7 mL) and N, N-dimethylformamide (0.2 mL) were added, and the mixture was stirred for 5 hours with heating under reflux. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.97 g) as a brown solid.
  • ⁇ Step 3> Synthesis of 2-chloro-5- (1-piperidinylsulfonyl) -3-pyridinecarboxylic acid (Example 25) In the same manner as in ⁇ Step 1>, (Example 70) in ⁇ Step 2> The title compound (0.51 g) was obtained as a white solid from the obtained compound (0.47 g).
  • ⁇ Step 2> Synthesis of 5- (1-piperidinylsulfonyl) -2-furancarboxylic acid ethyl ester (Example 71) Using the compound (0.64 g) obtained in ⁇ Step 1>, (Example 25) ) The title compound (0.41 g) was obtained as a colorless oil by the method according to ⁇ Step 1>.
  • Example 72 N- [4- (trifluoromethoxy) phenyl] -3-methyl-5- (1-piperidinylsulfonyl) -2-furancarboxamide ⁇ Step 1> 5- (Chlorosulfonyl) -3 Synthesis of -methyl-2-furancarboxylic acid methyl ester (Example 2) The title compound (1.5 g) was prepared from 3-methyl-2-furancarboxylic acid methyl ester (1.0 g) by the method according to ⁇ Step 1>. Was obtained as a brown oil.
  • ⁇ Step 2> Synthesis of 3-methyl-5- (1-piperidinylsulfonyl) -2-furancarboxylic acid methyl ester (Example 25) In the same manner as in ⁇ Step 1>, (Example 72) ⁇ Step 1 The title compound (1.1 g) was obtained as a brown solid from the compound (1.0 g) obtained in>.
  • ⁇ Step 3> Synthesis of 3-methyl-5- (1-piperidinylsulfonyl) -2-furancarboxylic acid (Example 25) In the same manner as in ⁇ Step 2>, (Example 72) in ⁇ Step 2> The title compound (0.88 g) was obtained as a brown solid from the obtained compound (1.0 g).
  • Example 73 N- (2-methoxyphenyl) -2-methyl-5- (1-piperidinylsulfonyl) -3-furancarboxamide ⁇ Step 1> 5- (Chlorosulfonyl) -2-methyl-3 Synthesis of -furancarboxylic acid methyl ester (Example 2) The title compound (1.6 g) was obtained as a brown oily substance from 2-methyl-3-furancarboxylic acid methyl ester (1.0 g) by the method according to ⁇ Step 1>. Got as.
  • ⁇ Step 2> Synthesis of 2-methyl-5- (1-piperidinylsulfonyl) -3-furancarboxylic acid methyl ester (Example 25) In the same manner as in ⁇ Step 1>, (Example 73) ⁇ Step 1 > (1.1 g) to give the title compound (0.85 g) as a brown solid.
  • ⁇ Step 3> Synthesis of 2-methyl-5- (1-piperidinylsulfonyl) -3-furancarboxylic acid (Example 25) In the same manner as in ⁇ Step 2>, (Example 73) in ⁇ Step 2> The title compound (0.85 g) was obtained as a brown solid from the obtained compound (1.0 g).
  • Example 74 N- (2-methoxyphenyl) -1-methyl-5- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxamide ⁇ Step 1> 1-methyl-5- (1- Synthesis of piperidinylsulfonyl) -1H-pyrrole-2-carboxylic acid methyl ester (Example 25) 5- (chlorosulfonyl) -1-methyl-1H-pyrrole-2-carboxylic acid by a method according to ⁇ Step 1> The title compound (1.2 g) was obtained as a white solid from the acid methyl ester (1.0 g).
  • ⁇ Step 2> Synthesis of 1-methyl-5- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxylic acid (Example 25) In the same manner as in ⁇ Step 2>, (Example 74) ⁇ Step The title compound (0.88 g) was obtained as a brown solid from the compound (1.0 g) obtained in 1>.
  • Example 75 N- (2-Methoxyphenyl) -1-methyl-4- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxamide 1-methyl
  • the title compound (35.7 mg) was obtained as a colorless oil from -4- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxylic acid (50.0 mg).
  • Example 76 N- (2-methoxyphenyl) -4- (1-piperidinylsulfonyl) -2-thiophenecarboxamide represented by the above formula (XI-1) by a method according to (Example 18) The title compound was obtained from the amine and the carboxylic acid represented by the formula (X-1).
  • Example 78 N-phenyl-N ′-[[5- (1-piperidinylsulfonyl) -2-thienyl] methyl] urea
  • the above formula (X-3) The title compound was obtained from the amine represented and the isocyanate represented by the formula (XI-4).
  • the reaction solution was diluted 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 dissolved in ethyl acetate and methanol, and the insoluble material was filtered off.
  • the solvent was evaporated under reduced pressure to obtain the title crude compound (0.90 g) as a pale yellow oily substance. .
  • Example 80 N- (2-methoxyphenyl) -3-[(1-piperidinesulfonyl) amino] benzamide 3-[(1-piperidinesulfonyl) amino] benzoic acid (in accordance with the method of Example 18) 75.0 mg) gave the title compound (31.6 mg) as a white solid.
  • Example 82 N- (1,4-Dihydro-2-oxo-2H-3,1-benzoxazin-8-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] 8-amino-1,4 synthesized in accordance with the method described in Journal of Medicinal Chemistry, 39, 4654-4666, 1996 by a method according to Benzamide (Example 18). -The title compound from dihydro-2H-3,1-benzoxazin-2-one (59.1 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg) 28.6 mg) was obtained as a yellow solid.
  • ⁇ Step 2> Synthesis of 1,2,3,4-tetrahydro-3- (3,4-dimethoxybenzyl) -2-oxo-8-nitroquinazoline (Example 83)
  • Compound obtained in ⁇ Step 1> 3.0 g) in methylene chloride (100.0 mL) was added triethylamine (3.6 mL) and 1,1′-carbonylbis-1H-imidazole (3.0 g) under ice cooling, and the mixture was warmed to room temperature and overnight. Stir.
  • a 1N aqueous hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with methylene chloride.
  • the extract was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
  • the residue obtained by distilling off the solvent under reduced pressure was triturated with diethyl ether to obtain the title compound (3.0 g) as a yellow solid.
  • ⁇ Step 3> Synthesis of 1,2,3,4-tetrahydro-2-oxo-8-nitroquinazoline (Example 83)
  • the compound (1.4 g) obtained in ⁇ Step 2> Acetic acid (20.0 mL) was added, the temperature was raised, and the mixture was heated to reflux for 2 hours.
  • Trifluoroacetic acid was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride, washed with 1N aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was triturated with diethyl ether-ethyl acetate to obtain the title compound (0.78 g) as a yellow solid.
  • ⁇ Step 4> Synthesis of 8-amino-1,2,3,4-tetrahydro-2-oxoquinazoline (Example 26) A method similar to ⁇ Step 4>, obtained in (Example 83) ⁇ Step 3> The title compound (0.48 g) was obtained as a purple solid from the obtained compound (0.78 g).
  • Example 84 N- (1-Methyl-1,2,3,4-tetrahydro-2-oxo-8-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide ⁇ Step 1> Synthesis of 1,2,3,4-tetrahydro-1-methyl-3- (3,4-dimethoxybenzyl) -2-oxo-8-nitroquinazoline (Example 83) Synthesis in ⁇ Step 2> To a solution of the compound (1.5 g) in N, N-dimethylformamide (50.0 mL), potassium carbonate (1.8 g) and iodomethane (0.8 mL) were added under ice cooling, and the mixture was warmed to room temperature and stirred overnight.
  • ⁇ Step 2> Synthesis of 1,2,3,4-tetrahydro-1-methyl-2-oxo-8-nitroquinazoline (Example 83) In the same manner as in ⁇ Step 3>, (Example 84) ⁇ Step 1 > (1.4 g) to give the title compound (0.75 g) as a yellow solid.
  • ⁇ Step 3> Synthesis of 8-amino-1,2,3,4-tetrahydro-1-methyl-2-oxoquinazoline (Example 26) In the same manner as in ⁇ Step 4>, (Example 84) ⁇ Step 2 > (0.75 g) to give the title compound (0.62 g) as a brown solid.
  • Example 85 N- (1-Methyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide 1,2,3,4-Tetrahydro-5-amino-1-methyl-2-oxoquinazoline synthesized according to the method described in the pamphlet of WO2008 / 091021 by the method according to (Example 18) The title compound (14.1 mg) was obtained from 63.8 mg) and 2-chloro-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
  • Example 86 N- (1-Ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl ] 5-amino-1,2,3,4-tetrahydro-1-ethyl-2-oxo synthesized according to the method described in the pamphlet of WO2008 / 091021 by the method according to Benzamide (Example 18) The title compound (11.2 mg) was obtained from quinazoline (68.8 mg) and 2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
  • Example 87 N- (1-Ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide
  • Example 18 5-amino-1,2,3,4-tetrahydro-1-ethyl-2-oxoquinazoline (68.8 mg) synthesized according to the method described in the pamphlet of WO2008 / 091021 And 5- (1-azetidinylsulfonyl) -2-chlorobenzoic acid (99.3 mg) gave the title compound (11.7 mg).
  • Example 88 N- (1,2,3,4-Tetrahydro-3-hydroxy-2-oxo-5-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide 5-amino-1,2,3,4-tetrahydro-3-hydroxy-2-oxoquinoline synthesized according to the method described in the pamphlet of WO2007 / 010383 by a method according to (Example 18) ( The title compound (2.3 mg) was obtained from 53.3 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
  • Example 89 N- (1,3-dihydro-2-oxo-2H-indol-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 18) 4-amino-1,3-dihydro-2H synthesized according to the method described in Bioorganic Medicinal Chemistry Letters, 8, 2675-2680, 1998, -The title compound (8.9 mg) was obtained from indol-2-one (59.1 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
  • Example 90 N- (1,2,3,4-Tetrahydro-2-oxo-5-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 91) ) N- (3,4-Dihydro-3-oxo-2H-1,4-benzoxazin-8-yl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 92) N— [1,3-Benzoxazol-2 (3H) -one-7-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 93) N- (5-quinolinyl ) -2-Chloro
  • ⁇ Step 2> Synthesis of N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) -2-chloro-5- (cyclobutylaminosulfonyl) benzamide
  • Method according to Example 18 From the compound (104.3 mg) obtained in ⁇ Step 1> of 8-amino-1,2,3,4-tetrahydro-2-naphthol (58.8 mg) and (Example 94), the title compound (16 .3 mg) was obtained.
  • Example 95 those with (B) and (A) attached are the 4-amino-2,3-dihydro-1H— obtained in Example 95 ⁇ Step 1>.
  • the examples are compounds obtained by using inden-2-ol (B) and 4-amino-2,3-dihydro-1H-inden-2-ol (A), respectively.
  • Step 2> Synthesis of N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (B) According to a method according to (Example 18), 4-amino-2,3-dihydro-1H-inden-2-ol (B) (53.7 mg) obtained in (Example 95) ⁇ Step 1> and 2- The title compound (5.9 mg) was obtained from chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
  • Example 96 N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (A)
  • Example 4-Amino-2,3-dihydro-1H-inden-2-ol (A) (53.7 mg) obtained in Example 95 ⁇ Step 1> according to the method of (Example 18) and 2- The title compound (5.5 mg) was obtained from chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
  • Example 97 N- (5,6,7,8-tetrahydronaphthalen-1-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
  • Example 98 N— [2- (tert-Butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-8-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
  • Example 99 N- [2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-5-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
  • Example 107 N- (1-Ethylindole-4-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide ⁇ Step 1> Synthesis of 1-ethyl-4-nitroindole 4-nitro To an acetone solution (21.0 mL) of indole (1.00 g), potassium hydroxide powder (1.73 g) and iodoethane (0.99 mL) were added under ice cooling, and the mixture was warmed to room temperature and stirred for 20 minutes. Toluene was added to the reaction solution and filtered, and 5% aqueous citric acid solution was added to the filtrate to separate the aqueous layer, followed by drying over anhydrous magnesium sulfate.
  • ⁇ Step 2> Synthesis of 4-amino-1-ethylindole (Example 26) In the same manner as in ⁇ Step 4>, (Example 107) From the compound (1.15 g) obtained in ⁇ Step 1>, the title The compound (0.85 g) was obtained as a brown solid.
  • Step 3> Synthesis of N- (1-ethylindol-4-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 107)
  • the title compound (14.3 mg) was obtained from the compound obtained in Step 2> (57.7 mg) and 2-chloro-5- (4-morpholinylsulfonyl) benzoic acid (110.1 mg).
  • Example 108 N- [1- (1-Methylethyl) -indol-4-yl] -2-chloro-5-[[(2-hydroxy-1,1-dimethylethyl) amino] sulfonyl] benzamide ⁇ Step 1> Synthesis of 1- (1-methylethyl) -4-nitroindole (Example 84) 4-Nitroindole (1.00 g) and 2-iodopropane (1.34 mL) according to the method of ⁇ Step 1> ) Gave the title compound (0.68 g) as a brown oil.
  • ⁇ Step 3> Synthesis of 2-chloro-5-[[(2-hydroxy-1,1-dimethylethyl) amino] sulfonyl] benzoic acid (Example 25) In the same manner as in ⁇ Step 1>, 2-amino- The title compound (8.12 g) was obtained as a white solid from 2-methyl-1-propanol (18.7 mL) and 2-chloro-5- (chlorosulfonyl) benzoic acid (10.0 g).
  • Example 109 N- [1- (2-hydroxyethyl) -indol-4-yl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide ⁇ Step 1> 1 Synthesis of — [2-[(tetrahydro-2H-pyran-2-yl) oxy] ethyl] -4-nitroindole (Example 84) 4-Nitroindole (1.00 g) by the method according to ⁇ Step 1> And 2- (2-bromoethoxy) tetrahydro-2H-pyran (1.96 mL) gave the title compound (1.70 g) as a brown oil.
  • ⁇ Step 2> Synthesis of 1- (2-hydroxyethyl) -4-nitroindole (Example 109)
  • p-Toluenesulfonic acid monohydrate (0.44 g) was added and stirred for 5 hours 30 minutes.
  • a 5% aqueous citric acid solution was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate.
  • Example 110 N- (1H-Indol-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 111) N- (3,3-dimethyl- 2,3-Dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 112) N- (3,3-dimethyl-2, 3-Dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 113) N- (3,3-dimethyl- 2,3-Dihydro-2-oxo
  • Example 118 N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(2,2-dimethylpropyl) amino ] Sulfonyl] benzamide
  • Step 1 Synthesis of 5-[[(2,2-dimethylpropyl) amino] sulfonyl] benzoic acid (Example 25) 2,2-dimethylpropylamine (Step 2) 1.16 mL) and 2-chloro-5- (chlorosulfonyl) benzoic acid (0.50 g) gave the title compound (0.33 g) as a white solid.
  • Example 119 N- (2,3-dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 18) 6-amino-1,3-dihydro-3-synthesized according to the method described in Journal of Medicinal Chemistry, 30, 1279-1287, 1987. The title compound (14.7 mg) was obtained from methyl-2H-indol-2-one (58.4 mg) and 2-chloro-5- (4-morpholinylsulfonyl) benzoic acid (110.1 mg).
  • Example 120 N- (2,3-Dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl ] 6-amino-1,3-dihydro-3-methyl-2H-indol-2-one (58.4 mg) and 2-chloro-5-[[(1, The title compound (11.7 mg) was obtained from 1-dimethylethyl) amino] sulfonyl] benzoic acid (105 mg).
  • Example 121 N- (2,3-Dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide (Example 18) ), 6-amino-1,3-dihydro-3-methyl-2H-indol-2-one (58.4 mg) and 5- (1-azetidinylsulfonyl) -2-chlorobenzoic acid ( From 99.3 mg), the title compound (9.2 mg) was obtained.
  • Example 122 N- (2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 123) ) N- (1,4-Benzodioxane-6-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example 124) N- (2,3-dihydro-2,2,3 3-Tetrafluoro-1,4-benzodioxin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
  • ⁇ Step 2> Synthesis of 4-acetyl-2,3-dihydro-2,2-dimethyl-6-nitro-4H-1,4-benzoxazine (Example 125)
  • Compound obtained in ⁇ Step 1> (2. 10 g) to a pyridine solution (30.0 mL), acetic anhydride (4.77 mL) and 4- (dimethylamino) pyridine (0.49 g) were added at room temperature and stirred overnight, and then the temperature was raised to 50 ° C. for 5 hours. The mixture was stirred at 120 ° C. for 5 hours and 30 minutes.
  • ⁇ Step 3> Synthesis of 4-acetyl-6-amino-2,3-dihydro-2,2-dimethyl-4H-1,4-benzoxazine (Example 26) In the same manner as in ⁇ Step 4>, Example 125) The title compound (0.92 g) was obtained as a brown solid from the compound (1.30 g) obtained in ⁇ Step 2>.
  • Example 126 N- (4-acetyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide 18) 4-acetyl-6-amino-3,4 synthesized according to the method described in Journal of Medicinal Chemistry, 32, 1627-1630, 1989, according to the method according to 18).
  • -Dihydro-4H-1,4-benzoxazine (69.2 mg) and 5- (1-azetidinylsulfonyl) -2-chlorobenzoic acid (99.3 mg) gave the title compound (20.4 mg). .
  • Example 127 N- (1,2,3,4-Tetrahydro-1-acetylquinolin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide 18)
  • the title compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to 18).
  • Example 128 N- [1,2,3,4-Tetrahydro-1- (trifluoroacetyl) quinolin-7-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] 1,2,3,4-tetrahydro-1- (trifluoroacetyl) -7-quinolinamine synthesized according to the method described in the pamphlet of International Publication No. 2007/010383 by the method according to Benzamide (Example 18) The title compound (3.1 mg) was obtained from (87.9 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
  • Example 129 N- (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] 7-amino-1,4-dihydro-2H-3,1-benzoxazin-2-one synthesized according to the method described in the pamphlet of International Publication No. 2008/091021 by a method according to benzamide (Example 18) From 71.0 mg and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg), the title compound (7.8 mg) was obtained as a white solid.
  • Example 130 N- (1,2,3,4-Tetrahydro-3-methyl-2-oxo-7-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide 7-amino-3-methyl-3,4-dihydro-1H-quinazolin-2-one synthesized according to the method described in the pamphlet of WO2008 / 091021 by a method according to (Example 18) (47 0.0 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (30.0 mg) gave the title compound (5.7 mg) as a white solid.
  • Example 131 N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 132) N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide Example 133) N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] Sulfonyl] benzamide
  • Example 134 and (Example 135) show optical resolution using the column for separation of optical isomers of the racemate obtained in (Example 133).
  • the enantiomer obtained as the first fraction is represented by (A)
  • the enantiomer obtained as the second fraction is represented by (B).
  • Example 134 (S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide
  • A Example 135
  • R -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide
  • Example 134 (S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide (Example 134) can also be obtained by the following method.
  • Step 1 Synthesis of methyl (S) -2- (2,4-dinitrophenoxy) propionate 60% oily sodium hydride in a solution of methyl- (L) -lactate (0.1 mL) in tetrahydrofuran (5.0 mL) (50 mg) was added, and the mixture was stirred for 10 min, 15-crown-5 (5 drops) and 2,4-dinitrofluorobenzene (0.14 mL) were added, and the mixture was stirred at 45 ° C. for 8 hr. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Example 136 N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide
  • Example 137 N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclobutylamino) sulfonyl] Benzamide (Example 138) N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1- Dimethylethyl) amino] sulfonyl] benzamide
  • Example 139 N- [3,4-dihydro-2- (2-hydroxyethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[methyl (1-Methylethyl) amino] sulfonyl] benzamide 6-amino-2- (2-hydroxyethyl) synthesized according to the method described in the pamphlet of International Publication No. 2008/091021 by the method according to Example 18 The title compound was obtained from 4H-benzo [1,4] oxazin-3-one (75.0 mg) and 2-chloro-5-[[methyl (1-methylethyl) amino] sulfonyl] benzoic acid (105.0 mg). (19.4 mg) was obtained.
  • Example 140 N- (3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1 -Dimethylethyl) amino] sulfonyl] benzamide 6-amino-3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazine (69.2 mg) and 2-chloro-5- [ The title compound (18.8 mg) was obtained from [(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (105.0 mg).
  • Example 141 N- (3,4-Dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5- (1-azetidinylsulfonyl) -2 -Chlorobenzamide (Example 142) N- (3,4-Dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4- Morpholinylsulfonyl) benzamide (Example 143) N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5 [[(1-Methylethyl) amino] sulfonyl
  • Example 148 N- [2-Methyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1-methyl Ethyl) amino] sulfonyl] benzamide ⁇ Step 1> Synthesis of 2-methyl-3-[(1-methylethyl) oxy] -6-nitro-2H-1,4-benzoxazine (Example 84) ⁇ Step 1> From 2-methyl-6-nitro-2H-benzo [b] [1,4] oxazin-3 (4H) -one (1.00 g), 2-iodopropane (0.94 mL), The compound (0.49 g) was obtained as a yellow oil.
  • ⁇ Step 2> Synthesis of 6-amino-2-methyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazine (Example 26) In the same manner as in ⁇ Step 4>, Example 148) The title compound (0.38 g) was obtained as a brown oil from the compound (0.43 g) obtained in ⁇ Step 1>.
  • Example 149 N- [3,4-dihydro-4- (2-hydroxyethyl) -2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5 — [[(1,1-dimethylethyl) amino] sulfonyl] benzamide represented by the formula (XI-1) and the formula (X-1) by a method according to Example 18 The title compound was obtained from carboxylic acid.
  • Example 150 N- (3,4-Dihydro-2,2,4-trimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 , 1-Dimethylethyl) amino] sulfonyl] benzamide ⁇ Step 1> Synthesis of 3,4-dihydro-2,2,4-trimethyl-6-nitro-2H-1,4-benzoxazin-3 (4H) -one
  • Example 84 3,4-Dihydro-2,2-dimethyl-6-nitro-2H-benzo [b] [1,4] oxazin-3 (4H) -one by the method according to ⁇ Step 1>
  • the title compound (0.96 g) was obtained as a yellow solid from 1.00 g) and iodomethane (0.84 mL).
  • ⁇ Step 2> Synthesis of 6-amino-2,2,4-trimethyl-2H-1,4-benzoxazin-3 (4H) -one (Example 26) In the same manner as in ⁇ Step 4>, (Example 150) The title compound (0.77 g) was obtained as a white solid from the compound (0.93 g) obtained in ⁇ Step 1>.
  • Example 151 N- (4-Ethyl-3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[ (1,1-Dimethylethyl) amino] sulfonyl] benzamide ⁇ Step 1> 4-Ethyl-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-3 (4H) Synthesis of —one (Example 84) 3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzoxazine [b] [1,4] oxazine-3 (by the method according to ⁇ Step 1>) The title compound (0.76 g) was obtained as a black solid from 4H) -one (1.00 g) and iodoethane (0.40 mL).
  • ⁇ Step 2> Synthesis of 6-amino-3,4-dihydro-2,2-dimethyl-4- (1-methylethyl) -2H-1,4-benzoxazin-3 (4H) -one (Example 26) ) 2,2-Dimethyl-4- (1-methylethyl) -6-nitro-2H-1,4-benzoxazine obtained in ⁇ Step 1> according to the method according to ⁇ Step 4>
  • the title compound (0.27 g) was obtained as a brown oil from 3 (4H) -one (0.30 g).
  • Example 153 N- [2,2-dimethyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide ⁇ Step 1> Synthesis of 6-amino-2,2-dimethyl-3-[(1-methylethyl) oxy] -2H-benzoxazine (Example 26) ⁇ Step 4> (Example 152) From 2,2-dimethyl-3-[(1-methylethyl) oxy] -6-nitro-2H-benzoxazine (0.53 g) obtained in ⁇ Step 1>, The title compound (0.47 g) was obtained as a brown oil.
  • ⁇ Step 2> Synthesis of 6-amino-3,4-dihydro-4- (2-hydroxyethyl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (Example 26) )
  • the title compound (0.55 g) was obtained as a brown solid from the compound (0.66 g) synthesized in (Example 154) ⁇ Step 1>.
  • Example 155 N- [3,4-dihydro-4- (2-hydroxyethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[(cyclo Butylamino) sulfonyl] benzamide (Example 156) N- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5- (1-azetidinyl) Sulfonyl) -2-chlorobenzamide
  • Example 157 N- (1,2,3,4-tetrahydro-2-oxo-7-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
  • Example 18 7-amino-3,4-dihydro-1H-quinazolin-2-one (58.8 mg) synthesized according to the method described in the pamphlet of WO 2008/091021 and 2-chloro- The title compound (3.5 mg) was obtained as a white solid from 5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
  • Example 163 N- (1,3-dimethyl-1,2,3,4-tetrahydro-2-oxo-6-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl Benzamide ⁇ Step 1> Synthesis of N- (2-amino-5-nitrobenzyl) methylamine (Example 83) According to the method according to ⁇ Step 1>, 2-amino-5-nitrobenzaldehyde (1.00 g) and The title compound (0.50 g) was obtained as an orange solid from a methylamine-tetrahydrofuran solution (3.6 mL, 2.0 M).
  • ⁇ Step 2> Synthesis of 3-methyl-6-nitro-3,4-dihydro-2 (1H) -quinazolinone (Example 83) In the same manner as ⁇ Step 2>, (Example 163) in ⁇ Step 1> The title compound (0.22 g) was obtained as a yellow solid from the obtained compound (0.50 g).
  • ⁇ Step 3> Synthesis of 1,3-dimethyl-6-nitro-3,4-dihydro-2 (1H) -quinazolinone (Example 84) In the same manner as in ⁇ Step 1>, (Example 163) ⁇ Step 2 > (120.0 mg) gave the title compound (90.0 mg) as a yellow solid.
  • ⁇ Step 4> Synthesis of 6-amino-1,3-dimethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 26) In the same manner as in ⁇ Step 4>, (Example 163) ⁇ Step 3 The title compound (30.0 mg) was obtained as a yellow solid from the compound (90.0 mg) obtained in>.
  • Example 164 N- (1,2,3,4-tetrahydro-2-oxo-6-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 18) ), The title compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1).
  • Example 165 N- (3,4-dihydro-2,2-dioxo-1H-2,1-benzothiazin-7-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example) 18-) 7-amino-2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazine (71.) synthesized according to the method described in the pamphlet of International Publication No. 2008/091021. 4 mg) and 2-chloro-5-[(cyclopentylamino) sulfonyl] benzoic acid (109.4 mg) gave the title compound (23.4 mg).
  • Example 166 N- (2,3-dihydro-3-hydroxy-1H-inden-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
  • Example 18 6-amino-2,3-dihydro-1H-inden-1-ol (53.7 mg) and 2-chloro-synthesized according to the method described in the pamphlet of WO 2007/010383. The title compound (16.1 mg) was obtained from 5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100 mg).

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Abstract

Disclosed is a long-chain fatty acid elongase (Elovl6) inhibitor, which is characterized by comprising at least one of a compound represented by formula (I), a pharmaceutically acceptable salt of the compound, and a solvate of the compound or the pharmaceutically acceptable salt as an active ingredient. Thus, provided is an Elovl6 inhibitor, particularly a prophylactic or therapeutic agent for NAFLD·NASH, diabetes, insulin resistance, obesity/adiposity, or the like.

Description

スルファモイル基を有するアリールカルボキサミド誘導体Arylcarboxamide derivatives having sulfamoyl groups
　本発明は、長鎖脂肪酸伸長酵素（Ｅｌｏｎｇａｔｉｏｎ　ｏｆ　ｖｅｒｙ　ｌｏｎｇ　ｃｈａｉｎ　ｆａｔｔｙ　ａｃｉｄｓ－ｌｉｋｅ　６：以下Ｅｌｏｖｌ６と記す）を阻害する化合物、とりわけ、式（Ｉ）で表されるスルファモイル基を有するアリールカルボキサミド誘導体を有効成分として含有するＥｌｏｖｌ６阻害剤、あるいはＥｌｏｖｌ６が関与する疾患とりわけ非アルコール性脂肪性肝疾患（ｎｏｎａｌｃｏｈｏｌｉｃ　ｆａｔｔｙ　ｌｉｖｅｒ　ｄｉｓｅａｓｅ：以下ＮＡＦＬＤと記す）・非アルコール性脂肪性肝炎（ｎｏｎａｌｃｏｈｏｌｉｃ　ｓｔｅａｔｏｈｅｐａｔｉｔｉｓ：以下ＮＡＳＨと記す）、糖尿病、２型糖尿病、インスリン抵抗性、肥満・肥満症の予防または治療剤に関する。 INDUSTRIAL APPLICABILITY The present invention is effective for compounds that inhibit long-chain fatty acid elongation enzymes (Elongation of long chain fatty acids-like 6: hereinafter referred to as Elovl6), in particular, arylcarboxamide derivatives having a sulfamoyl group represented by formula (I) Elovl6 inhibitor contained as a component, or diseases involving Elovl6, particularly nonalcoholic fatty liver disease (hereinafter referred to as NAFLD) / nonalcoholic steatohepatitis (hereinafter referred to as NASH) The present invention relates to a preventive or therapeutic agent for diabetes, type 2 diabetes, insulin resistance, obesity / obesity.
　近年、生活習慣病についての数多くの研究報告や薬物開発がなされてきているが、各種脂肪酸の生体における機能や役割に関する情報が増えつつあり、生活習慣病等の各種疾患との関わりが報告されている。特に、メタボリックシンドローム、糖尿病、肥満、動脈硬化性疾患、脳機能、癌などに及ぼす脂肪酸の影響について、論じられている。このような影響因子として注目されている脂肪酸の生合成経路は、上記のような関連疾患の治療標的として、近年注目されている。 In recent years, many research reports and drug developments on lifestyle-related diseases have been made, but information on the functions and roles of various fatty acids in the body is increasing, and their relation to various diseases such as lifestyle-related diseases has been reported. Yes. In particular, the effects of fatty acids on metabolic syndrome, diabetes, obesity, arteriosclerotic disease, brain function, cancer, etc. are discussed. The biosynthetic pathway of fatty acids that has attracted attention as such an influencing factor has recently attracted attention as a therapeutic target for the above-mentioned related diseases.
　脂肪酸の生合成は、グルコースが解糖系によって分解され生じたピルビン酸を出発物質として行われる。ピルビン酸は、ミトコンドリアにてクエン酸に変換後、サイトゾルに運搬され、ＡＴＰクエン酸リアーゼによりアセチル－ＣｏＡに変換される。アセチル－ＣｏＡはアセチル－ＣｏＡカルボキシラーゼ（ＡＣＣ）によってマロニル－ＣｏＡに変換される。さらに、脂肪酸合成酵素（ＦＡＳ）によりマロニル－ＣｏＡが脱炭酸的に縮合することで、炭素数が２個ずつ、反応サイクルごとに増加し、炭素数１６のパルミチン酸が生合成される。パルミチン酸（Ｃ１６：０）は、ステアロイル－ＣｏＡ不飽和化酵素－１（ＳＣＤ－１）及び長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）により、ステアリン酸（Ｃ１８：０）またはパルミトレイン酸（Ｃ１６：１）を経て、オレイン酸（Ｃ１８：１）に変換される。ＳＣＤ－１は飽和脂肪酸に二重結合を導入させる酵素であり、パルミチン酸をパルミトレイン酸へ、ステアリン酸をオレイン酸へ変換させる。Ｅｌｏｖｌ６は脂肪酸を２炭素分伸長させる酵素であり、パルミチン酸をステアリン酸へ、パルミトレイン酸をオレイン酸へ変換させる。また過剰な脂肪酸合成の亢進は中性脂肪の蓄積を誘発し、さらに肥満の形成へと進むことが知られている。 Fatty acid biosynthesis is carried out using pyruvic acid, which is produced by the decomposition of glucose by a glycolytic system, as a starting material. Pyruvate is converted to citrate by mitochondria, then transported to the cytosol, and converted to acetyl-CoA by ATP citrate lyase. Acetyl-CoA is converted to malonyl-CoA by acetyl-CoA carboxylase (ACC). Furthermore, malonyl-CoA is decarboxylated and condensed by fatty acid synthase (FAS), so that the number of carbon atoms increases by 2 for each reaction cycle, and 16-carbon palmitic acid is biosynthesized. Palmitic acid (C16: 0) can be obtained by stearic acid (C18: 0) or palmitoleic acid (C16: 1) by stearoyl-CoA desaturase-1 (SCD-1) and long-chain fatty acid elongation enzyme (Elovl6). It is then converted to oleic acid (C18: 1). SCD-1 is an enzyme that introduces a double bond into a saturated fatty acid, and converts palmitic acid into palmitoleic acid and stearic acid into oleic acid. Elovl6 is an enzyme that elongates fatty acids by 2 carbons and converts palmitic acid to stearic acid and palmitoleic acid to oleic acid. Further, it is known that excessive enhancement of fatty acid synthesis induces accumulation of neutral fat and further progresses to the formation of obesity.
　Ｅｌｏｖｌ６は、長鎖脂肪酸伸長酵素群であるＥＬＯＶＬ（Ｅｌｏｎｇａｔｉｏｎ　ｏｆ　ｖｅｒｙ　ｌｏｎｇ　ｃｈａｉｎ　ｆａｔｔｙ　ａｃｉｄｓ）ファミリーに属する酵素であり、様々な別称（Ｆａｔｔｙ　ａｃｙｌ－ＣｏＡ　ｅｌｏｎｇａｓｅ（ＦＡＥまたはＦＡＣＥ）、Ｌｏｎｇ　ｃｈａｉｎ　ｆａｔｔｙ　ａｃｙｌ　ｅｌｏｎｇａｓｅ（ＬＣＥ）等）を持つ。Ｅｌｏｖｌ６は、炭素数１２～１６の飽和及び一価不飽和脂肪酸の炭素鎖伸長反応を触媒する酵素であり、極めて広範囲に渡る組織（脳・腸・肝臓・脂肪組織・骨格筋・腎臓・精巣・皮膚）に発現しており、特に脂肪酸の生合成が盛んな肝臓に多く発現している（Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，２７６（４８），４５３５８－４５３６６，（２００１）（非特許文献１）及びＪ．Ｌｉｐｉｄ　Ｒｅｓ．，４３（６），９１１－９２０，（２００２）（非特許文献２））。 Elovl6 is an enzyme belonging to the ELOVL (Elongation of long chain acid acids) family of long chain fatty acid elongation enzymes, and has various aliases (Fatty acyl-CoA elongase (FAE or FACE), Long LC LC). ) Etc). Elovl6 is an enzyme that catalyzes the carbon chain elongation reaction of saturated and monounsaturated fatty acids having 12 to 16 carbon atoms, and covers a very wide range of tissues (brain, intestine, liver, adipose tissue, skeletal muscle, kidney, testis, Expressed in the skin), particularly in the liver where fatty acid biosynthesis is active (J. Biol. Chem., 276 (48), 45358-45366, (2001) (Non-patent Document 1)) J. Lipid Res., 43 (6), 911-920, (2002) (non-patent document 2)).
　遺伝的に繁殖させたＥｌｏｖｌ６欠損マウス（Ｅｌｏｖｌ６ノックアウトマウス）に関する研究で、高脂肪・高ショ糖食負荷モデルにおいて、野生型マウスとは異なり血糖値・血中インスリン・レプチン値の低下が認められた。更に耐糖能及びインスリン感受性の改善が認められ、Ｅｌｏｖｌ６とインスリン抵抗性との関連が示唆されている（Ｎａｔ．Ｍｅｄ．，１３（１０），１１９３－１２０２，（２００７）（非特許文献３））。また、国際公開第２００５／００５６６５号パンフレット（特許文献１）では、Ｅｌｏｖｌ６と肥満の直接的な関連性が示されている。一方で、摂食によりマウスＥｌｏｖｌ６の発現量が変化する報告もある（非特許文献２）。 A study on genetically bred Elovl6-deficient mice (Elovl6 knockout mice) showed a decrease in blood glucose, blood insulin, and leptin levels in a high-fat and high-sucrose diet load model, unlike wild-type mice . Furthermore, improvement in glucose tolerance and insulin sensitivity was observed, suggesting an association between Elovl6 and insulin resistance (Nat. Med., 13 (10), 1193-1202, (2007) (Non-patent Document 3)). . In addition, International Publication No. 2005/005665 pamphlet (Patent Document 1) shows a direct relationship between Elovl6 and obesity. On the other hand, there is a report that the expression level of mouse Elovl6 is changed by feeding (Non-patent Document 2).
　さて本発明の化合物の疾病治療の対象としては、生活習慣病に代表されるＥｌｏｖｌ６の活性亢進が関係する疾病が対象となるが、好ましくは、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、２型糖尿病、インスリン抵抗性あるいは肥満・肥満症が挙げられる。 The target of disease treatment of the compound of the present invention is a disease related to increased activity of Elovl6 represented by lifestyle-related diseases, but preferably NAFLD / NASH, diabetes, type 2 diabetes, insulin resistance Or obesity and obesity are mentioned.
　殊に最近では、生活習慣病の治療ターゲットとして肝臓が重要視されている。とりわけＮＡＦＬＤ及びＮＡＳＨは、病態や診断、治療等の理解及び整理がまだ充分には進んでおらず、特にＮＡＳＨは予後も不良であることから、有効な治療法の確立が切望されている。ＮＡＦＬＤ及びＮＡＳＨの発症には肥満、糖尿病、脂質代謝異常あるいは高血圧などとのかかわりが示唆され、とりわけＮＡＳＨは肝硬変や肝癌へ進展するとされているが、そのメカニズムは依然明らかにされていない。ＮＡＳＨの実験動物モデルも適切なものが乏しかったが、最近、ヒトのＮＡＳＨ病態に近いモデルマウスとして、ＳＴＡＭ　Ｍｉｃｅ　Ｃ５７ＢＬ／６Ｎ－ＮＡＳＨモデルが報告されている（日本特開第２００９－１７８１４３号パンフレット（特許文献２））。しかしながら、ＮＡＦＬＤやＮＡＳＨとＥｌｏｖｌ６の関与、更にはオレイン酸との関与については、いくつもの示唆がある。 Especially recently, the liver is regarded as important as a treatment target for lifestyle-related diseases. In particular, NAFLD and NASH are not yet fully understood and arranged for pathological conditions, diagnosis, treatment, etc., and especially NASH has a poor prognosis. Therefore, establishment of an effective treatment method is eagerly desired. The onset of NAFLD and NASH has been suggested to be associated with obesity, diabetes, abnormal lipid metabolism or hypertension, and NASH is considered to progress to cirrhosis and liver cancer, but the mechanism has not yet been clarified. Although the experimental animal model of NASH was not appropriate, the STAM Mice C57BL / 6N-NASH model has recently been reported as a model mouse close to human NASH pathology (Japanese Patent Laid-Open No. 2009-178143 ( Patent Document 2)). However, there are a number of suggestions regarding the involvement of NAFLD, NASH, and Elovl6, as well as the involvement of oleic acid.
　例えば、国際公開第２００８／１２０６５３号パンフレット（特許文献３）、国際公開第２００９／０３８０２１号パンフレット（特許文献４）及び国際公開第２００９／０４４７８８号パンフレット（特許文献５）には、Ｅｌｏｖｌ６阻害作用を有する化合物の薬物の治療標的として、糖尿病、肥満と並んで非アルコール性脂肪肝（ＮＡＦＬＤ）が挙げられている。
　そしてＮＡＳＨの基礎研究において、ＮＡＳＨと各種脂肪酸の関連、特に生体中におけるオレイン酸の増加が注目されている。例えば、ＮＡＳＨの動物モデルとして注目されている肝細胞特異的Ｐｔｅｎ（ｐｈｏｓｐｈａｔａｓｅ　ａｎｄ　ｔｅｎｓｉｎ　ｈｏｍｏｌｏｇ）欠損マウスにおいて、肝臓に含有される脂質の脂肪酸分画変化について報告がある。特にオレイン酸の増加が顕著であり、増悪因子的に説明されている（Ｊ．Ｃｌｉｎ．Ｉｎｖｅｓｔ．，１１３（１２），１７７４－１７８３（２００４）（非特許文献４））。また、ＮＡＳＨ患者においても、血漿中オレイン酸の増加がみられることが報告されている（Ｃｌｉｎ．　Ｎｕｔｒ．，２１（３），２１９－２２３（２００２）（非特許文献５））。 For example, International Publication No. 2008/120653 (Patent Document 3), International Publication No. 2009/038021 (Patent Document 4) and International Publication No. 2009/044788 (Patent Document 5) have an Elovl6 inhibitory action. Non-alcoholic fatty liver (NAFLD) is listed as a therapeutic target of the drug of the compound possessed along with diabetes and obesity.
In the basic research of NASH, attention has been paid to the relationship between NASH and various fatty acids, especially the increase of oleic acid in the living body. For example, in a hepatocyte-specific Pten (phosphate and tenthin homolog) -deficient mouse, which has been attracting attention as an animal model of NASH, there has been a report on a change in fatty acid fraction of lipid contained in the liver. In particular, the increase in oleic acid is remarkable and is explained as an exacerbation factor (J. Clin. Invest., 113 (12), 1774-1783 (2004) (Non-patent Document 4)). In addition, it has been reported that an increase in plasma oleic acid is also observed in NASH patients (Clin. Nutr., 21 (3), 219-223 (2002) (Non-patent Document 5)).
　かかるおり、最近、生体中のオレイン酸の増加抑制もしくは減少させる薬物がヒトのＮＡＦＬＤ・ＮＡＳＨの治療に有用な薬物になると期待される報告がされた。その代表例として、ＮＡＦＬＤ・ＮＡＳＨの臨床的知見において、ＥＰＡ（Ｅｉｃｏｓａｐｅｎｔａｅｎｏｉｃ　ａｃｉｄ）投与による治療の有効性を示唆する報告がある。具体的にはＮＡＳＨ患者において、ＥＰＡ投与による肝脂肪変性等に対する有効性が示唆されている（Ｊ．Ｃｌｉｎ．Ｇａｓｔｒｏｅｎｔｅｒｏｌ．，４２（４），４１３－４１８（２００８）（非特許文献６））。また、ＮＡＦＬＤ患者においても、ＥＰＡとＤＨＡからなるω３多価不飽和脂肪酸投与による肝脂肪変性の改善が報告されている（Ａｌｉｍｅｎｔ．Ｐｈａｒｍａｃｏｌ．Ｔｈｅｒ．，２３（８），１１４３－１１５１（２００６）（非特許文献７））。 Therefore, recently, it has been reported that a drug that suppresses or decreases the increase of oleic acid in a living body is expected to be a useful drug for treatment of human NAFLD / NASH. As a representative example, there is a report suggesting the effectiveness of treatment by administration of EPA (Eicosapentaenoic acid) in the clinical findings of NAFLD / NASH. Specifically, in patients with NASH, effectiveness against hepatic steatosis by EPA administration has been suggested (J. Clin. Gastroenterol., 42 (4), 413-418 (2008) (Non-patent Document 6)). In addition, in patients with NAFLD, improvement of hepatic steatosis by the administration of ω3 polyunsaturated fatty acid consisting of EPA and DHA has been reported (Alignment. Pharmacol. Ther., 23 (8), 1143-1151 (2006) ( Non-patent document 7)).
　このようなＥＰＡによるＮＡＦＬＤ・ＮＡＳＨ治療に関しては、上述したＮＡＳＨの増悪因子と考えられているオレイン酸の関与が、メカニズムの一つと考えられている。例えば、前記の肝細胞特異的Ｐｔｅｎ欠損マウスにおいて、ＥＰＡの脂肪性肝炎に対する有効性が示されており、ＥＰＡがオレイン酸／ステアリン酸の比を低下させることの有用性が説かれている（Ｊ．Ｈｅｐａｔｏｌ．，５０（３），５６２－５７１（２００９）（非特許文献８））。 Regarding such NAFLD / NASH treatment by EPA, the involvement of oleic acid, which is considered to be an aggravating factor of NASH, is considered as one of the mechanisms. For example, in the aforementioned hepatocyte-specific Pten-deficient mice, the effectiveness of EPA against steatohepatitis has been demonstrated, and the usefulness of EPA in reducing the ratio of oleic acid / stearic acid has been described (J Hepatol., 50 (3), 562-571 (2009) (non-patent document 8)).
　なお、高脂血症に対するＥＰＡ製剤（ＥＰＡ－Ｅ）の大規模臨床試験であるＪＥＬＩＳの知見において、ＥＰＡの投与による主要冠動脈イベントの発症抑制が報じられているが、同時に、ＥＰＡが血漿中オレイン酸を低下させることが報告されている（Ｊ．Ａｍ．Ｃｏｌｌ．Ｃａｒｄｉｏｌ．，４９（９）Ｓｕｐｐｌ．１，３４４Ａ（１００８－１２３）（２００７）（非特許文献９））。 In addition, JELIS, which is a large-scale clinical trial of an EPA preparation (EPA-E) for hyperlipidemia, reported that EPA administration suppressed the onset of major coronary events. It has been reported to reduce acid (J. Am. Coll. Cardiol., 49 (9) Suppl. 1, 344A (1008-123) (2007) (Non-patent Document 9)).
　また、ＥＰＡを混餌投与したマウスの肝臓において、Ｅｌｏｖｌ６の発現が低下していることが報告されている（非特許文献２）。 In addition, it has been reported that the expression of Elovl6 is reduced in the liver of mice fed with EPA (Non-patent Document 2).
　以上より、Ｅｌｏｖｌ６の阻害を通じて生体のオレイン酸を低下させる薬物は、ＮＡＦＬＤとりわけＮＡＳＨに対する予防または治療効果が期待される。 From the above, a drug that lowers oleic acid in the living body through inhibition of Elovl6 is expected to have a preventive or therapeutic effect on NAFLD, particularly NASH.
　ＮＡＦＬＤは、明らかな飲酒歴がないが、アルコール性肝障害に類似した肝脂肪沈着を特徴とする肝障害であり、単純性脂肪肝から脂肪性肝炎、線維化、肝硬変、肝癌までの肝障害を含む疾患群である。ＮＡＦＬＤは、一般に予後良好と考えられている単純性脂肪肝と、予後不良なＮＡＳＨとに分類される。ＮＡＳＨはＮＡＦＬＤの重症型と考えられており、ＮＡＦＬＤのうち肝細胞の炎症や線維化を伴う進行性の疾患である。アルコール性肝障害、ウイルス性肝炎や薬剤性肝障害の否定できる肝炎の多くがＮＡＳＨの病態であろうと推定されている。米国では人口の２０％がＮＡＦＬＤ、３％がＮＡＳＨであるとされ、日本においても検診受診者の８％がＮＡＦＬＤ、成人の０．５～１％がＮＡＳＨと推定されている。また、メタボリックシンドロームを背景に、脂質代謝異常、高血圧、糖尿病、インスリン抵抗性・耐糖能異常、肥満・肥満症等の合併頻度が非常に高く、生活習慣病の増加に伴い、今後、ＮＡＳＨの症例数の増加ならびに低年層への拡大が予想される。さらに肝炎を経て一部は星状細胞活性化による肝硬変、あるいは肝癌への進行が臨床的な問題である。 NAFLD is a liver disorder characterized by hepatic fat deposition similar to alcoholic liver disorder, although there is no clear drinking history, and hepatopathy from simple fatty liver to steatohepatitis, fibrosis, cirrhosis, and liver cancer It is a disease group including. NAFLD is classified into simple fatty liver, which is generally considered to have a good prognosis, and NASH, which has a poor prognosis. NASH is considered to be a severe form of NAFLD, and is a progressive disease of NAFLD with inflammation and fibrosis of hepatocytes. It has been estimated that many hepatitis that can be ruled out for alcoholic hepatopathy, viral hepatitis and drug-induced hepatopathy are NASH pathologies. In the United States, it is estimated that 20% of the population is NAFLD, 3% is NASH, and in Japan, it is estimated that 8% of screening patients are NAFLD and 0.5-1% of adults are NASH. In addition, with the background of metabolic syndrome, the frequency of complications such as abnormal lipid metabolism, hypertension, diabetes, insulin resistance / glucose tolerance, obesity / obesity, etc. is very high. The number is expected to increase as well as to the younger age group. In addition, hepatic cirrhosis due to stellate cell activation or progression to liver cancer is a clinical problem.
　ＮＡＦＬＤ及びＮＡＳＨは、合併症を伴う際にはその治療が優先され、とりわけＮＡＳＨは肝硬変・肝癌の可能性もあることから積極的な薬物療法が必要である。これまでに種々の病態改善を目指した治療方法が試みられ、その有効性が報告されているが、いまだ確立した治療法がないのが現状である（日本肝臓学会編「ＮＡＳＨ・ＮＡＦＬＤの診察ガイド」文光堂出版、２００６年８月２２日）。具体的には、ビグアナイド薬（メトホルミン）、ＰＰＡＲγ作動薬のチアゾリジン誘導体（ピオグリタゾン、ロシグリタゾン）、グリニド（ナテグリニド）などの糖尿病薬・インスリン抵抗性改善薬；ビタミン（ビタミンＥ、ビタミンＥ＋Ｃ）、ベタイン（コリン誘導体）、Ｎ－アセチルシステインなどの抗酸化剤；ＰＰＡＲα作動薬（フィブラート系薬剤（ゲムフィブロジル）、ＫＲＰ－１０１）、ＨＭＧ－ＣｏＡ還元酵素阻害剤（アトルバスタチン）、ＦＸＲ作動薬（ＩＮＴ－７４７）、プロブコールなどの脂質異常症治療剤；ウルソデオキシコール酸（ＵＤＣＡ）、ポリエンホスファチジルコリン（ＥＰＬ）などの肝庇護剤;アンジオテンシンII受容体拮抗剤（ロサルタン）などの高血圧治療剤；ＰＤＥ－４阻害剤（ＡＳＰ９８３１）、ＴＮＦα阻害剤（ペントキシフィリン）などの炎症性サイトカイン産生抑制剤が記載される。 Treatment of NAFLD and NASH is prioritized when accompanied by complications. In particular, NASH requires active pharmacotherapy because it may cause cirrhosis and liver cancer. Various treatment methods aimed at improving various pathological conditions have been tried so far, and their effectiveness has been reported, but there is no established treatment method yet (the Japan Society for Hepatology “NASH / NAFLD diagnosis guide” “Bunkodo Publishing, August 22, 2006). Specifically, biguanides (metformin), PPARγ agonist thiazolidine derivatives (pioglitazone, rosiglitazone), glinides (nateglinide) and other antidiabetic / insulin resistance improving drugs; vitamins (vitamin E, vitamin E + C), betaine ( Choline derivatives), antioxidants such as N-acetylcysteine; PPARα agonists (fibrates (gemfibrozil), KRP-101), HMG-CoA reductase inhibitors (atorvastatin), FXR agonists (INT-747), Antilipidemic agents such as probucol; liver protective agents such as ursodeoxycholic acid (UDCA) and polyenephosphatidylcholine (EPL); antihypertensive agents such as angiotensin II receptor antagonist (losartan); PDE-4 inhibitor (ASP9831) ), T Inflammatory cytokine production inhibitors such as NFα inhibitors (pentoxyphylline) are described.
　糖尿病は、複数の病因が起因となり発症する。一般的に、空腹時・食後または経口糖負荷試験時の高い血漿中グルコース濃度、あるいは慢性的な高血糖に特徴付けられる疾病である。制御不能な高血糖は、直接的または間接的に脂質代謝異常を呈し、最後は血管障害を引き起こす。従って糖尿病患者では、動脈硬化症、狭心症や心筋梗塞に代表される冠動脈性心疾患・脳梗塞・高血圧症・腎症・神経症や網膜症等の微小血管合併症の危険性が増大する。そのため慢性的な高血糖・脂質代謝異常・高血圧症の制御は、臨床における糖尿病の管理及び治療に重要である。 Diabetes develops due to multiple etiologies. Generally, it is a disease characterized by high plasma glucose concentration during fasting, postprandial or oral glucose tolerance test, or chronic hyperglycemia. Uncontrollable hyperglycemia directly or indirectly presents abnormal lipid metabolism and ultimately causes vascular injury. Therefore, in diabetic patients, the risk of microvascular complications such as coronary heart disease, cerebral infarction, hypertension, nephropathy, neuropathy, retinopathy such as arteriosclerosis, angina pectoris and myocardial infarction is increased. . Therefore, control of chronic hyperglycemia, dyslipidemia and hypertension is important for clinical management and treatment of diabetes.
　糖尿病は２種類に分類される。１型糖尿病（インスリン依存型糖尿病:ＩＤＤＭ）は、血糖調節ホルモンであるインスリンがほとんどまたは全く産出されない事を特徴とする。２型糖尿病（インスリン非依存性糖尿病：ＮＩＤＤＭ）は末梢のインスリン抵抗性の惹起とインスリン分泌不全を特徴とする。インスリン抵抗性とは、インスリン応答臓器である肝臓・骨格筋・脂肪組織におけるグルコース・脂質代謝に対する効果の耐性を示す。 Diabetes is classified into two types. Type 1 diabetes (insulin-dependent diabetes mellitus: IDDM) is characterized by little or no production of insulin, a blood glucose regulating hormone. Type 2 diabetes (non-insulin dependent diabetes mellitus: NIDDM) is characterized by peripheral insulin resistance and insulin secretion failure. Insulin resistance refers to resistance to effects on glucose and lipid metabolism in the liver, skeletal muscle, and adipose tissue that are insulin-responsive organs.
　２型糖尿病に対して有用な治療法はいまだ確立されておらず、食事・運動療法が中心となっている。これらの治療法のコンプライアンスは非常に悪い。その原因として、食生活の欧米化に伴う高カロリー食の摂取やライフスタイルの変化による生活習慣の変化が挙げられる。糖尿病の治療剤として、膵β細胞を刺激してインスリン分泌を促進するスルホニル尿素（トルブタミドやグリメピリド等）やグリニド（ミチグリニド）が挙げられる。しかし、これらの薬剤は投与無効や低血糖誘発作用、更に血漿インスリン値の上昇に伴うインスリン抵抗性の惹起作用の副作用が知られている。ビグアナイド（メトホルミン・ブホルミン）は、インスリン感受性を増加させ高血糖を改善する。しかし乳酸アシドーシスや吐き気・嘔吐などの副作用を誘発することが知られている。グリタゾン（ピオグリタゾン・ロシグリタゾン）はペルオキシソーム増殖因子活性化受容体（ＰＰＡＲ）のγサブタイプの作動薬であり、脂肪組織や肝臓・骨格筋のインスリン感受性を増加させ、慢性的な高血糖を改善する。しかし、浮腫や体重増加・更には重篤な副作用である肝障害を引き起こす事が知られている。特異的な糖尿病治療剤ではないこれらの薬物は、薬効と副作用の乖離が悪く、治療の満足度は低い。従って、経口投与でより高い有効性を示し、副作用の少ない糖尿病治療剤が求められている。
　肥満・肥満症はＢＭＩ（身体質量指数、ｋｇ／ｍ２）により評価され、日本肥満学会ではＢＭＩ２５以上を“肥満”、２型糖尿病や高血圧等の合併症を二つ以上持ち、内臓脂肪面積が１００ｃｍ２以上ある人を“肥満症”と定義している。なお、国際肥満対策委員会では、ＢＭＩが２５以上３０未満を前肥満、ＢＭＩが３０以上を肥満と定義している。肥満は心血管系疾患や糖尿病、ＮＡＦＬＤ・ＮＡＳＨ等の様々な生活習慣病の主要因として指摘されており、近年では肥満の診断や治療を積極的に行う動きが活発である。世界的にガイドラインや診断基準等が発表されており、肥満は疾患の一つとして認識されている。
　肥満・肥満症の治療の成果として、ＢＭＩを軽減することが挙げられる。治療方法として、食事療法や運動療法による生活習慣の改善がまず図られるが、そのような療法では充分な効果が得られなかった患者には薬物療法がとられる。よって近年、肥満・肥満症治療剤の開発が進められているが、抗肥満薬として現在承認されている薬剤は少ない。肥満症治療に用いられる薬剤として食欲抑制剤であるマジンドール（モノアミン再取り込み阻害剤）があるが、薬物依存性があるため投与期間が制限されており、肺高血圧症や各種精神神経症状等の副作用が知られている。脂肪分解酵素（リパーゼ）阻害剤であるオルリスタットは、痙攣性腹痛、放屁、軟便などの消化器系の副作用や様々な栄養素が吸収できなくなる副作用がある。また、カンナビノイド１型（ＣＢ－１）受容体拮抗薬の開発が精力的に進められている。具体的には、リモナバンの開発が進んでおり一部の国において発売となっていたが、悪心、抑うつ、不安などの副作用があり、各国での承認は困難な状況となっている。ペプチドＹＹ（ＰＹＹ）受容体拮抗薬であるＰＹＹ３－３６は食欲抑制効果が期待されているが、経口投与では薬効を示さず、経鼻スプレーとして開発されている。アドレナリンβ３受容体作動薬は幾つも開発が行われてきたが、有効性に人種間のばらつきがあり、開発中止になっているものが多い。従って、経口投与でより高い有効性を示し、副作用の少ない抗肥満薬が求められている。 A useful treatment for type 2 diabetes has not yet been established, and diet / exercise therapy is the focus. Compliance with these therapies is very poor. The cause of this is the change in lifestyle due to the intake of high-calorie foods and lifestyle changes accompanying the westernization of dietary habits. Examples of the therapeutic agent for diabetes include sulfonylureas (such as tolbutamide and glimepiride) and glinides (mitiglinide) that stimulate pancreatic β cells to promote insulin secretion. However, these drugs are known to have side effects of ineffective administration, hypoglycemia-inducing action, and insulin resistance-inducing action associated with increased plasma insulin levels. Biguanide (metformin buformin) increases insulin sensitivity and improves hyperglycemia. However, it is known to induce side effects such as lactic acidosis, nausea and vomiting. Glitazone (pioglitazone / rosiglitazone) is an agonist of the peroxisome proliferator-activated receptor (PPAR) gamma subtype that increases insulin sensitivity in adipose tissue, liver and skeletal muscle, and improves chronic hyperglycemia . However, it is known to cause edema, weight gain, and further liver damage which is a serious side effect. These drugs, which are not specific antidiabetic agents, have a poor divergence between drug efficacy and side effects, and treatment satisfaction is low. Accordingly, there is a need for a therapeutic agent for diabetes that exhibits higher efficacy by oral administration and has fewer side effects.
Obesity / obesity is evaluated by BMI (body mass index, kg / m 2 ). The Japanese Society of Obesity has BMI 25 or higher as “obesity”, two or more complications such as type 2 diabetes and hypertension, and visceral fat area A person who is 100 cm 2 or more is defined as “obesity”. The International Obesity Countermeasures Committee defines BMI of 25 or more and less than 30 as pre-obesity and BMI of 30 or more as obesity. Obesity has been pointed out as a major factor in various lifestyle-related diseases such as cardiovascular diseases, diabetes, NAFLD / NASH, and in recent years, there has been an active movement to actively diagnose and treat obesity. Guidelines and diagnostic criteria have been published worldwide, and obesity is recognized as one of the diseases.
As a result of the treatment of obesity / obesity, reduction of BMI can be mentioned. As a treatment method, improvement of lifestyle habits by diet therapy or exercise therapy is first attempted, but drug therapy is taken for patients who have not been able to obtain sufficient effects by such therapy. Therefore, in recent years, development of therapeutic agents for obesity / obesity has been promoted, but there are few drugs currently approved as anti-obesity agents. There is an appetite suppressant, mazindol (monoamine reuptake inhibitor), which is used for the treatment of obesity, but due to its drug dependence, the administration period is limited, and side effects such as pulmonary hypertension and various neuropsychiatric symptoms It has been known. Orlistat, a lipolytic enzyme (lipase) inhibitor, has gastrointestinal side effects such as convulsive abdominal pain, paralysis, and loose stool, and side effects that make it impossible to absorb various nutrients. In addition, development of cannabinoid type 1 (CB-1) receptor antagonists has been vigorously advanced. Specifically, rimonabant is being developed and sold in some countries, but there are side effects such as nausea, depression, and anxiety, making it difficult to approve in each country. PYY3-36, which is a peptide YY (PYY) receptor antagonist, is expected to have an appetite-suppressing effect, but does not exhibit a medicinal effect when administered orally and has been developed as a nasal spray. A number of adrenergic β3-receptor agonists have been developed, but the effectiveness varies among races, and many have been discontinued. Accordingly, there is a need for an anti-obesity drug that exhibits higher efficacy by oral administration and has fewer side effects.
　Ｅｌｏｖｌ６については、これまでに研究が少ないものの、この酵素の阻害と糖尿病あるいは肥満との関係はｓｉＲＮＡを用いてマウスでの効果が実証されている（特許文献１）。しかしながら、阻害活性を有する具体的な低分子化合物の報告はきわめて少なく、如何なる物質が、高い選択性を持ってこの酵素を強力に阻害するかについては殆ど知られてはいなかった。 Although there has been little research on Elovl6 so far, the relationship between inhibition of this enzyme and diabetes or obesity has been demonstrated in mice using siRNA (Patent Document 1). However, there are very few reports of specific low molecular weight compounds having inhibitory activity, and little is known about what substances strongly inhibit this enzyme with high selectivity.
　近年、Ｅｌｏｖｌ６阻害作用を有する化合物の研究が進められている。肥満治療剤として、例えば、特許文献３、特許文献４、特許文献５、特許文献６、特許文献７及び特許文献８が知られている。しかしながら、特許文献３ないし特許文献７には、本発明のようなスルファモイル基を有するアリールカルボキサミド誘導体の示唆は皆無である。特許文献８には、アリールスルホニル誘導体が開示されているが、本発明中の化合物、とりわけ式（ＩＩＩ）－Ｂで示される化合物のようにフェニル基に非芳香族のヘテロ環が縮合して形成される基がアミド結合の窒素原子に結合した化合物の開示はない。 In recent years, research on compounds having an inhibitory effect on Elovl6 is in progress. As an anti-obesity agent, for example, Patent Literature 3, Patent Literature 4, Patent Literature 5, Patent Literature 6, Patent Literature 7 and Patent Literature 8 are known. However, Patent Documents 3 to 7 do not suggest any arylcarboxamide derivatives having a sulfamoyl group as in the present invention. Patent Document 8 discloses an arylsulfonyl derivative, which is formed by condensation of a non-aromatic heterocycle with a phenyl group like the compound in the present invention, particularly the compound represented by the formula (III) -B. There is no disclosure of compounds in which the group to be bonded is bound to the nitrogen atom of the amide bond.
　スルファモイル基を有するアリールカルボキサミド誘導体に関する技術として、
国際公開第２００４／０５８７０９号パンフレット（特許文献９）；
国際公開第２００１／０６２７１８号パンフレット（特許文献１０）；
国際公開第２００５／０９２８８１号パンフレット（特許文献１１）；
国際公開第２００６／１２０１７８号パンフレット（特許文献１２）；
国際公開第２００１／０４７５０９号パンフレット（特許文献１３）；
国際公開第２００５／１１５３７４号パンフレット（特許文献１４）；
国際公開第２００３／１０３６４８号パンフレット（特許文献１５）；
国際公開第２００７／００２５５９号パンフレット（特許文献１６）；
が挙げられるが、Ｅｌｏｖｌ６阻害作用を有する化合物の開示はない。 As a technique related to arylcarboxamide derivatives having a sulfamoyl group,
International Publication No. 2004/058709 (Patent Document 9);
International Publication No. 2001/062718 (Patent Document 10);
International Publication No. 2005/092881 (Patent Document 11);
WO 2006/120178 pamphlet (Patent Document 12);
International Publication No. 2001/047509 (Patent Document 13);
International Publication No. 2005/115374 pamphlet (Patent Document 14);
International Publication No. 2003/103648 (Patent Document 15);
International Publication No. 2007/002559 (Patent Document 16);
However, there is no disclosure of a compound having an Elovl6 inhibitory action.
　特許文献９には、ＣＣＲ８阻害剤として、種々の縮環アリールスルホンアミド誘導体が開示されている。その中には、スルホンアミドの窒素原子に４－ピペリジニル基やシクロヘキシル基を有する誘導体が開示されているが、本発明のようなＥｌｏｖｌ６阻害作用を有する化合物の開示はない。 Patent Document 9 discloses various condensed arylsulfonamide derivatives as CCR8 inhibitors. Among them, derivatives having a 4-piperidinyl group or a cyclohexyl group at the nitrogen atom of sulfonamide are disclosed, but there is no disclosure of a compound having an Elovl6 inhibitory activity as in the present invention.
　特許文献１０には、ＣＲＦ受容体拮抗剤として、種々のベンズアミド誘導体が開示されている。その中には、アミド結合のカルボニルに特定のフェニル基が結合した誘導体が開示されているが、本発明のようなＥｌｏｖｌ６阻害作用を有する化合物の開示はない。 Patent Document 10 discloses various benzamide derivatives as CRF receptor antagonists. Among them, a derivative in which a specific phenyl group is bonded to the carbonyl of the amide bond is disclosed, but there is no disclosure of a compound having an Elovl6 inhibitory action as in the present invention.
　特許文献１１には、ＦＸａ阻害剤として、ピロリジン－３，４－ジカルボキサミド誘導体が開示されているが、本発明のようなＥｌｏｖｌ６阻害作用を有する化合物の開示はない。 Patent Document 11 discloses pyrrolidine-3,4-dicarboxamide derivatives as FXa inhibitors, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
　特許文献１２には、肥満と糖尿病処置のためのＮ－ハロアルキルスルホニルベンズアミドが開示されているが、本発明のようなＥｌｏｖｌ６阻害作用を有する化合物の開示はない。 Patent Document 12 discloses N-haloalkylsulfonylbenzamide for the treatment of obesity and diabetes, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
　特許文献１３には、インスリン感作剤として、チアゾリジンジオン誘導体が開示されているが、本発明のようなＥｌｏｖｌ６阻害作用を有する化合物の開示はない。 Patent Document 13 discloses a thiazolidinedione derivative as an insulin sensitizer, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
　特許文献１４には、ＣＲＴＨ２受容体リガンドとして、置換されたベンズアミド誘導体が開示されているが、本発明のようなＥｌｏｖｌ６阻害作用を有する化合物の開示はない。 Patent Document 14 discloses substituted benzamide derivatives as CRTH2 receptor ligands, but does not disclose a compound having an Elovl6 inhibitory activity as in the present invention.
　特許文献１５は、糖尿病治療剤として、フェノールや酢酸フェニル誘導体が開示されているが開示されているが、本発明のようなＥｌｏｖｌ６阻害作用を有する化合物の開示はない。 Patent Document 15 discloses phenol and phenyl acetate derivatives as antidiabetic agents, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
　特許文献１６は、ＬＸＲモジュレーターとして、ピラゾール誘導体が開示されているが、本発明のようなＥｌｏｖｌ６阻害作用を有する化合物の開示はない。 Patent Document 16 discloses a pyrazole derivative as an LXR modulator, but does not disclose a compound having an Elovl6 inhibitory action as in the present invention.
　さて、医薬品開発においては、目的とする薬理活性のみでなく、吸収、分布、代謝、排泄等の各種の面で厳しいクライテリアを満たすことが要求される。例えば、薬物相互作用、脱感受性ないし耐性、経口投与時の消化管吸収、小腸内への移行速度、吸収速度と初回通過効果、臓器バリアー、蛋白結合、薬物代謝酵素の誘導、排泄経路や体内クリアランス、適用方法（適用部位、方法、目的）等において種々の検討課題が要求され、これらを満たすものはなかなか見出されない。 Now, in drug development, it is required to satisfy severe 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.
　Ｅｌｏｖｌ６阻害剤の報告例は少なく、いまだ上市されるには至っていない。この阻害剤についても、上記の医薬品開発上の総合的課題は常に生じるであろう。より具体的には、例えば、代謝安定性が低く経口投与が困難であること、不整脈を起こす危険性があるｈＥＲＧ（human ether-a-go-go related gene）チャネルの阻害活性を示すこと、あるいは吸収性や持続性等の薬物動態が良好ではないなど、有用性や安全性の課題があり、これらの問題を解決し、且つ活性の高い化合物が求められていくのである。 There are few reports of Elovl6 inhibitors, and they have not yet been put on the market. For this inhibitor as well, the above overall challenges in drug development will always arise. More specifically, for example, it exhibits inhibitory activity on hERG (human ether-a-go-go related genes) channels that have low metabolic stability and are difficult to be administered orally, or that may cause arrhythmias, or There are problems of usefulness and safety such as poor pharmacokinetics such as absorbability and sustainability, and there is a demand for compounds that solve these problems and have high activity.
　加えて、Ｅｌｏｖｌ６阻害剤については、先述したＮＡＦＬＤ・ＮＡＳＨ、糖尿病、とりわけ２型糖尿病あるいはインスリン抵抗性、肥満・肥満症の治療に使用されている従来の薬物より、前出のような副作用の少ない化合物が求められているのである。 In addition, the Elovl6 inhibitor has fewer side effects than the above-mentioned conventional drugs used for the treatment of NAFLD / NASH, diabetes, especially type 2 diabetes or insulin resistance, obesity / obesity There is a need for compounds.
国際公開第２００５／００５６６５号パンフレットInternational Publication No. 2005/005665 Pamphlet 日本特開第２００９－１７８１４３号パンフレットJapanese Unexamined Patent Publication No. 2009-178143 国際公開第２００８／１２０６５３号パンフレットInternational Publication No. 2008/120653 Pamphlet 国際公開第２００９／０３８０２１号パンフレットInternational Publication No. 2009/038021 Pamphlet 国際公開第２００９／０４４７８８号パンフレットInternational Publication No. 2009/044788 Pamphlet 国際公開第２００９／０８１７８９号パンフレットInternational Publication No. 2009/081789 Pamphlet 国際公開第２００９／０９９０８６号パンフレットInternational Publication No. 2009/099086 Pamphlet 国際公開第２００９／１３１０６５号パンフレットInternational Publication No. 2009/131655 Pamphlet 国際公開第２００４／０５８７０９号パンフレットInternational Publication No. 2004/058709 Pamphlet 国際公開第２００１／０６２７１８号パンフレットInternational Publication No. 2001/062718 Pamphlet 国際公開第２００５／０９２８８１号パンフレットInternational Publication No. 2005/092881 Pamphlet 国際公開第２００６／１２０１７８号パンフレットInternational Publication No. 2006/120178 Pamphlet 国際公開第２００１／０４７５０９号パンフレットInternational Publication No. 2001/047509 Pamphlet 国際公開第２００５／１１５３７４号パンフレットInternational Publication No. 2005/115374 Pamphlet 国際公開第２００３／１０３６４８号パンフレットInternational Publication No. 2003/103648 Pamphlet 国際公開第２００７／００２５５９号パンフレットInternational Publication No. 2007/002559 Pamphlet
　上述したＮＡＦＬＤ・ＮＡＳＨなどに対する医療状況に鑑み、Ｅｌｏｖｌ６を阻害することにより、生体中（好ましくは血中）の脂肪酸組成を変動、とりわけパルミチン酸を上昇及び／またはオレイン酸を低下させる具体的な低分子化合物などが求められていた。 In view of the above-mentioned medical conditions for NAFLD / NASH and the like, by inhibiting Elovl6, the fatty acid composition in the living body (preferably in blood) is changed, in particular, palmitic acid is increased and / or oleic acid is decreased. Molecular compounds were sought.
　とりわけ、経口投与が可能であり、安全性が高く、有効性に優れ、他のＥＬＯＶＬファミリーや類似酵素に対する選択性の高いＥｌｏｖｌ６阻害剤、あるいはＥｌｏｖｌ６が関与する疾患の予防または治療剤（とりわけＮＡＦＬＤ・ＮＡＳＨ、糖尿病、２型糖尿病、インスリン抵抗性、肥満・肥満症の予防または治療剤）が求められている。 In particular, it can be administered orally and is highly safe, highly effective, and highly selective for other ELOVL families and similar enzymes, Elovl6 inhibitors, or preventive or therapeutic agents for diseases involving Elovl6 (particularly NAFLD · NASH, diabetes, type 2 diabetes, insulin resistance, obesity / obesity preventive or therapeutic agent) are demanded.
　特に、前述のような従来技術における問題点のような取り組むべき課題がある。より具体的に言えば、ＮＡＦＬＤ及びＮＡＳＨの治療薬としては確立した治療法自体がなく、有効な予防または治療剤を見出すこと自体が取り組むべき課題である。また、糖尿病の治療剤として、膵β細胞を刺激してインスリン分泌を促進するスルホニル尿素（トルブタミドやグリメピリド等）やグリニド（ミチグリニド）における投与無効や低血糖誘発作用、更に血漿インスリン値の上昇に伴うインスリン抵抗性の惹起作用の副作用など；ビグアナイド（メトフォルミン・ブフォルミン）におけるインスリン感受性を増加させ高血糖を改善するが、乳酸アシドーシスや吐き気・嘔吐などの副作用を誘発すること；グリダゾン（ピオグリタゾン・ロシグリタゾン）における浮腫や体重増加・更には重篤な副作用である肝障害を引き起こすことなどの取組むべき課題がある。あるいは、肥満・肥満症の治療剤として、食欲抑制剤（マジンドール）における薬物依存性、肺高血圧症や各種精神神経症状等の副作用；リパーゼ阻害剤（オルリスタット）における痙攣性腹痛、放屁、軟便などの消化器系の副作用や様々な栄養素が吸収できなくなる副作用；ＣＢ－１受容体拮抗薬（リモナバン）における悪心、抑うつ、不安などの副作用；ＰＹＹ受容体拮抗薬（ＰＹＹ３－３６）における経口投与が不可能であること；アドレナリンβ３受容体作動薬における有効性に人種間ばらつきがあることなどの課題がある。さらに、ｈＥＲＧ電流の抑制作用の低減、代謝安定性や吸収性の向上、経口投与可能性、薬物動態や溶解性の改善などの取組むべき課題がある。そして、これらの課題の少なくとも１つ以上を克服し、ヒトを含む哺乳動物に対して経口投与可能な薬剤、とりわけ臨床上使い勝手の良い、Ｅｌｏｖｌ６が関与する疾患の予防または治療剤（とりわけＮＡＦＬＤ・ＮＡＳＨ、糖尿病、２型糖尿病、インスリン抵抗性、肥満・肥満症の予防または治療剤）が望まれている。 In particular, there are issues to be addressed, such as the problems in the prior art as described above. More specifically, there is no established treatment itself as a therapeutic agent for NAFLD and NASH, and finding an effective preventive or therapeutic agent itself is an issue to be addressed. In addition, as a therapeutic agent for diabetes, sulfonylurea (tolbutamide, glimepiride, etc.) and glinide (mitiglinide) that stimulate pancreatic β-cells to stimulate insulin secretion are associated with ineffective administration, hypoglycemia-inducing action, and increased plasma insulin levels Side effects such as insulin resistance-inducing action; increase insulin sensitivity in biguanide (metformin / buformin) and improve hyperglycemia, but induce side effects such as lactic acidosis, nausea and vomiting; glidazone (pioglitazone / rosiglitazone) There are problems to be addressed, such as causing edema, weight gain and liver damage, which is a serious side effect. Or as a therapeutic agent for obesity / obesity, such as drug dependence in appetite suppressant (Mazindol), side effects such as pulmonary hypertension and various neuropsychiatric symptoms; Gastrointestinal side effects and side effects in which various nutrients cannot be absorbed; side effects such as nausea, depression and anxiety with CB-1 receptor antagonist (Rimonabant); oral administration with PYY receptor antagonist (PYY3-36) is not possible There are problems such as being able to do; racial variability in the effectiveness of adrenergic β3 receptor agonists. Furthermore, there are problems to be addressed such as reduction of hERG current inhibitory action, improvement of metabolic stability and absorbability, possibility of oral administration, improvement of pharmacokinetics and solubility. Then, it overcomes at least one of these problems and can be administered orally to mammals including humans, especially clinically usable prophylactic or therapeutic agents for diseases involving Elovl6 (especially NAFLD / NASH) , Diabetes, type 2 diabetes, insulin resistance, obesity / obesity prevention or treatment agent) is desired.
　本発明者らは、上記の課題を解決すべく、安全性が高く、及び／または有効性に優れたＥｌｏｖｌ６の機能を阻害する化合物を得るべく、鋭意研究を重ねてきた結果、式（Ｉ）で表されるスルファモイル基を有するアリールカルボキサミド誘導体またはそれらの製薬学的に許容される塩、またはそれらの溶媒和物が、Ｅｌｏｖｌ６を強力に阻害すること、そして、生体に投与した際に、血中脂肪酸組成の変動、とりわけパルミチン酸の上昇及びオレイン酸の低下をもたらすことなどを見出し、本発明を完成した。 In order to solve the above-mentioned problems, the present inventors have conducted extensive studies to obtain a compound that inhibits the function of Elovl6 that is highly safe and / or excellent in effectiveness. An arylcarboxamide derivative having a sulfamoyl group represented by the formula (1) or a pharmaceutically acceptable salt thereof, or a solvate thereof potently inhibits Elovl6, and when administered to a living body, The present invention was completed by finding out that the fatty acid composition fluctuates, in particular, that palmitic acid is increased and oleic acid is decreased.
　本発明は、式（Ｉ）で表されるスルファモイル基を有するアリールカルボキサミド誘導体またはそれらの製薬学的に許容される塩、またはそれらの溶媒和物、該誘導体を有効成分として含有する医薬組成物である。
　本発明の好ましい態様の化合物は、Ｅｌｏｖｌ６阻害活性を有する化合物、またはＥｌｏｖｌ６を阻害することにより、脂肪酸組成を変動とりわけパルミチン酸を上昇及び／またはオレイン酸を低下させる作用を有する化合物である。本発明のさらに好ましい態様の化合物を有効成分として含有する医薬組成物は、経口投与可能な、Ｅｌｏｖｌ６（とりわけその活性亢進）が関与する疾患、とりわけＮＡＦＬＤ・ＮＡＳＨ、糖尿病、２型糖尿病、インスリン抵抗性、肥満・肥満症の予防または治療剤として期待される。
　また、本発明のいくつかの態様の化合物群は、代謝安定性が高いこと、優れた経口吸収性をもつこと、溶解性が良好であること、あるいはｈＥＲＧチャネルの阻害作用が少ないこと、などの少なくとも一つ以上の特徴も有することから有用性が高い。 The present invention relates to an arylcarboxamide derivative having a sulfamoyl group represented by formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, a pharmaceutical composition containing the derivative as an active ingredient. is there.
The compound according to a preferred embodiment of the present invention is a compound having an Elovl6 inhibitory activity, or a compound having a function of changing the fatty acid composition by inhibiting Elovl6, particularly raising the palmitic acid and / or lowering the oleic acid. The pharmaceutical composition comprising the compound of a further preferred embodiment of the present invention as an active ingredient is an orally administrable disease involving Elovl6 (especially enhanced activity thereof), particularly NAFLD / NASH, diabetes, type 2 diabetes, insulin resistance It is expected as an agent for preventing or treating obesity / obesity.
In addition, the compound groups of some embodiments of the present invention have high metabolic stability, excellent oral absorption, good solubility, or little hERG channel inhibitory action, etc. It is highly useful because it also has at least one feature.
Ｅｌｏｖｌ６阻害化合物連投マウスにおける血漿中脂肪酸組成の変動、とりわけパルミチン酸上昇及びオレイン酸低下作用を示すグラフである。It is a graph which shows the fluctuation | variation of the fatty-acid composition in a plasma in an Elovl6 inhibitor compound continuous administration mouse | mouth, especially a palmitic acid raise and an oleic acid fall effect.
　本発明は、以下の態様に示される式（Ｉ）で表されるスルファモイル基を有するアリールカルボキサミド誘導体またはその塩またはそれらの溶媒和物、それらを有効成分とする医薬組成物、並びに当該誘導体またはその塩の医薬用途である。
　本発明の式（Ｉ）で表される化合物の分子量は特には限定されないが、分子量７００以下であることが好ましい。より好ましくは、分子量５５０以下である。かかる分子量の限定は、近年のドラッグデザインにおいて、化合物の構造を特定する際、薬理学的な特徴のある基本骨格に加え、他の大きな限定要因として日常的に用いられる。 The present invention relates to an arylcarboxamide derivative having a sulfamoyl group represented by the formula (I) represented by the following embodiment or a salt thereof or a solvate thereof, a pharmaceutical composition containing them as an active ingredient, and the derivative or a derivative thereof It is a medicinal use of salt.
The molecular weight of the compound represented by the formula (I) of the present invention is not particularly limited, but 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.
［本発明の態様］
［１］　本発明の態様１
　本発明の第１の態様は、
下記式（Ｉ）
Figure JPOXMLDOC01-appb-C000007
  
　（式中、ｎは、０～２の整数を表し；ｍ、ｐは０～４の整数を表し；Ｒ１、Ｒ２、Ｒ３、Ｒ４は、各々独立に水素原子またはハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６アルキル基を表し；Ｙは置換されていてもよい炭化水素基、または基：－ＮＲ５Ｒ６（Ｒ５、Ｒ６は、各々独立に、水素原子、置換されていてもよい炭化水素基または置換されていてもよいヘテロ環基を表し、Ｒ５、Ｒ６はそれらが結合する窒素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し；Ｒｉｎｇは、置換されていてもよい環状基を表し；Ｗは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－、－ＮＲ９ＣＯＮＲ１０－、または－ＮＲ１１－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１は、各々独立に水素原子またはＣ１～６アルキル基を表し、Ｒ７がＲ３またはＲ４と一緒になって、各々の結合している窒素原子、炭素原子と一緒に５～７員のシクロ環基を形成していてもよく、当該シクロ環基は、環内に二重結合を有していてもよく、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよい）を表し；Ｚは、置換されていてもよいＣ３～８のシクロアルキル基、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す。但し、Ｒｉｎｇが置換されていても良い又は－ＣＨ２－若しくは－ＣＨ２ＣＨ２－で架橋されていてもよい、ピペラジンまたはピペリジンであって、－（ＣＲ１Ｒ２）－Ｗ－（ＣＲ３Ｒ４）－Ｚがピペリジン若しくはピペラジンの１位に結合し、且つＹ－ＳＯ２－がピペラジンもしくはピペリジンの４位に結合している場合を除く）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [Aspect of the Invention]
[1] Aspect 1 of the present invention
The first aspect of the present invention is:
Formula (I)
Figure JPOXMLDOC01-appb-C000007
(Wherein n represents an integer of 0 to 2; m and p represent an integer of 0 to 4; R 1 , R 2 , R 3 and R 4 each independently represents a hydrogen atom or a halogen atom; represents OH, C 1 - 6 alkoxylated, halogenated C 1 - 6 one by one to five substituents which may C 1 to 6 alkyl groups of alkoxy; Y is optionally substituted hydrocarbon group, Or a group: —NR 5 R 6 (R 5 and R 6 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R 5 , R 6 May form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom, -OH, C 1 ~ 6 alkoxy, halogenated May be replaced by or may be substituted by 1-6 or in 1-5 substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl), the annular The group may further have a substituent); Ring represents an optionally substituted cyclic group; W represents —CONR 7 —, —NR 8 CO—, —NR 9 CONR 10 —. or -NR 11, - (R 7, R 8, R 9, R 10, R 11 each independently represent a hydrogen atom or a C 1 ~ 6 alkyl group, R 7 is taken together with R 3 or R 4 In addition, each bonded nitrogen atom and carbon atom may form a 5- to 7-membered cyclo group, and the cyclo group may have a double bond in the ring. Well, one carbon atom in the ring is an oxygen atom, sulfur atom or nitrogen Atom (said nitrogen atom, C 1 ~ halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with one to five substituents which may be straight or branched alkoxyl represents may) be replaced by 6 may be substituted by an alkyl group); Z is optionally substituted C 3 even though 1-8 cycloalkyl group, an optionally substituted aryl group, or Represents a heterocyclic group which may be substituted, provided that Ring is a piperazine or piperidine which may be substituted or may be bridged by —CH 2 — or —CH 2 CH 2 —, (CR 1 R 2) -W- ( CR 3 R 4) -Z is bonded to the 1-position of the piperidine or piperazine, and Y-SO 2 - is attached to the 4-position of the piperazine or piperidine Or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, the long-chain fatty acid elongation enzyme (Elovl6) An inhibitor.
　以下に、上記態様［１］阻害剤に用いられる上記式（Ｉ）の化合物中の各基について具体的に説明する。 Hereinafter, each group in the compound of the above formula (I) used for the embodiment [1] inhibitor will be specifically described.
　本発明の化合物に関する説明において、例えば「Ｃ１～６」とは、構成炭素原子数が１から６であることを示し、特に断らない限り、直鎖、分枝鎖または環状の基を表す。鎖状の基については「構成炭素数１ないし６の直鎖または分枝鎖」を意味する。また、環状の基についてはその「環の構成炭素員数」を意味する。 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”.
　「置換されていてもよい炭化水素基」の「炭化水素基」としては、脂肪族炭化水素基、脂環式炭化水素基およびアリール基が挙げられる。 The “hydrocarbon group” of “optionally substituted hydrocarbon group” includes an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, and an aryl group.
　「脂肪族炭化水素基」の例としては、直鎖もしくは分枝鎖の炭化水素基、例えば、アルキル基、アルケニル基、アルキニル基等が挙げられる。 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.
　「アルキル基」としては、例えば、Ｃ１～６（より好ましくはＣ１～４）の直鎖もしくは分枝鎖のアルキル基、例えば、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、ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１－メチルブチル、２－メチルブチル、１，２－ジメチルプロピル、ヘキシル、イソヘキシル、１－メチルペンチル、２－メチルペンチル、３－メチルペンチル、１，１－ジメチルブチル、１，２－ジメチルブチル、２，２－ジメチルブチル、１，３－ジメチルブチル、２，３－ジメチルブチル、３，３－ジメチルブチル、１－エチルブチル、２－エチルブチル、１，１，２－トリメチルプロピル、１，２，２－トリメチルプロピル、１－エチル－１－メチルプロピル、１－エチル－２－メチルプロピル等が挙げられる。 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.
　「アルケニル基」の例としては、Ｃ２～６の直鎖もしくは分枝鎖のアルケニル基、例えばビニル、アリル、イソプロペニル、２－メチルアリル、ブテニル、ペンテニル、ヘキセニル等が挙げられる。 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.
　「アルキニル基」の例としては、Ｃ２～６の直鎖もしくは分枝鎖のアルキニル基、例えばエチニル、１－プロピニル、２－プロピニル、ブチニル、ペンチニル、ヘキシニル等が挙げられる。 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.
　「脂環式炭化水素基」の例としては、飽和もしくは不飽和の脂環式炭化水素基を含み、例えば、シクロアルキル基、シクロアルケニル基、あるいはシクロアルカンジエニル基が挙げられる。 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.
　「シクロアルキル基」の例としては、Ｃ３～８のシクロアルキル基、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。 Examples of "cycloalkyl group", cycloalkyl groups of C 3 ~ 8, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
　「シクロアルケニル基」の例としては、Ｃ３～８のシクロアルケニル基、例えば、１－シクロプロペン－１－イル、１－シクロブテン－１－イル、１－シクロペンテン－１－イル、２－シクロペンテン－１－イル、３－シクロペンテン－１－イル、１－シクロヘキセン－１－イル、２－シクロヘキセン－１－イル、３－シクロヘキセン－１－イル、１－シクロヘプテン－１－イル、２－シクロヘプテン－１－イル、３－シクロヘプテン－１－イル、４－シクロヘプテン－１－イル、１－シクロオクテン－１－イル、２－シクロオクテン－１－イル、１－シクロオクテン－３－イル、１－シクロオクテン－４－イル等が挙げられる。 Examples of the "cycloalkenyl group", a cycloalkenyl group of C 3 ~ 8, e.g., 1-cyclopropene-1-yl, 1-cyclobutene-1-yl, 1-cyclopenten-2-cyclopentene - 1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclohepten-1-yl, 2-cyclohepten-1- Yl, 3-cyclohepten-1-yl, 4-cyclohepten-1-yl, 1-cycloocten-1-yl, 2-cycloocten-1-yl, 1-cycloocten-3-yl, 1-cyclooctene- 4-yl and the like can be mentioned.
　「シクロアルカンジエニル基」の例としては、Ｃ４～６のシクロアルカンジエニル基、例えば、２，４－シクロペンタジエンー１－イル、２，５－シクロヘキサジエン－１－イル等が挙げられる。 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 .
　「アリール基」の例としては、単環式もしくは縮環式のＣ６～１４アリール基、例えば、フェニル、ナフチル、ビフェニリル、２－アンスリル、フェナンスリル、アセナフチル等、或いはインダニル、テトラヒドロナフチル等の部分的に水素化された縮合アリール等が挙げられる。ここで部分的に水素化されたアリール基とは、部分的に水素化された縮合環から任意の水素原子を除いてできる１価の基を意味し、縮合環の芳香族部分の水素原子あるいは水素化された部分の水素原子のどちらが除かれてもよい。例えば、テトラヒドロナフチル基であれば、１，２，３，４－テトラヒドロナフタレン（１－イル、２－イル、３－イル、－４－イル、－５－イル、－６－イル、－７－イル、－８－イル）基などが含まれる。 Examples of "aryl group", a monocyclic or condensed cyclic C 6 ~ 14 aryl group, e.g., phenyl, naphthyl, biphenylyl, 2-anthryl, phenanthryl, acenaphthyl and the like, or indanyl, in part, such as a tetrahydronaphthyl And a condensed aryl hydrogenated. Here, the partially hydrogenated aryl group means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated condensed ring, and the hydrogen atom of the aromatic part of the condensed ring or Either hydrogen atom in the hydrogenated part may be removed. For example, when it is a tetrahydronaphthyl group, 1,2,3,4-tetrahydronaphthalene (1-yl, 2-yl, 3-yl, -4-yl, -5-yl, -6-yl, -7- Yl, -8-yl) groups and the like.
　「置換されていてもよいへテロ環基」の「へテロ環基」の例としては、ヘテロアリール基、飽和もしくは不飽和の非芳香族のヘテロ環基が挙げられる。これらの環は、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環、好ましくは３～１２員環の単環もしくは縮合環を有する環から任意の水素原子を除いてできる１価の基を意味する。 Examples of the “heterocyclic group” of the “optionally substituted heterocyclic group” include a heteroaryl group and a saturated or unsaturated non-aromatic heterocyclic group. These rings are 3- to 14-membered, preferably 3- to 12-membered monocycles containing at least one heteroatom (preferably 1 to 4) selected from N, O and S in addition to carbon atoms, A monovalent group formed by removing any hydrogen atom from a ring having a condensed ring.
　「ヘテロアリール基」としては、単環式もしくは縮環式のものがあるが、単環式のヘテロアリール基としては、環員数５～６のものが好ましく、例えば、ピロリル、フリル、チエニル、イミダゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、ピラゾリル、１，２，３－トリアゾリル、１，２，４－トリアゾリル、１，２，３－オキサジアゾリル、１，２，４－オキサジアゾリル、１，３，４－オキサジアゾリル、フラザニル、１，２，３－チアジアゾリル、１，２，４－チアジアゾリル、１，３，４－チアジアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、１，２，３－トリアジニル、１，２，４－トリアジニル、１，３，５－トリアジニル、２Ｈ－１，２，３－チアジアジニル、４Ｈ－１，２，４－チアジアジニル、６Ｈ－１，３，４－チアジアジニル等が挙げられる。 The “heteroaryl group” may be monocyclic or condensed, and the monocyclic heteroaryl group preferably has 5 to 6 ring members, such as 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, 1,3,5-triazinyl, 2H-1,2,3-thiadiazinyl 4H-1,2,4-thiadiazinyl, 6H-1,3,4-thiadiazinyl, or the like.
　また、縮環式のヘテロアリール基としては、環員数８～１４のものが好ましく、これには上記の５～６員のヘテロ環が１ないし複数個（好ましくは１～２個）の単環のアリール環（例えばベンゼン環等）もしくは単環のヘテロアリール基と縮合して形成された縮合環から任意の水素原子を除いてできる１価の基などが含まれる。当該任意の水素原子は縮合したいずれの環から除かれてもよい。 Further, the condensed heteroaryl group preferably has 8 to 14 ring members, and this includes one to a plurality of (preferably 1 to 2) monocyclic 5- to 6-membered heterocycles described above. A monovalent group formed by removing an arbitrary hydrogen atom from a condensed ring formed by condensation with an aryl ring (for example, a benzene ring) or a monocyclic heteroaryl group. The arbitrary hydrogen atom may be removed from any condensed ring.
　具体的には、インドリル、イソインドリル、１Ｈ－インダゾリル、ベンゾフラニル（－２－イル）、イソベンゾフラニル、ベンゾチエニル（－２－イル）、イソベンゾチエニル、ベンズインダゾリル、ベンゾオキサゾリル（－２－イル）、１，２－ベンゾイソオキサゾリル、ベンゾチアゾリル（－２－イル）、１，２－ベンゾイソチアゾリル、２Ｈ－ベンゾピラニル（－３－イル）、（１Ｈ－）ベンズイミダゾリル（－２－イル）、１Ｈ－ベンゾトリアゾリル、４Ｈ－１，４－ベンゾオキサジニル、４Ｈ－１，４－ベンゾチアジニル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキザリニル、フタラジニル、ナフチリジニル、プリニル、プテリジニル、カルバゾリル、カルボリニル、アクリジニル、フェノキサジニル、フェノチアジニル、フェナジニル、フェノキサチイニル、チアンスレニル、フェナンスリジニル、フェナンスロリニル、インドリジニル、（４，５，６，７－）テトラヒドロチアゾロ［５，４－ｃ］ピリジル（－２－イル）、（４，５，６，７－）テトラヒドロチエノ［３，２－ｃ］ピリジル、（１，２，３，４－）テトラヒドロイソキノリル（－６－イル）、チアゾロ［５，４－ｃ］ピリジル（－２－イル）、ピロロ［１，２－ｂ］ピリダジニル、ピラゾ［１，５－ａ］ピリジル、イミダゾ［１，２－ａ］ピリジル、イミダゾ［１，５－ａ］ピリジル、イミダゾ［１，２－ｂ］ピリダジニル、イミダゾ［１，５－ａ］ピリミジニル、［１，２，４］トリアゾロ［４，３－ａ］ピリジル、１，２，４－トリアゾロ［４，３－ｂ］ピリダジニル、クロメニル（２Ｈ－クロメニル）、１Ｈ－ピラゾロ［３，４－ｂ］ピリジル、［１，２，４］トリアゾロ［１，５－ａ］ピリミジニル等が挙げられる（括弧内の記載は好ましい態様を示している）。 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, fur Nothiazinyl, phenazinyl, phenoxathiinyl, 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, Romenyl (2H-chromenyl), 1H-pyrazolo [3,4-b] pyridyl, [1,2,4] triazolo [1,5-a] pyrimidinyl and the like (the description in parentheses indicates a preferred embodiment) )
　また、テトラヒドロキノリニル、テトラヒドロイソキノリニル、テトラヒドロベンゾキサゼピニル、テトラヒドロベンゾアゼピニル、テトラヒドロナフトピリジニル、テトラヒドロキノキサリニル、クロマニル、ジヒドロベンゾオキサジニル、３，４－ジヒドロ－２Ｈ－１，４－ベンゾチアジニル、ジヒドロベンゾチアゾリル、３，４－ジヒドロ－２Ｈ－１，４－ベンゾキサジニル、イソクロマニル、インドリニル、プテリジニル、２，３－ジヒドロベンゾ［ｂ］［１，４］ジオキシニル、１，２，３，４－テトラヒドロ－１－メチルキノリニル、１，３－ジヒドロ－１－オキソイソベンゾフラニル、６，７，８，９－テトラヒドロ－５Ｈ－シクロへプタ［ｂ］ピリジルなどの部分的に水素化された縮環式へテロアリール基等も挙げられる。ここで部分的に水素化された縮環式ヘテロアリール基等とは、上記の縮環式のヘテロアリール基では環員数８～１２のものが好ましく、これは５～６員のヘテロ環が１ないし複数個（好ましくは１～２個）のアリール環（例えばベンゼン環等）もしくは単環のヘテロアリール基と縮合して形成された部分的に水素化された縮合環から任意の水素原子を除いてできる１価の基を意味し、アリール環、ヘテロ環部分の水素原子あるいは水素化された部分の水素原子のどちらが除かれてもよい。例えば、テトラヒドロキノリニル基であれば、５，６，７，８－テトラヒドロキノリル基あるいは１，２，３，４－テトラヒドロキノリル基などが含まれる。これらの基には、任意の水素原子を除く位置により、例えば、５，６，７，８－テトラヒドロキノリル基であれば、－２－イル基、－３－イル基、－４－イル基、－５－イル基、－６－イル基、－７－イル基、－８－イル基などが例示され、１，２，３，４－テトラヒドロキノリル基であれば、例えば、－１－イル基、－２－イル基、－３－イル基、－４－イル基、－５－イル基、－６－イル基、－７－イル基、－８－イル基などが例示される。 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. Also included are partially hydrogenated condensed heteroaryl groups, etc.Here, the partially hydrogenated condensed heteroaryl group and the like are preferably those having the number of ring members of 8 to 12 in the above-mentioned condensed ring heteroaryl group. Any hydrogen atom is removed from a partially hydrogenated condensed ring formed by condensing with a plurality of (preferably 1 to 2) aryl rings (eg, benzene ring) or a monocyclic heteroaryl group. The hydrogen atom of the aryl ring, the heterocyclic part, or the hydrogen atom of the hydrogenated part may be removed. For example, a tetrahydroquinolinyl group includes a 5,6,7,8-tetrahydroquinolyl group or a 1,2,3,4-tetrahydroquinolyl group. In these groups, depending on the position excluding any hydrogen atom, for example, a 5,6,7,8-tetrahydroquinolyl group, a 2-yl group, a 3-yl group, a -4-yl group , -5-yl group, -6-yl group, -7-yl group, -8-yl group and the like. If it is a 1,2,3,4-tetrahydroquinolyl group, for example, -1- Ilyl group, 2-yl group, 3-yl group, -4-yl group, -5-yl group, -6-yl group, -7-yl group, -8-yl group and the like are exemplified.
　「非芳香族のヘテロ環基」の例としては、Ｎ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～８員の飽和もしくは部分的に不飽和の非芳香族のヘテロ環基が含まれる。例えば、アジリジニル、アゼチジニル、オキシラニル、オキセタニル、チエタニル、ピロリジニル、テトラヒドロフリル、チオラニル、ピラゾリニル、ピラゾリジニル、ピペリジル、テトラヒドロピラニル、ピペラジニル、モルホリニル、オキサゾリニル、チアゾリニル、チオモルホリニル、キヌクリジニル、オキセパニル等が挙げられ、当該非芳香族のヘテロ環から任意の水素原子を除いてできる１価の基を意味する。また、これら非芳香族のヘテロ環には、当該ヘテロ環がオキソで１～２置換された場合も含まれ、例えば、アゼチジノン、ピロリドン（例えば、２－ピロリドン）、ピラゾロン、ピラゾリジノン、ピペリドン（例えば、２－ピペリドン、４－ピペリドン）、オキサゾリジノン、３－オキソモルホリン等も含まれる。更に、これら非芳香族のヘテロ環（基）は、ＲＡ群、ＲＢ群もしくはＲＣ群から選ばれる任意の基で１～５置換されていてもよい。 Examples of “non-aromatic heterocyclic groups” include 3 to 8 membered saturated or partially unsaturated containing at least one heteroatom (preferably 1 to 4) selected from N, O, S Of non-aromatic heterocyclic groups. For example, aziridinyl, azetidinyl, oxiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, pyrazolinyl, pyrazolidinyl, piperidyl, tetrahydropyranyl, piperazinyl, morpholinyl, oxazolinyl, thiazolinyl, thiomorpholinyl, quinuclidinyl, oxacridinyl, oxacridinyl, oxacridinyl Means a monovalent group formed by removing any hydrogen atom from a heterocycle of the group. In addition, these non-aromatic heterocycles include cases where the heterocycle is substituted with 1 to 2 oxo groups, such as azetidinone, pyrrolidone (eg, 2-pyrrolidone), pyrazolone, pyrazolidinone, piperidone (eg, 2-piperidone, 4-piperidone), oxazolidinone, 3-oxomorpholine and the like are also included. Further, these non-aromatic heterocycles (groups) may be substituted with an arbitrary group selected from the R A group, the R B group or the R C group.
　Ｒｉｎｇの定義における「置換されていてもよい環状基」の「環状基」の例としては、前記「炭化水素基」として挙げられた「脂環式炭化水素基」および「アリール基」、前記「置換されていてもよいへテロ環基」の「へテロ環基」として挙げられた「ヘテロアリール基」または「飽和もしくは不飽和の非芳香族のヘテロ環基」等から、さらに任意の水素原子を１個除いて形成される２価の基を意味する。 Examples of “cyclic group” of “optionally substituted cyclic group” in the definition of Ring include “alicyclic hydrocarbon group” and “aryl group” mentioned above as “hydrocarbon group”, “ From the “heteroaryl group” or “saturated or unsaturated non-aromatic heterocyclic group” mentioned as the “heterocyclic group” of the “optionally substituted hetero ring group”, any hydrogen atom Means a divalent group formed by removing one of
　「ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６アルキル基」の例としては、以下のものが挙げられる。 Examples of "halogen atoms, -OH, C 1 - 6 alkoxylated, halogenated C 1 ~ 6 1 ~ 5 amino substituted C 1 optionally 1-6 alkyl group in either alkoxyl", are as follows Can be mentioned.
　例えば、「ハロゲン原子で１～５個置換されていてもよいＣ１～６アルキル基」とは、「ハロゲン化Ｃ１～６アルキル」として表される基である。上述した炭素数１ないし６の直鎖若しくは分枝鎖のアルキル基に加えて、当該炭素鎖が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、より好ましくは、ハロゲン原子で１～５個置換されていてもよいＣ１～４アルキル基、具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基に加え、例えば、トリフルオロメチル基、テトラフルオロエチル基、ペンタフルオロエチル基等が挙げられる。 For example, the "optionally 1-5 substituted by a halogen atom C 1 ~ 6 alkyl group", a group represented as "halogenated C 1 ~ 6 alkyl". In addition to the above-mentioned linear or branched alkyl group having 1 to 6 carbon atoms, it represents a group selected from groups in which the carbon chain is optionally substituted with 1 to 5 halogen atoms, more preferably a halogen atom with one to five substituted C 1 ~ 4 may optionally be alkyl groups, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, tert In addition to butyl group, for example, trifluoromethyl group, tetrafluoroethyl group, pentafluoroethyl group and the like can be mentioned.
　例えば、「－ＯＨで１～５個置換されていてもよいＣ１～６アルキル基」とは、ヒドロキシル基で１～５個置換されていてもよいＣ１～６アルキル基であり、「ヒドロキシ－Ｃ１～６アルキル」として表される基である。上述した炭素数１ないし６の直鎖若しくは分枝鎖のアルキル基に加えて、当該アルキル基にヒドロキシル基が１～５個置換した基をとりうるが、置換位置において数多くの位置異性体が存在する。具体的には、ヒドロキシメチル基のほか、ヒドロキシメチル、２－ヒドロキシエチル、１－ヒドロキシエチル、３－ヒドロキシ－１－プロピル、２－ヒドロキシ－１－プロピル、１－ヒドロキシ－１－プロピル、１－ヒドロキシ－１－メチル－１－エチル、２－ヒドロキシ－１－メチル－１－エチル、４－ヒドロキシ－１－ブチル、３－ヒドロキシ－１－ブチル、２－ヒドロキシ－１－ブチル、１－ヒドロキシ－１－ブチル、３－ヒドロキシ－２－メチルプロピル、２－ヒドロキシ－２－メチルプロピル、２－ヒドロキシ－１，１－ジメチル－１－エチル、１－ヒドロキシ－２－メチルプロピル、５－ヒドロキシ－１－ペンチル、４－ヒドロキシ－１－ペンチル、３－ヒドロキシ－１－ペンチル、２－ヒドロキシ－１－ペンチル、１－ヒドロキシ－１－ペンチル、４－ヒドロキシ－３－メチルブチル、４－ヒドロキシ－２－メチルブチル、４－ヒドロキシ－１－メチルブチル、３－ヒドロキシ－３－メチルブチル、３－ヒドロキシ－２－メチルブチル、３－ヒドロキシ－１－メチルブチル、２－ヒドロキシ－３－メチルブチル、２－ヒドロキシ－２－メチルブチル、２－ヒドロキシ－１－メチルブチル、３－ヒドロキシ－２，２－ジメチルプロピル、３－ヒドロキシ－１，１－ジメチルプロピル、６－ヒドロキシ－１－ヘキシル、４－ヒドロキシ－１，１－ジメチル－１－ブチル、４－ヒドロキシ－２，２－ジメチル－１－ブチル等が挙げられる。 For example, - the term "1-5 are also good C 1 ~ 6 alkyl group optionally substituted by OH" is a 1-5 substituted C 1 optionally 1-6 alkyl group with a hydroxyl group, "hydroxy is a group represented by -C 1 ~ 6 alkyl ". In addition to the linear or branched alkyl group having 1 to 6 carbon atoms described above, the alkyl group may be substituted with 1 to 5 hydroxyl groups, but there are many positional isomers at the substitution position. To do. 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 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 Si-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.
　例えば、「Ｃ１～６アルコキシルで１～５個置換されていてもよいＣ１～６アルキル基」とは、「Ｃ１～６アルコキシ－Ｃ１～６アルキル」として表される基である。上述した炭素数１ないし６の直鎖若しくは分枝鎖のアルキル基に加えて、当該炭素鎖が１～５個のＣ１～６アルコキシルで任意に置換されている基から選ばれる基を表し、より好ましくは、Ｃ１～３アルコキシルで１～３個置換されていてもよいＣ１～４アルキル基であり、具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基に加え、例えば、メトキシメチル基、メトキシエチル基、メトキシプロピル基等が挙げられる。 For example, "C 1 ~ 6 alkoxyl with 1-5 optionally substituted C 1 ~ 6 alkyl group" is a group represented by "C 1 ~ 6 alkoxy -C 1 ~ 6 alkyl". In addition to the alkyl group of straight or branched chain having 1 to carbon atoms mentioned above 6, represents a group selected from the groups the carbon chain is optionally substituted with 1-5 C 1 ~ 6 alkoxy, more preferably, a C 1-3 alkoxyl with 1-3 optionally substituted C 1 ~ 4 alkyl group, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl In addition to the group, sec-butyl group and tert-butyl group, for example, methoxymethyl group, methoxyethyl group, methoxypropyl group and the like can be mentioned.
　例えば、「ハロゲン化Ｃ１～６アルコキシルで１～５個置換されていてもよいＣ１～６アルキル基」とは、上述した炭素数１ないし６の直鎖若しくは分枝鎖のアルキル基に加えて、当該炭素鎖が１～５個のハロゲン化Ｃ１～６アルコキシルで任意に置換されている基から選ばれる基を表し、より好ましくはハロゲン化Ｃ１～３アルコキシルで１～３個置換されていてもよいＣ１～４アルキル基であり、具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基に加え、例えば、トリフルオロメトキシメチル基、トリフルオロメトキシエチル基、トリフルオロメトキシプロピル基等が挙げられる。 For example, "halide C 1 ~ 6 alkoxy which may be 1 to 5 substituents C 1 ~ 6 alkyl group", in addition to an alkyl group of straight or branched chain having 1 to carbon atoms mentioned above 6 Te represents a group selected from the group which the carbon chain is optionally substituted with 1-5 halogenated C 1 ~ 6 alkoxy, and more preferably is 1-3 substituents halogenated C 1-3 alkoxy a good C 1 ~ 4 alkyl group optionally, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, in addition to the tert- butyl group, for example, Examples thereof include a trifluoromethoxymethyl group, a trifluoromethoxyethyl group, a trifluoromethoxypropyl group, and the like.
　「Ｒ５、Ｒ６はそれらが結合する窒素原子とともに３～８員の環状基を形成してもよく」における３～８員の環状基の例としては、例えば、前記「非芳香族のヘテロ環基」の中の３～８員の飽和もしくは不飽和非芳香族のヘテロ環基のうち、アジリジニル、アゼチジニル、ピロリジニル、ピラゾリニル、ピラゾリジニル、ピペリジル、ピペラジニル、モルホリニル、オキサゾリニル、チオモルホリニル、キヌクリジニル、オキセパニル等が挙げられる。 Examples of the 3- to 8-membered cyclic group in “R 5 and R 6 may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded” include, for example, the above-mentioned “non-aromatic heterocycle” Among the 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic groups in the “ring group”, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, oxazolinyl, thiomorpholinyl, quinuclidinyl, oxepanyl, etc. Can be mentioned.
　Ｒ５、Ｒ６において「当該窒素原子がハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換された場合」としての当該環状基は、例えば、 R 5, "the nitrogen atom is a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with one to five substituents which may be straight or branched chain alkoxyl in R 6 the cyclic group as if "substituted with an alkyl group of C 1 ~ 6 of, for example,
　４－メチルピペラジン－１－イル、４－エチルピぺラジン－１－イル、４－プロピルピペラジン－１－イル、４－トリフルオロメチルピペラジン－１－イル、４－（２－ヒドロキシ－１－エチル）ピペラジン－１－イル、４－（３－ヒドロキシ－１－プロピル）ピペラジン－１－イル、４－（２－メトキシ－１－エチル）ピペラジン－１－イル、４－（３－メトキシ－１－プロピル）ピペラジン－１－イル、４－（２－トリフルオロメトキシ－１－エチル）ピペラジン－１－イル、４－（３－トリフルオロメトキシ－１－プロピル）ピペラジン－１－イル等が挙げられる。　 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-propylpiperazin-1-yl, 4-trifluoromethylpiperazin-1-yl, 4- (2-hydroxy-1-ethyl) Piperazin-1-yl, 4- (3-hydroxy-1-propyl) piperazin-1-yl, 4- (2-methoxy-1-ethyl) piperazin-1-yl, 4- (3-methoxy-1-propyl) ) Piperazin-1-yl, 4- (2-trifluoromethoxy-1-ethyl) piperazin-1-yl, 4- (3-trifluoromethoxy-1-propyl) piperazin-1-yl and the like. *
　式（Ｉ）で表される化合物の各基の定義における、「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環状基」、「Ｒ５、Ｒ６はそれらが結合する窒素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい」等の「置換基」に供される「置換基」としては、以下のＲＡ群の置換基が挙げられる。即ち、上記の各基は、これらで任意に１～５個で置換されていてもよい。 In the definition of each group of the compound represented by the formula (I), “optionally substituted hydrocarbon group”, “optionally substituted heterocyclic group”, “optionally substituted cyclic group” , “R 5 and R 6 may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, C 1 halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with one to five substituents which may be straight or branched alkoxyl The substituent may be substituted with an alkyl group of 1 to 6 ), and the cyclic group may further have a substituent. As the above, substituents of the following RA group can be mentioned. That is, each of the above groups may be optionally substituted with 1 to 5 of these groups.
　Ｚの定義における、「置換されていてもよいＣ３～８のシクロアルキル基」、「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」の「シクロアルキル基」、「アリール基」または「ヘテロ環基」とは、前述の「炭化水素基」の例として挙げられた「シクロアルキル基」もしくは「アリール基」、あるいは「へテロ環基」と同じ意味を表し、それらは、以下のＲＡ群の置換基をもって、任意に１～５個で置換されうる。 Z in the definition of "cycloalkyl group 1-8 optionally C 3 which may be substituted", "optionally substituted aryl" or "cycloalkyl group" of the "optionally substituted heterocyclic group" , “Aryl group” or “heterocyclic group” have the same meaning as “cycloalkyl group” or “aryl group” or “heterocyclic group” mentioned as examples of the “hydrocarbon group”. , they have the following R a group substituents may be substituted with one to five arbitrarily.
　ここで、前述および後述の式に用いているＲＡ群、ＲＢ群、ＲＣ群の置換基について説明する。 Here, R A group is used in the equation described above and below, R B group, for a substituent R C group is described.
　ＲＡ群の置換基としては、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、
ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、Ｃ１～６アルキルチオ－Ｃ１～６アルキル、Ｃ１～６アルキルスルフィニル－Ｃ１～６アルキル、Ｃ１～６アルキルスルホニル－Ｃ１～６アルキル、スルファモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルスルファモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルスルファモイル－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、アミノ－Ｃ１～６アルキル、モノ／ジＣ１～６アルキルアミノ－Ｃ１～６アルキル、Ｃ２～７アルカノイル－Ｃ１～６アルキル、
Ｃ３～８シクロアルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、
Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、
Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、モノ／ジＣ１～６アルキルスルファモイル、
モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルスルファモイルアミノ、モノ／ジＣ１～６アルキルカルバモイルアミノ、Ｃ２～７アルカノイルアミノ、
Ｃ１～６アルコキシカルボニル、モノ／ジＣ１～６アルキルカルバモイル、Ｃ２～７アルカノイル、
オキソ、ニトロ、シアノ、アミノ、保護されていてもよいヒドロキシル、メルカプト、保護されていてもよいカルボキシル、カルバモイル、スルファモイル、ホルミル、ホルミルアミノ、スルホ、Ｃ６～１４アリール、Ｃ６～１４アリール－Ｃ１～６アルキル、Ｃ６～１４アリールオキシ、Ｃ６～１４アリールチオ、Ｃ６～１４アリールスルフィニル、Ｃ６～１４アリールスルホニル、モノ／ジＣ６～１４アリールスルファモイル、モノ／ジＣ６～１４アリールアミノ、モノ／ジＣ６～１４アリールスルファモイルアミノ、Ｃ６～１４アリールオキシカルボニル、モノ／ジＣ６～１４アリールカルバモイル、Ｃ６～１４アリールカルボニル、Ｃ６～１４アリールカルボニルアミノ、へテロ環（当該環は、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環、好ましくは３～１２員環の単環もしくは縮合環を有する環）、ヘテロ環Ｃ１～６アルキル、ヘテロ環オキシ、ヘテロ環チオ、ヘテロ環スルフィニル、ヘテロ環スルホニル、モノ／ジヘテロ環スルファモイル、モノ／ジヘテロ環アミノ、モノ／ジヘテロ環スルファモイルアミノ、ヘテロ環オキシカルボニル、ヘテロ環カルバモイル、ヘテロ環カルボニル、ヘテロ環カルボニルアミノ、等の置換基が挙げられる。 As a substituent of the R A group,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom,
Halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkylthio -C 1 ~ 6 alkyl, C 1 ~ 6 alkylsulfinyl -C 1 ~ 6 alkyl, C 1 ~ 6 alkylsulfonyl -C 1 ~ 6 alkyl, sulfamoyl -C 1 ~ 6 alkyl, N-C 1 ~ 6 alkylsulfamoyl -C 1 ~ 6 alkyl, N, N-di-C 1 ~ 6 alkylsulfamoyl -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, amino -C 1-6 Al Le, mono / di C 1 ~ 6 alkyl amino -C 1 ~ 6 alkyl, C 2 ~ 7 alkanoyl -C 1 ~ 6 alkyl,
C 3 ~ 8 cycloalkyl, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl,
C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy,
C 1 ~ 6 alkylthio, C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, mono / di C 1 ~ 6 alkyl sulfamoyl,
Mono / di C 1 ~ 6 alkylamino, mono / di C 1 ~ 6 alkyl sulfamoylamino, mono / di C 1 ~ 6 alkylcarbamoyl amino, C 2 ~ 7 alkanoylamino,
C 1 ~ 6 alkoxycarbonyl, mono / di C 1 ~ 6 alkylcarbamoyl, C 2 ~ 7 alkanoyl,
Oxo, nitro, cyano, amino, optionally protected hydroxyl, mercapto, protected optionally carboxyl, carbamoyl, sulfamoyl, formyl, formylamino, sulfo, C 6 ~ 14 aryl, C 6 ~ 14 aryl -C 1-6 alkyl, C 6 ~ 14 aryloxy, C 6 ~ 14 arylthio, C 6 ~ 14 arylsulfinyl, C 6 ~ 14 arylsulfonyl, mono / di C 6 ~ 14 aryl sulfamoyl, mono / di C 6 ~ 14 arylamino, mono / di C 6 ~ 14 aryl sulfamoylamino, C 6 ~ 14 aryloxycarbonyl, mono / di C 6 ~ 14 aryl-carbamoyl, C 6 ~ 14 aryl-carbonyl, C 6 ~ 14 arylcarbonylamino, Heterocycle (the ring is carbon In addition, a ring having 3 to 14 membered ring, preferably 3 to 12 membered monocyclic or condensed ring containing at least one heteroatom (preferably 1 to 4) selected from N, O and S), heterocycle C 1 ~ 6 alkyl, heterocyclic oxy, heterocyclic thio, heterocyclic sulfinyl, heterocyclic sulfonyl, mono / diheterocyclic sulfamoyl, mono / diheterocyclic amino, mono / diheterocyclic sulfamoylamino, heterocyclic oxy carbonyl, Examples of the substituent include heterocyclic carbamoyl, heterocyclic carbonyl, and heterocyclic carbonylamino.
　当該ＲＡ群の置換基中のアルキル鎖部分、アリールまたはヘテロ環は、更にハロゲン原子、ハロゲン化Ｃ１～６アルキル、シアノ、保護されていてもよいヒドロキシル、アミノ、ニトロ、保護されていてもよいカルボキシル、カルバモイル、Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルカノイルアミノ、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、モノ／ジＣ１～６アルキルスルファモイル、モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルスルファモイルアミノ、Ｃ１～６アルコキシカルボニル、モノ／ジＣ１～６アルキルカルバモイル、Ｃ２～７アルカノイル、Ｃ６～１４アリール、およびへテロ環基（当該環は、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環、好ましくは３～１２員環の単環もしくは縮合環を有する環）からなる群から選ばれる基１～５個で置換されていてもよい。 The alkyl chain moiety in the substituent of the R A group, aryl or heteroaryl ring may further halogen atoms, halogenated C 1 ~ 6 alkyl, cyano, optionally protected hydroxyl, amino, nitro, be protected good carboxyl, carbamoyl, C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkanoylamino, C 1 ~ 6 alkylthio, C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, mono / di C 1 ~ 6 alkylsulfamoyl, mono / di C 1 ~ 6 alkylamino, mono / di C 1 ~ 6 alkyl sulfamoylamino, C 1 ~ 6 alkoxycarbonyl, mono / di C 1 ~ 6 alkylcarbamoyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 aryl, and a Hajime Tamaki (said ring, N in addition to carbon atoms, Selected from the group consisting of a 3 to 14-membered ring, preferably a 3 to 12-membered monocyclic or condensed ring containing at least one heteroatom (preferably 1 to 4) selected from O and S Optionally substituted with 1 to 5 groups.
　ここで、当該置換基ＲＡ群における各置換基と炭素数、直鎖、分枝鎖、環状などとの関係の例を以下に具体例として示す。 Here, a respective substituents and the number of carbon atoms in the substituent R A groups linear, branched, an example of the relationship, such as an annular Examples below.
　「ハロゲン原子」の例としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 Examples of “halogen atom” include fluorine atom, chlorine atom, bromine atom and iodine atom.
　「Ｃ１～６アルコキシル」とは、炭素数１ないし６の直鎖、分枝鎖もしくは環状のアルコキシル基をあらわすが、包括的にはＲＯ－（Ｒは上述に列記されたＣ１～６アルキル基）で表される基である。例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペンチルオキシ基、イソペンチルオキシ基、３－ペンチルオキシ基、ｔｅｒｔ－ペンチルオキシ基、ネオペンチルオキシ基、２－メチルブトキシ基、１，２－ジメチルプロポキシ基、１－エチルプロポキシ基、ヘキシルオキシ基、シクロプロピルオキシ基、シクロブチルオキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基、シクロプロピルメチルオキシ基、１－シクロプロピルエチルオキシ基、２－シクロプロピルエチルオキシ基、シクロブチルメチルオキシ基、２－シクロブチルエチルオキシ基、シクロペンチルメチルオキシ基等が挙げられる。 The "C 1 ~ 6 alkoxy", straight chain of 1 to 6 carbon atoms, represents a branched or cyclic alkoxyl group, the comprehensive RO- (R is C 1 ~ 6 alkyl cited in the above Group). For example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, 3-pentyloxy group, tert-pentyloxy Group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cyclohexane Examples include propylmethyloxy group, 1-cyclopropylethyloxy group, 2-cyclopropylethyloxy group, cyclobutylmethyloxy group, 2-cyclobutylethyloxy group, cyclopentylmethyloxy group and the like.
　「Ｃ１～６アルコキシカルボニル」とは、前述の炭素原子数１ないし６の直鎖、分枝鎖もしくは環状のアルコキシル基が結合したカルボニル基であり、ＲＯ－ＣＯ－（Ｒは上述に列記されたＣ１～６アルキル基）として表されるが、例えばメトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、ブトキシカルボニル基、イソブトキシカルボニル基、ｓｅｃ－ブトキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、ペンチルオキシカルボニル基、イソペンチルオキシカルボニル基、ネオペンチルオキシカルボニル基，ｔｅｒｔ－ペンチルオキシカルボニル基、ヘキシルオキシカルボニル基、シクロプロピルオキシカルボニル基、シクロブチルオキシカルボニル基、シクロペンチルオキシカルボニル基、シクロヘキシルオキシカルボニル基、シクロプロピルメチルオキシカルボニル基、１－シクロプロピルエチルオキシカルボニル基、２－シクロプロピルエチルオキシカルボニル基、シクロブチルメチルオキシカルボニル基、２－シクロブチルエチルオキシカルボニル基、シクロペンチルメチルオキシカルボニル基等が挙げられる。 The "C 1 ~ 6 alkoxycarbonyl", straight chain C 1 -C mentioned above 6, a carbonyl group branched or cyclic alkoxyl group is bonded, RO-CO- (R is listed above C 1 ~ 6 are represented as alkyl groups) was, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec- butoxycarbonyl group, tert- butoxy Carbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, cyclopropyloxycarbonyl group, cyclobutyloxycarbonyl group, cyclopentyloxy Carbonyl group, cyclohexyloxycarbonyl group, cyclopropylmethyloxycarbonyl group, 1-cyclopropylethyloxycarbonyl group, 2-cyclopropylethyloxycarbonyl group, cyclobutylmethyloxycarbonyl group, 2-cyclobutylethyloxycarbonyl group, cyclopentyl A methyloxycarbonyl group etc. are mentioned.
　「モノ／ジＣ１～６アルキルアミノ」とは、アミノ基の一つ又は二つの水素原子が「直鎖、分枝鎖もしくは環状のＣ１～６アルキル基」で置換されたアミノ基を意味する。具体的には、メチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基、ブチルアミノ基、イソブチルアミノ基、ペンチルアミノ基、イソペンチルアミノ基、ヘキシルアミノ基、イソヘキシルアミノ基、シクロプロピルアミノ基、シクロブチルアミノ基、シクロペンチルアミノ基、シクロヘキシルアミノ基、ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジイソプロピルアミノ基、ジブチルアミノ基、ジペンチルアミノ基、エチルメチルアミノ基、メチルプロピルアミノ基、エチルプロプルアミノ基、ブチルメチルアミノ基、ブチルエチルアミノ基、ブチルプロピルアミノ基、シクロプロピルメチルアミノ基、シクロブチルメチルアミノ基、シクロペンチルメチルアミノ基、シクロヘキシルメチルアミノ基等が挙げられる。 By "mono / di C 1 ~ 6 alkylamino" refers to one or two hydrogen atoms are "linear, branched or cyclic C 1 ~ 6 alkyl group" substituted amino group of the amino group To do. Specifically, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, isohexylamino group, cyclopropylamino Group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dipentylamino group, ethylmethylamino group, methylpropylamino group, ethyl Propylamino group, butylmethylamino group, butylethylamino group, butylpropylamino group, cyclopropylmethylamino group, cyclobutylmethylamino group, cyclopentylmethylamino group, cyclohexylmethylamino group And the like.
　「モノ／ジＣ１～６アルキルカルバモイル」とは、カルバモイル基の窒素原子上の一つ又は二つの水素原子が「直鎖、分枝鎖もしくは環状のＣ１～６アルキル基」で置換されたカルバモイル基を意味する。具体的には、例えばメチルカルバモイル基、エチルカルバモイル基、プロピルカルバモイル基、イソプロピルカルバモイル基、シクロプロピルカルバモイル基、ブチルカルバモイル基、イソブチルカルバモイル基、ペンチルカルバモイル基、イソペンチルカルバモイル基、ヘキシルカルバモイル基、イソヘキシルカルバモイル基、
シクロプロピルカルバモイル基、シクロブチルカルバモイル基、シクロペンチルカルバモイル基、シクロヘキシルカルバモイル基、Ｎ，Ｎ－ジメチルカルバモイル基、Ｎ，Ｎ－ジエチルカルバモイル基、Ｎ，Ｎ－ジプロピルカルバモイル基、Ｎ，Ｎ－ジ－イソプロピルカルバモイル基、Ｎ，Ｎ－ジブチルカルバモイル基、Ｎ，Ｎ－ジペンチルカルバモイル基、Ｎ，Ｎ－エチルメチルカルバモイル基、Ｎ，Ｎ－メチルプロピルカルバモイル基、Ｎ，Ｎ－エチルプロプルカルバモイル基、Ｎ，Ｎ－ブチルメチルカルバモイル基、Ｎ，Ｎ－ブチルエチルカルバモイル基、Ｎ，Ｎ－ブチルプロピルカルバモイル基、Ｎ，Ｎ－シクロプロピルメチルカルバモイル基、Ｎ，Ｎ－シクロブチルメチルカルバモイル基、Ｎ，Ｎ－シクロペンチルメチルカルバモイル基、Ｎ，Ｎ－シクロヘキシルメチルカルバモイル基等が挙げられる。 By "mono / di C 1 ~ 6 alkylcarbamoyl" substituted one or two hydrogen atoms on the nitrogen atom of the carbamoyl group is "linear, branched, or C 1 ~ 6 alkyl group cyclic" It means a carbamoyl group. Specifically, for example, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, pentylcarbamoyl group, isopentylcarbamoyl group, hexylcarbamoyl group, isohexyl A carbamoyl group,
Cyclopropylcarbamoyl group, cyclobutylcarbamoyl group, cyclopentylcarbamoyl group, cyclohexylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dipropylcarbamoyl group, N, N-di-isopropyl Carbamoyl group, N, N-dibutylcarbamoyl group, N, N-dipentylcarbamoyl group, N, N-ethylmethylcarbamoyl group, N, N-methylpropylcarbamoyl group, N, N-ethylpropylcarbamoyl group, N, N- Butylmethylcarbamoyl group, N, N-butylethylcarbamoyl group, N, N-butylpropylcarbamoyl group, N, N-cyclopropylmethylcarbamoyl group, N, N-cyclobutylmethylcarbamoyl group, N, N-cyclopentylmethylcarba Mo Le group, N, etc. N- cyclohexyl methylcarbamoyl group.
　「Ｃ１～６アルキルチオ」とは、炭素原子数１ないし６の直鎖、分枝鎖もしくは環状のアルキルチオ基を意味し、例えばメチルチオ基、エチルチオ基、プロピルチオ基、イソプロピルチオ基、ブチルチオ基、イソブチルチオ基、ｓｅｃ－ブチルチオ基、ｔｅｒｔ－ブチルチオ基、ペンチルチオ基、イソペンチルチオ基、ｔｅｒｔ－ペンチルチオ基、ネオペンチルチオ基、２－メチルブチルチオ基、１，２－ジメチルプロピルチオ基、１－エチルプロピルチオ基、ヘキシルチオ基、シクロプロピルチオ基、シクロブチルチオ基、シクロペンチルチオ基、シクロヘキシルチオ基、シクロプロピルメチルチオ基、１－シクロプロピルエチルチオ基、２－シクロプロピルエチルチオ基、シクロブチルメチルチオ基、２－シクロブチルエチルチオ基、シクロペンチルメチルチオ基等が挙げられる。 The "C 1 ~ 6 alkylthio", straight chain C 1 -C 6 refers to branched or cyclic alkylthio groups such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutyl Thio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, tert-pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group, 1-ethyl Propylthio group, hexylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cyclopropylmethylthio group, 1-cyclopropylethylthio group, 2-cyclopropylethylthio group, cyclobutylmethylthio group 2-cyclobutylethylthio group, Black cyclopentylmethyl thio group and the like.
　「Ｃ１～６アルキルスルフィニル」とは、炭素原子数１ないし６の直鎖、分枝鎖もしくは環状のアルキルスルフィニル基を意味し、例えばメチルスルフィニル基、エチルスルフィニル基、プロピルスルフィニル基、イソプロピルスルフィニル基、ブチルスルフィニル基、イソブチルスルフィニル基、ｓｅｃ－ブチルスルフィニル基、ｔｅｒｔ－ブチルスルフィニル基、ペンチルスルフィニル基、イソペンチルスルフィニル基、ｔｅｒｔ－ペンチルスルフィニル基、ネオペンチルスルフィニル基、２－メチルブチルスルフィニル基、１，２－ジメチルプロピルスルフィニル基、１－エチルプロピルスルフィニル基、ヘキシルスルフィニル基、シクロプロピルスルフィニル基、シクロブチルスルフィニル基、シクロペンチルスルフィニル基、シクロヘキシルスルフィニル基、シクロプロピルメチルスルフィニル基、１－シクロプロピルエチルスルフィニル基、２－シクロプロピルエチルスルフィニル基、シクロブチルメチルスルフィニル基、２－シクロブチルエチルスルフィニル基、シクロペンチルメチルスルフィニル基等が挙げられる。 The "C 1 ~ 6 alkylsulfinyl", straight chain C 1 -C 6 refers to branched or cyclic alkylsulfinyl group, for example, methylsulfinyl group, ethylsulfinyl group, propyl sulfinyl group, isopropyl sulfinyl group Butylsulfinyl 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, 1-ethylpropylsulfinyl group, hexylsulfinyl group, cyclopropylsulfinyl group, cyclobutylsulfinyl group, cyclopentylsulfinyl group, B hexyl sulfinyl group, cyclopropylmethyl sulfinyl group, 1-cyclopropylethyl sulfinyl group, 2-cyclopropylethyl sulfinyl group, cyclobutylmethyl sulfinyl group, 2-cyclobutyl-ethyl sulfinyl group, cyclopentylmethyl sulfinyl group and the like.
　「Ｃ１～６アルキルスルホニル」とは、炭素原子数１ないし６の直鎖、分枝鎖もしくは環状のアルキルスルホニル基を意味し、例えばメチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、イソプロピルスルホニル基、ブチルスルホニル基、イソブチルスルホニル基、ｓｅｃ－ブチルスルホニル基、ｔｅｒｔ－ブチルスルホニル基、ペンチルスルホニル基、イソペンチルスルホニル基、ｔｅｒｔ－ペンチルスルホニル基、ネオペンチルスルホニル基、２－メチルブチルスルホニル基、１，２－ジメチルプロピルスルホニル基、１－エチルプロピルスルホニル基、ヘキシルスルホニル基、シクロプロピルスルホニル基、シクロブチルスルホニル基、シクロペンチルスルホニル基、シクロヘキシルスルホニル基、シクロプロピルメチルスルホニル基、１－シクロプロピルエチルスルホニル基、２－シクロプロピルエチルスルホニル基、シクロブチルメチルスルホニル基、２－シクロブチルエチルスルホニル基、シクロペンチルメチルスルホニル基等が挙げられる。 The "C 1 ~ 6 alkylsulfonyl", straight chain C 1 -C 6 refers to branched or cyclic alkylsulfonyl groups such as 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, cyclopropylmethyl group Rusuruhoniru group, 1-cyclopropylethyl sulfonyl group, 2-cyclopropylethyl sulfonyl group, cyclobutylmethyl methylsulfonyl group, 2-cyclobutyl-ethyl sulfonyl group, cyclopentylmethyl sulfonyl group and the like.
　「モノ／ジＣ１～６アルキルスルファモイル」とは、スルファモイル基の窒素原子上の一つ又は二つの水素原子が「直鎖、分枝鎖もしくは環状のＣ１～６アルキル基」で置換されたスルファモイル基を意味する。具体的には、例えばメチルスルファモイル基、エチルスルファモイル基、プロピルスルファモイル基、イソプロピルスルファモイル基、シクロプロピルスルファモイル基、ブチルスルファモイル基、イソブチルスルファモイル基、ペンチルスルファモイル基、イソペンチルスルファモイル基、ヘキシルスルファモイル基、イソヘキシルスルファモイル基、シクロプロピルスルファモイル基、シクロブチルスルファモイル基、シクロペンチルスルファモイル基、シクロヘキシルスルファモイル基、Ｎ，Ｎ－ジメチルスルファモイル基、Ｎ，Ｎ－ジエチルスルファモイル基、Ｎ，Ｎ－ジプロピルスルファモイル基、Ｎ，Ｎ－ジ－イソプロピルスルファモイル基、Ｎ，Ｎ－ジブチルスルファモイル基、Ｎ，Ｎ－ジペンチルスルファモイル基、Ｎ，Ｎ－エチルメチルスルファモイル基、Ｎ，Ｎ－メチルプロピルスルファモイル基、Ｎ，Ｎ－エチルプロプルスルファモイル基、Ｎ，Ｎ－ブチルメチルスルファモイル基、Ｎ，Ｎ－ブチルエチルスルファモイル基、Ｎ，Ｎ－ブチルプロピルスルファモイル基、Ｎ，Ｎ－シクロプロピルメチルスルファモイル基、Ｎ，Ｎ－シクロブチルメチルスルファモイル基、Ｎ，Ｎ－シクロペンチルメチルスルファモイル基、Ｎ，Ｎ－シクロヘキシルメチルスルファモイル基等が挙げられる。 Substitution, the "mono / di C 1 ~ 6 alkyl sulfamoyl", one or two hydrogen atoms on the nitrogen atom of the sulfamoyl group "linear, branched or C 1 ~ 6 alkyl group cyclic" Means a modified sulfamoyl group. Specifically, for example, methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, cyclopropylsulfamoyl group, butylsulfamoyl group, isobutylsulfamoyl group, pentyl Sulfamoyl group, Isopentylsulfamoyl group, Hexylsulfamoyl group, Isohexylsulfamoyl group, Cyclopropylsulfamoyl group, Cyclobutylsulfamoyl group, Cyclopentylsulfamoyl group, Cyclohexylsulfamoyl group N, N-dimethylsulfamoyl group, N, N-diethylsulfamoyl group, N, N-dipropylsulfamoyl group, N, N-di-isopropylsulfamoyl group, N, N-dibutylsulfa Moyl group, N, N-dipentylsulfamoyl group, N, N Ethylmethylsulfamoyl group, N, N-methylpropylsulfamoyl group, N, N-ethylpropylsulfamoyl group, N, N-butylmethylsulfamoyl group, N, N-butylethylsulfamoyl group N, N-butylpropylsulfamoyl group, N, N-cyclopropylmethylsulfamoyl group, N, N-cyclobutylmethylsulfamoyl group, N, N-cyclopentylmethylsulfamoyl group, N, N -Cyclohexylmethylsulfamoyl group and the like.
　「保護されていてもよいヒドロキシル」の保護基としては、メチル基・ｔｅｒｔ－ブチル基・ベンジル基・トリチル基・メトキシメチル基等のアルキル系保護基、トリメチルシリル基・ｔｅｒｔ－ブチルジメチルシリル基等のシリル系保護基、ホルミル基・アセチル基・ベンゾイル基等のアシル系保護基、メトキシカルボニル基・ベンジルオキシカルボニル基等のカルボネート系保護基が挙げられる。 Examples of the protecting group of “optionally protected hydroxyl” 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.
　「保護されていてもよいカルボキシル」の保護基としては、メチル基・エチル基・ｔｅｒｔ－ブチル基・ベンジル基・ジフェニルメチル基・トリチル基等のアルキルエステル系保護基、トリメチルシリル基・ｔｅｒｔ－ブチルジメチルシリル基等のシリルエステル系保護基等が挙げられる。 Examples of the protecting group for “optionally protected carboxyl” 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-butyldimethyl group. Examples include silyl ester-based protecting groups such as silyl groups.
　ここで、「保護されていてもよいヒドロキシル」と「保護されていてもよいカルボキシル」における保護基とは、例えばグリーン（Ｇｒｅｅｎｅ）らのプロテクティブ・グループス・イン・オルガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、（米国）、第３版、１９９９年、等の成書にそれぞれの保護基として記載されているものを含む。 Here, the protecting group in “optionally protected hydroxyl” and “optionally protected carboxyl” refers to, for example, Greene et al. Protective Groups in Organic Synthesis in Protective Groups in (Organic Synthesis), (USA), 3rd edition, 1999, and the like are included as the respective protecting groups.
　「Ｃ３～８シクロアルキル－Ｃ１～６アルキル」とは、例えば、前記Ｃ３～８のシクロアルキル基、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が、上述した炭素数１ないし６の直鎖若しくは分枝鎖のアルキル基に１つ置換した基である。具体的にシクロプロピルメチル基、シクロブチルメチル基、シクロペンチルメチル基、シクロヘキシルメチル基、２－（シクロプロピル）エチル基、２－（シクロブチル）エチル基、２－（シクロペンチル）エチル基、２－（シクロヘキシル）エチル基等が挙げられる。 The "C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl", for example, a cycloalkyl group of the C 3 ~ 8, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, the above-described This is a group in which a linear or branched alkyl group having 1 to 6 carbon atoms is substituted. Specifically, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 2- (cyclopropyl) ethyl group, 2- (cyclobutyl) ethyl group, 2- (cyclopentyl) ethyl group, 2- (cyclohexyl) ) And the like.
　「Ｃ６～１４アリール－Ｃ１～６アルキル」とは、前記「Ｃ６～１４アリール基」が直鎖もしくは分枝鎖のＣ１～６アルキル基に置換した基（アラルキル基）であり、例えば、ベンジル基、１－ナフチルメチル基、２－ナフチルメチル基、フェネチル基、２－（１－ナフチル）エチル基、２－（２－ナフチル）エチル基等が挙げられる。 The "C 6 ~ 14 aryl -C 1 ~ 6 alkyl" is the "C 6 ~ 14 aryl group" is substituted with C 1 ~ 6 alkyl group straight or branched chain group (aralkyl group), Examples include benzyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, phenethyl group, 2- (1-naphthyl) ethyl group, 2- (2-naphthyl) ethyl group and the like.
　「ヘテロ環Ｃ１～６アルキル」とは、前記「ヘテロ環基」（例えば、ヘテロアリール基、飽和もしくは不飽和の非芳香族のヘテロ環基等）が直鎖もしくは分枝鎖のＣ１～６アルキル基に置換した基（ヘテロサイクリック－Ｃ１～６アルキル基）であり、例えば、ピロリルメチル、フリルメチル、チエニルメチル、イミダゾリルメチル、オキサゾリルメチル、イソオキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、１，２，３－トリアゾリルメチル、１，２，４－トリアゾリルメチル、１，２，３－オキサジアゾリルメチル、１，２，４－オキサジアゾリルメチル、１，３，４－オキサジアゾリルメチル、フラザニルメチル、１，２，３－チアジアゾリルメチル、１，２，４－チアジアゾリルメチル、１，３，４－チアジアゾリルメチル、テトラゾリルメチル、（２－、３－、４－）ピリジルメチル、ピリダジニルメチル、ピリミジニルメチル、ピラジニルメチル、１，２，３－トリアジニルメチル、１，２，４－トリアジニルメチル、１，２，５－トリアジニルメチル、１，３，５－トリアジニルメチル、２Ｈ－１，２，３－チアジアジニルメチル、４Ｈ－１，２，４－チアジアジニルメチル、６Ｈ－１，３，４－チアジアジニルメチル等の「単環式のヘテロアリール基」が置換した例、及び
　インドリルメチル、イソインドリルメチル、１Ｈ－インダゾリルメチル、ベンゾフラニル（－２－イル）メチル、イソベンゾフラニルメチル、ベンゾチエニル（－２－イル）メチル、イソベンゾチエニルメチル、ベンズインダゾリルメチル、ベンゾオキサゾリル（－２－イル）メチル、１，２－ベンゾイソオキサゾリルメチル、ベンゾチアゾリル（－２－イル）メチル、１，２－ベンゾイソチアゾリルメチル、２Ｈ－ベンゾピラニル（－３－イル）メチル、１Ｈ－ベンズイミダゾリル（－２－イル）メチル、１Ｈ－ベンゾトリアゾリルメチル、４Ｈ－１，４－ベンゾオキサジニルメチル、４Ｈ－１，４－ベンゾチアジニルメチル、キノリルメチル、イソキノリルメチル、シンノリニルメチル、キナゾリニルメチル、キノキザリニルメチル、フタラジニルメチル、ナフチリジニルメチル、プリニルメチル、プテリジニルメチル、カルバゾリルメチル、カルボリニルメチル、アクリジニルメチル、フェノキサジニルメチル、フェノチアジニルメチル、フェナジニルメチル、フェノキサチイニルメチル、チアンスレニルメチル、フェナンスリジニルメチル、フェナンスロリニルメチル、インドリジニルメチル、４，５，６，７－テトラヒドロチアゾロ［５，４－ｃ］ピリジル－２－イルメチル、４，５，６，７－テトラヒドロチエノ［３，２－ｃ］ピリジルメチル、１，２，３，４－テトラヒドロイソキノリル（－６－イル）メチル、チアゾロ［５，４－ｃ］ピリジル（－２－イル）メチル、ピロロ［１，２－ｂ］ピリダジニルメチル、ピラゾ［１，５－ａ］ピリジルメチル、イミダゾ［１，２－ａ］ピリジルメチル、イミダゾ［１，５－ａ］ピリジルメチル、イミダゾ［１，２－ｂ］ピリダジニルメチル、イミダゾ［１，５－ａ］ピリミジニルメチル、［１，２，４］トリアゾロ［４，３－ａ］ピリジルメチル、１，２，４－トリアゾロ［４，３－ｂ］ピリダジニルメチル、クロメニル（２Ｈ－クロメニル）メチル、１Ｈ－ピラゾロ［３，４－ｂ］ピリジルメチル、［１，２，４］トリアゾロ［１，５－ａ］ピリミジニルメチル等の「縮環式のヘテロアリール基」が置換した例、及び
　アゼチジニルメチル、オキシラニルメチル、オキセタニルメチル、チエタニルメチル、ピロリジニルメチル、テトラヒドロフリルメチル、チオラニルメチル、ピラゾリニルメチル、ピラゾリジニルメチル、ピペリジルメチル、テトラヒドロピラニルメチル、ピペラジニルメチル、モルホリニルメチル、オキサゾリニルメチル、チアゾリニルメチル、チオモルホリニルメチル、キヌクリジニルメチル、オキセパニルメチル等の「非芳香族のヘテロ環基（３～８員の飽和もしくは不飽和非芳香族のヘテロ環基）」が置換した例が挙げられる。 The "heterocycle C 1 ~ 6 alkyl", the "heterocyclic group" (e.g., a heteroaryl group, such as a heterocyclic group of a non-aromatic saturated or unsaturated) C 1 ~ of a linear or branched 6 is an alkyl group have been substituted (heterocyclic -C 1 ~ 6 alkyl group), for example, pyrrolylmethyl, furylmethyl, thienylmethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazoloxy Rylmethyl, pyrazolylmethyl, 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, , 3,4-thiadiazolylmethyl, tetrazolylmethyl, (2-, 3-, 4-) pyridylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, 1,2,3-triazinylmethyl, 1,2,4-triazinylmethyl, 1,2,5-triazinylmethyl, 1,3,5-triazinylmethyl, 2H-1,2,3-thiadiazinylmethyl, 4H-1, Examples of substituted “monocyclic heteroaryl groups” such as 2,4-thiadiazinylmethyl, 6H-1,3,4-thiadiazinylmethyl, and indolylmethyl, isoindolylmethyl, 1H-in Dazolylmethyl, benzofuranyl (-2-yl) methyl, isobenzofuranylmethyl, benzothienyl (-2-yl) methyl, isobenzothienylmethyl, benzindazolylmethyl, benzo Xazolyl (-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, syn Nolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, phthalazinylmethyl, naphthyridinylmethyl, purinylmethyl, pteridinylmethyl, carbazolylmethyl, carbolinylmethyl, acridinylmethyl, phenoxazinyl Methyl, phenothiazinylmethyl, phenazinylmethyl, phenoxathiinyl Til, thianthrenylmethyl, phenanthridinylmethyl, phenanthrolinylmethyl, indolizinylmethyl, 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridyl-2-ylmethyl 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, imidazo [1,5-a] pyridyl Methyl, imidazo [1,2-b] pyridazinylmethyl, imidazo [1,5-a] pyrimidinylmethyl, [1,2,4] triazolo [4,3-a] pyridylmethyl, 1,2,4 -Triazo B [4,3-b] pyridazinylmethyl, chromenyl (2H-chromenyl) methyl, 1H-pyrazolo [3,4-b] pyridylmethyl, [1,2,4] triazolo [1,5-a] Examples substituted by “condensed heteroaryl groups” such as pyrimidinylmethyl, and azetidinylmethyl, oxiranylmethyl, oxetanylmethyl, thietanylmethyl, pyrrolidinylmethyl, tetrahydrofurylmethyl, thiolanylmethyl, pyrazolinylmethyl, Pyrazolidinylmethyl, piperidylmethyl, tetrahydropyranylmethyl, piperazinylmethyl, morpholinylmethyl, oxazolinylmethyl, thiazolinylmethyl, thiomorpholinylmethyl, quinuclidinylmethyl, oxepanylmethyl Non-aromatic heterocyclic groups (3-8 membered saturated or unsaturated non-aromatic Heterocyclic group) ”is substituted.
　「Ｃ２～７アルカノイル」とは、「Ｃ２～７の直鎖、分枝鎖もしくは環状のアルキルカルボニル基」を意味し、例えばアセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基、ピバロイル基、ヘキサノイル基、シクロプロピルカルボニル基、シクロブチルカルボニル基、シクロペンチルカルボニル基、シクロヘキシルカルボニル基等が挙げられる。 The "C 2 ~ 7 alkanoyl", "linear C 2 ~ 7, branched or cyclic alkylcarbonyl group" means a such as acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl Group, pivaloyl group, hexanoyl group, cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group and the like.
　「Ｃ６～１４アリールカルボニル」とは、前記アリール基にカルボニル基が結合した基、例えば、ベンゾイル基、ナフチルカルボニル基等のＣ６～１４アリールカルボニル基が挙げられる。 The "C 6 ~ 14 aryl-carbonyl", group carbonyl group on the aryl group is bonded, for example, a benzoyl group and a C 6 ~ 14 aryl group such as a naphthyl group.
　「ヘテロ環カルボニル」とは、「ヘテロサイクリックカルボニル基」を意味し、前記へテロ環基（例えば、ヘテロアリール基、飽和もしくは不飽和の非芳香族のヘテロ環基等）にカルボニル基が結合した基、例えば、ピロリルカルボニル、フリルカルボニル、チエニルカルボニル、イミダゾリルカルボニル、オキサゾリルカルボニル、イソオキサゾリルカルボニル、チアゾリルカルボニル、イソチアゾリルカルボニル、ピラゾリルカルボニル、１，２，３－トリアゾリルカルボニル、１，２，４－トリアゾリルカルボニル、１，２，３－オキサジアゾリルカルボニル、１，２，４－オキサジアゾリルカルボニル、１，３，４－オキサジアゾリルカルボニル、フラザニルカルボニル、１，２，３－チアジアゾリルカルボニル、１，２，４－チアジアゾリルカルボニル、１，３，４－チアジアゾリルカルボニル、テトラゾリルカルボニル、ピリジルカルボニル、ピリダジニルカルボニル、ピリミジニルカルボニル、ピラジニルカルボニル、１，２，３－トリアジニルカルボニル、１，２，４－トリアジニルカルボニル、１，２，５－トリアジニルカルボニル、１，３，５－トリアジニルカルボニル、２Ｈ－１，２，３－チアジアジニルカルボニル、４Ｈ－１，２，４－チアジアジニルカルボニル、６Ｈ－１，３，４－チアジアジニルカルボニル等の「単環式のへテロアリール基」が結合したカルボニル基；
　インドリルカルボニル、イソインドリルカルボニル、１Ｈ－インダゾリルカルボニル、ベンゾフラニル（－２－イル）カルボニル、イソベンゾフラニルカルボニル、ベンゾチエニル（－２－イル）カルボニル、イソベンゾチエニルカルボニル、ベンズインダゾリルカルボニル、ベンゾオキサゾリル（－２－イル）カルボニル、１，２－ベンゾイソオキサゾリルカルボニル、ベンゾチアゾリル（－２－イル）カルボニル、１，２－ベンゾイソチアゾリルカルボニル、２Ｈ－ベンゾピラニル（－３－イル）カルボニル、（１Ｈ－）ベンズイミダゾリル（－２－イル）カルボニル、１Ｈ－ベンゾトリアゾリルカルボニル、４Ｈ－１，４－ベンゾオキサジニルカルボニル、４Ｈ－１，４－ベンゾチアジニルカルボニル、キノリルカルボニル、イソキノリルカルボニル、シンノリニルカルボニル、キナゾリニルカルボニル、キノキザリニルカルボニル、フタラジニルカルボニル、ナフチリジニルカルボニル、プリニルカルボニル、プテリジニルカルボニル、カルバゾリルカルボニル、カルボリニルカルボニル、アクリジニルカルボニル、フェノキサジニルカルボニル、フェノチアジニルカルボニル、フェナジニルカルボニル、フェノキサチイニルカルボニル、チアンスレニルカルボニル、フェナンスリジニルカルボニル、フェナンスロリニルカルボニル、インドリジニルカルボニル、４，５，６，７－テトラヒドロチアゾロ［５，４－ｃ］ピリジル（－２－イル）カルボニル、４，５，６，７－テトラヒドロチエノ［３，２－ｃ］ピリジルカルボニル、１，２，３，４－テトラヒドロイソキノリル（－６－イル）カルボニル、チアゾロ［５，４－ｃ］ピリジル（－２－イル）カルボニル、ピロロ［１，２－ｂ］ピリダジニルカルボニル、ピラゾ［１，５－ａ］ピリジルカルボニル、イミダゾ［１，２－ａ］ピリジルカルボニル、イミダゾ［１，５－ａ］ピリジルカルボニル、イミダゾ［１，２－ｂ］ピリダジニルカルボニル、イミダゾ［１，５－ａ］ピリミジニルカルボニル、［１，２，４］トリアゾロ［４，３－ａ］ピリジルカルボニル、１，２，４－トリアゾロ［４，３－ｂ］ピリダジニルカルボニル、クロメニル（２Ｈ－クロメニル）カルボニル、１Ｈ－ピラゾロ［３，４－ｂ］ピリジルカルボニル、［１，２，４］トリアゾロ［１，５－ａ］ピリミジニルカルボニル等の一部水素化されていてもよい「縮環式ヘテロアリール基」が結合したカルボニル基等が挙げられる（括弧内の記載は好ましい態様を示している）。 “Heterocyclic carbonyl” means “heterocyclic carbonyl group”, and a carbonyl group is bonded to the heterocyclic group (for example, a heteroaryl group, a saturated or unsaturated non-aromatic heterocyclic group, etc.). Groups such as pyrrolylcarbonyl, furylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, 1,2,3-triazolyl Rucarbonyl, 1,2,4-triazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl, 1,3,4-oxadiazolylcarbonyl, furazanyl Carbonyl, 1,2,3-thiadiazolylcarbonyl, 1,2,4-thia Azolylcarbonyl, 1,3,4-thiadiazolylcarbonyl, tetrazolylcarbonyl, pyridylcarbonyl, pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, 1,2,3-triazinylcarbonyl, 1, 2,4-triazinylcarbonyl, 1,2,5-triazinylcarbonyl, 1,3,5-triazinylcarbonyl, 2H-1,2,3-thiadiazinylcarbonyl, 4H-1,2, A carbonyl group to which a “monocyclic heteroaryl group” such as 4-thiadiazinylcarbonyl, 6H-1,3,4-thiadiazinylcarbonyl and the like is bonded;
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 Rucarbonyl, phenoxazinylcarbonyl, phenothiazinylcarbonyl, phenazinylcarbonyl, phenoxathiinylcarbonyl, 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 Tetrahydroisoquino Ru (-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, 4-b] pyridylcarbonyl, [1,2,4] triazolo [1,5-a] pyrimidinylcarbonyl and the like may be partially hydrogenated “fused heteroaryl group Carbonyl group etc. which "" couple | bonded etc. are mentioned (the description in a parenthesis has shown the preferable aspect).
　「Ｃ６～１４アリールスルホニル」とは、前記Ｃ６～１４アリール基にスルホニル基が結合した基、例えば、ベンゼンスルホニル基、ナフチルスルホニル基等のＣ６～１４アリールスルホニル基が挙げられる。 The "C 6 ~ 14 arylsulfonyl", the C 6 ~ 14 groups on the aryl group is a sulfonyl group attached, for example, benzenesulfonyl group, and a C 6 ~ 14 arylsulfonyl group such as a naphthylsulfonyl group.
　「ヘテロ環スルホニル」とは、「ヘテロサイクリックスルホニル基」を意味し、前記へテロ環基にスルホニル基が結合した基、例えば、ピロリルスルホニル、フリルスルホニル、チエニルスルホニル、イミダゾリルスルホニル、オキサゾリルスルホニル、イソオキサゾリルスルホニル、チアゾリルスルホニル、イソチアゾリルスルホニル、ピラゾリルスルホニル、１，２，３－トリアゾリルスルホニル、１，２，４－トリアゾリルスルホニル、１，２，３－オキサジアゾリルスルホニル、１，２，４－オキサジアゾリルスルホニル、１，３，４－オキサジアゾリルスルホニル、フラザニルスルホニル、１，２，３－チアジアゾリルスルホニル、１，２，４－チアジアゾリルスルホニル、１，３，４－チアジアゾリルスルホニル、テトラゾリルスルホニル、ピリジルスルホニル、ピリダジニルスルホニル、ピリミジニルスルホニル、ピラジニルスルホニル、１，２，３－トリアジニルスルホニル、１，２，４－トリアジニルスルホニル、１，２，５－トリアジニルスルホニル、１，３，５－トリアジニルスルホニル、２Ｈ－１，２，３－チアジアジニルスルホニル、４Ｈ－１，２，４－チアジアジニルスルホニル、６Ｈ－１，３，４－チアジアジニルスルホニル等の「単環式のへテロアリール基」を有する基；
インドリルスルホニル、イソインドリルスルホニル、１Ｈ－インダゾリルスルホニル、ベンゾフラニル（－２－イル）スルホニル、イソベンゾフラニルスルホニル、ベンゾチエニル（－２－イル）スルホニル、イソベンゾチエニルスルホニル、ベンズインダゾリルスルホニル、ベンゾオキサゾリル（－２－イル）スルホニル、１，２－ベンゾイソオキサゾリルスルホニル、ベンゾチアゾリル（－２－イル）スルホニル、１，２－ベンゾイソチアゾリルスルホニル、２Ｈ－ベンゾピラニル（－３－イル）スルホニル、（１Ｈ－）ベンズイミダゾリル（－２－イル）スルホニル、１Ｈ－ベンゾトリアゾリルスルホニル、４Ｈ－１，４－ベンゾオキサジニルスルホニル、４Ｈ－１，４－ベンゾチアジニルスルホニル、キノリルスルホニル、イソキノリルスルホニル、シンノリニルスルホニル、キナゾリニルスルホニル、キノキザリニルスルホニル、フタラジニルスルホニル、ナフチリジニルスルホニル、プリニルスルホニル、プテリジニルスルホニル、カルバゾリルスルホニル、カルボリニルスルホニル、アクリジニルスルホニル、フェノキサジニルスルホニル、フェノチアジニルスルホニル、フェナジニルスルホニル、フェノキサチイニルスルホニル、チアンスレニルスルホニル、フェナンスリジニルスルホニル、フェナンスロリニルスルホニル、インドリジニルスルホニル、４，５，６，７－テトラヒドロチアゾロ［５，４－ｃ］ピリジル（－２－イル）スルホニル、４，５，６，７－テトラヒドロチエノ［３，２－ｃ］ピリジルスルホニル、１，２，３，４－テトラヒドロイソキノリル（－６－イル）スルホニル、チアゾロ［５，４－ｃ］ピリジル（－２－イル）スルホニル、ピロロ［１，２－ｂ］ピリダジニルスルホニル、ピラゾ［１，５－ａ］ピリジルスルホニル、イミダゾ［１，２－ａ］ピリジルスルホニル、イミダゾ［１，５－ａ］ピリジルスルホニル、イミダゾ［１，２－ｂ］ピリダジニルスルホニル、イミダゾ［１，５－ａ］ピリミジニルスルホニル、［１，２，４］トリアゾロ［４，３－ａ］ピリジルスルホニル、１，２，４－トリアゾロ［４，３－ｂ］ピリダジニルスルホニル、クロメニル（２Ｈ－クロメニル）スルホニル、１Ｈ－ピラゾロ［３，４－ｂ］ピリジルスルホニル、［１，２，４］トリアゾロ［１，５－ａ］ピリミジニルスルホニル等一部水素化されていてもよい「縮環式のヘテロアリール基」が結合したスルホニル基が挙げられる（括弧内の記載は好ましい態様を示している）。 “Heterocyclic sulfonyl” means a “heterocyclic sulfonyl group” and is a group in which a sulfonyl group is bonded to the heterocyclic group, for example, pyrrolylsulfonyl, furylsulfonyl, thienylsulfonyl, imidazolylsulfonyl, oxazolyl. Sulfonyl, isoxazolylsulfonyl, thiazolylsulfonyl, isothiazolylsulfonyl, pyrazolylsulfonyl, 1,2,3-triazolylsulfonyl, 1,2,4-triazolylsulfonyl, 1,2,3-oxa Diazolylsulfonyl, 1,2,4-oxadiazolylsulfonyl, 1,3,4-oxadiazolylsulfonyl, furazanylsulfonyl, 1,2,3-thiadiazolylsulfonyl, 1,2,4-thiadiazo Rylsulfonyl, 1,3,4-thiadiazolylsulfonyl, tetrazolyl Sulfonyl, pyridylsulfonyl, pyridazinylsulfonyl, pyrimidinylsulfonyl, pyrazinylsulfonyl, 1,2,3-triazinylsulfonyl, 1,2,4-triazinylsulfonyl, 1,2,5-triazinyl Sulfonyl, 1,3,5-triazinylsulfonyl, 2H-1,2,3-thiadiazinylsulfonyl, 4H-1,2,4-thiadiazinylsulfonyl, 6H-1,3,4-thiadiazinyl A group having a “monocyclic heteroaryl group” such as sulfonyl;
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, phenoxathiinylsulfonyl, 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 Tetrahydroisoquino Ru (-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, etc., which may be partially hydrogenated “condensed heteroaryl group A sulfonyl group to which "is bonded (the description in parentheses indicates a preferred embodiment).
　本明細書において、後述する種々の式に用いられる「ＲＢ群」の置換基として、とりわけ窒素原子に結合する置換基を表し、例えば、水素原子、または以下のＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、Ｃ１～６アルキルチオ－Ｃ１～６アルキル、Ｃ１～６アルキルスルフィニル－Ｃ１～６アルキル、Ｃ１～６アルキルスルホニル－Ｃ１～６アルキル、スルファモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルスルファモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルスルファモイル－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、アミノ－Ｃ１～６アルキル、モノ／ジＣ１～６アルキルアミノ－Ｃ１～６アルキル、Ｃ２～７アルカノイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルキルスルホニル、モノ／ジＣ１～６アルキルスルファモイル、Ｃ１～６アルコキシカルボニル、モノ／ジＣ１～６アルキルカルバモイル、Ｃ２～７アルカノイル、カルバモイル、スルファモイル、Ｃ６～１４アリール、Ｃ６～１４アリール－Ｃ１～６アルキル、Ｃ６～１４アリールスルホニル、モノ／ジＣ６～１４アリールスルファモイル、Ｃ６～１４アリールオキシカルボニル、モノ／ジＣ６～１４アリールカルバモイル、Ｃ６～１４アリールカルボニル、へテロ環基（当該環は、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環、好ましくは３～１２員環の単環もしくは縮合環を有する環）、ヘテロ環Ｃ１～６アルキル、ヘテロ環スルホニル、モノ／ジヘテロ環スルファモイル、ヘテロ環オキシカルボニル、モノ／ジヘテロ環カルバモイル、ヘテロ環カルボニル、等の置換基が挙げられるが、「ＲＢ群」の置換基中のアルキル鎖部分、アリールまたはヘテロ環は更にハロゲン原子、ハロゲン化Ｃ１～６アルキル、シアノ、保護されていてもよいヒドロキシル、アミノ、ニトロ、保護されていてもよいカルボキシル、カルバモイル、Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルカノイルアミノ、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、モノ／ジＣ１～６アルキルスルファモイル、モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルスルファモイルアミノ、Ｃ１～６アルコキシカルボニル、モノ／ジＣ１～６アルキルカルバモイル、およびＣ２～７アルカノイルからなる群から選ばれる基１～５個で置換されていてもよい。 In the present specification, the substituent of the "group R B" as used in various formulas to be described later, especially a substituent attached to the nitrogen atom, for example, hydrogen atom or the following C 1 ~ 6 alkyl,, C 2 2-6 alkenyl, C 2 - 6 alkynyl, halogenated C 1 - 6 alkyl, hydroxy -C 1 - 6 alkyl, C 1 - 6 alkoxy -C 1 - 6 alkyl, C 1 - 6 alkylthio -C 1 - 6 alkyl, C 1 ~ 6 alkylsulfinyl -C 1 ~ 6 alkyl, C 1 ~ 6 alkylsulfonyl -C 1 ~ 6 alkyl, sulfamoyl -C 1 ~ 6 alkyl, N-C 1 ~ 6 alkylsulfamoyl -C 1 ~ 6 alkyl , N, N-di-C 1 ~ 6 alkylsulfamoyl -C 1 ~ 6 alkyl, carboxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy Carbonyl -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, amino -C 1 ~ 6 alkyl, mono / di C 1 ~ 6 alkyl amino -C 1 ~ 6 alkyl, C 2 ~ 7 alkanoyl -C 1 ~ 6 alkyl, C 3 ~ 8 cycloalkyl, C 3 ~ 8 cycloalkyl -C 1-6 alkyl, C 1-6 alkylsulfonyl, mono / di C 1-6 alkylsulfamoyl, C 1-6 alkoxycarbonyl, mono / di C 1-6 alkylcarbamoyl, C 2 ~ 7 alkanoyl, carbamoyl, sulfamoyl , C 6 ~ 14 aryl, C 6 ~ 14 aryl -C 1 ~ 6 alkyl, C 6 ~ 14 Arirusu Honiru, mono / di C 6 ~ 14 aryl sulfamoyl, C 6 ~ 14 aryloxycarbonyl, mono / di C 6 ~ 14 aryl-carbamoyl, C 6 ~ 14 aryl-carbonyl, Hajime Tamaki (said ring is a carbon atom In addition, a ring having 3 to 14 membered ring, preferably 3 to 12 membered monocyclic or condensed ring containing at least one heteroatom (preferably 1 to 4) selected from N, O and S), heterocycle C 1 ~ 6 alkyl, heterocyclic sulfonyl, mono / diheterocyclic sulfamoyl, a heterocyclic oxy carbonyl, mono / diheterocyclic carbamoyl, heterocyclic carbonyl, although substituents and the like, the substituent of "group R B" the alkyl chain moiety in the aryl or heteroaryl ring may further halogen atoms, halogenated C 1 ~ 6 alkyl, cyano, be protected There hydroxyl, amino, nitro, optionally protected carboxyl, carbamoyl, C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkanoylamino, C 1 ~ 6 alkylthio, C 1 ~ 6 alkylsulfinyl, C 1-6 alkylsulfonyl, mono / di C 1-6 alkylsulfamoyl, mono / di C 1-6 alkylamino, mono / di C 1-6 alkylsulfamoyl amino, C 1-6 alkoxycarbonyl, mono / di C 1 - 6 alkylcarbamoyl, and C 2 in group one to five selected from 1-7 group consisting alkanoyl may be substituted.
　本明細書において、後述する種々の式に用いられる「ＲＣ群」の置換基としては、以下に挙げられる置換基、例えば、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、Ｃ１～６アルキルチオ－Ｃ１～６アルキル、Ｃ１～６アルキルスルフィニル－Ｃ１～６アルキル、Ｃ１～６アルキルスルホニル－Ｃ１～６アルキル、スルファモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルスルファモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルスルファモイル－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、アミノ－Ｃ１～６アルキル、モノ／ジＣ１～６アルキルアミノ－Ｃ１～６アルキル、Ｃ２～７アルカノイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、モノ／ジＣ１～６アルキルスルファモイル、モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルスルファモイルアミノ、モノ／ジＣ１～６アルキルカルバモイルアミノ、Ｃ１～６アルコキシカルボニル、
モノ／ジＣ１～６アルキルカルバモイル、Ｃ２～７アルカノイル、Ｃ２～７アルカノイルアミノ、
オキソ、ニトロ、シアノ、アミノ、保護されていてもよいヒドロキシル、メルカプト、保護されていてもよいカルボキシル、カルバモイル、スルファモイル、ホルミル、ホルミルアミノ、スルホ、等の置換基が挙げられるが、当該置換基中の炭素原子（例：アルキル鎖部分）は、更にハロゲン原子、ハロゲン化Ｃ１～６アルキル、シアノ、保護されていてもよいヒドロキシル、アミノ、ニトロ、保護されていてもよいカルボキシル、カルバモイル、Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルカノイルアミノ、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、モノ／ジＣ１～６アルキルスルファモイル、モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルスルファモイルアミノ、Ｃ１～６アルコキシカルボニル、モノ／ジＣ１～６アルキルカルバモイル、およびＣ２～７アルカノイルからなる群から選ばれる基１～５個で置換されていてもよい。 In the present specification, substituents as the substituent of the "R C" group used in the various formulas described below, which are listed below, for example, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl , halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkylthio -C 1 ~ 6 alkyl, C 1 ~ 6 alkylsulfinyl -C 1 ~ 6 alkyl, C 1 ~ 6 alkylsulfonyl -C 1 ~ 6 alkyl, sulfamoyl -C 1 ~ 6 alkyl, N-C 1 ~ 6 alkylsulfamoyl -C 1 ~ 6 alkyl, N, N-di C 1 ~ 6 alkylsulfamoyl -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, amino -C 1 ~ 6 alkyl , mono / di C 1 ~ 6 alkyl amino -C 1 ~ 6 alkyl, C 2 ~ 7 alkanoyl -C 1 ~ 6 alkyl, C 3 ~ 8 cycloalkyl alkyl, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl, C 1-6 alkoxyl, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1-6 alkoxyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, mono / di C 1 ~ 6 alkyl sulfamoyl, mono / di C 1 ~ 6 alkylamino, mono / di C 1 ~ 6 alkyl sulfates Amoiruamino, mono / di C 1 ~ 6 alkylcarbamoyl amino, C 1 ~ 6 alkoxycarbonyl,
Mono / di C 1 ~ 6 alkylcarbamoyl, C 2 ~ 7 alkanoyl, C 2 ~ 7 alkanoylamino,
Examples of the substituent include oxo, nitro, cyano, amino, optionally protected hydroxyl, mercapto, optionally protected carboxyl, carbamoyl, sulfamoyl, formyl, formylamino, sulfo, etc. carbon atoms (e.g., alkyl chain moiety) further halogen atoms, halogenated C 1 ~ 6 alkyl, cyano, optionally protected hydroxyl, amino, nitro, optionally protected carboxyl, carbamoyl, C 1 1-6 alkyl, C 1 - 6 alkoxy, C 2 - 6 alkanoylamino, C 1 - 6 alkylthio, C 1 - 6 alkylsulfinyl, C 1 - 6 alkylsulfonyl, mono / di C 1 - 6 alkyl sulfamoyl, mono / di C 1 ~ 6 alkylamino, mono / di C 1 ~ 6 alkyl Sulfamoyl amino, C 1 - 6 alkoxycarbonyl, mono / di C 1 - 6 alkylcarbamoyl, and C 2 in group one to five selected from 1-7 group consisting alkanoyl may be substituted.
［１－１］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、Ｒ１、Ｒ２、Ｒ３、Ｒ４は、各々独立に水素原子またはハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６アルキル基を表す。 [1-1] In the compound of the above formula (I) used for the inhibitor of the above embodiment [1], R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom or a halogen atom, —OH. It represents a C 1 - 6 alkoxylated, halogenated C 1 - 6 one by one to five substituents which may C 1 to 6 alkyl groups of alkoxy.
［１－１－ａ］態様［１］の阻害剤に用いられる前記式（Ｉ）の化合物において、Ｒ１、Ｒ２、Ｒ３、Ｒ４は、各々独立に水素原子またはハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～３個置換されていてもよいＣ１～４アルキル基であることが好ましい。 [1-1-a] In the compound of the formula (I) used as the inhibitor of the embodiment [1], R 1 , R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom or —OH. is preferably-C 1 - 6 alkoxylated, halogenated C 1 ~ 6 1 ~ 3 or optionally substituted C 1 to 4 alkyl groups or alkoxyl.
［１－１－ｂ］態様［１］の阻害剤に用いられる前記式（Ｉ）の化合物において、　Ｒ１、Ｒ２、Ｒ３、Ｒ４が、それぞれ水素原子であることがより好ましい。 [1-1-b] In the compound of the formula (I) used as the inhibitor of the embodiment [1], it is more preferable that R 1 , R 2 , R 3 and R 4 are each a hydrogen atom.
［１－２］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、
Ｒｉｎｇは、置換されていてもよい環状基を表す。より具体的には、下記式（Ｉ）
Figure JPOXMLDOC01-appb-C000008
  
のＲｉｎｇ部分（波線の内側部分）は、ＲＡ群から任意に選ばれる基で１～５置換されていてもよい環状基を表し、当該「環状基」は前記態様［１］に記載の「炭化水素基」として挙げられた「脂環式炭化水素基」および「アリール基」、または「置換されていてもよいへテロ環基」の「へテロ環基」として挙げられた「ヘテロアリール基」もしくは「飽和もしくは不飽和の非芳香族のヘテロ環基」等から、さらに任意の水素原子を１個除いて形成される２価の基を意味する。また、当該Ｒｉｎｇにイミノ基が結合した環（例えば、後述ａ２１２の式が挙げられる）も当該Ｒｉｎｇに含まれるものとする。 [1-2] In the compound of the above formula (I) used as the inhibitor of the above aspect [1],
Ring represents a cyclic group which may be substituted. More specifically, the following formula (I)
Figure JPOXMLDOC01-appb-C000008
The Ring portion (the inner portion of the wavy line) of R 1 represents a cyclic group optionally substituted with 1 to 5 groups selected from the group R A , and the “cyclic group” is “ "Heteroaryl group" mentioned as "heterocyclic group" of "alicyclic hydrocarbon group" and "aryl group" mentioned as "hydrocarbon group" or "optionally substituted heterocyclic group" Or a “saturated or unsaturated non-aromatic heterocyclic group” or the like, and a divalent group formed by removing any one hydrogen atom. In addition, a ring in which an imino group is bonded to the Ring (for example, the formula a212 described below) is also included in the Ring.
　このＲｉｎｇ部分については以下に具体例を挙げるが、これに限定されるわけではない。下記の各々の部分構造式で表される２価の基のうち、－Ｓ（Ｏ）ｎ－との結合手には●マークを付した。当該２価の基は、式（Ｉ）にＲｉｎｇ部分として組み込まれることにより、それぞれ個別に式（Ｉ）のサブ態様を形成する。また、下記の各々の式中の－（ＲＡ）ｋ（ここでＲＡは、前記態様［１］に記載のＲＡ群から任意に選ばれる基を表し、ｋは０から５の整数を表す）において、ｋが２以上の場合、当該置換基ＲＡは同一であっても異なっていてもよく、任意に選ばれうる。但し、ｋの数は、それぞれの式ごとに置換可能な数を上限とする。ＲＢは、前記態様［１］に記載のＲＢ群から選ばれる任意の置換基である。 Specific examples of the Ring portion are given below, but the present invention is not limited thereto. Among the divalent groups represented by each of the following partial structural formulas, the bond to -S (O) n- is marked with a mark. The divalent groups are each incorporated into the formula (I) as a Ring moiety to individually form a sub-embodiment of formula (I). In each of the following formulas, — (R A ) k (wherein R A represents a group arbitrarily selected from the R A group described in the above embodiment [1], k represents an integer of 0 to 5) In the case where k is 2 or more, the substituents R A may be the same or different and may be arbitrarily selected. However, the upper limit of the number of k is the number that can be replaced for each formula. R B is an optionally substituted group selected from R B group according to the aspect [1].
［１－２－ａ］好ましくは、上記式（Ｉ）の化合物において、Ｒｉｎｇが、下記式（Ａ１）
Figure JPOXMLDOC01-appb-C000009
  
（式中、ｒは０～２の整数を表し、Ｖ１、Ｖ２、Ｖ３、Ｖ４は、各々独立に、－ＣＲＡ１ＲＡ２－、酸素原子、硫黄原子または－ＮＲＢ－から任意に選択される基であり、当該環状基の結合（破線）は単結合もしくは二重結合であり、芳香化していてもよく、ｒが０のときのＶ２－Ｖ４間の結合、或いは、ｒが１もしくは２のときのＶ３－Ｖ４間の結合は、前記のＣ６～１４のアリール基（部分的に水素化されていてもよい）、Ｃ３～８のシクロアルキル基または３～１４員環のヘテロ環基（部分的に水素化されていてもよい）のいずれかの環と任意の位置で縮合していてもよく、結果的に形成された縮合環のいずれかの位置にＲＡが結合していてもよく、Ｂは炭素原子もしくは窒素原子であり、－Ｓ（Ｏ）ｎ－と結合しており、ＲＡ１及びＲＡ２は各々独立に水素原子またはＲＡ、あるいは一緒になってオキソ基を表す）で表される２価の基；
　または、下記式（Ａ２）
Figure JPOXMLDOC01-appb-C000010
  
（式中、Ｃｙｃｌｅ１及びＣｙｃｌｅ２の２つの環は、各々前記のＣ６～１４のアリール基（部分的に水素化されていてもよい）、Ｃ３～８のシクロアルキル基または３～１４員環のヘテロ環基（部分的に水素化されていてもよい）にて説明される環から任意に選ばれ、任意の位置で縮合しており、一方の結合手（●－）はＣｙｃｌｅ１で－Ｓ（Ｏ）ｎ－と結合し、他方の結合手はＣｙｃｌｅ２で－（ＣＲ１ＣＲ２）ｍ－Ｗと結合しており、ＲＡは前記と同じであり、ｋは０～５の整数であり、ＲＡはＣｙｃｌｅ１またはＣｙｃｌｅ２で表される環のいずれに結合していてもよい）で表される２価の基を表す。 [1-2-a] Preferably, in the compound of the above formula (I), Ring is represented by the following formula (A1):
Figure JPOXMLDOC01-appb-C000009
(In the formula, r represents an integer of 0 to 2, and V 1 , V 2 , V 3 , and V 4 are each independently selected from —CR A1 R A2 —, an oxygen atom, a sulfur atom, or —NR B —. The bond (broken line) of the cyclic group is a single bond or a double bond, may be aromatized, a bond between V 2 and V 4 when r is 0, or r is coupled between V 3 -V 4 when the 1 or 2 aryl groups of said C 6 ~ 14 (or may be partially hydrogenated), a cycloalkyl group or 3 C 3 ~ 8 Any position of the resulting 14-membered heterocyclic group (which may be partially hydrogenated) may be fused at any position, and any position of the resulting fused ring may be bonded R a in, B is a carbon atom or a nitrogen atom, -S (O) combined with n- Cage, a divalent group represented by R A1 and R A2 each independently represent a hydrogen atom or R A, or together represent an oxo group);
Or the following formula (A2)
Figure JPOXMLDOC01-appb-C000010
(Wherein two rings of Cycle1 and Cycle2 each aryl group of said C 6 ~ 14 (or may be partially hydrogenated), a cycloalkyl group or 3 to 14-membered ring of C 3 ~ 8 Is optionally selected from the rings described in the heterocyclic group (which may be partially hydrogenated), and condensed at an arbitrary position, and one bond (●-) is Cycle 1 and —S (O) Bonded to n-, the other bond is Cycle 2 and bonded to-(CR 1 CR 2 ) m-W, R A is the same as above, k is an integer of 0 to 5 , R A represents a divalent group represented by any of the rings represented by Cycle 1 or Cycle 2).
［１－２－ａ－１］より好ましくは、式（Ｉ）の化合物において、Ｒｉｎｇが、下記式（Ａ１ａ）
Figure JPOXMLDOC01-appb-C000011
  
（式中、ｒは０～２の整数を表し、Ｖ１、Ｖ２、Ｖ３、Ｖ４は、各々独立に、－ＣＲＡ１ＲＡ２－、酸素原子、硫黄原子または－ＮＲＢ－から任意に選択される基であり、当該環状基の結合（破線）は適宜単結合もしくは二重結合をとり、芳香化していてもよく、ｒが０のときのＶ２－Ｖ４間の結合、或いは、ｒが１もしくは２のときのＶ３－Ｖ４間の結合は、前記のＣ６～１４のアリール基（部分的に水素化されていてもよい）、Ｃ３～８のシクロアルキル基または３～１４員環のヘテロ環基（部分的に水素化されていてもよい）のいずれかの環と任意の位置で縮合していてもよく、結果的に形成された縮合環のいずれかの位置にＲＡが結合していてもよく、ＲＡ１及びＲＡ２は各々独立に水素原子またはＲＡ、あるいは一緒になってオキソ基を表し、Ｖ４が－ＣＲＡ１ＲＡ２－である場合には、ＲＡ１とＲＡ２は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）で表される２価の基；
　下記式（Ａ１ｂ）
Figure JPOXMLDOC01-appb-C000012
  
（式中、ｒは０～２の整数を表し、Ｖ１、Ｖ２、Ｖ３、Ｖ４は、各々独立に、－ＣＲＡ３ＲＡ４－、酸素原子、硫黄原子または－ＮＲＢ－から任意に選択される基であり、当該環状基の結合（破線）は適宜単結合もしくは二重結合をとり、ｒが０のときのＶ２－Ｖ４間の結合、或いは、ｒが１もしくは２のときのＶ３－Ｖ４間の結合は、前記のＣ６～１４のアリール基（部分的に水素化されていてもよい）、Ｃ３～８のシクロアルキル基または３～１４員環のヘテロ環基（部分的に水素化されていてもよい）のいずれかの環と任意の位置で縮合していてもよく、結果的に形成された縮合環のいずれかの位置でＲＡが結合していてもよく、ＲＡ３及びＲＡ４は各々独立に水素原子またはＲＡ、あるいは一緒になってオキソ基を表し、Ｖ４が－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）で表される２価の基；
　または、下記式（Ａ２ａ）
Figure JPOXMLDOC01-appb-C000013
  
（式中、ｉ－１、ｉ－２は、各々独立に０～２の整数を表し、Ｃｙｃｌｅ２の環は、前記のＣ６のアリール基、Ｃ５～７のシクロアルキル基または５～７員環のヘテロ環基（部分的に水素化されていてもよい）で表された環中の任意の結合で縮合していることを表し、Ｂ１及びＢ２は各々独立に当該環を形成する炭素原子または窒素原子を表し（但しＢ１またはＢ２の少なくとも１つは窒素原子である）、－Ｓ（Ｏ）ｎ－と結合した窒素原子を含む環及びＣｙｃｌｅ２で表される環の結合（破線）は適宜単結合もしくは二重結合をとり、ＲＡは前記と同じであり、ｋは０～５の整数であり、ＲＡは－Ｓ（Ｏ）ｎ－と結合した窒素原子を含む環またはＣｙｃｌｅ２で表される環のいずれかに結合していてもよい）で表される２価の基を表す。 [1-2-a-1] More preferably, in the compound of the formula (I), Ring is represented by the following formula (A1a):
Figure JPOXMLDOC01-appb-C000011
(In the formula, r represents an integer of 0 to 2, and V 1 , V 2 , V 3 , and V 4 are each independently selected from —CR A1 R A2 —, an oxygen atom, a sulfur atom, or —NR B —. The bond (broken line) of the cyclic group may be a single bond or a double bond as appropriate and may be aromatized, a bond between V 2 and V 4 when r is 0, or , r is coupled between V 3 -V 4 when the 1 or 2 (which may be partially hydrogenated) aryl groups of said C 6 ~ 14, or a cycloalkyl group C 3 ~ 8 Any of the condensed ring formed may optionally be condensed with any ring of a 3 to 14-membered heterocyclic group (which may be partially hydrogenated). located may be bonded R a, R A1 and R A2 each independently represent a hydrogen atom or R a, there Represents an oxo group together, V 4 is -CR A1 R A2 - if it is, the R A1 and R A2 may form a 3- to 8-membered cyclic group together with the carbon atoms to which they are attached even better, the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 may be replaced by either by may be substituted with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group) alkoxyl, said cyclic group is more A divalent group represented by (which may have a substituent);
The following formula (A1b)
Figure JPOXMLDOC01-appb-C000012
(In the formula, r represents an integer of 0 to 2, and V 1 , V 2 , V 3 , and V 4 are each independently selected from —CR A3 R A4 —, an oxygen atom, a sulfur atom, or —NR B —. The bond (broken line) of the cyclic group is a single bond or a double bond as appropriate, a bond between V 2 and V 4 when r is 0, or r is 1 or 2 In some cases, the bond between V 3 and V 4 is a C 6 to 14 aryl group (which may be partially hydrogenated), a C 3 to 8 cycloalkyl group or a 3 to 14-membered heterocycle. It may be condensed at any position with any ring of the ring group (which may be partially hydrogenated), and R A is bonded at any position of the resulting condensed ring. even if well, R A3 and R A4 each independently represent a hydrogen atom or R A, or together oxo The stands, V 4 is -CR A3 R A4 - in the case of the R A3 and R A4 may form a 3-8 membered cyclic group together with the carbon atoms to which they are attached, said cyclic group , one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, one to either a halogen atom, -OH, C 1 - 6 alkoxylated, halogenated C 1 - 6 alkoxy 5 substituted may be substituted with an alkyl group of C 1 ~ 6 of which may linear or branched) may be replaced by, the cyclic groups further have a substituent A divalent group represented by:
Or the following formula (A2a)
Figure JPOXMLDOC01-appb-C000013
(Wherein, i-1, i-2 each independently represent an integer of 0-2, ring Cycle2 the aryl group of said C 6, cycloalkyl group or 5-7-membered C 5-7 This means that the ring is condensed at an arbitrary bond in the ring represented by the heterocyclic group (which may be partially hydrogenated), and B 1 and B 2 each independently form the ring A carbon atom or a nitrogen atom (provided that at least one of B 1 or B 2 is a nitrogen atom), a ring containing a nitrogen atom bound to —S (O) n— and a ring represented by Cycle 2 ( (Dashed line) is a single bond or a double bond as appropriate, R A is the same as above, k is an integer of 0 to 5, and R A is a ring containing a nitrogen atom bonded to —S (O) n—. Or a divalent group represented by (which may be bonded to any of the rings represented by Cycle 2). The
［１－２－ａ－２］より好ましくは、式（Ｉ）の化合物において、Ｒｉｎｇが、下記式（Ａ１ａａ）～（Ａ２ａｃ）のいずれかであり、Ｖ１ないしＶ４、ＲＡ、ｋ、ｒ、ｉ－１、ｉ－２、ＲＣは前記のとおりであり、Ｂ３は炭素原子または窒素原子である。
　下記式（Ａ１ａａ）
Figure JPOXMLDOC01-appb-C000014
  
（式中、ｒ、ｋ、Ｖ１、Ｖ２、Ｖ３、ＲＡ、ＲＣ、当該環状基の結合（破線）は前記と同一を表し、Ｂ３は当該環を形成する炭素原子または窒素原子を表す）で表される２価の基；
　下記式（Ａ１ｂａ）
Figure JPOXMLDOC01-appb-C000015
  
（式中、ｒ、ｋ、Ｖ２、Ｖ３、Ｖ４、ＲＡ、当該環状基の結合（破線）は前記と同一を表す）で表される２価の基；
　下記式（Ａ２ａａ）
Figure JPOXMLDOC01-appb-C000016
  
（式中、ｉ－１、ｉ－２、ｋ、Ｃｙｃｌｅ２の環、－Ｓ（Ｏ）ｎ－と結合した窒素原子を含む環及びＣｙｃle２で表される環の結合（破線）およびＲＡは、前記と同じであり、ＲＡは－Ｓ（Ｏ）ｎ－と結合した窒素原子を含む環またはＣｙｃｌｅ２で表される環のいずれかに結合していてもよい）で表される２価の基；
　下記式（Ａ２ａｂ）
Figure JPOXMLDOC01-appb-C000017
  
（式中、ｉ－１、ｉ－２、ｋ、Ｃｙｃｌｅ２の環、、－Ｓ（Ｏ）ｎ－と結合した窒素原子を含む環及びＣｙｃle２で表される環の結合（破線）及びＲＡは、前記と同じであり、ＲＡは－Ｓ（Ｏ）ｎ－と結合した窒素原子を含む環またはＣｙｃｌｅ２で表される環のいずれかに結合していてもよい）で表される２価の基；
または、下記式（Ａ２ａｃ）
Figure JPOXMLDOC01-appb-C000018
  
（式中、ｉ－２、ｋ、Ｃｙｃｌｅ２の環、－Ｓ（Ｏ）ｎ－と結合した窒素原子を含む環及びＣｙｃle２で表される環の結合（破線）およびＲＡは前記と同じであり、ＲＡは－Ｓ（Ｏ）ｎ－と結合した窒素原子を含む環またはＣｙｃｌｅ２で表される環のいずれかに結合していてもよい）で表される２価の基である。 [1-2-a-2] More preferably, in the compound of the formula (I), Ring is any one of the following formulas (A1aa) to (A2ac), and V 1 to V 4 , R A , k, r, i-1, i-2 and R C are as defined above, and B 3 is a carbon atom or a nitrogen atom.
The following formula (A1aa)
Figure JPOXMLDOC01-appb-C000014
(Wherein, r, k, V 1 , V 2 , V 3 , R A , R C , the bond of the cyclic group (broken line) represents the same as above, and B 3 represents the carbon atom or nitrogen forming the ring A divalent group represented by:
The following formula (A1ba)
Figure JPOXMLDOC01-appb-C000015
(Wherein, r, k, V 2 , V 3 , V 4 , R A , and the bond (broken line) of the cyclic group is the same as described above);
The following formula (A2aa)
Figure JPOXMLDOC01-appb-C000016
(Wherein the ring of i-1, i-2, k, Cycle2, the ring containing a nitrogen atom bonded to —S (O) n—, and the bond of the ring represented by Cycle2 (dashed line) and R A are R A is the same as defined above, and R A may be bonded to either a ring containing a nitrogen atom bonded to —S (O) n— or a ring represented by Cycle 2). ;
The following formula (A2ab)
Figure JPOXMLDOC01-appb-C000017
(Wherein, a ring of i-1, i-2, k, Cycle2, a ring containing a nitrogen atom bonded to -S (O) n-, and a bond of a ring represented by Cycle2 (dashed line)) and R A are And R A may be bound to either a ring containing a nitrogen atom bound to —S (O) n— or a ring represented by Cycle 2). Group;
Or the following formula (A2ac)
Figure JPOXMLDOC01-appb-C000018
(Wherein the ring of i-2, k, Cycle2, the ring containing a nitrogen atom bonded to -S (O) n-, and the bond of the ring represented by Cycle2 (dashed line) and RA are the same as above. , R A is a divalent group represented by a ring containing a nitrogen atom bonded to —S (O) n— or a ring represented by Cycle 2).
［１－２－ａ－３］より好ましくは、式（Ｉ）のＲｉｎｇ部分に、前記式（Ａ１）または（Ａ２）の特に好ましい態様の式を置き換えた、下記式（Ｉ－Ａ１ａａ）
Figure JPOXMLDOC01-appb-C000019
  
　　下記式（Ｉ－Ａ１ｂａ）
Figure JPOXMLDOC01-appb-C000020
  
　　下記式（Ｉ－Ａ２ａａ）
Figure JPOXMLDOC01-appb-C000021
  
　下記式（Ｉ－Ａ２ａｂ）
Figure JPOXMLDOC01-appb-C000022
  
または、下記式（Ｉ－Ａ２ａｃ）
Figure JPOXMLDOC01-appb-C000023
  
のいずれかである。 [1-2-a-3] More preferably, the ring moiety of formula (I) is replaced by the formula (I-A1aa) shown below, wherein the formula of the particularly preferred embodiment of formula (A1) or (A2) is replaced:
Figure JPOXMLDOC01-appb-C000019
The following formula (I-A1ba)
Figure JPOXMLDOC01-appb-C000020
The following formula (I-A2aa)
Figure JPOXMLDOC01-appb-C000021
The following formula (I-A2ab)
Figure JPOXMLDOC01-appb-C000022
Or the following formula (I-A2ac)
Figure JPOXMLDOC01-appb-C000023
One of them.
［１－２－ｂ］本態様の［１－２－ｂ］において、このＲｉｎｇ部分については以下に具体例を挙げるが、これに限定されるわけではない。下記の各々の部分構造式で表される２価の基のうち、－Ｓ（Ｏ）ｎ－との結合手には●マークを付した。当該２価の基は、式（Ｉ）にＲｉｎｇ部分として組み込まれることにより、それぞれ個別に式（Ｉ）のサブ態様を形成する。また、下記の各々の式中の－（ＲＡ）ｋ（ここでＲＡは、前記態様［１］に記載のＲＡ群から任意に選ばれる基を表し、ｋは０から５の整数を表す）において、ｋが２以上の場合、当該置換基ＲＡは同一であっても異なっていてもよく、任意に選ばれうる。但し、ｋの数は、それぞれの式ごとに置換可能な数を上限とする。ＲＢは、前記態様［１］に記載のＲＢ群から選ばれる任意の置換基である。 [1-2-b] In [1-2-b] of this embodiment, specific examples of the Ring portion are given below, but the present invention is not limited thereto. Among the divalent groups represented by each of the following partial structural formulas, the bond to -S (O) n- is marked with a mark. The divalent groups are each incorporated into the formula (I) as a Ring moiety to individually form a sub-embodiment of formula (I). In each of the following formulas, — (R A ) k (wherein R A represents a group arbitrarily selected from the R A group described in the above embodiment [1], k represents an integer of 0 to 5) In the case where k is 2 or more, the substituents R A may be the same or different and may be arbitrarily selected. However, the upper limit of the number of k is the number that can be replaced for each formula. R B is an optionally substituted group selected from R B group according to the aspect [1].
　上記態様［１］の各態様における阻害剤に用いられるそれぞれの式において、Ｒｉｎｇ部分としては、例えば、以下に示される（ａ１）～（ａ２１２）等から適宜選ばれうる。 In each formula used for the inhibitor in each aspect of the above aspect [1], the Ring moiety can be appropriately selected from (a1) to (a212) shown below, for example.
Figure JPOXMLDOC01-appb-C000024
  
Figure JPOXMLDOC01-appb-C000024
  
Figure JPOXMLDOC01-appb-C000025
  
Figure JPOXMLDOC01-appb-C000025
  
Figure JPOXMLDOC01-appb-C000026
  
Figure JPOXMLDOC01-appb-C000026
  
［１－２－ｂ－１］前記式（ａ１）～（ａ２１２）において、好ましくは、以下の式が挙げられる。 [1-2-b-1] In the above formulas (a1) to (a212), the following formulas are preferable.
Figure JPOXMLDOC01-appb-C000027
  
Figure JPOXMLDOC01-appb-C000027
  
Figure JPOXMLDOC01-appb-C000028
  
Figure JPOXMLDOC01-appb-C000028
  
［１－２－ｂ－２］前記式（ａ１）～（ａ２１２）において、より好ましくは、式（ａ１８）、（ａ３３）～（ａ３４）、（ａ３８）～（ａ４０）、（ａ４７）～（ａ５２）、（ａ７３）、（ａ１８３）、（ａ２０１）～（ａ２０２）、（ａ２０４）～（ａ２１０）、（ａ２１２）が挙げられる。更に好ましくは、式（ａ１８）、（ａ３３）～（ａ３４）、
（ａ１８３）、（ａ２０１）～（ａ２０２）、（ａ２０４）～（ａ２０６）、（ａ２０８）～（ａ２０９）が挙げられ、特に好ましくは式（ａ１８）である。 [1-2-b-2] In the formulas (a1) to (a212), more preferably, the formulas (a18), (a33) to (a34), (a38) to (a40), (a47) to (a a52), (a73), (a183), (a201) to (a202), (a204) to (a210), and (a212). More preferably, the formulas (a18), (a33) to (a34),
(A183), (a201) to (a202), (a204) to (a206), (a208) to (a209), and the formula (a18) is particularly preferable.
［１－２－ｂ－３］前記式（Ｉ）のＲｉｎｇ部分としては、具体的には、例えば下記式（Ｇ）または（Ｈ）
Figure JPOXMLDOC01-appb-C000029
  
（式中、Ｒ１７及びＲ１８は、各々独立に、水素原子またはＲＣ群から任意に選ばれる基を表し、Ｒ１７及びＲ１８は、それらが結合するベンゼン環上の炭素原子と５～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく；Ｅは、非存在、基：－ＣＲＡ３ＲＡ４－、エチレン基、酸素原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良く、Ｅが－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し、ＲＣ、ＲＡ３、ＲＡ４は前記と同一を表し、ＥとＷが結合した炭素原子との間の実線と破線は単結合もしくは二重結合であることを示す）で表される二価の基が挙げられる。
　Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子である場合を除く）；
より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。 [1-2-b-3] Specific examples of the Ring moiety in the formula (I) include the following formula (G) or (H):
Figure JPOXMLDOC01-appb-C000029
(Wherein R 17 and R 18 each independently represents a hydrogen atom or a group arbitrarily selected from the group R C , R 17 and R 18 represent a carbon atom on the benzene ring to which they are bonded and 5 to 5 An 8-membered cyclic group may be formed, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom, or a nitrogen atom (the nitrogen atom is a halogen atom, -OH, C 1- 6 replaced by may also) be substituted with an alkyl group of C 1 ~ 6 of which may straight or branched chain optionally substituted 1-5 with either an alkoxylated-halogenated C 1 ~ 6 alkoxy at best; E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 Izu alkoxyl May be substituted with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group in either, E is -CR A3 R A4 - in the case of the, R A3 And R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom ( the nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with one to five substituents which may be straight or branched chain alkoxyl of C 1 ~ 6 The cyclic group may further have a substituent), and R C , R A3 , and R A4 represent the same as described above. , Solid and broken lines between carbon atoms with E and W bonded Represents a single bond or a double bond).
R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 To 6 alkyl, C 1 to 6 alkoxy-C 1 to 6 alkyl, carboxy-C 1 to 6 alkyl, C 1 to 6 alkoxycarbonyl-C 1 to 6 alkyl, carbamoyl-C 1 to 6 alkyl, N—C 1 to 6 alkylcarbamoyl -C 1 ~ 6 alkyl, N, N-di-C 1 ~ 6 alkylcarbamoyl -C 1 ~ 6 alkyl, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or mono / di C 1 ~ 6 alkylamine Roh, a group selected from the group consisting of (unless R 17 is a hydrogen atom);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, a C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or a group selected from mono- / di-C 1 ~ 6 alkyl amino, and, R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
［１－２－ｃ］前記態様［１－２－ｂ］におけるＲｉｎｇとして例示された各基のうち、より具体的な基としては、以下のものが挙げられる。 [1-2-c] Among the groups exemplified as Ring in the embodiment [1-2-b], more specific groups include the following.
Figure JPOXMLDOC01-appb-C000030
  
Figure JPOXMLDOC01-appb-C000030
  
［１－２－ｄ］前記態様の［１－２－ｃ］におけるＲｉｎｇとして例示された各基のうち、好ましくは以下の基が挙げられる。 [1-2-d] Of the groups exemplified as Ring in [1-2-c] of the above embodiment, the following groups are preferable.
Figure JPOXMLDOC01-appb-C000031
  
Figure JPOXMLDOC01-appb-C000031
  
［１－２－ｅ］前記態様の［１－２－ｄ］におけるＲｉｎｇとして例示された各基のうち、より好ましくは以下の基が挙げられる。 [1-2-e] Among the groups exemplified as Ring in [1-2-d] of the above embodiment, the following groups are more preferable.
Figure JPOXMLDOC01-appb-C000032
  
Figure JPOXMLDOC01-appb-C000032
  
［１－２－ｆ］前記態様の［１－２－ｅ］におけるＲｉｎｇとして例示された各基のうち、更に好ましくは以下の基が挙げられる。 [1-2-f] Among the groups exemplified as Ring in [1-2-e] of the above embodiment, the following groups are more preferable.
Figure JPOXMLDOC01-appb-C000033
  
Figure JPOXMLDOC01-appb-C000033
  
［１－２－ｇ］前記態様の［１－２－ｆ］におけるＲｉｎｇとして例示された各基のうち、特に好ましくは、式（ａａ２１）～（ａａ２７）及び（ａａ２９）の基から選ばれる基が挙げられる。特別に好ましくは、式（ａａ２１）、式（ａａ２２）、式（ａａ２３）、式（ａａ２４）及び式（ａａ２５）の基から選ばれる基が挙げられる。 [1-2-g] Of the groups exemplified as Ring in [1-2-f] of the above embodiment, particularly preferably a group selected from the groups of formulas (aa21) to (aa27) and (aa29) Is mentioned. Particularly preferred are groups selected from the groups of formula (aa21), formula (aa22), formula (aa23), formula (aa24) and formula (aa25).
［１－３］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、Ｙは置換されていてもよい炭化水素基、または基：－ＮＲ５Ｒ６（Ｒ５、Ｒ６は、各々独立に、水素原子、置換されていてもよい炭化水素基または置換されていてもよいヘテロ環基を表し、Ｒ５、Ｒ６はそれらが結合する窒素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表す。 [1-3] In the compound of the above formula (I) used for the inhibitor of the embodiment [1], Y is an optionally substituted hydrocarbon group, or a group: —NR 5 R 6 (R 5 , R 6 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R 5 and R 6 are each a 3- to 8-membered member together with the nitrogen atom to which they are bonded. may form a cyclic group, said cyclic group is one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, halogen atom, -OH, C 1 ~ 6 alkoxy may be replaced by may also) be substituted by a halogenated C 1 - 6 one by one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl The cyclic group further has a substituent. May be present).
［１－３－ａ］Ｙで定義される「置換されていてもよい炭化水素基」として、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルキニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ６～１４のアリール基が挙げられる。これらは前記態様［１］に定義されている。 As "optionally substituted hydrocarbon group" defined [1-3-a] Y, straight-chain or min R C optionally substituted by a group selected C 1 ~ from group 6 alkyl Edakusari, straight-chain or branched alkenyl groups of R C is optionally C 2 even though - substituted with chosen groups arbitrarily from group 6, are optionally substituted with a group selected arbitrarily from R C group a straight-chain or branched alkynyl group of which may C 2 ~ 6, selected cycloalkyl group R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 8, the R C groups optionally substituted with the group and an aryl group optionally C 6 ~ 14 even. These are defined in the above aspect [1].
［１－３－ａ－１］Ｙで定義される「置換されていてもよい炭化水素基」としては、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ６～１４のアリール基であることが好ましい。 [1-3-a-1] is as the "optionally substituted hydrocarbon group" defined Y, straight of R C may be substituted with a group C 1 selected arbitrarily from the group 1-6 or branched chain alkyl group, optionally substituted by a group selected cycloalkyl group R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 8, or R C groups, optionally is preferably an aryl group optionally C 6 ~ 14.
［１－３－ａ－２］前記式（Ｉ）において、Ｙで定義される「置換されていてもよい炭化水素基」としては、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基であることがより好ましく、例えば、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、ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１－メチルブチル、２－メチルブチル、１，２－ジメチルプロピル、ヘキシルなどが挙げられ；
　ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基であることがより好ましく、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルなどが挙げられ；
　また、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ６～１４のアリール基であることがより好ましく、フェニルなどが挙げられる。 [1-3-a-2] In the above formula (I), the “optionally substituted hydrocarbon group” defined by Y may be substituted with a group arbitrarily selected from the RC group. more preferably a straight or branched chain alkyl group having optionally C 3 ~ 6, for example, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert- pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl and the like;
More preferably from R C group is a cycloalkyl group optionally C 3 ~ 6 optionally substituted by a group selected arbitrarily, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
Further, more preferably from R C group is an aryl group group which may C 6 ~ also be 14 substituted in the chosen arbitrarily, and the like phenyl.
［１－３－ｂ］前記式（Ｉ）において、Ｙが基：－ＮＲ５Ｒ６である場合には、Ｒ５、Ｒ６として、各々独立に、水素原子、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルキニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ６～１４のアリール基、ＲＣ群から任意に選ばれる基で置換されていてもよいヘテロ環基が挙げられる。これらは前記態様［１］に定義されている。 [1-3-b] In the formula (I), when Y is a group: —NR 5 R 6 , R 5 and R 6 are each independently selected from a hydrogen atom and an RC group. straight or branched chain alkyl group - optionally C 1 be substituted with group 6 to a linear or branched R C optionally substituted with a group C 2 selected in ~ from group 6 alkenyl group, straight chain or branched chain alkynyl group of R C is optionally C 2 even though - substituted with chosen groups arbitrarily from group 6, optionally substituted by a group selected arbitrarily from R C group cycloalkyl group which may C 3 ~ 8, aryl group R C may be substituted with chosen groups arbitrarily from the group C 6 ~ 14, optionally substituted by a group selected arbitrarily from R C group Good heterocyclic groups are mentioned. These are defined in the above aspect [1].
　また、Ｒ５、Ｒ６はそれらが結合する窒素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよい。 R 5 and R 6 may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, C 1 halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with one to five substituents which may be straight or branched alkoxyl To 6 alkyl groups), and the cyclic group may be further substituted with a group arbitrarily selected from the RC group.
［１－３－ｂ－１］Ｙが基：－ＮＲ５Ｒ６である場合に、Ｒ５、Ｒ６は、好ましくはＲ５Ａ、Ｒ６Ａとして、各々独立に、水素原子、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基であり、Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよい。 When [1-3-b-1] Y is a group: —NR 5 R 6 , R 5 and R 6 are preferably R 5A and R 6A each independently from a hydrogen atom or an RC group. straight or branched chain alkyl group having optionally C 1 ~ 6 be substituted with a chosen group optionally linear may be substituted by a group selected arbitrarily from R C group C 2 ~ 6 or branched alkenyl group, linear or branched alkynyl group of R C is optionally C 2 even though - optionally substituted with a group selected arbitrarily from group 6 or chosen groups arbitrarily from R C group, substituted cycloalkyl group which may C 3-8, R 5A, R 6A may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are attached, the cyclic group, the One carbon atom in the ring is an oxygen atom, sulfur atom or nitrogen atom (the nitrogen Atoms, straight or branched chain alkyl group having a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with 1-5 optionally substituted C 1 ~ 6 alkoxyl And the cyclic group may be further substituted with a group arbitrarily selected from the RC group.
［１－３－ｂ－２］Ｙが基：－ＮＲ５ＡＲ６Ａである場合に、当該基は下記式（Ｂ１）及び下記式（Ｂ２）
Figure JPOXMLDOC01-appb-C000034
  
（式中、Ｒ５Ａ、Ｒ６Ａは、前記と同じ意味を表し、ｘは０～２の整数を表し、ｙは０～３の整数を表し、Ｕは、基：－ＣＲ５ＢＲ６Ｂ－、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていても良く、Ｒ５Ｂ、Ｒ６Ｂは、各々独立に、水素原子、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルケニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルキニル基を表し、Ｒ５ＢとＲ６Ｂは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１～２個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）で置き換えられていてもよく、当該式（Ｂ２）の基はさらにＲＣ群から任意に選ばれる基で１ないし２個置換されていてもよい）で表される基を示す。 When [1-3-b-2] Y is a group: —NR 5A R 6A , the group is represented by the following formula (B1) and the following formula (B2)
Figure JPOXMLDOC01-appb-C000034
(Wherein R 5A and R 6A represent the same meaning as described above, x represents an integer of 0 to 2, y represents an integer of 0 to 3, U represents a group: —CR 5B R 6B —, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with one to five substituents which may be C 1 ~ alkoxyl 6 may be substituted with a linear or branched alkyl group, and each of R 5B and R 6B may independently be substituted with a hydrogen atom or a group arbitrarily selected from the R C group. 1 a linear or branched alkyl group having 1-6, straight or branched chain alkenyl groups of R C good C 2 - optionally substituted with chosen groups arbitrarily from group 6 or from R C group, linear good C 2 ~ 6 optionally substituted with chosen group optionally Alternatively, it represents a branched alkynyl group, and R 5B and R 6B may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, 2 to the oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 optionally substituted by any of halogen atom, -OH, C 1 - 6 alkoxylated, halogenated C 1 - 6 alkoxy may be replaced by may also be substituted with a straight or branched chain alkyl group having optionally C 1 ~ 6), is replaced in the cyclic group may have a substituent) And the group of the formula (B2) may be further substituted with one or two groups arbitrarily selected from the RC group.
［１－３－ｂ－３］前記式（Ｂ１）中のＲ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基である。 [1-3-b-3] R 5A in the formula (B1), as R 6A, preferably, R 5A or at least one constituent carbon atoms is 3 or more groups of R 6A. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari or substituted with chosen groups arbitrarily from R C group, a cycloalkyl group of C 3 ~ 8 may.
［１－３－ｂ－４］Ｙ中のＲ５Ａ、Ｒ６Ａとして、各々独立に、水素原子、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基であること（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である）がより好ましく；前記式（Ｂ２）中のＵはメチレン基、酸素原子、硫黄原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）であることがより好ましい。 As [1-3-b-4] R 5A, R 6A in Y, each independently, a hydrogen atom, linear R C optionally substituted by a group selected C 1 ~ from group 6 or it substituted alkyl group, or R C group branched with a group selected arbitrarily cycloalkyl group which may C 3 ~ 8 (provided that at least one constituent carbon atoms of R 5A or R 6A a is) are more preferable number 3 or more groups; U in the formula (B2) in a methylene group, an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom · -OH · C 1 ~ 6 alkoxy and more preferably is optionally substituted) with - a linear or branched alkyl group of halogenated C 1 ~ 6 or with 1-5 optionally substituted C 1 ~ 6 alkoxyl .
［１－３－ｂ－５］Ｙ中のＲ５Ａ、Ｒ６Ａとして、各々独立に、水素原子、Ｃ１～６の直鎖もしくは分枝鎖のアルキル基（例えば、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、ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１－メチルブチル、２－メチルブチル、１，２－ジメチルプロピル、ヘキシルなど）またはＣ３～６のシクロアルキル基（例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルなど）であること（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である）が更に好ましく；
Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに４～６員の環状基（当該環状基はその環内の炭素原子１個が酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）で置き換えられていてもよい）（例えば、アゼチジン－１－イル基、ピロリジン－１－イル基、ピペリジン－１－イル基、ピペラジン－１－イル基、４－メチルピペラジン－１－イル基、４－モルホリニル基など）を形成していることが更に好ましい。 [1-3-b-5] R 5A in Y, as R 6A, each independently, a hydrogen atom, a linear or branched alkyl group of C 1 ~ 6 (e.g., methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert- pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, etc.) or a cycloalkyl group of C 3 ~ 6 (For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) (provided that at least one of R 5A or R 6A is a group having 3 or more carbon atoms) is more preferable;
R 5A and R 6A are a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded (the cyclic group has one oxygen atom, sulfur atom or nitrogen atom in the ring (the nitrogen atom is a halogen atom) - -OH - C 1 with 1-6 linear or branched alkyl group of alkoxylated, halogenated C 1 - 6 or with 1-5 optionally substituted C 1 - 6 alkoxyl substituted by (E.g., azetidin-1-yl group, pyrrolidin-1-yl group, piperidin-1-yl group, piperazin-1-yl group, 4-methylpiperazin-1-yl) More preferably a 4-morpholinyl group).
［１－３－ｃ］基：Ｙ－として、より具体的には、以下の式（ｂ１）～（ｂ４６）で表される基（式（Ｉ）中、－Ｓ（Ｏ）ｎ－が結合した結合手を－として表したもの）が挙げられる。 More specifically, [1-3-c] group: Y— is a group represented by the following formulas (b1) to (b46) (wherein —S (O) n— is bonded in formula (I)) The bond is represented as-).
Figure JPOXMLDOC01-appb-C000035
  
Figure JPOXMLDOC01-appb-C000035
  
［１－３－ｄ］基：Ｙ－として、より具体的には、以下の式で表される基であることが好ましい。 More specifically, the group [1-3-d]: Y— is preferably a group represented by the following formula.
Figure JPOXMLDOC01-appb-C000036
  
Figure JPOXMLDOC01-appb-C000036
  
［１－３－ｅ］基：Ｙ－として、より具体的には、以下の式で表される基であることがより好ましい。 [1-3-e] group: Y— is more preferably a group represented by the following formula.
Figure JPOXMLDOC01-appb-C000037
  
Figure JPOXMLDOC01-appb-C000037
  
［１－３－ｆ］前記態様において基：Ｙ－として例示された各基のうち、更に好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基であり、具体的には、式（ｂ２３）、（ｂ２５）～（ｂ２９）、（ｂ３１）～（ｂ３６）、（ｂ３９）～（ｂ４０）が挙げられる。 [1-3-f] Among the groups exemplified as the group Y— in the above embodiment, more preferably, at least one of R 5A and R 6A is a group having 3 or more carbon atoms, Specifically, formulas (b23), (b25) to (b29), (b31) to (b36), and (b39) to (b40) may be mentioned.
［１－４］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、Ｚは、置換されていてもよいＣ３～８のシクロアルキル基、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す。より具体的には、下記式（Ｉ）
Figure JPOXMLDOC01-appb-C000038
  
のＺ部分（波線の右側部分）は、ＲＡ群から任意に選ばれる基で１～５置換されていてもよいＣ３～８のシクロアルキル基、ＲＡ群から任意に選ばれる基で１～５置換されていてもよいＣ６～１４のアリール基（一部水素化されてもよい環を含む）、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環でのヘテロアリール（一部水素化されてもよい環を含む）、または飽和もしくは不飽和の非芳香族のヘテロ環基（単環もしくは縮合環）が挙げられ、当該ヘテロアリール及び非芳香族のヘテロ環基はＲＡ群から任意に選ばれる基で１～５置換されていてもよく、態様［１］に記載されているものと同じ意味を表す。Ｚ部分の例として挙げられる以下に記載の各式は、上記式（Ｉ）中のＺ部分に置き換えた式として表しうる。 [1-4] In the compound of the above embodiment [1] above formula used in the inhibitor (I), Z is a cycloalkyl group of 1-8 optionally C 3 substituted, optionally substituted aryl Represents a group or an optionally substituted heterocyclic group. More specifically, the following formula (I)
Figure JPOXMLDOC01-appb-C000038
The Z moiety (the right side portion of the wavy line) a cycloalkyl group of R A may be 1-5 substituted with chosen groups arbitrarily from the group C 3 ~ 8, with a group selected arbitrarily from R A group 1 1-5 optionally substituted C 6 - 14 aryl group (including a ring which may be partially hydrogenated), N in addition to carbon atoms, O, at least one heteroatom selected from S (preferably 1 to 4) 3- to 14-membered heteroaryl (including rings that may be partially hydrogenated), or a saturated or unsaturated non-aromatic heterocyclic group (monocyclic or condensed ring) The heteroaryl and non-aromatic heterocyclic group may be substituted with 1 to 5 groups arbitrarily selected from the R A group, and have the same meaning as described in the embodiment [1]. To express. Each formula described below as an example of the Z moiety can be expressed as a formula in which the Z moiety in the formula (I) is replaced.
［１－４－ａ］Ｚで定義される基には、単環式の基と縮合環式の基があり、以下のような式（Ｃ１）または式（Ｃ２）
Figure JPOXMLDOC01-appb-C000039
  
（式中、Ｃｙｃｌｅ３及びＣｙｃｌｅ４の環は、各々独立で、前記のＣ３～８のシクロアルキル基、Ｃ６～１４のアリール基（部分的に水素化されてもよい環を含む）、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環でのヘテロアリール（部分的に水素化されてもよい環を含む）、または飽和もしくは不飽和の非芳香族のヘテロ環基から選ばれる環であり、Ｃｙｃｌｅ３とＣｙｃｌｅ４は、任意の位置で縮合しており、（ＣＲ３Ｒ４）ｐ－との結合手はＣｙｃｌｅ３で結合しており、ＲＡは前記と同じであり、ｋは０～５の整数であり、ＲＡはＣｙｃｌｅ３またはＣｙｃｌｅ４で表される環のいずれに結合していてもよい）で表される１価の基を表す。 The group defined by [1-4-a] Z includes a monocyclic group and a condensed cyclic group, and has the following formula (C1) or (C2)
Figure JPOXMLDOC01-appb-C000039
(Wherein ring of Cycle3 and Cycle4 are each independently a cycloalkyl group of said C 3 ~ 8, comprising a ring which may be an aryl group (partially hydrogenated in C 6 ~ 14), carbon atoms In addition, heteroaryl in a 3 to 14 membered ring containing at least one heteroatom (preferably 1 to 4) selected from N, O and S (including a ring which may be partially hydrogenated), Or a ring selected from a saturated or unsaturated non-aromatic heterocyclic group, and Cycle 3 and Cycle 4 are condensed at an arbitrary position, and a bond to (CR 3 R 4 ) p- is bound by Cycle 3 R A is as defined above, k is an integer of 0 to 5, and R A may be bonded to any of the rings represented by Cycle 3 or Cycle 4). Represents a group of
［１－４－ｂ］前記式（Ｉ）の化合物において、式（Ｉ）のＺ部分として、好ましくは、下記式（Ｄ）
Figure JPOXMLDOC01-appb-C000040
  
（式中、ＲＡは前記態様［１］に記載の置換基から任意に選ばれる基を表し、ｇは０～５の整数を表す）で表される基であり、；
または、下記式（Ｅ）
Figure JPOXMLDOC01-appb-C000041
  
（式中、ｊは０または１の整数を表し、ｆは０～２の整数を表し；Ｒ１２は、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、保護されていてもよいカルボキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよい非芳香族のヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～５アルカノイル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基を表し；
Ａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、カルボニル基または酸素原子を表し；
Ｇは単結合、メチレン基、カルボニル基またはスルホニル基を表し；
Ｌ１は、単結合、－ＣＲ１５ＡＲ１５Ｂ－、カルボニル基、酸素原子、－ＮＲ１６Ａ－または－Ｓ（Ｏ）ｔ－（ｔは０～２の整数）を表し；
Ｌ２は、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、カルボニル基、酸素原子、－ＮＲ１６Ｂ－または－Ｓ（Ｏ）ｔ－（ｔは０～２の整数）を表し；
Ｒ１３、Ｒ１６Ａ、Ｒ１６Ｂは、各々独立に、水素原子またはＲＢ群から任意に選ばれる基を表し；
Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄは、各々独立に、水素原子、ハロゲン原子、ＲＣ群から任意に選ばれる基で置換されていても良い炭化水素基、ＲＣ群から任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシカルボニル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いアミノ基、保護されていても良いヒドロキシル基、保護されていても良いカルボキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いカルバモイル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ２～７アルカノイル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキルチオ基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキルスルフィニル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキルスルホニル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良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、Ｒ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよく；Ａ、Ｇ、Ｌ１及びＬ２を構成に含む環における破線は適宜単結合もしくは二重結合をとり、当該環は芳香化していてもよいことを示し、Ａ、Ｇ、Ｌ１及びＬ２を構成に含む環はＲＡ群から任意に選ばれる基でさらに１置換されていてもよい）で表される基；
である。
　好ましくは、前記式（Ｅ）において、Ｒ１２が置換したフェニル基に非芳香族のヘテロ環が縮合した基、すなわち前記式（Ｅ）において、Ａ、Ｇ、Ｌ１及びＬ２を構成に含む環が芳香化していない基が挙げられる。 [1-4-b] In the compound of the formula (I), the Z moiety of the formula (I) is preferably the following formula (D)
Figure JPOXMLDOC01-appb-C000040
(Wherein R A represents a group arbitrarily selected from the substituents described in the above embodiment [1], and g represents an integer of 0 to 5);
Or the following formula (E)
Figure JPOXMLDOC01-appb-C000041
(Wherein j represents an integer of 0 or 1, f represents an integer of 0 to 2; R 12 represents a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or an optionally protected carboxyl group. group, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from groups, heterocyclic groups nonaromatic optionally substituted with chosen groups arbitrarily from R C group, R group optionally substituted C 1 to 4 alkoxy groups selected from group C optionally, R C good C 2 - optionally substituted with chosen groups arbitrarily from group 5 alkanoyl group, or R C group, optionally substituted with chosen group optionally good C 1 ~ 4 alkyl group mono- - or di - represents a group selected arbitrarily from an amino group which may be substituted;
A represents —NR 13 —, —CR 14A R 14B —, a carbonyl group or an oxygen atom;
G represents a single bond, a methylene group, a carbonyl group or a sulfonyl group;
L 1 represents a single bond, —CR 15A R 15B —, a carbonyl group, an oxygen atom, —NR 16A — or —S (O) t— (t is an integer of 0 to 2);
L 2 is a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), carbonyl group, oxygen atom, —NR 16B — or —S (O) t— (t is 0 to 2) An integer);
R 13, R 16A, R 16B are each independently, represent a group selected arbitrarily from a hydrogen atom or R B groups;
R 14A , R 14B , R 15A , R 15B , R 15C , R 15D are each independently a hydrogen atom, a halogen atom, or a hydrocarbon group optionally substituted with a group selected from the RC group, R optionally chosen heterocyclic group which may be substituted with a group from group C, are selected may be substituted by a group selected arbitrarily from R C group C 1 ~ 6 alkoxy group, a R C group optionally optionally substituted - or di - substituted good C 1 to 6 alkoxycarbonyl group with a group, mono optionally substituted with chosen group which may have C 1 ~ 6 alkyl group from R C group amino group, an optionally protected hydroxyl group, a mono-protected carboxyl group which may, R C good C 1 ~ optionally substituted with chosen groups arbitrarily from group 6 alkyl group - or di - location Which may be a carbamoyl group, R C optionally chosen optionally substituted C 2 ~ 7 alkanoyl group with a group from a group, it may be substituted by a group selected arbitrarily from R C group C 1 ~ 6 alkylthio group, R C optionally may be substituted by a group selected C 1 ~ 6 alkylsulfinyl group from group group optionally substituted C 1 ~ 6 alkylsulfonyl optionally selected from R C group group, mono optionally substituted with chosen group which may have C 1 ~ 6 alkyl group from R C group - or di - may be substituted sulfamoyl groups, chosen group optionally cyano group or a nitro group the stands, R 14A and R 14B, R 15A and R 15B, or R 15C and R 15D, may form a 3- to 8-membered cyclic group together with the carbon atoms to which they are attached The cyclic group is one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, one halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy or in may be replaced by 1 to may 5 is substituted with optionally substituted good C 1 - 6 straight or branched chain alkyl group), the cyclic group may further R C group The broken line in the ring containing A, G, L 1 and L 2 may take a single bond or a double bond as appropriate, and the ring may be aromatized. The ring containing A, G, L 1 and L 2 as a component may be further substituted with a group arbitrarily selected from the R A group;
It is.
Preferably, in the formula (E), a group in which a non-aromatic heterocycle is condensed to a phenyl group substituted by R 12 , that is, in the formula (E), A, G, L 1 and L 2 are included in the configuration. Examples include groups in which the ring is not aromatized.
　ここで、「ＲＣ群から任意に選ばれる基で置換されていてもよいヘテロ環基」のヘテロ環基としては、ＲＣ群から任意に選ばれる基で１～５置換されていてもよい炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環でのヘテロアリール、または飽和もしくは不飽和の非芳香族のヘテロ環基（単環もしくは縮合環）が挙げられ、態様［１］に記載されている。 Here, as the heterocyclic group of the "R C heterocyclic group which may be substituted with chosen groups arbitrarily from the group" may be 1-5 optionally substituted with a group selected arbitrarily from R C group Heteroaryl in 3 to 14 membered ring containing at least one heteroatom (preferably 1 to 4) selected from N, O and S in addition to carbon atom, or saturated or unsaturated non-aromatic heterocycle Groups (monocyclic or condensed) are mentioned and described in embodiment [1].
［１－４－ｃ］前記式（Ｄ）の基において、以下の態様が好ましい。 [1-4-c] In the group of the formula (D), the following embodiments are preferable.
［１－４－ｃ－１］　前記式（Ｄ）の基において、ｇは１～３の整数であることが好ましい。
［１－４－ｃ－２］　前記式（Ｄ）において、好ましいＲＡ群の置換基としては、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、Ｃ１～６アルキルチオ－Ｃ１～６アルキル、Ｃ１～６アルキルスルホニル－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、
Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、
Ｃ１～６アルキルチオ、モノ／ジＣ１～６アルキルスルファモイル、モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルスルファモイルアミノ、Ｃ１～６アルコキシカルボニル、モノ／ジＣ１～６アルキルカルバモイル、モノ／ジＣ６～１４アリールカルバモイル、
Ｃ２～７アルカノイル、Ｃ２～７アルカノイルアミノ、オキソ、ニトロ、シアノ、アミノ、保護されていてもよいヒドロキシル、メルカプト、保護されていてもよいカルボキシル、カルバモイル、スルファモイル、ホルミル、ホルミルアミノ、スルホ、Ｃ６～１４アリール、Ｃ６～１４アリール－Ｃ１～６アルキル、Ｃ６～１４アリールオキシ、Ｃ６～１４アリールチオ、モノ／ジＣ６～１４アリールスルファモイル、モノ／ジＣ６～１４アリールアミノ、モノ／ジＣ６～１４アリールスルファモイルアミノ、Ｃ６～１４アリールオキシカルボニル、Ｃ６～１４アリールカルボニル、
Ｃ６～１４アリールカルボニルアミノ、へテロ環基（当該環は、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環、好ましくは３～１２員環の単環もしくは縮合環を有する環）、ヘテロ環Ｃ１～６アルキル、ヘテロ環オキシ、ヘテロ環チオ、モノ／ジヘテロ環アミノ、ヘテロ環オキシカルボニル、ヘテロ環カルボニル、ヘテロ環カルボニルアミノ、等の置換基が挙げられ、
当該ＲＡ群の置換基中のアルキル鎖部分、アリールまたはヘテロ環は、更にハロゲン原子、トリフルオロメチル、シアノ、保護されていてもよいヒドロキシル、アミノ、ニトロ、保護されていてもよいカルボキシル、カルバモイル、Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルカノイルアミノ、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、モノ／ジＣ１～６アルキルスルファモイル、モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルスルファモイルアミノ、Ｃ１～６アルコキシカルボニル、モノ／ジＣ１～６アルキルカルバモイル、Ｃ２～７アルカノイル、
Ｃ６～１４アリール、およびへテロ環基（当該環は、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環、好ましくは３～１２員環の単環もしくは縮合環を有する環）からなる群から選ばれる基１～３個で置換されていてもよい。 [1-4-c-1] In the group of the formula (D), g is preferably an integer of 1 to 3.
[1-4-c-2] In Formula (D), examples of the substituent of the preferred R A groups, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, hydroxy -C 1-6 alkyl, C 1-6 alkoxy -C 1-6 alkyl, C 1-6 alkylthio -C 1-6 alkyl, C 1-6 alkylsulfonyl -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, C 3 ~ 8 cycloalkyl, C 3 ~ 8 cycloalkyl -C 1-6 alkyl,
C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy,
C 1 ~ 6 alkylthio, mono / di C 1 ~ 6 alkyl sulfamoyl, mono / di C 1 ~ 6 alkylamino, mono / di C 1 ~ 6 alkyl sulfamoylamino, C 1 ~ 6 alkoxycarbonyl, mono / di C 1 ~ 6 alkylcarbamoyl, mono / di C 6 ~ 14 aryl-carbamoyl,
C 2 ~ 7 alkanoyl, C 2 ~ 7 alkanoylamino, oxo, nitro, cyano, amino, optionally protected hydroxyl, mercapto, optionally protected carboxyl, carbamoyl, sulfamoyl, formyl, formylamino, sulfo, C 6 ~ 14 aryl, C 6 ~ 14 aryl -C 1 ~ 6 alkyl, C 6 ~ 14 aryloxy, C 6 ~ 14 arylthio, mono / di C 6 ~ 14 aryl sulfamoyl, mono / di C 6 ~ 14 arylamino, mono / di C 6 ~ 14 aryl sulfamoylamino, C 6 ~ 14 aryloxycarbonyl, C 6 ~ 14 aryl-carbonyl,
C 6 ~ 14 arylcarbonylamino, Hajime Tamaki (said ring is 3 to 14-membered ring containing at least one heteroatom selected in addition to carbon atoms from N, O, S (preferably 1 to 4) preferably 3 single ring or ring having a condensed ring of ~ 12-membered ring), heterocyclic C 1 - 6 alkyl, heterocyclic oxy, heterocyclic thio, mono / diheterocyclic amino, heterocyclic oxy carbonyl, heterocyclic carbonyl, Substituents such as heterocyclic carbonylamino, and the like,
The alkyl chain moiety, aryl or heterocycle in the substituent of the group A is further a halogen atom, trifluoromethyl, cyano, optionally protected hydroxyl, amino, nitro, optionally protected carboxyl, carbamoyl. , C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkanoylamino, C 1 ~ 6 alkylthio, C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, mono / di C 1 ~ 6 alkylsulfamoyl moil, mono / di C 1 ~ 6 alkylamino, mono / di C 1 ~ 6 alkyl sulfamoylamino, C 1 ~ 6 alkoxycarbonyl, mono / di C 1 ~ 6 alkylcarbamoyl, C 2 ~ 7 alkanoyl,
C 6 ~ 14 aryl, and a Hajime Tamaki (said ring, N in addition to carbon atoms, O, 3 ~ 14 membered ring containing at least one heteroatom selected from S (preferably 1 to 4), Preferably, it may be substituted with 1 to 3 groups selected from the group consisting of a 3- to 12-membered monocyclic ring or a ring having a condensed ring.
［１－４－ｃ－２ａ］前記式（Ｄ）の基において、より好ましいＲＡ群の置換基としては、Ｃ１～６アルキル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、Ｃ３～８シクロアルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、ハロゲン化Ｃ１～６アルコキシル、Ｃ１～６アルキルチオ、モノ／ジＣ１～６アルキルスルファモイル、モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルカルバモイル、モノ／ジＣ６～１４アリールカルバモイル、
Ｃ２～７アルカノイル、Ｃ２～７アルカノイルアミノ、オキソ、ニトロ、シアノ、アミノ、保護されていてもよいヒドロキシル、保護されていてもよいカルボキシル、カルバモイル、Ｃ６～１４アリール、Ｃ６～１４アリール－Ｃ１～６アルキル、Ｃ６～１４アリールオキシ、モノ／ジＣ６～１４アリールアミノ、Ｃ６～１４アリールカルボニルアミノ、へテロ環基（当該環は、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環、好ましくは３～１２員環の単環もしくは縮合環を有する環）、ヘテロ環カルボニル、ヘテロ環カルボニルアミノ、等の置換基が挙げられ、
当該ＲＡ群の置換基中のアルキル鎖部分、アリールまたはヘテロ環は、更にハロゲン原子、トリフルオロメチル、シアノ、保護されていてもよいヒドロキシル、アミノ、ニトロ、保護されていてもよいカルボキシル、カルバモイル、Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルカノイルアミノ、へテロ環基（当該環は、炭素原子以外にＮ、Ｏ、Ｓから選択される少なくとも１つのヘテロ原子（好ましくは１～４個）を含む３～１４員環、好ましくは３～１２員環の単環もしくは縮合環を有する環）からなる群から選ばれる基１～３個で置換されていてもよい。 In the group of [1-4-c-2a] Formula (D), more preferable examples of the substituent of the R A group, C 1 ~ 6 alkyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 1-6 alkyl, C 1 - 6 alkoxy -C 1 - 6 alkyl, C 3 - 8 cycloalkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 - 6 alkoxyl, halogenated C 1 - 6 alkoxy, C 1 ~ 6 alkylthio, mono / di C 1 ~ 6 alkyl sulfamoyl, mono / di C 1 ~ 6 alkylamino, mono / di C 1 ~ 6 alkylcarbamoyl, mono / di C 6 ~ 14 aryl-carbamoyl,
C 2 ~ 7 alkanoyl, C 2 ~ 7 alkanoylamino, oxo, nitro, cyano, amino, optionally protected hydroxyl, optionally protected carboxyl, carbamoyl, C 6 ~ 14 aryl, C 6 ~ 14 aryl -C 1 ~ 6 alkyl, C 6 ~ 14 aryloxy, mono / di C 6 ~ 14 arylamino, C 6 ~ 14 arylcarbonylamino, Hajime Tamaki (said ring, N in addition to carbon atoms, O, S A ring having 3 to 14 membered ring, preferably 3 to 12 membered monocyclic or condensed ring, containing at least one heteroatom selected from (preferably 1 to 4), heterocyclic carbonyl, heterocyclic carbonyl And substituents such as amino,
The alkyl chain part, aryl or heterocycle in the substituent of the group A is further halogen atom, trifluoromethyl, cyano, optionally protected hydroxyl, amino, nitro, optionally protected carboxyl, carbamoyl. , C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkanoylamino, Hajime Tamaki (said ring to, N in addition to carbon atoms, O, at least one heteroatom (preferably selected from S is 1 to 4) -containing 3 to 14-membered ring, preferably 3 to 12-membered ring having a monocyclic ring or condensed ring) may be substituted with 1 to 3 groups.
［１－４－ｃ－３］前記式（Ｄ）において、ＲＡの置換位置は、下記式（Ｄ’）中、Ｗ－（ＣＲ３Ｒ４）ｐ－の結合位置を１位とした場合、２位、３位、４位、５位及び６位に結合することができ、２位または４位であることが好ましい。ｇは１～３であることが好ましく、少なくとも置換基のひとつは２位または４位であることが好ましい。 [1-4-c-3] In the above formula (D), the substitution position of RA is the case where the bonding position of W- (CR 3 R 4 ) p- is the 1st position in the following formula (D ′) It can be bonded to the 2-position, 3-position, 4-position, 5-position and 6-position, and the 2-position or 4-position is preferred. g is preferably 1 to 3, and at least one of the substituents is preferably 2-position or 4-position.
Figure JPOXMLDOC01-appb-C000042
  
Figure JPOXMLDOC01-appb-C000042
  
［１－４－ｄ］前記式（Ｅ）の基において、以下の態様が好ましい。 [1-4-d] In the group of the above formula (E), the following embodiments are preferable.
［１－４－ｄ－１］前記式（Ｅ）の基において、ｊは０または１の整数を表し、ｆは０～２の整数を表す。ｊが０であることが好ましい。また、ｆが０または１であることが好ましく、より好ましくはｆが０である。ｊとｆとの組み合わせにおいて、ｊとｆがともに０であることが好ましい。 [1-4-d-1] In the group of the above formula (E), j represents an integer of 0 or 1, and f represents an integer of 0 to 2. j is preferably 0. Further, f is preferably 0 or 1, more preferably f is 0. In the combination of j and f, it is preferable that j and f are both 0.
［１－４－ｄ－２］前記式（Ｅ）の基において、Ｒ１２は、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、保護されていてもよいカルボキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよい非芳香族のヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～５アルカノイル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基が挙げられる。 [1-4-d-2] In the group of the above formula (E), R 12 is a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, an optionally protected carboxyl group, from the group R C. optionally chosen optionally substituted C 1 ~ 4 alkyl group with a group, selected heterocyclic group non-aromatic may be substituted by a group selected arbitrarily from R C group, the R C groups optionally is optionally substituted C 1 to 4 alkoxy groups with a group, R C optionally chosen optionally substituted C 2 even though 1-5 alkanoyl group with a group from groups or chosen groups arbitrarily from R C group, optionally substituted C 1 ~ mono 4 alkyl - or di - include groups selected arbitrarily from an amino group which may be substituted.
　これら「ＲＣ群から任意に選ばれる基で置換されていてもよい」のＲＣ群の置換基は、前記態様［１］に列挙された置換基が挙げられ、当該置換基１～３個で置換されていてもよい。 These substituents R C group "may be substituted with a group selected arbitrarily from R C" group, the aspect [1] listed substituents listed, 1-3 the substituent May be substituted.
　ここで、「ＲＣ群から任意に選ばれる基で置換されていてもよい非芳香族のヘテロ環基」の非芳香族のヘテロ環基としては、前記態様［１］で例示されたものと同じ意味を表し、例えば、アゼチジニル、モルホリニル、ピペリジニル、ピペラジニル、ピロリジニル、チアゾリニル、オキセパニル、チオモルホリニル等が挙げられる。 Here, examples of the non-aromatic heterocyclic group in the “non-aromatic heterocyclic group optionally substituted with a group arbitrarily selected from the RC group” include those exemplified in the above embodiment [1]. It represents the same meaning, and examples thereof include azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, oxepanyl, thiomorpholinyl and the like.
　また「ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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」において、Ｃ１～４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とは、アミノ基の一つ又は二つの水素原子が前記「Ｃ１～４アルキル基」で置換されていてもよいアミノ基を意味し、具体的には、アミノ基、メチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基、ブチルアミノ基、イソブチルアミノ基、ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジイソプロピルアミノ基、ジブチルアミノ基、エチルメチルアミノ基、メチルプロピルアミノ基、エチルプロプルアミノ基、ブチルメチルアミノ基、ブチルエチルアミノ基、ブチルプロピルアミノ基等が挙げられる。 In "mono optionally substituted with chosen group which may C 1 to 4 alkyl groups of R C group - - or di amino group which may be substituted", mono C 1 - 4 alkyl group - or di - the optionally substituted amino group means a one or two hydrogen atoms are the "C 1 ~ 4 alkyl group" in the optionally substituted amino group of the amino group, specifically Is amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, ethyl Methylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group, butylethylamino group, butylpropyl An amino group etc. are mentioned.
［１－４－ｄ－２ａ］好ましくは、前記式（Ｅ）のＲ１２としては、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基が挙げられる。ＲＣ群から任意に選ばれる基で置換されていてもよいとは、前記［１］でＲＣ群の置換基として列挙した基で置換されていてもよいことを意味し、例えば、Ｃ１～６アルキル、ハロゲン原子、アミノ、ヒドロキシル、Ｃ１～６アルコキシル、モノ／ジＣ１～６アルキルアミノ、オキソ等の置換基で置換されていてもよく、「置換されていてもよいＣ１～４アルキル」の置換基としては、例えば、ハロゲン原子、アミノ、ヒドロキシル、Ｃ１～６アルコキシル、モノ／ジＣ１～６アルキルアミノ、オキソ、テトラヒドロピラン－４－イル等の置換基が挙げられる。 [1-4-d-2a] Preferably, R 12 in the formula (E) is substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the group R C. optionally optionally C 1 be ~ 4 alkyl group, optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ~ 4 alkoxyl group, or R C group from R C group mono C 1 ~ 4 alkyl group - or di - include groups selected arbitrarily from an amino group which may be substituted. The term “optionally substituted with a group arbitrarily selected from the group RC” means that the group may be substituted with the groups listed as the substituents of the group RC in [1] above. For example, C 1 1-6 alkyl, halogen atom, amino, hydroxyl, C 1 - 6 alkoxy, mono / di C 1 - 6 alkylamino, may be substituted with a substituent oxo etc., "optionally substituted C 1 ~ Examples of the substituent of alkyl ", for example, a halogen atom, an amino, hydroxyl, C 1 ~ 6 alkoxy, mono / di C 1 ~ 6 alkyl amino, oxo, and substituted groups such as tetrahydropyran-4-yl.
［１－４－ｄ－２ｂ］より好ましいＲ１２としては、具体的には、水素原子、メチル基、エチル基、ヒドロキシメチル基、ヒドロキシエチル基、メトキシメチル基、メトキシエチル基、３－ヒドロキシプロポキシ基、トリフルオロメチル基；４－モルホリニル基、２，６－ジメチル－４－モルホリニル基、１－ピペリジニル基、４－オキソ－１－ピペリジニル基、４－ヒドロキシ－１－ピペリジニル基、４－メトキシ－１－ピペリジニル基、４，４－ジフルオロ－１－ピペリジニル基、１－ピペラジニル基、４－メチル－ピペラジニル基、ピロリジニル基、（３Ｓ）－フルオロ－ピロリジニル基、（３Ｓ）－ヒドロキシ－ピロリジニル基、チアゾリニル基、オキセパニル基、チオモルホリニル基、（２Ｓ）－ヒドロキシメチル－ピロリジニル基、（２Ｓ）－メトキシメチル－ピロリジニル基、；Ｎ，Ｎ－ジメチルアミノ基、Ｎ，Ｎ－ジエチルアミノ基、Ｎ，Ｎ－エチルメチルアミノ基、Ｎ，Ｎ－ビス（２－メトキシエチル）アミノ基、Ｎ－メチル－Ｎ－（２－メトキシエチル）アミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基、Ｎ－メチル－Ｎ－（２－ジメチルアミノエチル）アミノ基、Ｎ－メチル－Ｎ－（２－ヒドロキシエチル）アミノ基、Ｎ－メチル－Ｎ－（２－メトキシエチル）アミノ基、Ｎ－メチル－Ｎ－（テトラヒドロピラン－４－イル）アミノ基等が挙げられる。更に好ましいＲ１２としては、水素原子またはトリフルオロメチル基である。 [1-4-d-2b] More preferably, R 12 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. Group, trifluoromethyl 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 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- (tetrahydropyran-4-yl) amino group and the like. R 12 is more preferably a hydrogen atom or a trifluoromethyl group.
［１－４－ｄ－３］前記式（Ｅ）の基において、Ｒ１３、Ｒ１６Ａ、Ｒ１６Ｂは、各々独立に、水素原子またはＲＢ群から任意に選ばれる基を表す。Ｒ１３、Ｒ１６Ａ及びＲ１６Ｂは、各々独立に、水素原子、またはＣ１～６アルキル基（当該Ｃ１～６アルキル基は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、Ｃ６～１４アリール基、へテロ環基、Ｃ１～６アルキルスルホニル基、スルファモイル基、Ｃ１～６アルキルスルファモイル基、Ｃ２～７アルカノイル基、Ｃ１～６アルコキシカルボニル基、カルバモイル基もしくはＣ１～６アルキルカルバモイル基であることが好ましく、当該置換基中の炭素原子は、更にハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル及びアミノからなる群から選ばれる基１～５個で置換されていてもよい。 In the group of [1-4-d-3] wherein formula (E), R 13, R 16A, R 16B are each independently, represent a group selected arbitrarily from a hydrogen atom or R B groups. R 13, R 16A and R 16B are each independently a hydrogen atom or C 1 ~ 6 alkyl group (said C 1 ~ 6 alkyl group, a halogen atom · -OH · C 1 ~ 6 alkoxyl · C 1 ~, 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 ~ 6 alkylcarbamoyl - amino-mono / di C 1 ~ 6 alkylamino-C 2 ~ 7 alkanoyl, C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl or heteroaryl ring may be substituted), C 6 ~ 14 aryl group, heterocyclic group, C 1 ~ 6 alkylsulfonyl group, a sulfamoyl group, C 1 ~ 6 Arukirusurufu Amoiru group, C 2 ~ 7 alkanoyl group, C 1 ~ 6 alkoxycarbonyl group is preferably a carbamoyl group or a C 1 ~ 6 alkylcarbamoyl group, a carbon atom in the substituent is further halogen atoms · -OH · C 1 ~ in group one to five selected from the group consisting of 6 alkoxyl and amino which may be substituted.
［１－４－ｄ－３ａ］Ｒ１３、Ｒ１６Ａ及びＲ１６Ｂは、各々独立に、水素原子、Ｃ１～６アルキル基、へテロ環基、Ｃ１～６アルキルスルホニル基、Ｃ２～７アルカノイル基、Ｃ１～６アルコキシカルボニル基もしくはカルバモイル基であることがより好ましく、当該置換基中の炭素原子は、更にハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル及びアミノからなる群から選ばれる基１～５個で置換されていてもよい。 [1-4-d-3a] R 13, R 16A and R 16B are each independently a hydrogen atom, C 1 ~ 6 alkyl group, a heterocyclic group, C 1 ~ 6 alkylsulfonyl group, C 2 ~ 7 alkanoyl group, more preferably a C 1 ~ 6 alkoxycarbonyl group or a carbamoyl group, a carbon atom in the substituent group selected from the group further consisting of a halogen atom · -OH · C 1 ~ 6 alkoxyl and amino It may be substituted with 1 to 5 units.
［１－４－ｄ－３ｂ］より好ましいＲ１３、Ｒ１６Ａ及びＲ１６Ｂの置換基における「Ｃ１～６アルキル基」としては、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、ペンチル、イソペンチル、ネオペンチル、ｔｅｒｔ－ペンチル、１－メチルブチル、２－メチルブチル、１，２－ジメチルプロピル、ヘキシル、イソヘキシル、１－メチルペンチル、２－メチルペンチル、３－メチルペンチル、１，１－ジメチルブチル、１，２－ジメチルブチル、２，２－ジメチルブチル、１，３－ジメチルブチル、２，３－ジメチルブチル、３，３－ジメチルブチル、１－エチルブチル、２－エチルブチル、１，１，２－トリメチルプロピル、１，２，２－トリメチルプロピル、１－エチル－１－メチルプロピル、１－エチル－２－メチルプロピル、ｎ－ヘキシル等が挙げられ、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチルまたはｓｅｃ－ブチルであることが好ましい。 As "C 1 ~ 6 alkyl group" in [1-4-d-3b] More preferred R 13, substituents R 16A and R 16B, 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- Examples thereof include 1-methylpropyl, 1-ethyl-2-methylpropyl, n-hexyl and the like, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl is preferable.
［１－４－ｄ－３ｃ］式（Ｅ）で表される基においてＲ１３、Ｒ１６Ａ及びＲ１６Ｂは、各々独立に、水素原子、直鎖または分枝鎖のＣ１～４アルキル（当該Ｃ１～４アルキルは、ハロゲン原子・－ＯＨもしくはアミノで置換されていてもよい）、ヘテロアリール、Ｃ１～４アルキルスルホニル、Ｃ２～５アルカノイル（当該Ｃ２～５アルカノイルは、ハロゲン原子・－ＯＨもしくはアミノで置換されていてもよい）、Ｃ１～６アルコキシカルボニルもしくはカルバモイルであることが、特別に好ましい。より具体的には、水素原子、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、トリフルオロメチル、（２－）フルオロエチル、アミノメチル、（２－）アミノエチル、ヒドロキシメチル、（２－）ヒドロキシエチル、（３－）ヒドロキシプロパン－１－イル、（４－）ヒドロキシブチル、２－ヒドロキシ－２，２－ジメチルエチル、１，３－ジヒドロキシ－プロパン－２－イル、１－メチル－２－ヒドロキシエチル、２－ヒロドキシ－プロパン－１－イル、ピリジル、メチルスルホニル、アセチル、プロピオニル、トリフルオロアセチル、ヒドロキシアセチル、アミノアセチル、ｔｅｒｔ－ブトキシカルボニル、カルバモイル等（括弧内は好ましい態様を示している）が挙げられる。 R 13 in the group represented by [1-4-d-3c] formula (E), R 16A and R 16B are each independently a hydrogen atom, straight or branched C 1 ~ 4 alkyl (the C 1 ~ 4 alkyl may be substituted with a halogen atom, -OH or amino), heteroaryl, C 1 ~ 4 alkylsulfonyl, C 2 ~ 5 alkanoyl (the C 2 ~ 5 alkanoyl, halogen atom may be substituted with -OH or amino), it is, especially preferred is a C 1 ~ 6 alkoxycarbonyl or carbamoyl. More specifically, a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, trifluoromethyl, (2-) fluoroethyl, aminomethyl, (2-) aminoethyl, hydroxymethyl, ( 2-) Hydroxyethyl, (3-) hydroxypropan-1-yl, (4-) hydroxybutyl, 2-hydroxy-2,2-dimethylethyl, 1,3-dihydroxy-propan-2-yl, 1-methyl -2-hydroxyethyl, 2-hydroxy-propan-1-yl, pyridyl, methylsulfonyl, acetyl, propionyl, trifluoroacetyl, hydroxyacetyl, aminoacetyl, tert-butoxycarbonyl, carbamoyl, etc. (preferred embodiments are shown in parentheses) Are).
［１－４－ｄ―４］前記式（Ｅ）において、Ｌ１及びＬ２におけるｔは、０～２の整数を表し、０もしくは２であることが好ましい。 [1-4-d-4] In the above formula (E), t in L 1 and L 2 represents an integer of 0 to 2, and is preferably 0 or 2.
［１－４－ｄ－５］前記式（Ｅ）において、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ及びＲ１５Ｄとしては、各々独立に、水素原子、ハロゲン原子、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６アルキル基、ＲＣ群から任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で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または保護されていても良いヒドロキシル基から任意に選ばれる基が好ましく、またはＲ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄが、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよいことが好ましい。 [1-4-d-5] In the formula (E), R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently a hydrogen atom, a halogen atom, or a group R C. optionally substituted by a group selected C 1 ~ 6 alkyl group, R C optionally chosen heterocyclic group which may be substituted with a group from a group, substituted with a group selected arbitrarily from R C group or di - - optionally substituted amino group or optionally protected C 1 to 6 alkoxy group, mono optionally substituted with chosen groups which may be C 1 - 6 alkyl radical from R C group R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D together with the carbon atom to which they are bonded are preferred. An ˜8-membered cyclic group may be formed, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom, —OH · C 1 It is replaced by may also) be substituted with 1-6 linear or branched alkyl group of alkoxylated, halogenated C 1 - 6 or with 1-5 optionally substituted C 1 - 6 alkoxyl The cyclic group may be further substituted with a group arbitrarily selected from the RC group.
［１－４－ｄ－５ａ］Ｒ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、各々の組み合わせにおいて、同一であっても異なっていてもよいが、より好ましいＲ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄとしては、水素原子、ハロゲン原子、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていてもよいＣ１～６アルキル基、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていてもよいヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で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または保護されていても良いヒドロキシル基からなる群から選ばれる基が挙げられ、これらＲＣ群の置換基は、前記［１］で挙げられており、例えば、Ｃ１～６アルキル、ハロゲン原子、アミノ、ヒドロキシル、Ｃ１～６アルコキシル、モノ／ジＣ１～６アルキルアミノ、オキソ等の置換基で置換されていてもよい。「置換されていてもよいＣ１～６アルキル基」の置換基としては、例えば、ハロゲン原子、アミノ、ヒドロキシ、Ｃ１～６アルコキシル、モノ／ジＣ１～６アルキルアミノ、オキソ、テトラヒドロピラン－４－イル等の置換基が挙げられる。また、Ｒ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる置換基を有していてもよいが、より好ましい場合には、Ｃ３～８のシクロアルキル環として、シクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環、シクロヘプタン環、シクロオクタン環等が挙げられる。また、３～８員の飽和もしくは不飽和非芳香族のヘテロ環として、例えば、アジリジン環、アゼチジン環、オキシラン環、オキセタン環、チエタン環、ピロリジン環、テトラヒドロフラン環、チオラン環、、ピペリジン環、テトラヒドロピラン環、ピペラジン環、オキセパン環等が挙げられる。 [1-4-d-5a] R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D may be the same or different in each combination, but more preferable R 14A And R 14B , R 15A and R 15B , or R 15C and R 15D are C 1 to 6 which may be substituted with a group arbitrarily selected from a hydrogen atom, a halogen atom, and —OH · —NH 2 · —COOH. alkyl group, -OH · -NH2 · -COOH substituted with chosen groups arbitrarily from which may be a heterocyclic group, optionally substituted by a group selected C 1 ~ from R C group 6 alkoxyl group optionally group substituted with a chosen by mono also good C 1 ~ 6 alkyl group from R C group - is an optionally substituted amino group or a protected - or di Include groups also selected from the group consisting of a good hydroxyl group, the substituents of R C group, wherein are mentioned in [1], for example, C 1 ~ 6 alkyl, halogen atom, amino, hydroxyl, C 1-6 alkoxyl, mono / di C 1-6 alkylamino, optionally substituted with substituents oxo, and the like. The substituent of the "optionally substituted C 1 ~ 6 alkyl group", for example, a halogen atom, an amino, hydroxy, C 1 ~ 6 alkoxy, mono / di C 1 ~ 6 alkyl amino, oxo, tetrahydropyran - Examples include substituents such as 4-yl. R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group 1 carbon atoms within the oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy may be replaced by which may be substituted by straight-chain or branched-chain alkyl group which may C 1 ~ 6 have) been, the cyclic substituent groups which are further optionally selected from R C group may have, but if preferred, as the cycloalkyl ring C 3 ~ 8, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cyclohepta Ring, and a cyclooctane ring and the like. Examples of the 3- to 8-membered saturated or unsaturated non-aromatic heterocycle include, for example, aziridine ring, azetidine ring, oxirane ring, oxetane ring, thietane ring, pyrrolidine ring, tetrahydrofuran ring, thiolane ring, piperidine ring, tetrahydro ring Examples include a pyran ring, a piperazine ring, and an oxepane ring.
［１－４－ｄ－５ｂ］より好ましいＲ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄとしては、具体的には、水素原子、ハロゲン原子、ヒドロキシル基、メチル基、エチル基、ヒドロキシメチル基、ヒドロキシエチル基、メトキシメチル基、メトキシエチル基、トリフルオロメチル基；Ｎ，Ｎ－ジメチルアミノ基、Ｎ，Ｎ－ジエチルアミノ基、Ｎ，Ｎ－エチルメチルアミノ基、Ｎ，Ｎ－ビス（２－メトキシエチル）アミノ基、Ｎ－メチル－Ｎ－（２－メトキシエチル）アミノ基、Ｎ－メチル－Ｎ－シクロヘキシルアミノ基、Ｎ－メチル－Ｎ－（２－ジメチルアミノエチル）アミノ基、Ｎ－メチル－Ｎ－（２－ヒドロキシエチル）アミノ基、Ｎ－メチル－Ｎ－（２－メトキシエチル）アミノ基、Ｎ－メチル－Ｎ－（テトラヒドロピラン－４－イル）アミノ基等が挙げられる。また、より好ましくは、Ｒ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよい場合としては、シクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環、アジリジン環、アゼチジン環、オキシラン環、オキセタン環、チエタン環、ピロリジン環、テトラヒドロフラン環、チオラン環、ピペリジン環、テトラヒドロピラン環、ピペラジン環等が挙げられる。 [1-4-d-5b] More preferably, R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D are specifically a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, ethyl Group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, methoxyethyl group, trifluoromethyl 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- - (tetrahydropyran-4-yl) amino group and the like. More preferably, R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded. Examples include cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, aziridine ring, azetidine ring, oxirane ring, oxetane ring, thietane ring, pyrrolidine ring, tetrahydrofuran ring, thiolane ring, piperidine ring, tetrahydropyran ring, piperazine ring, etc. It is done.
［１－４－ｄ－５ｃ］更に好ましいＲ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄとしては、同一である場合には、水素原子、メチル基またはエチル基である。異なる場合には、いずれか一方が水素原子であり、他方が前記［１－４－ｄ－５ｂ］に挙げられる基（水素原子を除く）である。また、更に好ましいＲ１４Ａ及びＲ１４Ｂ、Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄが、それらが結合する炭素原子とともに３～８員の環状基を形成してもよい場合としては、シクロプロパン環、シクロブタン環、アジリジン環、アゼチジン環、オキシラン環、オキセタン環、チエタン環等が挙げられる。 [1-4-d-5c] More preferable R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D are the same when they are the same as a hydrogen atom, a methyl group, or an ethyl group. When they are different, either one is a hydrogen atom and the other is a group (excluding a hydrogen atom) listed in the above [1-4-d-5b]. Further, as a case where R 14A and R 14B , R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, Ring, cyclobutane ring, aziridine ring, azetidine ring, oxirane ring, oxetane ring, thietane ring and the like.
［１－４－ｄ－６］前記式（Ｅ）において、Ａは、－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、カルボニル基または酸素原子を表す。好ましくは、Ａは、－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基であり、より好ましくは－ＮＲ１３－である。 [1-4-d-6] In the above formula (E), A represents —NR 13 —, —CR 14A R 14B —, a carbonyl group or an oxygen atom. Preferably, A is —NR 13 —, —CR 14A R 14B — or a carbonyl group, more preferably —NR 13 —.
［１－４－ｄ－７］前記式（Ｅ）において、Ｇは、単結合、メチレン基、カルボニル基またはスルホニル基を表す。好ましくは、Ｇは、メチレン基、カルボニル基またはスルホニル基であり、より好ましくはメチレン基またはカルボニル基である。 [1-4-d-7] In the above formula (E), G represents a single bond, a methylene group, a carbonyl group or a sulfonyl group. Preferably, G is a methylene group, a carbonyl group or a sulfonyl group, more preferably a methylene group or a carbonyl group.
［１－４－ｄ－８］前記式（Ｅ）において、Ｌ１は、単結合、－ＣＲ１５ＡＲ１５Ｂ－、カルボニル基、酸素原子、－ＮＲ１６Ａ－または－Ｓ（Ｏ）ｔ－（ｔは０～２の整数）を表し、Ｌ２は、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、カルボニル基、酸素原子、－ＮＲ１６Ｂ－または－Ｓ（Ｏ）ｔ－（ｔは０～２の整数）を表す。好ましくは、Ｌ１は、－ＣＲ１５ＡＲ１５Ｂ－、酸素原子または－ＮＲ１６Ａ－であり、より好ましくは、Ｌ１は、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子である。Ｌ２は、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－が好ましい。より好ましくは、Ｌ２は、単結合、－（ＣＲ１５ＡＲ１５Ｂ）ｕ－（ｕは１または２の整数）または－ＮＲ１６Ｂ－である。Ｌ１は、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子であり、Ｌ２は、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－である組み合わせが好ましく、Ｌ１が、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子であり、Ｌ２は、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）または－ＮＲ１６Ｂ－である組み合わせがより好ましい。 [1-4-d-8] In the above formula (E), L 1 represents a single bond, —CR 15A R 15B —, a carbonyl group, an oxygen atom, —NR 16A — or —S (O) t— (t Represents an integer of 0 to 2, and L 2 represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), a carbonyl group, an oxygen atom, —NR 16B — or —S ( O) t- (t is an integer of 0 to 2). Preferably, L 1 is —CR 15A R 15B —, an oxygen atom or —NR 16A —, and more preferably, L 1 is —CR 15A R 15B — or an oxygen atom. L 2 is preferably a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom, or —NR 16B —. More preferably, L 2 is a single bond, — (CR 15A R 15B ) u— (u is an integer of 1 or 2) or —NR 16B —. L 1 is —CR 15A R 15B — or an oxygen atom, and L 2 is a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B —. A combination is preferred, L 1 is —CR 15A R 15B — or an oxygen atom, and L 2 is a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2) or —NR 16B A combination of-is more preferable.
［１－４－ｄ－９］前記式（Ｅ）において、Ａ、Ｇ、Ｌ１及びＬ２を構成に含む環における破線は適宜単結合もしくは二重結合をとり、当該環が芳香化していてもよいことを示す。 [1-4-d-9] In the above formula (E), the broken line in the ring containing A, G, L 1 and L 2 appropriately takes a single bond or a double bond, and the ring is aromatized. It is also good.
［１－４－ｄ－９ａ］前記式（Ｅ）において、Ａ、Ｇ、Ｌ１及びＬ２を構成に含む環は、芳香化していても、単結合及び／または二重結合で構成され芳香化していなくともよいが、芳香化していない場合であることが好ましい。 [1-4-d-9a] In the above formula (E), the ring containing A, G, L 1 and L 2 in the structure is composed of a single bond and / or a double bond and is aromatic. Although it does not need to be aromatized, it is preferable that it is not aromatized.
［１－４－ｄ－１０］前記式（Ｅ）において、Ａ、Ｇ、Ｌ１及びＬ２を構成に含む環において、好ましいＲＡ群の置換基として、Ｃ１～６アルキル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、Ｃ３～８シクロアルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、ハロゲン化Ｃ１～６アルコキシル、Ｃ１～６アルキルチオ、モノ／ジＣ１～６アルキルスルファモイル、モノ／ジＣ１～６アルキルアミノ、モノ／ジＣ１～６アルキルカルバモイル、モノ／ジＣ６～１４アリールカルバモイル、Ｃ２～７アルカノイル、Ｃ２～７アルカノイルアミノ、オキソ、ニトロ、シアノ、アミノ、保護されていてもよいヒドロキシル、保護されていてもよいカルボキシル、カルバモイル等の置換基が挙げられる。 In [1-4-d-10] Formula (E), A, G, in the ring containing the structure L 1 and L 2, preferred substituents for R A group, C 1 ~ 6 alkyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy -C 1 ~ 6 alkyl, C 3 ~ 8 cycloalkyl, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl, C 1 1-6 alkoxyl, halogenated C 1 - 6 alkoxyl, C 1 - 6 alkylthio, mono / di C 1 - 6 alkyl sulfamoyl, mono / di C 1 - 6 alkylamino, mono / di C 1 - 6 alkylcarbamoyl, mono / di C 6 ~ 14 aryl-carbamoyl, C 2 ~ 7 alkanoyl, C 2 ~ 7 alkanoylamino, oxo, nitro, cyano, amino, protected Also good hydroxyl, optionally protected carboxyl, include substituents carbamoyl and the like.
［１－４－ｄ－１１］前記式（Ｅ）において、Ｗ－（ＣＲ３Ｒ４）ｐ－あるいはＲ１２の置換位置は、下記式（Ｅ’）中のフェニル部分の炭素原子の位置で示すことができる。Ｗ－（ＣＲ３Ｒ４）ｐ－であれば、Ｌ１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番目または３番目の炭素原子に結合していることが好ましい。Ｗ－（ＣＲ３Ｒ４）ｐ－は、３番目の炭素原子に結合していることがより好ましい。 [1-4-d-11] In the above formula (E), the substitution position of W— (CR 3 R 4 ) p— or R 12 is the position of the carbon atom of the phenyl moiety in the following formula (E ′). Can show. In the case of W— (CR 3 R 4 ) p—, it is preferably bonded to the first or third carbon atom, counting clockwise from a position close to the carbon atom to which L 1 is bonded. More preferably, W— (CR 3 R 4 ) p— is bonded to the third carbon atom.
Figure JPOXMLDOC01-appb-C000043
  
Figure JPOXMLDOC01-appb-C000043
  
［１－４－ｄ－１２］前記式（Ｅ）において、好ましくは、下記式（Ｅ１）
Figure JPOXMLDOC01-appb-C000044
  
（式中、Ｒ１２、破線の定義は前記態様［１－４－ｂ］と同一の意味を表し；
Ａａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、またはカルボニル基を表し、
Ｇａはメチレン基、カルボニル基またはスルホニル基を表し、
Ｌ１ａは、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ１ａは酸素原子である）、
Ｌ２ａは、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ２ａは単結合または－（ＣＲ１５ＣＲ１５Ｄ）ｕ－である）；
Ｒ１３、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄ、Ｒ１６Ａ、Ｒ１６Ｂの定義は前記態様［１－４－ｂ］と同一の意味を表し、好ましい態様は前記態様［１－４－ｄ－３］及び［１－４－ｄ－５］と同一である）で表される基である。 [1-4-d-12] In the above formula (E), preferably, the following formula (E1)
Figure JPOXMLDOC01-appb-C000044
(Wherein R 12 and the definition of a broken line represent the same meaning as in the above embodiment [1-4-b];
A a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group,
G a represents a methylene group, a carbonyl group or a sulfonyl group,
L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom),
L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
The definitions of R 13 , R 14A , R 14B , R 15A , R 15B , R 15C , R 15D , R 16A , R 16B represent the same meaning as in the above embodiment [1-4-b], and a preferable embodiment is the above embodiment. The same as [1-4-d-3] and [1-4-d-5].
［１－４－ｄ－１２ａ］前記式（Ｅ１）において、より好ましくは、下記式（Ｅ１ａ）
Figure JPOXMLDOC01-appb-C000045
  
（式中、Ｒ１２、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａの定義は前記態様［１－４－ｂ］および［１－４－ｄ－１２］と同一の意味を表す）で表される基であり、ＡａとＧａ間の破線は当該元素間の結合が、適宜単結合もしくは二重結合をとり、Ａａ、Ｇａ、Ｌ１ａ及びＬ２ａを構成に含む環は芳香化していないことを示す。 [1-4-d-12a] In the formula (E1), more preferably, the following formula (E1a)
Figure JPOXMLDOC01-appb-C000045
(Wherein the definitions of R 12 , A a , G a , L 1a , and L 2a represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]). an that group, the dashed line between a a and G a is the bond between the elements, suitably take the single or double bond, ring containing a a, G a, the L 1a and L 2a in the configuration is aromatized Indicates not.
［１－４－ｄ－１２ｂ］前記式（Ｅ１）および（Ｅ１ａ）において、Ｗ－（ＣＲ３Ｒ４）ｐ－あるいはＲ１２の置換位置は、前記態様［１－４－ｄ－１１］と同様に、フェニル部分の炭素原子の位置で示すことができる。Ｗ－（ＣＲ３Ｒ４）ｐ－であれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。具体的には、下記式（Ｅ１‘－１）、（Ｅ１‘－２）（Ｅ１ａ‘－１）および（Ｅ１ａ’－２）が挙げられる。
Figure JPOXMLDOC01-appb-C000046
  
より好ましくは、式（Ｅ１ａ‘－１）および（Ｅ１ａ’－２）が挙げられ、更に好ましくは式（Ｅ１ａ‘－１）である。 [1-4-d-12b] In the above formulas (E1) and (E1a), the substitution position of W- (CR 3 R 4 ) p- or R 12 is the same as in the above-described embodiment [1-4-d-11]. Similarly, it can be indicated by the carbon atom position of the phenyl moiety. In the case of W- (CR 3 R 4 ) p-, it is preferably bonded to the first or third carbon atom counting clockwise from a position close to the carbon atom to which L 1a is bonded. Specific examples include the following formulas (E1′-1), (E1′-2) (E1a′-1) and (E1a′-2).
Figure JPOXMLDOC01-appb-C000046
More preferred are formulas (E1a′-1) and (E1a′-2), and even more preferred is formula (E1a′-1).
［１－４－ｄ－１２ｃ］上記式（Ｅ１‘－１）、（Ｅ１‘－２）（Ｅ１ａ‘－１）および（Ｅ１ａ’－２）において、特に好ましくは、Ａａは－ＮＲ１３－である。また、特に好ましくは、Ｇａがメチレン基またはカルボニル基であり、Ｌ２ａが単結合、－（ＣＲ１５ＡＲ１５Ｂ）ｕ－（ｕは１または２の整数）または－ＮＲ１６Ｂ－である。 [1-4-d-12c] In the above formulas (E1′-1), (E1′-2) (E1a′-1) and (E1a′-2), A a is preferably —NR 13 —. It is. Particularly preferably, G a is a methylene group or a carbonyl group, and L 2a is a single bond, — (CR 15A R 15B ) u— (u is an integer of 1 or 2) or —NR 16B —.
［１－４－ｅ］前記式（Ｉ）の化合物において、式（Ｉ）のＺ部分の具体例として、例えば、以下の（Ｃ１）～（ｃ２４０）で表される基が例示される。 [1-4-e] In the compound of the formula (I), specific examples of the Z moiety of the formula (I) include groups represented by the following (C1) to (c240).
Figure JPOXMLDOC01-appb-C000047
  
Figure JPOXMLDOC01-appb-C000047
  
Figure JPOXMLDOC01-appb-C000048
  
Figure JPOXMLDOC01-appb-C000048
  
Figure JPOXMLDOC01-appb-C000049
  
Figure JPOXMLDOC01-appb-C000049
  
［１－４－ｆ］前記式（Ｉ）の化合物において、式（Ｉ）のＺ部分の具体例として、前記式（Ｄ）または前記式（Ｅ）の各基が好ましく、その具体例としては、例えば、以下（ｃ１）～（ｃ６８）、（ｃ９３）～（ｃ２４０）に例示される基が挙げられる。 [1-4-f] In the compound of the formula (I), as specific examples of the Z moiety of the formula (I), each group of the formula (D) or the formula (E) is preferable, and specific examples thereof include Examples thereof include groups exemplified below in (c1) to (c68) and (c93) to (c240).
Figure JPOXMLDOC01-appb-C000050
  
Figure JPOXMLDOC01-appb-C000050
  
Figure JPOXMLDOC01-appb-C000051
  
Figure JPOXMLDOC01-appb-C000051
  
Figure JPOXMLDOC01-appb-C000052
  
Figure JPOXMLDOC01-appb-C000052
  
［１－４－ｆ－１］前記式（Ｉ）の化合物において、式（Ｉ）のＺ部分の具体例として、
より好ましくは、前記式（Ｄ）または前記式（Ｅ）の各基の具体例としては、例えば、以下に例示される基が挙げられる。 [1-4-f-1] In the compound of the formula (I), as a specific example of the Z moiety of the formula (I),
More preferably, specific examples of each group of the formula (D) or the formula (E) include the groups exemplified below.
Figure JPOXMLDOC01-appb-C000053
  
Figure JPOXMLDOC01-appb-C000053
  
Figure JPOXMLDOC01-appb-C000054
  
Figure JPOXMLDOC01-appb-C000054
  
Figure JPOXMLDOC01-appb-C000055
  
Figure JPOXMLDOC01-appb-C000055
  
Figure JPOXMLDOC01-appb-C000056
  
Figure JPOXMLDOC01-appb-C000056
  
［１－４－ｆ－２］　前記式（Ｉ）の化合物において、式（Ｉ）のＺ部分の具体例として、更に好ましくは、前記態様［１－４－ｆ－１］に例示される各基において、前記式（Ｅ）の各基の具体例として挙げられた（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１２５）～（ｃ１３２）、（ｃ１３４）～（ｃ１４０）、（ｃ１４４）～（ｃ１４７）、（ｃ１５１）～（ｃ１５３）、（ｃ１５６）～（ｃ１６５）、（ｃ１６７）～（ｃ１７７）、（ｃ１８４）～（ｃ１９５）、（ｃ２００）～（ｃ２０３）、（ｃ２０８）～（ｃ２４０）が挙げられる。 [1-4-f-2] In the compound of the formula (I), as a specific example of the Z moiety of the formula (I), more preferably, each of those exemplified in the embodiment [1-4-f-1] Group (c93) to (c117), (c121) to (c123), (c125) to (c132), (c134) to (c140), which are listed as specific examples of each group of the formula (E), (C144) to (c147), (c151) to (c153), (c156) to (c165), (c167) to (c177), (c184) to (c195), (c200) to (c203), (c208) ) To (c240).
［１－４－ｆ－３］　前記式（Ｉ）の化合物において、式（Ｉ）のＺ部分の具体例として、更に好ましくは、前記態様［１－４－ｆ－２］に例示される各基において、前記式（Ｅ）の各基の具体例として挙げられた（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１４４）～（ｃ１４７）、（ｃ１５１）～（ｃ１５３）、（ｃ１５６）～（ｃ１６５）、（ｃ１６７）～（ｃ１７７）、（ｃ１８９）～（ｃ１９４）、（ｃ２００）、（ｃ２０１）、（ｃ２０８）～（ｃ２４０）が挙げられる。
［１－４－ｆ－４］
前記式（Ｉ）の化合物において、式（Ｉ）のＺ部分の具体例として、特に好ましくは、前記態様［１－４－ｆ－３］に例示される各基において、前記式（Ｅ）の各基の具体例として挙げられた式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。特別に好ましくは、式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。 [1-4-f-3] In the compound of the formula (I), as specific examples of the Z moiety of the formula (I), more preferably, each of those exemplified in the embodiment [1-4-f-2] Group (c93) to (c117), (c121) to (c123), (c144) to (c147), (c151) to (c153), which are given as specific examples of each group of the formula (E), (C156) to (c165), (c167) to (c177), (c189) to (c194), (c200), (c201), (c208) to (c240).
[1-4-f-4]
In the compound of the formula (I), as a specific example of the Z moiety of the formula (I), particularly preferably, in each group exemplified in the embodiment [1-4-f-3], Formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), (c208) to (c240) listed as specific examples of each group Can be mentioned. Particularly preferred are the formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), (c208) to (c240).
［１－４－ｆ－５］態様［１－４－ｆ］に記載の（ｃ１）～（ｃ６８）、（ｃ９３）～（ｃ２４０）に例示される各基は、それ以上置換されていないか、または前記［１］のＲＡ群として定義された置換基１～３個で置換されていてもよい。 [1-4-f-5] Is each group exemplified in (c1) to (c68) and (c93) to (c240) described in the embodiment [1-4-f] further substituted? Alternatively, it may be substituted with 1 to 3 substituents defined as the group R A of [1].
［１－５］上記態様［１］の阻害剤に用いられる前記式（Ｉ）の化合物において、ｎは０～２の整数を表し、ｎは２であることが好ましい。 [1-5] In the compound of the formula (I) used as the inhibitor of the above embodiment [1], n represents an integer of 0 to 2, and n is preferably 2.
［１－６］上記態様［１］の阻害剤に用いられる前記式（Ｉ）に化合物において、ｍ、ｐは０～４の整数を表し、好ましくは、ｍは０または１であり、ｐは０～３である。より好ましくは、ｍは０であり、ｐは０または１である。 [1-6] In the compound represented by the formula (I) used for the inhibitor of the above embodiment [1], m and p each represents an integer of 0 to 4, preferably m is 0 or 1, and p is 0-3. More preferably, m is 0 and p is 0 or 1.
［１－７］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、Ｗは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－、－ＮＲ９ＣＯＮＲ１０－、または－ＮＲ１１－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１は、各々独立に水素原子またはＣ１～６アルキル基を表し、Ｒ７がＲ３またはＲ４と一緒になって、各々の結合している窒素原子、炭素原子と一緒に５～７員のシクロ環基を形成していてもよく、当該シクロ環基は、環内に二重結合を有していてもよく、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子、－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよい）を表す。 [1-7] In the compound of the above formula (I) used as the inhibitor of the above embodiment [1], W is —CONR 7 —, —NR 8 CO—, —NR 9 CONR 10 —, or —NR 11 - (R 7, R 8, R 9, R 10, R 11 each independently represent a hydrogen atom or a C 1 ~ 6 alkyl group, R 7 is taken together with R 3 or R 4, each of the bond May form a 5- to 7-membered cyclo ring group together with the nitrogen atom and carbon atom, and the cyclo group may have a double bond in the ring. one carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, a 1 to 5 substituents in any of -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy C 1 ~ 6 alkyl of good straight or branched chain optionally And may be substituted with a thio group).
［１－７－ａ］Ｗは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－であることが好ましく、－ＣＯＮＲ７－であることがより好ましい。
　ここで「Ｒ７がＲ３またはＲ４と一緒になって、各々の結合している窒素原子、炭素原子と一緒に５～７員のシクロ環基を形成していてもよく、当該シクロ環基は、環内に二重結合を有していてもよく、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子、－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく」とは、例えば、Ｗに定義される－ＣＯＮＲ７－の窒素原子とＲ７、および－（ＣＲ３Ｒ４）ｐ－において、ｐが３である場合に、以下のような下記式（Ｆ）の基を形成している場合を表す。 [1-7-a] W is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - is preferably, -CONR 7 - is more preferable.
Here, “R 7 may be taken together with R 3 or R 4 to form a 5- to 7-membered cyclo group together with each of the nitrogen and carbon atoms to which it is bonded. The group may have a double bond in the ring, and one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom, —OH · C 1- 6 replaced by may also) be substituted with an alkyl group of C 1 ~ 6 of which may straight or branched chain optionally substituted 1-5 with either an alkoxylated-halogenated C 1 ~ 6 alkoxy “May be” means, for example, that when p is 3 in the nitrogen atom of —CONR 7 — defined in W, R 7 , and — (CR 3 R 4 ) p—, the following The case where the group of Formula (F) is formed is represented.
Figure JPOXMLDOC01-appb-C000057
  
Figure JPOXMLDOC01-appb-C000057
  
［１－８］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、Ａ、Ｇ、Ｌ１及びＬ２を構成に含む環の員数は、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。 [1-8] In the compound of the above formula (I) used as the inhibitor of the above aspect [1], the number of rings containing A, G, L 1 and L 2 in the structure is 5 to 8. Preferably, it is 5-7, more preferably 5 or 6.
［１－９］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、以下のＡ群、Ｂ群、Ｃ群、Ｄ群に挙げられる各基を適宜組み合わせて得られる化合物は、適宜製造することが可能であり、本発明の式（Ｉ）で表される化合物の一部を構成する。 [1-9] A compound obtained by appropriately combining the following groups listed in Group A, Group B, Group C, and Group D in the compound of the above formula (I) used for the inhibitor of Embodiment [1] Can be produced as appropriate and constitutes a part of the compound represented by the formula (I) of the present invention.
Ａ群：前記態様［１－２－ｂ］に記載のＲｉｎｇとして例示された式（ａ１）～（ａ２１２）のいずれかの基、または前記態様［１－２－ｃ］に記載の式（ａａ１）～（ａａ６７）として例示されたいずれかの基。
Ｂ群：前記態様［１－３－ｃ］に記載のＹとして例示された式（ｂ１）～（ｂ４６）のいずれかの基。
Ｃ群：前記態様［１－４－ｅ］に記載のＺとして例示された式（ｃ１）～（ｃ２４０）のいずれかの基。
Ｄ群：Ｗとして定義された、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－、－ＮＲ９ＣＯＮＲ１０－または－ＮＲ１１－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１は、各々独立に水素原子またはＣ１～６アルキル基を表し、Ｒ７がＲ３またはＲ４と一緒になって、各々の結合している窒素原子、炭素原子と一緒に５～７員のシクロ環基を形成していてもよく、当該シクロ環基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子、－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよい）のいずれかの基。 Group A: any group of formulas (a1) to (a212) exemplified as Ring described in the embodiment [1-2-b], or the group represented by the formula (aa1) described in the embodiment [1-2-c] ) To any group exemplified as (aa67).
Group B: the group of any of formulas (b1) to (b46) exemplified as Y according to the embodiment [1-3-c].
Group C: A group of any one of formulas (c1) to (c240) exemplified as Z in the embodiment [1-4-e].
Group D: defined as W, -CONR 7 -, - NR 8 CO -, - NR 9 CONR 10 - or -NR 11 - (R 7, R 8, R 9, R 10, R 11 are each independently represents a hydrogen atom or a C 1 ~ 6 alkyl group, R 7 is taken together with R 3 or R 4, each of the nitrogen atom linked, a cyclic ring group having 5 to 7-membered together with the carbon atoms formed may have, the cyclic ring groups, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy, halogen may be replaced by reduction C 1 at 1-6 or with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group alkoxyl may be substituted)) Any of the groups.
［１－９－ａ］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、好ましくは、以下に示されるＡ群、Ｂ群、Ｃ群、Ｄ群の各基を適宜組み合わせて得られる化合物は、適宜製造することが可能であり、本発明の式（Ｉ）で表される化合物の一部を構成する。 [1-9-a] In the compound of the above formula (I) used as the inhibitor of the above embodiment [1], preferably each group of the following groups A, B, C and D is appropriately selected. The compound obtained in combination can be appropriately produced and constitutes a part of the compound represented by the formula (I) of the present invention.
Ａ群：前記態様［１－２－ｆ］に記載のＲｉｎｇとして例示された式（ａａ２１）～（ａａ３５）、（ａａ３７）～（ａａ３９）、（ａａ４１）～（ａａ５０）、（ａａ５２）、（ａａ５３）、（ａａ５５）、（ａａ５８）～（ａａ６０）、（ａａ６２）～（ａａ６６）のいずれかの基。
Ｂ群：前記態様［１－３－ｄ］に記載のＹとして例示された式（ｂ１３）、（ｂ１４）、（ｂ１７）、（ｂ２３）～（ｂ４０）のいずれかの基。
Ｃ群：前記態様［１－４－ｆ］に記載のＺとして例示された（ｃ１）～（ｃ６８）、（ｃ９３）～（ｃ２４０）のいずれかの基。
Ｄ群：Ｗとして定義された、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０は、各々独立に水素原子またはＣ１～６アルキル基を表し、Ｒ７がＲ３またはＲ４と一緒になって、各々の結合している窒素原子、炭素原子と一緒に５～７員のシクロ環基を形成していてもよく、当該シクロ環基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子、－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよい）のいずれかの基。 Group A: Formulas (aa21) to (aa35), (aa37) to (aa39), (aa41) to (aa50), (aa52), (a) exemplified as Rings described in the above embodiment [1-2-f] any group of aa53), (aa55), (aa58) to (aa60), (aa62) to (aa66);
Group B: The group of any one of formulas (b13), (b14), (b17), and (b23) to (b40) exemplified as Y in the embodiment [1-3-d].
Group C: The group of any one of (c1) to (c68) and (c93) to (c240) exemplified as Z in the embodiment [1-4-f].
Group D: defined as W, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or a C 1 ~ 6 Represents an alkyl group, and R 7 may be combined with R 3 or R 4 to form a 5- to 7-membered cyclo ring group together with the nitrogen atom and carbon atom to which each is bonded, cycloalkyl ring group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, one halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy or a group of the replaced may be) in may be substituted with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group) with or.
［１－９－ｂ］上記態様［１］の阻害剤に用いられる上記式（Ｉ）の化合物において、好ましくは、以下に示されるＡ群、Ｂ群、Ｃ群、Ｄ群の各基を適宜組み合わせて得られる化合物は、適宜製造することが可能であり、本発明の式（Ｉ）で表される化合物の一部を構成する。 [1-9-b] In the compound of the above formula (I) used for the inhibitor of the above embodiment [1], preferably each group of the following groups A, B, C and D is appropriately selected. The compound obtained in combination can be appropriately produced and constitutes a part of the compound represented by the formula (I) of the present invention.
Ａ群：前記態様［１－２－ｇ］に記載のＲｉｎｇとして例示された式（ａａ２１）～（ａａ２７）、（ａａ２９）のいずれかの基。
Ｂ群：前記態様［１－３－ｆ］に記載のＹとして例示された（ｂ２３）、（ｂ２５）～（ｂ２９）、（ｂ３１）～（ｂ３６）、（ｂ３９）～（ｂ４０）のいずれかの基。
Ｃ群：前記態様［１－４－ｆ－３］に記載のＺとして例示された（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１４４）～（ｃ１４７）、（ｃ１５１）～（ｃ１５３）、（ｃ１５６）～（ｃ１６５）、（ｃ１６７）～（ｃ１７７）、（ｃ１８９）～（ｃ１９４）、（ｃ２００）、（ｃ２０１）、（ｃ２０８）～（ｃ２４０）のいずれかの基。
Ｄ群：Ｗとして定義された、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０は、各々独立に水素原子またはＣ１～６アルキル基を表し、Ｒ７がＲ３またはＲ４と一緒になって、各々の結合している窒素原子、炭素原子と一緒に５～７員のシクロ環基を形成していてもよく、当該シクロ環基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子、－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよい）のいずれかの基。 Group A: A group of any of formulas (aa21) to (aa27) and (aa29) exemplified as Ring according to the embodiment [1-2-g].
Group B: any one of (b23), (b25) to (b29), (b31) to (b36), and (b39) to (b40) exemplified as Y in the embodiment [1-3-f] Base of.
Group C: (c93) to (c117), (c121) to (c123), (c144) to (c147), (c151) to (C93) to (c117) exemplified as Z in the embodiment [1-4-f-3] Any one of (c153), (c156) to (c165), (c167) to (c177), (c189) to (c194), (c200), (c201), (c208) to (c240)
Group D: defined as W, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or a C 1 ~ 6 Represents an alkyl group, and R 7 may be combined with R 3 or R 4 to form a 5- to 7-membered cyclo ring group together with the nitrogen atom and carbon atom to which each is bonded, cycloalkyl ring group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, one halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy or a group of the replaced may be) in may be substituted with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group) with or.
［１－１０］以上、本発明の態様［１－１］～［１－９］までの各々及びその好ましい態様を、更には置換基の定義を適宜組み合わせることにより、本発明の式（Ｉ）で表される化合物の好ましい態様を任意に形成しうる。 [1-10] Each of the embodiments [1-1] to [1-9] of the present invention and preferred embodiments thereof, and further by appropriately combining the definitions of substituents, the formula (I) of the present invention The preferable aspect of the compound represented by can be formed arbitrarily.
［１－１１］また、好ましい化合物として、以下のものが例示される。
Ｎ－（２－メトキシフェニル）－３－［（４－ヒドロキシ－１－ピペリジニル）スルホニル］ベンズアミド（実施例１）;
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－オキソ－１－ピペリジニル）スルホニル］ベンズアミド（実施例２）;
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－メチル－１－ピペリジニル）スルホニル］ベンズアミド（実施例３）;
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－ヒドロキシメチル－１－ピペリジニル）スルホニル］ベンズアミド（実施例４）;
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－アミノカルボニル－１－ピペリジニル）スルホニル］ベンズアミド（実施例５）;
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３－メチル－１－ピペリジニル）スルホニル］ベンズアミド（実施例６）;
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３－ヒドロキシ－１－ピペリジニル）スルホニル］ベンズアミド（実施例７）;
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３－アミノカルボニル－１－ピペリジニル）スルホニル］ベンズアミド（実施例８）；
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３－ヒドロキシメチル－１－ピペリジニル）スルホニル］ベンズアミド（実施例９）；
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３，５－ジメチル－１－ピペリジニル）スルホニル］ベンズアミド（実施例１０）；
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－トリフルオロメチル－１－ピロリジニル）スルホニル］ベンズアミド（実施例１１）；
Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（ヘキサヒドロ－１Ｈ－アゼピン－１－イル）スルホニル］ベンズアミド（実施例１２）；
Ｎ－（２－ヒドロキシフェニル）－２－クロロ－５－［（４－メチル－１－ピペリジニル）スルホニル］ベンズアミド（実施例１３）；
Ｎ－（２－メトキシフェニル）－３－（３－ペンチルアミノスルホニル）ベンズアミド（実施例１４）；
Ｎ－フェニル－５－（４－モルホリニルスルホニル）－２，４－ジメトキシベンズアミド（実施例１５）；
Ｎ－（２－エトキシフェニル）－５－（１－ピロリジニルスルホニル）－２－フルオロベンズアミド（実施例１６）；
Ｎ－（４－メトキシフェニル）－５－（４－モルホリニルスルホニル）－２－（４－モルホリニル）ベンズアミド（実施例１７）；
 
Ｎ－（２－メトキシフェニル）－２－ブロモ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例１８）；
Ｎ－（２－メトキシフェニル）－２－メトキシ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例１９）；
Ｎ－（２－メトキシフェニル）－２－（メチルアミノ）－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例２０）；
Ｎ－（２－メトキシフェニル）－２－［（フェニルメチル）アミノ］－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例２１）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－２－メチル－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例２２）；
Ｎ－（２－メトキシフェニル）－２－エテニル－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例２３）；　
Ｎ－（２－メトキシフェニル）－２－（３－ヒドロキシ－１－プロピン－１－イル）－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例２４）；
Ｎ－（２－メトキシフェニル）－３－ヨード－５－（１－ピペリジニルスルホニル）－ベンズアミド（実施例２５）；
Ｎ－（２－メトキシフェニル）－５－（ジメチルアミノ）－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例２６）；
Ｎ－（２－メトキシフェニル）－５－メチル－３－（１－ピペリジニルスルホニル）－ベンズアミド（実施例２７）；
Ｎ－（２－メトキシフェニル）－３－（１－ピペリジニルスルホニル）－５－フェニルベンズアミド（実施例２８）；
Ｎ－（２－メトキシフェニル）－５－（ヒドロキシメチル）－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例２９）；
Ｎ－（２－メトキシフェニル）－５－（１－ヒドロキシエチル）－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例３０）；
Ｎ－（２－メトキシフェニル）－５－エテニル－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例３１）；
Ｎ－（２－メトキシフェニル）－５－シアノ－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例３２）；
Ｎ－（２－メトキシフェニル）－５－（メトキシメチル）－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例３３）；
 
 
Ｎ－（２－メトキシフェニル）－５－［（アセチルアミノ）メチル］－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例３４）；
Ｎ－（２－メトキシフェニル）－５－［（ジメチルアミノ）メチル］－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例３５）；
Ｎ－（４－メトキシフェニル）－４－クロロ－３－（４－モルホリニルスルホニル）ベンズアミド（実施例３６）；
Ｎ－（２－ピリジニル）－４－ブロモ－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例３７）；
Ｎ－（４－エトキシフェニル）－４－フルオロ－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例３８）；
Ｎ－（４－メトキシフェニル）－４－メトキシ－３－（４－モルホニルスルホニル）ベンズアミド（実施例３９）；
Ｎ－［２－［［（４－クロロフェニル）アミノ］カルボニル］フェニル］－４－メチル－３－（４－モルホリニルスルホニル）ベンズアミド（実施例４０）；
Ｎ－（２，６－ジメチルフェニル）－２－フルオロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例４１）；
Ｎ－［２－ヒドロキシ－４－（トリフルオロメチル）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例４２）；
Ｎ－［２－（４－モルホリニル）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例４３）；
Ｎ－［２－（１－メチルエチル）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例４４）；
Ｎ－［（２－アミノカルボニル）フェニル］－３－（１－ピロリジニルスルホニル）ベンズアミド（実施例４５）；
Ｎ－［２’－メトキシ［１，１’－ビフェニル］－２－イル］－３－（１－ピロリジニルスルホニル）ベンズアミド（実施例４６）；
Ｎ－［（３－ピリジニル）フェニル－２－イル］－３－（１－ピロリジニルスルホニル）ベンズアミド（実施例４７）；
Ｎ－（４－ヒドロキシフェニル）－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例４８）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例４９）；
Ｎ－［４－（４－モルホリニル）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例５０）；
Ｎ－［４－（１－メチルエチル）フェニル］－３－（１－ピロリジニルスルホニル）ベンズアミド（実施例５１）；
Ｎ－（４－カルボキシフェニル）－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例５２）；
Ｎ－［３－［（１－メチルエチル）オキシ］フェニル］－３－（１－ピロリジニルスルホニル）ベンズアミド（実施例５３）；
Ｎ－［３－（トリフルオロメチル）フェニル］－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例５４）；
Ｎ－［３－［（シクロプロピルアミノ）カルボニル］フェニル］－３－（１－ピロリジニルスルホニル）ベンズアミド（実施例５５）；
Ｎ－［（１，３－ベンゾジオキソ－ル－５－イル）メチル］－３－（１－ピロリジニルスルホニル）ベンズアミド（実施例５６）；
２－クロロ－５－（１－ピペリジニルスルホニル）－Ｎ－（２－メトキシフェニル）ベンゼンメタンアミン（実施例５７）；
Ｎ－シクロヘキシル－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例５８）；
Ｎ－（１，２，３，４－テトラヒドロナフタレン－１－イル）－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例５９）；
［３，６－ジヒドロ－４－フェニル－１（２Ｈ）－ピリジニル］－［３－（１－ピペリジニルスルホニル）フェニル］メタノン（実施例６０）；
Ｎ－（ベンズイミダゾ－ル－２－イル）－３－（１－ピペリジニルスルホニル）ベンズアミド（実施例６１）；
Ｎ－［３－（１－ピペリジニルスルホニル）フェニル］－２－メトキシベンズアミド（実施例６２）；
Ｎ－（２－メトキシフェニル）－６－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－１Ｈ－インデン－４－カルボキシアミド（実施例６３）；
Ｎ－（２－メトキシフェニル）－３－（１－ピペリジニルスルホニル）－５，６，７，８－テトラヒドロ－１－ナフタレンカルボキシアミド（実施例６４）；
Ｎ－[４－（トリフルオロメトキシ）フェニル]－６－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－３－メチル－１Ｈ－インデン－４－カルボキシアミド（実施例６５）；
Ｎ－（２－メトキシフェニル）－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミド（実施例６６）；
 
Ｎ－（２－メトキシフェニル）－２－メチルスルホニル－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミド（実施例６７）；
Ｎ－（２－メトキシフェニル）－２－メチル－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミド（実施例６８）；
Ｎ－（２－メトキシフェニル）－２－アセチル－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミド（実施例６９）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）－３－ピリジンカルボキシアミド（実施例７０）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－５－（１－ピペリジニルスルホニル）－２－フランカルボキシアミド（実施例７１）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－３－メチル－５－（１－ピペリジニルスルホニル）－２－フランカルボキシアミド（実施例７２）；
Ｎ－（２－メトキシフェニル）－２－メチル－５－（１－ピペリジニルスルホニル）－３－フランカルボキシアミド（実施例７３）；
Ｎ－（２－メトキシフェニル）－１－メチル－５－（１－ピペリジニルスルホニル）－１Ｈ－ピロール－２－カルボキシアミド（実施例７４）；
Ｎ－（２－メトキシフェニル）－１－メチル－４－（１－ピペリジニルスルホニル）－１Ｈ－ピロール－２－カルボキシアミド（実施例７５）；
Ｎ－（２－メトキシフェニル）－４－（１－ピペリジニルスルホニル）－２－チオフェンカルボキシアミド（実施例７６）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－Ｎ’－［３－（１－ピペリジニルスルホニル）フェニル］ウレア（実施例７７）；
Ｎ－フェニル－Ｎ’－［［５－（１－ピペリジニルスルホニル）－２－チエニル］メチル］ウレア（実施例７８）；
Ｎ－（２－メトキシフェニル）－３－（シクロヘキシルスルホニル）ベンズアミド（実施例７９）；
Ｎ－（２－メトキシフェニル）－３－［（１－ピペリジンスルホニル）アミノ］ベンズアミド（実施例８０）；
Ｎ－（２－メトキシフェニル）－４－（１－ピロリジニルスルホニル）ベンズアミド（実施例８１）；
 
Ｎ－（１，４－ジヒドロ－２－オキソ－２Ｈ－３，１－ベンゾオキサジン－８－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例８２）；
Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－８－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例８３）；
Ｎ－（１－メチル－１，２，３，４－テトラヒドロ－２－オキソ－８－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例８４）；
Ｎ－（１－メチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例８５）；
Ｎ－（１－エチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例８６）；
Ｎ－（１－エチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－２－クロロ－５－（１－アゼチジニルスルホニル）ベンズアミド（実施例８７）；
Ｎ－（１，２，３，４－テトラヒドロ－３－ヒドロキシ－２－オキソ－５－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例８８）；
Ｎ－（１，３－ジヒドロ－２－オキソ－２Ｈ－インドール－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例８９）；
Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－５－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例９０）；
Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－８－イル）－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例９１）；
Ｎ－［１，３－ベンゾオキサゾール－２（３Ｈ）－オン－７－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例９２）；
Ｎ－（５－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例９３）；
Ｎ－（２－ヒドロキシ－１，２，３，４－テトラヒドロナフタレン－８－イル）－２－クロロ－５－（シクロブチルアミノスルホニル）ベンズアミド（実施例９４）；
Ｎ－（２，３－ジヒドロ－２－ヒドロキシ－１Ｈ－インデン－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ｂ）（実施例９５）；
Ｎ－（２，３－ジヒドロ－２－ヒドロキシ－１Ｈ－インデン－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ａ）（実施例９６）；
Ｎ－（５，６，７，８－テトラヒドロナフタレン－１－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例９７）；
Ｎ－［２－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，４－テトラヒドロイソキノリン－８－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例９８）；
Ｎ－［２－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，４－テトラヒドロイソキノリン－５－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例９９）；
Ｎ－（８－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１００）；
Ｎ－（１，４－ベンゾジオキサン－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１０１）；
Ｎ－（１Ｈ－インダゾール－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１０２）；
Ｎ－（２，２－ジメチル－２，３－ジヒドロベンゾフラン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１０３）；
Ｎ－（２，２－ジフルオロ－１，３－ベンゾジオキソール－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１０４）；
Ｎ－（１Ｈ－インドール－４－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル）］ベンズアミド（実施例１０５）；
Ｎ－（１－メチルインドール－４－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１０６）；
Ｎ－（１－エチルインドール－４－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド（実施例１０７）；
Ｎ－［１－（１－メチルエチル）－インドール－４－イル］－２－クロロ－５－［［（２－ヒドロキシ－１，１－ジメチルエチル）アミノ］スルホニル］－ベンズアミド（実施例１０８）；
Ｎ－［１－（２－ヒドロキシエチル）－インドール－４－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１０９）；
Ｎ－（１Ｈ－インドール－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１１０）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド（実施例１１１）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１１２）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１１３）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［（４－メチル－１－ピペラジニル）スルホニル］ベンズアミド（実施例１１４）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［（ジメチルアミノ）スルホニル］ベンズアミド（実施例１１５）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［（シクロヘキシルアミノ）スルホニル］ベンズアミド（実施例１１６）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［（シクロプロピルアミノ）スルホニル］ベンズアミド（実施例１１７）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（２，２－ジメチルプロピル）アミノ］スルホニル］ベンズアミド（実施例１１８）；
Ｎ－（２，３－ジヒドロ－３－メチル－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド（実施例１１９）；
Ｎ－（２，３－ジヒドロ－３－メチル－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１２０）；
Ｎ－（２，３－ジヒドロ－３－メチル－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－（１－アゼチジニルスルホニル）ベンズアミド（実施例１２１）；
Ｎ－（２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１２２）；
Ｎ－（１，４－ベンゾジオキサン－６－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド（実施例１２３）；
Ｎ－（２，３－ジヒドロ－２，２，３，３－テトラフルオロ－１，４－ベンゾジオキシン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１２４）；
Ｎ－（４－アセチル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１２５）；
Ｎ－（４－アセチル－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（１－アゼチジニルスルホニル）ベンズアミド（実施例１２６）；
Ｎ－（１，２，３，４－テトラヒドロ－１－アセチルキノリン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１２７）；
Ｎ－［１，２，３，４－テトラヒドロ－１－（２，２，２－トリフルオロアセチル）キノリン－７－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１２８）；
Ｎ－（１，４－ジヒドロ－２－オキソ－２Ｈ－３，１－ベンゾオキサジン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１２９）；
Ｎ－（１，２，３，４－テトラヒドロ－３－メチル－２－オキソ－７－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１３０）；
Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例１３１）；
Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド（実施例１３２）；
Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１３３）；
（Ｓ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ａ）（実施例１３４）；
（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ｂ）（実施例１３５）；
Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド（実施例１３６）；
Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［（シクロブチルアミノ）スルホニル］ベンズアミド（実施例１３７）；
Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１３８）；
Ｎ－［３，４－ジヒドロ－２－（２－ヒドロキシエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［メチル（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１３９）；
Ｎ－（３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１４０）；
Ｎ－（３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－（１－アゼチジニルスルホニル）－２－クロロベンズアミド（実施例１４１）；
Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド（実施例１４２）；
Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１４３）；
Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１４４）；
Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－（１－アゼチジニルスルホニル）－２－クロロベンズアミド（実施例１４５）；
Ｎ－（４－エチル－３，４－ジヒドロ－２メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（２－ヒドロキシ－１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１４６）；
Ｎ－［３，４－ジヒドロ－２－メチル－４－（１－メチルエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１４７）；
Ｎ－［２－メチル－３－［（１－メチルエチル）オキシ］－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１４８）；
Ｎ－［３，４－ジヒドロ－４－（２－ヒドロキシエチル）－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１４９）；
Ｎ－（３，４－ジヒドロ－２，２，４－トリメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１５０）；
Ｎ－（４－エチル－３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１５１）；
Ｎ－［３，４－ジヒドロ－２，２－ジメチル－４－（１－メチルエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１５２）；
Ｎ－［２，２－ジメチル－３－［（１－メチルエチル）オキシ］－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１５３）；
Ｎ－［３，４－ジヒドロ－４－（２－ヒドロキシエチル）－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１５４）；
Ｎ－［３，４－ジヒドロ－４－（２－ヒドロキシエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［（シクロブチルアミノ）スルホニル］ベンズアミド（実施例１５５）；
Ｎ－（３，４－ジヒドロ－４－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－（１－アゼチジニルスルホニル）－２－クロロベンズアミド（実施例１５６）；
Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－７－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１５７）；
Ｎ－（１，２，３，４－テトラヒドロ－１－メチル－２－オキソ－７－キノリノイル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１５８）；
Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－７－キノリノイル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１５９）；
Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１６０）；
Ｎ－（３，４－ジヒドロ－４－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１６１）；
Ｎ－（１，４－ジヒドロ－２－オキソ－２Ｈ－３，１－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１６２）；
Ｎ－（１，３－ジメチル－１，２，３，４－テトラヒドロ－２－オキソ－６－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１６３）；
Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－６－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１６４）；
Ｎ－（３，４－ジヒドロ－２，２－ジオキソ－１Ｈ－２，１－ベンゾチアジン－７－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド（実施例１６５）；
Ｎ－（２，３－ジヒドロ－３－ヒドロキシ－１Ｈ－インデン－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１６６）；
Ｎ－（５，６，７，８－テトラヒドロ－８－ヒドロキシ－２－ナフタレニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１６７）；
 
Ｎ－（５，６，７，８－テトラヒドロ－７－ヒドロキシ－２－ナフタレニル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド（実施例１６８）；
Ｎ－（５，６，７，８－テトラヒドロ－５－オキソ－２－ナフタレニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１６９）；
Ｎ－（５，６，７，８－テトラヒドロナフタレン－２－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１７０）；
Ｎ－［２－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，４－テトラヒドロイソキノリン－７－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１７１）；
Ｎ－（１，２，３，４－テトラヒドロイソキノリン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド・塩酸塩（実施例１７２）；
Ｎ－（６－キノリニル）－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド（実施例１７３）；
Ｎ－（６－キノキサリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１７４）；
Ｎ－（１Ｈ－インドール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１７５）；
Ｎ－（１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１７６）；
Ｎ－（１Ｈ－インダゾール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１７７）；
Ｎ－（１，３－ベンゾジオキソール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１７８）；
Ｎ－（ベンゾチアゾール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１７９）；
Ｎ－（１Ｈ－インダゾール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１８０）；
Ｎ－（２，３－ジヒドロ－２－オキソ－１Ｈ－ベンズイミダゾール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１８１）；
Ｎ－（２，２－ジフルオロ－１，３－ベンゾジオキソール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１８２）；
Ｎ－（２，３－ジヒドロ－２－オキソ－５－ベンゾオキサゾリル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド（実施例１８３）；
Ｎ－［２，３－ジヒドロ－２－オキソ－７－（トリフルオロメチル）－５－ベンゾオキサゾリル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１８４）；
Ｎ－（２－メチル－５－ベンゾオキサゾリル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例１８５）；
Ｎ－（ベンゾフラン－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１８６）；
Ｎ－（２，３－ジヒドロ－１－メチル－２－オキソ－１Ｈ－インドール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１８７）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－５－［［（１－メチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド（実施例１８８）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－フルオロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例１８９）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－［１－（１－ピペリジニルスルホニル）］－３－ピペリジンカルボキシアミド（実施例１９０）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－［１－（１－ピペリジニルスルホニル）］－３－ピペリジンカルボキシアミド（Ａ）（実施例１９１）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－［１－（１－ピペリジニルスルホニル）］－３－ピペリジンカルボキシアミド（Ｂ）（実施例１９２）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（シクロヘキシルスルホニル）－３－ピペリジンカルボキシアミド（実施例１９３）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－［（１－メチルエチル）スルホニル］－３－ピペリジンカルボキシアミド（実施例１９４）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（シクロペンチルスルホニル）－３－ピペリジンカルボキシアミド（実施例１９５）；
Ｎ－（２－メトキシフェニル）－１－［［メチル（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボキシアミド（実施例１９６）；
Ｎ－（２－メトキシフェニル）－１－（フェニルスルホニル）－３－ピペリジンカルボキシアミド（実施例１９７）；
Ｎ－［４－（４－モルホリニル）フェニル］－１－（１－ピペリジニルスルホニル）－３－ピペリジンカルボキサミド（実施例１９８）；
Ｎ－（４－フェノキシフェニル）－１－（１－ピペリジニルスルホニル）－３－ピペリジンカルボキシアミド（実施例１９９）；
Ｎ－（４－ヒドロキシフェニル）－１－（１－ピペリジニルスルホニル）－３－ピペリジンカルボキシアミド（実施例２００）；
Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－１－（１－ピロリジニルスルホニル）－３－ピペリジンカルボキシアミド（実施例２０１）；
Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－１－［（シクロペンチルアミノ）スルホニル］－３－ピペリジンカルボキシアミド（実施例２０２）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－（４－モルホリニルスルホニル）－３－ピペリジンカルボキシアミド（実施例２０３）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボキシアミド（実施例２０４）；
Ｎ－（２－メトキシフェニル）－１，２，５，６－テトラヒドロ－４－メチル－[１－（１－ピペリジニルスルホニル）]－３－ピリジンカルボキシアミド（実施例２０５）；
Ｎ－（２－メトキシフェニル）－１，２，３，６－テトラヒドロ－４－メチル－１－（１－ピペリジニルスルホニル）－３－ピリジンカルボキシアミド（実施例２０６）；
ｃｉｓ－Ｎ－［４－（トリフルオロメトキシ）フェニル］－４－メチル－１－（１－ピペリジニルスルホニル）]－３－ピペリジンカルボキシアミド（実施例２０７）；
ｔｒａｎｓ－Ｎ－［４－（トリフルオロメトキシ）フェニル］－４－メチル－１－[１－（１－ピペリジニルスルホニル）]－３－ピペリジンカルボキシアミド（実施例２０８）；
Ｎ－（２－メトキシフェニル）－１－（１－ピペリジニルスルホニル）－１，２，５，６－テトラヒドロ－３－ピリジンカルボキシアミド（実施例２０９）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－４，４－ジメチル－１－（１－ピペリジニルスルホニル）]－３－ピペリジンカルボキシアミド（実施例２１０）；
Ｎ－（２－メトキシフェニル）－８－（１－ピペリジニルスルホニル）－１，４－ジオキサ－８－アザスピロ[４，５]デカン－６－カルボキシアミド（実施例２１１）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－ピペリジニルスルホニル）－３－ピロリジンカルボキシアミド（実施例２１２）；
Ｎ－（２－メトキシフェニル）－１－（１－ピペリジニルスルホニル）－ヘキサヒドロ－１Ｈ－アゼピン－３－カルボキシアミド（実施例２１３）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－４，４－ジメチル－１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボキシアミド（実施例２１４）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－（シクロペンチルスルホニル）－４，４－ジメチル－３－ピペリジンカルボキシアミド（実施例２１５）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－４－（１－ピペリジニルスルホニル）－２－モルホリンカルボキシアミド（実施例２１６）；
Ｎ－（２－メトキシフェニル）－１－ベンジル－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド（実施例２１７）；
Ｎ－（２－メトキシフェニル）－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド（実施例２１８）；
Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－メチル－４－（４－モルホリニルスルホニル）－２－ピペラジンカルボキシアミド（実施例２１９）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－メチルエチル）－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド（実施例２２０）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－アセチル－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド（実施例２２１）；
Ｎ－[１－（１－ピペリジニルスルホニル）－ピペリジン－３－イル]－Ｎ’－［４－（トリフルオロメトキシ）フェニル］ウレア（実施例２２２）；
Ｎ－［１－（１－ピペリジニルスルホニル）－ピペリジン－３－イル]－４－（トリフルオロメトキシ）ベンズアミド（実施例２２３）；
Ｎ－（２－メトキシフェニル）－３－［［（１－メチルエチル）スルホニル］アミノ］－ピペリジン－１－カルボキシアミド（実施例２２４）；
Ｎ－（２－メトキシフェニル）－３－［（１－ピペリジニルスルホニル）アミノ］－１－ピペリジンカルボキシアミド（実施例２２５）；
Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－ピペリジニルスルホニル）－２－ピペリジンカルボキシアミド（実施例２２６）；
Ｎ－（２－メトキシフェニル）－２－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－１Ｈ－イソインドリン－４－カルボキシアミド（実施例２２７）；
 
Ｎ－（２－メトキシフェニル）－２－（１－ピペリジニルスルホニル）－１Ｈ－インドール－４－カルボキシアミド（実施例２２８）；
Ｎ－（２－メトキシフェニル）－１－メチル－２－（１－ピペリジニルスルホニル）－１Ｈ－インドール－４－カルボキシアミド（実施例２２９）；
Ｎ－（２－メチル－５－ベンゾオキサゾリル）－２－クロロ－５－［［メチル（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３０）；
Ｎ－［２－（１，１－ジメチルエチル）－５－ベンゾオキサゾリル）］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３１）；
Ｎ－［２－（トリフルオロメチル）－５－ベンゾオキサゾリル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３２）；
Ｎ－［２－（１－ヒドロキシ－１－メチルエチル）－２－クロロ－５－ベンゾオキサゾリル）］－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３３）；
Ｎ－（３，４－ジヒドロ－２，２－ジメチル－４－メチル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３４）；
Ｎ－［４－アミノカルボニル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３５）；
Ｎ－（３，４－ジヒドロ－２，２－ジメチル－４－メチルスルホニル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３６）；
Ｎ－（３，４－ジヒドロ－２，２－ジメチル－４－プロピオニル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３７）；
Ｎ－［４－（２－ヒドロキシアセチル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３８）；
Ｎ－［４－（２－アミノアセチル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２３９）；
Ｎ－[４－（２－ピリジニル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル]－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４０）；
Ｎ－［２，２－ジメチルクロマン－４－オン－６－イル　）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４１）；
Ｎ－（３，４－ジヒドロ－４－ヒドロキシ－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４２）；
Ｎ－（２，２－ジメチルクロメン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４３）；
Ｎ－（４－アミノ－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４４）；
Ｎ－（３，４－ジヒドロ－４－ジメチルアミノ－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４５）；
Ｎ－［３，４－ジヒドロ－４－（４－モルフォリニル）－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４６）；
Ｎ－［３，４－ジヒドロ－３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４７）；
Ｎ－［４－メチル－３，４－ジヒドロ－３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２４８）；
Ｎ－（２，３，４，５－テトラヒドロ－４－オキソ－１，５－ベンゾオキサゼピン－７－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル]ベンズアミド（実施例２４９）；
Ｎ－（２，３，４，５－テトラヒドロ－３，３－ジメチル－４－オキソ－１，５－ベンゾオキサゼピン－７－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２５０）；
Ｎ－（１―メチル―３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２５１）；
Ｎ－（３，４－ジヒドロ－４－エチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－８－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２５２）；
Ｎ－［１－（１－メチルエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２５３）；
Ｎ－［１－（２－ヒドロキシエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２５４）；
Ｎ－［１－（２－フルオロエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２５５）；
Ｎ－［１－エチル－３－メチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２５６）；
Ｎ－（１－エチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド（実施例２５７）；
（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド（実施例２５８）；
Ｎ－（３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド（実施例２５９）；
Ｎ－（４－アセチル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド（実施例２６０）；
Ｎ－［３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６（４Ｈ）－イル］－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド（実施例２６１）；
Ｎ－［３，４－ジヒドロ－４－メチル－３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６－イル］－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド（実施例２６２）；　
（Ｓ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２６３）；
（Ｒ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２６４）；
（Ｓ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド（実施例２６５）；
（Ｒ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド（実施例２６６）；
（Ｓ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２６７）；
（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド（実施例２６８）；
（Ｓ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド（実施例２６９）；
（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド（実施例２７０）
或いはこれらの製薬学的に許容される塩、またはそれらの溶媒和物、またはそれらの光学活性体が挙げられる。 [1-11] Examples of preferable compounds include the following.
N- (2-methoxyphenyl) -3-[(4-hydroxy-1-piperidinyl) sulfonyl] benzamide (Example 1);
N- (2-methoxyphenyl) -2-chloro-5-[(2-oxo-1-piperidinyl) sulfonyl] benzamide (Example 2);
N- (2-methoxyphenyl) -2-chloro-5-[(2-methyl-1-piperidinyl) sulfonyl] benzamide (Example 3);
N- (2-methoxyphenyl) -2-chloro-5-[(2-hydroxymethyl-1-piperidinyl) sulfonyl] benzamide (Example 4);
N- (2-methoxyphenyl) -2-chloro-5-[(2-aminocarbonyl-1-piperidinyl) sulfonyl] benzamide (Example 5);
N- (2-methoxyphenyl) -2-chloro-5-[(3-methyl-1-piperidinyl) sulfonyl] benzamide (Example 6);
N- (2-methoxyphenyl) -2-chloro-5-[(3-hydroxy-1-piperidinyl) sulfonyl] benzamide (Example 7);
N- (2-methoxyphenyl) -2-chloro-5-[(3-aminocarbonyl-1-piperidinyl) sulfonyl] benzamide (Example 8);
N- (2-methoxyphenyl) -2-chloro-5-[(3-hydroxymethyl-1-piperidinyl) sulfonyl] benzamide (Example 9);
N- (2-methoxyphenyl) -2-chloro-5-[(3,5-dimethyl-1-piperidinyl) sulfonyl] benzamide (Example 10);
N- (2-methoxyphenyl) -2-chloro-5-[(2-trifluoromethyl-1-pyrrolidinyl) sulfonyl] benzamide (Example 11);
N- (2-methoxyphenyl) -2-chloro-5-[(hexahydro-1H-azepin-1-yl) sulfonyl] benzamide (Example 12);
N- (2-hydroxyphenyl) -2-chloro-5-[(4-methyl-1-piperidinyl) sulfonyl] benzamide (Example 13);
N- (2-methoxyphenyl) -3- (3-pentylaminosulfonyl) benzamide (Example 14);
N-phenyl-5- (4-morpholinylsulfonyl) -2,4-dimethoxybenzamide (Example 15);
N- (2-ethoxyphenyl) -5- (1-pyrrolidinylsulfonyl) -2-fluorobenzamide (Example 16);
N- (4-methoxyphenyl) -5- (4-morpholinylsulfonyl) -2- (4-morpholinyl) benzamide (Example 17);
 
N- (2-methoxyphenyl) -2-bromo-5- (1-piperidinylsulfonyl) benzamide (Example 18);
N- (2-methoxyphenyl) -2-methoxy-5- (1-piperidinylsulfonyl) benzamide (Example 19);
N- (2-methoxyphenyl) -2- (methylamino) -5- (1-piperidinylsulfonyl) benzamide (Example 20);
N- (2-methoxyphenyl) -2-[(phenylmethyl) amino] -5- (1-piperidinylsulfonyl) benzamide (Example 21);
N- [4- (trifluoromethoxy) phenyl] -2-methyl-5- (1-piperidinylsulfonyl) benzamide (Example 22);
N- (2-methoxyphenyl) -2-ethenyl-5- (1-piperidinylsulfonyl) benzamide (Example 23);
N- (2-methoxyphenyl) -2- (3-hydroxy-1-propyn-1-yl) -5- (1-piperidinylsulfonyl) benzamide (Example 24);
N- (2-methoxyphenyl) -3-iodo-5- (1-piperidinylsulfonyl) -benzamide (Example 25);
N- (2-methoxyphenyl) -5- (dimethylamino) -3- (1-piperidinylsulfonyl) benzamide (Example 26);
N- (2-methoxyphenyl) -5-methyl-3- (1-piperidinylsulfonyl) -benzamide (Example 27);
N- (2-methoxyphenyl) -3- (1-piperidinylsulfonyl) -5-phenylbenzamide (Example 28);
N- (2-methoxyphenyl) -5- (hydroxymethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 29);
N- (2-methoxyphenyl) -5- (1-hydroxyethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 30);
N- (2-methoxyphenyl) -5-ethenyl-3- (1-piperidinylsulfonyl) benzamide (Example 31);
N- (2-methoxyphenyl) -5-cyano-3- (1-piperidinylsulfonyl) benzamide (Example 32);
N- (2-methoxyphenyl) -5- (methoxymethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 33);
 
 
N- (2-methoxyphenyl) -5-[(acetylamino) methyl] -3- (1-piperidinylsulfonyl) benzamide (Example 34);
N- (2-methoxyphenyl) -5-[(dimethylamino) methyl] -3- (1-piperidinylsulfonyl) benzamide (Example 35);
N- (4-methoxyphenyl) -4-chloro-3- (4-morpholinylsulfonyl) benzamide (Example 36);
N- (2-pyridinyl) -4-bromo-3- (1-piperidinylsulfonyl) benzamide (Example 37);
N- (4-ethoxyphenyl) -4-fluoro-3- (1-piperidinylsulfonyl) benzamide (Example 38);
N- (4-methoxyphenyl) -4-methoxy-3- (4-morpholinylsulfonyl) benzamide (Example 39);
N- [2-[[(4-Chlorophenyl) amino] carbonyl] phenyl] -4-methyl-3- (4-morpholinylsulfonyl) benzamide (Example 40);
N- (2,6-dimethylphenyl) -2-fluoro-5- (1-piperidinylsulfonyl) benzamide (Example 41);
N- [2-hydroxy-4- (trifluoromethyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 42);
N- [2- (4-morpholinyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 43);
N- [2- (1-methylethyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 44);
N-[(2-aminocarbonyl) phenyl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 45);
N- [2′-methoxy [1,1′-biphenyl] -2-yl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 46);
N-[(3-pyridinyl) phenyl-2-yl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 47);
N- (4-hydroxyphenyl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 48);
N- [4- (trifluoromethoxy) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 49);
N- [4- (4-morpholinyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 50);
N- [4- (1-methylethyl) phenyl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 51);
N- (4-carboxyphenyl) -3- (1-piperidinylsulfonyl) benzamide (Example 52);
N- [3-[(1-methylethyl) oxy] phenyl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 53);
N- [3- (trifluoromethyl) phenyl] -3- (1-piperidinylsulfonyl) benzamide (Example 54);
N- [3-[(Cyclopropylamino) carbonyl] phenyl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 55);
N-[(1,3-Benzodioxo-5-yl) methyl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 56);
2-chloro-5- (1-piperidinylsulfonyl) -N- (2-methoxyphenyl) benzenemethanamine (Example 57);
N-cyclohexyl-2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 58);
N- (1,2,3,4-tetrahydronaphthalen-1-yl) -3- (1-piperidinylsulfonyl) benzamide (Example 59);
[3,6-dihydro-4-phenyl-1 (2H) -pyridinyl]-[3- (1-piperidinylsulfonyl) phenyl] methanone (Example 60);
N- (benzimidazol-2-yl) -3- (1-piperidinylsulfonyl) benzamide (Example 61);
N- [3- (1-piperidinylsulfonyl) phenyl] -2-methoxybenzamide (Example 62);
N- (2-methoxyphenyl) -6- (1-piperidinylsulfonyl) -2,3-dihydro-1H-indene-4-carboxamide (Example 63);
N- (2-methoxyphenyl) -3- (1-piperidinylsulfonyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxamide (Example 64);
N- [4- (trifluoromethoxy) phenyl] -6- (1-piperidinylsulfonyl) -2,3-dihydro-3-methyl-1H-indene-4-carboxamide (Example 65);
N- (2-methoxyphenyl) -7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 66);
 
N- (2-methoxyphenyl) -2-methylsulfonyl-7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 67);
N- (2-methoxyphenyl) -2-methyl-7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 68);
N- (2-methoxyphenyl) -2-acetyl-7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 69);
N- [4- (trifluoromethoxy) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) -3-pyridinecarboxamide (Example 70);
N- [4- (trifluoromethoxy) phenyl] -5- (1-piperidinylsulfonyl) -2-furancarboxamide (Example 71);
N- [4- (trifluoromethoxy) phenyl] -3-methyl-5- (1-piperidinylsulfonyl) -2-furancarboxamide (Example 72);
N- (2-methoxyphenyl) -2-methyl-5- (1-piperidinylsulfonyl) -3-furancarboxamide (Example 73);
N- (2-methoxyphenyl) -1-methyl-5- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxamide (Example 74);
N- (2-methoxyphenyl) -1-methyl-4- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxamide (Example 75);
N- (2-methoxyphenyl) -4- (1-piperidinylsulfonyl) -2-thiophenecarboxamide (Example 76);
N- [4- (trifluoromethoxy) phenyl] -N ′-[3- (1-piperidinylsulfonyl) phenyl] urea (Example 77);
N-phenyl-N ′-[[5- (1-piperidinylsulfonyl) -2-thienyl] methyl] urea (Example 78);
N- (2-methoxyphenyl) -3- (cyclohexylsulfonyl) benzamide (Example 79);
N- (2-methoxyphenyl) -3-[(1-piperidinesulfonyl) amino] benzamide (Example 80);
N- (2-methoxyphenyl) -4- (1-pyrrolidinylsulfonyl) benzamide (Example 81);
 
N- (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-8-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 82) );
N- (1,2,3,4-tetrahydro-2-oxo-8-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 83);
N- (1-methyl-1,2,3,4-tetrahydro-2-oxo-8-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 84) ;
N- (1-Methyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 85) ;
N- (1-Ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Examples) 86);
N- (1-ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide (Example 87);
N- (1,2,3,4-Tetrahydro-3-hydroxy-2-oxo-5-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 88) ;
N- (1,3-dihydro-2-oxo-2H-indol-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 89);
N- (1,2,3,4-tetrahydro-2-oxo-5-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 90);
N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-8-yl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 91);
N- [1,3-benzoxazol-2 (3H) -one-7-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 92);
N- (5-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 93);
N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) -2-chloro-5- (cyclobutylaminosulfonyl) benzamide (Example 94);
N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (B) (Example 95);
N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (A) (Example 96);
N- (5,6,7,8-tetrahydronaphthalen-1-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 97);
N- [2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-8-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 98);
N- [2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-5-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 99);
N- (8-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 100);
N- (1,4-benzodioxan-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 101);
N- (1H-indazol-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 102);
N- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 103);
N- (2,2-difluoro-1,3-benzodioxol-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 104);
N- (1H-indol-4-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl)] benzamide (Example 105);
N- (1-methylindol-4-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 106);
N- (1-ethylindol-4-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 107);
N- [1- (1-Methylethyl) -indol-4-yl] -2-chloro-5-[[(2-hydroxy-1,1-dimethylethyl) amino] sulfonyl] -benzamide (Example 108) ;
N- [1- (2-hydroxyethyl) -indol-4-yl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 109);
N- (1H-Indol-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 110);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 111);
N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 112);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide ( Example 113);
N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[(4-methyl-1-piperazinyl) sulfonyl] benzamide (Examples) 114);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[(dimethylamino) sulfonyl] benzamide (Example 115);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[(cyclohexylamino) sulfonyl] benzamide (Example 116);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[(cyclopropylamino) sulfonyl] benzamide (Example 117);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(2,2-dimethylpropyl) amino] sulfonyl] benzamide ( Example 118);
N- (2,3-dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 119);
N- (2,3-dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Examples) 120);
N- (2,3-dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide (Example 121);
N- (2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 122);
N- (1,4-benzodioxan-6-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example 123);
N- (2,3-dihydro-2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] Benzamide (Example 124);
N- (4-acetyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino ] Sulfonyl] benzamide (Example 125);
N- (4-acetyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide (Example 126);
N- (1,2,3,4-tetrahydro-1-acetylquinolin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 127);
N- [1,2,3,4-Tetrahydro-1- (2,2,2-trifluoroacetyl) quinolin-7-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl Benzamide (Example 128);
N- (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 129 );
N- (1,2,3,4-Tetrahydro-3-methyl-2-oxo-7-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 130) ;
N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 131);
N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 132) );
N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 133);
(S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino ] Sulfonyl] benzamide (A) (Example 134);
(R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino ] Sulfonyl] benzamide (B) (Example 135);
N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example 136) ;
N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclobutylamino) sulfonyl] benzamide (Example 137) );
N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl Benzamide (Example 138);
N- [3,4-Dihydro-2- (2-hydroxyethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[methyl (1-methylethyl ) Amino] sulfonyl] benzamide (Example 139);
N- (3,4-Dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino ] Sulfonyl] benzamide (Example 140);
N- (3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5- (1-azetidinylsulfonyl) -2-chlorobenzamide Example 141);
N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide Example 142);
N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl Benzamide (Example 143);
N- (3,4-Dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino ] Sulfonyl] benzamide (Example 144);
N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5- (1-azetidinylsulfonyl) -2-chlorobenzamide Example 145);
N- (4-Ethyl-3,4-dihydro-2methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(2-hydroxy-1,1 -Dimethylethyl) amino] sulfonyl] benzamide (Example 146);
N- [3,4-Dihydro-2-methyl-4- (1-methylethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide (Example 147);
N- [2-Methyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl Benzamide (Example 148);
N- [3,4-dihydro-4- (2-hydroxyethyl) -2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1 , 1-Dimethylethyl) amino] sulfonyl] benzamide (Example 149);
N- (3,4-dihydro-2,2,4-trimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl ) Amino] sulfonyl] benzamide (Example 150);
N- (4-Ethyl-3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1- Dimethylethyl) amino] sulfonyl] benzamide (Example 151);
N- [3,4-dihydro-2,2-dimethyl-4- (1-methylethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[ (1-Methylethyl) amino] sulfonyl] benzamide (Example 152);
N- [2,2-Dimethyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1-methylethyl) amino ] Sulfonyl] benzamide (Example 153);
N- [3,4-dihydro-4- (2-hydroxyethyl) -2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[ (1-Methylethyl) amino] sulfonyl] benzamide (Example 154);
N- [3,4-dihydro-4- (2-hydroxyethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[(cyclobutylamino) sulfonyl] Benzamide (Example 155);
N- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5- (1-azetidinylsulfonyl) -2-chlorobenzamide (Example 156) );
N- (1,2,3,4-tetrahydro-2-oxo-7-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 157);
N- (1,2,3,4-Tetrahydro-1-methyl-2-oxo-7-quinolinoyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 158) ;
N- (1,2,3,4-tetrahydro-2-oxo-7-quinolinoyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 159);
N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 160) );
N- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 161);
N- (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 162) );
N- (1,3-dimethyl-1,2,3,4-tetrahydro-2-oxo-6-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 163);
N- (1,2,3,4-tetrahydro-2-oxo-6-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 164);
N- (3,4-dihydro-2,2-dioxo-1H-2,1-benzothiazin-7-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example 165);
N- (2,3-dihydro-3-hydroxy-1H-inden-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 166);
N- (5,6,7,8-tetrahydro-8-hydroxy-2-naphthalenyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 167);
 
N- (5,6,7,8-tetrahydro-7-hydroxy-2-naphthalenyl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example 168);
N- (5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 169);
N- (5,6,7,8-tetrahydronaphthalen-2-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 170);
N- [2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 171);
N- (1,2,3,4-tetrahydroisoquinolin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide hydrochloride (Example 172);
N- (6-quinolinyl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 173);
N- (6-quinoxalinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 174);
N- (1H-Indol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 175);
N- (1H-indol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 176);
N- (1H-indazol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 177);
N- (1,3-benzodioxol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 178);
N- (benzothiazol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 179);
N- (1H-indazol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 180);
N- (2,3-dihydro-2-oxo-1H-benzimidazol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 181);
N- (2,2-difluoro-1,3-benzodioxol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 182);
N- (2,3-dihydro-2-oxo-5-benzoxazolyl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example 183);
N- [2,3-dihydro-2-oxo-7- (trifluoromethyl) -5-benzoxazolyl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide Example 184);
N- (2-methyl-5-benzoxazolyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 185);
N- (benzofuran-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 186);
N- (2,3-dihydro-1-methyl-2-oxo-1H-indol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 187) ;
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -5-[[(1-methylethyl) amino] sulfonyl] -2- (trifluoromethyl) Benzamide (Example 188);
N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-fluoro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 189);
N- [4- (trifluoromethoxy) phenyl]-[1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (Example 190);
N- [4- (trifluoromethoxy) phenyl]-[1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (A) (Example 191);
N- [4- (trifluoromethoxy) phenyl]-[1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (B) (Example 192);
N- [4- (trifluoromethoxy) phenyl] -1- (cyclohexylsulfonyl) -3-piperidinecarboxamide (Example 193);
N- [4- (trifluoromethoxy) phenyl] -1-[(1-methylethyl) sulfonyl] -3-piperidinecarboxamide (Example 194);
N- [4- (trifluoromethoxy) phenyl] -1- (cyclopentylsulfonyl) -3-piperidinecarboxamide (Example 195);
N- (2-methoxyphenyl) -1-[[methyl (1-methylethyl) amino] sulfonyl] -3-piperidinecarboxamide (Example 196);
N- (2-methoxyphenyl) -1- (phenylsulfonyl) -3-piperidinecarboxamide (Example 197);
N- [4- (4-morpholinyl) phenyl] -1- (1-piperidinylsulfonyl) -3-piperidinecarboxamide (Example 198);
N- (4-phenoxyphenyl) -1- (1-piperidinylsulfonyl) -3-piperidinecarboxamide (Example 199);
N- (4-hydroxyphenyl) -1- (1-piperidinylsulfonyl) -3-piperidinecarboxamide (Example 200);
N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) -1- (1-pyrrolidinylsulfonyl) -3-piperidinecarboxamide (Example 201);
N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) -1-[(cyclopentylamino) sulfonyl] -3-piperidinecarboxamide (Example 202);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1- (4-morpholinylsulfonyl) -3-piperidinecarboxamide (Example 203);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1-[[(1-methylethyl) amino] sulfonyl] -3-piperidinecarboxamide Example 204);
N- (2-methoxyphenyl) -1,2,5,6-tetrahydro-4-methyl- [1- (1-piperidinylsulfonyl)]-3-pyridinecarboxamide (Example 205);
N- (2-methoxyphenyl) -1,2,3,6-tetrahydro-4-methyl-1- (1-piperidinylsulfonyl) -3-pyridinecarboxamide (Example 206);
cis-N- [4- (trifluoromethoxy) phenyl] -4-methyl-1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (Example 207);
trans-N- [4- (trifluoromethoxy) phenyl] -4-methyl-1- [1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (Example 208);
N- (2-methoxyphenyl) -1- (1-piperidinylsulfonyl) -1,2,5,6-tetrahydro-3-pyridinecarboxamide (Example 209);
N- [4- (trifluoromethoxy) phenyl] -4,4-dimethyl-1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (Example 210);
N- (2-methoxyphenyl) -8- (1-piperidinylsulfonyl) -1,4-dioxa-8-azaspiro [4,5] decan-6-carboxamide (Example 211);
N- [4- (trifluoromethoxy) phenyl] -1- (1-piperidinylsulfonyl) -3-pyrrolidinecarboxamide (Example 212);
N- (2-methoxyphenyl) -1- (1-piperidinylsulfonyl) -hexahydro-1H-azepine-3-carboxamide (Example 213);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -4,4-dimethyl-1-[[(1-methylethyl) amino] sulfonyl] -3 -Piperidinecarboxamide (Example 214);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1- (cyclopentylsulfonyl) -4,4-dimethyl-3-piperidinecarboxamide (Example 215) );
N- [4- (trifluoromethoxy) phenyl] -4- (1-piperidinylsulfonyl) -2-morpholinecarboxamide (Example 216);
N- (2-methoxyphenyl) -1-benzyl-4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 217);
N- (2-methoxyphenyl) -4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 218);
N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1-methyl-4- (4-morpholinylsulfonyl) -2-piperazinecarboxamide Example 219);
N- [4- (trifluoromethoxy) phenyl] -1- (1-methylethyl) -4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 220);
N- [4- (trifluoromethoxy) phenyl] -1-acetyl-4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 221);
N- [1- (1-piperidinylsulfonyl) -piperidin-3-yl] -N ′-[4- (trifluoromethoxy) phenyl] urea (Example 222);
N- [1- (1-piperidinylsulfonyl) -piperidin-3-yl] -4- (trifluoromethoxy) benzamide (Example 223);
N- (2-methoxyphenyl) -3-[[(1-methylethyl) sulfonyl] amino] -piperidine-1-carboxamide (Example 224);
N- (2-methoxyphenyl) -3-[(1-piperidinylsulfonyl) amino] -1-piperidinecarboxamide (Example 225);
N- [4- (trifluoromethoxy) phenyl] -1- (1-piperidinylsulfonyl) -2-piperidinecarboxamide (Example 226);
N- (2-methoxyphenyl) -2- (1-piperidinylsulfonyl) -2,3-dihydro-1H-isoindoline-4-carboxamide (Example 227);
 
N- (2-methoxyphenyl) -2- (1-piperidinylsulfonyl) -1H-indole-4-carboxamide (Example 228);
N- (2-methoxyphenyl) -1-methyl-2- (1-piperidinylsulfonyl) -1H-indole-4-carboxamide (Example 229);
N- (2-methyl-5-benzoxazolyl) -2-chloro-5-[[methyl (1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 230);
N- [2- (1,1-dimethylethyl) -5-benzoxazolyl)]-2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 231);
N- [2- (trifluoromethyl) -5-benzoxazolyl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 232);
N- [2- (1-hydroxy-1-methylethyl) -2-chloro-5-benzoxazolyl)]-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 233);
N- (3,4-dihydro-2,2-dimethyl-4-methyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino ] Sulfonyl] benzamide (Example 234);
N- [4-Aminocarbonyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1,1-dimethylethyl) Amino] sulfonyl] benzamide (Example 235);
N- (3,4-Dihydro-2,2-dimethyl-4-methylsulfonyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) Amino] sulfonyl] benzamide (Example 236);
N- (3,4-dihydro-2,2-dimethyl-4-propionyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino ] Sulfonyl] benzamide (Example 237);
N- [4- (2-hydroxyacetyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1,1 -Dimethylethyl) amino] sulfonyl] benzamide (Example 238);
N- [4- (2-Aminoacetyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1,1 -Dimethylethyl) amino] sulfonyl] benzamide (Example 239);
N- [4- (2-pyridinyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1,1- Dimethylethyl) amino] sulfonyl] benzamide (Example 240);
N- [2,2-dimethylchroman-4-one-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 241);
N- (3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] Benzamide (Example 242);
N- (2,2-dimethylchromen-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 243);
N- (4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] Benzamide (Example 244);
N- (3,4-dihydro-4-dimethylamino-2,2-dimethyl-2H-1-benzopyran-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl Benzamide (Example 245);
N- [3,4-dihydro-4- (4-morpholinyl) -2,2-dimethyl-2H-1-benzopyran-6-yl] -2-chloro-5-[[(1,1-dimethylethyl) Amino] sulfonyl] benzamide (Example 246);
N- [3,4-Dihydro-3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6-yl] -2-chloro-5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] benzamide (Example 247);
N- [4-Methyl-3,4-dihydro-3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6-yl] -2-chloro-5-[[(1 , 1-dimethylethyl) amino] sulfonyl] benzamide (Example 248);
N- (2,3,4,5-Tetrahydro-4-oxo-1,5-benzoxazepin-7-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl Benzamide (Example 249);
N- (2,3,4,5-Tetrahydro-3,3-dimethyl-4-oxo-1,5-benzoxazepin-7-yl) -2-chloro-5-[[(1,1- Dimethylethyl) amino] sulfonyl] benzamide (Example 250);
N- (1-Methyl-3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] Sulfonyl] benzamide (Example 251);
N- (3,4-dihydro-4-ethyl-3-oxo-2H-1,4-benzoxazin-8-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl Benzamide (Example 252);
N- [1- (1-Methylethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl Benzamide (Example 253);
N- [1- (2-hydroxyethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl Benzamide (Example 254);
N- [1- (2-Fluoroethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl Benzamide (Example 255);
N- [1-ethyl-3-methyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] Benzamide (Example 256);
N- (1-ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -5-[[(1,1-dimethylethyl) amino] sulfonyl] -2- (trifluoromethyl) Benzamide (Example 257);
(R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5-[[(1,1-dimethylethyl) amino] sulfonyl ] -2- (Trifluoromethyl) benzamide (Example 258);
N- (3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5-[[(1,1-dimethylethyl) amino] sulfonyl]- 2- (trifluoromethyl) benzamide (Example 259);
N- (4-acetyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl) -5-[[(1,1-dimethylethyl) amino] sulfonyl]- 2- (trifluoromethyl) benzamide (Example 260);
N- [3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6 (4H) -yl] -5-[[(1,1-dimethylethyl) amino] sulfonyl]- 2- (trifluoromethyl) benzamide (Example 261);
N- [3,4-Dihydro-4-methyl-3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6-yl] -5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] -2- (trifluoromethyl) benzamide (Example 262);
(S) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1- Dimethylethyl) amino] sulfonyl] benzamide (Example 263);
(R) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1- Dimethylethyl) amino] sulfonyl] benzamide (Example 264);
(S) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) ) Benzamide (Example 265);
(R) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) ) Benzamide (Example 266);
(S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl ) Amino] sulfonyl] benzamide (Example 267);
(R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1-dimethylethyl ) Amino] sulfonyl] benzamide (Example 268);
(S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide ( Example 269);
(R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide ( Example 270)
Alternatively, pharmaceutically acceptable salts thereof, solvates thereof, or optically active forms thereof can be mentioned.
［１－１１－ａ］また、前記態様［１－１１］に記載の化合物において、より好ましい化合物として、実施例８２～実施例９２、実施例９４～実施例９９、実施例１０１、実施例１０３、実施例１０４、　実施例１１１～実施例１７２、実施例１７８、実施例１８２～実施例１８５、実施例１８７～実施例１８９、実施例２３４～実施例２７０の各々の化合物、或いはこれらの製薬学的に許容される塩、またはそれらの溶媒和物、またはそれらの光学活性体が挙げられる。 [1-11-a] Further, in the compounds described in the embodiment [1-11], examples 82 to 92, examples 94 to 99, example 101, and example 103 are more preferable compounds. , Example 104, Example 111 to Example 172, Example 178, Example 182 to Example 185, Example 187 to Example 189, Example 234 to Example 270, or their pharmaceutical preparations Acceptable salts, or solvates thereof, or optically active forms thereof.
［１－１１－ｂ］また、前記態様［１－１１－ａ］に記載の化合物において、より好ましい化合物として、実施例８２～実施例９２、実施例１１１～実施例１２２、実施例１２５～実施例１６５、実施例１８３、実施例１８４、実施例１８７～実施例１８９、実施例２３４～実施例２７０の各々の化合物、或いはこれらの製薬学的に許容される塩、またはそれらの溶媒和物、またはそれらの光学活性体が挙げられる。 [1-11-b] In addition, in the compounds described in the above-mentioned embodiment [1-1-11-a], as preferred compounds, Examples 82 to 92, Examples 111 to 122, and Examples 125 to Example 165, Example 183, Example 184, Example 187 to Example 189, Example 234 to Example 270, or a pharmaceutically acceptable salt thereof, or a solvate thereof, Or those optically active substances are mentioned.
［１－１１－ｃ］前記態様［１－１１－ｂ］に記載の化合物において、さらに好ましくは、実施例８５～実施例９２、実施例１１１～実施例１２２、実施例１２５～実施例１５９、実施例１６５、実施例１８３、実施例１８４、実施例１８８、実施例１８９、実施例２３４～実施例２７０の各々の化合物、或いはこれらの製薬学的に許容される塩、またはそれらの溶媒和物、またはそれらの光学活性体が挙げられる。 [1-11-c] In the compound according to the embodiment [1-1-11-b], more preferably, Example 85 to Example 92, Example 111 to Example 122, Example 125 to Example 159, Example 165, Example 183, Example 184, Example 188, Example 189, Example 234 to Example 270, or a pharmaceutically acceptable salt thereof, or a solvate thereof Or an optically active substance thereof.
［１－１１－ｄ］前記態様［１－１１－ｃ］に記載の化合物において、特に好ましくは、実施例８５～実施例９２、実施例１１１～実施例１２２、実施例１２５～実施例１５９、実施例１６５、実施例１８３、実施例１８４、実施例１８８、実施例１８９、実施例２３４～実施例２４０、実施例２４７～実施例２７０の各々の化合物、或いはこれらの製薬学的に許容される塩、またはそれらの溶媒和物、またはそれらの光学活性体が挙げられる。 [1-11-d] In the compound according to the embodiment [1-1-11-c], particularly preferably, Example 85 to Example 92, Example 111 to Example 122, Example 125 to Example 159, Example 165, Example 183, Example 184, Example 188, Example 189, Example 234 to Example 240, Example 247 to Example 270, or a pharmaceutically acceptable compound thereof A salt, or a solvate thereof, or an optically active form thereof.
［１－１２］本発明の第１－１２の態様は、下記式（Ｉ）－Ａ
Figure JPOXMLDOC01-appb-C000058
  
（式中、Ｒ５Ａ及びＲ６Ａは、各々独立に、水素原子、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基を表し、Ｒ５Ａ及びＲ６Ａは、それらが結合する窒素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよく；ＷＡは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－を表し、Ｒ７、Ｒ８、Ｒ９、Ｒ１０は前記態様［１－７］と同一を表し；
Ｒｉｎｇ－Ａは、下記式（Ｇ）または（Ｈ）
Figure JPOXMLDOC01-appb-C000059
  
（式中、Ｒ１７及びＲ１８は、各々独立に、水素原子またはＲＣ群から任意に選ばれる基を表し、Ｒ１７及びＲ１８は、それらが結合するベンゼン環上の炭素原子と５～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく；Ｅは、非存在、基：－ＣＲＡ３ＲＡ４－、エチレン基、酸素原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良く、Ｅが－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し、ＲＣ、ＲＡ３、ＲＡ４は前記と同一を表し、ＥとＷが結合した炭素原子との間の実線と破線は単結合もしくは二重結合であることを示す）で表される二価の基であり；
ＺＡは、下記式（Ｄ）または下記式（Ｅ）
Figure JPOXMLDOC01-appb-C000060
  
（式中、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）を表す。但し、Ｒ１７が水素である場合を除く）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [1-12] The 1-12th aspect of the present invention is the following formula (I) -A
Figure JPOXMLDOC01-appb-C000058
(Wherein, R 5A and R 6A are each independently a hydrogen atom, a linear or branched alkyl group of R C optionally substituted by a group selected C 1 ~ from group 6, R straight or branched chain alkenyl group of C which may C 2 even though - substituted with chosen groups arbitrarily from group 6, which may be substituted by a group selected arbitrarily from R C group C 2 - 6 It represents a straight or branched alkynyl group or cycloalkyl group R C good C 3 ~ optionally substituted with chosen groups arbitrarily from the group 8,, R 5A and R 6A are they bind A 3- to 8-membered cyclic group may be formed together with a nitrogen atom. In the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom,- OH · C 1 to 6 alkoxyl and halogenated C 1 to 6 is 1-5 substituents in any of the alkoxylation may be replaced by may also) be substituted with an alkyl group of C 1 ~ 6 of which may straight or branched chain, said cyclic group Further, it may be substituted with a group arbitrarily selected from the group R C ; W A represents —CONR 7 —, —NR 8 CO— or —NR 9 CONR 10 —, and R 7 , R 8 , R 9 , R 10 represents the same as the above embodiment [1-7];
Ring-A is represented by the following formula (G) or (H)
Figure JPOXMLDOC01-appb-C000059
(Wherein R 17 and R 18 each independently represents a hydrogen atom or a group arbitrarily selected from the group R C , R 17 and R 18 represent a carbon atom on the benzene ring to which they are bonded and 5 to 5 An 8-membered cyclic group may be formed, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom, or a nitrogen atom (the nitrogen atom is a halogen atom, -OH, C 1- 6 replaced by may also) be substituted with an alkyl group of C 1 ~ 6 of which may straight or branched chain optionally substituted 1-5 with either an alkoxylated-halogenated C 1 ~ 6 alkoxy at best; E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 Izu alkoxyl May be substituted with one to five substituted C 1 of which may straight or branched chain optionally 1-6 alkyl group in either, E is -CR A3 R A4 - in the case of the, R A3 And R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom ( the nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with one to five substituents which may be straight or branched chain alkoxyl of C 1 ~ 6 The cyclic group may further have a substituent), and R C , R A3 , and R A4 represent the same as described above. , Solid and broken lines between carbon atoms with E and W bonded Represents a single bond or a double bond));
Z A is the following formula (D) or the following formula (E)
Figure JPOXMLDOC01-appb-C000060
(In the formula, R A , R 12 , A, G, L 1 , L 2 , g, j, f, and the definition of the broken line are defined in any one of the above embodiments [1], [1-1] to [1-10]. Represents the same meaning). Wherein R 17 is hydrogen), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. It is a chain fatty acid elongation enzyme (Elovl6) inhibitor.
　前記式（Ｉ）－Ａにおいて、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子である場合を除く）；
より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。 In the formula (I) -A, R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or model / Di C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, a C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or a group selected from mono- / di-C 1 ~ 6 alkyl amino, and, R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
［１－１３］本発明の第１－１３の態様は、下記式（Ｉ）－Ｂ
Figure JPOXMLDOC01-appb-C000061
  
（式中、Ｒ５Ａ、Ｒ６Ａ、ＷＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｊ、ｆ、破線及びそれらの定義中に定義される置換基は、前記と同一の意味を表し、Ｒｉｎｇ－Ａは、下記式（Ｇ）または（Ｈ）
Figure JPOXMLDOC01-appb-C000062
  
（式中、Ｒ１７、Ｒ１８、ＲＣ、Ｅ、破線及びその定義中の定義される置換基は、前記と同一の意味を表す）で表される基を表す。但し、Ｒ１７が水素である場合を除く）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [1-13] The 1-13th aspect of the present invention is the following formula (I) -B
Figure JPOXMLDOC01-appb-C000061
(Wherein R 5A , R 6A , W A , R 12 , A, G, L 1 , L 2 , j, f, the broken line and the substituents defined in those definitions have the same meaning as described above. Ring-A is represented by the following formula (G) or (H)
Figure JPOXMLDOC01-appb-C000062
(Wherein, R 17 , R 18 , R C , E, the broken line and the substituent defined in the definition represent the same meaning as described above). Provided that, as an active ingredient, at least one of a compound represented by the above formula (except when R 17 is hydrogen), or a pharmaceutically acceptable salt thereof or a solvate thereof, It is a long chain fatty acid elongation enzyme (Elovl6) inhibitor.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＷＡ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ｊ、ｆ、破線の定義及びそれらの定義中に定義される置換基、あるいは式（Ｄ）及び式（Ｅ）の基及びそれらの好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, R 5A , R 6A , W A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , j, f, the definition of broken lines and their definitions The substituent, or the group of the formula (D) and the formula (E) and preferred embodiments thereof are described in any one of the embodiments [1], [1-1] to [1-10] and [1-12]. The definition is the same as
　前記式（Ｉ）－Ｂにおいて、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子である場合を除く）；
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。 In the formula (I) -B, R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or model / Di C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, a C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or a group selected from mono- / di-C 1 ~ 6 alkyl amino, and, R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
［１－１４］本発明の第１－１４の態様は、下記式（ＩＩ）
Figure JPOXMLDOC01-appb-C000063
  
（式中、Ｒ５Ａ及びＲ６Ａは、各々独立に、水素原子、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ２～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基を表し、Ｒ５Ａ及びＲ６Ａは、それらが結合する窒素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよく；Ｒ１７及びＲ１８は、各々独立に、水素原子またはＲＣ群から任意に選ばれる基を表し、Ｒ１７及びＲ１８は、それらが結合する窒素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく；ＷＡは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－を表し、Ｒ７、Ｒ８、Ｒ９、Ｒ１０、ＲＡ、ＲＣ、ｇの定義は前記態様［１］、［１－１］～［１－１０］のいずれかと同一を表す。但し、Ｒ１７が水素である場合を除く）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [1-14] The 1-14th aspect of the present invention is the following formula (II)
Figure JPOXMLDOC01-appb-C000063
(Wherein, R 5A and R 6A are each independently a hydrogen atom, a linear or branched alkyl group of R C optionally substituted by a group selected C 1 ~ from group 6, R straight or branched chain alkenyl group of C which may C 2 even though - substituted with chosen groups arbitrarily from group 6, which may be substituted by a group selected arbitrarily from R C group C 2 - 6 It represents a straight or branched alkynyl group or cycloalkyl group R C good C 3 ~ optionally substituted with chosen groups arbitrarily from the group 8,, R 5A and R 6A are they bind A 3- to 8-membered cyclic group may be formed together with a nitrogen atom. In the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is a halogen atom,- OH · C 1 to 6 alkoxyl and halogenated C 1 to 6 is 1-5 substituents in any of the alkoxylation may be replaced by may also) be substituted with an alkyl group of C 1 ~ 6 of which may straight or branched chain, said cyclic group Further, it may be substituted with a group arbitrarily selected from the R C group; R 17 and R 18 each independently represents a hydrogen atom or a group arbitrarily selected from the R C group, and R 17 and R 18 are In addition, a 3- to 8-membered cyclic group may be formed together with the nitrogen atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or a nitrogen atom (the nitrogen atom is , substituted by a halogen atom, -OH, C 1 - 6 alkoxylated, halogenated C 1 - 6 one by one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl May be) W A represents —CONR 7 —, —NR 8 CO— or —NR 9 CONR 10 —, and R 7 , R 8 , R 9 , R 10 , R A , R C , g is the same as defined in any one of the above embodiments [1] and [1-1] to [1-10], except that R 17 is hydrogen), or a pharmaceutical It is a long-chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by containing at least one of its salts or solvates acceptable as an active ingredient.
　より具体的には、Ｒ７、Ｒ８、Ｒ９、Ｒ１０、ＲＡ、ＲＣ、ｇの定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］のいずれかに記載の定義と同じである。
　前記式（ＩＩ）において、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子である場合を除く）；
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。 More specifically, the definitions and preferred embodiments of R 7 , R 8 , R 9 , R 10 , R A , R C , and g are the same as those in the above embodiments [1], [1-1] to [1-10]. It is the same as the definition described in any one.
In the formula (II), R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl, C 1 1-6 alkoxyl, C 2 - 6 alkenyloxy, C 2 - 6 alkynyloxy, halogenated C 1 - 6 alkoxy or mono- A group selected from di C 1 ~ 6 alkylamino, made from the group (except when R 17 is a hydrogen atom);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, a C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or a group selected from mono- / di-C 1 ~ 6 alkyl amino, and, R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
［１－１５］本発明の第１－１５の態様は、下記式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000064
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ＷＡ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表す。但し、Ｒ１７が水素原子である場合を除く）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [1-15] The 1-15th aspect of the present invention is the following formula (III)
Figure JPOXMLDOC01-appb-C000064
(Wherein R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, and the definition of the broken line are defined in the above aspects [1], [1-1] To the same meaning as any one of [1-10] and [1-12], except that R 17 is a hydrogen atom), or a pharmaceutically acceptable compound thereof A long-chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by containing at least one of a salt or a solvate thereof as an active ingredient.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ＷＡ、ｊ、ｆ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, the definition of a broken line, and preferred embodiments are the above-described embodiments [1 ], [1-1] to [1-10] and [1-12] have the same definition as described in any one of [1-12].
　前記式（ＩＩＩ）において、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。 In the formula (III), as R 5A and R 6A , preferably, at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
　前記式（ＩＩＩ）において、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子・－ＯＨまたはアルコキシル基である場合を除く）；
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。
　Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）において、好ましくは、Ａを構成に含む環は芳香化しているものを含まない。 In the formula (III), R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl, C 1 1-6 alkoxyl, C 2 - 6 alkenyloxy, C 2 - 6 alkynyloxy, halogenated C 1 - 6 alkoxy or model / Di C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom · -OH or an alkoxyl group);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 is a group selected from alkylamino, and R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
In the formula (III), preferably, the ring containing A in the structure does not include an aromatic group.
　前記式（ＩＩＩ）において、ＲＡ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群の置換基は、ハロゲン原子、オキソ、ニトロ、シアノ、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ３～８シクロアルキル、Ｃ６～１４アリール、へテロ環、
保護されていてもよいヒドロキシル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、Ｃ６～１４アリールオキシ、ヘテロ環オキシ、
メルカプト、Ｃ１～６アルキルチオ、Ｃ６～１４アリールチオ、ヘテロ環チオ、Ｃ１～６アルキルスルフィニル、Ｃ６～１４アリールスルフィニル、ヘテロ環スルフィニル、Ｃ１～６アルキルスルホニル、Ｃ６～１４アリールスルホニル、ヘテロ環スルホニル、スルファモイル（当該スルファモイルは、Ｃ１～６アルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、スルホ、
アミノ（当該アミノは、Ｃ１～６アルキル・モノ／ジＣ１～６アルキルスルファモイル・モノ／ジＣ１～６アルキルカルバモイル・ホルミル・Ｃ２～７アルカノイル・Ｃ６～１４アリール・ヘテロ環・モノ／ジＣ６～１４アリールスルファモイル・モノ／ジヘテロ環スルファモイル・Ｃ６～１４アリールカルボニルもしくはヘテロ環カルボニルで置換されていてもよい）、
ホルミル、Ｃ２～７アルカノイル、Ｃ６～１４アリールカルボニル、ヘテロ環カルボニル、
保護されていてもよいカルボキシル、Ｃ１～６アルコキシカルボニル、Ｃ６～１４アリールオキシカルボニル、ヘテロ環オキシカルボニル、
カルバモイル（当該カルバモイルは、Ｃ１～６アルキル、Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）
から任意に選ばれる基を表す。 In the formula (III), the substituents of the group A are the same as defined in the embodiment [1]. That is, the substituent of the R A group is a halogen atom, oxo, nitro, cyano,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl, C 3 - 8 cycloalkyl, C 6 - 14 aryl or heteroaryl ring),
C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl, heterocycle,
Optionally protected hydroxyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy, C 6 ~ 14 aryloxy, heterocyclic oxy,
Mercapto, C 1 ~ 6 alkylthio, C 6 ~ 14 arylthio, heterocyclic thio, C 1 ~ 6 alkylsulfinyl, C 6 ~ 14 arylsulfinyl, heterocyclic sulfinyl, C 1 ~ 6 alkylsulfonyl, C 6 ~ 14 arylsulfonyl, heterocyclic sulfonyl, sulfamoyl (the sulfamoyl may be substituted with C 1 ~ 6 alkyl · C 6 ~ 14 aryl or heterocyclic), sulfo,
Amino (said amino, C 1 ~ 6 alkyl mono / di C 1 ~ 6 alkylsulfamoyl mono / di C 1 ~ 6 alkylcarbamoyl, formyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 aryl heterocycle mono / di C 6 ~ 14 may be substituted with an aryl sulfamoyl mono / diheterocyclic sulfamoyl-C 6 ~ 14 arylcarbonyl or heterocycle carbonyl),
Formyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 arylcarbonyl, heterocyclic carbonyl,
Optionally protected carboxyl, C 1 ~ 6 alkoxycarbonyl, C 6 ~ 14 aryloxycarbonyl, heterocyclic oxycarbonyl,
Carbamoyl (said carbamoyl, C 1 ~ 6 alkyl, optionally substituted with C 6 ~ 14 aryl or hetero ring)
Represents a group arbitrarily selected from
　前記式（ＩＩＩ）において、ＲＢ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＢ群の置換基は、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ３～８シクロアルキル、Ｃ６～１４アリール、へテロ環、
Ｃ１～６アルキルスルホニル、Ｃ６～１４アリールスルホニル、ヘテロ環スルホニル、スルファモイル（当該スルファモイルは、Ｃ１～６アルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ２～７アルカノイル、Ｃ６～１４アリールカルボニル、ヘテロ環カルボニル、
Ｃ１～６アルコキシカルボニル、Ｃ６～１４アリールオキシカルボニル、ヘテロ環オキシカルボニル、
カルバモイル（当該カルバモイルは、Ｃ１～６アルキル、Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）
から任意に選ばれる基を表す。 In the formula (III), substituent group R B are as defined according to the aspect [1]. That is, the substituent of the group R B is,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl, C 3 - 8 cycloalkyl, C 6 - 14 aryl or heteroaryl ring),
C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl, heterocycle,
C 1 ~ 6 alkylsulfonyl, C 6 ~ 14 arylsulfonyl, heterocyclic sulfonyl, sulfamoyl (the sulfamoyl may be substituted with C 1 ~ 6 alkyl · C 6 ~ 14 aryl or heterocycle),
C 2 ~ 7 alkanoyl, C 6 ~ 14 arylcarbonyl, heterocyclic carbonyl,
C 1 ~ 6 alkoxycarbonyl, C 6 ~ 14 aryloxycarbonyl, heterocyclic oxycarbonyl,
Carbamoyl (said carbamoyl, C 1 ~ 6 alkyl, optionally substituted with C 6 ~ 14 aryl or hetero ring)
Represents a group arbitrarily selected from
　前記式（ＩＩＩ）において、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＣ群の置換基は、ハロゲン原子、オキソ、ニトロ、シアノ、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイルもしくはＣ３～８シクロアルキルで置換されていてもよい）、
Ｃ３～８シクロアルキル、
保護されていてもよいヒドロキシル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、
メルカプト、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、スルファモイル、モノ／ジＣ１～６アルキルスルファモイル、スルホ、
アミノ（当該アミノは、Ｃ１～６アルキル・モノ／ジＣ１～６アルキルスルファモイル・モノ／ジＣ１～６アルキルカルバモイル・ホルミルもしくはＣ２～７アルカノイルで置換されていてもよい）、
ホルミル、Ｃ２～７アルカノイル、
保護されていてもよいカルボキシル、Ｃ１～６アルコキシカルボニル、
カルバモイルもしくはモノ／ジＣ１～６アルキルカルバモイルから任意に選ばれる基を表す。 In the formula (III), the substituents of the RC group are the same as defined in the embodiment [1]. That is, the substituent of the RC group includes a halogen atom, oxo, nitro, cyano,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl or C 3 - 8 cycloalkyl),
C 3 ~ 8 cycloalkyl,
Optionally protected hydroxyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy,
Mercapto, C 1 ~ 6 alkylthio, C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkyl sulfamoyl, sulfo,
Amino (said amino may be substituted by C 1 ~ 6 alkyl mono / di C 1 ~ 6 alkylsulfamoyl mono / di C 1 ~ 6 alkylcarbamoyl, formyl or C 2 ~ 7 alkanoyl),
Formyl, C 2 ~ 7 alkanoyl,
Optionally carboxyl which may be protected, C 1 ~ 6 alkoxycarbonyl,
Carbamoyl or mono / di-C 1 ~ 6 chosen group from alkylcarbamoyl optionally.
［１－１５－ａ］本発明の第１－１５－ａの態様は、下記式（ＩＩＩ）－Ａ
Figure JPOXMLDOC01-appb-C000065
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表し、Ｒ１７Ａは、ＲＣ群から任意に選ばれる基を表す（但し、Ｒ１７Ａは、－ＯＨまたはアルコキシル基である場合を除く））で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [1-15-a] The 1-15-a aspect of the present invention is the following formula (III) -A
Figure JPOXMLDOC01-appb-C000065
(Wherein R 5A , R 6A , R 12 , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above-mentioned embodiments [1], [1-1] to [1-] 10] and [1-12] have the same meanings, and R 17A represents a group arbitrarily selected from the R C group (except that R 17A is —OH or an alkoxyl group). Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, which is an inhibitor of long-chain fatty acid elongation enzyme (Elovl6) .
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, R 5A , R 6A , R 12 , R 18 , A a , G a , L 1a , L 2a , W A , the definition of a broken line and preferred embodiments are the above-described embodiments [1], [1- 1] to [1-10] and [1-12] have the same definitions as described in any one of [1-12].
　前記式（ＩＩＩ）－Ａにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。 In the formula (III) -A, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
　前記式（ＩＩＩ）－Ａにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。
　Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ａにおいて、好ましくは、Ａａを構成に含む環は芳香化しているものを含まない。 In the formula (III) -A, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and, R 18 is a hydrogen atom. More preferably, a group R 17A is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
In the formula (III) -A, preferably, the ring containing A a does not include an aromatic group.
　前記式（ＩＩＩ）－Ａにおいて、ＷＡあるいはＲ１２の置換位置は、フェニル部分の炭素原子の位置で示すことができる。ＷＡであれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。ＷＡは、３番目の炭素原子に結合していることがより好ましい。 In the above formula (III) -A, the substitution position of W A or R 12 can be indicated by the position of the carbon atom of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. W A is more preferably bonded to the third carbon atoms.
Figure JPOXMLDOC01-appb-C000066
  
Figure JPOXMLDOC01-appb-C000066
  
　前記式（ＩＩＩ）－Ａにおいて、ＲＡ群、ＲＢ群、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群、ＲＢ群、ＲＣ群の置換基は、前記態様［１－１５］に記載の定義と同じである。 In the formula (III) -A, the substituents in the groups R A , R B and R C are the same as defined in the embodiment [1]. That, R A group, R B group, the substituents R C groups are as defined according to the aspect [1-15].
［１－１５－ｂ］本発明の第１－１５－ｂの態様は、前記態様［１－１５－ａ］より好ましい態様であり、下記式（ＩＩＩ）－Ｂ
Figure JPOXMLDOC01-appb-C000067
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義は前記態様［１］、［１－１］～［１－１０］、［１－１２］及び［１－１５］のいずれかと同一の意味を表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。Ａａを構成に含む環は芳香化しているものを含まない。 [1-15-b] The embodiment 1-15-b of the present invention is a more preferred embodiment than the embodiment [1-15-a], and has the following formula (III) -B
Figure JPOXMLDOC01-appb-C000067
(In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to At least a compound represented by [1-10], [1-12] and [1-15], or a pharmaceutically acceptable salt or solvate thereof. It is a long chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by containing one as an active ingredient. The ring containing A a does not include those that are aromatized.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び、［１－１２］及び［１－１５］のいずれかに記載の定義と同じである。 More specifically, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , the definition and preferred embodiments of the broken line are the above-described embodiments [1], The definition is the same as described in any one of [1-1] to [1-10] and [1-12] and [1-15].
　前記式（ＩＩＩ）－Ｂにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。
　より好ましくは、Ｒ５Ａ、Ｒ６Ａは、各々独立に、水素原子、Ｃ１～６の直鎖もしくは分枝鎖のアルキル基またはＣ３～８のシクロアルキル基を表し（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である）、Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに４～６員の環状基を形成していてもよく、当該環状基はその環内の炭素原子が酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）で置き換えられていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、－ＮＲ５ＡＲ６Ａとして、より具体的には、以下の式で表わされることが好ましい。
Figure JPOXMLDOC01-appb-C000068
   In the formula (III) -B, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
More preferably, R 5A, R 6A are each independently a hydrogen atom, a cycloalkyl group of C 1 ~ linear or branched alkyl group or a C 3 ~ 8 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ~ 6 have been.
In the formula (III) -B, as —NR 5A R 6A , more specifically, it is preferably represented by the following formula.
Figure JPOXMLDOC01-appb-C000068
前記式（ＩＩＩ）－Ｂにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子であり、より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。 In the formula (III) -B, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and a R 18 is a hydrogen atom, more preferably, R 17A is C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
　前記式（ＩＩＩ）－Ｂにおいて、Ａａを含む縮合環は、下記式（Ｅ１ａ）
Figure JPOXMLDOC01-appb-C000069
  
（式中、Ｒ１２、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１－４－ｂ］および［１－４－ｄ－１２］と同一の意味を表す）で表される基であり、ＡａとＧａ間の破線は当該元素間の結合が、適宜単結合もしくは二重結合をとる。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ａａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、またはカルボニル基を表し、
Ｇａはメチレン基、カルボニル基またはスルホニル基を表し、
Ｌ１ａは、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ１ａは酸素原子である）、
Ｌ２ａは、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ２ａは単結合または－（ＣＲ１５ＣＲ１５Ｄ）ｕ－である）；
Ｒ１３、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄ、Ｒ１６Ａ、Ｒ１６Ｂの定義は前記態様［１－４－ｂ］と同一の意味を表し、好ましい態様は前記態様［１－４－ｄ－３］及び［１－４－ｄ－５］と同一である。
　第１－１５－ｂの態様において、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄは、各々独立に、水素原子、ハロゲン原子、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いＣ１～６アルキル基、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いアミノ基または保護されていても良いヒドロキシル基から任意に選ばれる基が好ましく、
Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、Ａａは－ＮＲ１３－であることが好ましい。 In the formula (III) -B, the condensed ring containing A a is represented by the following formula (E1a)
Figure JPOXMLDOC01-appb-C000069
(Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]). a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
In the above formula (III) -B and the above formula (E1a), R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group. good C 1 ~ 4 alkyl group, optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ~ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
In the formula (III) -B and the above formula (E1a), A a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group,
G a represents a methylene group, a carbonyl group or a sulfonyl group,
L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom),
L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
The definitions of R 13 , R 14A , R 14B , R 15A , R 15B , R 15C , R 15D , R 16A , R 16B represent the same meaning as in the above embodiment [1-4-b], and a preferable embodiment is the above embodiment. The same as [1-4-d-3] and [1-4-d-5].
In the 1-15-b embodiment, R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH · —NH 2. chosen optionally substituted C 1 ~ 6 alkyl group in group, -OH · --NH2 · optionally substituted with chosen groups arbitrarily from -COOH heterocyclic group, optionally selected from R C group optionally substituted C 1 to 6 alkoxy group with a group, mono group substituted by C 1 may also be ~ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group,
R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with 1-5 optionally substituted straight or alkoxyl substituted with an alkyl group of C 1 ~ 6 branched may be replaced by also good), the cyclic group may be further substituted by a group selected arbitrarily from R C groups.
In the formula (III) -B, A a is preferably —NR 13 —.
　式（Ｅ１ａ）において、ＷＡあるいはＲ１２の置換位置は、前記態様［１－４－ｄ－１１］と同様に、フェニル部分の炭素原子の位置で示すことができる。ＷＡであれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。
Figure JPOXMLDOC01-appb-C000070
  
式（Ｅ１ａ）においてＷＡの結合位置は、具体的には、下記式（Ｅ１ａ－１）－ｂおよび（Ｅ１ａ－２）－ｂであることが好ましい。
Figure JPOXMLDOC01-appb-C000071
   In formula (E1a), substitution positions of W A or R 12 is, similarly to the embodiment [1-4-d-11], can be indicated by the position of the carbon atoms of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms.
Figure JPOXMLDOC01-appb-C000070
Bonding position of W A in formula (E1a), specifically, it is preferably the following formula (E1a-1) -b and (E1a-2) -b.
Figure JPOXMLDOC01-appb-C000071
　前記式（Ｅ１ａ）において、より具体的には、以下に示される式から任意に選択される。
Figure JPOXMLDOC01-appb-C000072
  
Figure JPOXMLDOC01-appb-C000073
  
　前記式（Ｅ１ａ）において、具体的には、好ましくは、前記式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。より好ましくは、式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。 More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000073
In the formula (E1a), specifically, preferably, the formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), (c c208) to (c240). More preferable examples include formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), and (c208) to (c240).
　前記式（ＩＩＩ）－Ｂにおいて、ＷＡは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０は、各々独立に水素原子またはＣ１～６アルキル基を表す）を表し；－ＣＯＮＲ７－であることが好ましい。 In the formula (III) -B, W A is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or C 1 ~ 6 alkyl represents a group); -CONR 7 - is preferably.
　前記式（ＩＩＩ）－Ｂにおいて、ＲＡ群、ＲＢ群、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群、ＲＢ群、ＲＣ群の置換基は、前記態様［１－１５］に記載の定義と同じである。 In the formula (III) -B, the substituents of the groups R A , R B , and R C are the same as defined in the above embodiment [1]. That, R A group, R B group, the substituents R C groups are as defined according to the aspect [1-15].
［１－１５－ｃ］本発明の第１－１５－ｃの態様は、前記態様［１－１５－ｂ］より好ましい態様であり、下記式（ＩＩＩ）－Ｃ
Figure JPOXMLDOC01-appb-C000074
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１］、［１－１］～［１－１０］、［１－１２］、［１－１５］及び［１－１５－ｂ］のいずれかと同一の意味を表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [1-15-c] The embodiment 1-15-c of the present invention is a more preferred embodiment than the embodiment [1-15-b], and has the following formula (III) -C
Figure JPOXMLDOC01-appb-C000074
(Wherein, R 5A, R 6A, R 12, R 17A, R 18, A a, G a, L 1a, L 2a, the dashed defined above aspect [1], [1-1] - [1- 10], [1-12], [1-15] and any one of [1-15-b]), or a pharmaceutically acceptable salt thereof or a compound thereof A long-chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by containing at least one solvate as an active ingredient.
　前記式（ＩＩＩ）－Ｃにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。
　より好ましくは、Ｒ５Ａ、Ｒ６Ａは、各々独立に、水素原子、Ｃ１～６の直鎖もしくは分枝鎖のアルキル基またはＣ３～６のシクロアルキル基であり（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である）、Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに４～６員の環状基を形成していてもよく、当該環状基はその環内の炭素原子が酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）で置き換えられていてもよい。
　前記式（ＩＩＩ）－Ｃにおいて、－ＮＲ５ＡＲ６Ａとして、より具体的には、以下の式で表わされることが好ましい。
Figure JPOXMLDOC01-appb-C000075
   In the formula (III) -C, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
More preferably, R 5A, R 6A are each independently hydrogen atom, a linear or branched alkyl group or cycloalkyl group C 3 ~ 6 of C 1 ~ 6 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ~ 6 have been.
In the formula (III) -C, as —NR 5A R 6A , more specifically, it is preferably represented by the following formula.
Figure JPOXMLDOC01-appb-C000075
前記式（ＩＩＩ）－Ｃにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子であり、より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。 In the formula (III) -C, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and a R 18 is a hydrogen atom, more preferably, R 17A is C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
　前記式（ＩＩＩ）－Ｃにおいて、Ａａを含む縮合環は、下記式（Ｅ１ａ）
Figure JPOXMLDOC01-appb-C000076
  
（式中、Ｒ１２、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１－４－ｂ］および［１－４－ｄ－１２］と同一の意味を表す）で表される基であり、ＡａとＧａ間の破線は当該元素間の結合が、適宜単結合もしくは二重結合をとる。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ａａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、またはカルボニル基を表し、
Ｇａはメチレン基、カルボニル基またはスルホニル基を表し、
Ｌ１ａは、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ１ａは酸素原子である）、
Ｌ２ａは、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ２ａは単結合または－（ＣＲ１５ＣＲ１５Ｄ）ｕ－である）；
Ｒ１３、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄ、Ｒ１６Ａ、Ｒ１６Ｂの定義は前記態様［１－４－ｂ］と同一の意味を表し、好ましい態様は前記態様［１－４－ｄ－３］及び［１－４－ｄ－５］と同一である。
　第１－１５－ｂの態様において、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄは、各々独立に、水素原子、ハロゲン原子、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いＣ１～６アルキル基、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いアミノ基または保護されていても良いヒドロキシル基から任意に選ばれる基が好ましく、
Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、Ａａは－ＮＲ１３－であることが好ましい。 In the formula (III) -C, the condensed ring containing A a is represented by the following formula (E1a)
Figure JPOXMLDOC01-appb-C000076
(Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]). a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
In the above formula (III) -B and the above formula (E1a), R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group. good C 1 ~ 4 alkyl group, optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ~ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
In the formula (III) -B and the above formula (E1a), A a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group,
G a represents a methylene group, a carbonyl group or a sulfonyl group,
L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom),
L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
The definitions of R 13 , R 14A , R 14B , R 15A , R 15B , R 15C , R 15D , R 16A , R 16B represent the same meaning as in the above embodiment [1-4-b], and a preferable embodiment is the above embodiment. The same as [1-4-d-3] and [1-4-d-5].
In the 1-15-b embodiment, R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH · —NH 2. chosen optionally substituted C 1 ~ 6 alkyl group in group, -OH · --NH2 · optionally substituted with chosen groups arbitrarily from -COOH heterocyclic group, optionally selected from R C group optionally substituted C 1 to 6 alkoxy group with a group, mono group substituted by C 1 may also be ~ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group,
R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with 1-5 optionally substituted straight or alkoxyl substituted with an alkyl group of C 1 ~ 6 branched may be replaced by also good), the cyclic group may be further substituted by a group selected arbitrarily from R C groups.
In the formula (III) -B, A a is preferably —NR 13 —.
　式（Ｅ１ａ）において、－ＣＯＮＲ７－あるいはＲ１２の置換位置は、前記態様［１－４－ｄ－１１］と同様に、フェニル部分の炭素原子の位置で示すことができる。－ＣＯＮＲ７－であれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。
Figure JPOXMLDOC01-appb-C000077
  
式（Ｅ１ａ）において－ＣＯＮＲ７－の結合位置は、具体的には、下記式（Ｅ１ａ－１）－ｃおよび（Ｅ１ａ－２）－ｃであることが好ましい。
Figure JPOXMLDOC01-appb-C000078
   In the formula (E1a), the substitution position of —CONR 7 — or R 12 can be represented by the position of the carbon atom of the phenyl moiety, as in the above embodiment [1-4-d-11]. In the case of —CONR 7 —, it is preferable that L 1a is bonded to the first or third carbon atom, counting clockwise from a position close to the carbon atom to which L 1a is bonded.
Figure JPOXMLDOC01-appb-C000077
Specifically, the bonding position of —CONR 7 — in the formula (E1a) is preferably the following formulas (E1a-1) -c and (E1a-2) -c.
Figure JPOXMLDOC01-appb-C000078
　前記式（Ｅ１ａ）において、より具体的には、以下に示される式から任意に選択される。
 
Figure JPOXMLDOC01-appb-C000080
  
　前記式（Ｅ１ａ）において、具体的には、好ましくは、前記式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。より好ましくは、式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。 More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.

Figure JPOXMLDOC01-appb-C000080
In the formula (E1a), specifically, preferably, the formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), (c c208) to (c240). More preferable examples include formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), and (c208) to (c240).
　前記式（ＩＩＩ）－Ｃにおいて、ＲＡ群、ＲＢ群、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群、ＲＢ群、ＲＣ群の置換基は、前記態様［１－１５］に記載の定義と同じである。 In the formula (III) -C, the substituents of the groups A A , R B and R C are the same as defined in the above embodiment [1]. That, R A group, R B group, the substituents R C groups are as defined according to the aspect [1-15].
［１－１６］本発明の第１－１６の態様は、下記式（ＩＶ）
Figure JPOXMLDOC01-appb-C000081
  
（式中、Ｅは、非存在、基：－ＣＲＡ３ＲＡ４－、エチレン基、酸素原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良く、Ｅが－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し、ＥとＷが結合した炭素原子との間の実線と破線は単結合もしくは二重結合を形成しうることを示し、
ＹＡは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ６～１４のアリール基、または基：－ＮＲ５ＡＲ６Ａを表し；
Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＲＡ３、ＲＡ４、ＷＡの定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表し、ＺＡは、下記式（Ｄ）または下記式（Ｅ）
Figure JPOXMLDOC01-appb-C000082
  
（式中、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＲＡ３、ＲＡ４、ＷＡ、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆの定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 [1-16] The 1-16th aspect of the present invention is the following formula (IV)
Figure JPOXMLDOC01-appb-C000081
(Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 1 ~ 5 amino optionally substituted straight or branched chain with either an alkoxylated C With 1 to 6 alkyl groups The cyclic group may further have a substituent), and a solid line and a broken line between E and W bonded carbon atoms are simply Indicates that a bond or double bond can be formed;
Y A is substituted by a group selected from straight or branched chain alkyl groups of R C optionally substituted by a group selected C 1 ~ from group 6, the R C groups optionally good C 3 ~ cycloalkyl group 8, aryl group R C may be substituted with chosen groups arbitrarily from the group C 6 ~ 14 or group: represents -NR 5A R 6A;
R 5A, R 6A, R C , R A3, R A4, W A definition the aspect [1], the same meaning as any one of [1-1] - [1-10] and [1-12] Z A represents the following formula (D) or the following formula (E)
Figure JPOXMLDOC01-appb-C000082
(In the formula, R A , R 12 , A, G, L 1 , L 2 , g, j, f, and the definition of the broken line are defined in any one of the above embodiments [1], [1-1] to [1-10]. A long-chain fatty acid elongation, comprising as an active ingredient at least one of a compound represented by (in the same meaning) and a pharmaceutically acceptable salt or solvate thereof. It is an enzyme (Elovl6) inhibitor.
More specifically, definitions and preferred embodiments of R 5A , R 6A , R C , R A3 , R A4 , W A , R A , R 12 , A, G, L 1 , L 2 , g, j, f Is the same as defined in any one of Embodiments [1], [1-1] to [1-10] and [1-12].
［１－１７］本発明の第１－１７の態様は、下記式（ＩＶ－ａ）
Figure JPOXMLDOC01-appb-C000083
  
（式中、Ｅは、非存在、基：－ＣＲＡ３ＲＡ４－、エチレン基、酸素原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良く、Ｅが－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し、ＥとＷが結合した炭素原子との間の実線と破線は単結合もしくは二重結合を形成しうることを示し、Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＲＡ３、ＲＡ４、ＷＡの定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表し、ＺＡは、下記式（Ｄ）または下記式（Ｅ）
Figure JPOXMLDOC01-appb-C000084
  
（式中、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＷＡ、ＲＡ、ＲＡ３、ＲＡ４、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆの定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 [1-17] The 1-17th aspect of the present invention is the following formula (IV-a)
Figure JPOXMLDOC01-appb-C000083
(Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 1 ~ 5 amino optionally substituted straight or branched chain with either an alkoxylated C With 1 to 6 alkyl groups The cyclic group may further have a substituent), and the solid line and the broken line between the carbon atom to which E and W are bonded are simply binding or indicate that can form a double bond, R 5A, R 6A, R C, R A3, R A4, W definition of a is the aspect [1], [1-1] - [1-10] And [1-12] represents the same meaning, and Z A represents the following formula (D) or the following formula (E)
Figure JPOXMLDOC01-appb-C000084
(In the formula, R A , R 12 , A, G, L 1 , L 2 , g, j, f, and the definition of the broken line are defined in any one of the above embodiments [1], [1-1] to [1-10]. A long-chain fatty acid elongation, comprising as an active ingredient at least one of a compound represented by (in the same meaning) and a pharmaceutically acceptable salt or solvate thereof. It is an enzyme (Elovl6) inhibitor.
More specifically, definitions and preferred embodiments of R 5A , R 6A , R C , W A , R A , R A3 , R A4 , R 12 , A, G, L 1 , L 2 , g, j, f Is the same as defined in any one of Embodiments [1], [1-1] to [1-10] and [1-12].
［１－１８］本発明の第１－１８の態様は、下記式（Ｖ）
Figure JPOXMLDOC01-appb-C000085
  
（式中、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＢ、ＲＣ及びその置換基中の定義は、前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [1-18] The 1-18th aspect of the present invention is the following formula (V)
Figure JPOXMLDOC01-appb-C000085
(In the formula, n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R B , R C and the definitions in the substituents thereof are defined in the above-mentioned embodiments [1], [1 -1] to [1-10]), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient It is a long chain fatty acid elongation enzyme (Elovl6) inhibitor characterized by these.
　より具体的には、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＢ及びその置換基中の定義及び好ましい態様は、前記態様［１］及び［１－１］～［１－１０］のいずれかに記載の定義に記載の定義と同じである。 More specifically, n, m, p, Y , W, Z, R 1, R 2, R 3, R 4, R B and defined in the substituent and preferred embodiment, the aspect [1] and This is the same as the definition described in the definition described in any one of [1-1] to [1-10].
［１－１９］本発明の第１－１９の態様は、下記式（ＶＩ）
Figure JPOXMLDOC01-appb-C000086
  
（式中、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＣ及びその置換基中の定義は、前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤である。 [1-19] The 1-19th aspect of the present invention is the following formula (VI)
Figure JPOXMLDOC01-appb-C000086
(Wherein, n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the definitions in the substituents are defined in the above-mentioned embodiments [1], [1-1]. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient. It is a long chain fatty acid elongation enzyme (Elovl6) inhibitor.
　より具体的には、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＣ及びその置換基中の定義及び好ましい態様は、前記態様［１］及び［１－１］～［１－１０］のいずれかに記載の定義に記載の定義と同じである。 More specifically, the definitions and preferred embodiments of n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the substituents thereof are the above-described embodiments [1] and This is the same as the definition described in any one of [1-1] to [1-10].
　本明細書中、とりわけ本発明の第１の態様において、当該阻害剤に用いる化合物は、Ｅｌｏｖｌ６阻害作用を有し、Ｅｌｏｖｌ６が関与する各種疾患、例えば、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性、高インスリン血症、耐糖能異常（ＩＧＴ）・空腹時血糖異常（ＩＦＧ）、空腹時高血糖状態、肥満・肥満症、もしくはこれらに起因ないし関連する各種疾患の処置剤として有望な治療効果が期待できる。 In the present specification, particularly in the first aspect of the present invention, the compound used as the inhibitor has an Elovl6 inhibitory action, and various diseases involving Elovl6, such as NAFLD / NASH, diabetes, insulin resistance, high Expected to have promising therapeutic effects as a treatment for insulinemia, impaired glucose tolerance (IGT) / fasting glycemia (IFG), fasting hyperglycemia, obesity / obesity, or various diseases caused by or related to these .
　本発明のＥｌｏｖｌ６阻害剤は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性、高インスリン血症、耐糖能異常（ＩＧＴ）・空腹時血糖異常（ＩＦＧ）、空腹時高血糖状態、肥満・肥満症、もしくはこれらに起因ないし関連する各種疾患に有用である。 The Elovl6 inhibitor of the present invention is NAFLD / NASH, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT) / fasting blood glucose abnormality (IFG), fasting hyperglycemia, obesity / obesity, or It is useful for various diseases caused by or related to these.
　ここで定義される“ＮＡＦＬＤ”とは、明らかな飲酒歴がないが、アルコール性肝障害に類似した主に大滴性の肝脂肪沈着を特徴とする肝障害であり、単純性脂肪肝から脂肪性肝炎、線維化、肝硬変、肝癌までの肝障害を含む疾患群である。ウイルス性肝疾患、自己免疫疾患性肝疾患、ヘマクロトーシスやＷｉｌｓｏｎ病等の代謝性肝疾患などは除外される。ＮＡＦＬＤは非アルコール性脂肪肝とも言い、予後良好な単純性脂肪肝と、予後不良な進行性のＮＡＳＨを含む疾患概念である。
　“ＮＡＳＨ”は、ＮＡＦＬＤの重症型と考えられており、ＮＡＦＬＤのうち肝細胞の炎症や線維化を伴う進行性の疾患である。アルコール性肝障害、ウイルス性肝炎や薬剤性肝障害の否定できる肝炎の多くがＮＡＳＨの病態であるとされている。メタボリックシンドロームを背景に、脂質代謝異常、高血圧、糖尿病、インスリン抵抗性・耐糖能異常、肥満・肥満症等の合併頻度が非常に高く、病態が進展すると、肝硬変や肝癌への進行がみられる。これらの疾患が、ＮＡＦＬＤ・ＮＡＳＨに起因ないし関連する疾患である。
　ＮＡＦＬＤ・ＮＡＳＨの治療とは、本発明のＥｌｏｖｌ６阻害作用を有する化合物または当該化合物を含有する医薬組成物をＮＡＦＬＤ・ＮＡＳＨ患者に投与することを示す。上記の合併症を伴う際には、それらの治療が最優先治療である。それに加え、酸化ストレスやインスリン抵抗性などＮＡＳＨの重要な病態の改善が治療の成果として挙げられる。 “NAFLD” as defined here is a liver disorder characterized by mainly large-scale hepatic fat deposition, similar to alcoholic liver disorder, although there is no clear drinking history. It is a group of diseases including hepatic disorder such as hepatitis, fibrosis, cirrhosis, and liver cancer. Viral liver diseases, autoimmune disease liver diseases, metabolic liver diseases such as hemacrotosis and Wilson disease are excluded. NAFLD is also called non-alcoholic fatty liver and is a disease concept including simple fatty liver with good prognosis and progressive NASH with poor prognosis.
“NASH” is considered to be a severe form of NAFLD, and is a progressive disease of NAFLD accompanied by inflammation and fibrosis of hepatocytes. Many hepatitis that can be denied alcoholic liver disorder, viral hepatitis and drug-induced liver disorder are considered to be the pathological condition of NASH. Against the background of metabolic syndrome, the frequency of complications such as abnormal lipid metabolism, hypertension, diabetes, insulin resistance / glucose tolerance, obesity / obesity, etc. is very high. These diseases are caused by or related to NAFLD / NASH.
The treatment of NAFLD / NASH means that a compound having an Elovl6 inhibitory action of the present invention or a pharmaceutical composition containing the compound is administered to a NAFLD / NASH patient. When accompanied by the above complications, their treatment is the first priority treatment. In addition, improvement of NASH's important pathological conditions such as oxidative stress and insulin resistance can be mentioned as a result of treatment.
　また“糖尿病”とは、１型糖尿病（ＩＤＤＭ、インスリン依存性糖尿病として知られている）と２型糖尿病（ＮＩＤＤＭ、インスリン非依存性糖尿病として知られている）の両者を含む。 Also, “diabetes” includes both type 1 diabetes (IDDM, known as insulin-dependent diabetes) and type 2 diabetes (NIDDM, known as non-insulin-dependent diabetes).
　糖尿病は、空腹時血糖値が１２６ｍｇ／ｄｌ以上または随時血糖値もしくは７５ｇ経口ブドウ糖負荷試験（ＯＧＴＴ）２時間値が２００ｍｇ／ｄｌ以上を示す事を特徴とする。境界型である耐糖能障害とは、空腹時血糖値が１１０ｍｇ／ｄｌ以上１２６ｍｇ／ｄｌ未満である空腹時血糖異常（ＩＦＧ）、または７５ｇＯＧＴＴ２時間値が１４０ｍｇ／ｄｌ以上２００ｍｇ／ｄｌ未満である耐糖能異常（ＩＧＴ）をさす。 Diabetes is characterized by a fasting blood glucose level of 126 mg / dl or higher, or an occasional blood glucose level or a 75 g oral glucose tolerance test (OGTT) 2-hour value of 200 mg / dl or higher. Glucose intolerance, which is a boundary type, is a fasting blood glucose abnormality (IFG) in which a fasting blood glucose level is 110 mg / dl or more and less than 126 mg / dl, or a glucose tolerance having a 75 gOGTT 2 hour value of 140 mg / dl or more and less than 200 mg / dl. Indicates an abnormality (IGT).
　インスリン抵抗性とは、生体においてインスリンが血糖を降下させることが出来なくなった病態を指し、臨床において定量グルコースクランプ法やＨＯＭＡ－ＩＲにより評価される。インスリン抵抗性は高インスリン血症をきたし、高血圧症・冠動脈疾患のリスクとなることが知られている。 Insulin resistance refers to a pathological condition in which insulin is unable to lower blood sugar in the living body, and is clinically evaluated by quantitative glucose clamp method or HOMA-IR. It is known that insulin resistance causes hyperinsulinemia and is a risk of hypertension and coronary artery disease.
　糖尿病の治療とは、本発明のＥｌｏｖｌ６阻害作用を有する化合物または当該化合物を含有する医薬組成物を糖尿病患者に投与することを示す。治療の成果は、インスリン感受性を増加させ、上昇した血中インスリン及びグルコース濃度を低減させることにある。 Treatment of diabetes refers to administration of a compound having an Elovl6 inhibitory activity of the present invention or a pharmaceutical composition containing the compound to a diabetic patient. The outcome of treatment is to increase insulin sensitivity and reduce elevated blood insulin and glucose levels.
　また“肥満症”とは、「肥満に起因ないし関連する健康障害を合併するか、その合併が予測される場合で、医学的に減量を必要とする病態」と日本肥満学会により定義されている。ここで定義される“肥満”とは、ＢＭＩ（身体質量指数、ｋｇ／ｍ２）により評価される。一般的にＢＭＩが２５以上を肥満と診断する。治療の成果として、ＢＭＩを軽減することが挙げられる。 “Obesity” is defined by the Japanese Society of Obesity as “a medical condition that is associated with or is predicted to be associated with obesity and is a medical condition that requires medical weight loss”. . “Obesity” as defined herein is evaluated by BMI (body mass index, kg / m 2 ). Generally, a BMI of 25 or more is diagnosed as obesity. As a result of treatment, reduction of BMI can be mentioned.
［２］　本発明の第２の態様は、下記式（Ｉ）－Ａ
Figure JPOXMLDOC01-appb-C000087
  
（式中、Ｒ５Ａ、Ｒ６Ａ、ＷＡ、ＺＡ及びそれらの定義中に定義される置換基は、前記と同一の意味を表し、Ｒｉｎｇ－Ａは、下記式（Ｇ）または（Ｈ）
Figure JPOXMLDOC01-appb-C000088
  
（式中、Ｒ１７、Ｒ１８、ＲＣ、Ｅ、破線及びその定義中の定義される置換基は、前記と同一の意味を表す）で表される基を表す。但し、Ｒ１７が水素原子である場合；
Ｒｉｎｇ－Ａが式（Ｇ）である場合に、
　ＷＡが－ＮＲ８ＣＯ－であり、Ｒ１７、Ｒ１８がそれらが結合するベンゼン環上の炭素原子と５～８員の環状基を形成しており、且つＺＡが前記式（Ｄ）である場合（ＷＯ２００４／０５８７０９号公報）；
Ｒｉｎｇ－Ａが式（Ｇ）である場合に、
　ＷＡが－ＮＲ８ＣＯ－であり、ＺＡが前記式（Ｄ）であり、ＲＡがハロゲン原子、ヒドロキシル基、ニトロ基、Ｃ１～４アルキル基、トリフルオロメチル基、Ｃ１～４アルコキシル基、基：－Ｙ－Ｒ’（ここで、Ｙは－Ｏ－または－ＮＲ’’（Ｒ’’は水素原子またはＣ１～４アルキル）であり、Ｒ’は、アリール基、カルボキシ基及び低級アルコキシカルボニル基から選ばれる置換基で置換されていてもよいＣ１～４アルキル基、ハロゲン原子で置換されていても良いＣ１～４アルキルスルホニル基、またはカルボキシ基で置換されていてもよいアリール基）、アミノ基、カルボキシル基、Ｃ２～５アのアルコキシカルボニル基、Ｃ２～５アルカノイルアミノ基、アミノスルホニル基、Ｃ２～５アルカノイル基、Ｃ１～４アルキルスルホニル基、ＯＨ及びＣ１～４アルキルから選ばれる基で置換されていても良いカルバモイル基またはシアノ基からなる群から任意に選ばれる基であり、且つｇが１～３である場合（ＷＯ２００１／０６２７１８号公報）；
Ｒｉｎｇ－Ａが式（Ｇ）である場合に、
　ＷＡが、－ＣＯＮＲ７－であり、Ｒ１７がヒドロキシル基であり、且つＺＡが前記式（Ｄ）である場合（ＷＯ２００６／１２０１７８号公報、ＷＯ２００１／０４７５０９号公報、ＷＯ２００３／１０３６４８号公報）；
Ｒｉｎｇ－Ａが式（Ｇ）である場合に、
　ＷＡは、－ＮＲ８ＣＯ－であり、ＺＡが前記式（Ｄ）であり、且つＲＡが２位のカルボキシル基である場合（ＷＯ２００５／１１５３７４号公報）；
Ｒｉｎｇ－Ａが式（Ｇ）である場合に、
　ＷＡが－ＮＲ９ＣＯＮＲ１０－であり、Ｒ１７がヒドロキシル基であり、前記式（Ｄ）であり、且つＲＡが１Ｈ－ピラゾール－５－イル基である場合（ＷＯ２００７／００２５５９号公報）；
Ｒｉｎｇ－Ａが式（Ｇ）である場合に、
ＷＯ２００９／１３１０６５号公報に開示された化合物である場合；
Ｒｉｎｇ－Ａが式（Ｈ）である場合には、
　ＷＡが－ＣＯＮＲ７－であり、ＺＡが前記式（Ｄ）であり、且つＲＡがアリールまたはヘテロアリールである場合（ＷＯ２００５／０９２８８１号公報）；
を各々除く）
で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。 [2] A second aspect of the present invention is the following formula (I) -A
Figure JPOXMLDOC01-appb-C000087
(Wherein R 5A , R 6A , W A , Z A and the substituents defined in these definitions have the same meaning as described above, Ring-A represents the following formula (G) or (H)
Figure JPOXMLDOC01-appb-C000088
(Wherein R 17 , R 18 , R C , E, the broken line and the substituent defined in the definition represent the same meaning as described above). Provided that R 17 is a hydrogen atom;
When Ring-A is formula (G),
W A is —NR 8 CO—, R 17 and R 18 form a 5- to 8-membered cyclic group with the carbon atom on the benzene ring to which they are bonded, and Z A is the formula (D) (WO 2004/058709);
When Ring-A is formula (G),
W A is -NR 8 CO-, a Z A is the formula (D), R A is a halogen atom, a hydroxyl group, a nitro group, C 1 ~ 4 alkyl group, trifluoromethyl group, C 1 ~ 4 alkoxyl group, group: -Y-R '(wherein, Y is -O- or -NR''is a hydrogen atom or C 1 ~ 4 alkyl), R''(R' is an aryl group, a carboxy group and lower alkoxycarbonyl optionally substituted C 1 to 4 alkyl group with a substituent selected from the group, may be substituted by a halogen atom C 1 - 4 alkylsulfonyl group, or optionally substituted by a carboxy group aryl group), an amino group, a carboxyl group, C 2 ~ 5 a alkoxycarbonyl group, C 2 ~ 5 alkanoylamino group, aminosulfonyl group, C 2 ~ 5 alkanoyl group, C 1 ~ 4 a Alkylsulfonyl group, a group selected arbitrarily from OH and C 1 ~ group consisting of a carbamoyl group or a cyano group optionally substituted by a group selected from alkyl, and when g is 1 ~ 3 (WO2001 / 062718));
When Ring-A is formula (G),
W A is, -CONR 7 - a and a R 17 is a hydroxyl group, and when Z A is the formula (D) (WO2006 / 120178 discloses, WO2001 / 047 509 and JP WO2003 / 103,648) ;
When Ring-A is formula (G),
W A is —NR 8 CO—, Z A is the formula (D), and R A is a carboxyl group at the 2-position (WO 2005/115374);
When Ring-A is formula (G),
When W A is —NR 9 CONR 10 —, R 17 is a hydroxyl group, is the formula (D), and R A is a 1H-pyrazol-5-yl group (WO2007 / 002559) ;
When Ring-A is formula (G),
In the case of the compound disclosed in WO2009 / 131055;
When Ring-A is formula (H),
W A is —CONR 7 —, Z A is the above formula (D), and R A is aryl or heteroaryl (WO 2005/092881);
Except each)
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＷＡ、ＺＡ及びそれらの定義中に定義される置換基、あるいは式（Ｄ）及び式（Ｅ）の基、Ｒ１７、Ｒ１８、ＲＣ、Ｅ、破線及びそれらの好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, R 5A , R 6A , W A , Z A and substituents defined in the definitions thereof, or groups of formula (D) and formula (E), R 17 , R 18 , R C , E, a broken line and preferred embodiments thereof are the same as defined in any one of Embodiments [1], [1-1] to [1-10] and [1-12].
　前記式（Ｉ）－Ａにおいて、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子である場合を除く）；
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。 In the formula (I) -A, R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or model / Di C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, a C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or a group selected from mono- / di-C 1 ~ 6 alkyl amino, and, R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
　好ましい態様として、以下の態様も挙げられる。 Preferred embodiments include the following embodiments.
［２－１］本発明の第２－１の態様は、下記式（Ｉ）－Ｂ
Figure JPOXMLDOC01-appb-C000089
  
（式中、Ｒ５Ａ、Ｒ６Ａ、ＷＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｊ、ｆ、破線及びそれらの定義中に定義される置換基は、前記と同一の意味を表し、Ｒｉｎｇ－Ａは、下記式（Ｇ）または（Ｈ）
Figure JPOXMLDOC01-appb-C000090
  
（式中、Ｒ１７、Ｒ１８、ＲＣ、Ｅ、破線及びその定義中の定義される置換基は、前記と同一の意味を表す）で表される基を表す。但し、Ｒ１７が水素である場合を除く）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。 [2-1] The 2-1 aspect of the present invention is the following formula (I) -B
Figure JPOXMLDOC01-appb-C000089
(Wherein R 5A , R 6A , W A , R 12 , A, G, L 1 , L 2 , j, f, the broken line and the substituents defined in those definitions have the same meaning as described above. Ring-A is represented by the following formula (G) or (H)
Figure JPOXMLDOC01-appb-C000090
(Wherein R 17 , R 18 , R C , E, the broken line and the substituent defined in the definition represent the same meaning as described above). Provided that, as an active ingredient, at least one of a compound represented by the above formula (except when R 17 is hydrogen), or a pharmaceutically acceptable salt thereof or a solvate thereof, It is a pharmaceutical composition.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＷＡ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ｊ、ｆ、破線の定義及びそれらの定義中に定義される置換基、あるいは式（Ｄ）及び式（Ｅ）の基及びそれらの好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, defined R 5A, R 6A, W A , R 12, R 17, R 18, A, G, L 1, L 2, j, f, in dashed definitions and definitions of their The substituent, or the group of the formula (D) and the formula (E) and preferred embodiments thereof are described in any one of the embodiments [1], [1-1] to [1-10] and [1-12]. The definition is the same as
　前記式（Ｉ）－Ｂにおいて、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子である場合を除く）；
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。 In the formula (I) -B, R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or model / Di C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, a C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or a group selected from mono- / di-C 1 ~ 6 alkyl amino, and, R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
［２－２］本発明の第２－２の態様は、前記式（ＩＩ）で表される化合物（但し、Ｒ１７が水素原子である場合；
　ＷＡが－ＮＲ８ＣＯ－であり、Ｒ１７、Ｒ１８がそれらが結合するベンゼン環上の炭素原子と５～８員の環状基を形成しており、且つＺＡが前記式（Ｄ）である場合（ＷＯ２００４／０５８７０９号公報）；
　ＷＡが－ＮＲ８ＣＯ－であり、ＺＡが前記式（Ｄ）であり、ＲＡがハロゲン原子、ヒドロキシル基、ニトロ基、Ｃ１～４アルキル基、トリフルオロメチル基、Ｃ１～４アルコキシル基、基：－Ｙ－Ｒ’（ここで、Ｙは－Ｏ－または－ＮＲ’’（Ｒ’’は水素原子またはＣ１～４アルキル）であり、Ｒ’は、アリール基、カルボキシ基及び低級アルコキシカルボニル基から選ばれる置換基で置換されていてもよいＣ１～４アルキル基、ハロゲン原子で置換されていても良いＣ１～４アルキルスルホニル基、またはカルボキシ基で置換されていてもよいアリール基）、アミノ基、カルボキシル基、Ｃ２～５アルコキシカルボニル基、Ｃ２～５アルカノイルアミノ基、アミノスルホニル基、Ｃ２～５アルカノイル基、Ｃ１～４アルキルスルホニル基、ＯＨ及びＣ１～４アルキルから選ばれる基で置換されていても良いカルバモイル基またはシアノ基からなる群から任意に選ばれる基であり、且つｇが１～３である場合（ＷＯ２００１／０６２７１８号公報）；
　ＷＡが、－ＣＯＮＲ７－であり、Ｒ１７がヒドロキシル基であり、且つＺＡが前記式（Ｄ）である場合（ＷＯ２００６／１２０１７８号公報、ＷＯ２００１／０４７５０９号公報、ＷＯ２００３／１０３６４８号公報）；
　ＷＡは、－ＮＲ８ＣＯ－であり、ＺＡが前記式（Ｄ）であり、且つＲＡが２位のカルボキシル基である場合（ＷＯ２００５／１１５３７４号公報）；
　ＷＡが－ＮＲ９ＣＯＮＲ１０－であり、Ｒ１７がヒドロキシル基であり、前記式（Ｄ）であり、且つＲＡが１Ｈ－ピラゾール－５－イル基である場合（ＷＯ２００７／００２５５９号公報）；
を各々除く）、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。 [2-2] The 2-2 aspect of the present invention is a compound represented by the above formula (II) (provided that R 17 is a hydrogen atom;
W A is —NR 8 CO—, R 17 and R 18 form a 5- to 8-membered cyclic group with the carbon atom on the benzene ring to which they are bonded, and Z A is the formula (D) (WO 2004/058709);
W A is -NR 8 CO-, a Z A is the formula (D), R A is a halogen atom, a hydroxyl group, a nitro group, C 1 ~ 4 alkyl group, trifluoromethyl group, C 1 ~ 4 alkoxyl group, group: -Y-R '(wherein, Y is -O- or -NR''is a hydrogen atom or C 1 ~ 4 alkyl), R''(R' is an aryl group, a carboxy group and lower alkoxycarbonyl optionally substituted C 1 to 4 alkyl group with a substituent selected from the group, may be substituted by a halogen atom C 1 - 4 alkylsulfonyl group, or optionally substituted by a carboxy group aryl group), an amino group, a carboxyl group, C 2 ~ 5 alkoxycarbonyl group, C 2 ~ 5 alkanoylamino group, aminosulfonyl group, C 2 ~ 5 alkanoyl group, C 1 ~ 4 alkyl A sulfonyl group, a group selected arbitrarily from OH and C 1 ~ group consisting of a carbamoyl group or a cyano group optionally substituted by a group selected from alkyl, and when g is 1 ~ 3 (WO2001 / No. 062718);
W A is, -CONR 7 - a and a R 17 is a hydroxyl group, and when Z A is the formula (D) (WO2006 / 120178 discloses, WO2001 / 047 509 and JP WO2003 / 103,648) ;
W A is —NR 8 CO—, Z A is the formula (D), and R A is a carboxyl group at the 2-position (WO 2005/115374);
When W A is —NR 9 CONR 10 —, R 17 is a hydroxyl group, is the formula (D), and R A is a 1H-pyrazol-5-yl group (WO2007 / 002559) ;
Or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
　前記式（ＩＩ）おいて、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子である場合を除く）； Formula (II) Oite, R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 1-6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl, C 1-6 alkoxyl, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1-6 alkoxy or mono / C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom);
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。 More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, a C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or a group selected from mono- / di-C 1 ~ 6 alkyl amino, and, R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
［２－３］本発明の第２－３の態様は、下記式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000091
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ＷＡ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表す）で表される化合物（但し、Ｒ１７が水素原子である場合を除く）、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。 [2-3] The 2-3 aspect of the present invention is the following formula (III)
Figure JPOXMLDOC01-appb-C000091
(Wherein R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, and the definition of the broken line are defined in the above aspects [1], [1-1] ] To [1-10] and represents the same meaning as any of [1-12]) (except when R 17 is a hydrogen atom), or pharmaceutically acceptable A pharmaceutical composition comprising at least one of a salt or a solvate thereof as an active ingredient.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ＷＡ、ｊ、ｆ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, the definition of a broken line, and preferred embodiments are the above-described embodiments [1 ], [1-1] to [1-10] and [1-12] have the same definition as described in any one of [1-12].
　前記式（ＩＩＩ）において、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。 In the formula (III), as R 5A and R 6A , preferably, at least one of R 5A or R 6A is a group having 3 or more constituent carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
　前記式（ＩＩＩ）において、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子・－ＯＨまたはアルコキシル基である場合を除く）；
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。
　Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）において、好ましくは、Ａを構成に含む環は芳香化しているものを含まない。 In the formula (III), R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl, C 1 1-6 alkoxyl, C 2 - 6 alkenyloxy, C 2 - 6 alkynyloxy, halogenated C 1 - 6 alkoxy or model / Di C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom · -OH or an alkoxyl group);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 is a group selected from alkylamino, and R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
In the formula (III), preferably, the ring containing A in the structure does not include an aromatic group.
　前記式（ＩＩＩ）において、ＲＡ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群の置換基は、ハロゲン原子、オキソ、ニトロ、シアノ、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ３～８シクロアルキル、Ｃ６～１４アリール、へテロ環、
保護されていてもよいヒドロキシル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、Ｃ６～１４アリールオキシ、ヘテロ環オキシ、
メルカプト、Ｃ１～６アルキルチオ、Ｃ６～１４アリールチオ、ヘテロ環チオ、Ｃ１～６アルキルスルフィニル、Ｃ６～１４アリールスルフィニル、ヘテロ環スルフィニル、Ｃ１～６アルキルスルホニル、Ｃ６～１４アリールスルホニル、ヘテロ環スルホニル、スルファモイル（当該スルファモイルは、Ｃ１～６アルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、スルホ、
アミノ（当該アミノは、Ｃ１～６アルキル・モノ／ジＣ１～６アルキルスルファモイル・モノ／ジＣ１～６アルキルカルバモイル・ホルミル・Ｃ２～７アルカノイル・Ｃ６～１４アリール・ヘテロ環・モノ／ジＣ６～１４アリールスルファモイル・モノ／ジヘテロ環スルファモイル・Ｃ６～１４アリールカルボニルもしくはヘテロ環カルボニルで置換されていてもよい）、
ホルミル、Ｃ２～７アルカノイル、Ｃ６～１４アリールカルボニル、ヘテロ環カルボニル、
保護されていてもよいカルボキシル、Ｃ１～６アルコキシカルボニル、Ｃ６～１４アリールオキシカルボニル、ヘテロ環オキシカルボニル、
カルバモイル（当該カルバモイルは、Ｃ１～６アルキル、Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）
から任意に選ばれる基を表す。 In the formula (III), the substituents of the group A are the same as defined in the embodiment [1]. That is, the substituent of the R A group is a halogen atom, oxo, nitro, cyano,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl, C 3 - 8 cycloalkyl, C 6 - 14 aryl or heteroaryl ring),
C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl, heterocycle,
Optionally protected hydroxyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy, C 6 ~ 14 aryloxy, heterocyclic oxy,
Mercapto, C 1 ~ 6 alkylthio, C 6 ~ 14 arylthio, heterocyclic thio, C 1 ~ 6 alkylsulfinyl, C 6 ~ 14 arylsulfinyl, heterocyclic sulfinyl, C 1 ~ 6 alkylsulfonyl, C 6 ~ 14 arylsulfonyl, heterocyclic sulfonyl, sulfamoyl (the sulfamoyl may be substituted with C 1 ~ 6 alkyl · C 6 ~ 14 aryl or heterocyclic), sulfo,
Amino (said amino, C 1 ~ 6 alkyl mono / di C 1 ~ 6 alkylsulfamoyl mono / di C 1 ~ 6 alkylcarbamoyl, formyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 aryl heterocycle mono / di C 6 ~ 14 may be substituted with an aryl sulfamoyl mono / diheterocyclic sulfamoyl-C 6 ~ 14 arylcarbonyl or heterocycle carbonyl),
Formyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 arylcarbonyl, heterocyclic carbonyl,
Optionally protected carboxyl, C 1 ~ 6 alkoxycarbonyl, C 6 ~ 14 aryloxycarbonyl, heterocyclic oxycarbonyl,
Carbamoyl (said carbamoyl, C 1 ~ 6 alkyl, optionally substituted with C 6 ~ 14 aryl or hetero ring)
Represents a group arbitrarily selected from
　前記式（ＩＩＩ）において、ＲＢ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＢ群の置換基は、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ３～８シクロアルキル、Ｃ６～１４アリール、へテロ環、
Ｃ１～６アルキルスルホニル、Ｃ６～１４アリールスルホニル、ヘテロ環スルホニル、スルファモイル（当該スルファモイルは、Ｃ１～６アルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ２～７アルカノイル、Ｃ６～１４アリールカルボニル、ヘテロ環カルボニル、
Ｃ１～６アルコキシカルボニル、Ｃ６～１４アリールオキシカルボニル、ヘテロ環オキシカルボニル、
カルバモイル（当該カルバモイルは、Ｃ１～６アルキル、Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）
から任意に選ばれる基を表す。 In the formula (III), substituent group R B are as defined according to the aspect [1]. That is, the substituent of the group R B is,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl, C 3 - 8 cycloalkyl, C 6 - 14 aryl or heteroaryl ring),
C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl, heterocycle,
C 1 ~ 6 alkylsulfonyl, C 6 ~ 14 arylsulfonyl, heterocyclic sulfonyl, sulfamoyl (the sulfamoyl may be substituted with C 1 ~ 6 alkyl · C 6 ~ 14 aryl or heterocycle),
C 2 ~ 7 alkanoyl, C 6 ~ 14 arylcarbonyl, heterocyclic carbonyl,
C 1 ~ 6 alkoxycarbonyl, C 6 ~ 14 aryloxycarbonyl, heterocyclic oxycarbonyl,
Carbamoyl (said carbamoyl, C 1 ~ 6 alkyl, optionally substituted with C 6 ~ 14 aryl or hetero ring)
Represents a group arbitrarily selected from
　前記式（ＩＩＩ）において、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＣ群の置換基は、ハロゲン原子、オキソ、ニトロ、シアノ、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイルもしくはＣ３～８シクロアルキルで置換されていてもよい）、
Ｃ３～８シクロアルキル、
保護されていてもよいヒドロキシル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、
メルカプト、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、スルファモイル、モノ／ジＣ１～６アルキルスルファモイル、スルホ、
アミノ（当該アミノは、Ｃ１～６アルキル・モノ／ジＣ１～６アルキルスルファモイル・モノ／ジＣ１～６アルキルカルバモイル・ホルミルもしくはＣ２～７アルカノイルで置換されていてもよい）、
ホルミル、Ｃ２～７アルカノイル、
保護されていてもよいカルボキシル、Ｃ１～６アルコキシカルボニル、
カルバモイルもしくはモノ／ジＣ１～６アルキルカルバモイルから任意に選ばれる基を表す。 In the formula (III), the substituents of the RC group are the same as defined in the embodiment [1]. That is, the substituent of the RC group includes a halogen atom, oxo, nitro, cyano,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl or C 3 - 8 cycloalkyl),
C 3 ~ 8 cycloalkyl,
Optionally protected hydroxyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy,
Mercapto, C 1 ~ 6 alkylthio, C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkyl sulfamoyl, sulfo,
Amino (said amino may be substituted by C 1 ~ 6 alkyl mono / di C 1 ~ 6 alkylsulfamoyl mono / di C 1 ~ 6 alkylcarbamoyl, formyl or C 2 ~ 7 alkanoyl),
Formyl, C 2 ~ 7 alkanoyl,
Optionally carboxyl which may be protected, C 1 ~ 6 alkoxycarbonyl,
Carbamoyl or mono / di-C 1 ~ 6 chosen group from alkylcarbamoyl optionally.
［２－３－ａ］本発明の第２－３－ａの態様は、下記式（ＩＩＩ）－Ａ
Figure JPOXMLDOC01-appb-C000092
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義は前記態様［１］、［１－１］～［１－１０］、［１－１２］及び［１－１５］のいずれかと同一の意味を表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。 [2-3-a] The 2-3-a aspect of the present invention is the following formula (III) -A
Figure JPOXMLDOC01-appb-C000092
(In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to At least a compound represented by [1-10], [1-12] and [1-15], or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition comprising one as an active ingredient.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］、［１－１２］及び［１－１５］のいずれかに記載の定義と同じである。 More specifically, the definitions and preferred embodiments of R 5A , R 6A , R 12 , R 18 , A a , G a , L 1a , L 2a , W A , broken line are the above-mentioned embodiments [1], [1- 1] to [1-10], [1-12], and the same definition as described in any of [1-15].
　前記式（ＩＩＩ）－Ａにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。 In the formula (III) -A, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
　前記式（ＩＩＩ）－Ａにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子であり、より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。
　Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ａにおいて、好ましくは、Ａａを構成に含む環は芳香化しているものを含まない。 In the formula (III) -A, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and a R 18 is a hydrogen atom, more preferably, R 17A is C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
In the formula (III) -A, preferably, the ring containing A a does not include an aromatic group.
　前記式（ＩＩＩ）－Ａにおいて、ＷＡあるいはＲ１２の置換位置は、フェニル部分の炭素原子の位置で示すことができる。ＷＡであれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。ＷＡは、３番目の炭素原子に結合していることがより好ましい。 In the above formula (III) -A, the substitution position of W A or R 12 can be indicated by the position of the carbon atom of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. W A is more preferably bonded to the third carbon atoms.
　前記式（ＩＩＩ）－Ａにおいて、ＲＡ群、ＲＢ群、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群、ＲＢ群、ＲＣ群の置換基は、前記態様［２－３］に記載の定義と同じである。 In the formula (III) -A, the substituents in the groups R A , R B and R C are the same as defined in the embodiment [1]. That is, the substituents of the R A group, the R B group, and the R C group are the same as defined in the above embodiment [2-3].
［２－３－ｂ］本発明の第２－３－ｂの態様は、前記態様［２－３－ａ］より好ましい態様であり、下記式（ＩＩＩ）－Ｂ
Figure JPOXMLDOC01-appb-C000093
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義は前記態様［１］、［１－１］～［１－１０］、［１－１２］及び［１－１５］のいずれかと同一の意味を表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。Ａａを構成に含む環は芳香化しているものを含まない。 [2-3-b] The embodiment 2-3b of the present invention is a more preferred embodiment than the embodiment [2-3-a], and is represented by the following formula (III) -B
Figure JPOXMLDOC01-appb-C000093
(In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to At least a compound represented by [1-10], [1-12] and [1-15], or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition comprising one as an active ingredient. The ring containing A a does not include those that are aromatized.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び、［１－１２］及び［１－１５］のいずれかに記載の定義と同じである。 More specifically, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , the definition and preferred embodiments of the broken line are the above-described embodiments [1], The definition is the same as described in any one of [1-1] to [1-10] and [1-12] and [1-15].
　前記式（ＩＩＩ）－Ｂにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。
　より好ましくは、Ｒ５Ａ、Ｒ６Ａは、各々独立に、水素原子、Ｃ１～６の直鎖もしくは分枝鎖のアルキル基またはＣ３～８のシクロアルキル基を表し（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基であるり、Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに４～６員の環状基を形成していてもよく、当該環状基はその環内の炭素原子が酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）で置き換えられていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、－ＮＲ５ＡＲ６Ａとして、より具体的には、以下の式で表わされることが好ましい。
Figure JPOXMLDOC01-appb-C000094
   In the formula (III) -B, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
More preferably, R 5A, R 6A are each independently a hydrogen atom, a cycloalkyl group of C 1 ~ linear or branched alkyl group or a C 3 ~ 8 (where, R 5A or R At least one of 6A is a group having 3 or more carbon atoms, or R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded. carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ~ 6 have been.
In the formula (III) -B, as —NR 5A R 6A , more specifically, it is preferably represented by the following formula.
Figure JPOXMLDOC01-appb-C000094
　前記式（ＩＩＩ）－Ｂにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子であり、より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。 In the formula (III) -B, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and a R 18 is a hydrogen atom, more preferably, R 17A is C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
　前記式（ＩＩＩ）－Ｂにおいて、Ａａを含む縮合環は、下記式（Ｅ１ａ）
Figure JPOXMLDOC01-appb-C000095
  
（式中、Ｒ１２、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１－４－ｂ］および［１－４－ｄ－１２］と同一の意味を表す）で表される基であり、ＡａとＧａ間の破線は当該元素間の結合が、適宜単結合もしくは二重結合をとる。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ａａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、またはカルボニル基を表し、
Ｇａはメチレン基、カルボニル基またはスルホニル基を表し、
Ｌ１ａは、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ１ａは酸素原子である）、
Ｌ２ａは、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ２ａは単結合または－（ＣＲ１５ＣＲ１５Ｄ）ｕ－である）；
Ｒ１３、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄ、Ｒ１６Ａ、Ｒ１６Ｂの定義は前記態様［１－４－ｂ］と同一の意味を表し、好ましい態様は前記態様［１－４－ｄ－３］及び［１－４－ｄ－５］と同一である。
　第２－３－ｂの態様において、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄは、各々独立に、水素原子、ハロゲン原子、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いＣ１～６アルキル基、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いアミノ基または保護されていても良いヒドロキシル基から任意に選ばれる基が好ましく、
Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、Ａａは－ＮＲ１３－であることが好ましい。 In the formula (III) -B, the condensed ring containing A a is represented by the following formula (E1a)
Figure JPOXMLDOC01-appb-C000095
(Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]). a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
In the above formula (III) -B and the above formula (E1a), R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group. good C 1 ~ 4 alkyl group, optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ~ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
In the formula (III) -B and the above formula (E1a), A a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group,
G a represents a methylene group, a carbonyl group or a sulfonyl group,
L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom),
L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
The definitions of R 13 , R 14A , R 14B , R 15A , R 15B , R 15C , R 15D , R 16A , R 16B represent the same meaning as in the above embodiment [1-4-b], and a preferable embodiment is the above embodiment. The same as [1-4-d-3] and [1-4-d-5].
In the 2-3rd embodiment, R 14A , R 14B , R 15A , R 15B , R 15C , R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH · —NH 2. chosen optionally substituted C 1 ~ 6 alkyl group in group, -OH · --NH2 · optionally substituted with chosen groups arbitrarily from -COOH heterocyclic group, optionally selected from R C group optionally substituted C 1 to 6 alkoxy group with a group, mono group substituted by C 1 may also be ~ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group,
R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with 1-5 optionally substituted straight or alkoxyl substituted with an alkyl group of C 1 ~ 6 branched may be replaced by also good), the cyclic group may be further substituted by a group selected arbitrarily from R C groups.
In the formula (III) -B, A a is preferably —NR 13 —.
　式（Ｅ１ａ）において、ＷＡあるいはＲ１２の置換位置は、前記態様［１－４－ｄ－１１］と同様に、フェニル部分の炭素原子の位置で示すことができる。ＷＡであれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。
Figure JPOXMLDOC01-appb-C000096
  
式（Ｅ１ａ）においてＷＡの結合位置は、具体的には、下記式（Ｅ１ａ－１）－ｂおよび（Ｅ１ａ－２）－ｂであることが好ましい。
Figure JPOXMLDOC01-appb-C000097
   In formula (E1a), substitution positions of W A or R 12 is, similarly to the embodiment [1-4-d-11], can be indicated by the position of the carbon atoms of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms.
Figure JPOXMLDOC01-appb-C000096
Bonding position of W A in formula (E1a), specifically, it is preferably the following formula (E1a-1) -b and (E1a-2) -b.
Figure JPOXMLDOC01-appb-C000097
　前記式（Ｅ１ａ）において、より具体的には、以下に示される式から任意に選択される。
Figure JPOXMLDOC01-appb-C000098
  
Figure JPOXMLDOC01-appb-C000099
  
　前記式（Ｅ１ａ）において、具体的には、好ましくは、前記式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。より好ましくは、式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。 More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000099
In the formula (E1a), specifically, preferably, the formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), (c c208) to (c240). More preferable examples include formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), and (c208) to (c240).
　前記式（ＩＩＩ）－Ｂにおいて、ＷＡは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０は、各々独立に水素原子またはＣ１～６アルキル基を表す）を表し；－ＣＯＮＲ７－であることが好ましい。 In the formula (III) -B, W A is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or C 1 ~ 6 alkyl represents a group); -CONR 7 - is preferably.
　前記式（ＩＩＩ）－Ｂにおいて、ＲＡ群、ＲＢ群、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群、ＲＢ群、ＲＣ群の置換基は、前記態様［２－３］に記載の定義と同じである。 In the formula (III) -B, the substituents of the groups R A , R B , and R C are the same as defined in the above embodiment [1]. That is, the substituents of the R A group, the R B group, and the R C group are the same as defined in the above embodiment [2-3].
［２－３－ｃ］本発明の第２－３－ｃの態様は、前記態様［２－３－ｂ］より好ましい態様であり、下記式（ＩＩＩ）－Ｃ
Figure JPOXMLDOC01-appb-C000100
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１］、［１－１］～［１－１０］、［１－１２］、［１－１５］及び［１－１５－ｂ］のいずれかと同一の意味を表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。 [2-3-c] The embodiment 2-3-3 of the present invention is a more preferred embodiment than the embodiment [2-3-b], and is represented by the following formula (III) -C
Figure JPOXMLDOC01-appb-C000100
(In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , and the definition of the broken line are defined in the above aspects [1], [1-1] to [1-] 10], [1-12], [1-15] and any one of [1-15-b]), or a pharmaceutically acceptable salt thereof or a compound thereof A pharmaceutical composition comprising at least one solvate as an active ingredient.
　前記式（ＩＩＩ）－Ｃにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。
　より好ましくは、Ｒ５Ａ、Ｒ６Ａは、各々独立に、水素原子、Ｃ１～６の直鎖もしくは分枝鎖のアルキル基またはＣ３～６のシクロアルキル基であり（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である）、Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに４～６員の環状基を形成していてもよく、当該環状基はその環内の炭素原子が酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）で置き換えられていてもよい。
　前記式（ＩＩＩ）－Ｃにおいて、－ＮＲ５ＡＲ６Ａとして、より具体的には、以下の式で表わされることが好ましい。
Figure JPOXMLDOC01-appb-C000101
   In the formula (III) -C, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
More preferably, R 5A, R 6A are each independently hydrogen atom, a linear or branched alkyl group or cycloalkyl group C 3 ~ 6 of C 1 ~ 6 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ~ 6 have been.
In the formula (III) -C, as —NR 5A R 6A , more specifically, it is preferably represented by the following formula.
Figure JPOXMLDOC01-appb-C000101
　前記式（ＩＩＩ）－Ｃにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子であり、より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　前記式（ＩＩＩ）－Ｃにおいて、Ａａを含む縮合環は、下記式（Ｅ１ａ）
Figure JPOXMLDOC01-appb-C000102
  
（式中、Ｒ１２、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１－４－ｂ］および［１－４－ｄ－１２］と同一の意味を表す）で表される基であり、ＡａとＧａ間の破線は当該元素間の結合が、適宜単結合もしくは二重結合をとる。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ａａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、またはカルボニル基を表し、
Ｇａはメチレン基、カルボニル基またはスルホニル基を表し、
Ｌ１ａは、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ１ａは酸素原子である）、
Ｌ２ａは、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ２ａは単結合または－（ＣＲ１５ＣＲ１５Ｄ）ｕ－である）；
Ｒ１３、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄ、Ｒ１６Ａ、Ｒ１６Ｂの定義は前記態様［１－４－ｂ］と同一の意味を表し、好ましい態様は前記態様［１－４－ｄ－３］及び［１－４－ｄ－５］と同一である。
　第１－１５－ｂの態様において、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄは、各々独立に、水素原子、ハロゲン原子、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いＣ１～６アルキル基、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いアミノ基または保護されていても良いヒドロキシル基から任意に選ばれる基が好ましく、
Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、Ａａは－ＮＲ１３－であることが好ましい。 In the formula (III) -C, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and a R 18 is a hydrogen atom, more preferably, R 17A is C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
In the formula (III) -C, the condensed ring containing A a is represented by the following formula (E1a)
Figure JPOXMLDOC01-appb-C000102
(Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]). a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
In the above formula (III) -B and the above formula (E1a), R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group. good C 1 ~ 4 alkyl group, optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ~ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
In the formula (III) -B and the above formula (E1a), A a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group,
G a represents a methylene group, a carbonyl group or a sulfonyl group,
L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom),
L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
The definitions of R 13 , R 14A , R 14B , R 15A , R 15B , R 15C , R 15D , R 16A , R 16B represent the same meaning as in the above embodiment [1-4-b], and a preferable embodiment is the above embodiment. The same as [1-4-d-3] and [1-4-d-5].
In the 1-15-b embodiment, R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH · —NH 2. chosen optionally substituted C 1 ~ 6 alkyl group in group, -OH · --NH2 · optionally substituted with chosen groups arbitrarily from -COOH heterocyclic group, optionally selected from R C group optionally substituted C 1 to 6 alkoxy group with a group, mono group substituted by C 1 may also be ~ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group,
R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with 1-5 optionally substituted straight or alkoxyl substituted with an alkyl group of C 1 ~ 6 branched may be replaced by also good), the cyclic group may be further substituted by a group selected arbitrarily from R C groups.
In the formula (III) -B, A a is preferably —NR 13 —.
　式（Ｅ１ａ）において、－ＣＯＮＲ７－あるいはＲ１２の置換位置は、前記態様［１－４－ｄ－１１］と同様に、フェニル部分の炭素原子の位置で示すことができる。－ＣＯＮＲ７－であれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。
Figure JPOXMLDOC01-appb-C000103
  
式（Ｅ１ａ）において－ＣＯＮＲ７－の結合位置は、具体的には、下記式（Ｅ１ａ－１）－ｃおよび（Ｅ１ａ－２）－ｃであることが好ましい。
Figure JPOXMLDOC01-appb-C000104
  
　前記式（Ｅ１ａ）において、より具体的には、以下に示される式から任意に選択される。
Figure JPOXMLDOC01-appb-C000105
  
Figure JPOXMLDOC01-appb-C000106
  
　前記式（Ｅ１ａ）において、具体的には、好ましくは、前記式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。より好ましくは、式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。 In the formula (E1a), the substitution position of —CONR 7 — or R 12 can be represented by the position of the carbon atom of the phenyl moiety, as in the above embodiment [1-4-d-11]. In the case of —CONR 7 —, it is preferable that L 1a is bonded to the first or third carbon atom, counting clockwise from a position close to the carbon atom to which L 1a is bonded.
Figure JPOXMLDOC01-appb-C000103
Specifically, the bonding position of —CONR 7 — in the formula (E1a) is preferably the following formulas (E1a-1) -c and (E1a-2) -c.
Figure JPOXMLDOC01-appb-C000104
More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000106
In the formula (E1a), specifically, preferably, the formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), (c c208) to (c240). More preferable examples include formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), and (c208) to (c240).
［２－４］本発明の第２－４の態様は、下記式（ＩＶ）
Figure JPOXMLDOC01-appb-C000107
  
（式中、Ｅは、非存在、基：－ＣＲＡ３ＲＡ４－、エチレン基、酸素原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良く、Ｅが－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し、ＥとＷが結合した炭素原子との間の実線と破線は単結合もしくは二重結合を形成しうることを示し、
ＹＡは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ６～１４のアリール基、または基：－ＮＲ５ＡＲ６Ａを表し；
Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＷＡの定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表し、ＺＡは、下記式（Ｄ）または下記式（Ｅ）
Figure JPOXMLDOC01-appb-C000108
  
（式中、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表す）で表される化合物（但し、ＷＡが－ＣＯＮＲ７－であり、ＺＡが前記式（Ｄ）であり、且つＲＡがアリールまたはヘテロアリールである場合（ＷＯ２００５／０９２８８１号公報）を除く）、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、医薬組成物である。 [2-4] The 2-4th aspect of the present invention is the following formula (IV)
Figure JPOXMLDOC01-appb-C000107
(Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 1 ~ 5 amino optionally substituted straight or branched chain with either an alkoxylated C With 1 to 6 alkyl groups The cyclic group may further have a substituent), and a solid line and a broken line between E and W bonded carbon atoms are simply Indicates that a bond or double bond can be formed;
Y A is substituted by a group selected from straight or branched chain alkyl groups of R C optionally substituted by a group selected C 1 ~ from group 6, the R C groups optionally good C 3 ~ cycloalkyl group 8, aryl group R C may be substituted with chosen groups arbitrarily from the group C 6 ~ 14 or group: represents -NR 5A R 6A;
R 5A, R 6A, the definition of R C, W A the aspect [1], represent the same meaning as any one of [1-1] - [1-10] and [1-12], the Z A, The following formula (D) or the following formula (E)
Figure JPOXMLDOC01-appb-C000108
(In the formula, R A , R 12 , A, G, L 1 , L 2 , g, j, f, and the definition of the broken line are defined in any one of the above embodiments [1], [1-1] to [1-10]. (Wherein W A is —CONR 7 —, Z A is the above formula (D), and R A is aryl or heteroaryl (representing the same meaning)) WO 2005/092881)), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＷＡ、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆの定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, the definitions and preferred embodiments of R 5A , R 6A , R C , W A , R A , R 12 , A, G, L 1 , L 2 , g, j, f are the above-mentioned embodiments [1 ], [1-1] to [1-10] and [1-12] are the same as defined above.
［２－５］本発明の第２－５の態様は、下記式（ＩＶ－ａ）
Figure JPOXMLDOC01-appb-C000109
  
（式中、Ｅは、非存在、基：－ＣＲＡ３ＲＡ４－、エチレン基、酸素原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良く、Ｅが－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し、
ＥとＷが結合した炭素原子との間の実線と破線は単結合もしくは二重結合を形成しうることを示し、Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＷＡの定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表し、ＺＡは、下記式（Ｄ）または下記式（Ｅ）
Figure JPOXMLDOC01-appb-C000110
  
（式中、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表す）で表される化合物（但し、ＷＡが－ＣＯＮＲ７－であり、ＺＡが前記式（Ｄ）であり、且つＲＡがアリールまたはヘテロアリールである場合（ＷＯ２００５／０９２８８１号公報）を除く）、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。 [2-5] A second to fifth aspect of the present invention is the following formula (IV-a)
Figure JPOXMLDOC01-appb-C000109
(Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 1 ~ 5 amino optionally substituted straight or branched chain with either an alkoxylated C With 1 to 6 alkyl groups Which may be substituted), and the cyclic group may further have a substituent),
Solid and broken lines between the carbon atoms to which E and W is attached is shown that can form a single bond or a double bond, R 5A, R 6A, R C, the definition of W A is the aspect [1], [1-1] to [1-10] represents the same meaning as any one of [1-12], and Z A represents the following formula (D) or the following formula (E)
Figure JPOXMLDOC01-appb-C000110
(In the formula, R A , R 12 , A, G, L 1 , L 2 , g, j, f, and the definition of the broken line are defined in any one of the above embodiments [1], [1-1] to [1-10]. (Wherein W A is —CONR 7 —, Z A is the above formula (D), and R A is aryl or heteroaryl (representing the same meaning)) WO2005 / 092881)), or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
［２－６］本発明の第２－６の態様は、下記式（Ｖ）
Figure JPOXMLDOC01-appb-C000111
  
（式中、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＢ、ＲＣ及びその置換基中の定義は、前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）
で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、医薬組成物である。 [2-6] A second to sixth aspect of the present invention is the following formula (V)
Figure JPOXMLDOC01-appb-C000111
(In the formula, n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R B , R C and the definitions in the substituents thereof are defined in the above-mentioned embodiments [1], [1 -1] to [1-10] have the same meaning)
Or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
　より具体的には、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＢ及びその置換基中の定義及び好ましい態様は、前記態様［１］及び［１－１］～［１－１０］のいずれかに記載の定義に記載の定義と同じである。 More specifically, n, m, p, Y , W, Z, R 1, R 2, R 3, R 4, R B and defined in the substituent and preferred embodiment, the aspect [1] and This is the same as the definition described in the definition described in any one of [1-1] to [1-10].
［２－７］本発明の第２－７の態様は、下記式（ＶＩ）
Figure JPOXMLDOC01-appb-C000112
  
（式中、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＣ及びその置換基中の定義は、前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、医薬組成物である。 [2-7] A second to seventh aspect of the present invention is the following formula (VI)
Figure JPOXMLDOC01-appb-C000112
Wherein n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the definitions in the substituents are defined in the above-mentioned embodiments [1], [1-1] Or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, wherein the compound represents the same meaning as any one of [1-10]. A pharmaceutical composition.
　より具体的には、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＣ及びその置換基中の定義及び好ましい態様は、前記態様［１］及び［１－１］～［１－１０］のいずれかに記載の定義に記載の定義と同じである。 More specifically, the definitions and preferred embodiments of n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the substituents thereof are the above-described embodiments [1] and This is the same as the definition described in any one of [1-1] to [1-10].
［３］　本発明の第３の態様は、下記式（Ｉ）－Ｂ
Figure JPOXMLDOC01-appb-C000113
  
（式中、Ｒ５Ａ、Ｒ６Ａ、ＷＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｊ、ｆ、破線及びそれらの定義中に定義される置換基は、前記と同一の意味を表し、Ｒｉｎｇ－Ａは、下記式（Ｇ）または（Ｈ）
Figure JPOXMLDOC01-appb-C000114
  
（式中、Ｒ１７、Ｒ１８、ＲＣ、Ｅ、破線及びその定義中の定義される置換基は、前記と同一の意味を表す）で表される基を表す。
但し、Ｒｉｎｇ－Ａが式（Ｇ）である場合には、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基であり、Ｒ１７が水素原子・－ＯＨまたはアルコキシル基である場合の化合物及び“化合物リストＡ”に記載の各々の化合物を除く。Ｒｉｎｇ－Ａが式（Ｈ）である場合には、“化合物リストＢ－１”に記載の各々の化合物を除く）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。 [3] A third aspect of the present invention is the following formula (I) -B
Figure JPOXMLDOC01-appb-C000113
(Wherein R 5A , R 6A , W A , R 12 , A, G, L 1 , L 2 , j, f, the broken line and the substituents defined in those definitions have the same meaning as described above. Ring-A is represented by the following formula (G) or (H)
Figure JPOXMLDOC01-appb-C000114
(Wherein R 17 , R 18 , R C , E, the broken line and the substituent defined in the definition represent the same meaning as described above).
However, when Ring-A is the formula (G), at least one of R 5A or R 6A is a group having 3 or more carbon atoms, and R 17 is a hydrogen atom, —OH or an alkoxyl group. Exclude certain compounds and each compound listed in “Compound List A”. When Ring-A is the formula (H), it is a compound represented by “except for each compound described in“ Compound List B-1 ”), a salt thereof, or a solvate thereof.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＷＡ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ｊ、ｆ、破線の定義及びそれらの定義中に定義される置換基、あるいは式（Ｄ）及び式（Ｅ）の基及びそれらの好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, defined R 5A, R 6A, W A , R 12, R 17, R 18, A, G, L 1, L 2, j, f, in dashed definitions and definitions of their The substituent, or the group of the formula (D) and the formula (E) and preferred embodiments thereof are described in any one of the embodiments [1], [1-1] to [1-10] and [1-12]. The definition is the same as
　前記式（Ｉ）－Ｂにおいて、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子・－ＯＨまたはアルコキシル基である場合を除く）；
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　好ましい態様として、以下の態様も挙げられる。 In the formula (I) -B, R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1-6 alkyl, 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 1-6 alkyl, N-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, N, N-di-C 1 - 6 alkylcarbamoyl -C 1 - 6 alkyl, C 3 - 8 cycloalkyl -C 1 - 6 alkyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy or model / Di C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom · -OH or an alkoxyl group);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 is a group selected from alkylamino, and R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
The following aspects are also mentioned as a preferable aspect.
［３－１］本発明の第３－１の態様は、下記式（ＩＩＩ）
Figure JPOXMLDOC01-appb-C000115
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ＷＡ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表す）で表される化合物（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。また、Ｒ１７が水素原子・－ＯＨまたはアルコキシル基である場合の化合物、及び“化合物リストＡ”に記載の各々の化合物を除く）、またはその塩またはそれらの溶媒和物である。
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７、Ｒ１８、Ａ、Ｇ、Ｌ１、Ｌ２、ＷＡ、ｊ、ｆ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 [3-1] The 3-1 aspect of the present invention is the following formula (III)
Figure JPOXMLDOC01-appb-C000115
(Wherein R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, and the definition of the broken line are defined in the above aspects [1], [1-1] ] To [1-10] and [1-12] represent the same meanings), provided that at least one of R 5A and R 6A is a group having 3 or more carbon atoms. And a compound in which R 17 is a hydrogen atom, —OH or an alkoxyl group, and each compound described in “Compound List A”), or a salt thereof or a solvate thereof.
More specifically, R 5A , R 6A , R 12 , R 17 , R 18 , A, G, L 1 , L 2 , W A , j, f, the definition of a broken line, and preferred embodiments are the above-described embodiments [1 ], [1-1] to [1-10] and [1-12] have the same definition as described in any one of [1-12].
　前記式（ＩＩＩ）において、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。 In the formula (III), as R 5A and R 6A , preferably, at least one of R 5A or R 6A is a group having 3 or more constituent carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
　前記式（ＩＩＩ）において、Ｒ１７及びＲ１８は、好ましくは、各々独立に、水素原子、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり（Ｒ１７が水素原子・－ＯＨまたはアルコキシル基である場合を除く）；
　より好ましくは、Ｒ１７がＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子である。
　更に好ましくは、Ｒ１７がＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。特に好ましくは、Ｒ１７がハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。
　Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）において、好ましくは、Ａを構成に含む環は芳香化しているものを含まない。 In the formula (III), R 17 and R 18 are preferably, each independently, a hydrogen atom, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl, C 1 1-6 alkoxyl, C 2 - 6 alkenyloxy, C 2 - 6 alkynyloxy, halogenated C 1 - 6 alkoxy or model / Di C 1 ~ 6 alkyl amino, a group selected from the group consisting of (unless R 17 is a hydrogen atom · -OH or an alkoxyl group);
More preferably, R 17 is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 is a group selected from alkylamino, and R 18 is a hydrogen atom.
More preferably, a group R 17 is selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl, and, R 18 is a hydrogen atom. Particularly preferably, a group R 17 is selected from halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
In the formula (III), preferably, the ring containing A in the structure does not include an aromatic group.
　前記式（ＩＩＩ）において、ＲＡ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群の置換基は、ハロゲン原子、オキソ、ニトロ、シアノ、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ３～８シクロアルキル、Ｃ６～１４アリール、へテロ環、
保護されていてもよいヒドロキシル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、Ｃ６～１４アリールオキシ、ヘテロ環オキシ、
メルカプト、Ｃ１～６アルキルチオ、Ｃ６～１４アリールチオ、ヘテロ環チオ、Ｃ１～６アルキルスルフィニル、Ｃ６～１４アリールスルフィニル、ヘテロ環スルフィニル、Ｃ１～６アルキルスルホニル、Ｃ６～１４アリールスルホニル、ヘテロ環スルホニル、スルファモイル（当該スルファモイルは、Ｃ１～６アルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、スルホ、
アミノ（当該アミノは、Ｃ１～６アルキル・モノ／ジＣ１～６アルキルスルファモイル・モノ／ジＣ１～６アルキルカルバモイル・ホルミル・Ｃ２～７アルカノイル・Ｃ６～１４アリール・ヘテロ環・モノ／ジＣ６～１４アリールスルファモイル・モノ／ジヘテロ環スルファモイル・Ｃ６～１４アリールカルボニルもしくはヘテロ環カルボニルで置換されていてもよい）、
ホルミル、Ｃ２～７アルカノイル、Ｃ６～１４アリールカルボニル、ヘテロ環カルボニル、
保護されていてもよいカルボキシル、Ｃ１～６アルコキシカルボニル、Ｃ６～１４アリールオキシカルボニル、ヘテロ環オキシカルボニル、
カルバモイル（当該カルバモイルは、Ｃ１～６アルキル、Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）
から任意に選ばれる基を表す。 In the formula (III), the substituents of the group A are the same as defined in the embodiment [1]. That is, the substituent of the R A group is a halogen atom, oxo, nitro, cyano,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl, C 3 - 8 cycloalkyl, C 6 - 14 aryl or heteroaryl ring),
C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl, heterocycle,
Optionally protected hydroxyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy, C 6 ~ 14 aryloxy, heterocyclic oxy,
Mercapto, C 1 ~ 6 alkylthio, C 6 ~ 14 arylthio, heterocyclic thio, C 1 ~ 6 alkylsulfinyl, C 6 ~ 14 arylsulfinyl, heterocyclic sulfinyl, C 1 ~ 6 alkylsulfonyl, C 6 ~ 14 arylsulfonyl, heterocyclic sulfonyl, sulfamoyl (the sulfamoyl may be substituted with C 1 ~ 6 alkyl · C 6 ~ 14 aryl or heterocyclic), sulfo,
Amino (said amino, C 1 ~ 6 alkyl mono / di C 1 ~ 6 alkylsulfamoyl mono / di C 1 ~ 6 alkylcarbamoyl, formyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 aryl heterocycle mono / di C 6 ~ 14 may be substituted with an aryl sulfamoyl mono / diheterocyclic sulfamoyl-C 6 ~ 14 arylcarbonyl or heterocycle carbonyl),
Formyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 arylcarbonyl, heterocyclic carbonyl,
Optionally protected carboxyl, C 1 ~ 6 alkoxycarbonyl, C 6 ~ 14 aryloxycarbonyl, heterocyclic oxycarbonyl,
Carbamoyl (said carbamoyl, C 1 ~ 6 alkyl, optionally substituted with C 6 ~ 14 aryl or hetero ring)
Represents a group arbitrarily selected from
　前記式（ＩＩＩ）において、ＲＢ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＢ群の置換基は、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ３～８シクロアルキル、Ｃ６～１４アリール、へテロ環、
Ｃ１～６アルキルスルホニル、Ｃ６～１４アリールスルホニル、ヘテロ環スルホニル、スルファモイル（当該スルファモイルは、Ｃ１～６アルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
Ｃ２～７アルカノイル、Ｃ６～１４アリールカルボニル、ヘテロ環カルボニル、
Ｃ１～６アルコキシカルボニル、Ｃ６～１４アリールオキシカルボニル、ヘテロ環オキシカルボニル、
カルバモイル（当該カルバモイルは、Ｃ１～６アルキル、Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）
から任意に選ばれる基を表す。 In the formula (III), substituent group R B are as defined according to the aspect [1]. That is, the substituent of the group R B is,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl, C 3 - 8 cycloalkyl, C 6 - 14 aryl or heteroaryl ring),
C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl, heterocycle,
C 1 ~ 6 alkylsulfonyl, C 6 ~ 14 arylsulfonyl, heterocyclic sulfonyl, sulfamoyl (the sulfamoyl may be substituted with C 1 ~ 6 alkyl · C 6 ~ 14 aryl or heterocycle),
C 2 ~ 7 alkanoyl, C 6 ~ 14 arylcarbonyl, heterocyclic carbonyl,
C 1 ~ 6 alkoxycarbonyl, C 6 ~ 14 aryloxycarbonyl, heterocyclic oxycarbonyl,
Carbamoyl (said carbamoyl, C 1 ~ 6 alkyl, optionally substituted with C 6 ~ 14 aryl or hetero ring)
Represents a group arbitrarily selected from
　前記式（ＩＩＩ）において、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＣ群の置換基は、ハロゲン原子、オキソ、ニトロ、シアノ、
Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
（当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイルもしくはＣ３～８シクロアルキルで置換されていてもよい）、
Ｃ３～８シクロアルキル、
保護されていてもよいヒドロキシル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、
メルカプト、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、スルファモイル、モノ／ジＣ１～６アルキルスルファモイル、スルホ、
アミノ（当該アミノは、Ｃ１～６アルキル・モノ／ジＣ１～６アルキルスルファモイル・モノ／ジＣ１～６アルキルカルバモイル・ホルミルもしくはＣ２～７アルカノイルで置換されていてもよい）、
ホルミル、Ｃ２～７アルカノイル、
保護されていてもよいカルボキシル、Ｃ１～６アルコキシカルボニル、
カルバモイルもしくはモノ／ジＣ１～６アルキルカルバモイルから任意に選ばれる基を表す。 In the formula (III), the substituents of the RC group are the same as defined in the embodiment [1]. That is, the substituent of the RC group includes a halogen atom, oxo, nitro, cyano,
C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl or C 3 - 8 cycloalkyl),
C 3 ~ 8 cycloalkyl,
Optionally protected hydroxyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy,
Mercapto, C 1 ~ 6 alkylthio, C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkyl sulfamoyl, sulfo,
Amino (said amino may be substituted by C 1 ~ 6 alkyl mono / di C 1 ~ 6 alkylsulfamoyl mono / di C 1 ~ 6 alkylcarbamoyl, formyl or C 2 ~ 7 alkanoyl),
Formyl, C 2 ~ 7 alkanoyl,
Optionally carboxyl which may be protected, C 1 ~ 6 alkoxycarbonyl,
Carbamoyl or mono / di-C 1 ~ 6 chosen group from alkylcarbamoyl optionally.
［３－１－ａ］本発明の第３－１－ａの態様は、下記式（ＩＩＩ）－Ａ
Figure JPOXMLDOC01-appb-C000116
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義は前記態様［１］、［１－１］～［１－１０］、［１－１２］及び［１－１５］のいずれかと同一の意味を表す）で表される化合物（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基であり、“化合物リストＡ－１”に記載の各々の化合物を除く）、またはその塩またはそれらの溶媒和物である。 [3-1-a] The embodiment 3-1-a of the present invention is the following formula (III) -A
Figure JPOXMLDOC01-appb-C000116
(Wherein R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to A compound having the same meaning as any one of [1-10], [1-12] and [1-15] (provided that at least one of R 5A and R 6A has 3 carbon atoms) Or a salt thereof or a solvate thereof, excluding each compound described in “Compound List A-1”.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］、［１－１２］及び［１－１５］のいずれかに記載の定義と同じである。 More specifically, the definitions and preferred embodiments of R 5A , R 6A , R 12 , R 18 , A a , G a , L 1a , L 2a , W A , broken line are the above-mentioned embodiments [1], [1- 1] to [1-10], [1-12], and the same definition as described in any of [1-15].
　前記式（ＩＩＩ）－Ａにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。 In the formula (III) -A, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
　前記式（ＩＩＩ）－Ａにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子であり、より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　ＷＡは、－ＣＯＮＲ７－であることが好ましい。
　Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ａにおいて、好ましくは、Ａａを構成に含む環は芳香化しているものを含まない。 In the formula (III) -A, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and a R 18 is a hydrogen atom, more preferably, R 17A is C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
W A is, -CONR 7 - is preferably.
R 12 is preferably a hydrogen atom, a halogen atom, a protected hydroxyl group which may have, R C optionally chosen optionally substituted C 1 to 4 alkyl group with a group from a group, optionally from R C group mono chosen optionally substituted C 1 to 4 alkoxy groups or R C-optionally C 1 optionally substituted with chosen groups arbitrarily from group 4 alkyl group group - or di - substituted Or a group arbitrarily selected from amino groups.
In the formula (III) -A, preferably, the ring containing A a does not include an aromatic group.
　前記式（ＩＩＩ）－Ａにおいて、ＷＡあるいはＲ１２の置換位置は、フェニル部分の炭素原子の位置で示すことができる。ＷＡであれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。ＷＡは、３番目の炭素原子に結合していることがより好ましい。 In the above formula (III) -A, the substitution position of W A or R 12 can be indicated by the position of the carbon atom of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms. W A is more preferably bonded to the third carbon atoms.
　前記式（ＩＩＩ）－Ａにおいて、ＲＡ群、ＲＢ群、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群、ＲＢ群、ＲＣ群の置換基は、前記態様［３－１］に記載の定義と同じである。 In the formula (III) -A, the substituents in the groups R A , R B and R C are the same as defined in the embodiment [1]. That is, the substituents of the R A group, the R B group, and the R C group are the same as defined in the embodiment [3-1].
［３－１－ｂ］本発明の第３－１－ｂの態様は、前記態様［３－１－ａ］より好ましい態様であり、下記式（ＩＩＩ）－Ｂ
Figure JPOXMLDOC01-appb-C000117
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義は前記態様［１］、［１－１］～［１－１０］、［１－１２］及び［１－１５］のいずれかと同一の意味を表す）で表される化合物（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基であり、“化合物リストＡ－１”に記載の各々の化合物を除く）、またはその塩またはそれらの溶媒和物である。Ａａを構成に含む環は芳香化しているものを含まない。 [3-1-b] The embodiment 3-1b of the present invention is a more preferred embodiment than the embodiment [3-1-a], and is represented by the following formula (III) -B
Figure JPOXMLDOC01-appb-C000117
(Wherein R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , and the definition of the broken line are defined in the above embodiments [1], [1-1] to A compound having the same meaning as any one of [1-10], [1-12] and [1-15] (provided that at least one of R 5A and R 6A has 3 carbon atoms) Or a salt thereof or a solvate thereof, excluding each compound described in “Compound List A-1”. The ring containing A a does not include those that are aromatized.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、ＷＡ、破線の定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び、［１－１２］及び［１－１５］のいずれかに記載の定義と同じである。 More specifically, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , W A , the definition and preferred embodiments of the broken line are the above-described embodiments [1], The definition is the same as described in any one of [1-1] to [1-10] and [1-12] and [1-15].
　前記式（ＩＩＩ）－Ｂにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。
　より好ましくは、Ｒ５Ａ、Ｒ６Ａは、各々独立に、水素原子、Ｃ１～６の直鎖もしくは分枝鎖のアルキル基またはＣ３～８のシクロアルキル基を表し（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である）、Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに４～６員の環状基を形成していてもよく、当該環状基はその環内の炭素原子が酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）で置き換えられていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、－ＮＲ５ＡＲ６Ａとして、より具体的には、以下の式で表わされることが好ましい。
Figure JPOXMLDOC01-appb-C000118
   In the formula (III) -B, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
More preferably, R 5A, R 6A are each independently a hydrogen atom, a cycloalkyl group of C 1 ~ linear or branched alkyl group or a C 3 ~ 8 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ~ 6 have been.
In the formula (III) -B, as —NR 5A R 6A , more specifically, it is preferably represented by the following formula.
Figure JPOXMLDOC01-appb-C000118
　前記式（ＩＩＩ）－Ｂにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子であり、より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　前記式（ＩＩＩ）－Ｂにおいて、Ａａを含む縮合環は、下記式（Ｅ１ａ）
Figure JPOXMLDOC01-appb-C000119
  
（式中、Ｒ１２、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１－４－ｂ］および［１－４－ｄ－１２］と同一の意味を表す）で表される基であり、ＡａとＧａ間の破線は当該元素間の結合が、適宜単結合もしくは二重結合をとる。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ａａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、またはカルボニル基を表し、
Ｇａはメチレン基、カルボニル基またはスルホニル基を表し、
Ｌ１ａは、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ１ａは酸素原子である）、
Ｌ２ａは、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ２ａは単結合または－（ＣＲ１５ＣＲ１５Ｄ）ｕ－である）；
Ｒ１３、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄ、Ｒ１６Ａ、Ｒ１６Ｂの定義は前記態様［１－４－ｂ］と同一の意味を表し、好ましい態様は前記態様［１－４－ｄ－３］及び［１－４－ｄ－５］と同一である。
　第１－１５－ｂの態様において、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄは、各々独立に、水素原子、ハロゲン原子、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いＣ１～６アルキル基、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いアミノ基または保護されていても良いヒドロキシル基から任意に選ばれる基が好ましく、
Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、Ａａは－ＮＲ１３－であることが好ましい。 In the formula (III) -B, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and a R 18 is a hydrogen atom, more preferably, R 17A is C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
In the formula (III) -B, the condensed ring containing A a is represented by the following formula (E1a)
Figure JPOXMLDOC01-appb-C000119
(Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]). a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
In the above formula (III) -B and the above formula (E1a), R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group. good C 1 ~ 4 alkyl group, optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ~ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
In the formula (III) -B and the above formula (E1a), A a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group,
G a represents a methylene group, a carbonyl group or a sulfonyl group,
L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom),
L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
The definitions of R 13 , R 14A , R 14B , R 15A , R 15B , R 15C , R 15D , R 16A , R 16B represent the same meaning as in the above embodiment [1-4-b], and a preferable embodiment is the above embodiment. The same as [1-4-d-3] and [1-4-d-5].
In the 1-15-b embodiment, R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH · —NH 2. chosen optionally substituted C 1 ~ 6 alkyl group in group, -OH · --NH2 · optionally substituted with chosen groups arbitrarily from -COOH heterocyclic group, optionally selected from R C group optionally substituted C 1 to 6 alkoxy group with a group, mono group substituted by C 1 may also be ~ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group,
R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with 1-5 optionally substituted straight or alkoxyl substituted with an alkyl group of C 1 ~ 6 branched may be replaced by also good), the cyclic group may be further substituted by a group selected arbitrarily from R C groups.
In the formula (III) -B, A a is preferably —NR 13 —.
　式（Ｅ１ａ）において、ＷＡあるいはＲ１２の置換位置は、前記態様［１－４－ｄ－１１］と同様に、フェニル部分の炭素原子の位置で示すことができる。ＷＡであれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。
Figure JPOXMLDOC01-appb-C000120
  
式（Ｅ１ａ）においてＷＡの結合位置は、具体的には、下記式（Ｅ１ａ－１）－ｂおよび（Ｅ１ａ－２）－ｂであることが好ましい。
Figure JPOXMLDOC01-appb-C000121
  
　前記式（Ｅ１ａ）において、より具体的には、以下に示される式から任意に選択される。
Figure JPOXMLDOC01-appb-C000122
  
Figure JPOXMLDOC01-appb-C000123
  
　前記式（Ｅ１ａ）において、具体的には、好ましくは、前記式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。より好ましくは、式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。すなわち、下記の式が挙げられる。
Figure JPOXMLDOC01-appb-C000124
  
Figure JPOXMLDOC01-appb-C000125
  
　前記式（ＩＩＩ）－Ｂにおいて、ＷＡは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０は、各々独立に水素原子またはＣ１～６アルキル基を表す）を表し；－ＣＯＮＲ７－であることが好ましい。 In formula (E1a), substitution positions of W A or R 12 is, similarly to the embodiment [1-4-d-11], can be indicated by the position of the carbon atoms of the phenyl moiety. If W A, counting clockwise from the position close to the carbon atom to which L 1a is attached, is preferably bonded to the first or third carbon atoms.
Figure JPOXMLDOC01-appb-C000120
Bonding position of W A in formula (E1a), specifically, it is preferably the following formula (E1a-1) -b and (E1a-2) -b.
Figure JPOXMLDOC01-appb-C000121
More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000123
In the formula (E1a), specifically, preferably, the formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), (c c208) to (c240). More preferable examples include formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), and (c208) to (c240). That is, the following formula is mentioned.
Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000125
In the formula (III) -B, W A is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 each independently represent a hydrogen atom or C 1 ~ 6 alkyl represents a group); -CONR 7 - is preferably.
　前記式（ＩＩＩ）－Ｂにおいて、ＲＡ群、ＲＢ群、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群、ＲＢ群、ＲＣ群の置換基は、前記態様［３－１］に記載の定義と同じである。 In the formula (III) -B, the substituents of the groups R A , R B , and R C are the same as defined in the above embodiment [1]. That is, the substituents of the R A group, the R B group, and the R C group are the same as defined in the embodiment [3-1].
［３－１－ｃ］本発明の第３－１－ｃの態様は、前記態様［３－１－ｂ］より好ましい態様であり、下記式（ＩＩＩ）－Ｃ
Figure JPOXMLDOC01-appb-C000126
  
（式中、Ｒ５Ａ、Ｒ６Ａ、Ｒ１２、Ｒ１７Ａ、Ｒ１８、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１］、［１－１］～［１－１０］、［１－１２］、［１－１５］及び［３－１－ｂ］のいずれかと同一の意味を表す）で表される化合物（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基であり、“化合物リストＡ－１”に記載の化合物番号Ａ１～Ａ６、Ａ２０、Ａ１２７，Ａ１２８の化合物を除く）、またはその塩またはそれらの溶媒和物である。 [3-1-c] The embodiment 3-1c of the present invention is a more preferred embodiment than the embodiment [3-1-b], and is represented by the following formula (III) -C
Figure JPOXMLDOC01-appb-C000126
(In the formula, R 5A , R 6A , R 12 , R 17A , R 18 , A a , G a , L 1a , L 2a , and the definition of the broken line are defined in the above aspects [1], [1-1] to [1-] 10], [1-12], [1-15] and [3-1-b] having the same meaning as described above (provided that at least one of R 5A and R 6A is a constituent) A group having 3 or more carbon atoms, excluding the compounds of compound numbers A1 to A6, A20, A127, and A128 described in “Compound List A-1”), or a salt thereof or a solvate thereof.
　前記式（ＩＩＩ）－Ｃにおいて、Ｒ５Ａ、Ｒ６Ａとして、好ましくは、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である。すなわち、Ｒ５ＡまたはＲ６Ａの少なくとも１つは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルケニル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６の直鎖もしくは分枝鎖のアルキニル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～６のシクロアルキル基である。
　より好ましくは、Ｒ５Ａ、Ｒ６Ａは、各々独立に、水素原子、Ｃ１～６の直鎖もしくは分枝鎖のアルキル基またはＣ３～６のシクロアルキル基であり（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である）、Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに４～６員の環状基を形成していてもよく、当該環状基はその環内の炭素原子が酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）で置き換えられていてもよい。
　前記式（ＩＩＩ）－Ｃにおいて、－ＮＲ５ＡＲ６Ａとして、より具体的には、以下の式で表わされることが好ましい。
Figure JPOXMLDOC01-appb-C000127
   In the formula (III) -C, as R 5A and R 6A , preferably at least one of R 5A or R 6A is a group having 3 or more carbon atoms. That is, at least one of R 5A or R 6A is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 3 ~ from group 6, optionally from R C group chosen linear or branched alkenyl group of C 3 ~ 6 may be substituted with a group, a linear or min R C optionally substituted by a group selected C 3 ~ from group 6 alkynyl group Edakusari, or a cycloalkyl group of R C may be substituted with chosen groups arbitrarily from the group C 3 ~ 6.
More preferably, R 5A, R 6A are each independently hydrogen atom, a linear or branched alkyl group or cycloalkyl group C 3 ~ 6 of C 1 ~ 6 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms the oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom, 1-5 substituted with either a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of which may C 1 ~ 6 have been.
In the formula (III) -C, as —NR 5A R 6A , more specifically, it is preferably represented by the following formula.
Figure JPOXMLDOC01-appb-C000127
前記式（ＩＩＩ）－Ｃにおいて、Ｒ１７Ａは、好ましくは、Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシ－Ｃ１～６アルキル、カルボキシ－Ｃ１～６アルキル、Ｃ１～６アルコキシカルボニル－Ｃ１～６アルキル、カルバモイル－Ｃ１～６アルキル、Ｎ－Ｃ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｎ，Ｎ－ジＣ１～６アルキルカルバモイル－Ｃ１～６アルキル、Ｃ３～８シクロアルキル－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノ、からなる群から選ばれる基であり；より好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり；更に好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。特に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基である。
　Ｒ１８は水素原子であることが好ましい。
　Ｒ１７Ａ及びＲ１８の組み合わせにおいて、好ましくは、Ｒ１７ＡがＣ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル、ハロゲン原子、ハロゲン化Ｃ１～６アルキル、ヒドロキシ－Ｃ１～６アルキルまたはモノ／ジＣ１～６アルキルアミノから選ばれる基であり、且つ、Ｒ１８が水素原子であり、より好ましくは、Ｒ１７ＡがＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つ、Ｒ１８が水素原子である。更に好ましくは、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であり、且つＲ１８が水素原子である。
　前記式（ＩＩＩ）－Ｃにおいて、Ａａを含む縮合環は、下記式（Ｅ１ａ）
Figure JPOXMLDOC01-appb-C000128
  
（式中、Ｒ１２、Ａａ、Ｇａ、Ｌ１ａ、Ｌ２ａ、破線の定義は前記態様［１－４－ｂ］および［１－４－ｄ－１２］と同一の意味を表す）で表される基であり、ＡａとＧａ間の破線は当該元素間の結合が、適宜単結合もしくは二重結合をとる。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ｒ１２は、好ましくは、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基である。
　前記式（ＩＩＩ）－Ｂ及び上記式（Ｅ１ａ）において、Ａａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－、またはカルボニル基を表し、
Ｇａはメチレン基、カルボニル基またはスルホニル基を表し、
Ｌ１ａは、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ１ａは酸素原子である）、
Ｌ２ａは、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ２ａは単結合または－（ＣＲ１５ＣＲ１５Ｄ）ｕ－である）；
Ｒ１３、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄ、Ｒ１６Ａ、Ｒ１６Ｂの定義は前記態様［１－４－ｂ］と同一の意味を表し、好ましい態様は前記態様［１－４－ｄ－３］及び［１－４－ｄ－５］と同一である。
　第１－１５－ｂの態様において、Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄは、各々独立に、水素原子、ハロゲン原子、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いＣ１～６アルキル基、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いアミノ基または保護されていても良いヒドロキシル基から任意に選ばれる基が好ましく、
Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよい。
　前記式（ＩＩＩ）－Ｂにおいて、Ａａは－ＮＲ１３－であることが好ましい。 In the formula (III) -C, R 17A is preferably, C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, 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, C 3 ~ 8 cycloalkyl -C 1 ~ 6 alkyl or mono / di C 1 ~ 6 alkyl amino, is a group selected from the group consisting of; more preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ Alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 alkyl or a group selected from mono- / di-C 1 ~ 6 alkyl amino; more preferably, R 17A is C 1 ~ 6 alkyl, is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl. Particularly preferred is a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl.
R 18 is preferably a hydrogen atom.
In combination with R 17A and R 18, preferably, R 17A is C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, halogenated C 1 ~ 6 alkyl, hydroxy -C 1 ~ 6 a group selected from alkyl or mono / di C 1 ~ 6 alkyl amino, and a R 18 is a hydrogen atom, more preferably, R 17A is C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 A group selected from alkyl and R 18 is a hydrogen atom; More preferably, a group R 17A is selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, and R 18 is a hydrogen atom.
In the formula (III) -C, the condensed ring containing A a is represented by the following formula (E1a)
Figure JPOXMLDOC01-appb-C000128
(Wherein R 12 , A a , G a , L 1a , L 2a , and the definition of a broken line represent the same meaning as in the above embodiments [1-4-b] and [1-4-d-12]). a group represented by the dashed line between a a and G a is a bond between the elements, taking the appropriate single or double bond.
In the above formula (III) -B and the above formula (E1a), R 12 is preferably substituted with a hydrogen atom, a halogen atom, an optionally protected hydroxyl group, or a group arbitrarily selected from the RC group. good C 1 ~ 4 alkyl group, optionally substituted by a group selected arbitrarily from optionally substituted by a group selected C 1 ~ 4 alkoxyl group, or R C group from R C group C It is a group arbitrarily selected from amino groups which may be mono- or di-substituted with 1 to 4 alkyl groups.
In the formula (III) -B and the above formula (E1a), A a represents —NR 13 —, —CR 14A R 14B —, or a carbonyl group,
G a represents a methylene group, a carbonyl group or a sulfonyl group,
L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom),
L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
The definitions of R 13 , R 14A , R 14B , R 15A , R 15B , R 15C , R 15D , R 16A , R 16B represent the same meaning as in the above embodiment [1-4-b], and a preferable embodiment is the above embodiment. The same as [1-4-d-3] and [1-4-d-5].
In the 1-15-b embodiment, R 14A , R 14B , R 15A , R 15B , R 15C and R 15D are each independently selected from a hydrogen atom, a halogen atom, —OH · —NH 2. chosen optionally substituted C 1 ~ 6 alkyl group in group, -OH · --NH2 · optionally substituted with chosen groups arbitrarily from -COOH heterocyclic group, optionally selected from R C group optionally substituted C 1 to 6 alkoxy group with a group, mono group substituted by C 1 may also be ~ 6 alkyl group optionally selected from R C group - or di - amino optionally substituted Preferred is a group arbitrarily selected from a group or an optionally protected hydroxyl group,
R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with 1-5 optionally substituted straight or alkoxyl substituted with an alkyl group of C 1 ~ 6 branched may be replaced by also good), the cyclic group may be further substituted by a group selected arbitrarily from R C groups.
In the formula (III) -B, A a is preferably —NR 13 —.
　式（Ｅ１ａ）において、－ＣＯＮＲ７－あるいはＲ１２の置換位置は、前記態様［１－４－ｄ－１１］と同様に、フェニル部分の炭素原子の位置で示すことができる。－ＣＯＮＲ７－であれば、Ｌ１ａ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番目または３番目の炭素原子に結合していることが好ましい。
Figure JPOXMLDOC01-appb-C000129
  
式（Ｅ１ａ）において－ＣＯＮＲ７－の結合位置は、具体的には、下記式（Ｅ１ａ－１）－ｃおよび（Ｅ１ａ－２）－ｃであることが好ましい。
Figure JPOXMLDOC01-appb-C000130
  
　前記式（Ｅ１ａ）において、より具体的には、以下に示される式から任意に選択される。
Figure JPOXMLDOC01-appb-C000131
  
Figure JPOXMLDOC01-appb-C000132
  
　前記式（Ｅ１ａ）において、具体的には、好ましくは、前記式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。より好ましくは、式（ｃ９３）～（ｃ１１７）、（ｃ１２１）～（ｃ１２３）、（ｃ１５６）～（ｃ１５８）、（ｃ１６７）～（ｃ１７７）、（ｃ２０８）～（ｃ２４０）が挙げられる。 In the formula (E1a), the substitution position of —CONR 7 — or R 12 can be represented by the position of the carbon atom of the phenyl moiety, as in the above embodiment [1-4-d-11]. In the case of —CONR 7 —, it is preferable that L 1a is bonded to the first or third carbon atom, counting clockwise from a position close to the carbon atom to which L 1a is bonded.
Figure JPOXMLDOC01-appb-C000129
Specifically, the bonding position of —CONR 7 — in the formula (E1a) is preferably the following formulas (E1a-1) -c and (E1a-2) -c.
Figure JPOXMLDOC01-appb-C000130
More specifically, the formula (E1a) is arbitrarily selected from the formulas shown below.
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000132
In the formula (E1a), specifically, preferably, the formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), (c c208) to (c240). More preferable examples include formulas (c93) to (c117), (c121) to (c123), (c156) to (c158), (c167) to (c177), and (c208) to (c240).
　前記式（ＩＩＩ）－Ｃにおいて、ＲＡ群、ＲＢ群、ＲＣ群の置換基は前記態様［１］に記載の定義と同じである。すなわち、ＲＡ群、ＲＢ群、ＲＣ群の置換基は、前記態様［３－１］に記載の定義と同じである。 In the formula (III) -C, the substituents of the groups A A , R B and R C are the same as defined in the above embodiment [1]. That is, the substituents of the R A group, the R B group, and the R C group are the same as defined in the embodiment [3-1].
［３－２］本発明の第３－２の態様は、前記式（ＩＶ）
Figure JPOXMLDOC01-appb-C000133
  
（式中、Ｅは、非存在、基：－ＣＲＡ３ＲＡ４－、エチレン基、酸素原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良く、Ｅが－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し、ＥとＷが結合した炭素原子との間の実線と破線は単結合もしくは二重結合を形成しうることを示し、ＹＡは、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ３～８のシクロアルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ６～１４のアリール基、または基：－ＮＲ５ＡＲ６Ａを表し；
Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＷＡの定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表し、ＺＡは、下記式（Ｄ）または下記式（Ｅ）
Figure JPOXMLDOC01-appb-C000134
  
（式中、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表す。但し、ＷＡが－ＣＯＮＲ７－であり、ＺＡが前記式（Ｄ）であり、且つＲＡがアリールまたはヘテロアリールである場合（ＷＯ２００５／０９２８８１号公報）、及び“化合物リストＢ”に記載の各々の化合物を除く）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。 [3-2] The third aspect of the present invention is the above-described formula (IV)
Figure JPOXMLDOC01-appb-C000133
(Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 1 ~ 5 amino optionally substituted straight or branched chain with either an alkoxylated C With 1 to 6 alkyl groups The cyclic group may further have a substituent), and the solid line and the broken line between the carbon atom to which E and W are bonded are simply binding or indicate that can form a double bond, Y a is a straight-chain or branched-chain alkyl group of R C optionally substituted by a group selected C 1 ~ from group 6, R C cycloalkyl group - optionally C 3 optionally substituted with a group 8 selected arbitrarily from the group, aryl group R C may be substituted with chosen groups arbitrarily from the group C 6 - 14 or a group: Represents NR 5A R 6A ;
R 5A, R 6A, the definition of R C, W A the aspect [1], represent the same meaning as any one of [1-1] - [1-10] and [1-12], the Z A, The following formula (D) or the following formula (E)
Figure JPOXMLDOC01-appb-C000134
(In the formula, R A , R 12 , A, G, L 1 , L 2 , g, j, f, and the definition of the broken line are defined in any one of the above embodiments [1], [1-1] to [1-10]. It represents the same meaning). However, W A is -CONR 7 - a and a Z A is the formula (D), and when R A is aryl or heteroaryl (WO2005 / 092881 discloses), and according to "Compound List B" Or a salt thereof, or a solvate thereof.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＷＡ、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆの定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, the definitions and preferred embodiments of R 5A , R 6A , R C , W A , R A , R 12 , A, G, L 1 , L 2 , g, j, f are the above-mentioned embodiments [1 ], [1-1] to [1-10] and [1-12] are the same as defined above.
［３－３］本発明の第３－３の態様は、下記式（ＩＶ－ａ）
Figure JPOXMLDOC01-appb-C000135
  
（式中、Ｅは、非存在、基：－ＣＲＡ３ＲＡ４－、エチレン基、酸素原子または窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良く、Ｅが－ＣＲＡ３ＲＡ４－である場合には、ＲＡ３とＲＡ４は、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらに置換基を有していてもよい）を表し、ＥとＷが結合した炭素原子との間の実線と破線は単結合もしくは二重結合を形成しうることを示し、Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＷＡの定義は前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかと同一の意味を表し、ＺＡは、下記式（Ｄ）または下記式（Ｅ）
Figure JPOXMLDOC01-appb-C000136
  
（式中、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆ、破線の定義は前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）で表す。但し、ＷＡが－ＣＯＮＲ７－であり、ＺＡが前記式（Ｄ）であり、且つＲＡがアリールまたはヘテロアリールである場合（ＷＯ２００５／０９２８８１号公報）、及び“化合物リストＢ”に記載の各々の化合物を除く）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。 [3-3] The 3-3 aspect of the present invention is the following formula (IV-a)
Figure JPOXMLDOC01-appb-C000135
(Wherein, E is absent, group: -CR A3 R A4 -, ethylene group, an oxygen atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ may be substituted with 6 or with one to five substituted C 1 good straight or branched chain optionally 1-6 alkyl group alkoxyl, E is -CR A3 R A4 - in the case of R A3 and R A4 may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and in the cyclic group, one carbon atom in the ring is an oxygen atom, a sulfur atom or nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 1 ~ 5 amino optionally substituted straight or branched chain with either an alkoxylated C With 1 to 6 alkyl groups The cyclic group may further have a substituent), and the solid line and the broken line between the carbon atom to which E and W are bonded are simply And a definition of R 5A , R 6A , R C and W A is as defined in the above embodiments [1], [1-1] to [1-10] and [1-12] Z A represents the same meaning as any one of the following formulas (D) or (E)
Figure JPOXMLDOC01-appb-C000136
(In the formula, R A , R 12 , A, G, L 1 , L 2 , g, j, f, and the definition of the broken line are defined in any one of the above embodiments [1], [1-1] to [1-10]. It represents the same meaning). However, W A is -CONR 7 - a and a Z A is the formula (D), and when R A is aryl or heteroaryl (WO2005 / 092881 discloses), and according to "Compound List B" Or a salt thereof or a solvate thereof.
　より具体的には、Ｒ５Ａ、Ｒ６Ａ、ＲＣ、ＷＡ、ＲＡ、Ｒ１２、Ａ、Ｇ、Ｌ１、Ｌ２、ｇ、ｊ、ｆの定義及び好ましい態様は、前記態様［１］、［１－１］～［１－１０］及び［１－１２］のいずれかに記載の定義と同じである。 More specifically, the definitions and preferred embodiments of R 5A , R 6A , R C , W A , R A , R 12 , A, G, L 1 , L 2 , g, j, f are the above-mentioned embodiments [1 ], [1-1] to [1-10] and [1-12] are the same as defined above.
［３－４］本発明の第３－４の態様は、下記式（Ｖ）
Figure JPOXMLDOC01-appb-C000137
  
（式中、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＢ、ＲＣ及びその置換基中の定義は、前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）
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。 [3-4] The 3-4th aspect of the present invention is the following formula (V)
Figure JPOXMLDOC01-appb-C000137
(In the formula, n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R B , R C and the definitions in the substituents thereof are defined in the above-mentioned embodiments [1], [1 -1] to [1-10] have the same meaning)
Or a salt thereof or a solvate thereof.
　より具体的には、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＢ及びその置換基中の定義及び好ましい態様は、前記態様［１］及び［１－１］～［１－１０］のいずれかに記載の定義に記載の定義と同じである。 More specifically, n, m, p, Y , W, Z, R 1, R 2, R 3, R 4, R B and defined in the substituent and preferred embodiment, the aspect [1] and This is the same as the definition described in the definition described in any one of [1-1] to [1-10].
［３－５］本発明の第３－５の態様は、下記式（ＶＩ）
Figure JPOXMLDOC01-appb-C000138
  
（式中、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＣ及びその置換基中の定義は、前記態様［１］、［１－１］～［１－１０］のいずれかと同一の意味を表す）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。 [3-5] The 3-5th aspect of the present invention is the following formula (VI)
Figure JPOXMLDOC01-appb-C000138
Wherein n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the definitions in the substituents are defined in the above-mentioned embodiments [1], [1-1] To the same meaning as any one of [1-10], or a salt thereof or a solvate thereof.
　より具体的には、ｎ、ｍ、ｐ、Ｙ、Ｗ、Ｚ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、ＲＣ及びその置換基中の定義及び好ましい態様は、前記態様［１］及び［１－１］～［１－１０］のいずれかに記載の定義に記載の定義と同じである。 More specifically, the definitions and preferred embodiments of n, m, p, Y, W, Z, R 1 , R 2 , R 3 , R 4 , R C and the substituents thereof are the above-described embodiments [1] and This is the same as the definition described in any one of [1-1] to [1-10].
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159
［４］　本発明の第４の態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４の態様において、式（Ｉ）－Ｂの定義及び好ましい態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂの定義及び好ましい態様と同じである。 [4] A fourth aspect of the present invention is the compound represented by the formula (I) -B according to the aspect [2-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the above as an active ingredient.
In the fourth embodiment, the definition and preferred embodiment of the formula (I) -B are the same as the definition and preferred embodiment of the formula (I) -B described in the embodiment [2-1].
　好ましい態様として、以下の態様も挙げられる。 Preferred embodiments include the following embodiments.
［４－１］本発明の第４－１の態様は、前記態様［２－３］に記載の式（ＩＩＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４－１の態様において、式（ＩＩＩ）の定義及び好ましい態様は、前記態様［２－３］に記載の式（ＩＩＩ）の定義及び好ましい態様と同じである。 [4-1] The 4-1th aspect of the present invention is a compound represented by the formula (III) described in the above aspect [2-3], or a pharmaceutically acceptable salt thereof or a solvent thereof. A prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the Japanese as an active ingredient.
In the fourth embodiment, the definition and preferred embodiments of the formula (III) are the same as the definition and preferred embodiments of the formula (III) described in the embodiment [2-3].
［４－１－ａ］本発明の第４－１－ａの態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４－１－ａの態様において、式（ＩＩＩ）－Ａの定義及び好ましい態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａの定義及び好ましい態様と同じである。 [4-1-a] The 4-1a embodiment of the present invention is a compound represented by the formula (III) -A according to the embodiment [2-3-a], or a pharmaceutically acceptable It is a prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, which contains at least one of its salts or solvates thereof as an active ingredient.
In the 4-1a embodiment, the definition and preferred embodiment of the formula (III) -A are the same as the definition and preferred embodiment of the formula (III) -A described in the embodiment [2-3-a]. .
［４－１－ｂ］本発明の第４－１－ｂの態様は、前記態様［４－１－ａ］より好ましい態様であり、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４－１－ｂの態様において、式（ＩＩＩ）－Ｂの定義及び好ましい態様は、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂの定義及び好ましい態様と同じである。 [4-1-b] The embodiment 4-1b of the present invention is a more preferred embodiment than the embodiment [4-1-a], and is represented by the formula (III ) -B, NAFLD / NASH, diabetes, insulin resistance, characterized by containing at least one of the compound represented by -B, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient Or it is a preventive and / or therapeutic agent for obesity / obesity.
In the 4-1b embodiment, the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
［４－１－ｃ］本発明の第４－１－ｃの態様は、前記態様［４－１－ｂ］より好ましい態様であり、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４－１－ｃの態様において、式（ＩＩＩ）－Ｃの定義及び好ましい態様は、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃの定義及び好ましい態様と同じである。 [4-1-c] The embodiment 4-1c of the present invention is a more preferred embodiment than the embodiment [4-1-b], and is represented by the formula (III )-Containing a compound represented by -C, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, NAFLD / NASH, diabetes, insulin resistance Or it is a preventive and / or therapeutic agent for obesity / obesity.
In the embodiment 4-1c, the definition and preferred embodiments of the formula (III) -C are the same as the definitions and preferred embodiments of the formula (III) -C described in the embodiment [2-3-c]. .
［４－２］本発明の第４－２の態様は、前記態様［２－４］に記載の式（ＩＶ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４－２の態様において、式（ＩＶ）の定義及び好ましい態様は、前記態様［２－４］に記載の式（ＩＶ）の定義及び好ましい態様と同じである。 [4-2] The 4-2th aspect of the present invention is the compound represented by the formula (IV) according to the above aspect [2-4], or a pharmaceutically acceptable salt thereof or a solvent thereof. A prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the Japanese as an active ingredient.
In the 4-2th embodiment, the definition and preferred embodiment of the formula (IV) are the same as the definition and preferred embodiment of the formula (IV) described in the above embodiment [2-4].
［４－３］本発明の第４－３の態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４－３の態様において、式（ＩＶ－ａ）の定義及び好ましい態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）の定義及び好ましい態様と同じである。 [4-3] A fourth embodiment of the present invention is a compound represented by the formula (IV-a) according to the above embodiment [2-5], or a pharmaceutically acceptable salt thereof or a salt thereof. It is a prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the above solvates as an active ingredient.
In the fourth to third embodiments, the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the embodiment [2-5].
［４－４］本発明の第４－４の態様は、前記態様［２－６］に記載の式（Ｖ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４－４の態様において、式（Ｖ）の定義及び好ましい態様は、前記態様［２－６］に記載の式（Ｖ）の定義及び好ましい態様と同じである。 [4-4] The 4-4th aspect of the present invention is the compound represented by the formula (V) according to the above aspect [2-6], or a pharmaceutically acceptable salt thereof or a solvent thereof. A prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the Japanese as an active ingredient.
In the fourth to fourth embodiments, the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the embodiment [2-6].
［４－５］本発明の第４－５の態様は、前記態様［２－７］に記載の式（ＶＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤である。
　第４－５の態様において、式（ＶＩ）の定義及び好ましい態様は、前記態様［２－７］に記載の式（ＶＩ）の定義及び好ましい態様と同じである。 [4-5] The 4-5th aspect of the present invention is the compound represented by the formula (VI) according to the above aspect [2-7], or a pharmaceutically acceptable salt thereof or a solvent thereof. A prophylactic and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the Japanese as an active ingredient.
In the fourth to fifth embodiments, the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
［５］　本発明の第５の態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５の態様において、式（Ｉ）－Ｂの定義及び好ましい態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂの定義及び好ましい態様と同じである。 [5] A fifth aspect of the present invention is the compound represented by the formula (I) -B according to the aspect [2-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof. A method of preventing and / or treating NAFLD • NASH, diabetes, insulin resistance or obesity / obesity, comprising administering to a patient an effective amount of at least one of the following:
In the fifth embodiment, the definition and preferred embodiments of the formula (I) -B are the same as the definitions and preferred embodiments of the formula (I) -B described in the embodiment [2-1].
　好ましい態様として、以下の態様も挙げられる。 Preferred embodiments include the following embodiments.
［５－１］本発明の第５－１の態様は、前記態様［２－３］に記載の式（ＩＩＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５－１の態様において、式（ＩＩＩ）の定義及び好ましい態様は、前記態様［２－３］に記載の式（ＩＩＩ）の定義及び好ましい態様と同じである。 [5-1] The 5-1 aspect of the present invention is the compound represented by the formula (III) according to the aspect [2-3], or a pharmaceutically acceptable salt thereof, or a solvent thereof. A method for the prophylaxis and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, which comprises administering to a patient at least one effective amount of a Japanese product.
In the 5-1st aspect, the definition and preferred embodiment of the formula (III) are the same as the definition and preferred embodiment of the formula (III) described in the embodiment [2-3].
［５－１－ａ］本発明の第５－１－ａの態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５－１－ａの態様において、式（ＩＩＩ）－Ａの定義及び好ましい態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａの定義及び好ましい態様と同じである。 [5-1-a] The 5-1a embodiment of the present invention is a compound represented by the formula (III) -A according to the embodiment [2-3-a], or a pharmaceutically acceptable A method for the prevention and / or treatment of NAFLD • NASH, diabetes, insulin resistance or obesity / obesity, comprising administering to a patient an effective amount of at least one of a salt thereof or a solvate thereof.
In the 5-1a embodiment, the definition and preferred embodiment of the formula (III) -A are the same as the definition and preferred embodiment of the formula (III) -A described in the embodiment [2-3-a]. .
［５－１－ｂ］本発明の第５－１－ｂの態様は、前記態様［５－１－ａ］より好ましい態様であり、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５－１－ｂの態様において、式（ＩＩＩ）－Ｂの定義及び好ましい態様は、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂの定義及び好ましい態様と同じである。 [5-1-b] The embodiment 5-1b of the present invention is a more preferred embodiment than the embodiment [5-1-a], and is represented by the formula (III ) -B or at least one effective amount of a pharmaceutically acceptable salt or solvate thereof, comprising administering to a patient NAFLD • NASH, diabetes, insulin resistance or This is a method for preventing and / or treating obesity and obesity.
In the 5-1b embodiment, the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
［５－１－ｃ］本発明の第５－１－ｃの態様は、前記態様［５－１－ｂ］より好ましい態様であり、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５－１－ｃの態様において、式（ＩＩＩ）－Ｃの定義及び好ましい態様は、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃの定義及び好ましい態様と同じである。 [5-1-c] The embodiment 5-1c of the present invention is a more preferred embodiment than the embodiment [5-1-b], and is represented by the formula (III) described in the embodiment [2-3-c]. )-A compound represented by -C, or a pharmaceutically acceptable salt or solvate thereof, comprising administering to a patient an effective amount of NAFLD / NASH, diabetes, insulin resistance or This is a method for preventing and / or treating obesity and obesity.
In the 5-1c embodiment, the definition and preferred embodiment of the formula (III) -C are the same as the definition and preferred embodiment of the formula (III) -C described in the embodiment [2-3-c]. .
［５－２］本発明の第５－２の態様は、前記態様［２－４］に記載の式（ＩＶ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５－２の態様において、式（ＩＶ）の定義及び好ましい態様は、前記態様［２－４］に記載の式（ＩＶ）の定義及び好ましい態様と同じである。 [5-2] The 5-2th aspect of the present invention is the compound represented by the formula (IV) according to the above aspect [2-4], or a pharmaceutically acceptable salt thereof or a solvent thereof. A method for preventing and / or treating NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, comprising administering to a patient an effective amount of at least one of the Japanese products.
In the embodiment 5-2, the definition and preferred embodiment of the formula (IV) are the same as the definition and preferred embodiment of the formula (IV) described in the embodiment [2-4].
［５－３］本発明の第５－３の態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５－３の態様において、式（ＩＶ－ａ）の定義及び好ましい態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）の定義及び好ましい態様と同じである。 [5-3] A fifth to third aspect of the present invention is a compound represented by the formula (IV-a) according to the above aspect [2-5], a pharmaceutically acceptable salt thereof, or a salt thereof A method for the prophylaxis and / or treatment of NAFLD • NASH, diabetes, insulin resistance or obesity / obesity, comprising administering to a patient an effective amount of at least one solvate.
In the fifth to third embodiments, the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the embodiment [2-5].
［５－４］本発明の第５－４の態様は、前記態様［２－６］に記載の式（Ｖ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５－４の態様において、式（Ｖ）の定義及び好ましい態様は、前記態様［２－６］に記載の式（Ｖ）の定義及び好ましい態様と同じである。 [5-4] The 5-4th aspect of the present invention is the compound represented by the formula (V) according to the above aspect [2-6], or a pharmaceutically acceptable salt thereof or a solvent thereof. A method for the prophylaxis and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, which comprises administering to a patient at least one effective amount of a Japanese product.
In the fifth to fourth embodiments, the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the above embodiment [2-6].
［５－５］本発明の第５－５の態様は、前記態様［２－７］に記載の式（ＶＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法である。
　第５－５の態様において、式（ＶＩ）の定義及び好ましい態様は、前記態様［２－７］に記載の式（ＶＩ）の定義及び好ましい態様と同じである。 [5-5] A fifth to fifth aspect of the present invention is a compound represented by the formula (VI) according to the above aspect [2-7], or a pharmaceutically acceptable salt thereof or a solvent thereof A method for the prophylaxis and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, which comprises administering to a patient at least one effective amount of a Japanese product.
In the fifth to fifth embodiments, the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
［６］　本発明の第６の態様は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－１］に記載の式（Ｉ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６の態様において、式（Ｉ）－Ｂの定義及び好ましい態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂの定義及び好ましい態様と同じである。 [6] A sixth aspect of the present invention relates to the above aspect [2-1] for producing a medicament for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity. Use of the compound represented by the formula (I) -B as described, or a pharmaceutically acceptable salt or solvate thereof.
In the sixth embodiment, the definition and preferred embodiment of the formula (I) -B are the same as the definition and preferred embodiment of the formula (I) -B described in the embodiment [2-1].
　好ましい態様として、以下の態様も挙げられる。 Preferred embodiments include the following embodiments.
［６－１］本発明の第６－１の態様は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－３］に記載の式（ＩＩＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６－１の態様において、式（ＩＩＩ）の定義及び好ましい態様は、前記態様［２－３］に記載の式（ＩＩＩ）の定義及び好ましい態様と同じである。 [6-1] The 6-1 aspect of the present invention is the above aspect [2] -3], or a pharmaceutically acceptable salt or solvate thereof.
In the 6-1st embodiment, the definition and preferred embodiment of the formula (III) are the same as the definition and preferred embodiment of the formula (III) described in the embodiment [2-3].
［６－１－ａ］本発明の第６－１－ａの態様は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６－１－ａの態様において、式（ＩＩＩ）－Ａの定義及び好ましい態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａの定義及び好ましい態様と同じである。 [6-1-a] The embodiment of the 6-1-a of the present invention is for producing a medicament for the prevention and / or treatment of NAFLD • NASH, diabetes, insulin resistance or obesity / obesity, Use of the compound represented by the formula (III) -A described in the above embodiment [2-3-a], or a pharmaceutically acceptable salt thereof, or a solvate thereof.
In the 6-1-a embodiment, the definition and preferred embodiment of the formula (III) -A are the same as the definition and preferred embodiment of the formula (III) -A described in the embodiment [2-3-a]. .
［６－１－ｂ］本発明の第６－１－ｂの態様は、前記態様［６－１－ａ］より好ましい態様であり、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６－１－ｂの態様において、式（ＩＩＩ）－Ｂの定義及び好ましい態様は、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂの定義及び好ましい態様と同じである。 [6-1-b] The embodiment 6-1-b of the present invention is a more preferable embodiment than the embodiment [6-1-a], and is suitable for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity. A compound represented by the formula (III) -B according to the above embodiment [2-3-b], or a pharmaceutically acceptable salt thereof, for producing a medicament for prevention and / or treatment Use of those solvates.
In the 6-1-b embodiment, the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
［６－１－ｃ］本発明の第６－１－ｃの態様は、前記態様［６－１－ｂ］より好ましい態様であり、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６－１－ｃの態様において、式（ＩＩＩ）－Ｃの定義及び好ましい態様は、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃの定義及び好ましい態様と同じである。 [6-1-c] The embodiment 6-1-c of the present invention is a more preferred embodiment than the above embodiment [6-1-b], and is suitable for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity. A compound represented by the formula (III) -C according to the above embodiment [2-3-c], or a pharmaceutically acceptable salt thereof, for producing a medicament for prevention and / or treatment Use of those solvates.
In the embodiment of 6-1-c, the definition and preferred embodiments of the formula (III) -C are the same as the definitions and preferred embodiments of the formula (III) -C described in the embodiment [2-3-c]. .
［６－２］本発明の第６－２の態様は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－４］に記載の式（ＩＶ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６－２の態様において、式（ＩＶ）の定義及び好ましい態様は、前記態様［２－４］に記載の式（ＩＶ）の定義及び好ましい態様と同じである。 [6-2] The embodiment 6-2 of the present invention is the above embodiment [2] -4], or a pharmaceutically acceptable salt or solvate thereof.
In the 6-2nd embodiment, the definition and preferred embodiment of the formula (IV) are the same as the definition and preferred embodiment of the formula (IV) described in the embodiment [2-4].
［６－３］本発明の第６－３の態様は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－５］に記載の式（ＩＶ－ａ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６－３の態様において、式（ＩＶ－ａ）の定義及び好ましい態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）の定義及び好ましい態様と同じである。 [6-3] The sixth aspect of the present invention is the above aspect [2] for producing a medicament for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity. −5], or a pharmaceutically acceptable salt or solvate thereof.
In the sixth to third embodiments, the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the above embodiment [2-5].
［６－４］本発明の第６－４の態様は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－６］に記載の式（Ｖ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６－４の態様において、式（Ｖ）の定義及び好ましい態様は、前記態様［２－６］に記載の式（Ｖ）の定義及び好ましい態様と同じである。 [6-4] A sixth to fourth aspect of the present invention is the above aspect [2] −6], or a pharmaceutically acceptable salt or solvate thereof.
In the sixth to fourth embodiments, the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the above embodiment [2-6].
［６－５］本発明の第６－５の態様は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、前記態様［２－７］に記載の式（ＶＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の使用である。
　第６－５の態様において、式（ＶＩ）の定義及び好ましい態様は、前記態様［２－７］に記載の式（ＶＩ）の定義及び好ましい態様と同じである。 [6-5] A sixth to fifth aspect of the present invention is the above aspect [2] for producing a medicament for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity. −7], or a pharmaceutically acceptable salt or solvate thereof.
In the sixth to fifth embodiments, the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
［７］　本発明の第７の態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物である。
　第７の態様において、式（Ｉ）－Ｂの定義及び好ましい態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂの定義及び好ましい態様と同じである。 [7] A seventh aspect of the present invention is the compound represented by the formula (I) -B according to the aspect [2-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof. It is a pharmaceutical composition for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the following.
In the seventh embodiment, the definition and preferred embodiment of the formula (I) -B are the same as the definition and preferred embodiment of the formula (I) -B described in the embodiment [2-1].
　好ましい態様として、以下の態様も挙げられる。 Preferred embodiments include the following embodiments.
［７－１］本発明の第７－１の態様は、前記態様［２－３］に記載の式（ＩＩＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物である。
　第７－１の態様において、式（ＩＩＩ）の定義及び好ましい態様は、前記態様［２－３］に記載の式（ＩＩＩ）の定義及び好ましい態様と同じである。 [7-1] A seventh aspect of the present invention is a compound represented by the formula (III) according to the aforementioned aspect [2-3], or a pharmaceutically acceptable salt thereof or a solvent thereof. A pharmaceutical composition for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, comprising at least one of the Japanese as an active ingredient.
In the seventh embodiment, the definition and preferred embodiments of the formula (III) are the same as the definition and preferred embodiments of the formula (III) described in the embodiment [2-3].
［７－１－ａ］本発明の第７－１－ａの態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物である。
　第７－１－ａの態様において、式（ＩＩＩ）－Ａの定義及び好ましい態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａの定義及び好ましい態様と同じである。 [7-1-a] According to an embodiment 7-1-a of the present invention, the compound represented by the formula (III) -A according to the embodiment [2-3-a], or a pharmaceutically acceptable For the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of its salts or solvates thereof as an active ingredient It is a composition.
In the embodiment 7-1-a, the definition and preferred embodiment of the formula (III) -A are the same as the definition and preferred embodiment of the formula (III) -A described in the embodiment [2-3-a]. .
［７－１－ｂ］本発明の第７－１－ｂの態様は、前記態様［７－１－ａ］より好ましい態様であり、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物である。
　第７－１－ｂの態様において、式（ＩＩＩ）－Ｂの定義及び好ましい態様は、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂの定義及び好ましい態様と同じである。 [7-1-b] The embodiment 7-1-b of the present invention is a more preferred embodiment than the embodiment [7-1-a], and is represented by the formula (III) described in the embodiment [2-3-b]. ) -B, NAFLD / NASH, diabetes, insulin resistance, characterized by containing at least one of a compound represented by -B, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient Or it is a pharmaceutical composition for prevention and / or treatment of obesity / obesity.
In the 7-1-b embodiment, the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
［７－１－ｃ］本発明の第７－１－ｃの態様は、前記態様［７－１－ｂ］より好ましい態様であり、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物である。
　第７－１－ｃの態様において、式（ＩＩＩ）－Ｃの定義及び好ましい態様は、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃの定義及び好ましい態様と同じである。 [7-1-c] The embodiment 7-1-c of the present invention is a more preferred embodiment than the embodiment [7-1-b], and is represented by the formula (III) described in the embodiment [2-3-c]. )-Containing a compound represented by -C, or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient, NAFLD / NASH, diabetes, insulin resistance Or it is a pharmaceutical composition for prevention and / or treatment of obesity / obesity.
In the 7-1-c embodiment, the definition and preferred embodiment of the formula (III) -C are the same as the definition and preferred embodiment of the formula (III) -C described in the embodiment [2-3-c]. .
［７－２］本発明の第７－２の態様は、前記態様［２－４］に記載の式（ＩＶ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物である。
　第７－２の態様において、式（ＩＶ）の定義及び好ましい態様は、前記態様［２－４］に記載の式（ＩＶ）の定義及び好ましい態様と同じである。 [7-2] A seventh aspect of the present invention is a compound represented by the formula (IV) according to the aforementioned aspect [2-4], or a pharmaceutically acceptable salt thereof or a solvent thereof. A pharmaceutical composition for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the Japanese as an active ingredient.
In the seventh embodiment, the definition and preferred embodiment of the formula (IV) are the same as the definition and preferred embodiment of the formula (IV) described in the embodiment [2-4].
［７－３］本発明の第７－３の態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物である。
　第７－３の態様において、式（ＩＶ－ａ）の定義及び好ましい態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）の定義及び好ましい態様と同じである。 [7-3] A seventh aspect of the present invention is a compound represented by the formula (IV-a) according to the above aspect [2-5], or a pharmaceutically acceptable salt thereof, or a compound thereof It is a pharmaceutical composition for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, comprising at least one of the above solvates as an active ingredient.
In the seventh to third embodiments, the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the above embodiment [2-5].
［７－４］本発明の第７－４の態様は、前記態様［２－６］に記載の式（Ｖ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物である。
　第７－４の態様において、式（Ｖ）の定義及び好ましい態様は、前記態様［２－６］に記載の式（Ｖ）の定義及び好ましい態様と同じである。 [7-4] A seventh to fourth aspect of the present invention is the compound represented by the formula (V) according to the above aspect [2-6], or a pharmaceutically acceptable salt thereof or a solvent thereof. A pharmaceutical composition for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, comprising at least one of the Japanese as an active ingredient.
In the seventh to fourth embodiments, the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the above embodiment [2-6].
［７－５］本発明の第７－５の態様は、前記態様［２－７］に記載の式（ＶＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方のための医薬組成物である。
　第７－５の態様において、式（ＶＩ）の定義及び好ましい態様は、前記態様［２－７］に記載の式（ＶＩ）の定義及び好ましい態様と同じである。 [7-5] A seventh to fifth aspect of the present invention is a compound represented by the formula (VI) according to the above aspect [2-7], or a pharmaceutically acceptable salt thereof or a solvent thereof. A pharmaceutical composition for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity, characterized by containing at least one of the Japanese as an active ingredient.
In the seventh to fifth embodiments, the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
［８］　本発明の第８の態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つ、及び製薬学的担体とともに、他の薬物の有効成分を含有していてもよい医薬組成物である。
　ここで、他の薬物とは、同じ作用メカニズムの他の薬物（Ｅｌｏｖｌ６阻害剤）を含め、異なる作用メカニズムの薬物もしくは同種同効薬を包含する。例えば、同種同効薬としては、インスリン抵抗性改善薬・糖尿病薬、脂質低下薬・脂質異常症治療剤、抗肥満薬、高血圧治療剤、あるいはＮＡＳＨ治療に有効と考えられる治療剤等、種々の治療に用いられる薬物が挙げられる。
　また、他の薬物として、上記以外の異種の疾病を対象とする薬物をも包含する。
　第８の態様において、式（Ｉ）－Ｂの定義及び好ましい態様は、前記態様［２－１］に記載の式（Ｉ）－Ｂの定義及び好ましい態様と同じである。 [8] An eighth aspect of the present invention is the compound represented by the formula (I) -B according to the above aspect [2-1], or a pharmaceutically acceptable salt thereof, or a solvate thereof. A pharmaceutical composition that may contain an active ingredient of another drug together with at least one of the above and a pharmaceutical carrier.
Here, the other drug includes a drug having a different mechanism of action or an allotrope including another drug (Elovl6 inhibitor) having the same mechanism of action. For example, the same type of synergistic drugs include various drugs such as insulin resistance improving drugs / diabetic drugs, lipid lowering drugs / dyslipidemia drugs, anti-obesity drugs, antihypertensive drugs, or therapeutic agents considered effective for NASH treatment. Examples include drugs used for treatment.
In addition, other drugs include drugs targeting different types of diseases.
In the eighth embodiment, the definition and preferred embodiments of the formula (I) -B are the same as the definitions and preferred embodiments of the formula (I) -B described in the embodiment [2-1].
　好ましい態様として、以下の態様も挙げられる。 Preferred embodiments include the following embodiments.
［８－１］本発明の第８－１の態様は、前記態様［２－３］に記載の式（ＩＩＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つ、及び製薬学的担体とともに、他の薬物の有効成分を含有していもよい医薬組成物である。
　第８－１の態様において、式（ＩＩＩ）の定義及び好ましい態様は、前記態様［２－３］に記載の式（ＩＩＩ）の定義及び好ましい態様と同じである。 [8-1] The eighth aspect of the present invention is a compound represented by the formula (III) according to the aforementioned aspect [2-3], or a pharmaceutically acceptable salt thereof or a solvent thereof. It is a pharmaceutical composition which may contain an active ingredient of another drug together with at least one of the Japanese products and a pharmaceutical carrier.
In the 8-1st aspect, the definition and preferred aspect of the formula (III) are the same as the definition and preferred aspect of the formula (III) described in the above aspect [2-3].
［８－１－ａ］本発明の第８－１－ａの態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つ、及び製薬学的担体とともに、他の薬物の有効成分を含有していもよい医薬組成物である。
　第８－１－ａの態様において、式（ＩＩＩ）－Ａの定義及び好ましい態様は、前記態様［２－３－ａ］に記載の式（ＩＩＩ）－Ａの定義及び好ましい態様と同じである。 [8-1-a] The embodiment of 8-1-1a of the present invention is a compound represented by the formula (III) -A according to the embodiment [2-3-a], or a pharmaceutically acceptable The pharmaceutical composition may contain an active ingredient of another drug together with at least one of its salts or solvates thereof and a pharmaceutical carrier.
In the embodiment of 8-1-1a, the definition and preferred embodiments of the formula (III) -A are the same as the definitions and preferred embodiments of the formula (III) -A described in the embodiment [2-3-a]. .
［８－１－ｂ］本発明の第８－１－ｂの態様は、前記態様［８－１－ａ］より好ましい態様であり、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つ、及び製薬学的担体とともに、他の薬物の有効成分を含有していもよい医薬組成物である。Ａａを構成に含む環は芳香化しているものを含まない。
　第８－１－ｂの態様において、式（ＩＩＩ）－Ｂの定義及び好ましい態様は、前記態様［２－３－ｂ］に記載の式（ＩＩＩ）－Ｂの定義及び好ましい態様と同じである。 [8-1-b] The embodiment 8-1-b of the present invention is a more preferred embodiment than the embodiment [8-1-a], and is represented by the formula (III) described in the embodiment [2-3-b]. ) -B or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical that may contain an active ingredient of another drug together with a pharmaceutical carrier It is a composition. The ring containing A a does not include those that are aromatized.
In the 8-1-1b embodiment, the definition and preferred embodiment of the formula (III) -B are the same as the definition and preferred embodiment of the formula (III) -B described in the embodiment [2-3-b]. .
［８－１－ｃ］本発明の第８－１－ｃの態様は、前記態様［８－１－ｂ］より好ましい態様であり、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃで表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つ、及び製薬学的担体とともに、他の薬物の有効成分を含有していもよい医薬組成物である。
　第８－１－ｃの態様において、式（ＩＩＩ）－Ｃの定義及び好ましい態様は、前記態様［２－３－ｃ］に記載の式（ＩＩＩ）－Ｃの定義及び好ましい態様と同じである。 [8-1-c] Aspect 8-1-1 of the present invention is a more preferred embodiment than the above-mentioned embodiment [8-1-b], and is represented by the formula (III) described in the embodiment [2-3-c]. ) A pharmaceutical agent which may contain an active ingredient of another drug together with at least one of a compound represented by -C, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical carrier It is a composition.
In the embodiment of 8-1-1c, the definition and preferred embodiment of the formula (III) -C are the same as the definition and preferred embodiment of the formula (III) -C described in the embodiment [2-3-c]. .
［８－２］本発明の第８－２の態様は、前記態様［２－４］に記載の式（ＩＶ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつ、及び製薬学的担体とともに、他の薬物の有効成分を含有していもよい医薬組成物である。
　第８－２の態様において、式（ＩＶ）の定義及び好ましい態様は、前記態様［２－４］に記載の式（ＩＶ）の定義及び好ましい態様と同じである。 [8-2] The eighth aspect of the present invention is a compound represented by the formula (IV) according to the aforementioned aspect [2-4], or a pharmaceutically acceptable salt thereof or a solvent thereof. It is a pharmaceutical composition which may contain an active ingredient of another drug together with at least one of the Japanese products and a pharmaceutical carrier.
In the eighth embodiment, the definition and preferred embodiments of the formula (IV) are the same as the definition and preferred embodiments of the formula (IV) described in the embodiment [2-4].
［８－３］本発明の第８－３の態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくともひとつ、及び製薬学的担体とともに、他の薬物の有効成分を含有していもよい医薬組成物である。
　第８－３の態様において、式（ＩＶ－ａ）の定義及び好ましい態様は、前記態様［２－５］に記載の式（ＩＶ－ａ）の定義及び好ましい態様と同じである。 [8-3] An eighth aspect of the present invention is the compound represented by the formula (IV-a) according to the above aspect [2-5], or a pharmaceutically acceptable salt thereof, or a salt thereof. The pharmaceutical composition may contain an active ingredient of another drug together with at least one of the solvates of the above and a pharmaceutical carrier.
In the eighth to third embodiments, the definition and preferred embodiments of the formula (IV-a) are the same as the definitions and preferred embodiments of the formula (IV-a) described in the embodiment [2-5].
［８－４］本発明の第８－４の態様は、前記態様［２－６］に記載の式（Ｖ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つ、及び製薬学的担体とともに、他の薬物の有効成分を含有していもよい医薬組成物である。
　第８－４の態様において、式（Ｖ）の定義及び好ましい態様は、前記態様［２－６］に記載の式（Ｖ）の定義及び好ましい態様と同じである。 [8-4] The 8-4th aspect of the present invention is the compound represented by the formula (V) according to the above aspect [2-6], or a pharmaceutically acceptable salt thereof or a solvent thereof. It is a pharmaceutical composition which may contain an active ingredient of another drug together with at least one of the Japanese products and a pharmaceutical carrier.
In the eighth to fourth embodiments, the definition and preferred embodiments of the formula (V) are the same as the definitions and preferred embodiments of the formula (V) described in the above embodiment [2-6].
［８－５］本発明の第８－５の態様は、前記態様［２－７］に記載の式（ＶＩ）で表される化合物、または製薬学的に許容されるその塩またはそれらの溶媒和物の少なくとも１つ、及び製薬学的担体とともに、他の薬物の有効成分を含有していもよい医薬組成物である。
　第８－５の態様において、式（ＶＩ）の定義及び好ましい態様は、前記態様［２－７］に記載の式（ＶＩ）の定義及び好ましい態様と同じである。 [8-5] An eighth to fifth aspect of the present invention is the compound represented by formula (VI) according to the above aspect [2-7], or a pharmaceutically acceptable salt thereof or a solvent thereof. It is a pharmaceutical composition which may contain an active ingredient of another drug together with at least one of the Japanese products and a pharmaceutical carrier.
In the eighth to fifth embodiments, the definition and preferred embodiments of the formula (VI) are the same as the definitions and preferred embodiments of the formula (VI) described in the above embodiment [2-7].
　第２ないし第８の態様、並びにそれらの好ましい態様において、より好ましい置換基またはそれらの組み合わせは、第１の態様に記載されている。 In the second to eighth aspects and preferred aspects thereof, more preferred substituents or combinations thereof are described in the first aspect.
　上記本発明の態様［１］～［８］のそれぞれに記載の各態様において、Ｅｌｏｖｌ６阻害活性を適宜選択した方法（例えば、後述の薬理実験例３（Ｅｌｏｖｌ６酵素阻害試験）または薬理実験例４（細胞内Ｅｌｏｖｌ６酵素活性阻害試験））で測定した場合、ＩＣ５０値で、１μＭ以下が好ましく、より好ましくは１００ｎＭ以下、更に好ましくは３０ｎＭ以下、特に好ましくは１０ｎＭ以下である化合物を用いることが好ましい。
　前記本発明の態様において、「治療剤」とは疾患もしくは症状の治療だけでなく、疾患もしくは症状の改善も含むものとする。 In each of the above-described embodiments [1] to [8] of the present invention, a method in which Elovl6 inhibitory activity is appropriately selected (for example, Pharmacological Experimental Example 3 (Elovl6 Enzyme Inhibition Test) described later or Pharmacological Experimental Example 4 ( When measured by an intracellular Elovl6 enzyme activity inhibition test)), the IC 50 value is preferably 1 μM or less, more preferably 100 nM or less, still more preferably 30 nM or less, and particularly preferably 10 nM or less.
In the above aspect 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.
　以上の全ての態様において、「化合物」の文言を用いるとき、「その製薬学的に許容される塩」についても言及するものとする。また、本発明化合物は不斉炭素を有する場合があり、本発明化合物には、幾何異性体、互変異性体、光学異性体などの各種の立体異性体の混合物や単離されたものが含まれる。かかる立体異性体の単離、精製は、優先晶出やカラムクロマトグラフィーを用いた光学分割あるいは不斉合成を通じて当業者が通常の技術により為し得ることができる。 In all of the above embodiments, when the term “compound” is used, “the pharmaceutically acceptable salt” 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.
　本発明の式（Ｉ）で表される化合物は、酸付加塩を形成する場合がある。また、置換基の種類によっては塩基との塩を形成する場合もある。かかる塩としては、製薬学的に許容しうる塩であれば特に限定されないが、具体的には、塩酸、臭化水素酸、よう化水素酸、硫酸、硝酸、りん酸等の鉱酸類；蟻酸、酢酸、プロピオン酸、酪酸、吉草酸、エナント酸、カプリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、乳酸、ソルビン酸、マンデル酸等の脂肪族モノカルボン酸、安息香酸、サリチル酸等の芳香族モノカルボン酸、しゅう酸、マロン酸、こはく酸、フマル酸、マレイン酸、りんご酸、酒石酸等の脂肪族ジカルボン酸、くえん酸等の脂肪族トリカルボン酸などの有機カルボン酸類；メタンスルホン酸、エタンスルホン酸、２－ヒドロキシエタンスルホン酸等の脂肪族スルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の芳香族スルホン酸などの有機スルホン酸類；アスパラギン酸、グルタミン酸等の酸性アミノ酸類等との酸付加塩、及びナトリウム、カリウム、マグネシウム、カルシウム等のアルカリ金属もしくはアルカリ土類金属等の金属との塩、メチルアミン、エチルアミン、エタノールアミン、ピリジン、リシン、アルギニン、オルニチン等の有機塩基との塩や、アンモニウム塩等が挙げられる。 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.
　これらの塩は常法，例えば、当量の本発明化合物と所望の酸あるいは塩基等を含む溶液を混合し、所望の塩をろ取するか溶媒を留去して集めることにより得ることができる。また、本発明化合物またはその塩は、水、エタノール、グリセロールなどの溶媒と溶媒和物を形成しうる。 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.
　また、本発明化合物の塩には、モノ塩およびジ塩が含まれる。或いは本発明化合物は側鎖の置換基によっては、酸付加塩と塩基の塩の両方を同時に形成しうる。 In addition, 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.
　更に本発明は、本発明の式（Ｉ）で表される化合物の水和物、製薬学的に許容可能な各種溶媒和物や結晶多形のもの等も含まれる。尚、当然ながら本発明は、後述実施例に記載された化合物に限定されるものではなく、本発明の式（Ｉ）で示される化合物または製薬学的に許容される塩の全てを包含するものである。 Furthermore, the present invention also includes hydrates of 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.
［本発明化合物の製造方法］
　本発明に用いられる式（Ｉ）で表される化合物ならびに関連化合物は、以下に示される製造法により得ることができる。以下、各反応工程について説明する。 [Method for producing compound of the present invention]
The compound represented by the 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.
　製造法中の反応条件については、特に断らない限り、以下の如きとする。反応温度は、－７８℃から溶媒が還流する温度の範囲であり、反応時間は、反応が十分進行する時間である。また、反応に不活性な溶媒とは、例えばトルエン、キシレン、ベンゼン等の芳香族炭化水素系溶媒、メタノールおよびエタノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、アセトニトリル、水等の極性溶媒、トリエチルアミン、ピリジンなどの塩基性溶媒、酢酸等の有機酸溶媒、クロロホルム、ジクロロメタン、１，２－ジクロロエタン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、ジオキサン、ジメトキシエタン等のエーテル系溶媒等、もしくはこれらの混合溶媒であり、反応条件により適宜選択される。塩基とは、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、炭酸水素ナトリウム等の無機塩基、あるいはトリエチルアミン、ジエチルアミン、ピリジン、Ｎ，Ｎ－ジアルキルアニリン、リチウムジイソプロピルアミド、リチウムビス（トリメチルシリル）アミド等の有機塩基であり、酸とは、塩酸、硫酸等の無機酸、酢酸、トリフルオロ酢酸、メタンスルホン酸、ｐ－トルエンスルホン酸等の有機酸である。ただし、上記に記載したものに必ずしも限定されるものではない。 The reaction conditions in the production method are as follows unless otherwise specified. The reaction temperature ranges 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, alcohol solvents such as methanol and ethanol, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, and the like. Polar solvents, basic solvents such as triethylamine, pyridine, organic acid solvents such as acetic acid, halogen solvents such as chloroform, dichloromethane, 1,2-dichloroethane, ether solvents such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc. Or it is a mixed solvent of these, and it selects suitably by 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.
　本発明化合物である式（Ｉ）で表される化合物は、市販化合物または市販化合物から文献公知の方法等により容易に製造することが可能であり、以下に示す製造方法に従い製造することができる。また、式（Ｉ）-Ａ、式（Ｉ）－Ｂ、式（ＩＩ）、式（ＩＩＩ）、式（ＩＩＩ）－Ａ、式（ＩＩＩ）－Ｂ、式（ＩＩＩ）－Ｃ、式（ＩＶ）、式（ＩＶ－ａ）、式（Ｖ）及び式（ＶＩ）で表わされる化合物も、以下の製造方法に準じて製造することができる。 The compound represented by the formula (I) which is the compound of the present invention can be easily produced from a commercially available compound or a commercially available compound by methods known in the literature, and can be produced according to the production method shown below. In addition, formula (I) -A, formula (I) -B, formula (II), formula (III), formula (III) -A, formula (III) -B, formula (III) -C, formula (IV) ), Formula (IV-a), formula (V) and formula (VI) can also be produced according to the following production method.
　また、本発明は以下に説明する製造方法に、何ら限定されるものではない。 Further, the present invention is not limited to the manufacturing method described below.
　尚、例えば式（Ｉ）で表される化合物と記載する場合は、式（Ｉ）で表される化合物またはその塩およびそれらの溶媒和物を含むものとする。 In addition, when describing with the compound represented, for example by a formula (I), the compound represented by a formula (I) or its salt, and those solvates shall be included.
　以下、製造法を詳細に説明する。
　以下の説明中の式（Ｉ）、式（Ｉ－１）～式（Ｉ－１５）、式（Ｉ－１’）、式（Ｉ－２’）、式（Ｉ－９’）、式（Ｉ－１１’）、式（Ｉ－１１’’）、式（Ｘ）、式（Ｘ’）、式（Ｘ’’）、式（Ｘ’’’）、式（Ｘ－１）～式（Ｘ－２７）、式（Ｘ－６’）、式（Ｘ－７’）、式（Ｘ－８’）、式（ＸＩ）、式（ＸＩ－１）～式（ＸＩ－８）、式（ＸＩ－７’）、式（ＸＩ－８’）、式（ＸＩＩ）、式（ＸＩＩＩ）、式（ＸＩＩＩ－１）、式（ＸＩＩＩ－２）、式（ＸＩＶ）、式（ＸＩＶ－１）～式（ＸＩＶ－８）、式（ＸＩＶ－１’）、式（ＸＩＶ－１’’）、式（ＸＶ）、式（ＸＶＩ）、式（ＸＶＩ－１）～式（ＸＶＩ－５）、式（ＸＶＩＩ）、式（ＸＶＩＩＩ）、式（ＸＩＸ）、式（ＸＩＸ－１）、式（ＸＸ）、式（ＸＸ－１）～式（ＸＸ－４）、式（ＸＸＩ）、式（ＸＸＩ’）、式（ＸＸＩＩ）、式（ＸＸＩＩ－１）～式（ＸＸＩＩ－６）、式（ＸＸＩＩＩ）、式（ＸＸＩＩＩ－１）、式（ＸＸＩＩＩ－２）、式（ＸＸＩＶ）、式（ＸＸＩＶ－１）～式（ＸＸＩＶ－６）、式（ＸＸＩＶ－３’）で表される化合物中の、Ｙ、Ｗ、Ｚ、ＲＡ、ＲＢ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ９、Ｒ１０、Ｒ１１、ｋ、ｎ、ｍ、ｐは、特に断らない限り、式（Ｉ）に記載された先の定義と同一である。 Hereinafter, the production method will be described in detail.
In the following description, formula (I), formula (I-1) to formula (I-15), formula (I-1 ′), formula (I-2 ′), formula (I-9 ′), formula (I I-11 ′), Formula (I-11 ″), Formula (X), Formula (X ′), Formula (X ″), Formula (X ″ ′), Formula (X-1) to Formula (X X-27), Formula (X-6 ′), Formula (X-7 ′), Formula (X-8 ′), Formula (XI), Formula (XI-1) to Formula (XI-8), Formula (X XI-7 ′), formula (XI-8 ′), formula (XII), formula (XIII), formula (XIII-1), formula (XIII-2), formula (XIV), formula (XIV-1) to Formula (XIV-8), Formula (XIV-1 ′), Formula (XIV-1 ″), Formula (XV), Formula (XVI), Formula (XVI-1) to Formula (XVI-5), Formula (XVI-5) XVII), formula (XVIII), formula (XIX), formula (XIX-1), formula (XX), formula (XX-1) to formula (XX-4), formula (XX ), Formula (XXI ′), Formula (XXII), Formula (XXII-1) to Formula (XXII-6), Formula (XXIII), Formula (XXIII-1), Formula (XXIII-2), Formula (XXIV) Y, W, Z, R A , R B , R 1 , R 2 , R 3 in the compounds represented by formulas (XXIV-1) to (XXIV-6) and formula (XXIV-3 ′) , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , k, n, m, p are the previous definitions described in formula (I) unless otherwise specified. Is the same.
　ｍ’、ｐ’、ｑ、ｒは０～３の整数を表し、Ｐ１は、メチル基、ｔ－ブトキシカルボニル基等の保護基を、Ｘは、ハロゲン原子（Ｆ、Ｃｌ、Ｂｒ、Ｉ）、Ｌは、ハロゲン原子、リン酸エステル等の脱離性置換基、Ｍはリチウム（Ｌｉ）、マグネシウムハライド（ＭｇＸ、Ｘはハロゲン原子）、ホウ酸エステル等を表す。 m ′, p ′, q and r each represent an integer of 0 to 3, P 1 represents a protecting group such as a methyl group or a t-butoxycarbonyl group, and X represents a halogen atom (F, Cl, Br, I) , L represents a detachable substituent such as a halogen atom or phosphate ester, M represents lithium (Li), magnesium halide (MgX, X is a halogen atom), borate ester, or the like.
　Ｒ２３、Ｒ２４は、各々独立にＲＡ中で定義される官能基から任意に選ばれる基を表し、Ｒ２３がＲ２４と一緒になって結合している炭素原子を含む５～７員のシクロ環基を形成してもよい。 R 23 and R 24 each independently represents a group arbitrarily selected from the functional groups defined in R A , and a 5- to 7-membered group containing a carbon atom to which R 23 is bonded together with R 24 May be formed.
　ＶＡは、－ＣＯＯＨ、－ＮＨＲ８、－ＮＨＲ９、－ＣＨＯ、－ＮＨＲ１１、－Ｈ、－ＣＯＮＨ２、－ＣＯＮＨＲ７、－Ｌを表す。ＶＢは、－ＮＨＲ７、－ＣＯＯＨ、－ＮＨＲ１０、－ＮＣＯ、－ＮＨＲ１１、－ＣＨＯ、－Ｌ、－ＣＯＮＨ２、－ＣＯＮＨＲ８、ＶＣは、－ＮＨＲ７、－ＮＣＯ、－Ｌを表し、ＶＤは、水素原子、－Ｌ、－ＳＨを表し、ＶＥは、水素原子、－Ｌを表し、ＶＦは水素原子、－Ｌを表し、ＶＧは、水素原子、－Ｌを表し、ＶＨは－Ｌを表す。 V A represents —COOH, —NHR 8 , —NHR 9 , —CHO, —NHR 11 , —H, —CONH 2 , —CONHR 7 , —L. V B is —NHR 7 , —COOH, —NHR 10 , —NCO, —NHR 11 , —CHO, —L, —CONH 2 , —CONHR 8 , V C is —NHR 7 , —NCO, —L represents, V D is a hydrogen atom, -L represents -SH, V E represents a hydrogen atom, a -L, V F is hydrogen atom, a -L, V G represents a hydrogen atom, a -L VH represents -L.
　また、Ｒｉｎｇ’は置換フェニル環、置換ピリジン環、置換フラン環等を含むアリール基を、Ｒｉｎｇ’’は式（Ｉ）において（ＣＲ１Ｒ２）ｍとの接合部に窒素原子が存在する場合を、Ｒｉｎｇ’’’は式（Ｉ）においてＳ（Ｏ）ｎとの接合部に窒素原子が存在する場合を表す。 Ring 'is an aryl group including a substituted phenyl ring, a substituted pyridine ring, a substituted furan ring, etc., and Ring''is a nitrogen atom at the junction with (CR 1 R 2 ) m in formula (I) , Ring ′ ″ represents the case where a nitrogen atom is present at the junction with S (O) n in formula (I).
［製造法１］ [Production Method 1]
　式（Ｉ）で表される化合物は、式（Ｘ）で表される化合物および式（ＸＩ）で表される化合物を用いて、反応式１の方法で製造することができる。 The compound represented by Formula (I) can be produced by the method of Reaction Formula 1 using the compound represented by Formula (X) and the compound represented by Formula (XI).
Figure JPOXMLDOC01-appb-C000160
  
Figure JPOXMLDOC01-appb-C000160
  
（製造法１－１）
　特に前記式（Ｉ）においてＷが－ＣＯＮＲ７－である式（Ｉ－１）で表される化合物は、反応式２の方法で製造することができる。 (Production method 1-1)
In particular, the compound represented by the formula (I-1) in which W is —CONR 7 — in the formula (I) can be produced by the method of the reaction formula 2.
Figure JPOXMLDOC01-appb-C000161
  
Figure JPOXMLDOC01-appb-C000161
  
　式（Ｘ－１）で表される化合物、および式（ＸＩ－１）で表される化合物を用い、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－１）で表される化合物を製造することができる。また、式（Ｘ－１）で表される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－１）で表される化合物を製造することができる。 Using a compound represented by the formula (X-1) and a compound represented by the formula (XI-1), a method known in the literature, for example, (Experimental Chemistry Course, 4th Edition, 22. Organic Synthesis IV, Acid, Amino Acid, Peptide, 191-309, 1992, Maruzen) and the like, 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (WSC HCl), benzotriazole-1-iroxytris (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) -4-methylmorpholinium chloride (DMTMM) in the presence of a halogen solvent such as dichloromethane and chloroform, an ether solvent such as diethyl ether and tetrahydrofuran, toluene Base solvents such as triethylamine and pyridine in solvents not involved in the reaction such as aromatic hydrocarbon solvents such as benzene, polar solvents such as N, N-dimethylformamide, alcohol solvents such as methanol, ethanol and 2-propanol. The compound represented by the formula (I-1) can be produced by reacting in the presence or absence at a temperature at which the solvent is refluxed from 0 ° C. In addition, when the compound represented by the formula (X-1) is converted to acid chloride (Experimental Chemistry Course, 4th edition, 22 Organic Synthesis IV, Acid, Amino Acid, Peptide, 144-146, 1992, Maruzen) In the presence of a base such as triethylamine or pyridine, a halogen solvent such as dichloromethane or chloroform, an ether solvent such as diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene or benzene, N, The compound represented by the formula (I-1) can be produced by reacting in a solvent such as N-dimethylformamide that does not participate in the reaction at a temperature at which the solvent is refluxed from 0 ° C.
（製造法１－２）
　特に前記式（Ｉ）においてＷが－ＮＲ８ＣＯ－である式（Ｉ－２）で表される化合物は、反応式３の方法で製造することができる。 (Production method 1-2)
In particular, the compound represented by the formula (I-2) in which W is —NR 8 CO— in the formula (I) can be produced by the method of the reaction formula 3.
Figure JPOXMLDOC01-appb-C000162
  
Figure JPOXMLDOC01-appb-C000162
  
　式（Ｘ－２）で表される化合物、および式（ＸＩ－２）で表される化合物を用い、（製造法１－１）と同様の方法により式（Ｉ－２）で表される化合物を製造することができる。 A compound represented by formula (I-2) by a method similar to (Production Method 1-1) using a compound represented by formula (X-2) and a compound represented by formula (XI-2) Can be manufactured.
（製造法１－３）
　特に前記式（Ｉ）においてＷが－ＮＲ９ＣＯＮＲ１０－である式（Ｉ－３）で表される化合物は、反応式４の方法で製造することができる。 (Production method 1-3)
In particular, the compound represented by the formula (I-3) in which W is —NR 9 CONR 10 — in the formula (I) can be produced by the method of the reaction formula 4.
Figure JPOXMLDOC01-appb-C000163
  
Figure JPOXMLDOC01-appb-C000163
  
　式（Ｘ－３）で表される化合物、および式（ＸＩ－３）で表される化合物を用い、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）、４４（１３）、２２１９－２２２８、２００１年に記載された方法に準じて、トリフォスゲン、１，１’－カルボニルジイミダゾール（ＣＤＩ）等のカルボニル化試薬の存在下、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、トリエチルアミン等の塩基存在下または非存在下、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、アセトニトリル等の極性溶媒等の反応に関与しない溶媒中、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｉ－３）で表される化合物を製造することができる。 Using a compound represented by the formula (X-3) and a compound represented by the formula (XI-3), a method known in the literature, for example, Journal of Medicinal Chemistry, 44 (13 ), 2219-2228, in accordance with the method described in 2001, sodium hydride, lithium hydroxide, sodium hydroxide in the presence of a carbonylating reagent such as triphosgene, 1,1′-carbonyldiimidazole (CDI) In the presence or absence of bases such as potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, and aromatics such as toluene and benzene Group hydrocarbon Solvent, in a solvent which does not participate in the reaction, such as a polar solvent such as acetonitrile, by reacting at a temperature at which the solvent refluxes from -78 ° C., can be prepared a compound represented by the formula (I-3).
（製造法１－４）
　特に前記式（Ｉ）においてＷが－ＮＲ９ＣＯＮＨ－である式（Ｉ－４）で表される化合物は、反応式５の方法で製造することができる。 (Production method 1-4)
In particular, the compound represented by the formula (I-4) in which W is —NR 9 CONH— in the formula (I) can be produced by the method of the reaction formula 5.
Figure JPOXMLDOC01-appb-C000164
  
Figure JPOXMLDOC01-appb-C000164
  
　式（Ｘ－３）で表される化合物、および式（ＸＩ－４）で表される化合物を用い、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）、５１（５）、１２３１－１２４１、２００８年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または非存在下、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、アセトニトリル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－４）で表される化合物を製造することができる。 Using a compound represented by formula (X-3) and a compound represented by formula (XI-4), a method known in the literature, for example, Journal of Medicinal Chemistry, 51 (5 ), 1231-11241, in accordance with the method described in 2008, in the presence or absence of a base such as triethylamine or pyridine, a halogen solvent such as dichloromethane or chloroform, an ether solvent such as diethyl ether or tetrahydrofuran, It is represented by the formula (I-4) 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 an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as acetonitrile. Compounds can be produced.
（製造法１－５）
　特に前記式（Ｉ）においてＷが－ＮＲ１１－である式（Ｉ－５）で表される化合物は、反応式６の方法で製造することができる。 (Production method 1-5)
In particular, the compound represented by the formula (I-5) in which W is —NR 11 — in the formula (I) can be produced by the method of the reaction formula 6.
Figure JPOXMLDOC01-appb-C000165
  
Figure JPOXMLDOC01-appb-C000165
  
　式（Ｘ－４）で表される化合物、および式（ＸＩ－５）で表される化合物を用い、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）、２３（１２）、１４０５－１４１０、１９８０年に記載された方法に準じて、酢酸等の酸触媒存在下または非存在下、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、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、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、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、イミンを形成後、水素化ホウ素ナトリウムなどの還元剤存在下、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、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、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（Ｉ－５）で表される化合物を製造することができる。 Using a compound represented by the formula (X-4) and a compound represented by the formula (XI-5), methods known in the literature, for example, Journal of Medicinal Chemistry, 23 (12 ), 1405-1410, according to the method described in 1980, in the presence or absence of an acid catalyst such as acetic acid, halogen solvents such as dichloromethane and chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, Using solvents such as ether solvents such as 1,4-dioxane, polar solvents such as N, N-dimethylformamide, alcohol solvents such as methanol, ethanol and 2-propanol, or a mixed solvent thereof. The reaction is carried out at a temperature at which the solvent refluxes from 0 ° C., After forming the amine, in the presence of a reducing agent such as sodium borohydride, an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, a polar solvent such as N, N-dimethylformamide, Using a solvent that does not participate in the reaction, such as an alcohol solvent such as methanol, ethanol, 2-propanol, or a mixed solvent thereof, the reaction is performed at a temperature at which the solvent refluxes from 0 ° C., and is represented by the formula (I-5). Can be produced.
（製造法１－６）
　特に前記式（Ｉ）においてＷが－ＮＲ１１－である式（Ｉ－６）で表される化合物は、反応式７の方法で製造することができる。 (Production method 1-6)
In particular, the compound represented by the formula (I-6) in which W is —NR 11 — in the formula (I) can be produced by the method of the reaction formula 7.
Figure JPOXMLDOC01-appb-C000166
  
Figure JPOXMLDOC01-appb-C000166
  
　式（Ｘ－５）で表される化合物、および式（ＸＩ－６）で表される化合物を用い、（製造法１－５）と同様の方法により式（Ｉ－６）で表される化合物を製造することができる。 A compound represented by formula (I-6) by a method similar to (Production Method 1-5) using a compound represented by formula (X-5) and a compound represented by formula (XI-6) Can be manufactured.
（製造法１－７）
　特に前記式（Ｉ）においてＷが－ＣＯＮＲ７－である式（Ｉ－７）で表される化合物及び式（Ｉ－１）で表される化合物は、反応式８の方法で製造することができる。 (Production method 1-7)
In particular, the compound represented by the formula (I-7) and the compound represented by the formula (I-1) in which W is —CONR 7 — in the formula (I) can be prepared by the method of the reaction formula 8. it can.
Figure JPOXMLDOC01-appb-C000167
  
Figure JPOXMLDOC01-appb-C000167
  
＜工程１＞
　式（Ｘ－６）で表される化合物、および式（ＸＩ－７）で表される化合物を用い、文献公知の方法、例えば（実験化学講座　第４版　２４　有機合成ＩＶ　ヘテロ元素・典型金属元素化合物、３１９－４１９頁、１９９２年、丸善）等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、トリエチルアミン等の塩基存在下または非存在下、メタノール、エタノール、アセトン、Ｎ，Ｎ－ジメチルホルムアミド、１，４－ジオキサン、テトラヒドロフラン、水等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｉ－７）で表される化合物を製造することができる。 <Step 1>
Using a compound represented by the formula (X-6) and a compound represented by the formula (XI-7), a method known in the literature, for example, (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element) Compound, 319-419, 1992, Maruzen) and the like, such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, etc. In the presence or absence of a base, using a solvent inert to the reaction such as methanol, ethanol, acetone, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, water, or a mixed solvent thereof, −78 A compound represented by the formula (I-7) can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C.
＜工程２＞
　式（Ｉ－７）で表される化合物、および式（ＸＩ－７’）で表される化合物を用い、＜工程１＞と同様の方法により、式（Ｉ－１）で表される化合物を製造することができる。 <Process 2>
Using the compound represented by formula (I-7) and the compound represented by formula (XI-7 ′), the compound represented by formula (I-1) was synthesized in the same manner as in <Step 1>. Can be manufactured.
＜工程３＞
　式（Ｘ－６）で表される化合物、および式（ＸＩ－７’）で表される化合物を用い、＜工程１＞と同様の方法により、式（Ｘ－６’）で表される化合物を製造することができる。 <Step 3>
A compound represented by formula (X-6 ′) using a compound represented by formula (X-6) and a compound represented by formula (XI-7 ′) in the same manner as in <Step 1> Can be manufactured.
＜工程４＞
　式（Ｘ－６’）で表される化合物、および式（ＸＩ－７）で表される化合物を用い、＜工程１＞と同様の方法により、式（Ｉ－１）で表される化合物を製造することができる。 <Step 4>
Using the compound represented by the formula (X-6 ′) and the compound represented by the formula (XI-7), the compound represented by the formula (I-1) was synthesized in the same manner as in <Step 1>. Can be manufactured.
（製造法１－８）
　特に前記式（Ｉ）においてＷが－ＮＲ８ＣＯ－である式（Ｉ－８）及び式（Ｉ－２）で表される化合物は、反応式９の方法で製造することができる。 (Production method 1-8)
In particular, the compounds represented by formula (I-8) and formula (I-2) in which W is —NR 8 CO— in formula (I) can be produced by the method of reaction scheme 9.
Figure JPOXMLDOC01-appb-C000168
  
Figure JPOXMLDOC01-appb-C000168
  
＜工程１＞
　式（ＸＩ－８）で表される化合物、および式（Ｘ－７）で表される化合物を用い、（製造法１－７）＜工程１＞と同様の方法により、式（Ｉ－８）で表される化合物を製造することができる。 <Step 1>
Using the compound represented by the formula (XI-8) and the compound represented by the formula (X-7), in the same manner as in (Production Method 1-7) <Step 1>, the compound represented by the formula (I-8) The compound represented by these can be manufactured.
＜工程２＞
　式（Ｉ－８）で表される化合物、および式（Ｘ－７’）で表される化合物を用い、（製造法１－７）＜工程１＞と同様の方法により、式（Ｉ－２）で表される化合物を製造することができる。 <Process 2>
Using the compound represented by the formula (I-8) and the compound represented by the formula (X-7 ′), (Production Method 1-7) In the same manner as in <Step 1>, the compound represented by the formula (I-2 ) Can be produced.
＜工程３＞
　式（ＸＩ－８）で表される化合物、および式（Ｘ－７’）で表される化合物を用い、（製造法１－７）＜工程１＞と同様の方法により、式（ＸＩ－８’）で表される化合物を製造することができる。 <Step 3>
Using the compound represented by the formula (XI-8) and the compound represented by the formula (X-7 ′), the compound of the formula (XI-8) was prepared in the same manner as in (Production Method 1-7) <Step 1>. A compound represented by ') can be produced.
＜工程４＞
　式（ＸＩ－８’）で表される化合物、および式（Ｘ－７）で表される化合物を用い、（製造法１－７）＜工程１＞と同様の方法により、式（Ｉ－２）で表される化合物を製造することができる。 <Step 4>
Using the compound represented by the formula (XI-8 ′) and the compound represented by the formula (X-7), the same procedure as in (Production Method 1-7) <Step 1> was carried out. ) Can be produced.
　上記反応式１～９の原料となる式（Ｘ）および式（Ｘ－１）～式（Ｘ－８）で表される化合物およびその誘導体は、文献公知の方法またはそれに準じて、たとえば、下記反応式１０から反応式１３に従って製造することができる。 The compounds represented by the formulas (X) and (X-1) to (X-8), which are the raw materials of the above reaction formulas 1 to 9, and derivatives thereof are known in the literature or modifications thereof, for example, It can be produced according to Reaction Scheme 10 to Reaction Scheme 13.
Figure JPOXMLDOC01-appb-C000169
  
Figure JPOXMLDOC01-appb-C000169
  
　式（Ｘ－８）で表される化合物および式（Ｘ－９）で表される化合物を用い、文献公知の方法、例えば（実験化学講座　第４版　２５　有機合成ＶＩＩ　有機金属試薬による合成、３８９－４２７頁、１９９２年、丸善）等に記載された方法に準じて、式（Ｘ－８）で表される化合物もしくは式（Ｘ－９）で表される化合物を有機金属試薬にした後、テトラキストリフェニルフォスフィンパラジウム、ニッケル（ＩＩ）アセチルアセトネート（Ｎｉ（ａｃａｃ）２）等の金属触媒存在下、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等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｘ）で表される化合物を製造することができる。 Using a compound represented by the formula (X-8) and a compound represented by the formula (X-9), a method known in the literature, for example, (Experimental Chemistry Course 4th Edition 25 Organic Synthesis VII Synthesis with an organometallic reagent, 389 -427, 1992, Maruzen) and the like, after converting the compound represented by the formula (X-8) or the compound represented by the formula (X-9) to an organometallic reagent, In the presence of a metal catalyst such as tetrakistriphenylphosphine palladium and nickel (II) acetylacetonate (Ni (acac) 2 ), halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, toluene, benzene Using a solvent inert to the reaction, such as an aromatic hydrocarbon solvent such as In by reacting, it is possible to produce a compound represented by the formula (X).
Figure JPOXMLDOC01-appb-C000170
  
Figure JPOXMLDOC01-appb-C000170
  
＜工程１＞
　式（Ｘ－１０）で表される化合物、および式（Ｘ－１１）で表される化合物を用い、文献公知の方法、例えば（実験化学講座　第４版　２４　有機合成ＩＶ　ヘテロ元素・典型金属元素化合物、３１９－４１９頁、１９９２年、丸善）等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、トリエチルアミン等の塩基存在下または非存在下、ヨウ化銅（Ｉ）、テトラキストリフェニルフォスフィンパラジウム等の金属触媒存在下または非存在下、メタノール、エタノール、アセトン、Ｎ，Ｎ－ジメチルホルムアミド、１，４－ジオキサン、テトラヒドロフラン、水等の反応に不活性な溶媒、もしくはこれらの混合溶媒を用いて、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｘ－１２）で表される化合物を製造することができる。 <Step 1>
Using a compound represented by the formula (X-10) and a compound represented by the formula (X-11), a method known in the literature, for example, (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element) Compound, 319-419, 1992, Maruzen) and the like, such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, triethylamine, etc. In the presence or absence of a base, in the presence or absence of a metal catalyst such as copper (I) iodide, tetrakistriphenylphosphine palladium, methanol, ethanol, acetone, N, N-dimethylformamide, 1,4-dioxane , Tetrahydrofuran, water, etc., and a solvent inert from the reaction, or a mixed solvent thereof. By reacting at the refluxing temperature, the compound represented by the formula (X-12) can be produced.
＜工程２＞
　式（Ｘ－１２）で表される化合物を用い、文献公知の方法、例えば（実験化学講座　第４版　２４　有機合成ＩＶ　ヘテロ元素・典型金属元素化合物、３１９－４１９頁、１９９２年、丸善）等に記載された方法に準じて、過酸化水素、過ヨウ素酸ナトリウム、過ヨウ素酸テトラブチルアンモニウム、３－クロロ過安息香酸、臭素等の酸化剤存在下、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、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など反応に関与しない溶媒、もしくはこれらの混合溶媒を用いて、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｘ－１３）で表される化合物を製造することができる。 <Process 2>
A method known in the literature using a compound represented by the formula (X-12), such as (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element Compound, 319-419, 1992, Maruzen) In the presence of an oxidizing agent such as hydrogen peroxide, sodium periodate, tetrabutylammonium periodate, 3-chloroperbenzoic acid, bromine, etc., halogenated solvents such as dichloromethane and chloroform, diethyl Use a solvent that does not participate in the reaction, such as ether solvents such as ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, or a mixed solvent thereof, and react at a temperature at which the solvent refluxes from −78 ° C. Thus, a compound represented by the formula (X-13) can be produced.
＜工程３＞
　式（Ｘ－１３）で表される化合物を用い、文献公知の方法、例えば（実験化学講座　第４版　２４　有機合成ＩＶ　ヘテロ元素・典型金属元素化合物、３１９－４１９頁、１９９２年、丸善）等に記載された方法に準じて、過酸化水素、過ヨウ素酸ナトリウム、過酢酸、２－クロロ過安息香酸、過マンガン酸カリウム、過ホウ素酸ナトリウム、塩素等の酸化剤存在下、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、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、酢酸、トリフルオロ酢酸等の有機酸、水などの溶媒、もしくはこれらの混合溶媒を用いて、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｘ’）で表される化合物を製造することができる。 <Step 3>
A method known in the literature using a compound represented by the formula (X-13), such as (Experimental Chemistry Course 4th Edition 24 Organic Synthesis IV Heteroelement / Typical Metal Element Compound, 319-419, 1992, Maruzen), etc. In accordance with the method described in the above, in the presence of an oxidizing agent such as hydrogen peroxide, sodium periodate, peracetic acid, 2-chloroperbenzoic acid, potassium permanganate, sodium perborate, chlorine, dichloromethane, chloroform, etc. A halogen solvent, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, an ether solvent such as 1,4-dioxane, an organic acid such as acetic acid or trifluoroacetic acid, a solvent such as water, or a mixed solvent thereof. The compound represented by the formula (X ′) can be produced by reacting at a temperature at which the solvent is refluxed from −78 ° C.
＜工程４＞
　式（Ｘ－１２）で表される化合物を用い、＜工程３＞と同様の方法により、式（Ｘ’）で表される化合物を製造することができる。 <Step 4>
Using the compound represented by the formula (X-12), the compound represented by the formula (X ′) can be produced by the same method as in <Step 3>.
Figure JPOXMLDOC01-appb-C000171
  
Figure JPOXMLDOC01-appb-C000171
  
　式（Ｘ－１４）で表される化合物、および式（Ｘ－１５）で表される化合物を用い、文献公知の方法、例えば（実験化学講座　第４版　２４　有機合成ＩＶ　ヘテロ元素・典型金属元素化合物、３１９－４１９頁、１９９２年、丸善）等に記載された方法に準じて、塩化アルミニウム、三フッ化ホウ素、三臭化ホウ素、四塩化チタン等のＬｅｗｉｓ酸存在下及び非存在下、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、アセトン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（Ｘ’’）で表される化合物を製造することができる。 Using a compound represented by the formula (X-14) and a compound represented by the formula (X-15), a method known in the literature, for example, (Experimental Chemistry Course, 4th Edition, 24. Organic Synthesis IV, heteroelements, typical metal elements. Compound, 319-419, 1992, Maruzen) in the presence and absence of Lewis acid such as aluminum chloride, boron trifluoride, boron tribromide, titanium tetrachloride, dichloromethane, etc. In a solvent that does not participate in the reaction, such as a halogen solvent such as chloroform, an ether solvent such as diethyl ether or tetrahydrofuran, or a polar solvent such as acetone, the reaction is performed at a temperature at which the solvent is refluxed from 0 ° C. A compound represented by ') can be produced.
Figure JPOXMLDOC01-appb-C000172
  
Figure JPOXMLDOC01-appb-C000172
  
＜工程１＞
　式（Ｘ－１６）で表される化合物を用い、文献公知の方法、例えばプロテクティブ・グループス・イン・オーガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、（米国）、第３版、１９９９年等に記載された方法に準じて、式（Ｘ－１７）で表される化合物を製造することができる。 <Step 1>
Using a compound represented by the formula (X-16), a method known in the literature, for example, Protective Groups in Organic Synthesis, (USA), 3rd edition, 1999, etc. The compound represented by the formula (X-17) can be produced according to the method described.
＜工程２＞
　式（Ｘ－１７）で表される化合物を用い、（反応式１１）＜工程３＞と同様の方法により、式（Ｘ－１８）で表される化合物を製造することができる。 <Process 2>
Using the compound represented by the formula (X-17), the compound represented by the formula (X-18) can be produced by the same method as in (Reaction Scheme 11) <Step 3>.
＜工程３＞
　式（Ｘ－１６）で表される化合物を用い、（反応式１１）＜工程３＞と同様の方法により、式（Ｘ－１８）で表される化合物を同様に製造することができる。 <Step 3>
Using the compound represented by the formula (X-16), the compound represented by the formula (X-18) can be similarly produced by the same method as in (Reaction Scheme 11) <Step 3>.
＜工程４＞
　式（Ｘ－１８）で表される化合物、および式（Ｘ－１９）で表される化合物を用い、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）、５０（３）、５６６－５８４、２００７年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または非存在下、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、アセトニトリル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（Ｘ’’’）で表される化合物を製造することができる。 <Step 4>
Using a compound represented by the formula (X-18) and a compound represented by the formula (X-19), a method known in the literature, for example, Journal of Medicinal Chemistry, 50 (3 ) 566-584, according to the method described in 2007, in the presence or absence of a base such as triethylamine or pyridine, a halogen-based solvent such as dichloromethane or chloroform, an ether-based solvent such as diethyl ether or tetrahydrofuran, It is represented by the formula (X ′ ″) by reacting at a temperature at which the solvent is refluxed from 0 ° C. in a solvent not involved in the reaction such as an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as acetonitrile. Can be produced.
　さらに上記反応式１３の中間体となる式（Ｘ－１８）で表される化合物は、下記反応式１４に従っても製造することができる。 Furthermore, the compound represented by the formula (X-18) which is an intermediate of the above reaction formula 13 can also be produced according to the following reaction formula 14.
Figure JPOXMLDOC01-appb-C000173
  
Figure JPOXMLDOC01-appb-C000173
  
＜工程１＞
　式（Ｘ－２０）で表される化合物および硫酸等のスルホニル化剤を用いて、文献公知の方法、例えばオーガニック・プロセス・リサーチ・アンド・デベロップメント（Ｏｒｇａｎｉｃ　ｐｒｏｃｅｓｓ　Ｒｅｓｅａｒｃｈ　＆　Ｄｅｖｅｌｏｐｍｅｎｔ）、６（６）、７６７－７７２、２００２年に記載された方法に準じて、硫酸等の酸存在下もしくは非存在下、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、アセトン等の極性溶媒等の反応に関与しない溶媒もしくは無溶媒中、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｘ－２１）で表される化合物を製造することができる。 <Step 1>
Using a compound represented by the formula (X-20) and a sulfonylating agent such as sulfuric acid, a method known in the literature, for example, Organic Process Research & Development, 6 (6), 767-772, in accordance with the method described in 2002, in the presence or absence of an acid such as sulfuric acid, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, toluene, benzene and the like A compound represented by the formula (X-21) by reacting at a temperature at which the solvent is refluxed from −78 ° C. in a solvent that does not participate in the reaction, such as an aromatic hydrocarbon solvent, a polar solvent such as acetone, or the like, without solvent. Can be manufactured.
＜工程２＞
　式（Ｘ－２１）で表される化合物を用い、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）、５０（３）、５６６－５８４、２００７年に記載された方法に準じて、チオニルクロライド、塩化ホスホリル、Ｎ－クロロコハク酸イミド（ＮＣＳ）等の脱水試薬存在下、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等の反応に関与しない溶媒中、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｘ－１８）で表される化合物を製造することができる。 <Process 2>
A method known in the literature using a compound represented by the formula (X-21), for example, a method described in Journal of Medicinal Chemistry, 50 (3), 566-584, 2007 In the presence of dehydrating reagents such as thionyl chloride, phosphoryl chloride, N-chlorosuccinimide (NCS), etc., halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, and aromatics such as toluene and benzene A compound represented by the formula (X-18) can be produced by reacting at a temperature at which the solvent is refluxed from −78 ° C. in a solvent that does not participate in the reaction, such as a group hydrocarbon solvent.
＜工程３＞
　式（Ｘ－２０）で表される化合物、およびクロロスルフォン酸等のスルホニル化剤を用い、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）、５１（９）、２８０７－２８１５、２００８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、アセトン等の極性溶媒等の反応に関与しない溶媒中もしくは無溶媒で、０℃から溶媒が還流する温度で反応させることにより、式（Ｘ－１８）で表される化合物を製造することができる。 <Step 3>
Using a compound represented by the formula (X-20) and a sulfonylating agent such as chlorosulfonic acid, a method known in the literature, for example, Journal of Medicinal Chemistry, 51 (9), 2807 In accordance with the method described in 2815, 2008, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as acetone The compound represented by the formula (X-18) can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C. in a solvent that does not participate in the reaction or without solvent.
［製造法２］
式（Ｉ－５）および式（Ｉ－６）で表される化合物は、式（Ｉ）においてＷがアミド結合である式（Ｉ－１’）で表される化合物を還元することによっても製造することができる。 [Production Method 2]
The compounds represented by formula (I-5) and formula (I-6) can also be produced by reducing the compound represented by formula (I-1 ′) in which W is an amide bond in formula (I). can do.
（製造法２－１）
　特に前記式（Ｉ）においてＷが－ＮＲ１１－である式（Ｉ－５）で表される化合物は、反応式１５の方法で製造することができる。 (Production method 2-1)
In particular, the compound represented by the formula (I-5) in which W is —NR 11 — in the formula (I) can be produced by the method of the reaction formula 15.
Figure JPOXMLDOC01-appb-C000174
  
Figure JPOXMLDOC01-appb-C000174
  
　式（Ｉ－１’）で表される化合物を用いて、文献公知の方法、例えば（実験化学講座　第４版　２６　有機合成ＶＩＩＩ　不斉合成・還元・糖・標識化合物、１５９－２６６頁、１９９２年、丸善）等に記載された方法に準じて、水素化ジイソブチルアルミニウム（ＤＩＢＡＬ）、リチウムアルミニウムハイドライド（ＬＡＨ）等の還元剤存在下、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等の反応に関与しない溶媒中で－７８℃から溶媒が還流する温度で反応させることにより式（Ｉ－５）で表される化合物を同様に製造することができる。 Using a compound represented by the formula (I-1 ′), a method known in the literature, for example, (Experimental Chemistry Course, 4th Edition, 26, Organic Synthesis VIII, Asymmetric Synthesis / Reduction / Sugar / Label Compound, 159-266, 1992 In the presence of a reducing agent such as diisobutylaluminum hydride (DIBAL) or lithium aluminum hydride (LAH), a halogen-based solvent such as dichloromethane or chloroform, diethyl ether, tetrahydrofuran or the like. The compound represented by the formula (I-5) is obtained by reacting at a temperature at which the solvent is refluxed from −78 ° C. in a solvent that does not participate in the reaction such as an ether solvent, an aromatic hydrocarbon solvent such as toluene and benzene. It can be manufactured similarly.
（製造法２－２）
　特に前記式（Ｉ）においてＷが－ＮＲ１１－である式（Ｉ－６）で表される化合物は、反応式１６の方法で製造することができる。 (Production method 2-2)
In particular, the compound represented by the formula (I-6) in which W is —NR 11 — in the formula (I) can be produced by the method of the reaction scheme 16.
Figure JPOXMLDOC01-appb-C000175
  
Figure JPOXMLDOC01-appb-C000175
  
　式（Ｉ－２’）で表される化合物を用い、（製造法２－１）と同様の方法により式（Ｉ－６）で表される化合物を製造することができる。 Using the compound represented by the formula (I-2 '), the compound represented by the formula (I-6) can be produced by the same method as (Production Method 2-1).
［製造法３］
　式（Ｉ）においてＲｉｎｇがＲｉｎｇ’’、ｍが０、Ｗが－ＣＯＮＲ７－である式（Ｉ－９）で表される化合物は、式（ＸＩＩ）で表される化合物と式（ＸＩＩＩ）で表される化合物を用いて、反応式１７の方法で製造することができる。 [Production Method 3]
In the formula (I), a compound represented by the formula (I-9) in which Ring is Ring ″, m is 0, and W is —CONR 7 — includes a compound represented by the formula (XII) and a formula (XIII) It can manufacture by the method of Reaction formula 17 using the compound represented by these.
Figure JPOXMLDOC01-appb-C000176
  
Figure JPOXMLDOC01-appb-C000176
  
（製造法３－１）
　特に前記式（Ｉ－９）で表される化合物は、式（ＸＩＩ）で表される化合物および式（ＸＩＩＩ－１）で表される化合物を用いて、反応式１８の方法で製造することができる。 (Production method 3-1)
In particular, the compound represented by the formula (I-9) can be produced by the method of the reaction formula 18 using the compound represented by the formula (XII) and the compound represented by the formula (XIII-1). it can.
Figure JPOXMLDOC01-appb-C000177
  
Figure JPOXMLDOC01-appb-C000177
  
　式（ＸＩＩ）で表される化合物、および式（ＸＩＩＩ－１）で表される化合物を用い、（製造法１－３）と同様の方法により、式（Ｉ－９）で表される化合物を製造することができる。 Using the compound represented by the formula (XII) and the compound represented by the formula (XIII-1), the compound represented by the formula (I-9) was prepared in the same manner as in (Production Method 1-3). Can be manufactured.
（製造法３－２）
　特に前記式（Ｉ－９）においてＲ７が－Ｈである式（Ｉ－９’）で表される化合物は、反応式１９の方法で製造することができる。 (Production method 3-2)
In particular, the compound represented by the formula (I-9 ′) in which R 7 is —H in the formula (I-9) can be produced by the method of the reaction formula 19.
Figure JPOXMLDOC01-appb-C000178
  
Figure JPOXMLDOC01-appb-C000178
  
　式（ＸＩＩ）で表される化合物、および式（ＸＩＩＩ－２）で表される化合物を用い、（製造法１－４）と同様の方法により、式（Ｉ－９’）で表される化合物を製造することができる。 A compound represented by the formula (I-9 ′) using the compound represented by the formula (XII) and the compound represented by the formula (XIII-2) in the same manner as in (Production Method 1-4) Can be manufactured.
［製造法４］
　式（Ｉ）で表される化合物は、式（ＸＩＶ）で表される化合物と式（ＸＶ）で表される化合物を用いて、反応式２０の方法で製造することができる。 [Production Method 4]
The compound represented by the formula (I) can be produced by the method of the reaction formula 20 using the compound represented by the formula (XIV) and the compound represented by the formula (XV).
（反応式）
Figure JPOXMLDOC01-appb-C000179
   (Reaction formula)
Figure JPOXMLDOC01-appb-C000179
（製造法４－１）
特に前記式（Ｉ）においてＹが－ＮＲ５Ｒ６、ｎが２である式（Ｉ－１０）で表される化合物は、反応式２１の方法で製造することができる。 (Production method 4-1)
In particular, the compound represented by the formula (I-10) in which Y is —NR 5 R 6 and n is 2 in the above formula (I) can be produced by the method of reaction scheme 21.
Figure JPOXMLDOC01-appb-C000180
  
Figure JPOXMLDOC01-appb-C000180
  
　式（ＸＩＶ－１）で表される化合物、および式（Ｘ－１９）で表される化合物を用い、（反応式１３）＜工程４＞と同様の方法により、式（Ｉ－１０）で表される化合物を同様に製造することができる。 Using the compound represented by the formula (XIV-1) and the compound represented by the formula (X-19), the compound represented by the formula (I-10) was prepared in the same manner as in (Reaction Scheme 13) <Step 4>. The resulting compound can be prepared analogously.
　上記反応式２１の原料となる式（ＸＩＶ－１）で表される化合物およびその誘導体は、文献公知の方法またはそれに準じて、たとえば、下記反応式２２から反応式２４に従って製造することができる。 The compound represented by the formula (XIV-1) as a raw material of the above reaction formula 21 and its derivative can be produced according to a method known in the literature or in accordance with, for example, the following reaction formula 22 to the following reaction formula 24.
Figure JPOXMLDOC01-appb-C000181
  
Figure JPOXMLDOC01-appb-C000181
  
　式（ＸＩＶ－２）で表される化合物を用い、（反応式１４）＜工程３＞と同様の方法により、式（ＸＩＶ－１’）で表される化合物を製造することができる。 Using the compound represented by the formula (XIV-2), the compound represented by the formula (XIV-1 ′) can be produced by the same method as in (Reaction Scheme 14) <Step 3>.
Figure JPOXMLDOC01-appb-C000182
  
Figure JPOXMLDOC01-appb-C000182
  
　式（ＸＩＶ－３）で表される化合物および式（ＸＩ－１）で表される化合物を用いて、（製造法１－１）と同様の方法により、式（ＸＩＶ－１’’）で表される化合物を同様に製造することができる。 Using the compound represented by the formula (XIV-3) and the compound represented by the formula (XI-1), the compound represented by the formula (XIV-1 ″) was prepared in the same manner as in (Production Method 1-1). The resulting compound can be prepared analogously.
Figure JPOXMLDOC01-appb-C000183
  
Figure JPOXMLDOC01-appb-C000183
  
＜工程１＞
　式（ＸＩＶ－４）で表される化合物を用い、（反応式１３）＜工程１＞と同様の方法により、式（ＸＩＶ－５）で表される化合物を製造することができる。 <Step 1>
Using the compound represented by the formula (XIV-4), the compound represented by the formula (XIV-5) can be produced by the same method as in (Reaction Scheme 13) <Step 1>.
＜工程２＞
　式（ＸＩＶ－５）で表される化合物を用い、（反応式１１）＜工程３＞と同様の方法により、式（ＸＩＶ－１）で表される化合物を製造することができる。 <Process 2>
Using the compound represented by the formula (XIV-5), the compound represented by the formula (XIV-1) can be produced by the same method as in (Reaction Formula 11) <Step 3>.
＜工程３＞
　式（ＸＩＶ－４）で表される化合物を用い、（反応式１１）＜工程３＞と同様の方法により、式（ＸＩＶ－１）で表される化合物を製造することができる。 <Step 3>
Using the compound represented by the formula (XIV-4), the compound represented by the formula (XIV-1) can be produced by the same method as in (Reaction Formula 11) <Step 3>.
　上記反応式２４の原料となる式（ＸＩＶ－４）で表される化合物は、文献公知の方法またはそれに準じて、たとえば、下記反応式２５に従って製造することができる。 The compound represented by the formula (XIV-4), which is a raw material of the above reaction scheme 24, can be produced according to a method known in the literature or according thereto, for example, according to the following reaction scheme 25
Figure JPOXMLDOC01-appb-C000184
  
Figure JPOXMLDOC01-appb-C000184
  
　式（ＸＩＶ－６）で表される化合物および式（ＸＩ）で表される化合物を用いて、（製造法１－１）から（製造法１－８）と同様の方法により、式（ＸＩＶ－４）で表される化合物を製造することができる。 Using the compound represented by the formula (XIV-6) and the compound represented by the formula (XI), by the same method as in (Production Method 1-1) to (Production Method 1-8), the compound of the formula (XIV- The compound represented by 4) can be produced.
（製造法４－２）
　特に前記式（Ｉ）においてｎが０、１、２である式（Ｉ－１１）で表される化合物、式（Ｉ－１１’）で表される化合物および式（Ｉ－１１’’）で表される化合物は、反応式２６の方法で製造することができる。 (Production method 4-2)
In particular, in the formula (I), the compound represented by the formula (I-11), the compound represented by the formula (I-11 ′) and the formula (I-11 ″) in which n is 0, 1, 2 The represented compound can be produced by the method of Reaction Scheme 26.
Figure JPOXMLDOC01-appb-C000185
  
Figure JPOXMLDOC01-appb-C000185
  
＜工程１＞
　式（ＸＩＶ－５）で表される化合物、および式（Ｘ－１１）で表される化合物を用い、（反応式１１）＜工程１＞と同様の方法により、式（Ｉ－１１）で表される化合物を同様に製造することができる。　 <Step 1>
Using the compound represented by the formula (XIV-5) and the compound represented by the formula (X-11), it is represented by the formula (I-11) by the same method as in (Reaction Scheme 11) <Step 1>. The resulting compound can be prepared analogously.
＜工程２＞
　式（Ｉ－１１）で表される化合物を用い、（反応式１１）＜工程２＞と同様の方法により、式（Ｉ－１１’）で表される化合物を製造することができる。 <Process 2>
Using the compound represented by the formula (I-11), the compound represented by the formula (I-11 ′) can be produced by the same method as in (Reaction Formula 11) <Step 2>.
＜工程３＞
　式（Ｉ－１１’）で表される化合物を用い、（反応式１１）＜工程３＞と同様の方法により、式（Ｉ－１１’’）で表される化合物を製造することができる。 <Step 3>
Using the compound represented by the formula (I-11 ′), the compound represented by the formula (I-11 ″) can be produced by the same method as in (Reaction Formula 11) <Step 3>.
＜工程４＞
　式（Ｉ－１１）で表される化合物を用い、（反応式１１）＜工程３＞と同様の方法により、式（Ｉ－１１’’）で表される化合物を製造することができる。 <Step 4>
Using the compound represented by the formula (I-11), the compound represented by the formula (I-11 ″) can be produced by the same method as in (Reaction Scheme 11) <Step 3>.
　上記反応式２６の式（Ｉ－１１）で表される化合物は、反応式２７の方法でも製造することができる。 The compound represented by the formula (I-11) in the above reaction scheme 26 can also be produced by the method of the reaction scheme 27.
Figure JPOXMLDOC01-appb-C000186
  
Figure JPOXMLDOC01-appb-C000186
  
　式（ＸＩＶ－７）で表される化合物、および式（ＸＩＶ－８）で表される化合物を用い、（反応式１１）＜工程１＞と同様の方法により、式（Ｉ―１１）で表される化合物を製造することができる。 Using the compound represented by the formula (XIV-7) and the compound represented by the formula (XIV-8), it is represented by the formula (I-11) by the same method as in (Reaction Scheme 11) <Step 1>. Can be produced.
［製造法５］
式（Ｉ）においてｎが２である式（Ｉ－１２）で表される化合物は、式（ＸＶＩ）で表される化合物および式（ＸＶＩＩ）で表される化合物を用いて、反応式２８の方法で製造することができる。 [Production Method 5]
The compound represented by the formula (I-12) in which n is 2 in the formula (I) is obtained by using the compound represented by the formula (XVI) and the compound represented by the formula (XVII). It can be manufactured by the method.
Figure JPOXMLDOC01-appb-C000187
  
Figure JPOXMLDOC01-appb-C000187
  
（製造法５－１）
　特に前記式（Ｉ－１２）においてＲｉｎｇがＲｉｎｇ’’’である式（Ｉ－１３）で表される化合物は、反応式２９の方法で製造することができる。 (Production method 5-1)
In particular, the compound represented by the formula (I-13) in which Ring is Ring ′ ″ in the formula (I-12) can be produced by the method of the reaction formula 29.
Figure JPOXMLDOC01-appb-C000188
  
Figure JPOXMLDOC01-appb-C000188
  
　式（ＸＶＩ－１）で表される化合物、および式（Ｘ－１５）で表される化合物を用い、（反応式１３）＜工程４＞と同様の方法により、式（Ｉ－１３）を製造することが出来る。 Using the compound represented by formula (XVI-1) and the compound represented by formula (X-15), formula (I-13) is produced in the same manner as in (Reaction Scheme 13) <Step 4>. I can do it.
　上記反応式２９の原料となる式（ＸＶＩ－１）で表される化合物は、文献公知の方法またはそれに準じて、たとえば、下記反応式３０に従って製造することができる。 The compound represented by the formula (XVI-1), which is a raw material of the above reaction formula 29, can be produced according to a method known in the literature or according thereto, for example, according to the following reaction formula 30.
Figure JPOXMLDOC01-appb-C000189
  
Figure JPOXMLDOC01-appb-C000189
  
＜工程１＞
　式（ＸＶＩ－２）で表される化合物、及び式（ＸＩ）で表される化合物を用い、（製造法１－１）から（製造法１－８）と同様の方法により、式（ＸＶＩ－３）で表される化合物を製造することができる。 <Step 1>
Using the compound represented by the formula (XVI-2) and the compound represented by the formula (XI), by the same method as in (Production Method 1-1) to (Production Method 1-8), the compound of the formula (XVI- The compound represented by 3) can be produced.
＜工程２＞
　式（ＸＶＩ－３）で表される化合物を用い、文献公知の方法、例えばプロテクティブ・グループス・イン・オーガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、（米国）、第３版、１９９９年等に記載された方法に準じて、式（ＸＶＩ－１）で表される化合物を同様に製造することができる。 <Process 2>
Using a compound represented by the formula (XVI-3), a method known in the literature, for example, Protective Groups in Organic Synthesis, (USA), 3rd edition, 1999, etc. The compound represented by the formula (XVI-1) can be similarly produced according to the described method.
（製造法５－２）
　特に前記式（Ｉ－１２）においてＲｉｎｇがＲｉｎｇ’である式（Ｉ－１４）で表される化合物は、反応式３１の方法で製造することができる。 (Production method 5-2)
In particular, the compound represented by the formula (I-14) in which Ring is Ring ′ in the formula (I-12) can be produced by the method of the reaction formula 31.
Figure JPOXMLDOC01-appb-C000190
  
Figure JPOXMLDOC01-appb-C000190
  
　式（ＸＶＩ－４）で表される化合物、および式（Ｘ－１５）で表される化合物を用い、（反応式１２）と同様の方法により、式（Ｉ－１４）で表される化合物を同様に製造することができる。 Using the compound represented by the formula (XVI-4) and the compound represented by the formula (X-15), the compound represented by the formula (I-14) was synthesized in the same manner as in (Reaction Scheme 12). It can be manufactured similarly.
　上記反応式３１の原料となる式（ＸＶＩ－４）で表される化合物は、文献公知の方法またはそれに準じて、たとえば、下記反応式３２に従って製造することができる。 The compound represented by the formula (XVI-4), which is a raw material of the above reaction scheme 31, can be produced according to a method known in the literature or according thereto, for example, according to the following reaction scheme 32.
Figure JPOXMLDOC01-appb-C000191
  
Figure JPOXMLDOC01-appb-C000191
  
　式（ＸＶＩ－５）で表される化合物および式（ＸＩ）で表される化合物を用い、（製造法１－１）から（製造法１－８）と同様の方法により、式（ＸＶＩ－４）で表される化合物を製造することができる。 Using the compound represented by the formula (XVI-5) and the compound represented by the formula (XI), the compound of the formula (XVI-4) was prepared in the same manner as in (Production Method 1-1) to (Production Method 1-8). ) Can be produced.
［製造法６］
式（Ｉ）で表される化合物は、式（ＸＶＩＩＩ）で表される化合物および式（ＸＩＸ）を用いて、反応式３３の方法で製造することができる。 [Production Method 6]
The compound represented by the formula (I) can be produced by the method of the reaction scheme 33 using the compound represented by the formula (XVIII) and the formula (XIX).
Figure JPOXMLDOC01-appb-C000192
  
Figure JPOXMLDOC01-appb-C000192
  
（製造法６－１）
　特に前記式（Ｉ）においてＲｉｎｇ＝Ｒｉｎｇ’’である式（Ｉ－１５）で表される化合物は、反応式３４の方法で製造することができる。 (Production method 6-1)
In particular, the compound represented by the formula (I-15) in which Ring = Ring ″ in the formula (I) can be produced by the method of the reaction formula 34.
Figure JPOXMLDOC01-appb-C000193
  
Figure JPOXMLDOC01-appb-C000193
  
　式（ＸＩＩ）で表される化合物、および式（ＸＩＸ－１）で表される化合物を用い、（製造法１－７）＜工程１＞と同様の方法により、式（Ｉ―１５）で表される化合物を同様に製造することができる。 Using the compound represented by the formula (XII) and the compound represented by the formula (XIX-1), it is represented by the formula (I-15) by the same method as in (Production Method 1-7) <Step 1>. The resulting compound can be prepared analogously.
（製造法６－２）
　特に前記式（Ｉ）で表される化合物は、式（Ｘ－８）で表される化合物および式（ＸＩＸ－１）を用いて、反応式３５の方法で製造することができる。 (Production method 6-2)
In particular, the compound represented by the formula (I) can be produced by the method of the reaction formula 35 using the compound represented by the formula (X-8) and the formula (XIX-1).
Figure JPOXMLDOC01-appb-C000194
  
Figure JPOXMLDOC01-appb-C000194
  
　式（Ｘ－８）で表される化合物、および式（ＸＩＸ－１）で表される化合物を用い、（反応式１０）と同様の方法により、式（Ｉ）で表される化合物を同様に製造することができる。 Using the compound represented by the formula (X-8) and the compound represented by the formula (XIX-1), the compound represented by the formula (I) was similarly prepared in the same manner as in (Scheme 10). Can be manufactured.
　上記反応式１～９の中間体となる式（Ｘ）においてＲｉｎｇが含窒素炭化水素環である化合物およびその誘導体は、例えば式（Ｘ－２２）、式（Ｘ－２３）、式（Ｘ－２４）、式（Ｘ－２５）、式（Ｘ－２６）、式（Ｘ－２７）で表される化合物は、文献公知の方法またはそれに準じて、例えば、下記反応式３６から反応式３９に従って製造することができる。 In the formula (X), which is an intermediate of the above reaction formulas 1 to 9, the compound in which Ring is a nitrogen-containing hydrocarbon ring and derivatives thereof include, for example, formula (X-22), formula (X-23), formula (X— 24), the compound represented by the formula (X-25), the formula (X-26), and the formula (X-27) can be prepared according to a method known in the literature or according to, for example, the following reaction formula 36 to reaction formula 39. Can be manufactured.
Figure JPOXMLDOC01-appb-C000195
  
Figure JPOXMLDOC01-appb-C000195
  
＜工程１＞
　式（ＸＸ）で表される化合物を用い、ｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基、ｐ－トルエンスルフォニル基等の保護基を、文献公知の方法、例えばプロテクティブ・グループス・イン・オーガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、（米国）、第３版、１９９９年等に記載された方法に準じて導入し、式（ＸＸ－１）で表される化合物を同様に製造することができる。 <Step 1>
Using a compound represented by the formula (XX), protecting groups such as tert-butoxycarbonyl group, benzyloxycarbonyl group, p-toluenesulfonyl group and the like can be prepared by methods known in the literature, for example, Protective Groups in Organic Synthesis. The compound represented by the formula (XX-1) can be produced in the same manner by introducing according to the method described in (Protective Groups in Organic Synthesis), (USA), 3rd edition, 1999, etc.
＜工程２＞
　式（ＸＸ－１）で表される化合物を用い、文献公知の方法、例えばテトラへドロン（Ｔｅｔｒａｈｅｄｒｏｎ）、６３（４２）、１０５４９－１０５６１、２００７年に記載された方法に準じて、ジエチルフォスフォノクロライド、トリフルオロメタンスルフォン酸無水物等の存在下、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、アセトン等の極性溶媒等の反応に関与しない溶媒中もしくは無溶媒で、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（ＸＸ－２）で表される化合物を同様に製造することができる。 <Process 2>
Using a compound represented by the formula (XX-1), according to a method known in the literature, for example, a method described in Tetrahedron, 63 (42), 10549-10561, 2007, diethylphosphono In the presence of chloride, trifluoromethanesulfonic anhydride, etc., halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as acetone, etc. The reaction is represented by the formula (XX-2) by reacting in a solvent that does not participate in the reaction in the absence of a solvent in the presence or absence of a base such as triethylamine or pyridine at a temperature at which the solvent refluxes from 0 ° C. Compounds can be prepared similarly.
＜工程３＞
　式（ＸＸ－２）で表される化合物、及び式（ＸＸＩ）で表される化合物を用い、文献公知の方法、例えばジャーナル・オブ・ザ・アメリカン・ケミカル・ソサイエティー（Ｊｏｕｒｎａｌ　ｏｆ　ｔｈｅ　Ａｍｅｒｉｃａｎ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｅｔｙ）、１２７（４３）、１４９８８－１４９８９、２００５年に記載された方法に準じて、ヨウ化銅、テトラキストリフェニルフォスフィンパラジウム等の触媒存在下または非存在下、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、アセトン等の極性溶媒等の反応に関与しない溶媒中で、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、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（ＸＸ－３）で表される化合物を同様に製造することができる。 <Step 3>
Using a compound represented by the formula (XX-2) and a compound represented by the formula (XXI), a method known in the literature, for example, Journal of the American Chemical Society (JOURNAL OF THE AMERICAN CHEMICAL SOCIETY) 127 (43), 14988-1489, 2005, in the presence or absence of a catalyst such as copper iodide, tetrakistriphenylphosphine palladium, a halogenated solvent such as dichloromethane and chloroform, Sodium hydride, lithium hydroxide, sodium hydroxide, water in solvents not involved in the reaction, such as ether solvents such as diethyl ether and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and benzene, and polar solvents such as acetone Potassium oxide, lithium carbonate The compound represented by the formula (XX-3) is similarly reacted by reacting at 0 ° C. at a temperature at which the solvent is refluxed in the presence or absence of a base such as sodium carbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine and the like. Can be manufactured.
＜工程４＞
　式（ＸＸ－３）で表される化合物を用い、文献公知の方法、例えばプロテクティブ・グループス・イン・オーガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、（米国）、第３版、１９９９年等に記載された方法に準じて脱保護を行い、式（ＸＸ－４）で表される化合物を同様に製造することができる。 <Step 4>
Using a compound represented by the formula (XX-3), a method known in the literature, for example, Protective Groups in Organic Synthesis, (USA), 3rd edition, 1999, etc. The compound represented by the formula (XX-4) can be produced in the same manner by deprotecting according to the method described.
＜工程５＞
　式（ＸＸ－４）で表される化合物を用い、及び式（Ｘ－１５）で表される化合物を用いて、（反応式１３）＜工程４＞と同様の方法により、式（Ｘ－２２）で表される化合物を同様に製造することができる。 <Step 5>
Using the compound represented by the formula (XX-4) and using the compound represented by the formula (X-15), a compound of the formula (X-22) is prepared in the same manner as in (Reaction Scheme 13) <Step 4>. ) Can be produced in the same manner.
＜工程６＞
　式（Ｘ－２２）で表される化合物、及び式（ＸＸＩ’）で表される化合物を用い、文献公知の方法、例えばジャーナル・オブ・ザ・アメリカン・ケミカル・ソサイエティー（Ｊｏｕｒｎａｌ　ｏｆ　ｔｈｅ　Ａｍｅｒｉｃａｎ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｅｔｙ）、１２７（４３）、１４９８８－１４９８９、２００５年に記載された方法に準じて、シアン化銅、トリフルオロメタンスルフォン酸銅存在下または非存在下、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、アセトン等の極性溶媒等の反応に関与しない溶媒中で０℃から溶媒が還流する温度で反応させることにより式（Ｘ－２３）で表される化合物を同様に製造することができる。 <Step 6>
Using a compound represented by the formula (X-22) and a compound represented by the formula (XXI ′), a method known in the literature, for example, Journal of the American Chemical Society ) 127 (43), 14988-1489, 2005, in the presence or absence of copper cyanide, copper trifluoromethanesulfonate, halogen solvents such as dichloromethane and chloroform, diethyl ether, 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 an ether solvent such as tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as acetone, the formula (X— 23) In the same manner, the compound represented by Can.
＜工程７＞
　式（Ｘ－２２）で表される化合物を用い、文献公知の方法、例えば（実験化学講座　第４版　２６　有機合成ＶＩＩＩ　不斉合成・還元・糖・標識化合物、１５９－２６６頁、１９９２年、丸善）等に記載された方法に準じて、パラジウム－炭素（Ｐｄ－Ｃ）、ラネーニッケル（Ｒａｎｅｙ－Ｎｉ）等の触媒存在下、水素ガス雰囲気下にて、メタノール、エタノール等のアルコール系溶媒、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、酢酸エチル、酢酸メチル等の極性溶媒等の反応に関与しない溶媒中、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させることにより、式（Ｘ－２４）で表される化合物を同様に製造することができる。 <Step 7>
Using a compound represented by the formula (X-22), a method known in the literature, such as (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992, In the presence of a catalyst such as palladium-carbon (Pd—C) or Raney nickel (Raney-Ni) in an atmosphere of hydrogen gas, an alcoholic solvent such as methanol or ethanol, diethyl 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 an ether solvent such as ether and tetrahydrofuran, a polar solvent such as ethyl acetate and methyl acetate, or a mixed solvent thereof, a formula is obtained. The compound represented by (X-24) can be similarly produced.
Figure JPOXMLDOC01-appb-C000196
  
Figure JPOXMLDOC01-appb-C000196
  
＜工程１＞
　式（ＸＸＩＩ）で表される化合物を用い、ベンジル基、ｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基、ｐ－トルエンスルフォニル基等の保護基を、文献公知の方法、例えばプロテクティブ・グループス・イン・オーガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、（米国）、第３版、１９９９年等に記載された方法に準じて導入し、式（ＸＸＩＩ－１）で表される化合物を同様に製造することができる。 <Step 1>
Using a compound represented by the formula (XXII), a protecting group such as a benzyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group or the like can be formed by a method known in the literature, for example, Protective Groups in. Introducing according to the method described in Organic Synthesis (Protective Groups in Organic Synthesis), (US), 3rd edition, 1999, etc., and similarly producing the compound represented by the formula (XXII-1) Can do.
＜工程２＞
　式（ＸＸＩＩ－１）で表される化合物文献公知の方法、例えば（実験化学講座　第４版　２６　有機合成ＶＩＩＩ　不斉合成・還元・糖・標識化合物、１５９－２６６頁、１９９２年、丸善）等に記載された方法に準じて、水素化ジイソブチルアルミニウム（ＤＩＢＡＬ）、リチウムアルミニウムハイドライド等の還元剤存在下、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、アセトン等の極性溶媒等の反応に関与しない溶媒中で－７８℃から溶媒が還流する温度で反応させることにより式（ＸＸＩＩ－２）で表される化合物を同様に製造することができる。 <Process 2>
Compounds represented by formula (XXII-1), known methods such as (experimental chemistry course 4th edition 26 organic synthesis VIII asymmetric synthesis / reduction / sugar / labeled compound, 159-266, 1992, Maruzen) In the presence of a reducing agent such as diisobutylaluminum hydride (DIBAL) or lithium aluminum hydride, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, toluene, benzene, etc. In a similar manner, the compound represented by the formula (XXII-2) is reacted by reacting at a temperature at which the solvent refluxes from −78 ° C. in a solvent such as an aromatic hydrocarbon solvent, a polar solvent such as acetone. Can be manufactured.
＜工程３＞
　式（ＸＸＩＩ－２）で表される化合物を用いて、文献公知の方法、例えば（実験化学講座　第４版　２６　有機合成ＶＩＩＩ　不斉合成・還元・糖・標識化合物、１５９－２６６頁、１９９２年、丸善）等に記載された方法に準じて、トリエチルシラン、トリアセトキシヒドロホウ酸ナトリウム等の還元剤及びトリフルオロ酢酸、三フッ化ホウ素ジメチルエーテル錯体存在下、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、アセトン等の極性溶媒等の反応に関与しない溶媒中で－７８℃から溶媒が還流する温度で反応させることにより式（ＸＸＩＩ－３）で表される化合物を同様に製造することができる。 <Step 3>
Using a compound represented by the formula (XXII-2), a method known in the literature, for example, (Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, 159-266, 1992) In the presence of reducing agents such as triethylsilane and sodium triacetoxyhydroborate and trifluoroacetic acid and boron trifluoride dimethyl ether complex, halogen solvents such as dichloromethane and chloroform, diethyl By reacting at a temperature at which the solvent is refluxed from −78 ° C. in a solvent not involved in the reaction, such as an ether solvent such as ether and tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene and benzene, and a polar solvent such as acetone. The compound represented by (XXII-3) can be similarly produced.
＜工程４＞
　式（ＸＸＩＩ－３）で表される化合物および式（Ｘ－９）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）、３７（１３）、２０４３－２０５８、１９９４年に記載された方法に準じて、リチウムジイソプロピルアミド（ＬＤＡ）、ビス（トリメチルシリル）アミドリチ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等の反応に関与しない溶媒中で、０℃から溶媒が還流する温度で反応させることにより、式（ＸＸＩＩ－４）で表される化合物を同様に製造することができる。 <Step 4>
Using a compound represented by the formula (XXII-3) and the formula (X-9), a method known in the literature, for example, Journal of Medicinal Chemistry, 37 (13), 2043-2058, According to the method described in 1994, in the presence of a base such as lithium diisopropylamide (LDA) or bis (trimethylsilyl) amidolithium, an ether solvent such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon such as toluene or benzene. A compound represented by the formula (XXII-4) can be similarly produced by reacting in a solvent such as a solvent that does not participate in the reaction at a temperature from 0 ° C. to the reflux of the solvent.
＜工程５＞
　式（ＸＸＩＩ－４）で表される化合物用い、文献公知の方法、例えばジャーナル・オブ・ザ・アメリカン・ケミカル・ソサイエティー（Ｊｏｕｒｎａｌ　ｏｆ　ｔｈｅ　Ａｍｅｒｉｃａｎ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｅｔｙ）、１２５（１５）、４５４１－４５５０、２００３年に記載された方法に準じて、テトラフルオロホウ酸トリメチルオキソニウム、テトラフルオロホウ酸トリメチルオキソニウム等のアルキル化剤存在下、水素化ホウ素ナトリウム、水素化ジイソプロピルアルミニウム（ＤＩＢＡＬ）等の還元剤を、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等の反応に関与しない溶媒中で、０℃から溶媒が還流する温度で反応させることにより、式（ＸＸＩＩ－５）で表される化合物を同様に製造することができる。 <Step 5>
A method known in the literature using a compound represented by the formula (XXII-4), for example, Journal of the American Chemical Society, 125 (15), 4541-4550, 2003 In the presence of an alkylating agent such as trimethyloxonium tetrafluoroborate or trimethyloxonium tetrafluoroborate, a reducing agent such as sodium borohydride, diisopropylaluminum hydride (DIBAL), In a solvent that does not participate in the reaction, such as an ether solvent such as diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon solvent such as toluene or benzene, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. to form the formula (XXII-5 ) The compound can be prepared analogously.
＜工程６＞
　式（ＸＸＩＩ－５）で表される化合物を用い、反応式３０＜工程２＞と同様の方法により、式（ＸＸＩＩ－６）で表される化合物を同様に製造することができる。 <Step 6>
The compound represented by the formula (XXII-6) can be similarly produced using the compound represented by the formula (XXII-5) by the same method as in Reaction Scheme 30 <Step 2>.
＜工程７＞
　式（ＸＸＩＩ－６）で表される化合物を用い、及び式（Ｘ－１５）で表される化合物を用いて、反応式１３＜工程４＞と同様の方法により、式（Ｘ－２３）で表される化合物を同様に製造することができる。 <Step 7>
Using the compound represented by the formula (XXII-6) and the compound represented by the formula (X-15), in the same manner as in the reaction formula 13 <Step 4>, the compound represented by the formula (X-23) The represented compounds can be similarly prepared.
Figure JPOXMLDOC01-appb-C000197
  
Figure JPOXMLDOC01-appb-C000197
  
＜工程１＞
　式（ＸＸＩＩＩ）で表される化合物、および式（ＸＸＩＩＩ－１）で表される化合物を用い、製造法１－７＜工程１＞と同様の方法により、式（ＸＸＩＩＩ－２）で表される化合物を同様に製造することができる。 <Step 1>
Using the compound represented by the formula (XXIII) and the compound represented by the formula (XXIII-1), it is represented by the formula (XXIII-2) by the same method as in Production Method 1-7 <Step 1>. Compounds can be prepared similarly.
＜工程２＞
　式（ＸＸＩＩＩ－２）で表される化合物、および式（Ｘ－９）で表される化合物を用い、文献公知の方法、例えば（実験化学講座　第４版　２５　有機合成ＶＩＩ　有機金属試薬による合成、１９９２年、丸善）等に記載された方法に準じて、リチウム、マグネシウム等の金属、もしくはブチルリチウム、臭化エチルマグネシウム等の有機金属試薬存在下、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等の反応に関与しない溶媒中で、－７８℃から溶媒が還流する温度で反応させることにより、式（Ｘ－２５）で表される化合物を同様に製造することができる。 <Process 2>
Using a compound represented by the formula (XXIII-2) and a compound represented by the formula (X-9), a method known in the literature, for example (Experimental Chemistry Course 4th Edition 25 Organic Synthesis VII Synthesis with an organometallic reagent, 1992, Maruzen) etc., in the presence of a metal such as lithium or magnesium, or an organic metal reagent such as butyllithium or ethylmagnesium bromide, an ether solvent such as diethyl ether or tetrahydrofuran, toluene, A compound represented by the formula (X-25) is similarly produced by reacting at a temperature at which the solvent is refluxed from −78 ° C. in a solvent not involved in the reaction such as an aromatic hydrocarbon solvent such as benzene. be able to.
Figure JPOXMLDOC01-appb-C000198
  
Figure JPOXMLDOC01-appb-C000198
  
＜工程１＞
　式（ＸＸＩＶ）で表される化合物、および式（ＸＸＩＶ－１）で表され化合物を用い、（反応式１３）工程１と同様の方法により、式（ＸＸＩＶ－２）で表される化合物を同様に製造することができる。 <Step 1>
Using the compound represented by the formula (XXIV) and the compound represented by the formula (XXIV-1), the compound represented by the formula (XXIV-2) was prepared in the same manner as in Step 1 of (Reaction Scheme 13). Can be manufactured.
＜工程２＞
　式（ＸＸＩＶ－２）で表される化合物、および式（Ｘ－１５）で表される化合物を用い、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）、４９（２１）、６３７１－６３９０、２００６年に記載された方法に準じて、ブチルリチウム、リチウムジイソプロピルアミド（ＬＤＡ）、ビス（トリメチルシリル）アミドリチ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等の反応に関与しない溶媒中で、－７８℃から溶媒が還流する温度で反応させることにより、式（ＸＸＩＶ－３）で表される化合物を同様に製造することができる。 <Process 2>
Using a compound represented by the formula (XXIV-2) and a compound represented by the formula (X-15), a method known in the literature, for example, Journal of Medicinal Chemistry, 49 (21 ), 6371-6390, according to the method described in 2006, in the presence of a base such as butyllithium, lithium diisopropylamide (LDA), bis (trimethylsilyl) amidolithium, an ether solvent such as diethyl ether or tetrahydrofuran, toluene In the same manner, a compound represented by the formula (XXIV-3) is produced by reacting at a temperature at which the solvent is refluxed from −78 ° C. in a solvent such as benzene or an aromatic hydrocarbon solvent. can do.
＜工程３＞
　式（ＸＸＩＶ－３）で表される化合物を、および式（Ｘ－９）で表される化合物を用いて、反応式３８＜工程２＞と同様の方法により、式（Ｘ－２６）で表される化合物を同様に製造することができる。 <Step 3>
Using the compound represented by the formula (XXIV-3) and the compound represented by the formula (X-9), the compound represented by the formula (X-26) was prepared in the same manner as in Reaction Scheme 38 <Step 2>. The resulting compound can be prepared analogously.
＜工程４＞
　式（ＸＸＩＶ－２）で表される化合物、および式（Ｘ－９）で表される化合物を用い、反応式３８＜工程２＞と同様の方法により、式（ＸＸＩＶ－４）で表される化合物を同様に製造することができる。 <Step 4>
Using the compound represented by the formula (XXIV-2) and the compound represented by the formula (X-9), it is represented by the formula (XXIV-4) by the same method as in Reaction Scheme 38 <Step 2>. Compounds can be prepared similarly.
＜工程５＞
　式（ＸＸＩＶ－４）で表される化合物、および式（Ｘ－１５）で表される化合物を用いて、＜工程２＞と同様の方法により、式（Ｘ－２６）で表される化合物を同様に製造することができる。 <Step 5>
Using the compound represented by the formula (XXIV-4) and the compound represented by the formula (X-15), the compound represented by the formula (X-26) was synthesized in the same manner as in <Step 2>. It can be manufactured similarly.
＜工程６＞
　式（Ｘ－２６）で表される化合物を用い、反応式３０＜工程２＞と同様の方法により、式（Ｘ－２７）で表される化合物を同様に製造することができる。 <Step 6>
Using the compound represented by the formula (X-26), the compound represented by the formula (X-27) can be similarly produced in the same manner as in Reaction Scheme 30 <Step 2>.
　上記反応式３９の中間体となる式（ＸＸＩＶ－３）においてＹが－ＮＲ５Ｒ６である式（ＸＸＩＶ－３’）で表される化合物は、下記反応式４０に従って製造することができる。
Figure JPOXMLDOC01-appb-C000199
   The compound represented by the formula (XXIV-3 ′) in which Y is —NR 5 R 6 in the formula (XXIV-3) which is an intermediate of the above Reaction Scheme 39 can be produced according to the following Reaction Formula 40.
Figure JPOXMLDOC01-appb-C000199
＜工程１＞
　式（ＸＸＩＶ－２）で表される化合物を用い、（反応式３９）工程２と同様の方法により、式（ＸＸＩＶ－５）で表される化合物を同様に製造することができる。 <Step 1>
The compound represented by the formula (XXIV-5) can be produced in the same manner by using the compound represented by the formula (XXIV-2) by the same method as in the step 2 of (Reaction Scheme 39).
＜工程２＞
　式（ＸＸＩＶ－５）で表される化合物を用い、（反応式１４）工程２と同様の方法により、式（ＸＸＩＶ－６）で表される化合物を同様に製造することができる。 <Process 2>
Using the compound represented by the formula (XXIV-5), the compound represented by the formula (XXIV-6) can be similarly produced by the same method as in Step 2 of (Reaction Scheme 14).
＜工程３＞
　式（ＸＸＩＶ－２）で表される化合物を用い、（反応式３９）工程２と同様の方法により、式（ＸＸＩＶ－６）で表される化合物を同様に製造することができる。 <Step 3>
The compound represented by the formula (XXIV-6) can be produced in the same manner by using the compound represented by the formula (XXIV-2) by the same method as in the step 2 of (Reaction Scheme 39).
＜工程４＞
　式（ＸＸＩＶ－６）で表される化合物、および式（Ｘ－１９）で表される化合物を用い、（反応式１３）工程４と同様の方法により、式（ＸＸＩＶ－３’）で表される化合物を同様に製造することができる。 <Step 4>
Using the compound represented by the formula (XXIV-6) and the compound represented by the formula (X-19), (Reaction Scheme 13) represented by the formula (XXIV-3 ′) by the same method as in Step 4 Can be prepared similarly.
　上記の各製造法により合成した各化合物に置換基として水酸基、アミノ基、カルボキシル基等の反応性基がある場合には、各製造工程においてこれらの基を適宜保護し、適当な段階で当該保護基を除去することで製造できる。こうした保護基の導入・除去の方法は、保護される基あるいは保護基のタイプにより適宜行われるが、例えばグリーン（Ｇｒｅｅｎｅ）らのプロテクティブ・グループス・イン・オルガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）、（米国）、第３版、１９９９年、等の成書に記載の方法により行うことができる。 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 performed 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, and the like.
　また、式（Ｉ）であらわされる化合物に存在する官能基については、公知の方法またはこれに準じて他の官能基へと変換することも可能である。 Further, the functional group present in the compound represented by the formula (I) can be converted to other functional groups according to a known method or a similar method.
　例えば、官能基として１級あるいは２級アミノ基を有する場合には、ハロゲン化アルキルによるアルキル化、アルデヒドによる還元的アルキル化、カルボン酸誘導体によるアシル化、スルホニルクロリドによるスルホンアミド化、カルバモイルクロリドによるウレア化などを行うことができる。 For example, when a functional group has a primary or secondary amino group, alkylation with an alkyl halide, reductive alkylation with an aldehyde, acylation with a carboxylic acid derivative, sulfonamidation with a sulfonyl chloride, urea with a carbamoyl chloride Etc. can be performed.
　また、官能基としてハロゲン原子を有する場合は、１級あるいは２級アミンによるアミノ化を行うことができる。この反応は、塩基あるいは金属触媒存在下でも行うことができる。塩基としては、溶媒の種類及びそれぞれの反応性に応じて、炭酸カリウム、炭酸セシウム、水酸基ナトリウム、水酸化カリウム、水素化ナトリウムなどの無機塩基、あるいはトリエチルアミン、ピリジン、Ｎ、Ｎ－ジアルキルアニリン、リチウムジイソプロピルアミドなどの有機塩基、金属触媒としては銅、ヨウ化銅などの銅触媒、酢酸パラジウム、テトラキストリフェニルホスフィンパラジウムなどのパラジウム触媒などを用いることができる。 In addition, when the functional group has a halogen atom, amination with a primary or secondary amine can be performed. This reaction can also be performed in the presence of a base or a metal catalyst. Bases include inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or triethylamine, pyridine, N, N-dialkylaniline, lithium depending on the type of solvent and the respective reactivity. As an organic base such as diisopropylamide and a metal catalyst, copper catalysts such as copper and copper iodide, palladium catalysts such as palladium acetate and tetrakistriphenylphosphine palladium can be used.
　また、官能基にカルボキシル基を有する場合は、縮合剤を用いて、１級あるいは２級アミンによるアミド基に変換することができる。縮合剤としては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）、ジシクロカルボジイミド（ＤＣＣ）などを用いることができる。アミド基への変換はカルボキシル基を塩化チオニル、オキザリルクロリドなどを用いて酸ハロゲン化物に変換後、１級あるいは２級アミンと反応させることによって行うことができる。 In addition, when the functional group has a carboxyl group, it can be converted to an amide group by a primary or secondary amine using a condensing agent. As the condensing agent, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), dicyclocarbodiimide (DCC), or the like can be used. Conversion to an amide group can be carried out by converting the carboxyl group to an acid halide using thionyl chloride, oxalyl chloride, etc., and then reacting with a primary or secondary amine.
　ただし、上記に記載したものに必ずしも限定されるものではない。 However, it is not necessarily limited to those described above.
［本発明化合物を含有する併用剤］
　本発明化合物や医薬組成物は、医療現場で行われている一般的な方法で、他の薬物もしくは薬剤と併用することも可能である。特にＥｌｏｖｌ６阻害剤仲介状態の予防・進行遅延・治療における使用、中でもＮＡＳＨ、ＮＡＦＬＤ、糖尿病、インスリン抵抗性、高インスリン血症、耐糖能異常（ＩＧＴ）・空腹時血糖異常（ＩＦＧ）、空腹時高血糖状態、肥満・肥満症、もしくはこれらに起因ないし関連する各種疾患からなる群から選択される少なくとも１つの疾患において使用するものである。 [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. Use in prevention, progression, and treatment of Elovl6 inhibitor-mediated conditions, especially NASH, NAFLD, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT), fasting glucose abnormalities (IFG), fasting high It is used in at least one disease selected from the group consisting of glycemic state, obesity / obesity, or various diseases caused or related to these.
　例えば、インスリン抵抗性改善薬・糖尿病薬としては、１）ＰＰＡＲγ作動薬（具体的には、ピオグリタゾン、ロシグリタゾン、トログリタゾン、シグリタゾン、ダルグリタゾン、エングリタゾン、ネトグリタゾン、ＣＬＸ０９２１、ＧＷ－０２０７、ＬＧ－１００６４１、ＬＹ－３００５１２等）、２）ビグアナイド類（具体的には、メトホルミン、ブホルミン、フェンホルミン等）、３）スルホニル尿素類（具体的には、トルブタミド、クロルプロパミド、グリベンクラミド、グリピジド、、グリメピリド、グリクラジド、グリペンチド、アセトヘキサミド、グリキドン、グリソラミド、トラザミド等）、４）速効型インスリン分泌促進剤（具体的には、ナテグリニド、ミチグリニド、レパグリニド等）５）αグルコシダーゼ阻害剤（具体的には、アカルボース、ボグリボース、カミグリボース、アジポシン、エミグリテート、ミグリトール、プラジミシン－Ｑ、サルボスタチン、ＣＫＤ－７１１、ＭＯＲ－１４等）、６）インスリンまたはインスリン誘導体（具体的には、インスリン亜鉛懸濁液、インスリンリスプロ、インスリンアスパルト、レギュラーインスリン、ＮＰＨインスリン、インスリングラルギン、インスリンデテミル、混合型インスリン等）、７）ＧＬＰ－１及びＧＬＰ－１作動薬（具体的には、リラグルチド等）、８）ジペプチジルペプチダーゼ（ＤＰＰ）－４阻害剤（具体的には、シタグリプチン、ビルダグリプチン、アログリプチン、サクサグリプチン、ＮＶＰ－ＤＰＰ－７２８等）、９）α２拮抗薬（具体的には、ミダグリゾール、イサグリドール、デリグリドール、イダゾキサン、エファロキサン等）等が挙げられる。 For example, 1) PPARγ agonist (specifically, pioglitazone, rosiglitazone, troglitazone, siglitazone, darglitazone, englitazone, netoglitazone, CLX0921, GW-0207, LG- 2) biguanides (specifically metformin, buformin, phenformin, etc.), 3) sulfonylureas (specifically, tolbutamide, chlorpropamide, glibenclamide, glipizide, glimepiride, etc.) 4) Fast-acting insulin secretagogues (specifically, nateglinide, mitiglinide, repaglinide, etc.) 5) α-glucosidase inhibitor (instrument) Physically, acarbose, voglibose, camiglybose, adiposine, emiglitate, miglitol, prazimycin-Q, sarvostatin, CKD-711, MOR-14, etc.), 6) insulin or insulin derivatives (specifically, insulin zinc suspension) Fluid, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, mixed insulin, etc.), 7) GLP-1 and GLP-1 agonists (specifically, liraglutide, etc.), 8) Dipeptidyl peptidase (DPP) -4 inhibitors (specifically sitagliptin, vildagliptin, alogliptin, saxagliptin, NVP-DPP-728, etc.), 9) α2 antagonists (specifically midaglyzol, isaglidol, Riguridoru, idazoxan, include Efarokisan etc.) and the like.
　その他、脂質低下薬・脂質異常症治療剤が挙げられる。例えば、１）ω３脂肪酸類（具体的には、イコサペント酸エチル（ＥＰＡ－Ｅ製剤）、ドコサヘキサエン酸（ＤＨＡ）等）、２）ＨＭＧ－ＣｏＡ還元酵素阻害剤（具体的には、アトルバスタチン、シンバスタチン、ピタバスタチン、イタバスタチン、フルバスタチン、ロバスタチン、プラバスタチン、リバスタチン、ロスバスタチン等）３）ＨＭＧ－ＣｏＡ合成酵素阻害剤、４）コレステロール吸収阻害剤（具体的には、エゼチミブ）、５）アシル－ＣｏＡ・コレステロールアシル転移酵素（ＡＣＡＴ）阻害剤、６）ＣＥＴＰ阻害剤、７）スクアレン合成酵素阻害剤、８）抗酸化剤（具体的には、プロブコール等）、９）ＰＰＡＲα作動薬（具体的には、クロフィブラート、エトフィブラート、フェノフィブラート、ベザフィブラート、シプロフィブラート、ゲムフィブロジル、ＫＲＰ－１０１等）、１０）ＰＰＡＲδ作動薬、１１）ＬＸＲ作動薬、１２）ＦＸＲ作動薬（具体的には、ＩＮＴ－７４７等）、１３）ＭＴＴＰ阻害剤、１４）スクアレンエポシダーゼ阻害剤、１５）胆汁酸吸収阻害剤（具体的には、コレスチラミン、コレスチポール等）等が挙げられる。
　その他、抗肥満薬が挙げられる。具体的には、１）ＣＢ－１受容体拮抗薬（具体的には、リモナバン、ＳＲ－１４７７７８、ＢＡＹ－６５－２５２０等）２）モノアミン再取り込み阻害剤（具体的には、シブトラミン、マジンドール等）、３）セロトニン再取り込み阻害剤（具体的には、フルオキセチン、パロキセチン等）４）リパーゼ阻害剤（具体的には、オルリスタット、セチリスタット等）５）ニューロペプチドＹ（ＮＰＹ）受容体拮抗薬（具体的には、Ｓ－２３６７等）６）ペプチドＹＹ（ＰＹＹ）受容体拮抗薬、７）アドレナリンβ３受容体作動薬（具体的には、ＫＲＰ－２０４、ＴＲＫ－３８０／ＴＡＣ－３０１等）等が挙げられる。 Other examples include lipid-lowering drugs and dyslipidemic agents. For example, 1) ω3 fatty acids (specifically ethyl icosapentate (EPA-E preparation), docosahexaenoic acid (DHA), etc.), 2) HMG-CoA reductase inhibitor (specifically atorvastatin, simvastatin, Pitavastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, etc.) 3) HMG-CoA synthetase inhibitor, 4) cholesterol absorption inhibitor (specifically, ezetimibe), 5) acyl-CoA / cholesterol acyl Transferase (ACAT) inhibitor, 6) CETP inhibitor, 7) squalene synthase inhibitor, 8) antioxidant (specifically, probucol, etc.), 9) PPARα agonist (specifically, clofibrate) , Etofibrate, fenofibrate, bezafibrate, cipro Fibrate, gemfibrozil, KRP-101, etc.), 10) PPARδ agonist, 11) LXR agonist, 12) FXR agonist (specifically, INT-747, etc.), 13) MTTP inhibitor, 14) squalene eposidase Inhibitors, 15) bile acid absorption inhibitors (specifically, cholestyramine, colestipol, etc.) and the like.
In addition, an anti-obesity drug is mentioned. Specifically, 1) CB-1 receptor antagonist (specifically, rimonabant, SR-147778, BAY-6-2520, etc.) 2) Monoamine reuptake inhibitor (specifically sibutramine, mazindol, etc.) 3) Serotonin reuptake inhibitors (specifically fluoxetine, paroxetine, etc.) 4) Lipase inhibitors (specifically, orlistat, cetiristat, etc.) 5) Neuropeptide Y (NPY) receptor antagonist (specific) Specifically, S-2367 etc.) 6) Peptide YY (PYY) receptor antagonist, 7) Adrenergic β3 receptor agonist (specifically, KRP-204, TRK-380 / TAC-301 etc.) Can be mentioned.
　ＮＡＦＬＤ・ＮＡＳＨの薬物治療に関しては確立したものがいまだないが、肥満、糖尿病、脂質異常症、高血圧などの生活習慣病を合併する際には、これらの合併症に対する薬物療法がとられる。すなわち、上記の糖尿病薬、脂質異常症治療剤、抗肥満薬に加え、高血圧治療剤等が挙げられる。高血圧治療剤として具体的には、１）利尿薬（具体的には、ヒドロクロロチアジド、フロセミド、スピロノラクトン、エプレレノン、クロルタリドン等）、２）カルシウム拮抗薬（具体的には、シルニジピン、アムロジピン、ベニジピン、ニフェジピン、ニカルジピン、ニルバジピン、アゼルニジピン、マニジピン、ニトレンジピン、パルニジピン、ニソルジピン、エホニジピン、フェロジピン、アラニジピン、ジルチアゼム、ベラパミル、ベプリジル等）、３）アンジオテンシン変換酵素阻害剤（具体的には、カプトプリル、アラセプリル、イミダプリル、エナラプリル、シラザプリル、テモカプリル、デラプリル、リシノプリル、ベナゼプリル等）、４）アンジオテンシン受容体拮抗薬（具体的には、ロサルタン、バルサルタン、カンデサルタン、テルミサルタン、オルメサルタン、イルベサルタン、エプロサルタン等）５）α２受容体作働薬、６）交感神経遮断薬、等が挙げられる。
　その他、ＮＡＳＨ治療に有効と考えられる治療剤として、例えば、１）抗酸化剤（具体的には、ビタミンＥ、ビタミンＣ、ベタイン、Ｎ－アセチルシステイン等）、２）肝庇護薬（具体的には、ＵＤＣＡ、ＥＰＬ、タウリン、グリチルリチン、小柴胡湯等）、３）抗炎症剤（具体的には、ＡＳＰ９８３１やペントキシフィリン等のサイトカイン産生抑制剤、ロイコトリエン受容体拮抗剤、ロイコトリエン生合成阻害剤、ＮＳＡＩＤｓ、ＣＯＸ－２選択的阻害剤、Ｍ２／Ｍ３拮抗剤、コルチコステロイド、ファルネシル酸プレドニゾロンなどのステロイド、ヒスタミン受容体拮抗剤、サラゾスルファピリジン、メサラジンなどのアミノサリチル酸等）、４）免疫抑制剤（具体的には、アザチオプリン、６－メルカプトプリン、タクロリムス等）、５）Ｃ型肝炎ウイルス用の抗ウイルス薬（具体的には、インターフェロン、プロテアーゼ阻害剤、ヘリカーゼ阻害剤、ポリメラーゼ阻害剤等）等が挙げられる。 Although there is no established pharmacotherapy for NAFLD / NASH, pharmacotherapy for these complications is taken when complicating lifestyle diseases such as obesity, diabetes, dyslipidemia, and hypertension. That is, in addition to the above-mentioned diabetes drugs, dyslipidemic agents, anti-obesity agents, antihypertensive agents and the like can be mentioned. Specific examples of antihypertensive agents include 1) diuretics (specifically, hydrochlorothiazide, furosemide, spironolactone, eplerenone, chlorthalidone, etc.), 2) calcium antagonists (specifically, cilnidipine, amlodipine, benidipine, nifedipine, Nicardipine, nilvadipine, azelnidipine, manidipine, nitrendipine, parnidipine, nisoldipine, efonidipine, felodipine, alanidipine, diltiazem, verapamil, bepridil, etc.), 3) angiotensin converting enzyme inhibitors (specifically captopril, alacepril, imidapril, enapril, enapril 4) angiotensin receptor antagonists (specifically, losartan, valsartan, cande), temocapril, delapril, lisinopril, benazepril, etc.) Rutan, telmisartan, olmesartan, irbesartan, eprosartan, etc.) 5) [alpha] 2 receptor agonists, 6) sympatholytic, and the like.
Other therapeutic agents that are considered effective for NASH treatment include, for example, 1) antioxidants (specifically, vitamin E, vitamin C, betaine, N-acetylcysteine, etc.), 2) liver protective drugs (specifically, UDCA, EPL, taurine, glycyrrhizin, Sho-saiko-to, etc.) 3) Anti-inflammatory agents (specifically, cytokine production inhibitors such as ASP9831 and pentoxyphyllin, leukotriene receptor antagonists, leukotriene biosynthesis inhibitors) , NSAIDs, COX-2 selective inhibitors, M2 / M3 antagonists, corticosteroids, steroids such as prednisolone farnesylate, histamine receptor antagonists, aminosalicylic acids such as salazosulfapyridine, mesalazine, etc.), 4) immune Inhibitors (specifically, azathioprine, 6-mercaptopurine, tacrolimus, etc.) 5) The hepatitis C virus for antiviral agents (specifically, interferon, a protease inhibitor, helicase inhibitor, a polymerase inhibitor, etc.) and the like.
　他の薬物と併用して用いるだけではなく、他の治療法と合わせて治療を行うことも可能である。例えば、体重コントロール・運動療法・食事療法による生活習慣の改善や放射線療法等が挙げられる。
　ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、肥満以外のＥｌｏｖｌ６が関与する疾患には、それぞれの領域で使用されている薬物との併用が可能である。 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, lifestyle improvement by weight control, exercise therapy, diet therapy, radiation therapy, and the like can be mentioned.
Diseases involving Elovl6 other than NAFLD / NASH, diabetes and obesity can be used in combination with drugs used in the respective fields.
　上記疾患に対して既存薬と併用することにより、既存薬の投薬量を下げることが可能であり、既存薬の副作用を軽減することが可能となる。もちろん、当該薬物を用いた併用方法は、上記疾患に限定されるものではなく、且つ併用される薬物は上記に例示した化合物に限定されない。 In combination with existing drugs for the above diseases, the dosage of existing drugs can be reduced, and the side effects of existing drugs can be reduced. 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.
　本発明化合物と併用される薬物とを組み合わせて使用する場合は、別々の製剤であっても、合剤であっても良い。また、別々の製剤においては、両者を同時に服用することも、時間をずらして投与することも可能である。 In the case of using in combination with a drug used in combination with the compound of the present invention, 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.
［本発明の予防・治療剤の製剤化］
　本発明の医薬は、医薬組成物の形態で投与される。
　本発明の医薬組成物は、本発明の式（Ｉ）で表される化合物の少なくとも一つ以上を含んでいればよく、医薬上許容される添加剤と組み合わせてつくられる。より詳細には、賦形剤（例；乳糖、白糖、マンニット、結晶セルロース、ケイ酸、トウモロコシデンプン、バレイショデンプン）、結合剤（例；セルロース類（ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ））、結晶セルロース、糖類（乳糖、マンニット、白糖、ソルビトール、エリスリトール、キシリトール）、デンプン類（トウモロコシデンプン、バレイショデンプン）、α化デンプン、デキストリン、ポリビニルピロリドン（ＰＶＰ）、マクロゴール、ポリビニルアルコール（ＰＶＡ））、滑沢剤（例；ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、カルボキシメチルセルロース）、崩壊剤（例；デンプン類（トウモロコシデンプン、バレイショデンプン）、カルボキシメチルスターチナトリウム、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポピドン）、被膜剤（例；セルロース類（ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ））、アミノアルキルメタクリレートコポリマーＥ、メタクリル酸コポリマーＬＤ）、可塑剤（例；クエン酸トリエチル、マクロゴール）、隠蔽剤（例；酸化チタン）、着色剤、香味剤、防腐剤（例；塩化ベンザルコニウム、パラオキシ安息香酸エステル）、等張化剤（例；グリセリン、塩化ナトリウム、塩化カルシウム、マンニトール、ブドウ糖）、ｐＨ調節剤（例；水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、塩酸、硫酸、リン酸緩衝液などの緩衝液）、安定化剤（例；糖、糖アルコール、キサンタンガム）、分散剤、酸化防止剤（例；アスコルビン酸、ブチルヒドロキシアニソール（ＢＨＡ）、没食子酸プロピル、ｄｌ－α－トコフェロール）、緩衝剤、保存剤（例；パラベン、ベンジルアルコール、塩化ベンザルコニウム）、芳香剤（例；バニリン、ｌ－メントール、ローズ油）、溶解補助剤（例；ポリオキシエチレン硬化ヒマシ油、ポリソルベート８０、ポリエチレングリコール、リン脂質コレステロール、トリエタノールアミン）、吸収促進剤（例；グリコール酸ナトリウム、エデト酸ナトリウム、カプリン酸ナトリウム、アシルカルニチン類、リモネン）、ゲル化剤、懸濁化剤、または乳化剤、一般的に用いられる適当な添加剤または溶媒の類を、本発明の化合物と適宜組み合わせて種々の剤形とすることが出来る。 [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 only needs to contain at least one compound represented by the formula (I) of the present invention, and is prepared 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), carbox Methyl 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.
　種々の剤形とは、錠剤、カプセル剤、顆粒剤、散剤、丸剤、エアゾール剤、吸入剤、軟膏剤、貼付剤、坐剤、注射剤、トローチ剤、液剤、酒精剤、懸濁剤、エキス剤、エリキシル剤等があげられる。また、経口、皮下投与、筋肉内投与、鼻腔内投与、経皮投与、静脈内投与、動脈内投与、神経周囲投与、硬膜外投与、硬膜下腔内投与、脳室内投与、直腸内投与、吸入等により患者に投与し得る。 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 patients by inhalation and the like.
　本発明化合物の投与量は、通常成人１日当たり０．００５ｍｇ～３．０ｇ、好ましくは０．０５ｍｇ～２．５ｇ、より好ましくは０．１ｍｇ～１．５ｇであるが、症状あるいは投与経路に応じて適宜増減できる。 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.
　全量を１回あるいは２－６回に分割して経口または非経口投与することや、点滴静注等、連続投与することも可能である。 The entire amount can be divided into 1 or 2-6 doses, orally or parenterally, or can be administered continuously by intravenous infusion.
　なお、本明細書において引用された全ての刊行物、例えば先行技術文献、及び公開公報、特許公報その他の特許文献は、その全体が参照として本明細書に組み入れられる。 It should be noted that all publications cited in the present specification, for example, prior art documents, publications, patent gazettes and other patent documents, are incorporated herein by reference in their entirety.
［薬理実験例］
　以下に実験例を挙げて、本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。 [Pharmacological experiment example]
Hereinafter, the present invention will be specifically described with reference to experimental examples, but the present invention is not limited to these examples.
薬理実験例１：ヒトＥｌｏｖｌ６発現プラスミドの構築
　ＧｅｎＢａｎｋにあるＮＣＢＩ ＲｅｆＳｅｑのヒトＥｌｏｖｌ６遺伝子配列（ＮＭ＿０２４０９０）に記載されている配列を、Ｈｕｍａｎ　ＭＴＣ　Ｐａｎｅｌ　Ｉ（クロンテック）のＬｉｖｅｒを鋳型としてＰＣＲにより増幅した。得られたヒトＥｌｏｖｌ６遺伝子をＥＦ－１αプロモーターを有する発現プラスミドｐＥＦ２ｃｅｗに導入して、ヒトＥｌｏｖｌ６発現プラスミドｐＴＫ－３０８８を構築した。 Pharmacological Experiment Example 1: Construction of Human Elovl6 Expression Plasmid The sequence described in NCBI RefSeq's human Elovl6 gene sequence (NM — 024090) in GenBank was amplified by PCR using the Human MTC Panel I (Clontech) Liver as a template. The obtained human Elovl6 gene was introduced into an expression plasmid pEF2cew having an EF-1α promoter to construct a human Elovl6 expression plasmid pTK-3088.
薬理実験例２：Ｅｌｏｖｌ６酵素源の調製
　２Ｌの培養用フラスコにヒト腎臓由来細胞株ＦｒｅｅＳｔｙｌｅＴＭ　２９３Ｆ細胞（インビトロジェン）を播種した。一晩培養後、２９３Ｆ細胞専用遺伝子導入試薬（２９３ｆｅｃｔｉｎ、インビトロジェン）を用い、薬理実験例１で得たヒトＥｌｏｖｌ６発現プラスミドｐＴＫ－３０８８を導入した。２日間培養後、細胞を回収し、プロテアーゼインヒビターとして５０ｍＬあたり１錠のＣｏｍｐｌｅｔｅ　ＥＤＴＡ－ｆｒｅｅ（Ｒｏｃｈｅ）を含むバッファーＡ（１０ｍＭ　Ｔｒｉｓ－ＨＣｌ、０．２５Ｍ　Ｓｕｃｒｏｓｅ、１ｍＭ　ＥＤＴＡ－２Ｎａ、ｐＨ７．４）に懸濁させた。超音波破砕機にて細胞を破砕し、６００ｇ、４℃で１０分間遠心した。この上清を８０００ｇ、４℃で１０分間遠心した。さらにその上清を１０５０００ｇ、４℃で６０分間遠心した。得られた沈殿を５０ｍＬあたり１錠のＣｏｍｐｌｅｔｅ　ＥＤＴＡ　Ｆｒｅｅ（Ｒｏｃｈｅ）を含むバッファーＢ（１００ｍＭ　Ｔｒｉｓ－ＨＣｌ、１ｍＭ　ＥＤＴＡ－２Ｎａ、ｐＨ７．４）で懸濁し、これをＥｌｏｖｌ６酵素源とした。 Pharmacological Experimental Example 2: Preparation of Elovl6 Enzyme Source A human kidney-derived cell line FreeStyle ™ 293F cells (Invitrogen) was seeded in a 2 L culture flask. After overnight culture, the human Elovl6 expression plasmid pTK-3088 obtained in Pharmacological Experiment Example 1 was introduced using a 293F cell-specific gene introduction reagent (293fectin, Invitrogen). After culturing for 2 days, the cells were collected and placed in Buffer A (10 mM Tris-HCl, 0.25 M Sucrose, 1 mM EDTA-2Na, pH 7.4) containing 1 tablet of Complete EDTA-free (Roche) as a protease inhibitor. Suspended. Cells were disrupted with an ultrasonic disrupter and centrifuged at 600 g for 10 minutes at 4 ° C. The supernatant was centrifuged at 8000 g and 4 ° C. for 10 minutes. The supernatant was further centrifuged at 105000 g, 4 ° C. for 60 minutes. The obtained precipitate was suspended in buffer B (100 mM Tris-HCl, 1 mM EDTA-2Na, pH 7.4) containing 1 tablet of Complete EDTA Free (Roche) per 50 mL, and this was used as the Elovl6 enzyme source.
薬理実験例３：Ｅｌｏｖｌ６酵素阻害試験
　被検化合物をジメチルスルホキシド（ＤＭＳＯ）に３０ｍＭとなるように溶解し、更にＤＭＳＯで希釈し、評価濃度の１００倍濃縮溶液を調製した。その後、９６ウェルアッセイプレート（Ｎｕｎｃ）へ１ウェルあたり１μＬ添加し、更に基質溶液８９μＬ（２０μＭ　パルミトイル－ＣｏＡ、１ｍＭ　ＮＡＤＰＨ（還元型ニコチンアミドアデニンジヌクレオチドリン酸）、２．７μＭ［１４Ｃ］マロニル－ＣｏＡ（９２５ｋＢｑ／ｍＬ、Ｍｏｒａｖｅｋ））を各ウェルに加え５分間プレインキュベーションした。次に、薬理実験例２で得たヒトＥｌｏｖｌ６（２．５μｇ／μＬ）を１０μＬ添加し、シールにてプレート上部を密閉し３７℃で１５分間穏やかに攪拌しながらインキュベーションした。その後、各ウェルに１００μＬの２８％ナトリウムメトキシドを加え反応を停止させ、６５℃で２時間インキュベートしアシル－ＣｏＡを加水分解させた。更に１００μＬの６Ｎ塩化水素溶液を加え反応溶液を酸性にした。酵素反応溶液をあらかじめリン酸緩衝液を通液させておいた９６ウェルＭｕｌｔｉＳｃｒｅｅｎＨＴＳ－ＦＢプレート（Ｍｉｌｌｉｐｏｒｅ）に吸着させ、未反応のマロニル－ＣｏＡを除去するために各ウェルをリン酸緩衝液で洗浄した後、一晩室温にて乾燥させた。その後、各ウェルに５０μＬのシンチレーター（Ａｑｕａｚｏｌ（ＰｅｒｋｉｎＥｌｍｅｒ））を加えプレート上部・下部をシールし、固定された［１４Ｃ］の放射活性をマイクロプレートシンチレーションカウンター（１４５０ＭｉｃｒｏＢｅｔａ(R)　ＴＲＩＬＵＸ（ＰｅｒｋｉｎＥｌｍｅｒ））にて測定し、酵素活性すなわちオレイン酸合成能とした。被検化合物によるヒトＥｌｏｖｌ６の酵素阻害活性は、被検化合物を含まないＤＭＳＯ１μＬ添加ウェルの放射活性能をコントロールとし算出した。 Pharmacological Experiment Example 3: Elovl6 Enzyme Inhibition Test A test compound was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 30 mM, and further diluted with DMSO to prepare a 100-fold concentrated solution of the evaluation concentration. Thereafter, 1 μL per well was added to a 96-well assay plate (Nunc), and further 89 μL of substrate solution (20 μM palmitoyl-CoA, 1 mM NADPH (reduced nicotinamide adenine dinucleotide phosphate), 2.7 μM [ 14 C] malonyl- CoA (925 kBq / mL, Moravek)) was added to each well and preincubated for 5 minutes. Next, 10 μL of human Elovl6 (2.5 μg / μL) obtained in Pharmacological Experiment Example 2 was added, the top of the plate was sealed with a seal, and incubated at 37 ° C. for 15 minutes with gentle agitation. Thereafter, 100 μL of 28% sodium methoxide was added to each well to stop the reaction and incubated at 65 ° C. for 2 hours to hydrolyze acyl-CoA. Further, 100 μL of 6N hydrogen chloride solution was added to make the reaction solution acidic. The enzyme reaction solution was adsorbed on a 96-well MultiScreen HTS-FB plate (Millipore) that had been passed through a phosphate buffer, and each well was washed with a phosphate buffer to remove unreacted malonyl-CoA. Then, it was dried overnight at room temperature. Thereafter, the scintillator of 50μL per well (Aquazol (PerkinElmer)) Seal the plate upper and lower added, microplate scintillation counter and radioactivity of the fixed [14 C] (1450MicroBeta (R ) TRILUX (PerkinElmer)) And measured as enzyme activity, that is, oleic acid synthesis ability. The enzyme inhibitory activity of human Elovl6 by the test compound was calculated using the radioactivity in wells containing 1 μL of DMSO not containing the test compound as a control.
　本発明化合物のＥｌｏｖｌ６酵素阻害活性すなわちオレイン酸合成阻害活性はＩＣ５０値で表し、ＩＣ５０値が１００ｎＭ未満の本発明の化合物をＡとして、また、ＩＣ５０値が１００ｎＭ以上・１μＭ未満の化合物をＢとして表１に示した。 Elovl6 enzyme inhibitory activity i.e. oleic acid synthesis inhibitory activity of the present compounds are represented by an IC 50 value, a compound of the present invention the IC 50 values less than the 100nM as A, also, an IC 50 value is the compound of less than 100nM or · 1 [mu] M B is shown in Table 1.
Figure JPOXMLDOC01-appb-T000200
  
Figure JPOXMLDOC01-appb-T000200
  
薬理実験例４：細胞内Ｅｌｏｖｌ６酵素活性阻害試験
　１０ｃｍ２ディッシュに１×１０６細胞個のマウス肝臓由来細胞株ＡＭＬ１２（ＡＴＣＣ）を播種した。一晩培養後、ＦｕＧＥＮＥ６（Ｒｏｃｈｅ）を用いて、薬理実験例１で得られたヒトＥｌｏｖｌ６発現プラスミドｐＴＫ－３０８８およびネオマイシン耐性遺伝子を含むｐＳＶ２－ｎｅｏを導入した。一晩培養後、Ｇｅｎｅｔｉｃｉｎ（インビトロジェン）を含む培地に交換し、更に１週間培養を行い、Ｅｌｏｖｌ６安定発現ＡＭＬ１２細胞株を得た。更にこれを限外希釈法により、モノクローナル細胞株を作製し、ＡＭＬ１２－Ｅｌｏｖｌ６細胞株と命名した。 Pharmacological Experiment Example 4: Intracellular Elovl6 Enzyme Activity Inhibition Test 1 × 10 6 mouse liver-derived cell line AML12 (ATCC) was seeded in a 10 cm 2 dish. After overnight culture, using FuGENE6 (Roche), the human Elovl6 expression plasmid pTK-3088 obtained in Pharmacological Experiment Example 1 and pSV2-neo containing the neomycin resistance gene were introduced. After overnight culture, the medium was replaced with a medium containing Geneticin (Invitrogen), and further cultured for 1 week to obtain an Elovl6 stable expression AML12 cell line. Furthermore, a monoclonal cell line was prepared by the ultradilution method and named AML12-Elovl6 cell line.
　ＡＭＬ１２－Ｅｌｏｖｌ６細胞株は、１０％牛胎児血清、デキサメタゾン、動物細胞培養用添加剤（ＩＴＳ　Ｌｉｑｕｉｄ　Ｍｅｄｉａ　Ｓｕｐｐｌｅｍｅｎｔ（シグマ））を加えたＤＭＥＭ／Ｆ１２培地（ＧＩＢＣＯ）で維持し、５％ＣＯ２下、３７℃で培養した。１２ウェル細胞培養プレート（コーニング）に約２×１０５個のＡＭＬ１２－Ｅｌｏｖｌ６細胞を播種し一晩培養した。薬理実験例３に記載した方法で調製した被検化合物を評価濃度となるように添加し、１５分間前培養後、［３Ｈ］－パルミチン酸（１８５ＭＢｑ／ｍＬ、ＰｅｒｋｉｎＥｌｍｅｒ）を各ウェルに加え、さらに２時間培養した。各ウェルをリン酸緩衝液で洗浄後、４５０μＬのバッファー（１．８Ｍ　水酸化ナトリウム、０．２２ｍｇ／ｍＬ　フォスファチジルコリン）を加え細胞を溶解させた。その後、細胞溶解溶液を回収し６５℃で１時間インキュベート後、２５０μＬの６Ｍ塩酸を加え、ヘキサンにて脂肪酸を抽出し、ＳｐｅｅｄＶａｃ（ＳＡＶＡＮＴ）を用い脂肪酸抽出液を乾固した。乾固した抽出液を１７５μＬのバッファーＢ（メタノール：酢酸：水＝８４．９：０．１：１５）で再溶解し、ラジオＨＰＬＣにて［３Ｈ］でラベル化した脂肪酸を測定し、炭素数１８と炭素数１６の量比（Ｃ１８／Ｃ１６比）を算出し、細胞内Ｅｌｏｖｌ６酵素活性すなわちステアリン酸・オレイン酸合成能とした。被検化合物による細胞内Ｅｌｏｖｌ６酵素活性阻害活性は、被検化合物を含まないＤＭＳＯ添加ウェルのＣ１８／Ｃ１６比をコントロールとし算出した。 The AML12-Elovl6 cell line was maintained in DMEM / F12 medium (GIBCO) supplemented with 10% fetal bovine serum, dexamethasone, and animal cell culture additives (ITS Liquid Media Supplement (Sigma)) under 5% CO 2 , Cultured at 37 ° C. Approximately 2 × 10 5 AML12-Elovl6 cells were seeded in a 12-well cell culture plate (Corning) and cultured overnight. The test compound prepared by the method described in Pharmacological Experiment Example 3 was added to the evaluation concentration, and after pre-culture for 15 minutes, [ 3 H] -palmitic acid (185 MBq / mL, PerkinElmer) was added to each well, The culture was further continued for 2 hours. After washing each well with a phosphate buffer, 450 μL of buffer (1.8 M sodium hydroxide, 0.22 mg / mL phosphatidylcholine) was added to lyse the cells. Thereafter, the cell lysis solution was collected and incubated at 65 ° C. for 1 hour, 250 μL of 6M hydrochloric acid was added, the fatty acid was extracted with hexane, and the fatty acid extract was dried using SpeedVac (SAVANT). The dried extract was redissolved with 175 μL of buffer B (methanol: acetic acid: water = 84.9: 0.1: 15), and the fatty acid labeled with [ 3 H] was measured by radio HPLC. The quantity ratio between C18 and C16 (C18 / C16 ratio) was calculated and used as the intracellular Elovl6 enzyme activity, that is, the ability to synthesize stearic acid / oleic acid. The intracellular Elovl6 enzyme activity inhibitory activity of the test compound was calculated using the C18 / C16 ratio of the DMSO-added well not containing the test compound as a control.
　本発明化合物の阻害活性はＩＣ５０値で表し、ＩＣ５０値が１００ｎＭ未満の本発明の化合物をＡとして、また、ＩＣ５０値が１００ｎＭ以上・１μＭ未満の化合物をＢとして表２に示した。 Inhibitory activity of the compounds of the invention expressed as an IC 50 value, an IC 50 value as the compound A of the present invention of less than 100nM, also, an IC 50 value is shown in Table 2. Compound of less 100nM or · 1 [mu] M as B.
Figure JPOXMLDOC01-appb-T000201
  
Figure JPOXMLDOC01-appb-T000201
  
薬理実験例５：ｉｎ　ｖｉｖｏにおける遊離脂肪酸組成分析
（１）マウスへのＥｌｏｖｌ６阻害化合物の連続投与
　７週齢のＢＫＳ．Ｃｇ－ｍ＋／＋Ｌｅｐｒｄｂ／Ｊマウスを２週間馴化し、馴化後のマウスに、実施例１４０の化合物を２．５ｍＬ／ｋｇの容量（溶媒：ポリエチレングリコール４００（ＰＥＧ　４００））にて経口投与した。投与は２８日間、毎日朝晩２回行った。最終投与日の翌日、４時間絶食下で同マウスの眼窩静脈叢より採血を行い、得られた血液を遠心分離（７０００ｒｐｍ、１５分間、４℃）し血漿を調製した。 Pharmacological Experimental Example 5: Analysis of free fatty acid composition in vivo (1) Continuous administration of Elovl6 inhibitory compound to mice 7-week-old BKS. Cg-m + / + Lepr db / J mice were acclimated for 2 weeks, and the acclimated mice were orally administered the compound of Example 140 in a volume of 2.5 mL / kg (solvent: polyethylene glycol 400 (PEG 400)). . Administration was performed twice daily in the morning and evening for 28 days. The day after the last administration day, blood was collected from the orbital venous plexus of the same mouse under fasting for 4 hours, and the obtained blood was centrifuged (7000 rpm, 15 minutes, 4 ° C.) to prepare plasma.
（２）マウス血漿中の遊離脂肪酸組成分析
　薬理実験例５（１）で調製した血漿サンプルに、脂肪酸組成分析の内部標準となる１００μＭマーガリン酸溶液を同量混和したのち、エタノールを１０倍量添加した。溶液を充分に撹拌したのち遠心（１０，０００ｒｐｍ、５分間、４℃）し、上清をＳｐｅｅｄＶａｃにて約１時間濃縮した。濃縮したサンプルを「エステル型短鎖・長鎖脂肪酸分析キット（ＹＭＣ－ＰａｃｋＦＡ）」（ＹＭＣ）に供し、キットに添付されたマニュアルに準じて脂肪酸組成分析を行った。サンプル中に含まれるパルミチン酸（Ｃ１６：０）、パルミトレイン酸（Ｃ１６：１）、ステアリン酸（Ｃ１８：０）およびオレイン酸（Ｃ１８：１）の脂肪酸の含有比をもとめ、各血漿中の脂肪酸組成比とした。すなわち、上記４種脂肪酸の合計モル濃度を１として各脂肪酸モル濃度比を算出し、血漿中脂肪酸組成比とした。
　各脂肪酸組成の分析結果を図１に示した。図１に示すように、Ｅｌｏｖｌ６阻害化合物の投与による血中脂肪酸組成の変動、とりわけパルミチン酸の上昇及びオレイン酸の低下を確認した。 (2) Analysis of free fatty acid composition in mouse plasma After mixing the same amount of 100 μM margaric acid solution, which is an internal standard for fatty acid composition analysis, into the plasma sample prepared in Pharmacological Experiment Example 5 (1), add 10 times the amount of ethanol. did. The solution was sufficiently stirred and then centrifuged (10,000 rpm, 5 minutes, 4 ° C.), and the supernatant was concentrated with SpeedVac for about 1 hour. The concentrated sample was subjected to “Ester type short chain / long chain fatty acid analysis kit (YMC-PackFA)” (YMC), and fatty acid composition analysis was performed according to the manual attached to the kit. The fatty acid composition in each plasma was determined by determining the content ratio of fatty acids of palmitic acid (C16: 0), palmitoleic acid (C16: 1), stearic acid (C18: 0) and oleic acid (C18: 1) contained in the sample. Ratio. That is, each fatty acid molar concentration ratio was calculated by setting the total molar concentration of the above four fatty acids to 1, and was used as the plasma fatty acid composition ratio.
The analysis result of each fatty acid composition is shown in FIG. As shown in FIG. 1, changes in blood fatty acid composition due to administration of the Elovl6 inhibitor compound, particularly an increase in palmitic acid and a decrease in oleic acid were confirmed.
薬理実験例６：溶解性試験
（１）ＤＭＳＯ析出溶解性（Ｋｉｎｅｔｉｃ　Ｓｏｌｕｂｉｌｉｔｙ）
　本発明の化合物の１０ｍＭのＤＭＳＯ溶液を最終濃度１００μＭとなるように５０ｍＭリン酸緩衝液（ｐＨ７．４）に添加する。その溶液を室温で１．５時間、６００ｒｐｍにて撹拌しながらインキュベーションした後、フィルタープレート（４μｍ、ＭｕｌｔｉＳｃｒｅｅｎ Ｓｏｌｕｂｉｌｉｔｙフィルタープレート（Ｍｉｌｌｉｐｏｒｅ））でろ過し、プレートリーダー（Ｐｏｗｅｒｓｃａｎ　ＨＴ（大日本製薬））を用いて、ろ液の吸光度を最大吸収波長で測定する。同時に、試験化合物の既知濃度（１、３、１０、３０、１００μＭ）を添加したＤＭＳＯ溶液を検量線標準溶液として各々の標準溶液吸光度を測定し、検量線を作成する。ろ液および標準溶液の吸光度値より化合物の溶解度（μＭ）を算出する。 Pharmacological Experiment Example 6: Solubility Test (1) DMSO Precipitation Solubility (Kinetic Solubility)
A 10 mM DMSO solution of the compound of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 μM. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, then filtered through a filter plate (4 μm, MultiScreen Solidity filter plate (Millipore)), and using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). Then, the absorbance of the filtrate is measured at the maximum absorption wavelength. At the same time, the absorbance of each standard solution is measured using a DMSO solution to which a known concentration (1, 3, 10, 30, 100 μM) of the test compound is added as a calibration curve standard solution, and a calibration curve is created. The solubility (μM) of the compound is calculated from the absorbance values of the filtrate and standard solution.
（２）結晶溶解性（Ｔｈｅｒｍｏｄｙｎａｍｉｃ　Ｓｏｌｕｂｉｌｉｔｙ）
　本発明の化合物を１ｍｇ／ｍＬとなるように水に添加する。その溶液を３７℃で２４時間静置した後、遠心分離する。得られた上清をＨＰＬＣにて分析し、最大吸収波長にてピークを検出し、ピーク面積を測定する。同様に試験化合物の既知濃度（０．０３、０．１、０．３、１、３、１０μｇ／ｍＬ）を添加したＤＭＳＯ溶液を検量線標準溶液として各々のピーク面積を測定し、検量線のピーク面積より化合物の溶解度（μｇ／ｍＬ）を算出する。 (2) Crystal solubility (Thermodynamic Solubility)
The compound of the present invention is added to water so as to be 1 mg / mL. The solution is allowed to stand at 37 ° C. for 24 hours and then centrifuged. The obtained supernatant is analyzed by HPLC, the peak is detected at the maximum absorption wavelength, and the peak area is measured. Similarly, each peak area was measured using a DMSO solution to which a known concentration of a test compound (0.03, 0.1, 0.3, 1, 3, 10 μg / mL) was added as a standard curve standard solution. The solubility (μg / mL) of the compound is calculated from the peak area.
薬理実験例７：代謝安定性試験
　本発明の化合物の１０ｍＭのＤＭＳＯ溶液を最終濃度１μＭとなるように肝ミクロソーム溶液（ヒト、マウス;ＸｅｎｏＴｅｃｈ）、ＮＡＤＰＨ生成溶液（β－ＮＡＤＰ、Ｇｌｕｃｏｓｅ－６－Ｐｈｏｓｐｈａｔｅ、Ｇ－６－ＰＤＨ（Ｙ）、ＭｇＣｌ２を含む水）に添加する。その溶液を３７℃で２０分間インキュベートした後、アセトニトリルで反応停止する。反応液をフィルタープレート（ＭｕｌｔｉＳｃｒｅｅｎＨＴＳ－ＨＶプレート（Ｍｉｌｌｉｐｏｒｅ））で遠心ろ過し、高速液体クロマトグラム/マススペクトロメトリーを用いて、ろ液中の試験化合物を測定する。同様に反応時間０分のサンプルをコントロールとして測定し、ミクロソーム反応サンプルとコントロールの比より、分解率（％）を算出する。 Pharmacological Experiment Example 7: Metabolic Stability Test Liver microsome solution (human, mouse; XenoTech), NADPH generating solution (β-NADP, Glucose-6-phosphate) with 10 mM DMSO solution of the compound of the present invention to a final concentration of 1 μM , G-6-PDH (Y), water containing MgCl 2 ). The solution is incubated at 37 ° C. for 20 minutes and then quenched with acetonitrile. The reaction solution is subjected to centrifugal filtration using a filter plate (MultiScreen HTS-HV plate (Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and the degradation rate (%) is calculated from the ratio of the microsome reaction sample and the control.
薬理実験例８：パッチクランプ法によるｈＥＲＧ阻害試験
　ｈＥＲＧ（ｈｕｍａｎ ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ）チャネルに対する作用を全自動パッチクランプシステム（Ｐａｔｃｈｌｉｎｅｒ（Ｎａｎｉｏｎ））を用いて測定する。細胞（ｈＥＲＧ－ＨＥＫ（Ｕｐｓｔａｔｅ））のｈＥＲＧ　ＩKr電流を確認するため、膜電位を－８０ｍＶに保持して定期的に脱分極パルスを加える。発生した電流が安定した後、試験化合物を添加する。試験化合物のｈＥＲＧチャネルに対する作用は、４０ｍＶ、０．５秒間の脱分極パルスに続く－４０ｍＶ、０．５秒間の再分極パルスによって誘導されるテール電流の変化によって確認する。刺激は１０秒に１回の頻度で行う。測定は室温で行う。ｈＥＲＧチャネル阻害率は、試験化合物適用前の最大テール電流に対する適用２分後のテール電流の減少率（抑制率）として算出する。
　この抑制率を算出することにより、薬物によるＱＴ延長とそれに続く致死的な副作用（心室頻拍や突然死など）を誘発する可能性が示される。 Pharmacological experiment example 8: hERG inhibition test by patch clamp method The effect on hERG (human ether-a-go-related gene) channel is measured using a fully automatic patch clamp system (Patchliner (Nanion)). In order to confirm the hERG I Kr current of the cells (hERG-HEK (Upstate)), a depolarizing pulse is periodically applied while maintaining the membrane potential at −80 mV. After the generated current has stabilized, the test compound is added. The effect of the test compound on the hERG channel is confirmed by a change in tail current induced by a 40 mV, 0.5 second depolarizing pulse followed by a -40 mV, 0.5 second repolarizing pulse. Stimulation is performed once every 10 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 2 minutes after application with respect to the maximum tail current before application of the test compound.
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.
薬理実験例９：ファーマコキネティクス試験（マウスカセットＰＫ）
　本発明の化合物を７あるいは８週齢の雄性Ｃ５７ＢＬ／６Ｊ　Ｊｃｌに１ｍｇ／ｋｇ（投与溶媒は、ＤＭＳＯ：Ｔｗｅｅｎ８０：超純水＝１：１：８、１０ｍＬ／ｋｇ）で経口単回投与した後、０．２５、０．５、１、２時間後に腹大静脈より採血する。血液を遠心分離（３０００ｒｐｍ、１５分間、４℃）して得られた血漿を用いて、高速液体クロマトグラム/マススペクトロメトリーにて、血漿中の試験化合物を測定する。同時に試験化合物の既知濃度（０．０１、０．０２、０．０５、０．１、０．２、０．５、１μｇ／ｍＬ）を添加した標準溶液を用いて作成した検量線より血漿中濃度（μｇ／ｍＬ）を算出し、最高血漿中濃度をＣｍａｘ（μｇ／ｍＬ）とする。 Pharmacological Experiment Example 9: Pharmacokinetics test (mouse cassette PK)
After a single oral administration of the compound of the present invention to 7- or 8-week-old male C57BL / 6J Jcl at 1 mg / kg (administration solvent: DMSO: Tween 80: ultrapure water = 1: 1: 8, 10 mL / kg) 0.25, 0.5, 1, 2 hours later, blood is collected from the abdominal vena cava. Using plasma obtained by centrifuging blood (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Simultaneously in the plasma from a standard curve prepared using a standard solution to which a known concentration of the test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added The concentration (μg / mL) is calculated, and the maximum plasma concentration is defined as Cmax (μg / mL).
薬理実験例１０：安全性試験
　本発明の化合物をマウスまたはラットに単回で経口投与し、死亡例は認められず、目立った行動異常も観察されないことにより、本発明化合物の安全性が示される。 Pharmacological experiment example 10: Safety test The compound of the present invention is orally administered to a mouse or rat once, and no deaths are observed, and no remarkable behavioral abnormality is observed, which shows the safety of the compound of the present invention. .
　以上の結果より、本発明の化合物は、優れたＥｌｏｖｌ６酵素活性阻害作用及び脂肪酸組成の変動、とりわけパルミチン酸の上昇及びオレイン酸低下作用を有することが示された。
　更に、本発明の化合物は、上記の試験を行うことにより、溶解性、代謝安定性、薬物動態、ｈＥＲＧチャネル阻害作用の回避等の１つの点において良好であることが確認される。
　従って、本発明の化合物は、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、２型糖尿病、インスリン抵抗性や肥満・肥満症の予防または治療剤として期待される。 From the above results, it was shown that the compound of the present invention has an excellent Elovl6 enzyme activity inhibitory effect and a change in fatty acid composition, particularly an increase in palmitic acid and a decrease in oleic acid.
Furthermore, it is confirmed that the compound of the present invention is good in one point such as solubility, metabolic stability, pharmacokinetics, and avoidance of hERG channel inhibitory effect by conducting the above test.
Therefore, the compound of the present invention is expected as an agent for preventing or treating NAFLD / NASH, diabetes, type 2 diabetes, insulin resistance and obesity / obesity.
　本発明の化合物は、Ｅｌｏｖｌ６阻害作用を有し、Ｅｌｏｖｌ６が関与する各種疾患、例えば、ＮＡＳＨ、ＮＡＦＬＤ、糖尿病、インスリン抵抗性、高インスリン血症、耐糖能異常（ＩＧＴ）・空腹時血糖異常（ＩＦＧ）、空腹時高血糖状態、肥満・肥満症、もしくはこれらに起因ないし関連する各種疾患の処置剤として有望な治療効果が期待できる。 The compound of the present invention has an Elovl6 inhibitory action, and various diseases involving Elovl6, such as NASH, NAFLD, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT) / fasting blood glucose abnormality (IFG) ), A promising therapeutic effect can be expected as a therapeutic agent for a fasting hyperglycemia state, obesity / obesity, or various diseases caused or related thereto.
　特に本発明の化合物は、ＮＡＳＨ、ＮＡＦＬＤ、糖尿病、インスリン抵抗性、高インスリン血症、耐糖能異常（ＩＧＴ）・空腹時血糖異常（ＩＦＧ）、空腹時高血糖状態、肥満・肥満症、もしくはこれらに起因ないし関連する各種疾患に有用である。 In particular, the compounds of the present invention include NASH, NAFLD, diabetes, insulin resistance, hyperinsulinemia, impaired glucose tolerance (IGT) / fasting blood glucose abnormality (IFG), fasting hyperglycemia, obesity / obesity, or these It is useful for various diseases caused by or related to.
　ここで定義される“ＮＡＦＬＤ”とは、明らかな飲酒歴がないが、アルコール性肝障害に類似した主に大滴性の肝脂肪沈着を特徴とする肝障害であり、単純性脂肪肝から脂肪性肝炎、線維化、肝硬変、肝癌までの肝障害を含む疾患群である。ウイルス性肝疾患、自己免疫疾患性肝疾患、ヘマクロトーシスやＷｉｌｓｏｎ病等の代謝性肝疾患などは除外される。ＮＡＦＬＤは非アルコール性脂肪肝とも言い、予後良好な単純性脂肪肝と、予後不良な進行性のＮＡＳＨを含む疾患概念である。
　“ＮＡＳＨ”は、ＮＡＦＬＤの重症型と考えられており、ＮＡＦＬＤのうち肝細胞の炎症や線維化を伴う進行性の疾患である。アルコール性肝障害、ウイルス性肝炎や薬剤性肝障害の否定できる肝炎の多くがＮＡＳＨの病態であるとされている。メタボリックシンドロームを背景に、脂質代謝異常、高血圧、糖尿病、インスリン抵抗性・耐糖能異常、肥満・肥満症等の合併頻度が非常に高く、病態が進展すると、肝硬変や肝癌への進行がみられる。これらの疾患が、ＮＡＦＬＤ・ＮＡＳＨに起因ないし関連する疾患である。
　ＮＡＦＬＤ・ＮＡＳＨの治療とは、本発明のＥｌｏｖｌ６阻害作用を有する化合物または当該化合物を含有する医薬組成物をＮＡＦＬＤ・ＮＡＳＨ患者に投与することを示す。上記の合併症を伴う際には、それらの治療が最優先治療である。それに加え、酸化ストレスやインスリン抵抗性などＮＡＳＨの重要な病態の改善が治療の成果として挙げられる。 “NAFLD” as defined here is a liver disorder characterized by mainly large-scale hepatic fat deposition, similar to alcoholic liver disorder, although there is no clear drinking history. It is a group of diseases including hepatic disorder such as hepatitis, fibrosis, cirrhosis, and liver cancer. Viral liver diseases, autoimmune disease liver diseases, metabolic liver diseases such as hemacrotosis and Wilson disease are excluded. NAFLD is also called non-alcoholic fatty liver and is a disease concept including simple fatty liver with good prognosis and progressive NASH with poor prognosis.
“NASH” is considered to be a severe form of NAFLD, and is a progressive disease of NAFLD accompanied by inflammation and fibrosis of hepatocytes. Many hepatitis that can be denied alcoholic liver disorder, viral hepatitis and drug-induced liver disorder are considered to be the pathological condition of NASH. Against the background of metabolic syndrome, the frequency of complications such as abnormal lipid metabolism, hypertension, diabetes, insulin resistance / glucose tolerance, obesity / obesity, etc. is very high. These diseases are caused by or related to NAFLD / NASH.
The treatment of NAFLD / NASH means that a compound having an Elovl6 inhibitory action of the present invention or a pharmaceutical composition containing the compound is administered to a NAFLD / NASH patient. When accompanied by the above complications, their treatment is the first priority treatment. In addition, improvement of NASH's important pathological conditions such as oxidative stress and insulin resistance can be mentioned as a result of treatment.
　また“糖尿病”とは、１型糖尿病（ＩＤＤＭ、インスリン依存性糖尿病として知られている）と２型糖尿病（ＮＩＤＤＭ、インスリン非依存性糖尿病として知られている）の両者を含む。 Also, “diabetes” includes both type 1 diabetes (IDDM, known as insulin-dependent diabetes) and type 2 diabetes (NIDDM, known as non-insulin-dependent diabetes).
　糖尿病は、空腹時血糖値が１２６ｍｇ／ｄｌ以上または随時血糖値もしくは７５ｇ経口ブドウ糖負荷試験（ＯＧＴＴ）２時間値が２００ｍｇ／ｄｌ以上を示す事を特徴とする。境界型である耐糖能障害とは、空腹時血糖値が１１０ｍｇ／ｄｌ以上１２６ｍｇ／ｄｌ未満である空腹時血糖異常（ＩＦＧ）、または７５ｇＯＧＴＴ２時間値が１４０ｍｇ／ｄｌ以上２００ｍｇ／ｄｌ未満である耐糖能異常（ＩＧＴ）をさす。 Diabetes is characterized by a fasting blood glucose level of 126 mg / dl or higher, or an occasional blood glucose level or a 75 g oral glucose tolerance test (OGTT) 2-hour value of 200 mg / dl or higher. Glucose intolerance, which is a boundary type, is a fasting blood glucose abnormality (IFG) in which a fasting blood glucose level is 110 mg / dl or more and less than 126 mg / dl, or a glucose tolerance having a 75 gOGTT 2 hour value of 140 mg / dl or more and less than 200 mg / dl. Indicates an abnormality (IGT).
　“インスリン抵抗性”とは、生体においてインスリンが血糖を降下させることが出来なくなった病態を指し、臨床において定量グルコースクランプ法やＨＯＭＡ－ＩＲにより評価される。インスリン抵抗性は高インスリン血症をきたし、高血圧症・冠動脈疾患のリスクとなることが知られている。 “Insulin resistance” refers to a pathological condition in which insulin is unable to lower blood sugar in a living body, and is clinically evaluated by a quantitative glucose clamp method or HOMA-IR. It is known that insulin resistance causes hyperinsulinemia and is a risk of hypertension and coronary artery disease.
　糖尿病の治療とは、本発明に係わる化合物または組成物を糖尿病患者に投与することを示す。治療の成果は、インスリン感受性を増加させ、上昇した血中インスリン及びグルコース濃度を低減させることにある。 Treatment of diabetes refers to administration of a compound or composition according to the present invention to a diabetic patient. The outcome of treatment is to increase insulin sensitivity and reduce elevated blood insulin and glucose levels.
　また“肥満症”とは、「肥満に起因ないし関連する健康障害を合併するか、その合併が予測される場合で、医学的に減量を必要とする病態」と日本肥満学会により定義されている。ここで定義される“肥満”とは、ＢＭＩ（身体質量指数、ｋｇ／ｍ２）により評価される。一般的にＢＭＩが２５以上を肥満と判断する。治療の成果として、ＢＭＩを軽減することが挙げられる。 “Obesity” is defined by the Japanese Society of Obesity as “a medical condition that is associated with or is predicted to be associated with obesity and is a medical condition that requires medical weight loss”. . “Obesity” as defined herein is evaluated by BMI (body mass index, kg / m 2 ). Generally, a BMI of 25 or more is determined to be obese. As a result of treatment, reduction of BMI can be mentioned.
［製剤例］
　以下に、本発明の医薬組成物の例を挙げる。 [Formulation example]
The following are examples of the pharmaceutical composition of the present invention.
製剤例１　錠剤
　　実施例２３の化合物　　　　　　　　　　１００ｇ
　　乳糖　　　　　　　　　　　　　　　　　１３７ｇ
　　結晶セルロース　　　　　　　　　　　　　３０ｇ
　　ヒドロキシプロピルセルロース　　　　　　１５ｇ
　　カルボキシメチルスターチナトリウム　　　１５ｇ
　　ステアリン酸マグネシウム　　　　　　　　　３ｇ
　上記成分を秤量した後，均一に混合する。この混合物を打錠して重量１５０mgの錠剤とする。 Formulation Example 1 Compound of Tablet Example 23 100 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.
製剤例２　フィルムコーティング
　　ヒドロキシプロピルメチルセルロース　　　　９ｇ
　　マクロゴール６０００　　　　　　　　　　　１ｇ
　　酸化チタン　　　　　　　　　　　　　　　　２ｇ
　上記成分を秤量した後，ヒドロキシプロピルメチルセルロース、マクロゴール６０００を水に溶解、酸化チタンを分散させる。この液を、製剤例１の錠剤３００ｇにフィルムコーティングし、フィルムコート錠を得る。 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.
製剤例３　カプセル剤
　　実施例５１の化合物　　　　　　　　　　　５０ｇ
　　乳糖　　　　　　　　　　　　　　　　　４３５ｇ
　　ステアリン酸マグネシウム　　　　　　　　１５ｇ
　上記成分を秤量した後、均一に混合する。混合物をカプセル封入器にて適当なハードカプセルに重量３００ｍｇずつ充填し、カプセル剤とする。 Formulation Example 3 Capsule Example 51 Compound 50 g
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.
製剤例４　カプセル剤
　　実施例１０１の化合物　　　　　　　　　１００ｇ
　　乳糖　　　　　　　　　　　　　　　　　　６３ｇ
　　トウモロコシデンプン　　　　　　　　　　２５ｇ
　　ヒドロキシプロピルセルロース　　　　　　１０ｇ
　　タルク　　　　　　　　　　　　　　　　　　２ｇ
　上記成分を秤量した後、実施例１０１の化合物、乳糖、トウモロコシデンプンを均一に混合し、ヒドロキシプロピルセルロースの水溶液を加え、湿式造粒法により顆粒を製造する。この顆粒にタルクを均一に混合し，適当なハードカプセルに重量２００mgずつ充填し，カプセル剤とする。 Formulation Example 4 Capsule Example 101 Compound 100 g
Lactose 63g
Corn starch 25g
Hydroxypropylcellulose 10g
Talc 2g
After weighing the above components, the compound of Example 101, 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 with the granules, and 200 mg in weight is filled into suitable hard capsules to form capsules.
製剤例５　散剤
　　実施例１１６の化合物　　　　　　　　　２００ｇ
　　乳糖　　　　　　　　　　　　　　　　　７９０ｇ
　　ステアリン酸マグネシウム　　　　　　　　１０ｇ
　上記成分をそれぞれ秤量した後、均一に混合し、２０％散剤とする。 Formulation Example 5 Compound of Powder Example 116 200 g
790 g of lactose
Magnesium stearate 10g
After weighing each of the above components, they are mixed uniformly to form a 20% powder.
製剤例６　顆粒剤、細粒剤
　　実施例１９４の化合物　　　　　　　　　１００ｇ
　　乳糖　　　　　　　　　　　　　　　　　２００ｇ
　　結晶セルロース　　　　　　　　　　　　１００ｇ
　　部分α化デンプン　　　　　　　　　　　　５０ｇ
　　ヒドロキシプロピルセルロース　　　　　　５０ｇ
　上記成分を秤量した後、実施例１９４の化合物、乳糖、結晶セルロース，部分α化デンプンを加えて均一に混合し、ヒドロキシプロピルセルロース（ＨＰＣ）の水溶液を加え、湿式造粒法により顆粒又は細粒を製造する。この顆粒又は細粒を乾燥し、顆粒剤又は細粒剤とする。 Formulation Example 6 Granules, Fine Granules Compound of Example 194 100 g
Lactose 200g
Crystalline cellulose 100g
Partially pregelatinized starch 50g
Hydroxypropylcellulose 50g
After weighing the above components, the compound of Example 194, lactose, crystalline cellulose, and partially pregelatinized starch were added and mixed uniformly, an aqueous solution of hydroxypropylcellulose (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.
製剤例７　クリーム剤
　実施例２０１の化合物　　　　　　　　　　　０．５ｇ
　酢酸ｄｌ－α－トコフェロール　　　　　　　０．１ｇ
　グリチルレチン酸ステアリル　　　　　　　　０．０５ｇ
　ステアリン酸　　　　　　　　　　　　　　　３ｇ
　高級アルコール　　　　　　　　　　　　　　１ｇ
　スクワラン　　　　　　　　　　　　　　　１０ｇ
　ミリスチン酸オクチルドデシル　　　　　　　３ｇ
　トリメチルグリシン　　　　　　　　　　　　７ｇ
　防腐剤　　　　　　　　　　　　　　　　　　適量
　けん化剤　　　　　　　　　　　　　　　　　適量
　上記成分を秤量した後、実施例２０１の化合物を混和して溶解する。精製水を適量加えて５０ｇにして、クリーム製剤とする。 Formulation Example 7 Cream Compound of Example 201 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 201 is mixed and dissolved. An appropriate amount of purified water is added to make 50 g to obtain a cream formulation.
　次に、本発明をさらに詳細に説明するために実施例をあげるが、本発明はこれに限定されるものではない。 Next, examples are given to describe the present invention in more detail, but the present invention is not limited thereto.
　次に、本発明をさらに詳細に説明するために実施例をあげるが、本発明はこれに限定されるものではない。
　核磁気共鳴スペクトル（ＮＭＲ）の測定には、ジェオールＪＮＭ－ＥＣＸ３００（ＪＥＯＬ　ＪＮＭ－ＥＣＸ３００）ＦＴ－ＮＭＲ（日本電子（株）製）、ジェオールＪＮＭ－ＥＣＸ４００（ＪＥＯＬ　ＪＮＭ－ＥＣＸ４００）ＦＴ－ＮＭＲ（日本電子（株）製）を用いた。ＬＣ ＭａｓｓはＷａｔｅｒｓ　ＦｒａｃｔｉｏｎＬｙｎｘ　ＭＳシステム（Ｗａｔｅｒｓ製）を用い、カラムにはＷａｔｅｒｓ製、ＳｕｎＦｉｒｅカラム（４．６ｍｍ×５ｃｍ、５μｍ）を、移動相にはアセトニトリル、０．０５％酢酸水溶液を用いて、アセトニトリル：０．０５％酢酸水溶液＝１：９（０分）～９：１（５分）～９：１（７．５分）のグラジエント条件を用いて分析した。ただし、実施例１１８、実施例１９１、実施例１９２、実施例２０７、実施例２０８、実施例２１１、実施例２１２、実施例２４９、実施例２６３及び実施例２６４は移動相にはメタノール、０．０５％酢酸水溶液を用いて、メタノール：０．０５％酢酸水溶液＝１：９（０分）～１０：０（５分）～１０：０（７分）のグラジエント条件を用いて分析した。 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 (Waters), Waters column, SunFire column (4.6 mm × 5 cm, 5 μm), mobile phase acetonitrile, 0.05% acetic acid aqueous solution, acetonitrile. : 0.05% acetic acid aqueous solution = 1: 9 (0 minutes) to 9: 1 (5 minutes) to 9: 1 (7.5 minutes). However, Example 118, Example 191, Example 192, Example 207, Example 208, Example 211, Example 212, Example 249, Example 263, and Example 264 are methanol in the mobile phase, 0. The analysis was performed using a 05% acetic acid aqueous solution and methanol: 0.05% acetic acid aqueous solution = 1: 9 (0 minutes) to 10: 0 (5 minutes) to 10: 0 (7 minutes).
（実施例１）Ｎ－（２－メトキシフェニル）－３－［（４－ヒドロキシ－１－ピペリジニル）スルホニル］ベンズアミド
＜工程１＞３－（クロロスルホニル）－Ｎ－（２－メトキシフェニル）べンズアミドの合成
　３－（クロロスルホニル）ベンゾイルクロリド（１．０ｇ）の塩化メチレン溶液（５．０ｍＬ）に、氷冷下ｏ－アニシジン（０．５ｍＬ）、トリエチルアミン（０．６ｍＬ）を加え１０分撹拌した。反応溶液に水を入れ酢酸エチルで抽出し、０．５規定塩酸、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をエ－テルで洗浄し、標記化合物（１．３ｇ）をベージュ色の固体として得た。 Example 1 N- (2-methoxyphenyl) -3-[(4-hydroxy-1-piperidinyl) sulfonyl] benzamide <Step 1> 3- (Chlorosulfonyl) -N- (2-methoxyphenyl) benzamide Synthesis of 3- (chlorosulfonyl) benzoyl chloride (1.0 g) in methylene chloride (5.0 mL) was added o-anisidine (0.5 mL) and triethylamine (0.6 mL) under ice-cooling and stirred for 10 minutes. . Water was added to the reaction solution, extracted with ethyl acetate, washed successively with 0.5N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was washed with ether to obtain the title compound (1.3 g) as a beige solid.
＜工程２＞Ｎ－（２－メトキシフェニル）－３－［（４－ヒドロキシ－１－ピペリジニル）スルホニル］ベンズアミドの合成
　実施例１＜工程１＞で得られた化合物（５０．０ｍｇ）の塩化メチレン溶液（１．０ｍＬ）に、氷冷下トリエチルアミン（２６μＬ）、４－ヒドロキシピペリジン（１６．３ｍｇ）を加え、室温で終夜撹拌した。反応溶液に水を入れ酢酸エチルで抽出し、０．５規定塩酸、０．５規定水酸化ナトリウム水溶液、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をＬＣ Ｍａｓｓで分取精製し、標記化合物（４４．０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -3-[(4-hydroxy-1-piperidinyl) sulfonyl] benzamide Example 1 Methylene chloride of the compound (50.0 mg) obtained in <Step 1> To the solution (1.0 mL) were added triethylamine (26 μL) and 4-hydroxypiperidine (16.3 mg) under ice cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate, washed successively with 0.5N hydrochloric acid, 0.5N aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by fractionation using LC Mass to obtain the title compound (44.0 mg) as a white solid.
（実施例２）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－オキソ－１－ピペリジニル）スルホニル］ベンズアミド
＜工程１＞２－クロロ－５－（クロロスルホニル）安息香酸の合成
　クロロスルホン酸（１０．６ｍＬ）に２－クロロ安息香酸（５．０ｇ）を加え、９５℃で４時間、室温で終夜撹拌した。氷水に反応液を入れ、沈殿した結晶を濾過し標記化合物（６．４ｇ）を白色固体として得た。 Example 2 N- (2-methoxyphenyl) -2-chloro-5-[(2-oxo-1-piperidinyl) sulfonyl] benzamide <Step 1> of 2-chloro-5- (chlorosulfonyl) benzoic acid Synthesis 2-Chlorobenzoic acid (5.0 g) was added to chlorosulfonic acid (10.6 mL), and the mixture was stirred at 95 ° C. for 4 hours and at room temperature overnight. The reaction solution was poured into ice water, and the precipitated crystals were filtered to obtain the title compound (6.4 g) as a white solid.
＜工程２＞Ｎ－（２－メトキシフェニル）－５－（クロロスルホニル）－２－クロロべンズアミドの合成
　実施例２＜工程１＞で得られた化合物（１．５ｇ）のトルエン溶液（５．０ｍＬ）に塩化チオニル（２．１ｍＬ）を加え、８０℃で５時間撹拌した。減圧下溶媒を留去して調製した２－クロロ－５－（クロロスルホニル）ベンゾイルクロリドを用いて、（実施例１）＜工程１＞の方法に準じて標記化合物（１．６ｇ）を淡いベージュ色の固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -5- (chlorosulfonyl) -2-chlorobenzamide Example 2 Toluene solution (1.5 g) of the compound (1.5 g) obtained in <Step 1>. 0 mL) was added with thionyl chloride (2.1 mL), and the mixture was stirred at 80 ° C. for 5 hours. Using 2-chloro-5- (chlorosulfonyl) benzoyl chloride prepared by distilling off the solvent under reduced pressure, the title compound (1.6 g) was pale beige according to the method of (Example 1) <Step 1>. Obtained as a colored solid.
＜工程３＞Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－オキソ－１－ピペリジニル）スルホニル］ベンズアミドの合成
　（実施例１）＜工程２＞に準ずる方法で、実施例２＜工程２＞で得られた化合物（１００．０ｍｇ）より標記化合物（３．３ｍｇ）を白色固体として得た。 <Step 3> Synthesis of N- (2-methoxyphenyl) -2-chloro-5-[(2-oxo-1-piperidinyl) sulfonyl] benzamide (Example 1) In the same manner as in <Step 2>, The title compound (3.3 mg) was obtained as a white solid from the compound (100.0 mg) obtained in 2 <Step 2>.
（実施例３）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－メチル－１－ピペリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（２２．６ｍｇ）を白色固体として得た。 (Example 3) N- (2-methoxyphenyl) -2-chloro-5-[(2-methyl-1-piperidinyl) sulfonyl] benzamide (Example 1) A method according to <Step 2> (Example 2) The title compound (22.6 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例４）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－ヒドロキシメチル－１－ピペリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（１５．２ｍｇ）を無色油状物質として得た。 (Example 4) N- (2-methoxyphenyl) -2-chloro-5-[(2-hydroxymethyl-1-piperidinyl) sulfonyl] benzamide (Example 1) Example 2) The title compound (15.2 mg) was obtained as a colorless oil from the compound (50.0 mg) obtained in <Step 2>.
（実施例５）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－アミノカルボニル－１－ピペリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（１１．８ｍｇ）を白色固体として得た。 (Example 5) N- (2-methoxyphenyl) -2-chloro-5-[(2-aminocarbonyl-1-piperidinyl) sulfonyl] benzamide (Example 1) Example 2) The title compound (11.8 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例６）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３－メチル－１－ピペリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（４２．４ｍｇ）を白色固体として得た。 (Example 6) N- (2-methoxyphenyl) -2-chloro-5-[(3-methyl-1-piperidinyl) sulfonyl] benzamide (Example 1) A method according to <Step 2> (Example 2) The title compound (42.4 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例７）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３－ヒドロキシ－１－ピペリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（３０．９ｍｇ）を白色固体として得た。 (Example 7) N- (2-methoxyphenyl) -2-chloro-5-[(3-hydroxy-1-piperidinyl) sulfonyl] benzamide (Example 1) According to the method of <Step 2>, (Example 2) The title compound (30.9 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例８）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３－アミノカルボニル－１－ピペリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（８．４ｍｇ）を白色固体として得た。 (Example 8) N- (2-methoxyphenyl) -2-chloro-5-[(3-aminocarbonyl-1-piperidinyl) sulfonyl] benzamide (Example 1) Example 2) The title compound (8.4 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例９）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３－ヒドロキシメチル－１－ピペリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（６．７ｍｇ）を白色固体として得た。 (Example 9) N- (2-methoxyphenyl) -2-chloro-5-[(3-hydroxymethyl-1-piperidinyl) sulfonyl] benzamide (Example 1) Example 2) The title compound (6.7 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例１０）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（３，５－ジメチル－１－ピペリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（７．９ｍｇ）を白色固体として得た。 (Example 10) N- (2-methoxyphenyl) -2-chloro-5-[(3,5-dimethyl-1-piperidinyl) sulfonyl] benzamide (Example 1) A method according to <Step 2> Example 2) The title compound (7.9 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例１１）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（２－（トリフルオロメチル）－１－ピロリジニル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（２７．０ｍｇ）を無色油状物質として得た。 (Example 11) N- (2-methoxyphenyl) -2-chloro-5-[(2- (trifluoromethyl) -1-pyrrolidinyl) sulfonyl] benzamide (Example 1) By a method according to <Step 2> (Example 2) The title compound (27.0 mg) was obtained as a colorless oily substance from the compound (50.0 mg) obtained in <Step 2>.
（実施例１２）Ｎ－（２－メトキシフェニル）－２－クロロ－５－［（ヘキサヒドロ－１Ｈ－アゼピン－１－イル）スルホニル］ベンズアミド
　（実施例１）＜工程２＞に準ずる方法で、（実施例２）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（４１．１ｍｇ）を白色固体として得た。 (Example 12) N- (2-methoxyphenyl) -2-chloro-5-[(hexahydro-1H-azepin-1-yl) sulfonyl] benzamide (Example 1) In a method according to <Step 2>, ( Example 2) The title compound (41.1 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例１３）Ｎ－（２－ヒドロキシフェニル）－２－クロロ－５－［（４－メチル－１－ピペリジニル）スルホニル］ベンズアミド
　２－クロロ－５－（クロロスルホニル）安息香酸（５０．０ｍｇ）の塩化メチレン溶液（２．０ｍＬ）に、氷冷下４－メチルピペリジン（１９．１μＬ）、トリエチルアミン（３０．１μＬ）を加え室温で終夜撹拌した。反応溶液に２－アミノフェノ－ル（２１．４ｍｇ）、ＷＳＣ－ＨＣｌ（４５．０ｍｇ）、１－ヒドロキシベンゾトリアゾール（３．２ｍｇ）を加え終夜撹拌した。減圧下溶媒を留去して得られた残渣をＬＣ Ｍａｓｓにより分取精製し、標記化合物（８．６ｍｇ）を白色固体として得た。 Example 13 N- (2-Hydroxyphenyl) -2-chloro-5-[(4-methyl-1-piperidinyl) sulfonyl] benzamide 2-chloro-5- (chlorosulfonyl) benzoic acid (50.0 mg) To a methylene chloride solution (2.0 mL) was added 4-methylpiperidine (19.1 μL) and triethylamine (30.1 μL) under ice cooling, and the mixture was stirred at room temperature overnight. To the reaction solution, 2-aminophenol (21.4 mg), WSC-HCl (45.0 mg) and 1-hydroxybenzotriazole (3.2 mg) were added and stirred overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by LC Mass to obtain the title compound (8.6 mg) as a white solid.
　（実施例１３）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１４）Ｎ－（２－メトキシフェニル）－３－（３－ペンチルアミノスルホニル）ベンズアミド
（実施例１５）Ｎ－フェニル－５－（４－モルホリニルスルホニル）－２，４－ジメトキシベンズアミド
（実施例１６）Ｎ－（２－エトキシフェニル）－５－（１－ピロリジニルスルホニル）－２－フルオロベンズアミド
（実施例１７）Ｎ－（４－メトキシフェニル）－５－（４－モルホリニルスルホニル）－２－（４－モルホリニル）ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 13).
(Example 14) N- (2-methoxyphenyl) -3- (3-pentylaminosulfonyl) benzamide (Example 15) N-phenyl-5- (4-morpholinylsulfonyl) -2,4-dimethoxybenzamide Example 16 N- (2-Ethoxyphenyl) -5- (1-pyrrolidinylsulfonyl) -2-fluorobenzamide (Example 17) N- (4-methoxyphenyl) -5- (4-morpholy Nylsulfonyl) -2- (4-morpholinyl) benzamide
（実施例１８）Ｎ－（２－メトキシフェニル）－２－ブロモ－５－（１－ピペリジニルスルホニル）ベンズアミド
　ｏ－アニシジン（１４０．０ｍｇ）の塩化メチレン溶液（４．０ｍＬ）に、室温で２－ブロモ－５－（１－ピペリジニルスルホニル）安息香酸（４００．０ｍｇ）、ＷＳＣ－ＨＣｌ（２３０．０ｍｇ）を加え終夜撹拌した。反応溶液に水を加え塩化メチレンで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をエ－テルでトリチュレ－トし、標記化合物（３５０．０ｍｇ）を淡桃色固体として得た。 Example 18 N- (2-methoxyphenyl) -2-bromo-5- (1-piperidinylsulfonyl) benzamide o-anisidine (140.0 mg) in methylene chloride solution (4.0 mL) at room temperature 2-Bromo-5- (1-piperidinylsulfonyl) benzoic acid (400.0 mg) and WSC-HCl (230.0 mg) were added and stirred overnight. Water was added to the reaction solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was triturated with ether to obtain the title compound (350.0 mg) as a pale pink solid.
（実施例１９）Ｎ－（２－メトキシフェニル）－２－メトキシ－５－（１－ピペリジニルスルホニル）ベンズアミド
　（実施例１８）で合成したＮ－（２－メトキシフェニル）－２－ブロモ－５－（１－ピペリジニルスルホニル）ベンズアミド（１００．０ｍｇ）に、８Ｍアンモニア－メタノール溶液（２．０ｍＬ）を加え、オートクレーブ中１２０℃で５時間撹拌した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝５０：５０～３０：７０）で精製し、標記化合物（１０．０ｍｇ）を白色固体として得た。 (Example 19) N- (2-methoxyphenyl) -2-methoxy-5- (1-piperidinylsulfonyl) benzamide N- (2-methoxyphenyl) -2-bromo- synthesized in Example 18 To 5- (1-piperidinylsulfonyl) benzamide (100.0 mg) was added 8M ammonia-methanol solution (2.0 mL), and the mixture was stirred at 120 ° C. for 5 hours in an autoclave. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 50: 50 to 30:70) to give the title compound (10.0 mg) as white Obtained as a solid.
（実施例２０）Ｎ－（２－メトキシフェニル）－２－（メチルアミノ）－５－（１－ピペリジニルスルホニル）ベンズアミド
　（実施例１８）で得られたＮ－（２－メトキシフェニル）－２－ブロモ－５－（１－ピペリジニルスルホニル）ベンズアミド（５０ｍｇ）に、メチルアミン（４０％メタノ－ル溶液、２．０ｍＬ）を加え、オートクレーブ中、１２０℃で４時間、室温で終夜撹拌した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝６０：４０～４０：６０）で精製し標記化合物（２１．０ｍｇ）を白色固体として得た。 Example 20 N- (2-Methoxyphenyl) -2- (methylamino) -5- (1-piperidinylsulfonyl) benzamide N- (2-methoxyphenyl)-obtained in Example 18 Methylamine (40% methanol solution, 2.0 mL) was added to 2-bromo-5- (1-piperidinylsulfonyl) benzamide (50 mg), and the mixture was stirred in an autoclave at 120 ° C. for 4 hours and at room temperature overnight. did. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 60: 40 to 40:60) to give the title compound (21.0 mg) as a white solid Got as.
（実施例２１）Ｎ－（２－メトキシフェニル）－２－［（フェニルメチル）アミノ］－５－（１－ピペリジニルスルホニル）ベンズアミド
　（実施例１８）で得られたＮ－（２－メトキシフェニル）－２－ブロモ－５－（１－ピペリジニルスルホニル）ベンズアミド（１００．０ｍｇ）にベンジルアミン（０．５ｍＬ）を加え、１３０℃で１時間撹拌した。反応溶液に１規定塩酸を加え酢酸エチルで抽出し、１規定塩酸で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をエ－テルに溶かし、１規定水酸化ナトリウム、水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をエ－テルでトリチュレ－トし標記化合物（８．０ｍｇ）を白色固体として得た。 (Example 21) N- (2-methoxyphenyl) -2-[(phenylmethyl) amino] -5- (1-piperidinylsulfonyl) benzamide N- (2-methoxy obtained in Example 18) Benzylamine (0.5 mL) was added to (phenyl) -2-bromo-5- (1-piperidinylsulfonyl) benzamide (100.0 mg), and the mixture was stirred at 130 ° C. for 1 hour. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in ether, washed with 1N sodium hydroxide and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was triturated with ether to obtain the title compound (8.0 mg) as a white solid.
（実施例２２）Ｎ－［４－（トリフルオロメトキシ）フェニル］－２－メチル－５－（１－ピペリジニルスルホニル）ベンズアミド
　（実施例１８）に準ずる方法で、２－メチル－５－（１－ピペリジニルスルホニル）安息香酸（１００．０ｍｇ）と４－（トリフルオロメトキシ）アニリン（４９．４μＬ）より、標記化合物（４１．８ｍｇ）を白色固体として得た。 (Example 22) N- [4- (trifluoromethoxy) phenyl] -2-methyl-5- (1-piperidinylsulfonyl) benzamide (Example 18) The title compound (41.8 mg) was obtained as a white solid from 1-piperidinylsulfonyl) benzoic acid (100.0 mg) and 4- (trifluoromethoxy) aniline (49.4 μL).
（実施例２３）Ｎ－（２－メトキシフェニル）－２－エテニル－５－（１－ピペリジニルスルホニル）ベンズアミド　
　（実施例１８）で得られたＮ－（２－メトキシフェニル）－２－ブロモ－５－（１－ピペリジニルスルホニル）ベンズアミド（６０．０ｍｇ）、カリウムビニルトリフルオロボレ－ト（１７．７ｍｇ）、酢酸パラジウム（４．７ｍｇ）、トリフェニルホスフィン（１３．９ｍｇ）、ジ－ｔｅｒｔ－ブチルフェノ－ル（１．０ｍｇ）のテトラヒドロフラン溶液（４．０ｍＬ）に１規定水酸化ナトリウム水溶液（０．７ｍＬ）を加え、アルゴン雰囲気下、６５℃で４時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝６０：４０～４０：６０）で精製し、標記化合物（４．０ｍｇ）を淡黄色固体として得た。 Example 23 N- (2-Methoxyphenyl) -2-ethenyl-5- (1-piperidinylsulfonyl) benzamide
N- (2-methoxyphenyl) -2-bromo-5- (1-piperidinylsulfonyl) benzamide (60.0 mg) obtained in (Example 18), potassium vinyl trifluoroborate (17.7 mg) ), Palladium acetate (4.7 mg), triphenylphosphine (13.9 mg), di-tert-butylphenol (1.0 mg) in tetrahydrofuran (4.0 mL) and 1N aqueous sodium hydroxide solution (0.7 mL). And stirred at 65 ° C. for 4 hours under an argon atmosphere. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, 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 = 60: 40 to 40:60), and the title compound (4.0 mg) was palely purified. Obtained as a yellow solid.
（実施例２４）Ｎ－（２－メトキシフェニル）－２－（３－ヒドロキシ－１－プロピン－１－イル）－５－（１－ピペリジニルスルホニル）ベンズアミド
　（実施例１８）で得られた化合物（５０．０ｍｇ）、テトラキストリフェニルホスフィンパラジウム（１２．７ｍｇ）、ヨウ化銅（１．１ｍｇ）、トリエチルアミン（１．０ｍＬ）のテトラヒドロフラン溶液（３．０ｍＬ）に、プロパルギルアルコ－ル（９．６μＬ）を加え、マイクロウェ－ブ反応装置を用いて反応（１２０℃，３０分）を行った。反応溶液をＬＣ ＭＡＳＳで分取精製し、標記化合物（１６．５ｍｇ）を無色アモルファスとして得た。 Example 24 Obtained with N- (2-methoxyphenyl) -2- (3-hydroxy-1-propyn-1-yl) -5- (1-piperidinylsulfonyl) benzamide (Example 18) To a solution of the compound (50.0 mg), tetrakistriphenylphosphine palladium (12.7 mg), copper iodide (1.1 mg), triethylamine (1.0 mL) in tetrahydrofuran (3.0 mL) was added propargyl alcohol (9. 6 μL) was added and the reaction was carried out using a microwave reactor (120 ° C., 30 minutes). The reaction solution was separated and purified by LC MASS to obtain the title compound (16.5 mg) as a colorless amorphous.
（実施例２５）Ｎ－（２－メトキシフェニル）－３－ヨード－５－（１－ピペリジニルスルホニル）－ベンズアミド
＜工程１＞５－（１－ピペリジニルスルホニル）イソフタル酸ジメチルエステルの合成
　５－（クロロスルホニル）イソフタル酸ジメチルエステル（２３．３ｇ）のテトラヒドロフラン溶液（５０．０ｍＬ）に、氷冷下ピペリジン（２２．７ｇ）を加え室温で４時間撹拌した。減圧下溶媒を留去した後、水を加え沈殿物を濾過し、標記化合物（２６．１ｇ）を白色固体として得た。 Example 25 N- (2-Methoxyphenyl) -3-iodo-5- (1-piperidinylsulfonyl) -benzamide <Step 1> Synthesis of 5- (1-piperidinylsulfonyl) isophthalic acid dimethyl ester Piperidine (22.7 g) was added to a tetrahydrofuran solution (50.0 mL) of 5- (chlorosulfonyl) isophthalic acid dimethyl ester (23.3 g) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. After evaporating the solvent under reduced pressure, water was added and the precipitate was filtered to obtain the title compound (26.1 g) as a white solid.
＜工程２＞５－メトキシカルボニル－３－（１－ピペリジニルスルホニル）安息香酸の合成
　（実施例２５）＜工程１＞で得られた化合物（７．０ｇ）のメタノ－ル溶液（７００．０ｍＬ）に、１規定水酸化ナトリウム水溶液（２０．５ｍＬ）を加え、加熱還流下３時間撹拌した。減圧下溶媒を留去した後、アセトンを加え沈殿物を濾過し、得られた固体を水に懸濁させた。懸濁液に濃塩酸を加え１時間撹拌した後、沈殿物を濾過し標記化合物（６．５ｇ）を白色固体として得た。 <Step 2> Synthesis of 5-methoxycarbonyl-3- (1-piperidinylsulfonyl) benzoic acid (Example 25) A methanol solution of the compound (7.0 g) obtained in <Step 1> (700. 0 mL) was added 1N aqueous sodium hydroxide solution (20.5 mL), and the mixture was stirred with heating under reflux for 3 hours. After the solvent was distilled off under reduced pressure, acetone was added and the precipitate was filtered, and the resulting solid was suspended in water. Concentrated hydrochloric acid was added to the suspension and stirred for 1 hour, and then the precipitate was filtered to obtain the title compound (6.5 g) as a white solid.
＜工程３＞５－（ｔｅｒｔ－ブトキシカルボニルアミノ）－３－（１－ピペリジニルスルホニル）安息香酸メチルの合成
　（実施例２５）＜工程２＞で得られた化合物（５００．０ｍｇ）のトルエン溶液（２０．０ｍＬ）にジフェニルホスホリルアジド（０．３６ｍＬ）、ｔｅｒｔ－ブチルアルコール（０．３ｍＬ）、トリエチルアミン（０．２３ｍＬ）を加え、固体が完全に溶解するまで撹拌した。１００℃で５時間撹拌し、反応溶液を水で洗浄した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝７０：３０～４０：６０）で精製し標記化合物（１１７ｍｇ）を無色アモルファスとして得た。 <Step 3> Synthesis of methyl 5- (tert-butoxycarbonylamino) -3- (1-piperidinylsulfonyl) benzoate (Example 25) Toluene of the compound (500.0 mg) obtained in <Step 2> To the solution (20.0 mL) were added diphenylphosphoryl azide (0.36 mL), tert-butyl alcohol (0.3 mL) and triethylamine (0.23 mL), and the mixture was stirred until the solid was completely dissolved. The mixture was stirred at 100 ° C. for 5 hours, and the reaction solution was washed with water. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 70: 30 to 40:60) to obtain the title compound (117 mg) as a colorless amorphous. It was.
＜工程４＞５－アミノ－３－（１－ピペリジニルスルホニル）安息香酸メチル塩酸塩の合成
　（実施例２５）＜工程３＞で得られた化合物（１２０．０ｍｇ）の酢酸エチル溶液（１．０ｍＬ）に、室温で４規定塩酸－酢酸エチル溶液（１．０ｍＬ）を加え終夜撹拌した。沈殿物を濾過し、酢酸エチルで洗浄して標記化合物（７６ｍｇ）を白色固体として得た。 <Step 4> Synthesis of methyl 5-amino-3- (1-piperidinylsulfonyl) benzoate hydrochloride (Example 25) Ethyl acetate solution (10.0 mg) of the compound (120.0 mg) obtained in <Step 3> 0 mL) was added 4N hydrochloric acid-ethyl acetate solution (1.0 mL) at room temperature and stirred overnight. The precipitate was filtered and washed with ethyl acetate to give the title compound (76 mg) as a white solid.
＜工程５＞３－ヨード－５－（１－ピペリジニルスルホニル）安息香酸メチルの合成
　（実施例２５）＜工程４＞で得られた化合物（７５．０ｍｇ）の２規定塩酸（２．０ｍＬ）懸濁液に、氷冷下、亜硝酸ナトリウム（１５．５ｍｇ）水溶液を加え、１時間撹拌した。この反応溶液を氷冷下、ヨウ化カリウム（７４．４ｍｇ）水溶液に滴下し、同温で１時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝８０：２０～６０：４０）で精製し、標記化合物（５２．０ｍｇ）を白色固体として得た。 <Step 5> Synthesis of methyl 3-iodo-5- (1-piperidinylsulfonyl) benzoate (Example 25) 2N hydrochloric acid (2.0 mL) of the compound (75.0 mg) obtained in <Step 4> ) An aqueous solution of sodium nitrite (15.5 mg) was added to the suspension under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was added dropwise to an aqueous solution of potassium iodide (74.4 mg) under ice cooling, and stirred at the same temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, 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 = 80: 20 to 60:40) to give the title compound (52.0 mg) as white Obtained as a solid.
＜工程６＞３－ヨード５－（１－ピペリジニルスルホニル）安息香酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２５）＜工程５＞で得られた化合物（５２．０ｍｇ）より、標記化合物（４９ｍｇ）を白色固体として得た。 <Step 6> Synthesis of 3-iodo 5- (1-piperidinylsulfonyl) benzoic acid (Example 25) A compound obtained in (Step 25) <Step 5> by the method according to <Step 2> From 52.0 mg), the title compound (49 mg) was obtained as a white solid.
＜工程７＞Ｎ－（２－メトキシフェニル）－３－ヨード５－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２５）＜工程６＞で得られた化合物（４９．０ｍｇ）より、標記化合物（４６ｍｇ）を白色固体として得た。 <Step 7> Synthesis of N- (2-methoxyphenyl) -3-iodo 5- (1-piperidinylsulfonyl) benzamide (Example 25), obtained in (Example 25) <Step 6> The title compound (46 mg) was obtained as a white solid from the obtained compound (49.0 mg).
（実施例２６）Ｎ－（２－メトキシフェニル）－５－（ジメチルアミノ）－３－（１－ピペリジニルスルホニル）ベンズアミド
＜工程１＞３－（クロロスルホニル）－５－ニトロ安息香酸の合成
　発煙硝酸（２．０ｍＬ）、濃硫酸（３．０ｍＬ）に、氷冷下３－（クロロスルホニル）安息香酸（１．０ｇ）を加え、室温で終夜撹拌し、さらに加熱還流下２時間撹拌した。反応溶液を氷水に入れトルエンで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣を再結晶（ヘキサン－ジエチルエーテル）し、標記化合物（７０ｍｇ）を淡黄色固体として得た。 Example 26 N- (2-Methoxyphenyl) -5- (dimethylamino) -3- (1-piperidinylsulfonyl) benzamide <Step 1> Synthesis of 3- (chlorosulfonyl) -5-nitrobenzoic acid 3- (Chlorosulfonyl) benzoic acid (1.0 g) was added to fuming nitric acid (2.0 mL) and concentrated sulfuric acid (3.0 mL) under ice-cooling, and the mixture was stirred overnight at room temperature, and further stirred for 2 hours with heating under reflux. . The reaction solution was placed in ice water, extracted with toluene, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was recrystallized (hexane-diethyl ether) to obtain the title compound (70 mg) as a pale yellow solid.
＜工程２＞５－ニトロ－３－（１－ピペリジニルスルホニル）安息香酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例２６）＜工程１＞で得られた化合物（７０．０ｍｇ）より標記化合物（８４．０ｍｇ）を黄色固体として得た。 <Step 2> Synthesis of 5-nitro-3- (1-piperidinylsulfonyl) benzoic acid (Example 25) In the same manner as in <Step 1>, the compound obtained in (Example 26) <Step 1> (70.0 mg) gave the title compound (84.0 mg) as a yellow solid.
＜工程３＞Ｎ－（２－メトキシフェニル）－５－ニトロ－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２６）＜工程２＞で得られた化合物（８４．０ｍｇ）より標記化合物（６７ｍｇ）を深緑色固体として得た。 <Step 3> Synthesis of N- (2-methoxyphenyl) -5-nitro-3- (1-piperidinylsulfonyl) benzamide (Example 18) According to (Example 26) <Step 2> The title compound (67 mg) was obtained as a deep green solid from the obtained compound (84.0 mg).
＜工程４＞Ｎ－（２－メトキシフェニル）－５－アミノ－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例２６）＜工程３＞で得られた化合物（６７．０ｍｇ）のメタノ－ル溶液（２．０ｍＬ）に、室温で１０％パラジウム－炭素（Ｐｄ／Ｃ）（７．０ｍｇ）を加え、水素ガス雰囲気下終夜撹拌した。触媒を除去後、ジエチルエ－テルでトリチュレ－トし、標記化合物（６０．０ｍｇ）を淡褐色固体として得た。 <Step 4> Synthesis of N- (2-methoxyphenyl) -5-amino-3- (1-piperidinylsulfonyl) benzamide (Example 26) Compound (67.0 mg) obtained in <Step 3> To a methanol solution (2.0 mL) was added 10% palladium-carbon (Pd / C) (7.0 mg) at room temperature, and the mixture was stirred overnight under a hydrogen gas atmosphere. After removing the catalyst, the product was triturated with diethyl ether to obtain the title compound (60.0 mg) as a light brown solid.
＜工程５＞Ｎ－（２－メトキシフェニル）－５－（ジメチルアミノ）－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　３６％ホルムアルデヒド水溶液（０．５ｍＬ）に濃硫酸（１９０．０ｍｇ）を加え、氷冷下、（実施例２６）＜工程４＞で得られた化合物（３０．０ｍｇ）のテトラヒドロフラン溶液（０．５ｍＬ）を滴下し、その後、水素化ホウ素ナトリウム（２９．２ｍｇ）を加え撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝５０：５０～２０：８０）で精製し、標記化合物（２８．０ｍｇ）を薄茶色固体として得た。 <Step 5> Synthesis of N- (2-methoxyphenyl) -5- (dimethylamino) -3- (1-piperidinylsulfonyl) benzamide 36% formaldehyde aqueous solution (0.5 mL) in concentrated sulfuric acid (190.0 mg) Under ice cooling, a tetrahydrofuran solution (0.5 mL) of the compound (30.0 mg) obtained in <Example 4><Step4> was added dropwise, and then sodium borohydride (29.2 mg) was added. Added and stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with water, 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 = 50: 50 to 20:80), and the title compound (28.0 mg) was diluted with light brown Obtained as a colored solid.
（実施例２７）Ｎ－（２－メトキシフェニル）－５－メチル－３－（１－ピペリジニルスルホニル）－ベンズアミド
＜工程１＞３－（クロロスルホニル）－５－メチル安息香酸の合成
　（実施例２）＜工程１＞に準ずる方法で，３－メチル安息香酸（４．０ｇ）より標記化合物（４．５ｇ）を褐色固体として得た。 Example 27 N- (2-Methoxyphenyl) -5-methyl-3- (1-piperidinylsulfonyl) -benzamide <Step 1> Synthesis of 3- (chlorosulfonyl) -5-methylbenzoic acid Example 2) The title compound (4.5 g) was obtained as a brown solid from 3-methylbenzoic acid (4.0 g) by a method according to <Step 1>.
＜工程２＞５－メチル－３－（１－ピペリジニルスルホニル）安息香酸の合成
　（実施例２５）＜工程１＞に準ずる方法で，（実施例２７）＜工程１＞で得られた化合物（４．５ｇ）より標記化合物（４．２ｇ）を淡褐色固体として得た。 <Step 2> Synthesis of 5-methyl-3- (1-piperidinylsulfonyl) benzoic acid (Example 25) A compound obtained in (Step 27) <Step 1> according to the method of <Step 1> (4.5 g) gave the title compound (4.2 g) as a light brown solid.
＜工程３＞Ｎ－（２－メトキシフェニル）－５－メチル－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２７）＜工程２＞で得られた化合物（３００．０ｍｇ）より標記化合物（４３．０ｍｇ）を白色固体として得た。 <Step 3> Synthesis of N- (2-methoxyphenyl) -5-methyl-3- (1-piperidinylsulfonyl) benzamide (Example 18), (Example 27) <Step 2> The title compound (43.0 mg) was obtained as a white solid from the obtained compound (300.0 mg).
（実施例２８）Ｎ－（２－メトキシフェニル）－３－（１－ピペリジニルスルホニル）－５－フェニルベンズアミド
　（実施例２５）＜工程７＞で得られたＮ－（２－メトキシフェニル）－３－ヨード５－（１－ピペリジニルスルホニル）ベンズアミド（２０．０ｍｇ）、フェニルボロン酸（９．８ｍｇ）、炭酸ナトリウム（３０．０ｍｇ）のトルエン－エタノ－ル溶液（１．５ｍＬ，２：１）に、アルゴン雰囲気下テトラキストリフェニルホスフィンパラジウム（３．０ｍｇ）を加え、加熱還流下４時間撹拌した。この反応溶液を氷冷下、ヨウ化カリウム（７４．４ｍｇ）水溶液に滴下し１時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝８０：２０～５０：５０）で精製し、標記化合物（１０．０ｍｇ）を白色固体として得た。 (Example 28) N- (2-methoxyphenyl) -3- (1-piperidinylsulfonyl) -5-phenylbenzamide (Example 25) N- (2-methoxyphenyl) obtained in <Step 7> -3-Iodo 5- (1-piperidinylsulfonyl) benzamide (20.0 mg), phenylboronic acid (9.8 mg), sodium carbonate (30.0 mg) in toluene-ethanol (1.5 mL, 2 1) was added tetrakistriphenylphosphine palladium (3.0 mg) under an argon atmosphere, and the mixture was stirred with heating under reflux for 4 hours. This reaction solution was added dropwise to an aqueous solution of potassium iodide (74.4 mg) under ice cooling and stirred for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, 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 = 80: 20 to 50:50) to give the title compound (10.0 mg) as a white Obtained as a solid.
（実施例２９）Ｎ－（２－メトキシフェニル）－５－（ヒドロキシメチル）－３－（１－ピペリジニルスルホニル）ベンズアミド
＜工程１＞５－（ヒドロキシメチル）－３－（１－ピペリジニルスルホニル）安息香酸メチルの合成
　（実施例２５）＜工程２＞で得られた化合物（２３０ｍｇ）のテトラヒドロフラン溶液（１．０ｍＬ）に、氷冷下１規定ボラン－テトラヒドロフラン錯体のテトラヒドロフラン溶液（３．０ｍＬ）を加え、同温で２時間撹拌した。反応溶液にメタノ－ル（１．０ｍＬ）を加え、さらに１時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、有機層を飽和炭酸ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、標記化合物（１６０ｍｇ）を無色の粘性物質として得た。 Example 29 N- (2-Methoxyphenyl) -5- (hydroxymethyl) -3- (1-piperidinylsulfonyl) benzamide <Step 1> 5- (Hydroxymethyl) -3- (1-piperidi Synthesis of methyl (nylsulfonyl) benzoate (Example 25) A tetrahydrofuran solution (1.0 mL) of the compound (230 mg) obtained in <Step 2> was added to a tetrahydrofuran solution (3. 0 mL) was added and stirred at the same temperature for 2 hours. Methanol (1.0 mL) was added to the reaction solution, and the mixture was further stirred for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (160 mg) as a colorless viscous substance.
＜工程２＞５－（ヒドロキシメチル）－３－（１－ピペリジニルスルホニル）安息香酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２９）＜工程１＞で得られた化合物（１５０．０ｍｇ）より標記化合物（１００．０ｍｇ）を無色の粘性物質として得た <Step 2> Synthesis of 5- (hydroxymethyl) -3- (1-piperidinylsulfonyl) benzoic acid (Example 25) In the same manner as <Step 2>, obtained in (Example 29) <Step 1> The title compound (100.0 mg) was obtained as a colorless viscous substance from the obtained compound (150.0 mg).
＜工程３＞Ｎ－（２－メトキシフェニル）－５－（ヒドロキシメチル）－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２９）＜工程２＞で得られた化合物（９０．０ｍｇ）より標記化合物（４７．０ｍｇ）を白色固体として得た。 <Step 3> Synthesis of N- (2-methoxyphenyl) -5- (hydroxymethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 29) <Step From the compound obtained in 2> (90.0 mg), the title compound (47.0 mg) was obtained as a white solid.
（実施例３０）Ｎ－（２－メトキシフェニル）－５－（１－ヒドロキシエチル）－３－（１－ピペリジニルスルホニル）ベンズアミド
＜工程１＞Ｎ－（２－メトキシフェニル）－５－ホルミル－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例２９）＜工程３＞で得られた化合物（５００．０ｍｇ）の塩化メチレン溶液（２０．０ｍＬ）に、室温で二酸化マンガン（１．１ｇ）を加え終夜撹拌した。反応液を濾過し、減圧下溶媒を留去して得られた固体をエ－テルでトリチュレ－トし、標記化合物（４１０．０ｍｇ）を白色固体として得た。 (Example 30) N- (2-methoxyphenyl) -5- (1-hydroxyethyl) -3- (1-piperidinylsulfonyl) benzamide <Step 1> N- (2-methoxyphenyl) -5-formyl Synthesis of -3- (1-piperidinylsulfonyl) benzamide (Example 29) To a methylene chloride solution (20.0 mL) of the compound (500.0 mg) obtained in <Step 3> was added manganese dioxide (1 0.1 g) was added and stirred overnight. The reaction solution was filtered and the solvent was distilled off under reduced pressure. The resulting solid was triturated with ether to obtain the title compound (410.0 mg) as a white solid.
＜工程２＞Ｎ－（２－メトキシフェニル）－５－（１－ヒドロキシエチル）－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例３０）＜工程１＞で得られた化合物（１００．０ｍｇ）のテトラヒドロフラン溶液（１．０ｍＬ）に、氷冷下メチルマグネシウムブロミドのテトラヒドロフラン溶液（１．０Ｍ、０．６ｍＬ）を加え室温で２時間撹拌した。反応溶液に１規定塩酸を加え酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝６０：４０）で精製し、標記化合物（６２．０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -5- (1-hydroxyethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 30) Compound obtained in <Step 1> A tetrahydrofuran solution (1.0 M, 0.6 mL) of methylmagnesium bromide was added to a tetrahydrofuran solution (1.0 mL) of 100.0 mg) under ice cooling, and the mixture was stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, 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 = 60: 40) to obtain the title compound (62.0 mg) as a white solid. .
（実施例３１）Ｎ－（２－メトキシフェニル）－５－エテニル－３－（１－ピペリジニルスルホニル）ベンズアミド
　（実施例３０）＜工程２＞で得られた化合物（３２．０ｍｇ）のトルエン溶液（２．０ｍＬ）に触媒量のｐ－トルエンスルホン酸を加え、加熱還流下６時間撹拌した。反応溶液をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝７０：３０～５０：５０）で精製し、標記化合物（８．０ｍｇ）を白色固体として得た。
  (Example 31) N- (2-methoxyphenyl) -5-ethenyl-3- (1-piperidinylsulfonyl) benzamide (Example 30) Toluene of the compound obtained in <Step 2> (32.0 mg) A catalytic amount of p-toluenesulfonic acid was added to the solution (2.0 mL), and the mixture was stirred with heating under reflux for 6 hours. The reaction solution was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 70: 30-50: 50) to obtain the title compound (8.0 mg) as a white solid.
（実施例３２）Ｎ－（２－メトキシフェニル）－５－シアノ－３－（１－ピペリジニルスルホニル）ベンズアミド
＜工程１＞Ｎ－（２－メトキシフェニル）－５－［（ヒドロキシイミノ）メチル］－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例３０）＜工程１＞で得られた化合物（２００．０ｍｇ）のエタノ－ル溶液（５．０ｍＬ）にヒドロキシアミン塩酸塩（１００．０ｍｇ）、酢酸ナトリウム（１２０．０ｍｇ）を加え、加熱還流下５時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して標記化合物（２３０．０ｍｇ）を無色アモルファスとして得た。 Example 32 N- (2-Methoxyphenyl) -5-cyano-3- (1-piperidinylsulfonyl) benzamide <Step 1> N- (2-Methoxyphenyl) -5-[(hydroxyimino) methyl Synthesis of 3- (1-piperidinylsulfonyl) benzamide (Example 30) Hydroxyamine hydrochloride (5.0 mL) was added to an ethanol solution (5.0 mL) of the compound (200.0 mg) obtained in <Step 1>. 100.0 mg) and sodium acetate (120.0 mg) were added, and the mixture was stirred with heating under reflux for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (230.0 mg) as a colorless amorphous.
＜工程２＞Ｎ－（２－メトキシフェニル）－５－シアノ－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例３２）＜工程１＞で得られた化合物（６０．０ｍｇ）の塩化メチレン溶液（２．０ｍＬ）に、室温で２－クロロ－１，３－ジメチルイミダゾリニウムクロリド（２９．０ｍｇ）、トリエチルアミン（５０．０μＬ）を加え２時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、有機層を水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝７０：３０～５０：５０）で精製し、標記化合物（２２．０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -5-cyano-3- (1-piperidinylsulfonyl) benzamide (Example 32) Compound (60.0 mg) obtained in <Step 1> To a methylene chloride solution (2.0 mL) were added 2-chloro-1,3-dimethylimidazolinium chloride (29.0 mg) and triethylamine (50.0 μL) at room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and then 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 = 70: 30 to 50:50) to give the title compound (22.0 mg) as white Obtained as a solid.
（実施例３３）Ｎ－（２－メトキシフェニル）－５－（メトキシメチル）－３－（１－ピペリジニルスルホニル）ベンズアミド
＜工程１＞Ｎ－（２－メトキシフェニル）－５－（クロロメチル）－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例３２）＜工程２＞に準ずる方法で、（実施例２９）＜工程３＞で得られた化合物（５００．０ｍｇ）より標記化合物（２５０．０ｍｇ）を白色固体として得た。 (Example 33) N- (2-methoxyphenyl) -5- (methoxymethyl) -3- (1-piperidinylsulfonyl) benzamide <Step 1> N- (2-methoxyphenyl) -5- (chloromethyl) ) Synthesis of 3- (1-piperidinylsulfonyl) benzamide (Example 32) In accordance with <Step 2>, the title was obtained from the compound (500.0 mg) obtained in (Example 29) <Step 3>. The compound (250.0 mg) was obtained as a white solid.
＜工程２＞Ｎ－（２－メトキシフェニル）－５－（メトキシメチル）－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例３３）＜工程１＞で得られた化合物（４０．０ｍｇ）のメタノ－ル溶液（１．０ｍＬ）にナトリウムメトキシド（２８％メタノ－ル溶液、０．１ｍＬ）を加え、室温で終夜、６０℃で４時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出液；ｎ－へキサン：酢酸エチル＝７０：３０～５０：５０）で精製し、標記化合物（２１．０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -5- (methoxymethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 33) The compound obtained in <Step 1> (40. Sodium methoxide (28% methanol solution, 0.1 mL) was added to a methanol solution (1.0 mL) of 0 mg), and the mixture was stirred at room temperature overnight and at 60 ° C. for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, 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 = 70: 30 to 50:50) to give the title compound (21.0 mg) as white Obtained as a solid.
（実施例３４）Ｎ－（２－メトキシフェニル）－５－［（アセチルアミノ）メチル］－３－（１－ピペリジニルスルホニル）ベンズアミド
＜工程１＞Ｎ－（２－メトキシフェニル）－５－（アミノメチル）－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例３２）＜工程１＞で合成した化合物（１８０．０ｍｇ）のエタノ－ル溶液（５．０ｍＬ）に、１規定塩酸（１０．０ｍＬ）、亜鉛（８５．０ｍｇ）を加え室温で２時間、７０℃で１時間撹拌した。亜鉛（２００．０ｍｇ）を再度加え、７０℃で２時間、室温で終夜撹拌した。反応溶液を濾過し、減圧下溶媒を留去して得られた残渣をメタノ－ルに溶解させ、１規定水酸化ナトリウムで塩基性にした。沈殿物を濾過して除去した後、減圧下溶媒を留去して得られた残渣を酢酸エチルに溶かし、水、１規定塩酸で順次洗浄した。水層を酢酸エチルで洗浄後、炭酸カリウムで塩基性に戻し、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して標記化合物（５２．０ｍｇ）を淡黄色固体として得た。 (Example 34) N- (2-methoxyphenyl) -5-[(acetylamino) methyl] -3- (1-piperidinylsulfonyl) benzamide <Step 1> N- (2-methoxyphenyl) -5- Synthesis of (Aminomethyl) -3- (1-piperidinylsulfonyl) benzamide (Example 32) 1 N in an ethanol solution (5.0 mL) of the compound (180.0 mg) synthesized in <Step 1> Hydrochloric acid (10.0 mL) and zinc (85.0 mg) were added, and the mixture was stirred at room temperature for 2 hours and at 70 ° C. for 1 hour. Zinc (200.0 mg) was added again and stirred at 70 ° C. for 2 hours and at room temperature overnight. The reaction solution was filtered, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methanol and made basic with 1N sodium hydroxide. After removing the precipitate by filtration, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed successively with water and 1N hydrochloric acid. The aqueous layer was washed with ethyl acetate, made basic with potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (52.0 mg) as a pale yellow solid.
＜工程２＞Ｎ－（２－メトキシフェニル）－５－［（アセチルアミノ）メチル）］－３－（１－ピペリジニルスルホニル）ベンズアミドの合成
　（実施例３４）＜工程１＞で合成した化合物（２０．０ｍｇ）のピリジン溶液（０．５ｍＬ）に無水酢酸（３滴）を加え、室温で３時間撹拌した。その後、水（５ｍＬ）を加え、さらに終夜撹拌した。反応溶液に水を加え酢酸エチルで抽出し、水、１規定塩酸で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をエ－テルでトリチュレ－トし、標記化合物（１３．０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -5-[(acetylamino) methyl)]-3- (1-piperidinylsulfonyl) benzamide (Example 34) Compound synthesized in <Step 1> Acetic anhydride (3 drops) was added to a pyridine solution (0.5 mL) of (20.0 mg), and the mixture was stirred at room temperature for 3 hours. Then, water (5 mL) was added and further stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed successively with water and 1N hydrochloric acid, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was triturated with ether to obtain the title compound (13.0 mg) as a white solid.
（実施例３５）Ｎ－（２－メトキシフェニル）－５－［（ジメチルアミノ）メチル］－３－（１－ピペリジニルスルホニル）ベンズアミド
　ジメチルアミン－テトラヒドロフラン溶液（２．０Ｍ、１．０ｍＬ）に、氷冷下（実施例３３）＜工程１＞で合成した化合物（３０．０ｍｇ）加え、室温で終夜撹拌した。反応溶液に水を加え酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をエ－テルでトリチュレ－トし、標記化合物（２２．０ｍｇ）を白色固体として得た。 Example 35 N- (2-methoxyphenyl) -5-[(dimethylamino) methyl] -3- (1-piperidinylsulfonyl) benzamide In a dimethylamine-tetrahydrofuran solution (2.0 M, 1.0 mL) Under ice-cooling (Example 33), the compound synthesized in <Step 1> (30.0 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was triturated with ether to obtain the title compound (22.0 mg) as a white solid.
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例３６）Ｎ－（４－メトキシフェニル）－４－クロロ－３－（４－モルホリニルスルホニル）ベンズアミド
（実施例３７）Ｎ－（２－ピリジニル）－４－ブロモ－３－（１－ピペリジニルスルホニル）ベンズアミド
（実施例３８）Ｎ－（４－エトキシフェニル）－４－フルオロ－３－（１－ピペリジニルスルホニル）ベンズアミド
（実施例３９）Ｎ－（４－メトキシフェニル）－４－メトキシ－３－（４－モルホニルスルホニル）ベンズアミド
（実施例４０）Ｎ－［２－［［（４－クロロフェニル）アミノ］カルボニル］フェニル］－４－メチル－３－（４－モルホリニルスルホニル）ベンズアミド
（実施例４１）Ｎ－（２，６－ジメチルフェニル）－２－フルオロ－５－（１－ピペリジニルスルホニル）ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 36 N- (4-Methoxyphenyl) -4-chloro-3- (4-morpholinylsulfonyl) benzamide (Example 37) N- (2-pyridinyl) -4-bromo-3- (1 -Piperidinylsulfonyl) benzamide (Example 38) N- (4-Ethoxyphenyl) -4-fluoro-3- (1-piperidinylsulfonyl) benzamide (Example 39) N- (4-methoxyphenyl)- 4-Methoxy-3- (4-morpholinylsulfonyl) benzamide (Example 40) N- [2-[[(4-Chlorophenyl) amino] carbonyl] phenyl] -4-methyl-3- (4-morpholine Nylsulfonyl) benzamide (Example 41) N- (2,6-dimethylphenyl) -2-fluoro-5- (1-piperidinylsulfonyl) benzamide
　（実施例１３）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例４２）Ｎ－［２－ヒドロキシ－４－（トリフルオロメチル）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例４３）Ｎ－［２－（４－モルホリニル）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例４４）Ｎ－［２－（１－メチルエチル）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例４５）Ｎ－［（２－アミノカルボニル）フェニル］－３－（１－ピロリジニルスルホニル）ベンズアミド
（実施例４６）Ｎ－［２’－メトキシ［１，１’－ビフェニル］－２－イル］－３－（１－ピロリジニルスルホニル）ベンズアミド
（実施例４７）Ｎ－［（３－ピリジニル）フェニル－２－イル］－３－（１－ピロリジニルスルホニル）ベンズアミド
（実施例４８）Ｎ－（４－ヒドロキシフェニル）－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例４９）Ｎ－［４－（トリフルオロメトキシ）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例５０）Ｎ－［４－（４－モルホリニル）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例５１）Ｎ－［４－（１－メチルエチル）フェニル］－３－（１－ピロリジニルスルホニル）ベンズアミド
（実施例５２）Ｎ－（４－カルボキシフェニル）－３－（１－ピペリジニルスルホニル）ベンズアミド
（実施例５３）Ｎ－［３－［（１－メチルエチル）オキシ］フェニル］－３－（１－ピロリジニルスルホニル）ベンズアミド
（実施例５４）Ｎ－［３－（トリフルオロメチル）フェニル］－３－（１－ピペリジニルスルホニル）ベンズアミド
（実施例５５）Ｎ－［３－［（シクロプロピルアミノ）カルボニル］フェニル］－３－（１－ピロリジニルスルホニル）ベンズアミド
（実施例５６）Ｎ－［（１，３－ベンゾジオキソ－ル－５－イル）メチル］－３－（１－ピロリジニルスルホニル）ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 13).
Example 42 N- [2-Hydroxy-4- (trifluoromethyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 43) N- [2- (4- Morpholinyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 44) N- [2- (1-methylethyl) phenyl] -2-chloro-5- (1-piperidi) Nylsulfonyl) benzamide (Example 45) N-[(2-aminocarbonyl) phenyl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 46) N- [2′-methoxy [1,1′- Biphenyl] -2-yl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 47) N-[(3-pyridinyl) phenyl-2-yl] -3- (1-pyrrolidinylsulfo ) Benzamide (Example 48) N- (4-hydroxyphenyl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 49) N- [4- (trifluoromethoxy) phenyl]- 2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 50) N- [4- (4-morpholinyl) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example Example 51) N- [4- (1-methylethyl) phenyl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 52) N- (4-carboxyphenyl) -3- (1-piperidinyl) Sulfonyl) benzamide (Example 53) N- [3-[(1-Methylethyl) oxy] phenyl] -3- (1-pyrrolidinylsulfonyl) benzamide (Example 54) N- [3- (trifluoromethyl) phenyl] -3- (1-piperidinylsulfonyl) benzamide (Example 55) N- [3-[(cyclopropylamino) carbonyl] phenyl] -3- ( 1-Pyrrolidinylsulfonyl) benzamide (Example 56) N-[(1,3-Benzodioxo-5-yl) methyl] -3- (1-pyrrolidinylsulfonyl) benzamide
（実施例５７）２－クロロ－５－（１－ピペリジニルスルホニル）－Ｎ－（２－メトキシフェニル）ベンゼンメタンアミン
　Ｎ－（２－メトキシフェニル）－５－（１－ピペリジニルスルホニル）－２－クロロベンズアミド（５０．０ｍｇ）のテトラヒドロフラン溶液（０．５ｍＬ）に、氷冷下ボラン－テトラヒドロフラン錯体のテトラヒドロフラン溶液（１．０Ｍ，０．６ｍＬ）を加え、室温で３０分撹拌した。さらにボラン－テトラヒドロフラン（１Ｍテトラヒドロフラン溶液、０．３ｍＬ）を加え加熱還流下１時間撹拌した。反応溶液に１規定塩酸を加え、５０℃で１時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、１規定水酸化ナトリウム水溶液、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をＬＣ Ｍａｓｓにより分取精製し、標記化合物（１１．９ｍｇ）を無色油状物質として得た。 Example 57 2-Chloro-5- (1-piperidinylsulfonyl) -N- (2-methoxyphenyl) benzenemethanamine N- (2-methoxyphenyl) -5- (1-piperidinylsulfonyl) A tetrahydrofuran solution (1.0 M, 0.6 mL) of borane-tetrahydrofuran complex was added to a tetrahydrofuran solution (0.5 mL) of -2-chlorobenzamide (50.0 mg) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Further, borane-tetrahydrofuran (1M tetrahydrofuran solution, 0.3 mL) was added, and the mixture was stirred for 1 hour with heating under reflux. 1N Hydrochloric acid was added to the reaction solution, and the mixture was stirred at 50 ° C. for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed successively with 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by LC Mass to obtain the title compound (11.9 mg) as a colorless oil.
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミン、および前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例５８）Ｎ－シクロヘキシル－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例５９）Ｎ－（１，２，３，４－テトラヒドロナフタレン－１－イル）－３－（１－ピペリジニルスルホニル）ベンズアミド
（実施例６０）［３，６－ジヒドロ－４－フェニル－１（２Ｈ）－ピリジニル］－［３－（１－ピペリジニルスルホニル）フェニル］メタノン
（実施例６１）Ｎ－（ベンズイミダゾ－ル－２－イル）－３－（１－ピペリジニルスルホニル）ベンズアミド
（実施例６２）Ｎ－［３－（１－ピペリジニルスルホニル）フェニル］－２－メトキシベンズアミド By the method according to Example 18, the following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1).
(Example 58) N-cyclohexyl-2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 59) N- (1,2,3,4-tetrahydronaphthalen-1-yl) -3- (1-Piperidinylsulfonyl) benzamide (Example 60) [3,6-Dihydro-4-phenyl-1 (2H) -pyridinyl]-[3- (1-piperidinylsulfonyl) phenyl] methanone (Example 61) N- (Benzimidazol-2-yl) -3- (1-piperidinylsulfonyl) benzamide (Example 62) N- [3- (1-piperidinylsulfonyl) phenyl] -2-methoxy Benzamide
（実施例６３）Ｎ－（２－メトキシフェニル）－６－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－１Ｈ－インデン－４－カルボキシアミド
＜工程１＞６－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－１Ｈ－インデン－４－カルボン酸
　（実施例２５）＜工程１＞に準ずる方法で、ドイツ公開第７５／２５２０６４４号パンフレットに記載の方法に従い合成した２，３－ジヒドロ－１Ｈ－インデン－６－（クロロスルホニル）－４－カルボン酸（１２０．０ｍｇ）より、標記化合物（６３．０ｍｇ）を茶色固体として得た。 Example 63 N- (2-methoxyphenyl) -6- (1-piperidinylsulfonyl) -2,3-dihydro-1H-indene-4-carboxamide <Step 1> 6- (1-Piperidy Nylsulfonyl) -2,3-dihydro-1H-indene-4-carboxylic acid (Example 25) 2,3 synthesized according to the method described in <Patent Step 1> according to the method described in German Offenlegungsschrift 75/2520644 -Dihydro-1H-indene-6- (chlorosulfonyl) -4-carboxylic acid (120.0 mg) gave the title compound (63.0 mg) as a brown solid.
＜工程２＞Ｎ－（２－メトキシフェニル）－６－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－１Ｈ－インデン－４－カルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例６３）＜工程１＞で得られた化合物（５０．０ｍｇ）より標記化合物（３１ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -6- (1-piperidinylsulfonyl) -2,3-dihydro-1H-indene-4-carboxamide (Example 18) Example 63 The title compound (31 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 1>.
（実施例６４）Ｎ－（２－メトキシフェニル）－３－（１－ピペリジニルスルホニル）－５，６，７，８－テトラヒドロ－１－ナフタレンカルボキシアミド
＜工程１＞３－（１－ピペリジニルスルホニル）－５，６，７，８－テトラヒドロ－１－ナフタレンカルボン酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、ドイツ公開第７５／２５２０６４４号パンフレットに記載の方法に従い合成した３－（クロロスルホニル）－５，６，７，８－テトラヒドロ－１－ナフタレンカルボン酸（１４０．０ｍｇ）より、標記化合物（１７０．０ｍｇ）を褐色の粘性物質として得た。 Example 64 N- (2-methoxyphenyl) -3- (1-piperidinylsulfonyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxamide <Step 1> 3- (1-Pi Synthesis of (peridinylsulfonyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (Example 25) According to the method described in <Step 1> and synthesized according to the method described in German pamphlet No. 75/252644. The title compound (170.0 mg) was obtained as a brown viscous substance from 3- (chlorosulfonyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (140.0 mg).
＜工程２＞Ｎ－（２－メトキシフェニル）－３－（１－ピペリジニルスルホニル）－５，６，７，８－テトラヒドロ－１－ナフタレンカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例６４）＜工程１＞で得られた化合物（１６０．０ｍｇ）より標記化合物（２３．０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -3- (1-piperidinylsulfonyl) -5,6,7,8-tetrahydro-1-naphthalenecarboxamide (Method 18) (Example 64) The title compound (23.0 mg) was obtained as a white solid from the compound (160.0 mg) obtained in <Step 1>.
（実施例６５）Ｎ－[４－（トリフルオロメトキシ）フェニル]－６－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－３－メチル－１Ｈ－インデン－４－カルボキシアミド
＜工程１＞２－（２－カルボキシ－１－メチルエテニル）安息香酸の合成
　ジャーナル・オブ・メディシナル・ケミストリー（Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ），２６，１７６４－１７６６，１９９６年に記載の方法に従い合成したエチル　２－（１，３－ジヒドロ－１－メチル－３－オキソイソベンゾフラン－１－イル）酢酸（６００．０ｍｇ）のメタノール溶液（１０．０ｍＬ）に、１規定水酸化ナトリウム水溶液（１０．０ｍＬ）を入れ加熱還流下４時間撹拌した。減圧下溶媒を留去し１規定塩酸を加えた後、沈殿物を濾過した。得られた固体を酢酸エチルに溶解させ、水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し標記化合物（４３０．０ｍｇ、Ｅ：Ｚ＝３：１）を淡黄色固体として得た。 Example 65 N- [4- (trifluoromethoxy) phenyl] -6- (1-piperidinylsulfonyl) -2,3-dihydro-3-methyl-1H-indene-4-carboxamide <Step 1 > Synthesis of 2- (2-carboxy-1-methylethenyl) benzoic acid Ethyl synthesized according to the method described in Journal of Medicinal Chemistry, 26, 1764-1766, 1996 2- (1 , 3-Dihydro-1-methyl-3-oxoisobenzofuran-1-yl) acetic acid (600.0 mg) in methanol (10.0 mL) was charged with 1N aqueous sodium hydroxide (10.0 mL) and heated to reflux. Stir for 4 hours. After evaporating the solvent under reduced pressure and adding 1N hydrochloric acid, the precipitate was filtered. The obtained solid was dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (430.0 mg, E: Z = 3: 1) as a pale yellow solid.
＜工程２＞３－（２－カルボキシフェニル）酪酸の合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例６５）＜工程１＞で得られた化合物（３００．０ｍｇ）より標記化合物（２８０．０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of 3- (2-carboxyphenyl) butyric acid (Example 26) In the same manner as <Step 4>, the title was obtained from the compound (300.0 mg) obtained in (Example 65) <Step 1>. The compound (280.0 mg) was obtained as a white solid.
＜工程３＞２，３－ジヒドロ－３－メチル－１－オキソ－１Ｈ－インデン－４－カルボン酸の合成
　（実施例６５）＜工程２＞で得られた化合物（２８０．０ｍｇ）、塩化ナトリウム（９０．０ｍｇ）に、塩化アルミニウム（９００．０ｍｇ）を加え、１５０℃で４時間加熱した。混合物に氷冷した１規定塩酸を加え固体を沈殿させ酢酸エチルで抽出し、水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し得られた残渣をジエチルエーテルでトリチュレートすることで標記化合物（１００．０ｍｇ）を淡褐色固体として得た。 <Step 3> Synthesis of 2,3-dihydro-3-methyl-1-oxo-1H-indene-4-carboxylic acid (Example 65) Compound (280.0 mg) obtained in <Step 2>, sodium chloride (90.0 mg) was added with aluminum chloride (900.0 mg) and heated at 150 ° C. for 4 hours. 1N hydrochloric acid cooled with ice was added to the mixture to precipitate a solid, which was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was triturated with diethyl ether to obtain the title compound (100.0 mg) as a light brown solid.
＜工程４＞２，３－ジヒドロ－１－ヒドロキシ－３－メチル－１Ｈ－インデン－４－カルボン酸の合成
　（実施例６５）＜工程３＞で得られた化合物（１００．０ｍｇ）のメタノール溶液（５．０ｍＬ）に、室温で水素化ホウ素ナトリウムを加え終夜撹拌した。反応溶液に１規定塩酸を加え酸性にし酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して標記粗化合物（１００．０ｍｇ）を淡褐色固体として得た。 <Step 4> Synthesis of 2,3-dihydro-1-hydroxy-3-methyl-1H-indene-4-carboxylic acid (Example 65) Methanol solution of the compound (100.0 mg) obtained in <Step 3> (5.0 mL) was added sodium borohydride at room temperature and stirred overnight. The reaction solution was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (100.0 mg) as a light brown solid.
＜工程５＞２，３－ジヒドロ－３－メチル－１Ｈ－インデン－４－カルボン酸の合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例６５）＜工程４＞で得られた粗化合物（１００．０ｍｇ）より標記化合物（９１．０ｍｇ）を白色固体として得た。 <Step 5> Synthesis of 2,3-dihydro-3-methyl-1H-indene-4-carboxylic acid (Example 26) A method similar to <Step 4>, obtained in (Example 65) <Step 4>. The crude compound (100.0 mg) gave the title compound (91.0 mg) as a white solid.
＜工程６＞６－（クロロスルホニル）－２，３－ジヒドロ－３－メチル－１Ｈ－インデン－４－カルボン酸の合成
　（実施例６５）＜工程５＞で得られた化合物（９０．０ｍｇ）にクロロスルホン酸（１．０ｍＬ）を加え、１００℃で４時間撹拌した。反応溶液を氷水にあけ、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し標記化合物（１２０．０ｍｇ）を淡褐色固体として得た。 <Step 6> Synthesis of 6- (chlorosulfonyl) -2,3-dihydro-3-methyl-1H-indene-4-carboxylic acid (Example 65) Compound obtained in <Step 5> (90.0 mg) To the mixture, chlorosulfonic acid (1.0 mL) was added, and the mixture was stirred at 100 ° C. for 4 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (120.0 mg) as a light brown solid.
＜工程７＞６－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－３－メチル－１Ｈ－インデン－４－カルボン酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例６５）＜工程６＞で得られた化合物（１２０．０ｍｇ）より標記化合物（５４．０ｍｇ）を淡褐色固体として得た。 <Step 7> Synthesis of 6- (1-piperidinylsulfonyl) -2,3-dihydro-3-methyl-1H-indene-4-carboxylic acid (Example 25) In the same manner as in <Step 1>, ( Example 65 The title compound (54.0 mg) was obtained as a pale-brown solid from the compound (120.0 mg) obtained in <Step 6>.
＜工程８＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－６－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－３－メチル－１Ｈ－インデン－４－カルボキシアミドの合成
　（実施例６５）＜工程７＞で得られた化合物（２５．０ｍｇ）を用いて、（実施例１８）に準じる方法により標記化合物（１８．０ｍｇ）を白色固体として得た。 <Step 8> Synthesis of N- [4- (trifluoromethoxy) phenyl] -6- (1-piperidinylsulfonyl) -2,3-dihydro-3-methyl-1H-indene-4-carboxamide Example 65) The title compound (18.0 mg) was obtained as a white solid by the method according to (Example 18) using the compound (25.0 mg) obtained in <Step 7>.
（実施例６６）Ｎ－（２－メトキシフェニル）－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミド
＜工程１＞１，２，３，４－テトラヒドロイソキノリン－５－カルボン酸メチルエステルの合成
　イソキノリン－５－カルボン酸メチルエステル（３．１ｇ）のテトラヒドロフラン溶液（６０．０ｍＬ）に、氷冷下にて２規定塩酸（４０．９ｍＬ）、シアノ水素化ホウ素ナトリウム（５．１ｇ）を加え０℃で１時間撹拌した。反応溶液に飽和炭酸水素ナトリウム溶液を加え酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝５０：５０）で精製し、標記化合物（２．２ｇ）を得た。 (Example 66) N- (2-methoxyphenyl) -7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide <Step 1> 1,2,3 Synthesis of 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester To a tetrahydrofuran solution (60.0 mL) of isoquinoline-5-carboxylic acid methyl ester (3.1 g) was added 2N hydrochloric acid (40.9 mL) under ice-cooling, Sodium cyanoborohydride (5.1 g) was added and stirred at 0 ° C. for 1 hour. A saturated sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with water, 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 = 50: 50) to obtain the title compound (2.2 g).
＜工程２＞２－（トリフルオロアセチル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボン酸メチルエステルの合成
　（実施例６６）＜工程１＞で得られた化合物（２．２ｇ）、トリエチルアミン（６．３ｍＬ）の塩化メチレン溶液（４０．０ｍＬ）に、氷冷下無水トリフルオロ酢酸（３．５ｍＬ）を加え室温で３時間撹拌した。反応溶液に０．５規定塩酸を加え塩化メチレンで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝９０：１０）で精製し、標記化合物（２．４ｇ）を白色固体として得た。 <Step 2> Synthesis of 2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid methyl ester (Example 66) Compound obtained in <Step 1> (2.2 g) To a methylene chloride solution (40.0 mL) of triethylamine (6.3 mL) was added trifluoroacetic anhydride (3.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. 0.5N Hydrochloric acid was added to the reaction solution, the mixture was extracted with methylene chloride, 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 = 90: 10) to obtain the title compound (2.4 g) as a white solid. .
＜工程３＞７－（クロロスルホニル）－２－（トリフルオロアセチル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボン酸の合成
　クロロスルホン酸（８．３ｍＬ）に、氷冷下（実施例６６）＜工程２＞で得られた化合物（２．４ｇ）を加え、１００℃まで昇温し２時間撹拌した。反応溶液を氷水にあけ、析出した固体を濾取し減圧乾燥して標記化合物（３．２ｇ）を褐色固体として得た。 <Step 3> Synthesis of 7- (chlorosulfonyl) -2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid To chlorosulfonic acid (8.3 mL) under ice-cooling ( Example 66) The compound obtained in <Step 2> (2.4 g) was added, and the temperature was raised to 100 ° C. and stirred for 2 hours. The reaction solution was poured into ice water, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (3.2 g) as a brown solid.
＜工程４＞７－（１－ピペリジニルスルホニル）－２－（トリフルオロアセチル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボン酸の合成
　（実施例６６）＜工程３＞で得られた化合物（１．９ｇ）を用いて、（実施例２５）＜工程１＞に準じる方法により標記化合物（１．６ｇ）を褐色固体として得た。 <Step 4> Synthesis of 7- (1-piperidinylsulfonyl) -2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (Example 66) In <Step 3> Using the obtained compound (1.9 g), the title compound (1.6 g) was obtained as a brown solid by a method according to (Example 25) <Step 1>.
＜工程５＞Ｎ－（２－メトキシフェニル）－７－（１－ピペリジニルスルホニル）－２－（トリフルオロアセチル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例６６）＜工程４＞で得られた化合物（１．０ｇ）より標記化合物（１．２ｇ）を白色固体として得た。 <Step 5> Synthesis of N- (2-methoxyphenyl) -7- (1-piperidinylsulfonyl) -2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide In the same manner as in Example 18), the title compound (1.2 g) was obtained as a white solid from the compound (1.0 g) obtained in (Example 66) <Step 4>.
＜工程６＞Ｎ－（２－メトキシフェニル）－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミドの合成
　（実施例６６）＜工程５＞で得られた化合物（１．２ｇ）のメタノール懸濁液（２５．０ｍＬ）に、室温で炭酸カリウム（１．３ｇ）を加え３時間撹拌した。反応溶液を減圧留去し得られた残渣を水に溶かし、塩化メチレンで抽出した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：塩化メチレン＝２０：８０）で精製し、標記化合物（０．４０ｇ）を無色アモルファスとして得た。 <Step 6> Synthesis of N- (2-methoxyphenyl) -7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 66) <Step 5> To a methanol suspension (25.0 mL) of the compound (1.2 g) obtained in 1 above, potassium carbonate (1.3 g) was added at room temperature and stirred for 3 hours. The residue obtained by evaporating the reaction solution under reduced pressure was dissolved in water, extracted with methylene chloride, 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: methylene chloride = 20: 80) to obtain the title compound (0.40 g) as a colorless amorphous product. .
（実施例６７）Ｎ－（２－メトキシフェニル）－２－メチルスルホニル－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミド
　（実施例６６）＜工程６＞で合成した化合物（５０．０ｍｇ）、ジイソプロピルエチルアミン（２４μＬ）の塩化メチレン溶液（１．０ｍＬ）に、室温でメタンスルホニルクロリドを加え２時間撹拌した。反応溶液に１規定塩酸を加え塩化メチレンで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣を酢酸エチルでトリチュレートし、標記化合物（３６．８ｍｇ）を白色固体として得た。 Example 67 N- (2-methoxyphenyl) -2-methylsulfonyl-7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 66) Methanesulfonyl chloride was added to a methylene chloride solution (1.0 mL) of the compound synthesized in <Step 6> (50.0 mg) and diisopropylethylamine (24 μL) at room temperature and stirred for 2 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with methylene chloride and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was triturated with ethyl acetate to obtain the title compound (36.8 mg) as a white solid.
（実施例６８）Ｎ－（２－メトキシフェニル）－２－メチル－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミド
　（実施例６６）＜工程６＞で合成した化合物（５０．０ｍｇ）の塩化メチレン溶液（１．０ｍＬ）に、室温で３６％ホルムアルデヒド溶液（９０μＬ）を加え１時間撹拌した。トリアセトキシ水素化ホウ素ナトリウム（１１０．０ｍｇ）を加え終夜撹拌し、反応溶液を氷水にあけ塩化メチレンで抽出した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝７０：３０）で精製し、標記化合物（５１．６ｍｇ）を無色アモルファスとして得た。 (Example 68) N- (2-methoxyphenyl) -2-methyl-7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 66) < A 36% formaldehyde solution (90 μL) was added to a methylene chloride solution (1.0 mL) of the compound synthesized in Step 6> (50.0 mg) at room temperature and stirred for 1 hour. Sodium triacetoxyborohydride (110.0 mg) was added and stirred overnight. The reaction solution was poured into ice water and extracted with methylene chloride, 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 = 70: 30) to obtain the title compound (51.6 mg) as a colorless amorphous product. .
（実施例６９）Ｎ－（２－メトキシフェニル）－２－アセチル－７－（１－ピペリジニルスルホニル）－１，２，３，４－テトラヒドロイソキノリン－５－カルボキシアミド
　（実施例６６）＜工程６＞で合成した化合物（５０．０ｍｇ）の塩化メチレン溶液（１．０ｍＬ）に、トリエチルアミン（４４μＬ）、無水酢酸（２２０μＬ）を加え３時間撹拌した。反応溶液に水を加え塩化メチレンで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝１０：９０）で精製し、標記化合物（５４．９ｍｇ）を無色アモルファスとして得た。 (Example 69) N- (2-methoxyphenyl) -2-acetyl-7- (1-piperidinylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-5-carboxamide (Example 66) < Triethylamine (44 μL) and acetic anhydride (220 μL) were added to a methylene chloride solution (1.0 mL) of the compound synthesized in Step 6> (50.0 mg) and stirred for 3 hours. Water was added to the reaction solution, extracted with methylene chloride, 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 = 10: 90) to obtain the title compound (54.9 mg) as a colorless amorphous product. .
（実施例７０）Ｎ－［４－（トリフルオロメトキシ）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）－３－ピリジンカルボキシアミド
＜工程１＞２－ヒドロキシ－５－スルホ－３－ピリジンカルボン酸の合成
　６０％硫酸（１５．０ｍＬ）に、室温で２－ヒドロキシ－３－ピリジンカルボン酸（１０．０ｇ）を加え、１４０℃で１０時間撹拌した。反応溶液に水を加え析出した固体を濾趣した。得られた固体をアセトン中で撹拌した後、濾取し減圧乾燥することで標記化合物（７．０ｇ）を白色固体として得た。 Example 70 N- [4- (trifluoromethoxy) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) -3-pyridinecarboxamide <Step 1> 2-hydroxy-5-sulfo- Synthesis of 3-pyridinecarboxylic acid 2-hydroxy-3-pyridinecarboxylic acid (10.0 g) was added to 60% sulfuric acid (15.0 mL) at room temperature, and the mixture was stirred at 140 ° C. for 10 hours. Water was added to the reaction solution, and the precipitated solid was filtered off. The obtained solid was stirred in acetone, then collected by filtration and dried under reduced pressure to obtain the title compound (7.0 g) as a white solid.
＜工程２＞２－クロロ－５－（クロロスルホニル）－３－ピリジンカルボン酸の合成
　（実施例７０）＜工程１＞で得られた化合物（１．０ｇ）のトルエン溶液（５．０ｍＬ）に塩化チオニル（１．７ｍＬ）、Ｎ，Ｎ－ジメチルホルムアミド（０．２ｍＬ）を加え、加熱還流下５時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、標記化合物（０．９７ｇ）を褐色固体として得た。 <Step 2> Synthesis of 2-chloro-5- (chlorosulfonyl) -3-pyridinecarboxylic acid (Example 70) To a toluene solution (5.0 mL) of the compound (1.0 g) obtained in <Step 1> Thionyl chloride (1.7 mL) and N, N-dimethylformamide (0.2 mL) were added, and the mixture was stirred for 5 hours with heating under reflux. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.97 g) as a brown solid.
＜工程３＞２－クロロ－５－（１－ピペリジニルスルホニル）－３－ピリジンカルボン酸の合成
　（実施例２５）＜工程１＞に準じる方法で、（実施例７０）＜工程２＞で得られた化合物（０．４７ｇ）より標記化合物（０．５１ｇ）を白色固体として得た。 <Step 3> Synthesis of 2-chloro-5- (1-piperidinylsulfonyl) -3-pyridinecarboxylic acid (Example 25) In the same manner as in <Step 1>, (Example 70) in <Step 2> The title compound (0.51 g) was obtained as a white solid from the obtained compound (0.47 g).
＜工程４＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－２－クロロ－５－（１－ピペリジニルスルホニル）－３－ピリジンカルボキシアミド
　（実施例１８）に準ずる方法で、（実施例７０）＜工程３＞で得られた化合物（１００．０ｍｇ）より標記化合物（２０．４ｍｇ）を白色固体として得た。 <Step 4> N- [4- (trifluoromethoxy) phenyl] -2-chloro-5- (1-piperidinylsulfonyl) -3-pyridinecarboxamide (Example 18) 70) The title compound (20.4 mg) was obtained as a white solid from the compound (100.0 mg) obtained in <Step 3>.
（実施例７１）Ｎ－［４－（トリフルオロメトキシ）フェニル］－５－（１－ピペリジニルスルホニル）－２－フランカルボキシアミド
＜工程１＞５－（クロロスルホニル）－２－フランカルボン酸エチルエステルの合成
　発煙硫酸（０．６ｍL）に、室温で２－フランカルボン酸エチルエステル（４．５ｇ）を加え終夜撹拌した。反応溶液に氷水、炭酸バリウムを加え加熱還流下３時間撹拌した。反応溶液を濾過した後、減圧下溶媒を留去し得られた残渣をエタノールに溶解させ、加熱還流下２時間撹拌した。反応溶液を濾過し、飽和炭酸ナトリウム水溶液を加えｐＨを７．５～８．０にした後再度濾過し、濾過した濾液を減圧下溶媒を留去し粗化合物（０．７２ｇ）を白色固体として得た。得られた粗化合物（０．７２ｇ）を五塩化リン（１．２３ｇ）に溶解し、１５０℃で６時間撹拌した後、反応溶液を氷水に注ぎ反応停止した。塩化メチレンで抽出し、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去し、標記化合物（０．６４ｇ）を得た。 Example 71 N- [4- (trifluoromethoxy) phenyl] -5- (1-piperidinylsulfonyl) -2-furancarboxamide <Step 1> 5- (Chlorosulfonyl) -2-furancarboxylic acid Synthesis of ethyl ester To fuming sulfuric acid (0.6 mL), 2-furancarboxylic acid ethyl ester (4.5 g) was added at room temperature and stirred overnight. Ice water and barium carbonate were added to the reaction solution, and the mixture was stirred for 3 hours with heating under reflux. After filtering the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethanol and stirred for 2 hours with heating under reflux. The reaction solution is filtered, and saturated aqueous sodium carbonate solution is added to adjust the pH to 7.5 to 8.0, followed by filtration. The filtrate is evaporated under reduced pressure to remove the crude compound (0.72 g) as a white solid. Obtained. The obtained crude compound (0.72 g) was dissolved in phosphorus pentachloride (1.23 g) and stirred at 150 ° C. for 6 hours, and then the reaction solution was poured into ice water to stop the reaction. After extraction with methylene chloride and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (0.64 g).
＜工程２＞５－（１－ピペリジニルスルホニル）－２－フランカルボン酸エチルエステルの合成
　（実施例７１）＜工程１＞で得た化合物（０．６４ｇ）を用いて、（実施例２５）＜工程１＞に準じる方法により標記化合物（０．４１ｇ）を無色油状物質として得た。 <Step 2> Synthesis of 5- (1-piperidinylsulfonyl) -2-furancarboxylic acid ethyl ester (Example 71) Using the compound (0.64 g) obtained in <Step 1>, (Example 25) ) The title compound (0.41 g) was obtained as a colorless oil by the method according to <Step 1>.
＜工程３＞５－（１－ピペリジニルスルホニル）－２－フランカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例７１）＜工程２＞で得られた化合物（２００．０ｍｇ）より標記化合物（１８９．０ｍｇ）を得た。 <Step 3> Synthesis of 5- (1-piperidinylsulfonyl) -2-furancarboxylic acid (Example 25) In the same manner as in <Step 2>, the compound obtained in (Example 71) <Step 2> The title compound (189.0 mg) was obtained from (200.0 mg).
＜工程４＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－５－（１－ピペリジニルスルホニル）－２－フランカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例７１）＜工程３＞で得られた化合物（７７．０ｍｇ）より標記化合物（３２．１ｍｇ）を白色固体として得た。
  <Step 4> Synthesis of N- [4- (trifluoromethoxy) phenyl] -5- (1-piperidinylsulfonyl) -2-furancarboxamide (Example 71) The title compound (32.1 mg) was obtained as a white solid from the compound (77.0 mg) obtained in <Step 3>.
（実施例７２）Ｎ－［４－（トリフルオロメトキシ）フェニル］－３－メチル－５－（１－ピペリジニルスルホニル）－２－フランカルボキシアミド
＜工程１＞５－（クロロスルホニル）－３－メチル－２－フランカルボン酸メチルエステルの合成
　（実施例２）＜工程１＞に準ずる方法で、３－メチル－２－フランカルボン酸メチルエステル（１．０ｇ）より標記化合物（１．５ｇ）を褐色油状物質として得た。 Example 72 N- [4- (trifluoromethoxy) phenyl] -3-methyl-5- (1-piperidinylsulfonyl) -2-furancarboxamide <Step 1> 5- (Chlorosulfonyl) -3 Synthesis of -methyl-2-furancarboxylic acid methyl ester (Example 2) The title compound (1.5 g) was prepared from 3-methyl-2-furancarboxylic acid methyl ester (1.0 g) by the method according to <Step 1>. Was obtained as a brown oil.
＜工程２＞３－メチル－５－（１－ピペリジニルスルホニル）－２－フランカルボン酸メチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例７２）＜工程１＞で得られた化合物（１．０ｇ）より標記化合物（１．１ｇ）を褐色固体として得た。 <Step 2> Synthesis of 3-methyl-5- (1-piperidinylsulfonyl) -2-furancarboxylic acid methyl ester (Example 25) In the same manner as in <Step 1>, (Example 72) <Step 1 The title compound (1.1 g) was obtained as a brown solid from the compound (1.0 g) obtained in>.
＜工程３＞３－メチル－５－（１－ピペリジニルスルホニル）－２－フランカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例７２）＜工程２＞で得られた化合物（１．０ｇ）より標記化合物（０．８８ｇ）を褐色固体として得た。 <Step 3> Synthesis of 3-methyl-5- (1-piperidinylsulfonyl) -2-furancarboxylic acid (Example 25) In the same manner as in <Step 2>, (Example 72) in <Step 2> The title compound (0.88 g) was obtained as a brown solid from the obtained compound (1.0 g).
＜工程４＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－３－メチル－５－（１－ピペリジニルスルホニル）－２－フランカルボキシアミドの合成
　（実施例７２）＜工程３＞で得られた化合物（１００．０ｍｇ）を用いて、（実施例１８）に準ずる方法により標記化合物（３１．０ｍｇ）を無色固体として得た。 <Step 4> Synthesis of N- [4- (trifluoromethoxy) phenyl] -3-methyl-5- (1-piperidinylsulfonyl) -2-furancarboxamide (Example 72) Obtained in <Step 3> Using the obtained compound (100.0 mg), the title compound (31.0 mg) was obtained as a colorless solid by the method according to (Example 18).
（実施例７３）Ｎ－（２－メトキシフェニル）－２－メチル－５－（１－ピペリジニルスルホニル）－３－フランカルボキシアミド
＜工程１＞５－（クロロスルホニル）－２－メチル－３－フランカルボン酸メチルエステルの合成
　（実施例２）＜工程１＞に準じる方法で、２－メチル－３－フランカルボン酸メチルエステル（１．０ｇ）より標記化合物（１．６ｇ）を褐色油状物質として得た。 Example 73 N- (2-methoxyphenyl) -2-methyl-5- (1-piperidinylsulfonyl) -3-furancarboxamide <Step 1> 5- (Chlorosulfonyl) -2-methyl-3 Synthesis of -furancarboxylic acid methyl ester (Example 2) The title compound (1.6 g) was obtained as a brown oily substance from 2-methyl-3-furancarboxylic acid methyl ester (1.0 g) by the method according to <Step 1>. Got as.
＜工程２＞２－メチル－５－（１－ピペリジニルスルホニル）－３－フランカルボン酸メチルエステルの合成
　（実施例２５）＜工程１＞に準じる方法で、（実施例７３）＜工程１＞で得られた化合物（１．１ｇ）より標記化合物（０．８５ｇ）を褐色固体として得た。 <Step 2> Synthesis of 2-methyl-5- (1-piperidinylsulfonyl) -3-furancarboxylic acid methyl ester (Example 25) In the same manner as in <Step 1>, (Example 73) <Step 1 > (1.1 g) to give the title compound (0.85 g) as a brown solid.
＜工程３＞２－メチル－５－（１－ピペリジニルスルホニル）－３－フランカルボン酸の合成
　（実施例２５）＜工程２＞に準じる方法で、（実施例７３）＜工程２＞で得られた化合物（１．０ｇ）より標記化合物（０．８５ｇ）を褐色固体として得た。 <Step 3> Synthesis of 2-methyl-5- (1-piperidinylsulfonyl) -3-furancarboxylic acid (Example 25) In the same manner as in <Step 2>, (Example 73) in <Step 2> The title compound (0.85 g) was obtained as a brown solid from the obtained compound (1.0 g).
＜工程４＞Ｎ－（２－メトキシフェニル）－２－メチル－５－（１－ピペリジニルスルホニル）－３－フランカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例７３）＜工程３＞で得られた化合物（５０．０ｍｇ）より標記化合物（１８．１ｍｇ）を白色固体として得た。 <Step 4> Synthesis of N- (2-methoxyphenyl) -2-methyl-5- (1-piperidinylsulfonyl) -3-furancarboxamide (Example 73) The title compound (18.1 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 3>.
（実施例７４）Ｎ－（２－メトキシフェニル）－１－メチル－５－（１－ピペリジニルスルホニル）－１Ｈ－ピロール－２－カルボキシアミド
＜工程１＞１－メチル－５－（１－ピペリジニルスルホニル）－１Ｈ－ピロール－２－カルボン酸メチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、５－（クロロスルホニル）－１－メチル－１Ｈ－ピロール－２－カルボン酸メチルエステル（１．０ｇ）より標記化合物（１．２ｇ）を白色固体として得た。 Example 74 N- (2-methoxyphenyl) -1-methyl-5- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxamide <Step 1> 1-methyl-5- (1- Synthesis of piperidinylsulfonyl) -1H-pyrrole-2-carboxylic acid methyl ester (Example 25) 5- (chlorosulfonyl) -1-methyl-1H-pyrrole-2-carboxylic acid by a method according to <Step 1> The title compound (1.2 g) was obtained as a white solid from the acid methyl ester (1.0 g).
＜工程２＞１－メチル－５－（１－ピペリジニルスルホニル）－１Ｈ－ピロール－２－カルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例７４）＜工程１＞で得られた化合物（１．０ｇ）より標記化合物（０．８８ｇ）を褐色固体として得た。 <Step 2> Synthesis of 1-methyl-5- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxylic acid (Example 25) In the same manner as in <Step 2>, (Example 74) <Step The title compound (0.88 g) was obtained as a brown solid from the compound (1.0 g) obtained in 1>.
＜工程３＞Ｎ－（２－メトキシフェニル）－１－メチル－５－（１－ピペリジニルスルホニル）－１Ｈ－ピロール－２－カルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例７４）＜工程２＞で得られた化合物（６０．０ｍｇ）より標記化合物（１３．２ｍｇ）を白色固体として得た。 <Step 3> Synthesis of N- (2-methoxyphenyl) -1-methyl-5- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxamide (Example 18) Example 74) The title compound (13.2 mg) was obtained as a white solid from the compound (60.0 mg) obtained in <Step 2>.
（実施例７５）Ｎ－（２－メトキシフェニル）－１－メチル－４－（１－ピペリジニルスルホニル）－１Ｈ－ピロール－２－カルボキシアミド
　（実施例１８）に準ずる方法で、１－メチル－４－（１－ピペリジニルスルホニル）－１Ｈ－ピロール－２－カルボン酸（５０．０ｍｇ）より標記化合物（３５．７ｍｇ）を無色油状物質として得た。 Example 75 N- (2-Methoxyphenyl) -1-methyl-4- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxamide 1-methyl The title compound (35.7 mg) was obtained as a colorless oil from -4- (1-piperidinylsulfonyl) -1H-pyrrole-2-carboxylic acid (50.0 mg).
（実施例７６）Ｎ－（２－メトキシフェニル）－４－（１－ピペリジニルスルホニル）－２－チオフェンカルボキシアミド
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より標記化合物を得た。 Example 76 N- (2-methoxyphenyl) -4- (1-piperidinylsulfonyl) -2-thiophenecarboxamide represented by the above formula (XI-1) by a method according to (Example 18) The title compound was obtained from the amine and the carboxylic acid represented by the formula (X-1).
（実施例７７）Ｎ－［４－（トリフルオロメトキシ）フェニル］－Ｎ’－［３－（１－ピペリジニルスルホニル）フェニル］ウレア
　３－（１－ピペリジニルスルホニル）アニリン（１００．０ｍｇ）の塩化メチレン溶液（３．０ｍＬ）に、室温で４－（トリフルオロメトキシ）フェニルイソシアナート（７６．３μＬ）を入れ終夜撹拌した。反応溶液をＬＣ Ｍａｓｓにより分取精製することにより標記化合物（４５．０ｍｇ）を白色固体として得た。 Example 77 N- [4- (trifluoromethoxy) phenyl] -N ′-[3- (1-piperidinylsulfonyl) phenyl] urea 3- (1-piperidinylsulfonyl) aniline (100.0 mg ) In methylene chloride (3.0 mL) was charged with 4- (trifluoromethoxy) phenyl isocyanate (76.3 μL) at room temperature and stirred overnight. The reaction solution was separated and purified by LC Mass to obtain the title compound (45.0 mg) as a white solid.
（実施例７８）Ｎ－フェニル－Ｎ’－［［５－（１－ピペリジニルスルホニル）－２－チエニル］メチル］ウレア
　（実施例７７）に準じる方法で、前記式（Ｘ－３）で表されるアミンおよび前記式（ＸＩ－４）表されるイソシアネートより標記化合物を得た。 Example 78 N-phenyl-N ′-[[5- (1-piperidinylsulfonyl) -2-thienyl] methyl] urea In a method according to Example 77, the above formula (X-3) The title compound was obtained from the amine represented and the isocyanate represented by the formula (XI-4).
（実施例７９）Ｎ－（２－メトキシフェニル）－３－（シクロヘキシルスルホニル）ベンズアミド
＜工程１＞３－（シクロヘキシルチオ）安息香酸の合成
　３－メルカプト安息香酸（１．０ｇ）のテトラヒドロフラン－水溶液（４．５ｍＬ，１：２）に、室温でシクロヘキセン（０．６６ｍＬ）を加え終夜撹拌した。さらに５０℃で１０時間撹拌した後、シクロヘキセン（０．６６ｍＬ）、テトラヒドロフラン（１．５ｍＬ）を加え終夜撹拌した。反応溶液を酢酸エチルで希釈し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去しえられた残渣を酢酸エチル、メタノールに溶解し、不溶物を濾過した後、減圧下溶媒を留去し標記粗化合物（０．９０ｇ）を淡黄色油状物質として得た。 (Example 79) N- (2-methoxyphenyl) -3- (cyclohexylsulfonyl) benzamide <Step 1> Synthesis of 3- (cyclohexylthio) benzoic acid 3-mercaptobenzoic acid (1.0 g) in tetrahydrofuran-water solution ( To 4.5 mL, 1: 2), cyclohexene (0.66 mL) was added at room temperature and stirred overnight. After further stirring at 50 ° C. for 10 hours, cyclohexene (0.66 mL) and tetrahydrofuran (1.5 mL) were added and stirred overnight. The reaction solution was diluted 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 dissolved in ethyl acetate and methanol, and the insoluble material was filtered off. The solvent was evaporated under reduced pressure to obtain the title crude compound (0.90 g) as a pale yellow oily substance. .
＜工程２＞Ｎ－（２－メトキシフェニル）－３－（シクロヘキシルチオ）ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例７９）＜工程１＞で得られた化合物（０．３０ｇ）より標記化合物（０．１８ｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methoxyphenyl) -3- (cyclohexylthio) benzamide In the same manner as in (Example 18), the compound (0.30 g) obtained in (Example 79) <Step 1> ) Gave the title compound (0.18 g) as a white solid.
＜工程３＞Ｎ－（２－メトキシフェニル）－３－（シクロヘキシルスルホニル）ベンズアミドの合成
　（実施例７９）＜工程２＞で得られた化合物（３０．０ｍｇ）の塩化メチレン溶液（１．０ｍＬ）に、室温でｍ－クロロ過安息香酸（８２．４ｍｇ）を加え３０分撹拌した。反応溶液を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して標記化合物（３１．６ｍｇ）を無色アモルファスとして得た。 <Step 3> Synthesis of N- (2-methoxyphenyl) -3- (cyclohexylsulfonyl) benzamide (Example 79) Methylene chloride solution (1.0 mL) of the compound (30.0 mg) obtained in <Step 2> To the mixture, m-chloroperbenzoic acid (82.4 mg) was added at room temperature and stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (31.6 mg) as a colorless amorphous.
（実施例８０）Ｎ－（２－メトキシフェニル）－３－［（１－ピペリジンスルホニル）アミノ］ベンズアミド
　（実施例１８）に準ずる方法で、３－［（１－ピペリジンスルホニル）アミノ］安息香酸（７５．０ｍｇ）より標記化合物（３１．６ｍｇ）を白色固体として得た。 Example 80 N- (2-methoxyphenyl) -3-[(1-piperidinesulfonyl) amino] benzamide 3-[(1-piperidinesulfonyl) amino] benzoic acid (in accordance with the method of Example 18) 75.0 mg) gave the title compound (31.6 mg) as a white solid.
（実施例８１）Ｎ－（２－メトキシフェニル）－４－（１－ピロリジニルスルホニル）ベンズアミド
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より標記化合物を得た。 (Example 81) N- (2-methoxyphenyl) -4- (1-pyrrolidinylsulfonyl) benzamide In a method according to (Example 18), the amine represented by the above formula (XI-1) and the above formula The title compound was obtained from the carboxylic acid represented by (X-1).
（実施例８２）Ｎ－（１，４－ジヒドロ－２－オキソ－２Ｈ－３，１－ベンゾオキサジン－８－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、ジャーナル・オブ・メディシナル・ケミストリー（Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ），３９，４６５４－４６６６，１９９６年に記載された方法に準じて合成した８－アミノ－１，４－ジヒドロ－２Ｈ－３，１－ベンゾオキサジン－２－オン（５９．１ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より標記化合物（２８．６ｍｇ）を黄色固体として得た。 Example 82 N- (1,4-Dihydro-2-oxo-2H-3,1-benzoxazin-8-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] 8-amino-1,4 synthesized in accordance with the method described in Journal of Medicinal Chemistry, 39, 4654-4666, 1996 by a method according to Benzamide (Example 18). -The title compound from dihydro-2H-3,1-benzoxazin-2-one (59.1 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg) 28.6 mg) was obtained as a yellow solid.
（実施例８３）Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－８－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞Ｎ－（２－アミノ－３－ニトロベンジル）－Ｎ－（３，４－ジメトキシベンシル）アミンの合成
　２－アミノ－３－ニトロベンズアルデヒド（３．４ｇ）のメタノール溶液（１００．０ｍＬ）に、室温で３，４－ジメトキシベンジルアミン（３．４ｇ）を加え終夜撹拌した。反応溶液に、氷冷下水素化ホウ素ナトリウム（３．０ｇ）を加え、室温まで昇温し終夜撹拌した。反応溶液に水を加え塩化メチレンで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をＮ，Ｎ－ジメチルホルムアミド（５０．０ｍＬ）に溶解し、氷冷下イミダゾール（２．３ｇ）、ｔｅｒｔ－ブチルジメチルシリルクロリドを（２．５ｇ）を加えた後、室温にて３時間撹拌した。反応溶液に水を加え酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝１００：０～９５：５）で精製し、標記化合物（３．０ｇ）を淡紫色固体として得た。 Example 83 N- (1,2,3,4-Tetrahydro-2-oxo-8-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of N- (2-amino-3-nitrobenzyl) -N- (3,4-dimethoxybenzyl) amine To a methanol solution (100.0 mL) of 2-amino-3-nitrobenzaldehyde (3.4 g), 3,4-Dimethoxybenzylamine (3.4 g) was added at room temperature and stirred overnight. To the reaction solution was added sodium borohydride (3.0 g) under ice cooling, and the mixture was warmed to room temperature and stirred overnight. Water was added to the reaction solution, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in N, N-dimethylformamide (50.0 mL), and imidazole (2.3 g) and tert-butyldimethylsilyl chloride (2.5 g) were added under ice cooling. And then stirred at room temperature for 3 hours. Water was added to the reaction solution, 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 95: 5) to give the title compound (3.0 g) as a pale purple color. Obtained as a solid.
＜工程２＞１，２，３，４－テトラヒドロ－３－（３，４－ジメトキシベンジル）－２－オキソ－８－ニトロキナゾリンの合成
　（実施例８３）＜工程１＞で得られた化合物（３．０ｇ）の塩化メチレン溶液（１００．０ｍＬ）に、氷冷下トリエチルアミン（３．６ｍＬ）、１，１’－カルボニルビス－１Ｈ－イミダゾール（３．０ｇ）を加え、室温まで昇温し終夜撹拌した。反応溶液に１規定塩酸水溶液を加え塩化メチレンで抽出し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をジエチルエーテルでトリチュレートすることにより標記化合物（３．０ｇ）を黄色固体として得た。 <Step 2> Synthesis of 1,2,3,4-tetrahydro-3- (3,4-dimethoxybenzyl) -2-oxo-8-nitroquinazoline (Example 83) Compound obtained in <Step 1> 3.0 g) in methylene chloride (100.0 mL) was added triethylamine (3.6 mL) and 1,1′-carbonylbis-1H-imidazole (3.0 g) under ice cooling, and the mixture was warmed to room temperature and overnight. Stir. A 1N aqueous hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The extract was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was triturated with diethyl ether to obtain the title compound (3.0 g) as a yellow solid.
＜工程３＞１，２，３，４－テトラヒドロ－２－オキソ－８－ニトロキナゾリンの合成
　（実施例８３）＜工程２＞で得られた化合物（１．４ｇ）に、氷冷下トリフルオロ酢酸（２０．０ｍＬ）を加えた後、昇温し２時間加熱還流した。トリフルオロ酢酸を減圧下留去し得られた残渣を塩化メチレンに溶解し、１規定水酸化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し得られた残渣をジエチルエーテル－酢酸エチルでトリチュレートすることに、標記化合物（０．７８ｇ）を黄色固体として得た。 <Step 3> Synthesis of 1,2,3,4-tetrahydro-2-oxo-8-nitroquinazoline (Example 83) The compound (1.4 g) obtained in <Step 2> Acetic acid (20.0 mL) was added, the temperature was raised, and the mixture was heated to reflux for 2 hours. Trifluoroacetic acid was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride, washed with 1N aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was triturated with diethyl ether-ethyl acetate to obtain the title compound (0.78 g) as a yellow solid.
＜工程４＞８－アミノ－１，２，３，４－テトラヒドロ－２－オキソキナゾリンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例８３）＜工程３＞で得られた化合物（０．７８ｇ）より標記化合物（０．４８ｇ）を紫色固体として得た。 <Step 4> Synthesis of 8-amino-1,2,3,4-tetrahydro-2-oxoquinazoline (Example 26) A method similar to <Step 4>, obtained in (Example 83) <Step 3> The title compound (0.48 g) was obtained as a purple solid from the obtained compound (0.78 g).
＜工程５＞Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－８－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例８３）＜工程４＞で得られた化合物（５８．７ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（１３．７ｍｇ）を白色固体として得た。 <Step 5> Synthesis of N- (1,2,3,4-tetrahydro-2-oxo-8-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 18) (Example 83) The compound (58.7 mg) obtained in <Step 4> and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100. 0 mg) gave the title compound (13.7 mg) as a white solid.
（実施例８４）Ｎ－（１－メチル－１，２，３，４－テトラヒドロ－２－オキソ－８－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞１，２，３，４－テトラヒドロ－１－メチル－３－（３，４－ジメトキシベンジル）－２－オキソ－８－ニトロキナゾリンの合成
　（実施例８３）＜工程２＞で合成した化合物（１．５ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（５０．０ｍＬ）に、氷冷下炭酸カリウム（１．８ｇ）、ヨードメタン（０．８ｍＬ）を加え、室温まで昇温した後終夜撹拌した。反応溶液に水を加え酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をジエチルエーテルでトリチュレートすることにより標記化合物（１．５ｇ）を黄色固体として得た。 Example 84 N- (1-Methyl-1,2,3,4-tetrahydro-2-oxo-8-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 1,2,3,4-tetrahydro-1-methyl-3- (3,4-dimethoxybenzyl) -2-oxo-8-nitroquinazoline (Example 83) Synthesis in <Step 2> To a solution of the compound (1.5 g) in N, N-dimethylformamide (50.0 mL), potassium carbonate (1.8 g) and iodomethane (0.8 mL) were added under ice cooling, and the mixture was warmed to room temperature and stirred overnight. did. Water was added to the reaction solution, 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 triturated with diethyl ether to obtain the title compound (1.5 g) as a yellow solid.
＜工程２＞１，２，３，４－テトラヒドロ－１－メチル－２－オキソ－８－ニトロキナゾリンの合成
　（実施例８３）＜工程３＞に準ずる方法で、（実施例８４）＜工程１＞で得た化合物（１．４ｇ）より標記化合物（０．７５ｇ）を黄色固体として得た。 <Step 2> Synthesis of 1,2,3,4-tetrahydro-1-methyl-2-oxo-8-nitroquinazoline (Example 83) In the same manner as in <Step 3>, (Example 84) <Step 1 > (1.4 g) to give the title compound (0.75 g) as a yellow solid.
＜工程３＞８－アミノ－１，２，３，４－テトラヒドロ－１－メチル－２－オキソキナゾリンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例８４）＜工程２＞で得た化合物（０．７５ｇ）より標記化合物（０．６２ｇ）を茶色固体として得た。 <Step 3> Synthesis of 8-amino-1,2,3,4-tetrahydro-1-methyl-2-oxoquinazoline (Example 26) In the same manner as in <Step 4>, (Example 84) <Step 2 > (0.75 g) to give the title compound (0.62 g) as a brown solid.
＜工程４＞Ｎ－（１－メチル－１，２，３，４－テトラヒドロ－２－オキソ－８－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例８４）＜工程３＞で得られた化合物（６３．８ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（１１．７ｍｇ）を白色固体として得た。 <Step 4> N- (1-Methyl-1,2,3,4-tetrahydro-2-oxo-8-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide Synthesis According to the method according to Example 18, the compound (63.8 mg) obtained in <Step 3> of Example 84 and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid The title compound (11.7 mg) was obtained as a white solid from the acid (100.0 mg).
（実施例８５）Ｎ－（１－メチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した１，２，３，４－テトラヒドロ－５－アミノ－１－メチル－２－オキソキナゾリン（６３．８ｍｇ）と２－クロロ－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（１４．１ｍｇ）を得た。 Example 85 N- (1-Methyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide 1,2,3,4-Tetrahydro-5-amino-1-methyl-2-oxoquinazoline synthesized according to the method described in the pamphlet of WO2008 / 091021 by the method according to (Example 18) The title compound (14.1 mg) was obtained from 63.8 mg) and 2-chloro-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
（実施例８６）Ｎ－（１－エチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した５－アミノ－１，２，３，４－テトラヒドロ－１－エチル－２－オキソキナゾリン（６８．８ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（１１．２ｍｇ）を得た。 Example 86 N- (1-Ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl ] 5-amino-1,2,3,4-tetrahydro-1-ethyl-2-oxo synthesized according to the method described in the pamphlet of WO2008 / 091021 by the method according to Benzamide (Example 18) The title compound (11.2 mg) was obtained from quinazoline (68.8 mg) and 2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
（実施例８７）Ｎ－（１－エチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－２－クロロ－５－（１－アゼチジニルスルホニル）ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した５－アミノ－１，２，３，４－テトラヒドロ－１－エチル－２－オキソキナゾリン（６８．８ｍｇ）と５－（１－アゼチジニルスルホニル）－２－クロロ安息香酸（９９．３ｍｇ）より、標記化合物（１１．７ｍｇ）を得た。 Example 87 N- (1-Ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide (Example 18) 5-amino-1,2,3,4-tetrahydro-1-ethyl-2-oxoquinazoline (68.8 mg) synthesized according to the method described in the pamphlet of WO2008 / 091021 And 5- (1-azetidinylsulfonyl) -2-chlorobenzoic acid (99.3 mg) gave the title compound (11.7 mg).
（実施例８８）Ｎ－（１，２，３，４－テトラヒドロ－３－ヒドロキシ－２－オキソ－５－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００７／０１０３８３号のパンフレットに記載された方法に従い合成した５－アミノ－１，２，３，４－テトラヒドロ－３－ヒドロキシ－２－オキソキノリン（５３．３ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）をより、標記化合物（２．３ｍｇ）を得た。 Example 88 N- (1,2,3,4-Tetrahydro-3-hydroxy-2-oxo-5-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide 5-amino-1,2,3,4-tetrahydro-3-hydroxy-2-oxoquinoline synthesized according to the method described in the pamphlet of WO2007 / 010383 by a method according to (Example 18) ( The title compound (2.3 mg) was obtained from 53.3 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
（実施例８９）Ｎ－（１，３－ジヒドロ－２－オキソ－２Ｈ－インドール－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、バイオオーガニック・メディシナル・ケミストリー・レターズ（Ｂｉｏｏｒｇａｎｉｃ　　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　Ｌｅｔｔｅｒｓ），８，２６７５－２６８０，１９９８年に記載された方法に準じて合成した４－アミノ－１，３－ジヒドロ－２Ｈ－インドール－２－オン（５９．１ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（８．９ｍｇ）を得た。 Example 89 N- (1,3-dihydro-2-oxo-2H-indol-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 18) 4-amino-1,3-dihydro-2H synthesized according to the method described in Bioorganic Medicinal Chemistry Letters, 8, 2675-2680, 1998, -The title compound (8.9 mg) was obtained from indol-2-one (59.1 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例９０）Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－５－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例９１）Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－８－イル）－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例９２）Ｎ－［１，３－ベンゾオキサゾール－２（３Ｈ）－オン－７－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例９３）Ｎ－（５－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 90 N- (1,2,3,4-Tetrahydro-2-oxo-5-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 91) ) N- (3,4-Dihydro-3-oxo-2H-1,4-benzoxazin-8-yl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 92) N— [1,3-Benzoxazol-2 (3H) -one-7-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 93) N- (5-quinolinyl ) -2-Chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
（実施例９４）Ｎ－（２－ヒドロキシ－１，２，３，４－テトラヒドロナフタレン－８－イル）－２－クロロ－５－（シクロブチルアミノスルホニル）ベンズアミド
＜工程１＞２－クロロ－５－（シクロブチルアミノスルホニル）安息香酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、シクロブチルアミン（３．３６ｍＬ）と２－クロロ－５－（クロロスルホニル）安息香酸（５．００ｇ）より、標記化合物（４．８８ｇ）を白色固体として得た。 Example 94 N- (2-Hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) -2-chloro-5- (cyclobutylaminosulfonyl) benzamide <Step 1> 2-Chloro-5 Synthesis of — (cyclobutylaminosulfonyl) benzoic acid (Example 25) Cyclobutylamine (3.36 mL) and 2-chloro-5- (chlorosulfonyl) benzoic acid (5.00 g) by the method according to <Step 1> From the above, the title compound (4.88 g) was obtained as a white solid.
＜工程２＞Ｎ－（２－ヒドロキシ－１，２，３，４－テトラヒドロナフタレン－８－イル）－２－クロロ－５－（シクロブチルアミノスルホニル）ベンズアミドの合成
　（実施例１８）に準ずる方法で、８－アミノ－１，２，３，４－テトラヒドロ－２－ナフトール（５８．８ｍｇ）と（実施例９４）＜工程１＞で得られた化合物（１０４．３ｍｇ）より、標記化合物（１６．３ｍｇ）を得た。 <Step 2> Synthesis of N- (2-hydroxy-1,2,3,4-tetrahydronaphthalen-8-yl) -2-chloro-5- (cyclobutylaminosulfonyl) benzamide Method according to Example 18 From the compound (104.3 mg) obtained in <Step 1> of 8-amino-1,2,3,4-tetrahydro-2-naphthol (58.8 mg) and (Example 94), the title compound (16 .3 mg) was obtained.
　下記、（実施例９５）、（実施例９６）における（Ｂ）、（Ａ）を付したものは、実施例９５＜工程１＞において得られた４－アミノ－２，３－ジヒドロ－１Ｈ－インデン－２－オール（Ｂ）、４－アミノ－２，３－ジヒドロ－１Ｈ－インデン－２－オール（Ａ）をそれぞれ用いて得られた実施例化合物であることを示す。 In the following (Example 95) and (Example 96), those with (B) and (A) attached are the 4-amino-2,3-dihydro-1H— obtained in Example 95 <Step 1>. The examples are compounds obtained by using inden-2-ol (B) and 4-amino-2,3-dihydro-1H-inden-2-ol (A), respectively.
（実施例９５）Ｎ－（２，３－ジヒドロ－２－ヒドロキシ－１Ｈ－インデン－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ｂ）
＜工程１＞４－アミノ－２，３－ジヒドロ－１Ｈ－インデン－２－オールの光学分割
　国際公開第２００６／１１６５６３号の方法に従って合成した（Ｒａｃ）－４－アミノ－２，３－ジヒドロ－１Ｈ－インデン－２－オール（４．８ｇ）を分取クロマトグラフィー（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＡＤ－Ｈ　（５ｃｍ×２５ｃｍ）、溶出液；ｎ－ヘキサン：２－プロパノール：メタノール：ジエチルアミン＝８０：１５：５：０．１、流速：４７ｍＬ／分、ＵＶ：２３７ｎｍ検出）を用いて光学分割を行うことで標記化合物の各エナンチオマーを、第一分画（２．１ｇ、白色固体、９９．５％ｅｅ、リテンションタイム８．６分、〔α〕２９ Ｄ＝－２７．１（ｃ０．１、エタノール））：（エナンチオマーＡ：４－アミノ－２，３－ジヒドロ－１Ｈ－インデン－２－オール（Ａ））、および第二分画（２．２ｇ、白色固体、９８．２％ｅｅ、リテンションタイム９．６分、〔α〕２９ Ｄ＝＋３８．９（ｃ０．１、エタノール）：（エナンチオマーＢ：４－アミノ－２，３－ジヒドロ－１Ｈ－インデン－２－オール（Ｂ））として得た。光学純度はキラルカラムで決定した。（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＡＤ－Ｈ　（０．４６ｃｍ×２５．０ｃｍ）、溶出液；ｎ－ヘキサン：２－プロパノール：メタノール：ジエチルアミン＝８０：１５：５：０．１、流速：１．０ｍＬ／分、ＵＶ：２３７ｎｍ検出）。 Example 95 N- (2,3-Dihydro-2-hydroxy-1H-inden-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (B)
<Step 1> Optical resolution of 4-amino-2,3-dihydro-1H-inden-2-ol (Rac) -4-amino-2,3-dihydro- synthesized according to the method of International Publication No. 2006/116563 1H-inden-2-ol (4.8 g) was subjected to preparative chromatography (column: CHIRALPAK AD-H (5 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent; n-hexane: 2-propanol: methanol: Each enantiomer of the title compound was subjected to optical resolution using diethylamine = 80: 15: 5: 0.1, flow rate: 47 mL / min, UV: 237 nm detection), and 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: 4- Mino-2,3-dihydro -1H- inden-2-ol (A)), and a second fraction (2.2 g, white solid, 98.2% ee, retention time 9.6 min, [α] 29 D = + 38.9 (c0.1, ethanol): (enantiomer B: 4-amino-2,3-dihydro-1H-inden-2-ol (B)) The optical purity was determined on a 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).
＜工程２＞Ｎ－（２，３－ジヒドロ－２－ヒドロキシ－１Ｈ－インデン－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ｂ）の合成
　（実施例１８）に準ずる方法で、（実施例９５）＜工程１＞で得た４－アミノ－２，３－ジヒドロ－１Ｈ－インデン－２－オール（Ｂ）（５３．７ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（５．９ｍｇ）を得た。 <Step 2> Synthesis of N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (B) According to a method according to (Example 18), 4-amino-2,3-dihydro-1H-inden-2-ol (B) (53.7 mg) obtained in (Example 95) <Step 1> and 2- The title compound (5.9 mg) was obtained from chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
（実施例９６）Ｎ－（２，３－ジヒドロ－２－ヒドロキシ－１Ｈ－インデン－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ａ）
　（実施例１８）に準ずる方法で、実施例９５＜工程１＞で得た実施例４－アミノ－２，３－ジヒドロ－１Ｈ－インデン－２－オール（Ａ）（５３．７ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（５．５ｍｇ）を得た。 Example 96 N- (2,3-dihydro-2-hydroxy-1H-inden-4-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (A)
Example 4-Amino-2,3-dihydro-1H-inden-2-ol (A) (53.7 mg) obtained in Example 95 <Step 1> according to the method of (Example 18) and 2- The title compound (5.5 mg) was obtained from chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例９７）Ｎ－（５，６，７，８－テトラヒドロナフタレン－１－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例９８）Ｎ－［２－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，４－テトラヒドロイソキノリン－８－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例９９）Ｎ－［２－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，４－テトラヒドロイソキノリン－５－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１００）Ｎ－（８－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１０１）Ｎ－（１，４－ベンゾジオキサン－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１０２）Ｎ－（１Ｈ－インダゾール－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１０３）Ｎ－（２，２－ジメチル－２，３－ジヒドロベンゾフラン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１０４）Ｎ－（２，２－ジフルオロ－１，３－ベンゾジオキソール－４－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１０５）Ｎ－（１Ｈ－インドール－４－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル）］ベンズアミド
（実施例１０６）Ｎ－（１－メチルインドール－４－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 97 N- (5,6,7,8-tetrahydronaphthalen-1-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 98) N— [2- (tert-Butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-8-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 99) N- [2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-5-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 100) N- (8-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 101) N- (1,4-Benzodioxy N-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 102) N- (1H-indazol-7-yl) -2-chloro-5- [ [(1-Methylethyl) amino] sulfonyl] benzamide (Example 103) N- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) -2-chloro-5-[[(1-methyl Ethyl) amino] sulfonyl] benzamide (Example 104) N- (2,2-difluoro-1,3-benzodioxol-4-yl) -2-chloro-5-[[(1-methylethyl) amino ] Sulfonyl] benzamide (Example 105) N- (1H-indol-4-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl)] benzamide (Example 106) N- ( - methylindole-4-yl) -2-chloro-5 - [[(1,1-dimethylethyl) amino] sulfonyl] benzamide
（実施例１０７）Ｎ－（１－エチルインドール－４－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド
＜工程１＞１－エチル－４－ニトロインドールの合成
　４－ニトロインドール（１．００ｇ）のアセトン溶液（２１．０ｍＬ）に、氷冷下水酸化カリウム粉末（１．７３ｇ）、ヨードエタン（０．９９ｍＬ）を加え室温まで昇温し２０分撹拌した。反応溶液にトルエンを加え濾過し、濾液に５％クエン酸水溶液を加え水層を分離した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝１００：０～８０：２０）で精製し、標記化合物（１．１６ｇ）を茶色油状物質として得た。 Example 107 N- (1-Ethylindole-4-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide <Step 1> Synthesis of 1-ethyl-4-nitroindole 4-nitro To an acetone solution (21.0 mL) of indole (1.00 g), potassium hydroxide powder (1.73 g) and iodoethane (0.99 mL) were added under ice cooling, and the mixture was warmed to room temperature and stirred for 20 minutes. Toluene was added to the reaction solution and filtered, and 5% aqueous citric acid solution was added to the filtrate to separate the aqueous layer, followed by drying over anhydrous magnesium 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 (1.16 g) as a brown oil. Obtained as material.
＜工程２＞４－アミノ－１－エチルインドールの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１０７）＜工程１＞で得られた化合物（１．１５ｇ）より、標記化合物（０．８５ｇ）を茶色固体として得た。 <Step 2> Synthesis of 4-amino-1-ethylindole (Example 26) In the same manner as in <Step 4>, (Example 107) From the compound (1.15 g) obtained in <Step 1>, the title The compound (0.85 g) was obtained as a brown solid.
＜工程３＞Ｎ－（１－エチルインドール－４－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１０７）＜工程２＞で得られた化合物（５７．７ｍｇ）と２－クロロ－５－（４－モルホリニルスルホニル）安息香酸（１１０．１ｍｇ）より、標記化合物（１４．３ｍｇ）を得た。 <Step 3> Synthesis of N- (1-ethylindol-4-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 107) The title compound (14.3 mg) was obtained from the compound obtained in Step 2> (57.7 mg) and 2-chloro-5- (4-morpholinylsulfonyl) benzoic acid (110.1 mg).
（実施例１０８）Ｎ－［１－（１－メチルエチル）－インドール－４－イル］－２－クロロ－５－［［（２－ヒドロキシ－１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞１－（１－メチルエチル）－４－ニトロインドールの合成
　（実施例８４）＜工程１＞に準ずる方法で、４－ニトロインドール（１．００ｇ）と２－ヨードプロパン（１．３４ｍＬ）より、標記化合物（０．６８ｇ）を茶色油状物質として得た。 Example 108 N- [1- (1-Methylethyl) -indol-4-yl] -2-chloro-5-[[(2-hydroxy-1,1-dimethylethyl) amino] sulfonyl] benzamide < Step 1> Synthesis of 1- (1-methylethyl) -4-nitroindole (Example 84) 4-Nitroindole (1.00 g) and 2-iodopropane (1.34 mL) according to the method of <Step 1> ) Gave the title compound (0.68 g) as a brown oil.
＜工程２＞４－アミノ－１－（１－メチルエチル）インドールの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１０８）＜工程１＞で得られた化合物（０．６７ｇ）より標記化合物（０．５４ｇ）を茶色油状物質として得た。 <Step 2> Synthesis of 4-amino-1- (1-methylethyl) indole (Example 26) In the same manner as in <Step 4>, the compound (0. 67g) gave the title compound (0.54 g) as a brown oil.
＜工程３＞２－クロロ－５－［［（２－ヒドロキシ－１，１－ジメチルエチル）アミノ］スルホニル］安息香酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、２－アミノ－２－メチル－１－プロパノール（１８．７ｍＬ）と２－クロロ－５－（クロロスルホニル）安息香酸（１０．０ｇ）より、標記化合物（８．１２ｇ）を白色固体として得た。 <Step 3> Synthesis of 2-chloro-5-[[(2-hydroxy-1,1-dimethylethyl) amino] sulfonyl] benzoic acid (Example 25) In the same manner as in <Step 1>, 2-amino- The title compound (8.12 g) was obtained as a white solid from 2-methyl-1-propanol (18.7 mL) and 2-chloro-5- (chlorosulfonyl) benzoic acid (10.0 g).
＜工程４＞Ｎ－［１－（１－メチルエチル）－インドール－４－イル］－２－クロロ－５－［［（２－ヒドロキシ－１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、＜工程２＞で得られたアミン（６３．４ｍｇ）と（実施例１０８）＜工程３＞で得られた化合物（１１０．８ｍｇ）より、標記化合物（１１．１ｍｇ）を得た。 <Step 4> N- [1- (1-Methylethyl) -indol-4-yl] -2-chloro-5-[[(2-hydroxy-1,1-dimethylethyl) amino] sulfonyl] benzamide The title compound (11.1 mg) was prepared from the amine (63.4 mg) obtained in <Step 2> and the compound obtained in <Example 3) <Step 3> (110.8 mg) by the method according to Example 18). )
（実施例１０９）Ｎ－［１－（２－ヒドロキシエチル）－インドール－４－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞１－［２－[（テトラヒドロ－２Ｈ－ピラン－２－イル）オキシ]エチル］－４－ニトロインドールの合成
　（実施例８４）＜工程１＞に準ずる方法で、４－ニトロインドール（１．００ｇ）と２－（２－ブロモエトキシ）テトラヒドロ－２Ｈ－ピラン（１．９６ｍＬ）より、標記化合物（１．７０ｇ）を茶色油状物質として得た。 Example 109 N- [1- (2-hydroxyethyl) -indol-4-yl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide <Step 1> 1 Synthesis of — [2-[(tetrahydro-2H-pyran-2-yl) oxy] ethyl] -4-nitroindole (Example 84) 4-Nitroindole (1.00 g) by the method according to <Step 1> And 2- (2-bromoethoxy) tetrahydro-2H-pyran (1.96 mL) gave the title compound (1.70 g) as a brown oil.
＜工程２＞１－（２－ヒドロキシエチル）－４－ニトロインドールの合成
　（実施例１０９）＜工程１＞で得られた化合物（１．６９ｇ）のメタノール溶液（３９．０ｍＬ）に、室温でｐ－トルエンスルホン酸・一水和物（０．４４ｇ）を加え５時間３０分撹拌した。反応溶液に５％クエン酸水溶液を加え酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝１００：０～５０：５０）で精製し、標記化合物（０．６３ｇ）を茶色油状物質として得た。 <Step 2> Synthesis of 1- (2-hydroxyethyl) -4-nitroindole (Example 109) To a methanol solution (39.0 mL) of the compound (1.69 g) obtained in <Step 1> at room temperature p-Toluenesulfonic acid monohydrate (0.44 g) was added and stirred for 5 hours 30 minutes. A 5% aqueous citric acid solution was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous magnesium 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 50:50) to give the title compound (0.63 g) as a brown oil Obtained as material.
＜工程３＞４－アミノ－１－（２－ヒドロキシエチル）－インドールの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１０９）＜工程２＞で得られた化合物（０．６３ｇ）より、標記化合物（０．５４ｇ）を茶色油状物質として得た。 <Step 3> Synthesis of 4-amino-1- (2-hydroxyethyl) -indole (Example 26) In the same manner as in <Step 4>, compound (0) obtained in (Example 109) <Step 2> .63 g) gave the title compound (0.54 g) as a brown oil.
＜工程４＞Ｎ－［１－（２－ヒドロキシエチル）－インドール－４－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１０９）＜工程３＞で得られた化合物（６３．４ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１０５．０ｍｇ）より、標記化合物（５．２ｍｇ）を得た。 <Step 4> Synthesis of N- [1- (2-hydroxyethyl) -indol-4-yl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 18) ) In accordance with (Example 109) <Step 3> and the compound (63.4 mg) obtained from 2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (105 (0.0 mg) gave the title compound (5.2 mg).
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１１０）Ｎ－（１Ｈ－インドール－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１１１）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド
（実施例１１２）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１１３）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１１４）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［（４－メチル－１－ピペラジニル）スルホニル］ベンズアミド
（実施例１１５）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［（ジメチルアミノ）スルホニル］ベンズアミド
（実施例１１６）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［（シクロヘキシルアミノ）スルホニル］ベンズアミド
（実施例１１７）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［（シクロプロピルアミノ）スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 110 N- (1H-Indol-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 111) N- (3,3-dimethyl- 2,3-Dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 112) N- (3,3-dimethyl-2, 3-Dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 113) N- (3,3-dimethyl- 2,3-Dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 114) N- (3 3-jime Ru-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[(4-methyl-1-piperazinyl) sulfonyl] benzamide (Example 115) N- (3 3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[(dimethylamino) sulfonyl] benzamide (Example 116) N- (3,3-dimethyl -2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[(cyclohexylamino) sulfonyl] benzamide (Example 117) N- (3,3-dimethyl-2, 3-Dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[(cyclopropylamino) sulfonyl] benzamide
（実施例１１８）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（２，２－ジメチルプロピル）アミノ］スルホニル］ベンズアミド
＜工程１＞５－［［（２，２－ジメチルプロピル）アミノ］スルホニル］安息香酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、２，２－ジメチルプロピルアミン（１．１６ｍＬ）と２－クロロ－５－（クロロスルホニル）安息香酸（０．５０ｇ）より、標記化合物（０．３３ｇ）を白色固体として得た。 Example 118 N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(2,2-dimethylpropyl) amino ] Sulfonyl] benzamide <Step 1> Synthesis of 5-[[(2,2-dimethylpropyl) amino] sulfonyl] benzoic acid (Example 25) 2,2-dimethylpropylamine (Step 2) 1.16 mL) and 2-chloro-5- (chlorosulfonyl) benzoic acid (0.50 g) gave the title compound (0.33 g) as a white solid.
＜工程２＞Ｎ－（３，３－ジメチル－１，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（２，２－ジメチルプロピル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１１８）＜工程１＞で得られた化合物（８６．８ｍｇ）と６－アミノ－３，３－ジメチル－２，３－ジヒドロインドール－２－オン（５０．０ｍｇ）より、標記化合物（１３．０ｍｇ）を白色固体として得た。 <Step 2> N- (3,3-dimethyl-1,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(2,2-dimethylpropyl) amino] Synthesis of Sulfonyl] benzamide In the same manner as in Example 18, the compound (86.8 mg) obtained in <Example 1><Step1> and 6-amino-3,3-dimethyl-2,3-dihydro The title compound (13.0 mg) was obtained as a white solid from indol-2-one (50.0 mg).
（実施例１１９）Ｎ－（２，３－ジヒドロ－３－メチル－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド
　（実施例１８）に準ずる方法で、ジャーナル・オブ・メディシナル・ケミストリー（Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ），３０，１２７９－１２８７，１９８７年に記載された方法に準じて合成した６－アミノ－１，３－ジヒドロ－３－メチル－２Ｈ－インドール－２－オン（５８．４ｍｇ）と２－クロロ－５－（４－モルホリニルスルホニル）安息香酸（１１０．１ｍｇ）より、標記化合物（１４．７ｍｇ）を得た。 Example 119 N- (2,3-dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide (Example 18) 6-amino-1,3-dihydro-3-synthesized according to the method described in Journal of Medicinal Chemistry, 30, 1279-1287, 1987. The title compound (14.7 mg) was obtained from methyl-2H-indol-2-one (58.4 mg) and 2-chloro-5- (4-morpholinylsulfonyl) benzoic acid (110.1 mg).
（実施例１２０）Ｎ－（２，３－ジヒドロ－３－メチル－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、６－アミノ－１，３－ジヒドロ－３－メチル－２Ｈ－インドール－２－オン（５８．４ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１０５ｍｇ）より、標記化合物（１１．７ｍｇ）を得た。 Example 120 N- (2,3-Dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl ] 6-amino-1,3-dihydro-3-methyl-2H-indol-2-one (58.4 mg) and 2-chloro-5-[[(1, The title compound (11.7 mg) was obtained from 1-dimethylethyl) amino] sulfonyl] benzoic acid (105 mg).
（実施例１２１）Ｎ－（２，３－ジヒドロ－３－メチル－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－（１－アゼチジニルスルホニル）ベンズアミド
　（実施例１８）に準ずる方法で、６－アミノ－１，３－ジヒドロ－３－メチル－２Ｈ－インドール－２－オン（５８．４ｍｇ）と５－（１－アゼチジニルスルホニル）－２－クロロ安息香酸（９９．３ｍｇ）より、標記化合物（９．２ｍｇ）を得た。 Example 121 N- (2,3-Dihydro-3-methyl-2-oxo-1H-indol-6-yl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide (Example 18) ), 6-amino-1,3-dihydro-3-methyl-2H-indol-2-one (58.4 mg) and 5- (1-azetidinylsulfonyl) -2-chlorobenzoic acid ( From 99.3 mg), the title compound (9.2 mg) was obtained.
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１２２）Ｎ－（２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１２３）Ｎ－（１，４－ベンゾジオキサン－６－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド
（実施例１２４）Ｎ－（２，３－ジヒドロ－２，２，３，３－テトラフルオロ－１，４－ベンゾジオキシン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 122 N- (2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 123) ) N- (1,4-Benzodioxane-6-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example 124) N- (2,3-dihydro-2,2,3 3-Tetrafluoro-1,4-benzodioxin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
（実施例１２５）Ｎ－（４－アセチル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞３，４－ジヒドロ－２，２－ジメチル－６－ニトロ－２Ｈ－１，４－ベンゾオキサジンの合成
　２，２－ジメチル－６－ニトロ－２Ｈ－ベンゾ［ｂ］［１，４］オキサジン－３（４Ｈ）－オン（２．７４ｇ）のテトラヒドロフラン溶液（１５０．０ｍＬ）に、氷冷下ボラン－テトラヒドロフラン錯体のテトラヒドロフラン溶液（６１．６ｍＬ、１．０Ｍ）を滴下した後、昇温し１時間３０分加熱還流した。反応溶液を室温まで冷やしメタノールを加えた後、１規定塩酸を加え４０分加熱還流した。冷却後、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝８０：２０）で精製し、標記化合物（２．２１ｇ）を橙色固体として得た。 Example 125 N- (4-acetyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1 -Dimethylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine 2,2-dimethyl-6-nitro-2H -To a tetrahydrofuran solution (150.0 mL) of benzo [b] [1,4] oxazin-3 (4H) -one (2.74 g), a tetrahydrofuran solution (61.6 mL, 1. 0M) was added dropwise, and the temperature was raised and the mixture was heated to reflux for 1 hour 30 minutes. The reaction solution was cooled to room temperature, methanol was added, 1N hydrochloric acid was added, and the mixture was heated to reflux for 40 min. After cooling, the mixture was extracted with ethyl acetate 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 = 80: 20) to obtain the title compound (2.21 g) as an orange solid.
＜工程２＞４－アセチル－２，３－ジヒドロ－２，２－ジメチル－６－ニトロ－４Ｈ－１，４－ベンゾオキサジンの合成
　（実施例１２５）＜工程１＞で得た化合物（２．１０ｇ）のピリジン溶液（３０．０ｍＬ）に、室温で無水酢酸（４．７７ｍＬ）、４－（ジメチルアミノ）ピリジン（０．４９ｇ）を加え終夜撹拌した後、昇温し５０℃で５時間、１２０℃で５時間３０分撹拌した。反応溶液にクエン酸水溶液を加え酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝７０：３０）で精製し、標記化合物（１．４２ｇ）を茶色固体として得た。 <Step 2> Synthesis of 4-acetyl-2,3-dihydro-2,2-dimethyl-6-nitro-4H-1,4-benzoxazine (Example 125) Compound obtained in <Step 1> (2. 10 g) to a pyridine solution (30.0 mL), acetic anhydride (4.77 mL) and 4- (dimethylamino) pyridine (0.49 g) were added at room temperature and stirred overnight, and then the temperature was raised to 50 ° C. for 5 hours. The mixture was stirred at 120 ° C. for 5 hours and 30 minutes. To the reaction solution was added an aqueous citric acid solution, 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 = 70: 30) to obtain the title compound (1.42 g) as a brown solid.
＜工程３＞４－アセチル－６－アミノ－２，３－ジヒドロ－２，２－ジメチル－４Ｈ－１，４－ベンゾオキサジンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１２５）＜工程２＞で得られた化合物（１．３０ｇ）より標記化合物（０．９２ｇ）を茶色固体として得た。 <Step 3> Synthesis of 4-acetyl-6-amino-2,3-dihydro-2,2-dimethyl-4H-1,4-benzoxazine (Example 26) In the same manner as in <Step 4>, Example 125) The title compound (0.92 g) was obtained as a brown solid from the compound (1.30 g) obtained in <Step 2>.
＜工程４＞Ｎ－（４－アセチル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１２５）＜工程３＞で得られた化合物（７９．３ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（９９．３ｍｇ）より標記化合物（１８．８ｍｇ）を得た。 <Step 4> N- (4-acetyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1- Synthesis of dimethylethyl) amino] sulfonyl] benzamide In the same manner as in Example 18, the compound (79.3 mg) obtained in (Example 125) <Step 3> and 2-chloro-5-[[(1 , 1-Dimethylethyl) amino] sulfonyl] benzoic acid (99.3 mg) gave the title compound (18.8 mg).
（実施例１２６）Ｎ－（４－アセチル－３，４－ジヒドロ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（１－アゼチジニルスルホニル）ベンズアミド
　（実施例１８）に準ずる方法で、ジャーナル・オブ・メディシナル・ケミストリー（Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ），３２，１６２７－１６３０，１９８９年に記載された方法に準じて合成した４－アセチル－６－アミノ－３，４－ジヒドロ－４Ｈ－１，４－ベンゾオキサジン（６９．２ｍｇ）と５－（１－アゼチジニルスルホニル）－２－クロロ安息香酸（９９．３ｍｇ）より、標記化合物（２０．４ｍｇ）を得た。 Example 126 N- (4-acetyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (1-azetidinylsulfonyl) benzamide 18) 4-acetyl-6-amino-3,4 synthesized according to the method described in Journal of Medicinal Chemistry, 32, 1627-1630, 1989, according to the method according to 18). -Dihydro-4H-1,4-benzoxazine (69.2 mg) and 5- (1-azetidinylsulfonyl) -2-chlorobenzoic acid (99.3 mg) gave the title compound (20.4 mg). .
（実施例１２７）Ｎ－（１，２，３，４－テトラヒドロ－１－アセチルキノリン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より標記化合物を得た。 Example 127 N- (1,2,3,4-Tetrahydro-1-acetylquinolin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide 18) The title compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to 18).
（実施例１２８）Ｎ－［１，２，３，４－テトラヒドロ－１－（トリフルオロアセチル）キノリン－７－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００７／０１０３８３号のパンフレットに記載された方法に従い合成した１，２，３，４－テトラヒドロ－１－（トリフルオロアセチル）－７－キノリンアミン（８７．９ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（３．１ｍｇ）を得た。 Example 128 N- [1,2,3,4-Tetrahydro-1- (trifluoroacetyl) quinolin-7-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] 1,2,3,4-tetrahydro-1- (trifluoroacetyl) -7-quinolinamine synthesized according to the method described in the pamphlet of International Publication No. 2007/010383 by the method according to Benzamide (Example 18) The title compound (3.1 mg) was obtained from (87.9 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
（実施例１２９）Ｎ－（１，４－ジヒドロ－２－オキソ－２Ｈ－３，１－ベンゾオキサジン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した７－アミノ－１，４－ジヒドロ－２Ｈ－３，１－ベンゾオキサジン－２－オン（７１．０ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（７．８ｍｇ）を白色固体として得た。 Example 129 N- (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] 7-amino-1,4-dihydro-2H-3,1-benzoxazin-2-one synthesized according to the method described in the pamphlet of International Publication No. 2008/091021 by a method according to benzamide (Example 18) From 71.0 mg and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg), the title compound (7.8 mg) was obtained as a white solid.
（実施例１３０）Ｎ－（１，２，３，４－テトラヒドロ－３－メチル－２－オキソ－７－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した７－アミノ－３－メチル－３，４－ジヒドロ－１Ｈ－キナゾリン－２－オン（４７．０ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（３０．０ｍｇ）より、標記化合物（５．７ｍｇ）を白色固体として得た。 Example 130 N- (1,2,3,4-Tetrahydro-3-methyl-2-oxo-7-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide 7-amino-3-methyl-3,4-dihydro-1H-quinazolin-2-one synthesized according to the method described in the pamphlet of WO2008 / 091021 by a method according to (Example 18) (47 0.0 mg) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (30.0 mg) gave the title compound (5.7 mg) as a white solid.
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より標記化合物を得た。
（実施例１３１）Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例１３２）Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド
（実施例１３３）Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド In the same manner as in Example 18, the title compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1).
Example 131 N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 132) N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4-morpholinylsulfonyl) benzamide Example 133) N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] Sulfonyl] benzamide
　（実施例１３４）、（実施例１３５）に、（実施例１３３）で得たラセミ体の光学異性体分離用カラムを用いた光学分割について示す。光学異性体分離用カラムを用いた分取クロマトグラフィーにて、第一分画として得られたエナンチオマーを（Ａ）で表し、第二分画として得られたエナンチオマーを（Ｂ）で表す。 (Example 134) and (Example 135) show optical resolution using the column for separation of optical isomers of the racemate obtained in (Example 133). In the preparative chromatography using the optical isomer separation column, the enantiomer obtained as the first fraction is represented by (A), and the enantiomer obtained as the second fraction is represented by (B).
（実施例１３４）（Ｓ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ａ）
（実施例１３５）（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド（Ｂ）
　（実施例１３３）で得た化合物（２６９．０ｍｇ）を分取クロマトグラフィー（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＯＪ－Ｈ　（２．０ｃｍ×２５ｃｍ）、溶出液；ｎ－ヘキサン：エタノール＝５０：５０、流速：１５．０ｍＬ／分、ＵＶ：２３７ｎｍ検出）を用いて光学分割を行うことで標記化合物の各エナンチオマーを、第一分画（５１．３ｍｇ、白色固体、＞９８％ｅｅ、リテンションタイム１３．８分：（エナンチオマーＡ：実施例１３４）、および第二分画（５０．５ｍｇ、白色固体、＞９８％ｅｅ、リテンションタイム１９．４分、：（エナンチオマーＢ：実施例１３５）として得た。
　光学純度はキラルカラムで決定した。（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＯＪ－Ｈ　（０．４６ｃｍ×２５．０ｃｍ）、溶出液；ｎ－ヘキサン：エタノール＝５０：５０、流速：０．６ｍＬ／分、ＵＶ：２３７ｎｍ検出）。 Example 134 (S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide (A)
Example 135 (R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide (B)
The compound (269.0 mg) obtained in (Example 133) was subjected to preparative chromatography (column: CHIRALPAK OJ-H (2.0 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent; n-hexane: ethanol = 50:50, flow rate: 15.0 mL / min, UV: 237 nm detection) to give each enantiomer of the title compound in the first fraction (51.3 mg, white solid,> 98% ee, Retention time 13.8 minutes: (Enantiomer A: Example 134), and second fraction (50.5 mg, white solid,> 98% ee, retention time 19.4 minutes,: (Enantiomer B: Example 135) Got as.
The optical purity was determined with a chiral column. (Column: CHIRALPAK OJ-H (0.46 cm × 25.0 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent: n-hexane: ethanol = 50: 50, flow rate: 0.6 mL / min, UV: 237 nm detection) .
（実施例１３４）（Ｓ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１３４）は以下の方法によっても得られる。
＜工程１＞（Ｓ）－２－（２，４－ジニトロフェノキシ）プロピオン酸メチルの合成
　メチル－（Ｌ）－ラクテート（０．１ｍＬ）のテトラヒドロフラン（５．０ｍＬ）溶液に６０％油状水素化ナトリウム（５０ｍｇ）を加え、１０分撹拌した後、１５－クラウン－５（５滴）、２，４－ジニトロフルオロベンゼン（０．１４ｍＬ）を加え、４５℃で８時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝９２：８～８５：１５）で精製し、標記化合物（１２７ｍｇ）を得た。 Example 134 (S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide (Example 134) can also be obtained by the following method.
<Step 1> Synthesis of methyl (S) -2- (2,4-dinitrophenoxy) propionate 60% oily sodium hydride in a solution of methyl- (L) -lactate (0.1 mL) in tetrahydrofuran (5.0 mL) (50 mg) was added, and the mixture was stirred for 10 min, 15-crown-5 (5 drops) and 2,4-dinitrofluorobenzene (0.14 mL) were added, and the mixture was stirred at 45 ° C. for 8 hr. Water was added to the reaction solution, 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 = 92: 8 to 85:15) to obtain the title compound (127 mg).
＜工程２＞（Ｓ）－６－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オンの合成
　（実施例１３４）＜工程１＞で得られた化合物（１２０ｍｇ）のメタノール（５．０ｍＬ）溶液に、室温で１０％パラジウム－炭素（Ｐｄ／Ｃ）（２０ｍｇ）を加え、水素ガス雰囲気下終夜撹拌した。反応溶液をろ過後、減圧下溶媒を留去し、得られた粗生成物に、トルエン、酢酸を加え加熱還流下６時間撹拌した。反応溶液に１規定水酸化ナトリウム水溶液を加え、酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して標記化合物（６５ｍｇ）を得た。 <Step 2> Synthesis of (S) -6-amino-2-methyl-2H-benzo [1,4] oxazin-3- (4H) -one (Example 134) Compound obtained in <Step 1> To a solution of 120 mg) in methanol (5.0 mL) was added 10% palladium-carbon (Pd / C) (20 mg) at room temperature, and the mixture was stirred overnight under a hydrogen gas atmosphere. After filtering the reaction solution, the solvent was distilled off under reduced pressure. To the obtained crude product, toluene and acetic acid were added, and the mixture was stirred for 6 hours with heating under reflux. 1N Aqueous sodium hydroxide solution was added to the reaction solution, 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 (65 mg).
＜工程３＞（Ｓ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で２－クロロ－５－［（１－メチルエチル）アミノ］スルホニル安息香酸（１００ｍｇ）、（実施例１３４）＜工程２＞で得られた化合物（７７ｍｇ）より標記化合物（１００ｍｇ）を得た。
　得られた化合物をキラルカラムクロマトグラフィー（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＯＪ－Ｈ　（０．４６ｃｍ×２５ｃｍ）、溶出液；ｎ－ヘキサン：エタノール＝５０：５０、流速：０．６ｍＬ／分、ＵＶ：２３７ｎｍ検出）を用いて分析した結果、ラセミ体を分析した時の第一ピークと一致した（リテンションタイム１５．３分）。従って第一ピークをＳ体、第二ピークをＲ体とした。 <Step 3> (S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1- Synthesis of methylethyl) amino] sulfonyl] benzamide 2-Chloro-5-[(1-methylethyl) amino] sulfonylbenzoic acid (100 mg) according to the method according to Example 18 (Example 134) <Step 2> The title compound (100 mg) was obtained from the compound (77 mg) obtained in 1.
The obtained compound was subjected to chiral column chromatography (column: CHIRALPAK OJ-H (0.46 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent; n-hexane: ethanol = 50: 50, flow rate: 0.6 mL / min , UV: 237 nm detection), and coincided with the first peak when the racemate was analyzed (retention time 15.3 minutes). Therefore, the first peak was designated as S-form and the second peak as R-form.
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１３６）Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド
（実施例１３７）Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［（シクロブチルアミノ）スルホニル］ベンズアミド
（実施例１３８）Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 136 N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide Example 137 N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclobutylamino) sulfonyl] Benzamide (Example 138) N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1- Dimethylethyl) amino] sulfonyl] benzamide
（実施例１３９）Ｎ－［３，４－ジヒドロ－２－（２－ヒドロキシエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［メチル（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した６－アミノ－２－（２－ヒドロキシエチル）－４Ｈ－ベンゾ［１，４］オキサジン－３－オン（７５．０ｍｇ）と２－クロロ－５－［［メチル（１－メチルエチル）アミノ］スルホニル］安息香酸（１０５．０ｍｇ）より、標記化合物（１９．４ｍｇ）を得た。 Example 139 N- [3,4-dihydro-2- (2-hydroxyethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[methyl (1-Methylethyl) amino] sulfonyl] benzamide 6-amino-2- (2-hydroxyethyl) synthesized according to the method described in the pamphlet of International Publication No. 2008/091021 by the method according to Example 18 The title compound was obtained from 4H-benzo [1,4] oxazin-3-one (75.0 mg) and 2-chloro-5-[[methyl (1-methylethyl) amino] sulfonyl] benzoic acid (105.0 mg). (19.4 mg) was obtained.
（実施例１４０）Ｎ－（３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　６－アミノ－３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン（６９．２ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１０５．０ｍｇ）より、標記化合物（１８．８ｍｇ）を得た。 Example 140 N- (3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1 -Dimethylethyl) amino] sulfonyl] benzamide 6-amino-3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazine (69.2 mg) and 2-chloro-5- [ The title compound (18.8 mg) was obtained from [(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (105.0 mg).
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１４１）Ｎ－（３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－（１－アゼチジニルスルホニル）－２－クロロベンズアミド
（実施例１４２）Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド
（実施例１４３）Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１４４）Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１４５）Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－（１－アゼチジニルスルホニル）－２－クロロベンズアミド
（実施例１４６）Ｎ－（４－エチル－３，４－ジヒドロ－２メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（２－ヒドロキシ－１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１４７）Ｎ－［３，４－ジヒドロ－２－メチル－４－（１－メチルエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 141 N- (3,4-Dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5- (1-azetidinylsulfonyl) -2 -Chlorobenzamide (Example 142) N- (3,4-Dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4- Morpholinylsulfonyl) benzamide (Example 143) N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5 [[(1-Methylethyl) amino] sulfonyl] benzamide (Example 144) N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-Chloro-5-[[( , 1-dimethylethyl) amino] sulfonyl] benzamide (Example 145) N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5 -(1-Azetidinylsulfonyl) -2-chlorobenzamide (Example 146) N- (4-Ethyl-3,4-dihydro-2methyl-3-oxo-2H-1,4-benzoxazine-6- Yl) -2-chloro-5-[[(2-hydroxy-1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 147) N- [3,4-dihydro-2-methyl-4- (1) -Methylethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
（実施例１４８）Ｎ－［２－メチル－３－［（１－メチルエチル）オキシ］－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞２－メチル－３－［（１－メチルエチル）オキシ］－６－ニトロ－２Ｈ－１，４－ベンゾオキサジンの合成
　（実施例８４）＜工程１＞に準ずる方法で、２－メチル－６－ニトロ－２Ｈ－ベンゾ［ｂ］［１，４］オキサジン－３（４Ｈ）－オン（１．００ｇ）、２－ヨードプロパン（０．９４ｍＬ）より、標記化合物（０．４９ｇ）を黄色油状物質として得た。 Example 148 N- [2-Methyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1-methyl Ethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 2-methyl-3-[(1-methylethyl) oxy] -6-nitro-2H-1,4-benzoxazine (Example 84) <Step 1> From 2-methyl-6-nitro-2H-benzo [b] [1,4] oxazin-3 (4H) -one (1.00 g), 2-iodopropane (0.94 mL), The compound (0.49 g) was obtained as a yellow oil.
＜工程２＞６－アミノ－２－メチル－３－［（１－メチルエチル）オキシ］－２Ｈ－１，４－ベンゾオキサジンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１４８）＜工程１＞で得られた化合物（０．４３ｇ）より標記化合物（０．３８ｇ）を茶色油状物質として得た。 <Step 2> Synthesis of 6-amino-2-methyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazine (Example 26) In the same manner as in <Step 4>, Example 148) The title compound (0.38 g) was obtained as a brown oil from the compound (0.43 g) obtained in <Step 1>.
＜工程３＞Ｎ－［２－メチル－３－［（１－メチルエチル）オキシ］－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、（実施例１４８）＜工程２＞で得られた化合物（７９．３ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より標記化合物（９６．６ｍｇ）を無色アモルファスとして得た。 <Step 3> N- [2-Methyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1-methylethyl ) Amino] sulfonyl] benzamide In the same manner as in Example 18, the compound obtained in (Example 148) <Step 2> (79.3 mg) and 2-chloro-5-[[(1-methylethyl) The title compound (96.6 mg) was obtained as a colorless amorphous form from amino] sulfonyl] benzoic acid (100.0 mg).
（実施例１４９）Ｎ－［３，４－ジヒドロ－４－（２－ヒドロキシエチル）－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より標記化合物を得た。 Example 149 N- [3,4-dihydro-4- (2-hydroxyethyl) -2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5 — [[(1,1-dimethylethyl) amino] sulfonyl] benzamide represented by the formula (XI-1) and the formula (X-1) by a method according to Example 18 The title compound was obtained from carboxylic acid.
（実施例１５０）Ｎ－（３，４－ジヒドロ－２，２，４－トリメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞３，４－ジヒドロ－２，２，４－トリメチル－６－ニトロ－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オンの合成
　（実施例８４）＜工程１＞に準ずる方法で、３，４－ジヒドロ－２、２－ジメチル－６－ニトロ－２Ｈ－ベンゾ［ｂ］［１，４］オキサジン－３（４Ｈ）－オン（１．００ｇ）とヨードメタン（０．８４ｍＬ）より、標記化合物（０．９６ｇ）を黄色固体として得た。 Example 150 N- (3,4-Dihydro-2,2,4-trimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 , 1-Dimethylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 3,4-dihydro-2,2,4-trimethyl-6-nitro-2H-1,4-benzoxazin-3 (4H) -one Example 84 3,4-Dihydro-2,2-dimethyl-6-nitro-2H-benzo [b] [1,4] oxazin-3 (4H) -one by the method according to <Step 1> The title compound (0.96 g) was obtained as a yellow solid from 1.00 g) and iodomethane (0.84 mL).
＜工程２＞６－アミノ－２，２，４－トリメチル－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１５０）＜工程１＞で得られた化合物（０．９３ｇ）より標記化合物（０．７７ｇ）を白色固体として得た。 <Step 2> Synthesis of 6-amino-2,2,4-trimethyl-2H-1,4-benzoxazin-3 (4H) -one (Example 26) In the same manner as in <Step 4>, (Example 150) The title compound (0.77 g) was obtained as a white solid from the compound (0.93 g) obtained in <Step 1>.
＜工程３＞Ｎ－（３，４－ジヒドロ－２，２，４－トリメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１５０）＜工程２＞で得られた化合物（７４．２ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１０５．０ｍｇ）より標記化合物（２９．６ｍｇ）を得た。 <Step 3> N- (3,4-dihydro-2,2,4-trimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1, Synthesis of 1-dimethylethyl) amino] sulfonyl] benzamide Using a method similar to that in Example 18, the compound (74.2 mg) obtained in (Example 150) <Step 2> and 2-chloro-5-[[ The title compound (29.6 mg) was obtained from (1,1-dimethylethyl) amino] sulfonyl] benzoic acid (105.0 mg).
（実施例１５１）Ｎ－（４－エチル－３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞４－エチル－３，４－ジヒドロ－２，２－ジメチル－６－ニトロ－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オンの合成
　（実施例８４）＜工程１＞に準ずる方法で、３，４－ジヒドロ－２，２－ジメチル－６－ニトロ－２Ｈ－ベンゾオキサジン［ｂ］［１，４］オキサジン－３（４Ｈ）－オン（１．００ｇ）、ヨードエタン（０．４０ｍＬ）より、標記化合物（０．７６ｇ）を黒色固体として得た。 Example 151 N- (4-Ethyl-3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[ (1,1-Dimethylethyl) amino] sulfonyl] benzamide <Step 1> 4-Ethyl-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-3 (4H) Synthesis of —one (Example 84) 3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzoxazine [b] [1,4] oxazine-3 (by the method according to <Step 1>) The title compound (0.76 g) was obtained as a black solid from 4H) -one (1.00 g) and iodoethane (0.40 mL).
＜工程２＞６－アミノ－４－エチル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１５１）＜工程１＞で得られた化合物（０．７０ｇ）より標記化合物（０．６２ｇ）を茶色固体として得た。 <Step 2> Synthesis of 6-amino-4-ethyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (Example 26) <Step 4> The title compound (0.62 g) was obtained as a brown solid from the compound (0.70 g) obtained in (Example 151) <Step 1>.
＜工程３＞Ｎ－（４－エチル－３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、（実施例１５１）＜工程２＞で得られた化合物（７５．５ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（８６．０ｍｇ）を白色固体として得た。 <Step 3> N- (4-ethyl-3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[( 1,1-Dimethylethyl) amino] sulfonyl] benzamide (Example 151) The compound (75.5 mg) obtained in <Step 2> and 2-chloro-5-[[ From (1,1-dimethylethyl) amino] sulfonyl] benzoic acid (100.0 mg), the title compound (86.0 mg) was obtained as a white solid.
（実施例１５２）Ｎ－［３，４－ジヒドロ－２，２－ジメチル－４－（１－メチルエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞３，４－ジヒドロ－２，２－ジメチル－４－（１－メチルエチル）－６－ニトロ－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オンの合成
　（実施例８４）＜工程１＞に準ずる方法で、３，４－ジヒドロ－２，２－ジメチル－６－ニトロ－２Ｈ－ベンゾ［ｂ］［１，４］オキサジン－３（４Ｈ）－オン（１．００ｇ）、２－ヨードプロパン（０．９４ｍＬ）より、標記化合物（０．３１ｇ）を黄色固体として得た。また、この時、２，２－ジメチル－３－［（１－メチルエチル）オキシ］－６－ニトロ－２Ｈ－ベンゾオキサジン（０．５４ｇ）を黄色固体として得た。 Example 152 N- [3,4-dihydro-2,2-dimethyl-4- (1-methylethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro -5-[[(1-Methylethyl) amino] sulfonyl] benzamide <Step 1> 3,4-Dihydro-2,2-dimethyl-4- (1-methylethyl) -6-nitro-2H-1,4 Synthesis of —benzoxazin-3 (4H) -one (Example 84) 3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo [b] [1] by the method according to <Step 1> , 4] Oxazin-3 (4H) -one (1.00 g) and 2-iodopropane (0.94 mL) gave the title compound (0.31 g) as a yellow solid. At this time, 2,2-dimethyl-3-[(1-methylethyl) oxy] -6-nitro-2H-benzoxazine (0.54 g) was obtained as a yellow solid.
＜工程２＞６－アミノ－３，４－ジヒドロ－２，２－ジメチル－４－（１－メチルエチル）－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１５２）＜工程１＞で得た２，２－ジメチル－４－（１－メチルエチル）－６－ニトロ－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オン（０．３０ｇ）より標記化合物（０．２７ｇ）を茶色油状物質として得た。 <Step 2> Synthesis of 6-amino-3,4-dihydro-2,2-dimethyl-4- (1-methylethyl) -2H-1,4-benzoxazin-3 (4H) -one (Example 26) ) 2,2-Dimethyl-4- (1-methylethyl) -6-nitro-2H-1,4-benzoxazine obtained in <Step 1> according to the method according to <Step 4> The title compound (0.27 g) was obtained as a brown oil from 3 (4H) -one (0.30 g).
＜工程３＞Ｎ－［３，４－ジヒドロ－２，２－ジメチル－４－（１－メチルエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、（実施例１５２）＜工程２＞で得られた化合物（８４．４ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（１６１．８ｍｇ）を無色アモルファスとして得た。 <Step 3> N- [3,4-dihydro-2,2-dimethyl-4- (1-methylethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro- 5-[[(1-Methylethyl) amino] sulfonyl] benzamide (Example 152) The compound (84.4 mg) obtained in <Step 2> and 2-chloro-5 were prepared in the same manner as in Example 18. The title compound (161.8 mg) was obtained as colorless amorphous from-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
（実施例１５３）Ｎ－［２，２－ジメチル－３－［（１－メチルエチル）オキシ］－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞６－アミノ－２，２－ジメチル－３－［（１－メチルエチル）オキシ］－２Ｈ－ベンゾオキサジンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１５２）＜工程１＞で得た２，２－ジメチル－３－［（１－メチルエチル）オキシ］－６－ニトロ－２Ｈ－ベンゾオキサジン（０．５３ｇ）より、標記化合物（０．４７ｇ）を茶色油状物質として得た。 Example 153 N- [2,2-dimethyl-3-[(1-methylethyl) oxy] -2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1 -Methylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 6-amino-2,2-dimethyl-3-[(1-methylethyl) oxy] -2H-benzoxazine (Example 26) <Step 4> (Example 152) From 2,2-dimethyl-3-[(1-methylethyl) oxy] -6-nitro-2H-benzoxazine (0.53 g) obtained in <Step 1>, The title compound (0.47 g) was obtained as a brown oil.
＜工程２＞Ｎ－（２，２－ジメチル－４－（１－メチルエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、実施例１５３＜工程１＞で得られた化合物（８４．４ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（１１８．６ｍｇ）を白色固体として得た。 <Step 2> N- (2,2-dimethyl-4- (1-methylethyl) -3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 Synthesis of -methylethyl) amino] sulfonyl] benzamide In the same manner as in Example 18, the compound (84.4 mg) obtained in Example 153 <Step 1> and 2-chloro-5-[[(1- The title compound (118.6 mg) was obtained as a white solid from (methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
（実施例１５４）Ｎ－［３，４－ジヒドロ－４－（２－ヒドロキシエチル）－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞３，４－ジヒドロ－４－（２－ヒドロキシエチル）－２，２－ジメチル－６－ニトロ－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オンの合成
　２，２－ジメチル－６－ニトロ－２Ｈ－ベンゾオキサジン［ｂ］［１，４］オキサジン－３（４Ｈ）－オン（１．００ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（１０．０ｍＬ）に、室温で６０％油状水素化ナトリウム（０．２７ｇ）、２－（２－ブロモエトキシ）テトラヒドロ－２Ｈ－ピラン（１．４３ｍＬ）を加え終夜撹拌した。反応溶液に水を加え酢酸エチルで抽出、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をメタノール（５０．０ｍＬ）に溶解し、室温でｐ－トルエンスルホン酸・一水和物を加え２時間撹拌した。反応溶液に５％クエン酸水溶液を加え酢酸エチルで抽出し水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝１００：０～７０：３０）で精製し、標記化合物（０．７２ｇ）を茶色固体として得た。 Example 154 N- [3,4-dihydro-4- (2-hydroxyethyl) -2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro -5-[[(1-Methylethyl) amino] sulfonyl] benzamide <Step 1> 3,4-Dihydro-4- (2-hydroxyethyl) -2,2-dimethyl-6-nitro-2H-1,4 -Synthesis of benzoxazin-3 (4H) -one 2,2-dimethyl-6-nitro-2H-benzoxazine [b] [1,4] oxazin-3 (4H) -one (1.00 g) N, To an N-dimethylformamide solution (10.0 mL), 60% oily sodium hydride (0.27 g) and 2- (2-bromoethoxy) tetrahydro-2H-pyran (1.43 mL) were added at room temperature and stirred overnight. Water was added to the reaction solution, 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 dissolved in methanol (50.0 mL), p-toluenesulfonic acid monohydrate was added at room temperature, and the mixture was stirred for 2 hr. To the reaction solution was added 5% aqueous citric acid solution, 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 = 100: 0 to 70:30) to give the title compound (0.72 g) as brown Obtained as a solid.
＜工程２＞６－アミノ－３，４－ジヒドロ－４－（２－ヒドロキシエチル）－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－３（４Ｈ）－オンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１５４）＜工程１＞で合成した化合物（０．６６ｇ）より標記化合物（０．５５ｇ）を茶色固体として得た。 <Step 2> Synthesis of 6-amino-3,4-dihydro-4- (2-hydroxyethyl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (Example 26) ) By the method according to <Step 4>, the title compound (0.55 g) was obtained as a brown solid from the compound (0.66 g) synthesized in (Example 154) <Step 1>.
＜工程３＞Ｎ－［３，４－ジヒドロ－４－（２－ヒドロキシエチル）－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１５４）＜工程２＞で合成した化合物（８５．２ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（０．１８ｇ）を無色アモルファスとして得た。 <Step 3> N- [3,4-dihydro-4- (2-hydroxyethyl) -2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro- Synthesis of 5-[[(1-methylethyl) amino] sulfonyl] benzamide The compound (85.2 mg) synthesized in (Step 154) <Step 2> and 2-chloro- The title compound (0.18 g) was obtained as a colorless amorphous form from 5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より標記化合物を得た。
（実施例１５５）Ｎ－［３，４－ジヒドロ－４－（２－ヒドロキシエチル）－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［（シクロブチルアミノ）スルホニル］ベンズアミド
（実施例１５６）Ｎ－（３，４－ジヒドロ－４－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－（１－アゼチジニルスルホニル）－２－クロロベンズアミド In the same manner as in Example 18, the title compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1).
Example 155 N- [3,4-dihydro-4- (2-hydroxyethyl) -3-oxo-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[(cyclo Butylamino) sulfonyl] benzamide (Example 156) N- (3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5- (1-azetidinyl) Sulfonyl) -2-chlorobenzamide
（実施例１５７）Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－７－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した７－アミノ－３，４－ジヒドロ－１Ｈ－キナゾリン－２－オン（５８．８ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（３．５ｍｇ）を白色固体として得た。 Example 157 N- (1,2,3,4-tetrahydro-2-oxo-7-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide Example 18 7-amino-3,4-dihydro-1H-quinazolin-2-one (58.8 mg) synthesized according to the method described in the pamphlet of WO 2008/091021 and 2-chloro- The title compound (3.5 mg) was obtained as a white solid from 5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１５８）Ｎ－（１，２，３，４－テトラヒドロ－１－メチル－２－オキソ－７－キノリノイル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１５９）Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－７－キノリノイル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１６０）Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１６１）Ｎ－（３，４－ジヒドロ－４－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－７－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 158 N- (1,2,3,4-Tetrahydro-1-methyl-2-oxo-7-quinolinoyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide Example 159 N- (1,2,3,4-tetrahydro-2-oxo-7-quinolinoyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide Example 160) N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide ( Example 161) N- (3,4-Dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl) -2-chloro-5-[[(1-methylethyl) amino ] Sulfonyl] Nzuamido
（実施例１６２）Ｎ－（１，４－ジヒドロ－２－オキソ－２Ｈ－３，１－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞６－アミノ－１，４－ジヒドロ－２－オキソ－２Ｈ－３，１－ベンゾオキサジンの合成
　（実施例２６）＜工程４＞に準ずる方法で、３，４－ジヒドロ－６－ニトロ－２Ｈ－３，１－ベンゾオキサジン－２－オン（０．５０ｇ）より、標記化合物（７１．０ｍｇ）を得た。
＜工程２＞Ｎ－（１，４－ジヒドロ－２－オキソ－２Ｈ－３，１－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１６２）＜工程１＞で得られた化合物（７１．０ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（３０．０ｍｇ）より、標記化合物（１６．２ｍｇ）を白色固体として得た。 Example 162 N- (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] Benzamide <Step 1> Synthesis of 6-amino-1,4-dihydro-2-oxo-2H-3,1-benzoxazine Example 26 According to the method according to <Step 4>, 3,4-dihydro-6 The title compound (71.0 mg) was obtained from -nitro-2H-3,1-benzoxazin-2-one (0.50 g).
<Step 2> N- (1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 162) The compound (71.0 mg) obtained in <Step 1> and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] were prepared according to the method of Example 18). The title compound (16.2 mg) was obtained as a white solid from benzoic acid (30.0 mg).
（実施例１６３）Ｎ－（１，３－ジメチル－１，２，３，４－テトラヒドロ－２－オキソ－６－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞Ｎ－（２－アミノ－５－ニトロベンジル）メチルアミンの合成
　（実施例８３）＜工程１＞に準ずる方法で、２－アミノ－５－ニトロベンズアルデヒド（１．００ｇ）とメチルアミン－テトラヒドロフラン溶液（３．６ｍＬ、２．０Ｍ）より、標記化合物（０．５０ｇ）を橙色固体として得た。
＜工程２＞３－メチル－６－ニトロ－３，４－ジヒドロ－２（１Ｈ）－キナゾリノンの合成
　（実施例８３）＜工程２＞に準ずる方法で、（実施例１６３）＜工程１＞で得た化合物（０．５０ｇ）より標記化合物（０．２２ｇ）を黄色固体として得た。
＜工程３＞１，３－ジメチル－６－ニトロ－３，４－ジヒドロ－２（１Ｈ）－キナゾリノンの合成
　（実施例８４）＜工程１＞に準ずる方法で、（実施例１６３）＜工程２＞で得られた化合物（１２０．０ｍｇ）より標記化合物（９０．０ｍｇ）を黄色固体として得た。
＜工程４＞６－アミノ－１，３－ジメチル－３，４－ジヒドロ－２（１Ｈ）－キナゾリノンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１６３）＜工程３＞で得られた化合物（９０．０ｍｇ）より標記化合物（３０．０ｍｇ）を黄色固体として得た。
＜工程５＞Ｎ－（１，３－ジメチル－１，２，３，４－テトラヒドロ－２－オキソ－７－キナゾリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニルベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１６３）＜工程４＞で得られた化合物（４３．２ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（３０．０ｍｇ）より標記化合物（２．１ｍｇ）を白色固体として得た。 Example 163 N- (1,3-dimethyl-1,2,3,4-tetrahydro-2-oxo-6-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl Benzamide <Step 1> Synthesis of N- (2-amino-5-nitrobenzyl) methylamine (Example 83) According to the method according to <Step 1>, 2-amino-5-nitrobenzaldehyde (1.00 g) and The title compound (0.50 g) was obtained as an orange solid from a methylamine-tetrahydrofuran solution (3.6 mL, 2.0 M).
<Step 2> Synthesis of 3-methyl-6-nitro-3,4-dihydro-2 (1H) -quinazolinone (Example 83) In the same manner as <Step 2>, (Example 163) in <Step 1> The title compound (0.22 g) was obtained as a yellow solid from the obtained compound (0.50 g).
<Step 3> Synthesis of 1,3-dimethyl-6-nitro-3,4-dihydro-2 (1H) -quinazolinone (Example 84) In the same manner as in <Step 1>, (Example 163) <Step 2 > (120.0 mg) gave the title compound (90.0 mg) as a yellow solid.
<Step 4> Synthesis of 6-amino-1,3-dimethyl-3,4-dihydro-2 (1H) -quinazolinone (Example 26) In the same manner as in <Step 4>, (Example 163) <Step 3 The title compound (30.0 mg) was obtained as a yellow solid from the compound (90.0 mg) obtained in>.
<Step 5> N- (1,3-Dimethyl-1,2,3,4-tetrahydro-2-oxo-7-quinazolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonylbenzamide (Example 163) The compound (43.2 mg) obtained in <Step 4> and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] were prepared according to the method of Example 18). The title compound (2.1 mg) was obtained as a white solid from benzoic acid (30.0 mg).
（実施例１６４）Ｎ－（１，２，３，４－テトラヒドロ－２－オキソ－６－キノリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より標記化合物を得た。 Example 164 N- (1,2,3,4-tetrahydro-2-oxo-6-quinolinyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 18) ), The title compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1).
（実施例１６５）Ｎ－（３，４－ジヒドロ－２，２－ジオキソ－１Ｈ－２，１－ベンゾチアジン－７－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した７－アミノ－２，２－ジオキソ－３，４－ジヒドロ－１Ｈ－２，１－ベンゾチアジン（７１．４ｍｇ）と２－クロロ－５－［（シクロペンチルアミノ）スルホニル］安息香酸（１０９．４ｍｇ）より、標記化合物（２３．４ｍｇ）を得た。 Example 165 N- (3,4-dihydro-2,2-dioxo-1H-2,1-benzothiazin-7-yl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide (Example) 18-) 7-amino-2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazine (71.) synthesized according to the method described in the pamphlet of International Publication No. 2008/091021. 4 mg) and 2-chloro-5-[(cyclopentylamino) sulfonyl] benzoic acid (109.4 mg) gave the title compound (23.4 mg).
（実施例１６６）Ｎ－（２，３－ジヒドロ－３－ヒドロキシ－１Ｈ－インデン－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、国際公開第２００７／０１０３８３号のパンフレットに記載された方法に従い合成した６－アミノ－２，３－ジヒドロ－１Ｈ－インデン－１－オール（５３．７ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００ｍｇ）より標記化合物（１６．１ｍｇ）を得た。 Example 166 N- (2,3-dihydro-3-hydroxy-1H-inden-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide Example 18 6-amino-2,3-dihydro-1H-inden-1-ol (53.7 mg) and 2-chloro-synthesized according to the method described in the pamphlet of WO 2007/010383. The title compound (16.1 mg) was obtained from 5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100 mg).
（実施例１６７）Ｎ－（５，６，７，８－テトラヒドロ－８－ヒドロキシ－２－ナフタレニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞１，２，３，４－テトラヒドロ－７－ニトロ－１－ナフトールの合成
　７－ニトロ－１－テトラロン（１０．１ｇ）のエタノール溶液（１００．０ｍＬ）に、氷冷下にて水素化ホウ素ナトリウム（２．０ｇ）を加え、室温で１時間撹拌した。反応溶液を氷水に注ぎ、酢酸エチルで抽出した。有機相を水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し標記粗化合物（１１．０ｇ）を得た。
＜工程２＞７－アミノ－１，２，３，４－テトラヒドロ－１－ナフトールの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１６７）＜工程１＞で得られた化合物（１０．２ｇ）より標記化合物（６．５ｇ）を桃色固体として得た。
＜工程３＞Ｎ－（５，６，７，８－テトラヒドロ－８－ヒドロキシ－２－ナフタレニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１６７）＜工程２＞で得られた化合物（５５．４ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より標記化合物（２０．５ｍｇ）を得た。 Example 167 N- (5,6,7,8-tetrahydro-8-hydroxy-2-naphthalenyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 1,2,3,4-tetrahydro-7-nitro-1-naphthol Sodium borohydride in an ethanol solution (100.0 mL) of 7-nitro-1-tetralone (10.1 g) under ice-cooling (2.0 g) was added and stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase 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 (11.0 g).
<Step 2> Synthesis of 7-amino-1,2,3,4-tetrahydro-1-naphthol (Example 26) According to <Step 4>, obtained in (Example 167) <Step 1>. The title compound (6.5 g) was obtained as a pink solid from the compound (10.2 g).
<Step 3> Synthesis of N- (5,6,7,8-tetrahydro-8-hydroxy-2-naphthalenyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Examples) 18)) (Example 167) The compound (55.4 mg) obtained in <Step 2> and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (100. The title compound (20.5 mg) was obtained from 0 mg).
（実施例１６８）Ｎ－（５，６，７，８－テトラヒドロ－７－ヒドロキシ－２－ナフタレニル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド
＜工程１＞７－ニトロ－１，２，３，４－テトラヒドロ－２－ナフトールの合成
　（実施例１６７）＜工程１＞に準ずる方法で、ジャーナル・オブ・ジ・アメリカン・ケミカル・ソサイエティー（Ｊｏｕｒｎａｌ　ｏｆ　ｔｈｅ　Ａｍｅｒｉｃａｎ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｅｔｙ）、１１９、１２７２２－１２７２６、１９９７年に記載された方法に準じて合成した７－ニトロ－２－テトラロン（９．８ｇ）より標記化合物（７．２ｇ）を得た。 Example 168 N- (5,6,7,8-tetrahydro-7-hydroxy-2-naphthalenyl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide <Step 1> 7-Nitro-1 Synthesis of 1,2,3,4-tetrahydro-2-naphthol (Example 167) Journal of the American Chemical Society, 119, according to the method according to <Step 1> The title compound (7.2 g) was obtained from 7-nitro-2-tetralone (9.8 g) synthesized according to the method described in 12722-12726, 1997.
＜工程２＞７－アミノ－１，２，３，４－テトラヒドロ－２－ナフトールの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１６８）＜工程１＞で得られた化合物（７．２ｇ）より標記化合物（５．８ｇ）を桃色固体として得た。 <Step 2> Synthesis of 7-amino-1,2,3,4-tetrahydro-2-naphthol (Example 26) According to <Step 4>, obtained in (Example 168) <Step 1>. The title compound (5.8 g) was obtained as a pink solid from the compound (7.2 g).
＜工程３＞Ｎ－（５，６，７，８－テトラヒドロ－７－ヒドロキシ－２－ナフタレニル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１６８）＜工程２＞で得られた化合物（５８．８ｍｇ）と２－クロロ－５－［（シクロペンチルアミノ）スルホニル］安息香酸（１０９．４ｍｇ）より標記化合物（２４．７ｍｇ）を得た。 <Step 3> Synthesis of N- (5,6,7,8-tetrahydro-7-hydroxy-2-naphthalenyl) -2-chloro-5-[(cyclopentylamino) sulfonyl] benzamide A method according to Example 18 (Example 168) From the compound (58.8 mg) obtained in <Step 2> and 2-chloro-5-[(cyclopentylamino) sulfonyl] benzoic acid (109.4 mg), the title compound (24.7 mg) Got.
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１６９）Ｎ－（５，６，７，８－テトラヒドロ－５－オキソ－２－ナフタレニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１７０）Ｎ－（５，６，７，８－テトラヒドロナフタレン－２－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１７１）Ｎ－［２－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，４－テトラヒドロイソキノリン－７－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 169 N- (5,6,7,8-tetrahydro-5-oxo-2-naphthalenyl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 170) ) N- (5,6,7,8-tetrahydronaphthalen-2-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 171) N- [2- ( tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-7-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
（実施例１７２）Ｎ－（１，２，３，４－テトラヒドロイソキノリン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド・塩酸塩
＜工程１＞Ｎ－［２－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，４－テトラヒドロイソキノリン－６－イル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成　
　（実施例１８）に準ずる方法で、６－アミノ－２－Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－１，２，３，４－テトラヒドロイソキノリン（８９．４ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より標記化合物（１８．８ｍｇ）を得た。 Example 172 N- (1,2,3,4-tetrahydroisoquinolin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide hydrochloride <Step 1> Synthesis of N- [2- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
In accordance with a method according to (Example 18), 6-amino-2-N- (tert-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline (89.4 mg) and 2-chloro-5-[[( The title compound (18.8 mg) was obtained from 1-methylethyl) amino] sulfonyl] benzoic acid (100.0 mg).
＜工程２＞Ｎ－（１，２，３，４－テトラヒドロイソキノリン－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド・塩酸塩の合成
　（実施例１７２）＜工程１＞で得られた化合物（１３．７ｍｇ）のジオキサン溶液（０．５０ｍＬ）に、室温で４規定塩酸－ジオキサン溶液（０．５０ｍＬ）を加え終夜撹拌した。減圧下溶媒を留去し、減圧乾燥することで標記化合物（１１．５ｍｇ）を得た。 <Step 2> Synthesis of N- (1,2,3,4-tetrahydroisoquinolin-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide hydrochloride 172) A 4N hydrochloric acid-dioxane solution (0.50 mL) was added to a dioxane solution (0.50 mL) of the compound obtained in <Step 1> (13.7 mg) at room temperature, and the mixture was stirred overnight. The title compound (11.5 mg) was obtained by evaporating the solvent under reduced pressure and drying under reduced pressure.
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１７３）Ｎ－（６－キノリニル）－２－クロロ－５－（１－ピペリジニルスルホニル）ベンズアミド
（実施例１７４）Ｎ－（６－キノキサリニル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１７５）Ｎ－（１Ｈ－インドール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１７６）Ｎ－（１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１７７）Ｎ－（１Ｈ－インダゾール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１７８）Ｎ－（１，３－ベンゾジオキソール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１７９）Ｎ－（ベンゾチアゾール－６－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１８０）Ｎ－（１Ｈ－インダゾール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１８１）Ｎ－（２，３－ジヒドロ－２－オキソ－１Ｈ－ベンズイミダゾール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１８２）Ｎ－（２，２－ジフルオロ－１，３－ベンゾジオキソール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１８３）Ｎ－（２，３－ジヒドロ－２－オキソ－５－ベンゾオキサゾリル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 173 N- (6-quinolinyl) -2-chloro-5- (1-piperidinylsulfonyl) benzamide (Example 174) N- (6-quinoxalinyl) -2-chloro-5-[[( 1-methylethyl) amino] sulfonyl] benzamide (Example 175) N- (1H-Indol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 176) ) N- (1H-Indol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 177) N- (1H-indazol-6-yl) -2 -Chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 178) N- (1,3-benzodioxol-5-yl) -2-chloro-5- [(1-Methylethyl) amino] sulfonyl] benzamide (Example 179) N- (Benzothiazol-6-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 180) N- (1H-indazol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 181) N- (2,3-dihydro-2-oxo -1H-benzimidazol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 182) N- (2,2-difluoro-1,3-benzodio Xol-5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 183) N- (2,3-dihydro-2- Kiso-5-benzoxazolyl) -2-chloro-5 - [(cyclopentylamino) sulfonyl] benzamide
（実施例１８４）Ｎ－［２，３－ジヒドロ－２－オキソ－７－（トリフルオロメチル）－５－ベンゾオキサゾリル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞２－ベンジルオキシ－３，５－ジニトロベンゾトリフルオリドの合成
　２－クロロ－３，５－ジニトロベンゾトリフルオリド（５．０ｇ）、ベンジルアルコール（２．１０ｍＬ）のテトラヒドロフラン溶液（１００．０ｍＬ）に、室温でｔ－ブトキシカリウム（４．１４ｇ）を加え終夜撹拌した。反応溶液に水を入れ酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９０：１０～７０：３０）で精製し、標記化合物（１．６７ｇ）を白色固体として得た。 Example 184 N- [2,3-dihydro-2-oxo-7- (trifluoromethyl) -5-benzoxazolyl] -2-chloro-5-[[(1-methylethyl) amino] [Sulfonyl] benzamide <Step 1> Synthesis of 2-benzyloxy-3,5-dinitrobenzotrifluoride Tetrahydrofuran solution of 2-chloro-3,5-dinitrobenzotrifluoride (5.0 g) and benzyl alcohol (2.10 mL) (100.0 mL) was added t-butoxypotassium (4.14 g) at room temperature and stirred overnight. Water was added to the reaction solution, 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 purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 90: 10 to 70:30) to give the title compound (1.67 g) as a white solid. Obtained.
＜工程２＞２，４－ジアミノ－６－（トリフルオロメチル）フェノール・２塩酸塩の合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例１８４）＜工程１＞で得た化合物（１．５０ｇ）より標記化合物（１．１３ｇ）を淡紫色固体として得た。 <Step 2> Synthesis of 2,4-diamino-6- (trifluoromethyl) phenol dihydrochloride (Example 26) According to <Step 4>, obtained in (Example 184) <Step 1> The title compound (1.13 g) was obtained as a pale purple solid from the compound (1.50 g).
＜工程３＞５－アミノ－７－（トリフルオロメチル）－２（３Ｈ）－ベンゾオキサゾロンの合成
　（実施例８３）＜工程２＞に準ずる方法で、（実施例１８４）＜工程２＞で得られた化合物（３００ｍｇ）より標記化合物（９８．０ｍｇ）を淡紫色固体として得た。 <Step 3> Synthesis of 5-amino-7- (trifluoromethyl) -2 (3H) -benzoxazolone (Example 83) According to <Step 2>, obtained in (Example 184) <Step 2> The title compound (98.0 mg) was obtained as a pale purple solid from the obtained compound (300 mg).
＜工程４＞Ｎ－［２，３－ジヒドロ－２－オキソ－７－（トリフルオロメチル）－５－ベンゾオキサゾリル］－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例１８４）＜工程３＞で得られた５－アミノ－７－（トリフルオロメチル）－２（３Ｈ）－ベンゾオキサゾロン（４７．１ｍｇ）、２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（６０．０ｍｇ）より、標記化合物（４８．０ｍｇ）を白色固体として得た。 <Step 4> N- [2,3-dihydro-2-oxo-7- (trifluoromethyl) -5-benzoxazolyl] -2-chloro-5-[[(1-methylethyl) amino] sulfonyl Synthesis of benzamide 5-amino-7- (trifluoromethyl) -2 (3H) -benzoxazolone (47.1 mg) obtained in (Example 184) <Step 3> by a method according to (Example 18) ), 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (60.0 mg), gave the title compound (48.0 mg) as a white solid.
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１８５）Ｎ－（２－メチル－５－ベンゾオキサゾリル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１８６）Ｎ－（ベンゾフラン－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
（実施例１８７）Ｎ－（２，３－ジヒドロ－１－メチル－２－オキソ－１Ｈ－インドール－５－イル）－２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 185 N- (2-Methyl-5-benzoxazolyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 186) N- (benzofuran -5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide (Example 187) N- (2,3-dihydro-1-methyl-2-oxo-1H-indole -5-yl) -2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzamide
（実施例１８８）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－５－［［（１－メチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド
＜工程１＞５－（メチルチオ）－２－（トリフルオロメチル）安息香酸の合成
　５－フルオロ－２－（トリフルオロメチル）安息香酸（１．０ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（１０．０ｍＬ）に、室温でナトリウムチオメトキシド（１．３５ｇ）を加え終夜撹拌した。反応溶液に水を入れ、析出した固体を濾別し水、ヘキサンで順次洗浄した後、減圧乾燥して標記化合物（０．６５ｇ）を白色固体として得た。 Example 188 N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -5-[[(1-methylethyl) amino] sulfonyl] -2- (Trifluoromethyl) benzamide <Step 1> Synthesis of 5- (methylthio) -2- (trifluoromethyl) benzoic acid N, N- of 5-fluoro-2- (trifluoromethyl) benzoic acid (1.0 g) To a dimethylformamide solution (10.0 mL), sodium thiomethoxide (1.35 g) was added at room temperature and stirred overnight. Water was added to the reaction solution, and the precipitated solid was separated by filtration, washed successively with water and hexane, and then dried under reduced pressure to obtain the title compound (0.65 g) as a white solid.
＜工程２＞５－（クロロスルホニル）－２－（トリフルオロメチル）安息香酸の合成
　（実施例１８８）＜工程１＞で得られた化合物（２００．０ｍｇ）のクロロベンゼン－水（２．２ｍＬ、１０：１）溶液に、塩素ガスを室温で５時間バブリングした。析出した固体を濾趣しヘキサンで洗浄した後、減圧乾燥して標記粗化合物（９８．０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of 5- (chlorosulfonyl) -2- (trifluoromethyl) benzoic acid (Example 188) The compound (200.0 mg) obtained in <Step 1> in chlorobenzene-water (2.2 mL, 10: 1) Chlorine gas was bubbled through the solution at room temperature for 5 hours. The precipitated solid was filtered, washed with hexane, and dried under reduced pressure to give the title crude compound (98.0 mg) as a white solid.
＜工程３＞５－［（１－メチルエチル）アミノスルホニル］－２－（トリフルオロメチル）安息香酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例１８８）＜工程２＞で得られた粗化合物（６５．０ｍｇ）とイソプロピルアミン（９６μＬ）より標記粗化合物（３６．０ｍｇ）を白色固体として得た。 <Step 3> Synthesis of 5-[(1-methylethyl) aminosulfonyl] -2- (trifluoromethyl) benzoic acid (Example 25) In the same manner as in <Step 1>, (Example 188) <Step 2 > The crude compound (65.0 mg) obtained in> and isopropylamine (96 μL) gave the title crude compound (36.0 mg) as a white solid.
＜工程４＞Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－５－［［（１－メチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミドの合成
　（実施例１８）に準ずる方法で（実施例１８８）＜工程３＞で得られた粗化合物（３０．０ｍｇ）と６－アミノ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール（１７．０ｍｇ）より、標記化合物（２８ｍｇ）を白色固体として得た。 <Step 4> N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -5-[[(1-methylethyl) amino] sulfonyl] -2- ( Synthesis of (trifluoromethyl) benzamide (Example 188) The crude compound (30.0 mg) obtained in <Step 3> and 6-amino-3,3-dimethyl-2-oxo by a method similar to Example 18) The title compound (28 mg) was obtained as a white solid from -2,3-dihydro-1H-indole (17.0 mg).
（実施例１８９）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－フルオロ－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より標記化合物を得た。 Example 189 N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-fluoro-5-[[(1-methylethyl) amino] sulfonyl The title compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to benzamide (Example 18).
（実施例１９０）Ｎ－［４－（トリフルオロメトキシ）フェニル］－［１－（１－ピペリジニルスルホニル）］－３－ピペリジンカルボキシアミド
＜工程１＞[１－（１－ピペリジニルスルホニル）]－３－ピペリジンカルボン酸エチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、ニペコチン酸エチル（５．０ｍＬ）と１－ピペリジンスルホニルクロリド（７．１ｇ）より標記化合物（９．５ｇ）を橙色油状物質として得た。 Example 190 N- [4- (trifluoromethoxy) phenyl]-[1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide <Step 1> [1- (1-piperidinylsulfonyl) )] Synthesis of 3-piperidinecarboxylic acid ethyl ester (Example 25) By a method according to <Step 1>, the title compound (9) was prepared from ethyl nipecotate (5.0 mL) and 1-piperidinesulfonyl chloride (7.1 g). 0.5 g) was obtained as an orange oil.
＜工程２＞［１－（１－ピペリジニルスルホニル）]－３－ピペリジンカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例１９０）＜工程１＞で得られた化合物（１．０ｇ）より標記化合物（０．４４ｇ）を白色固体として得た。 <Step 2> Synthesis of [1- (1-piperidinylsulfonyl)]-3-piperidinecarboxylic acid (Example 25) A method similar to <Step 2>, obtained in (Example 190) <Step 1> The title compound (0.44 g) was obtained as a white solid from the obtained compound (1.0 g).
＜工程３＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－［１－（１－ピペリジニルスルホニル）］－３－ピペリジンカルボキシアミド
　（実施例１８）に準ずる方法で、（実施例１９０）＜工程２＞で得られた化合物（１００．０ｍｇ）より標記化合物（３９．２ｍｇ）を白色固体として得た。 <Step 3> N- [4- (trifluoromethoxy) phenyl]-[1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (Example 190) The title compound (39.2 mg) was obtained as a white solid from the compound (100.0 mg) obtained in <Step 2>.
　（実施例１９１）、（実施例１９２）に、（実施例１９０）で得たラセミ体の光学異性体分離用カラムを用いた光学分割について示す。光学異性体分離用カラムを用いた分取クロマトグラフィーにて、得られた第一分画としてエナンチオマーを（Ａ）で表し、第二分画として得られたエナンチオマーを（Ｂ）で表す。
（実施例１９１）Ｎ－［４－（トリフルオロメトキシ）フェニル］－［１－（１－ピペリジニルスルホニル）］－３－ピペリジンカルボキシアミド（Ａ） (Example 191) and (Example 192) show optical resolution using the column for separation of optical isomers of the racemate obtained in (Example 190). In preparative chromatography using a column for optical isomer separation, an enantiomer is represented by (A) as the obtained first fraction, and an enantiomer obtained as the second fraction is represented by (B).
Example 191 N- [4- (trifluoromethoxy) phenyl]-[1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (A)
（実施例１９２）Ｎ－［４－（トリフルオロメトキシ）フェニル］－［１－（１－ピペリジニルスルホニル）］－３－ピペリジンカルボキシアミド（Ｂ）
　（実施例１９０）で得られた化合物（２０４．９ｍｇ）を分取クロマトグラフィー（カラム：(株)ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＡＤ－Ｈ　（２．０ｃｍ×２５．０ｃｍ）、溶出液；ｎ－へキサン：イソプロパノール＝５０：５０、流速：１５ｍＬ／分、ＵＶ：２３７ｎｍ検出）を用いて光学分割を行うことで標記化合物の各エナンチオマーを第一分画（５１．０ｍｇ、白色固体、＞９８％ｅｅ、リテンションタイム６．３分：エナンチオマーＡ：実施例１９１）、および第二分画（５６．２ｍｇ、白色固体、＞９８％ｅｅ、リテンションタイム１１．２分：エナンチオマーＢ：実施例１９２）として得た。光学純度はキラルカラムで決定した。（カラム：(株)ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＡＤ－Ｈ　（０．４６ｃｍ×２５．０ｃｍ）、溶出液；ｎ－へキサン：イソプロパノール＝５０：５０、流速：０．６ｍＬ／分、ＵＶ：２３７ｎｍ検出）。 Example 192 N- [4- (trifluoromethoxy) phenyl]-[1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide (B)
Compound (204.9 mg) obtained in (Example 190) was subjected to preparative chromatography (column: CHIRALPAK AD-H (2.0 cm × 25.0 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent: n-to Each enantiomer of the title compound was first fractionated (51.0 mg, white solid,> 98% ee) by optical resolution using xylene: isopropanol = 50: 50, flow rate: 15 mL / min, UV: 237 nm detection). , Retention time 6.3 minutes: enantiomer A: Example 191) and second fraction (56.2 mg, white solid,> 98% ee, retention time 11.2 minutes: enantiomer B: Example 192) It was. The optical purity was determined with a chiral column. (Column: CHIRALPAK AD-H (0.46 cm × 25.0 cm) manufactured by Daicel Chemical Industries, Ltd.), eluent: n-hexane: isopropanol = 50: 50, flow rate: 0.6 mL / min, UV: 237 nm detection ).
（実施例１９３）Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（シクロヘキシルスルホニル）－３－ピペリジンカルボキシアミド
＜工程１＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（ｔｅｒｔ－ブトキシカルボニル）－３－ピペリジンカルボキシアミドの合成
　（実施例１８）に準じる方法で、１－（ｔｅｒｔ－ブトキシカルボニル）－３－ピペリジンカルボン酸（５．０ｇ）より、標記化合物（４．６ｇ）を淡褐色固体として得た。 Example 193 N- [4- (trifluoromethoxy) phenyl] -1- (cyclohexylsulfonyl) -3-piperidinecarboxamide <Step 1> N- [4- (trifluoromethoxy) phenyl] -1- ( Synthesis of tert-butoxycarbonyl) -3-piperidinecarboxamide From the 1- (tert-butoxycarbonyl) -3-piperidinecarboxylic acid (5.0 g) in the same manner as in Example 18, the title compound (4.6 g ) Was obtained as a light brown solid.
＜工程２＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－３－ピペリジンカルボキシアミドの合成
　（実施例１７２）＜工程２＞に準ずる方法で、（実施例１９３）＜工程１＞で得られた化合物（２．０ｇ）より標記化合物（２６０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- [4- (trifluoromethoxy) phenyl] -3-piperidinecarboxamide (Example 172) According to <Step 2>, obtained in (Example 193) <Step 1> The title compound (260 mg) was obtained as a white solid from the obtained compound (2.0 g).
＜工程３＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（シクロヘキシルスルホニル）－３－ピペリジンカルボキシアミドの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例１９３）＜工程２＞で得られた化合物（７０．０ｍｇ）より標記化合物（１２．０ｍｇ）を白色固体として得た。 <Step 3> Synthesis of N- [4- (trifluoromethoxy) phenyl] -1- (cyclohexylsulfonyl) -3-piperidinecarboxamide (Example 25) In the same manner as in <Step 1>, (Example 193) The title compound (12.0 mg) was obtained as a white solid from the compound (70.0 mg) obtained in <Step 2>.
（実施例１９４）Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－［（１－メチルエチル）スルホニル］－３－ピペリジンカルボキシアミド
　（実施例２５）＜工程１＞に準ずる方法で、（実施例１９３）＜工程２＞で得られた化合物（７０．０ｍｇ）より標記化合物（１１．０ｍｇ）を淡黄色固体として得た。 (Example 194) N- [4- (trifluoromethoxy) phenyl] -1-[(1-methylethyl) sulfonyl] -3-piperidinecarboxamide (Example 25) A method according to <Step 1>, ( Example 193) The title compound (11.0 mg) was obtained as a pale yellow solid from the compound (70.0 mg) obtained in <Step 2>.
（実施例１９５）Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（シクロペンチルスルホニル）－３－ピペリジンカルボキシアミド
　（実施例２５）＜工程１＞に準ずる方法で、（実施例１９３）＜工程２＞で得られた化合物（７０．０ｍｇ）より標記化合物（１１．０ｍｇ）を白色固体として得た。 (Example 195) N- [4- (trifluoromethoxy) phenyl] -1- (cyclopentylsulfonyl) -3-piperidinecarboxamide (Example 25) In the same manner as in <Step 1>, (Example 193) < The title compound (11.0 mg) was obtained as a white solid from the compound (70.0 mg) obtained in Step 2>.
　（実施例１９０）＜工程１＞に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるスルホニルクロリドより下記化合物を得た。
（実施例１９６）Ｎ－（２－メトキシフェニル）－１－［［メチル（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボキシアミド
（実施例１９７）Ｎ－（２－メトキシフェニル）－１－（フェニルスルホニル）－３－ピペリジンカルボキシアミド Example 190 The following compound was obtained from an amine represented by the formula (XI-1) and a sulfonyl chloride represented by the formula (X-1) by a method according to <Step 1>.
Example 196 N- (2-methoxyphenyl) -1-[[methyl (1-methylethyl) amino] sulfonyl] -3-piperidinecarboxamide (Example 197) N- (2-methoxyphenyl) -1 -(Phenylsulfonyl) -3-piperidinecarboxamide
　（実施例１８）に準じる方法で、前記式（ＸＩ－１）で表されるアミンおよび前記式（Ｘ－１）で表されるカルボン酸より下記化合物を得た。
（実施例１９８）Ｎ－［４－（４－モルホリニル）フェニル］－１－（１－ピペリジニルスルホニル）－３－ピペリジンカルボキサミド
（実施例１９９）Ｎ－（４－フェノキシフェニル）－１－（１－ピペリジニルスルホニル）－３－ピペリジンカルボキシアミド
（実施例２００）Ｎ－（４－ヒドロキシフェニル）－１－（１－ピペリジニルスルホニル）－３－ピペリジンカルボキシアミド
（実施例２０１）Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－１－（１－ピロリジニルスルホニル）－３－ピペリジンカルボキシアミド The following compound was obtained from the amine represented by the formula (XI-1) and the carboxylic acid represented by the formula (X-1) by a method according to (Example 18).
Example 198 N- [4- (4-morpholinyl) phenyl] -1- (1-piperidinylsulfonyl) -3-piperidinecarboxamide (Example 199) N- (4-phenoxyphenyl) -1- ( 1-piperidinylsulfonyl) -3-piperidinecarboxamide (Example 200) N- (4-hydroxyphenyl) -1- (1-piperidinylsulfonyl) -3-piperidinecarboxamide (Example 201) N- (3,4-Dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) -1- (1-pyrrolidinylsulfonyl) -3-piperidinecarboxamide
（実施例２０２）Ｎ－（３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－１－［（シクロペンチルアミノ）スルホニル］－３－ピペリジンカルボキシアミド
＜工程１＞１－［（シクロペンチルアミノ）スルホニル］－３－ピペリジンカルボン酸のの合成
　（実施例２５）＜工程１＞に準ずる方法で、１－（クロロスルホニル）－３－ピペリジンカルボン酸エチルエステル（１．５ｇ）より合成した１－［（シクロペンチルアミノ）スルホニル］－３－ピペリジンカルボン酸エチルエステルの粗化合物を用いて、（実施例２５）＜工程２＞に準ずる方法で、標記化合物（１．３ｇ）を白色固体として得た。 Example 202 N- (3,4-Dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) -1-[(cyclopentylamino) sulfonyl] -3-piperidinecarboxamide <Step 1 > Synthesis of 1-[(cyclopentylamino) sulfonyl] -3-piperidinecarboxylic acid (Example 25) 1- (chlorosulfonyl) -3-piperidinecarboxylic acid ethyl ester (1. Using the crude compound of 1-[(cyclopentylamino) sulfonyl] -3-piperidinecarboxylic acid ethyl ester synthesized from 5 g), the title compound (1.3 g) was prepared in the same manner as in (Example 25) <Step 2>. Was obtained as a white solid.
＜工程２＞Ｎ－[３，４－ジヒドロー２－（２Ｈ）－１，４－ベンゾオキサジン－６－イル]－１－［（シクロペンチルアミノ）スルホニル］－３－ピペリジンカルボキシアミド
の合成
　（実施例１８）に準ずる方法で、（実施例２０２）＜工程１＞で得られた化合物（５０．０ｍｇ）より標記化合物（５．２ｍｇ）を無色油状物質として得た。 <Step 2> Synthesis of N- [3,4-dihydro-2- (2H) -1,4-benzoxazin-6-yl] -1-[(cyclopentylamino) sulfonyl] -3-piperidinecarboxamide (Examples) The title compound (5.2 mg) was obtained as a colorless oil from the compound (50.0 mg) obtained in (Example 202) <Step 1> by a method according to 18).
（実施例２０３）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－（４－モルホリニルスルホニル）－３－ピペリジンカルボキシアミド
＜工程１＞１－（４－モルホリニルスルホニル）－３－ピペリジンカルボン酸の合成
　（実施例２０２）＜工程１＞に準ずる方法で、１－（クロロスルホニル）－３－ピペリジンカルボン酸エチルエステル（１．５ｇ）より、標記化合物（１．３ｇ）を白色固体として得た。 Example 203 N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1- (4-morpholinylsulfonyl) -3-piperidinecarboxamide < Step 1> Synthesis of 1- (4-morpholinylsulfonyl) -3-piperidinecarboxylic acid (Example 202) According to the method of <Step 1>, 1- (chlorosulfonyl) -3-piperidinecarboxylic acid ethyl ester ( 1.5 g) gave the title compound (1.3 g) as a white solid.
＜工程２＞Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－（４－モルホリニルスルホニル）－３－ピペリジンカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２０３）＜工程１＞で得られた化合物（５０．０ｍｇ）より標記化合物（２．６ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1- (4-morpholinylsulfonyl) -3-piperidinecarboxamide In the same manner as in Example 18, the title compound (2.6 mg) was obtained as a white solid from the compound (50.0 mg) obtained in (Example 203) <Step 1>.
（実施例２０４）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボキシアミド
＜工程１＞１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボン酸の合成
　（実施例２０２）＜工程１＞に準ずる方法で、１－（クロロスルホニル）－３－ピペリジンカルボン酸エチルエステル（１．５ｇ）より、標記化合物（１．１ｇ）を白色固体として得た。 Example 204 N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1-[[(1-methylethyl) amino] sulfonyl] -3- Piperidine Carboxamide <Step 1> Synthesis of 1-[[(1-methylethyl) amino] sulfonyl] -3-piperidinecarboxylic acid (Example 202) 1- (chlorosulfonyl)- The title compound (1.1 g) was obtained as a white solid from 3-piperidinecarboxylic acid ethyl ester (1.5 g).
＜工程２＞Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２０４）＜工程１＞で得られた化合物（５０．０ｍｇ）より標記化合物（５．１ｍｇ）を白色固体として得た。 <Step 2> N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1-[[(1-methylethyl) amino] sulfonyl] -3-piperidine Synthesis of Carboxamide By the method according to (Example 18), the title compound (5.1 mg) was obtained as a white solid from the compound (50.0 mg) obtained in (Example 204) <Step 1>.
（実施例２０５）Ｎ－（２－メトキシフェニル）－１，２，５，６－テトラヒドロ－４－メチル－[１－（１－ピペリジニルスルホニル）]－３－ピリジンカルボキシアミド
＜工程１＞１－（ｔｅｒｔ－ブトキシカルボニル）－１，２，５，６－テトラヒドロ－４－メチル－３－ピリジンカルボン酸メチルエステルの合成
　水素化ナトリウム（６００ｍｇ）のエーテル（２５．０ｍＬ）溶液に、氷冷下１－（ｔｅｒｔ－ブトキシカルボニル）－４－オキソ－３－ピペリジンカルボン酸メチルエステル（３．０ｇ）を加え室温で３０分撹拌した。その後、氷冷下にてジエチルクロロホスフェート（２．０ｍＬ）を加え室温で終夜撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝８５：１５～５０：５０）で精製し、リン酸エステル中間体（２．４ｇ）を得た。
　ヨウ化銅（１．２ｇ）のジエチルエーテル溶液（２０．０ｍＬ）に、氷冷下メチルリチウム（１．１Mジエチルエーテル溶液、１１．０ｍＬ）を加え、得られたリン酸エステル中間体（１．２ｇ）を－７８℃で加え、－７８℃から０℃まで３時間かけて昇温した。反応溶液に１規定塩酸を加え酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。その後、減圧下溶媒を留去して標記化合物（０．６９ｇ）を黄色油状物質として得た。 Example 205 N- (2-methoxyphenyl) -1,2,5,6-tetrahydro-4-methyl- [1- (1-piperidinylsulfonyl)]-3-pyridinecarboxamide <Step 1> Synthesis of 1- (tert-butoxycarbonyl) -1,2,5,6-tetrahydro-4-methyl-3-pyridinecarboxylic acid methyl ester To a solution of sodium hydride (600 mg) in ether (25.0 mL), ice-cooled 1- (tert-Butoxycarbonyl) -4-oxo-3-piperidinecarboxylic acid methyl ester (3.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, diethyl chlorophosphate (2.0 mL) was added under ice cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to the reaction solution, 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 = 85: 15-50: 50) to give a phosphate ester intermediate (2.4 g). )
To a diethyl ether solution (20.0 mL) of copper iodide (1.2 g), methyl lithium (1.1 M diethyl ether solution, 11.0 mL) was added under ice cooling, and the resulting phosphate ester intermediate (1. 2 g) was added at −78 ° C., and the temperature was raised from −78 ° C. to 0 ° C. over 3 hours. 1N Hydrochloric acid was added to the reaction solution, the mixture was extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain the title compound (0.69 g) as a yellow oily substance.
＜工程２＞１，２，５，６－テトラヒドロ－４－メチル－３－ピリジンカルボン酸メチルエステルの合成
　（実施例１７２）＜工程２＞に準ずる方法で、（実施例２０５）＜工程１＞で得られた化合物（４９０ｍｇ）より、標記化合物（２８５ｍｇ）を得た。 <Step 2> Synthesis of 1,2,5,6-tetrahydro-4-methyl-3-pyridinecarboxylic acid methyl ester (Example 172) In the same manner as in <Step 2>, (Example 205) <Step 1> The title compound (285 mg) was obtained from the compound obtained in step (490 mg).
＜工程３＞１－（１－ピペリジニルスルホニル）－１，２，５，６－テトラヒドロ－４－メチル－３－ピリジンカルボン酸メチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例２０５）＜工程２＞で得られた化合物（２８０ｍｇ）より標記化合物（４０２ｍｇ）を無色油状物質として得た。 <Step 3> Synthesis of 1- (1-piperidinylsulfonyl) -1,2,5,6-tetrahydro-4-methyl-3-pyridinecarboxylic acid methyl ester (Example 25) Method according to <Step 1> (Example 205) The title compound (402 mg) was obtained as a colorless oil from the compound (280 mg) obtained in <Step 2>.
＜工程４＞１－（１－ピペリジニルスルホニル）－１，２，５，６－テトラヒドロ－４－メチル－３－ピリジンカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２０５）＜工程３＞で得られた化合物（３４０ｍｇ）より標記化合物（３１０ｍｇ）を得た。 <Step 4> Synthesis of 1- (1-piperidinylsulfonyl) -1,2,5,6-tetrahydro-4-methyl-3-pyridinecarboxylic acid (Example 25) In a method according to <Step 2>, Example 205 The title compound (310 mg) was obtained from the compound (340 mg) obtained in <Step 3>.
＜工程５＞Ｎ－（２－メトキシフェニル）－１，２，５，６－テトラヒドロ－４－メチル－１－（１－ピペリジニルスルホニル）－３－ピリジンカルボキシアミドの合成
　（実施例１８）に準じる方法で、（実施例２０５）＜工程４＞で得られた化合物（５７．０　ｍｇ）より標記化合物（１０．０ｍｇ）を無色油状物質として得た。 <Step 5> Synthesis of N- (2-methoxyphenyl) -1,2,5,6-tetrahydro-4-methyl-1- (1-piperidinylsulfonyl) -3-pyridinecarboxamide (Example 18) In the same manner as in Example 205, the title compound (10.0 mg) was obtained as a colorless oil from the compound (57.0 mg) obtained in <Example 4><Step4>.
（実施例２０６）Ｎ－（２－メトキシフェニル）－１，２，３，６－テトラヒドロ－４－メチル－１－（１－ピペリジニルスルホニル）－３－ピリジンカルボキシアミド
　（実施例２０５）＜工程５＞において、標記化合物（３．９ｍｇ）を無色油状物質として同時に得た。 Example 206 N- (2-methoxyphenyl) -1,2,3,6-tetrahydro-4-methyl-1- (1-piperidinylsulfonyl) -3-pyridinecarboxamide (Example 205) < In Step 5>, the title compound (3.9 mg) was obtained at the same time as a colorless oil.
（実施例２０７）ｃｉｓ－Ｎ－［４－（トリフルオロメトキシ）フェニル］－４－メチル－１－（１－ピペリジニルスルホニル）－３－ピペリジンカルボキシアミド
（実施例２０８）ｔｒａｎｓ－Ｎ－［４－（トリフルオロメトキシ）フェニル］－４－メチル－１－（１－ピペリジニルスルホニル）－３－ピペリジンカルボキシアミド
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２０５）＜工程５＞で得られた化合物（５０．０ｍｇ）より標記化合物［（ｃｉｓ体、実施例２０７、２７．１ｍｇ）、（ｔｒａｎｓ体、実施例２０８、３．３ｍｇ）］をそれぞれ白色固体として得た。 Example 207 cis-N- [4- (trifluoromethoxy) phenyl] -4-methyl-1- (1-piperidinylsulfonyl) -3-piperidinecarboxamide (Example 208) trans-N- [ 4- (Trifluoromethoxy) phenyl] -4-methyl-1- (1-piperidinylsulfonyl) -3-piperidinecarboxamide (Example 26) In the same manner as in <Step 4>, (Example 205) < The title compound [(cis isomer, Example 207, 27.1 mg), (trans isomer, Example 208, 3.3 mg)] was obtained as a white solid from the compound (50.0 mg) obtained in step 5>. .
（実施例２０９）Ｎ－（２－メトキシフェニル）－１－（１－ピペリジニルスルホニル）－１，２，５，６－テトラヒドロ－３－ピリジンカルボキシアミド
＜工程１＞１－（１－ピペリジニルスルホニル）－１，２，５，６－テトラヒドロ－３－ピリジンカルボン酸メチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、１，２，５，６－テトラヒドロ－３－ピリジンカルボン酸メチルエステル（３．０ｇ）より標記化合物（１．６ｇ）を白色固体として得た。 Example 209 N- (2-methoxyphenyl) -1- (1-piperidinylsulfonyl) -1,2,5,6-tetrahydro-3-pyridinecarboxamide <Step 1> 1- (1-Pi Synthesis of Peridinylsulfonyl) -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid methyl ester (Example 25) 1,2,5,6-tetrahydro-3- The title compound (1.6 g) was obtained as a white solid from pyridinecarboxylic acid methyl ester (3.0 g).
＜工程２＞１－（１－ピペリジニルスルホニル）－１，２，５，６－テトラヒドロ－３－ピリジンカルボン酸の合成
　（実施例２５）＜工程２＞に準じる方法で、（実施例２０９）＜工程１＞で得られた化合物（１．５ｇ）より標記化合物（１．１ｇ）を得た。 <Step 2> Synthesis of 1- (1-piperidinylsulfonyl) -1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (Example 25) In the same manner as in <Step 2> (Example 209) ) The title compound (1.1 g) was obtained from the compound (1.5 g) obtained in <Step 1>.
＜工程３＞Ｎ－（２－メトキシフェニル）－１－（１－ピペリジニルスルホニル）－１，２，５，６－テトラヒドロ－３－ピリジンカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２０９）＜工程２＞で得られた化合物（１００．０ｍｇ）より標記化合物（２７．９ｍｇ）を白色固体として得た。 <Step 3> Synthesis of N- (2-methoxyphenyl) -1- (1-piperidinylsulfonyl) -1,2,5,6-tetrahydro-3-pyridinecarboxamide (Method 18) (Example 209) The title compound (27.9 mg) was obtained as a white solid from the compound (100.0 mg) obtained in <Step 2>.
（実施例２１０）Ｎ－［４－（トリフルオロメトキシ）フェニル］－４，４－ジメチル－１－（１－ピペリジニルスルホニル）]－３－ピペリジンカルボキシアミド
＜工程１＞１－ベンジル－６－ヒドロキシ－４，４－ジメチルピペリジン－２－オンの合成
　テトラへドロン（Ｔｅｔｒａｈｅｄｒｏｎ），３４，１５６７－１５６９，１９７８年に記載の方法に従い合成した１－ベンジル－４，４－ジメチルピペリジン－２、６－ジオン（５．１ｇ）の塩化メチレン溶液（１０．０ｍＬ）に、－７８℃で水素化ジイソブチルアルミニウム（０．９９Ｍトルエン溶液、２２．３ｍＬ）を加え、同温で２時間撹拌した。水素化ジイソブチルアルミニウム（０．９９Ｍトルエン溶液、１１ｍＬ）を加え、さらに２時間撹拌した後、反応溶液にメタノール、飽和酒石酸ナトリウムカリウム水溶液を加え、塩化メチレンで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝７５：２５～５０：５０）で精製し、標記化合物（４．４ｇ）を黄色油状物質として得た。 Example 210 N- [4- (trifluoromethoxy) phenyl] -4,4-dimethyl-1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide <Step 1> 1-Benzyl-6 Synthesis of -hydroxy-4,4-dimethylpiperidin-2-one 1-benzyl-4,4-dimethylpiperidin-2 synthesized according to the method described in Tetrahedron, 34, 1567-1569, 1978, To a methylene chloride solution (10.0 mL) of 6-dione (5.1 g), diisobutylaluminum hydride (0.99 M toluene solution, 22.3 mL) was added at −78 ° C., and the mixture was stirred at the same temperature for 2 hours. Diisobutylaluminum hydride (0.99 M toluene solution, 11 mL) was added, and the mixture was further stirred for 2 hours. Methanol and saturated aqueous sodium potassium tartrate were added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 75: 25 to 50:50). The title compound (4.4 g) was obtained as a yellow oil.
＜工程２＞１－ベンジル－４，４－ジメチルピペリジン－２－オンの合成
　（実施例２１０）＜工程１＞で得られた化合物（４．４ｇ）の塩化メチレン溶液（７０．０ｍＬ）に、トリフルオロ酢酸（３５．０ｍＬ）、トリエチルシラン（３．２ｍＬ）を加え、室温で２時間撹拌した。減圧下溶媒を留去し得られた残渣を酢酸エチルに溶解させ炭酸ナトリウム水溶液で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝７５：２５）で精製し標記化合物（４．１ｇ）を得た。 <Step 2> Synthesis of 1-benzyl-4,4-dimethylpiperidin-2-one (Example 210) To a methylene chloride solution (70.0 mL) of the compound (4.4 g) obtained in <Step 1>, Trifluoroacetic acid (35.0 mL) and triethylsilane (3.2 mL) were added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was dissolved in ethyl acetate, washed with an aqueous sodium carbonate solution, and the organic layer was 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 = 75: 25) to obtain the title compound (4.1 g).
＜工程３＞１－ベンジル－４，４－ジメチル－２－オキソ－３－ピペリジンカルボン酸メチルエステルの合成
　ジイソプロピルアミン（３．２ｍＬ）のテトラヒドロフラン（１５．０ｍＬ）溶液に－７８℃でｎ－ブチルリチウム（１．６３Ｍへキサン溶液、１４．０ｍＬ）を加え、同温で３０分撹拌した。その後、（実施例２１０）＜工程２＞で得られた化合物（３．３ｇ）のテトラヒドロフラン（１５．０ｍＬ）溶液を加え１時間撹拌した後、クロロギ酸メチル（１．８ｍＬ）を加え０℃まで昇温した。反応溶液に飽和塩化アンモニウム水溶液を加え塩化メチレンで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝８５：１５～５０：５０）で精製し、標記粗化合物（４．１ｇ）を得た。 <Step 3> Synthesis of 1-benzyl-4,4-dimethyl-2-oxo-3-piperidinecarboxylic acid methyl ester n-butyl in a solution of diisopropylamine (3.2 mL) in tetrahydrofuran (15.0 mL) at −78 ° C. Lithium (1.63 M hexane solution, 14.0 mL) was added, and the mixture was stirred at the same temperature for 30 min. Thereafter, a solution of the compound (3.3 g) obtained in Example 210 <Step 2> in tetrahydrofuran (15.0 mL) was added and stirred for 1 hour, and then methyl chloroformate (1.8 mL) was added to 0 ° C. The temperature rose. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with methylene chloride, 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 50:50) to give the title crude compound (4.1 g). Obtained.
＜工程４＞１－ベンジル－４，４－ジメチル－３－ピペリジンカルボン酸メチルエステルの合成
　（実施例２１０）＜工程３＞で得られた化合物（１．０ｇ）の塩化メチレン溶液（２５．０ｍＬ）に、トリメチルオキソニウムテトラフルオロボレート（１．３ｇ）、２，６－ジ－ｔｅｒｔ－ブチル－４－メチルピリジン（２．６ｇ）を加え、室温で終夜撹拌した。反応溶液にメタノールを加え、０℃で水素化ホウ素ナトリウム（０．８０ｇ）を加え同温で３時間撹拌した。その後、飽和炭酸水素ナトリウム水溶液を加え塩化メチレンで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝１００：０～９０：１０）で精製し、標記化合物（０．６３ｇ）を得た。 <Step 4> Synthesis of 1-benzyl-4,4-dimethyl-3-piperidinecarboxylic acid methyl ester (Example 210) A methylene chloride solution (25.0 mL) of the compound (1.0 g) obtained in <Step 3> ) Were added trimethyloxonium tetrafluoroborate (1.3 g) and 2,6-di-tert-butyl-4-methylpyridine (2.6 g), and the mixture was stirred at room temperature overnight. Methanol was added to the reaction solution, sodium borohydride (0.80 g) was added at 0 ° C., and the mixture was stirred at the same temperature for 3 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with methylene chloride, 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 (0.63 g). It was.
＜工程５＞１－ベンジル－４，４－ジメチル－３－ピペリジンカルボン酸の合成
　（実施例２５）＜工程２＞に準じる方法で、（実施例２１０）＜工程４＞で得られた化合物（６２０ｍｇ）より標記化合物（３６２ｍｇ）を得た。 <Step 5> Synthesis of 1-benzyl-4,4-dimethyl-3-piperidinecarboxylic acid (Example 25) In the same manner as in <Step 2>, the compound (Example 210) obtained in <Step 4> ( The title compound (362 mg) was obtained from 620 mg).
＜工程６＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－ベンジル－４，４－ジメチル－３－ピペリジンカルボキシアミドの合成
　（実施例２１０）＜工程５＞で得られた化合物（１５０．０ｍｇ）の塩化メチレン（５．０ｍＬ）溶液に、室温でオキザリルクロリド（０．２５ｍＬ），Ｎ，Ｎ－ジメチルホルムアミド（２滴）を加え３時間撹拌した。減圧下溶媒を留去して得られた残渣を４－（トリフルオロメトキシ）アニリン（７０．４μＬ）、ピリジン（０．４ｍＬ）の塩化メチレン溶液（５．０ｍＬ）に氷冷下滴下し、室温で終夜撹拌した。反応溶液に水を加え塩化メチレンで抽出し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝８５：１５～６６：３４）で精製し、標記化合物（１２４．８ｍｇ）を得た。 <Step 6> Synthesis of N- [4- (trifluoromethoxy) phenyl] -1-benzyl-4,4-dimethyl-3-piperidinecarboxamide (Example 210) Compound (150) obtained in <Step 5> 0.0 mg) in methylene chloride (5.0 mL) was added oxalyl chloride (0.25 mL) and N, N-dimethylformamide (2 drops) at room temperature and stirred for 3 hours. The residue obtained by distilling off the solvent under reduced pressure was added dropwise to a methylene chloride solution (5.0 mL) of 4- (trifluoromethoxy) aniline (70.4 μL) and pyridine (0.4 mL) at room temperature. And stirred overnight. Water was added to the reaction solution, extracted with methylene chloride, 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 66:34) to obtain the title compound (124.8 mg). It was.
＜工程７＞Ｎ－[４－（トリフルオロメトキシ）フェニル]－４，４－ジメチル－３－ピペリジンカルボキシアミドの合成    
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２１０）＜工程６＞で得られた化合物（１１０．０ｍｇ）より標記化合物（６５．３ｍｇ）を得た。 <Step 7> Synthesis of N- [4- (trifluoromethoxy) phenyl] -4,4-dimethyl-3-piperidinecarboxamide
(Example 26) By the method according to <Step 4>, the title compound (65.3 mg) was obtained from the compound (110.0 mg) obtained in (Example 210) <Step 6>.
＜工程８＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－４，４－ジメチル－１－（１－ピペリジニルスルホニル）]－３－ピペリジンカルボキシアミドの合成       
　（実施例２５）＜工程１＞に準じる方法で、（実施例２１０）＜工程７＞で得られた化合物（６５．０ｍｇ）より標記化合物（９１．９ｍｇ）を白色固体として得た。 <Step 8> Synthesis of N- [4- (trifluoromethoxy) phenyl] -4,4-dimethyl-1- (1-piperidinylsulfonyl)]-3-piperidinecarboxamide
(Example 25) By the method according to <Step 1>, the title compound (91.9 mg) was obtained as a white solid from the compound (65.0 mg) obtained in (Example 210) <Step 7>.
（実施例２１１）Ｎ－（２－メトキシフェニル）－８－（１－ピペリジニルスルホニル）－１，４－ジオキサ－８－アザスピロ[４，５]デカン－６－カルボキシアミド
＜工程１＞１－（１－ピペリジニルスルホニル）－４－オキソ－３－ピペリジンカルボン酸メチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、４－オキソ－３－ピペリジンカルボン酸メチルエステル（５．０ｇ）より標記化合物（７．５ｇ）を得た。 Example 211 N- (2-methoxyphenyl) -8- (1-piperidinylsulfonyl) -1,4-dioxa-8-azaspiro [4,5] decan-6-carboxamide <Step 1> 1 Synthesis of-(1-piperidinylsulfonyl) -4-oxo-3-piperidinecarboxylic acid methyl ester (Example 25) 4-oxo-3-piperidinecarboxylic acid methyl ester (5 The title compound (7.5 g) was obtained from 0.0 g).
＜工程２＞８－（１－ピペリジニルスルホニル）－１，４－ジオキサ－８－アザスピロ[４，５]デカン－６－カルボン酸メチルエステルの合成
　（実施例２１１）＜工程１＞で得られた化合物（０．５０ｇ）のベンゼン溶液（１０．０ｍＬ）に、エチレングリコール（０．１４ｍＬ）、ｐ－トルエンスルホン酸・一水和物（３１．３ｍｇ）を加え、加熱還流下、２４時間撹拌した。反応溶液に水を加え塩化メチレンで抽出し、飽和炭酸水素ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝７５：２５～６６：３４）で精製し、標記化合物（０．４５ｇ）を得た。 <Step 2> Synthesis of 8- (1-piperidinylsulfonyl) -1,4-dioxa-8-azaspiro [4,5] decane-6-carboxylic acid methyl ester (Example 211) Obtained in <Step 1> Ethylene glycol (0.14 mL) and p-toluenesulfonic acid monohydrate (31.3 mg) were added to a benzene solution (10.0 mL) of the obtained compound (0.50 g), and the mixture was heated under reflux for 24 hours. Stir. Water was added to the reaction solution, extracted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, 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 = 75: 25 to 66:34) to obtain the title compound (0.45 g). It was.
＜工程３＞８－（１－ピペリジニルスルホニル）－１，４－ジオキサ－８－アザスピロ[４，５]デカン－６－カルボン酸の合成
　（実施例２５）＜工程２＞に準じる方法で、（実施例２１１）＜工程２＞で得られた化合物（０．４４ｇ）より標記化合物（０．３４ｇ）を得た。 <Step 3> Synthesis of 8- (1-piperidinylsulfonyl) -1,4-dioxa-8-azaspiro [4,5] decane-6-carboxylic acid (Example 25) In a method according to <Step 2> Example 211 The title compound (0.34 g) was obtained from the compound (0.44 g) obtained in <Step 2>.
＜工程４＞Ｎ－（２－メトキシフェニル）－８－（１－ピペリジニルスルホニル）－１，４－ジオキサ－８－アザスピロ[４，５]デカン－６－カルボキシアミドの合成
　（実施例２１０）＜工程６＞に準じる方法で、（実施例２１１）＜工程３＞で得られた化合物（０．１７ｇ）より標記化合物（０．２６ｍｇ）を橙色油状物質として得た。 <Step 4> Synthesis of N- (2-methoxyphenyl) -8- (1-piperidinylsulfonyl) -1,4-dioxa-8-azaspiro [4,5] decan-6-carboxamide (Example 210) ) By the method according to <Step 6>, the title compound (0.26 mg) was obtained as an orange oily substance from the compound (0.17 g) obtained in (Example 211) <Step 3>.
（実施例２１２）Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－ピペリジニルスルホニル）－３－ピロリジンカルボキシアミド
＜工程１＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（ｔｅｒｔ－ブトキシカルボニル）－３－ピロリジンカルボキシアミドの合成
　（実施例１８）に準じる方法で、１－（ｔｅｒｔ－ブトキシカルボニル）－３－ピロリジンカルボン酸（２．０ｇ）より、標記化合物（３．４ｇ）を得た。 Example 212 N- [4- (trifluoromethoxy) phenyl] -1- (1-piperidinylsulfonyl) -3-pyrrolidinecarboxamide <Step 1> N- [4- (trifluoromethoxy) phenyl] Synthesis of 1- (tert-butoxycarbonyl) -3-pyrrolidinecarboxamide The title compound was obtained from 1- (tert-butoxycarbonyl) -3-pyrrolidinecarboxylic acid (2.0 g) by a method according to Example 18. (3.4 g) was obtained.
＜工程２＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－３－ピロリジンカルボキシアミドの合成
　（実施例１７２）＜工程２＞に準ずる方法で、（実施例２１２）＜工程１＞で得られた化合物（０．１ｇ）より標記化合物（６７．８ｍｇ）を得た。 <Step 2> Synthesis of N- [4- (trifluoromethoxy) phenyl] -3-pyrrolidinecarboxamide (Example 172) According to <Step 2>, obtained in (Example 212) <Step 1>. The title compound (67.8 mg) was obtained from the obtained compound (0.1 g).
＜工程３＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－ピペリジンスルホニル）－３－ピロリジンカルボキシアミドの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例２１２）＜工程２＞で得られた化合物（６７．０ｍｇ）より標記化合物（９５．２ｍｇ）を白色固体として得た。 <Step 3> Synthesis of N- [4- (trifluoromethoxy) phenyl] -1- (1-piperidinesulfonyl) -3-pyrrolidinecarboxamide (Example 25) In the same manner as in <Step 1>, (Example 212) The title compound (95.2 mg) was obtained as a white solid from the compound (67.0 mg) obtained in <Step 2>.
（実施例２１３）Ｎ－（２－メトキシフェニル）－１－（１－ピペリジニルスルホニル）－ヘキサヒドロ－１Ｈ－アゼピン－３－カルボキシアミド
＜工程１＞１－ベンジル－２－オキソ－ヘキサヒドロ－１Ｈ－アゼピン－３－カルボン酸メチルエステルの合成
　（実施例２１０）＜工程３＞に準ずる方法で、１－ベンジル－ヘキサヒドロ－２Ｈ－アゼピン－２－オン（２．０ｇ）より標記化合物（１．５ｇ）を得た。 Example 213 N- (2-methoxyphenyl) -1- (1-piperidinylsulfonyl) -hexahydro-1H-azepine-3-carboxamide <Step 1> 1-Benzyl-2-oxo-hexahydro-1H -Synthesis of azepine-3-carboxylic acid methyl ester (Example 210) The title compound (1.5 g) was prepared from 1-benzyl-hexahydro-2H-azepin-2-one (2.0 g) by a method according to <Step 3>. )
＜工程２＞１－ベンジル－ヘキサヒドロ－１Ｈ－アゼピン－３－カルボン酸メチルエステルの合成
　（実施例２１０）＜工程４＞に準ずる方法で、（実施例２１３）＜工程１＞で得られた化合物（１．４ｇ）より標記化合物（０．４３ｇ）を得た。 <Step 2> Synthesis of 1-benzyl-hexahydro-1H-azepine-3-carboxylic acid methyl ester (Example 210) In the same manner as in <Step 4>, the compound obtained in (Example 213) <Step 1> The title compound (0.43 g) was obtained from (1.4 g).
＜工程３＞ヘキサヒドロ－１Ｈ－アゼピン－３－カルボン酸メチルエステルの合成
の合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２１３）＜工程２＞で得られた化合物（０．４３ｇ）より標記化合物（０．２７ｇ）を得た。 <Step 3> Synthesis of Synthesis of Hexahydro-1H-azepine-3-carboxylic acid methyl ester (Example 26) In the same manner as in <Step 4>, (Example 213) Compound (0) obtained in <Step 2> .43g) gave the title compound (0.27g).
＜工程４＞１－（１－ピペリジニルスルホニル）－ヘキサヒドロ－１Ｈ－アゼピン－３－カルボン酸メチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例２１３）＜工程３＞で得られた化合物（０．２６ｇ）より標記化合物（０．４３ｇ）を得た。 <Step 4> Synthesis of 1- (1-piperidinylsulfonyl) -hexahydro-1H-azepine-3-carboxylic acid methyl ester (Example 25) In the same manner as in <Step 1>, (Example 213) <Step The title compound (0.43 g) was obtained from the compound (0.26 g) obtained in 3>.
＜工程５＞１－（１－ピペリジニルスルホニル）－ヘキサヒドロ－１Ｈ－アゼピン－３－カルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２１３）＜工程４＞で得られた化合物（０．４１ｇ）より標記化合物（０．３９ｇ）を得た。 <Step 5> Synthesis of 1- (1-piperidinylsulfonyl) -hexahydro-1H-azepine-3-carboxylic acid (Example 25) In the same manner as in <Step 2>, (Example 213) <Step 4> The title compound (0.39 g) was obtained from the compound (0.41 g) obtained in 1.
＜工程６＞Ｎ－（２－メトキシフェニル）－１－（１－ピペリジニルスルホニル）－ヘキサヒドロ－１Ｈ－アゼピン－３－カルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２１３）＜工程５＞で得られた化合物（２００ｍｇ）より標記化合物（２１０ｍｇ）を淡黄色固体として得た。 <Step 6> Synthesis of N- (2-methoxyphenyl) -1- (1-piperidinylsulfonyl) -hexahydro-1H-azepine-3-carboxamide (Example 213) ) The title compound (210 mg) was obtained as a pale yellow solid from the compound (200 mg) obtained in <Step 5>.
（実施例２１４）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－４，４－ジメチル－１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボキシアミド
＜工程１＞４，４－ジメチル－３－ピペリジンカルボン酸メチルエステルの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２１０）＜工程４＞で得られた化合物（３．２０ｇ）より標記化合物（２．０５ｇ）を得た。 Example 214 N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -4,4-dimethyl-1-[[(1-methylethyl) amino ] Sulfonyl] -3-piperidinecarboxamide <Step 1> Synthesis of 4,4-dimethyl-3-piperidinecarboxylic acid methyl ester (Example 26) In the same manner as in <Step 4>, (Example 210) <Step 4 The title compound (2.05 g) was obtained from the compound obtained in the above (3.20 g).
＜工程２＞４，４－ジメチル－１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボン酸メチルメチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例２１４）＜工程１＞で得られた化合物（１５０ｍｇ）より標記化合物（７８．５ｍｇ）を得た。 <Step 2> Synthesis of 4,4-dimethyl-1-[[(1-methylethyl) amino] sulfonyl] -3-piperidinecarboxylic acid methyl methyl ester (Example 25) In the same manner as in <Step 1>, ( Example 214) The title compound (78.5 mg) was obtained from the compound (150 mg) obtained in <Step 1>.
＜工程３＞４，４－ジメチル－１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２１４）＜工程２＞で得られた化合物（７０．０ｍｇ）より標記化合物（７０．０ｍｇ）を得た。 <Step 3> Synthesis of 4,4-dimethyl-1-[[(1-methylethyl) amino] sulfonyl] -3-piperidinecarboxylic acid (Example 25) In the same manner as in <Step 2> (Example 214) ) The title compound (70.0 mg) was obtained from the compound (70.0 mg) obtained in <Step 2>.
＜工程４＞Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－４，４－ジメチル－１－［［（１－メチルエチル）アミノ］スルホニル］－３－ピペリジンカルボキシアミドの合成
　（実施例２１０）＜工程６＞に準じる方法で、（実施例２１４）＜工程３＞で得られた化合物（７０．０ｍｇ）より標記化合物（１０４．９ｍｇ）を橙色固体として得た。 <Step 4> N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -4,4-dimethyl-1-[[(1-methylethyl) amino] Synthesis of Sulfonyl] -3-piperidinecarboxamide (Example 210) The title compound (104.9 mg) was prepared from the compound (70.0 mg) obtained in (Example 214) <Step 3> according to the method of <Step 6>. ) Was obtained as an orange solid.
（実施例２１５）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－（シクロペンチルスルホニル）－４，４－ジメチル－３－ピペリジンカルボキシアミド
＜工程１＞１－（シクロペンチルスルホニル）－４，４－ジメチル－３－ピペリジンカルボン酸メチルメチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例２１４）＜工程１＞で得られた化合物（１５０．０ｍｇ）より標記化合物（６５．６ｍｇ）を得た。 Example 215 N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1- (cyclopentylsulfonyl) -4,4-dimethyl-3-piperidinecarboxy Amide <Step 1> Synthesis of 1- (cyclopentylsulfonyl) -4,4-dimethyl-3-piperidinecarboxylic acid methyl methyl ester (Example 25) According to the method of <Step 1>, (Example 214) <Step 1 The title compound (65.6 mg) was obtained from the compound obtained in <15> (150.0 mg).
＜工程２＞１－（シクロペンチルスルホニル）－４，４－ジメチル－３－ピペリジンカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２１５）＜工程１＞で得た化合物（６０．０ｍｇ）より標記化合物（６０．５ｍｇ）を得た。 <Step 2> Synthesis of 1- (cyclopentylsulfonyl) -4,4-dimethyl-3-piperidinecarboxylic acid (Example 25) A method similar to <Step 2>, obtained in (Example 215) <Step 1> The title compound (60.5 mg) was obtained from the compound (60.0 mg).
＜工程３＞Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－（シクロペンチルスルホニル）－４，４－ジメチル－３－ピペリジンカルボキシアミドの合成
　（実施例２１０）＜工程６＞に準ずる方法で、（実施例２１５）＜工程２＞で得た化合物（５６．０ｍｇ）より標記化合物（４７．８ｍｇ）を白色固体として得た。 <Step 3> N- (3,3-Dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1- (cyclopentylsulfonyl) -4,4-dimethyl-3-piperidinecarboxamide (Example 210) By the method according to <Step 6>, the title compound (47.8 mg) was obtained as a white solid from the compound (56.0 mg) obtained in (Example 215) <Step 2>.
（実施例２１６）Ｎ－［４－（トリフルオロメトキシ）フェニル］－４－（１－ピペリジニルスルホニル）－２－モルホリンカルボキシアミド
＜工程１＞４－（１－ピペリジニルスルホニル）－２－モルホリンカルボン酸メチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、２－モルホリンカルボン酸メチルエステル（１．２０ｇ）と１－ピペリジンスルホニルクロリド（２．２８ｇ）より標記化合物（２．４０ｇ）を無色油状物質として得た。 Example 216 N- [4- (trifluoromethoxy) phenyl] -4- (1-piperidinylsulfonyl) -2-morpholinecarboxamide <Step 1> 4- (1-Piperidinylsulfonyl) -2 -Synthesis of morpholine carboxylic acid methyl ester (Example 25) By the method according to <Step 1>, the title compound (2) was obtained from 2-morpholine carboxylic acid methyl ester (1.20 g) and 1-piperidinesulfonyl chloride (2.28 g). .40 g) was obtained as a colorless oil.
＜工程２＞４－（１－ピペリジニルスルホニル）－２－モルホリンカルボン酸の合成
　（実施例２５）＜工程２＞に準じる方法で、（実施例２１６）＜工程１＞で得られた化合物（２．４０ｇ）より標記化合物（１．８７ｇ）を白色固体として得た。 <Step 2> Synthesis of 4- (1-piperidinylsulfonyl) -2-morpholinecarboxylic acid (Example 25) Compound obtained in (Step 216) <Step 1> by a method according to <Step 2> The title compound (1.87 g) was obtained as a white solid from (2.40 g).
＜工程３＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－４－（１－ピペリジニルスルホニル）－２－モルホリンカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２１６）＜工程２＞で得られた化合物（１００．０ｍｇ）と４－（トリフルオロメトキシ）アニリン（７５μＬ）より標記化合物（４４．８ｍｇ）を白色固体として得た。 <Step 3> Synthesis of N- [4- (trifluoromethoxy) phenyl] -4- (1-piperidinylsulfonyl) -2-morpholinecarboxamide (Example 216) The title compound (44.8 mg) was obtained as a white solid from the compound (100.0 mg) obtained in <Step 2> and 4- (trifluoromethoxy) aniline (75 μL).
（実施例２１７）Ｎ－（２－メトキシフェニル）－１－ベンジル－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド
＜工程１＞１－ベンジル－４－（ｔｅｒｔ－ブトキシカルボニル）－２－ピペラジンカルボン酸ベンジルエステル
　国際公開第２００５／０４４７９７号に記載された方法により合成した４－（ｔｅｒｔ－ブトキシカルボニル）－２－ピペラジンカルボン酸の粗化合物（５．０ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（１００．０ｍＬ）に、室温で炭酸カリウム（９．０ｇ）、ベンジルブロミド（１０．３ｍＬ）を加え終夜撹拌した。反応溶液に水を加え酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９５：５～８０：２０）で精製して、標記化合物（１．５７ｇ）を無色油状物質として得た。 Example 217 N- (2-methoxyphenyl) -1-benzyl-4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide <Step 1> 1-Benzyl-4- (tert-butoxycarbonyl) -2-Piperazinecarboxylic acid benzyl ester 4- (tert-butoxycarbonyl) -2-piperazinecarboxylic acid crude compound (5.0 g) synthesized by the method described in WO 2005/044797 To a dimethylformamide solution (100.0 mL), potassium carbonate (9.0 g) and benzyl bromide (10.3 mL) were added at room temperature and stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 95: 5 to 80:20) to give the title compound (1.57 g). Was obtained as a colorless oil.
＜工程２＞１－ベンジル－２－ピペラジンカルボン酸ベンジルエステルの合成
　（実施例１７２）＜工程２＞に準じる方法で、（実施例２１７）＜工程１＞で得られた化合物（１．５７ｇ）より標記化合物（１．２２ｇ）を無色油状物質として得た。 <Step 2> Synthesis of 1-benzyl-2-piperazinecarboxylic acid benzyl ester (Example 172) In the same manner as in <Step 2>, (Example 217) Compound obtained in <Step 1> (1.57 g) This gave the title compound (1.22 g) as a colorless oil.
＜工程３＞１－ベンジル－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボン酸ベンジルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例２１７）＜工程２＞で得られた化合物（１．２２ｇ）と１－ピペリジンスルホニルクロリド（１．０８ｇ）より標記化合物（１．６２ｇ）を白色固体として得た。 <Step 3> Synthesis of 1-benzyl-4- (1-piperidinylsulfonyl) -2-piperazinecarboxylic acid benzyl ester (Example 25) In the same manner as in <Step 1>, (Example 217) <Step 2 The title compound (1.62 g) was obtained as a white solid from the compound obtained in (1.22 g) and 1-piperidinesulfonyl chloride (1.08 g).
＜工程４＞　１－ベンジル－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２１７）＜工程３＞で得られた化合物（１．５５ｇ）より、標記粗化合物（０．９６ｇ）を白色固体として得た。 <Step 4> Synthesis of 1-benzyl-4- (1-piperidinylsulfonyl) -2-piperazinecarboxylic acid (Example 25) In the same manner as in <Step 2>, (Example 217) in <Step 3> From the obtained compound (1.55 g), the title crude compound (0.96 g) was obtained as a white solid.
＜工程５＞Ｎ－（２－メトキシフェニル）－１－ベンジル－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２１７）＜工程４＞で得られた化合物（０．２５ｇ）、ｏ－アニシジン（０．１２ｍＬ）より標記化合物（４．８ｍｇ）を白色固体として得た。 <Step 5> Synthesis of N- (2-methoxyphenyl) -1-benzyl-4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 217) The title compound (4.8 mg) was obtained as a white solid from the compound (0.25 g) obtained in <Step 4> and o-anisidine (0.12 mL).
（実施例２１８）Ｎ－（２－メトキシフェニル）－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２１７）＜工程５＞により得られた化合物（６０．０ｍｇ）より標記化合物（３４．０ｍｇ）を淡黄色アモルファスとして得た。 (Example 218) N- (2-methoxyphenyl) -4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 26) In the same manner as in <Step 4>, (Example 217) < The title compound (34.0 mg) was obtained as a pale yellow amorphous product from the compound (60.0 mg) obtained in Step 5>.
（実施例２１９）Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－メチル－４－（４－モルホリニルスルホニル）－２－ピペラジンカルボキシアミド
＜工程１＞１－ベンジル－４－（４－モルホリニルスルホニル）－２－ピペラジンカルボン酸ベンジルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例２１７）＜工程２＞で得られた化合物（１．５０ｇ）と４－モルホリンスルホニルクロリド（１．０８ｇ）より、標記化合物（１．３０ｇ）を淡黄色油状物質として得た。 Example 219 N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1-methyl-4- (4-morpholinylsulfonyl) -2- Piperazine Carboxamide <Step 1> Synthesis of 1-benzyl-4- (4-morpholinylsulfonyl) -2-piperazinecarboxylic acid benzyl ester (Example 25) In the same manner as in <Step 1>, (Example 217) From the compound (1.50 g) obtained in <Step 2> and 4-morpholinesulfonyl chloride (1.08 g), the title compound (1.30 g) was obtained as a pale yellow oily substance.
＜工程２＞１－ベンジル－４－（４－モルホリニルスルホニル）－２－ピペラジンカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２１９）＜工程１＞で得られた化合物（１．３０ｇ）より標記化合物（０．２５ｇ）を白色固体として得た。 <Step 2> Synthesis of 1-benzyl-4- (4-morpholinylsulfonyl) -2-piperazinecarboxylic acid (Example 25) In the same manner as in <Step 2>, (Example 219) in <Step 1> The title compound (0.25 g) was obtained as a white solid from the obtained compound (1.30 g).
＜工程３＞Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール６－イル）－１－ベンジル－４－（４－モルホリニルスルホニル）－２－ピペラジンカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２１９）＜工程２＞で得られた化合物（０．２５ｇ）、６－アミノ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール（０．１２ｇ）より、標記粗化合物（０．２５ｇ）を淡黄色固体として得た。 <Step 3> N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol6-yl) -1-benzyl-4- (4-morpholinylsulfonyl) -2-piperazinecarboxy Synthesis of amide According to the method of Example 18, the compound obtained in Example 219 <Step 2> (0.25 g), 6-amino-3,3-dimethyl-2-oxo-2,3 -Dihydro-1H-indole (0.12 g) gave the title crude compound (0.25 g) as a pale yellow solid.
＜工程４＞Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール６－イル）－４－（４－モルホリニルスルホニル）－２－ピペラジンカルボキシアミドの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２１９）＜工程３＞で得られた粗化合物（０．２５ｇ）より標記化合物（０．１４ｇ）を白色固体として得た。 <Step 4> Synthesis of N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol6-yl) -4- (4-morpholinylsulfonyl) -2-piperazinecarboxamide Example 26) By a method according to <Step 4>, the title compound (0.14 g) was obtained as a white solid from the crude compound (0.25 g) obtained in (Example 219) <Step 3>.
＜工程５＞Ｎ－（３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－１－メチル－４－（４－モルホリニルスルホニル）－２－ピペラジンカルボキシアミドの合成
　（実施例６８）に準ずる方法で、（実施例２１９）＜工程４＞で得られた化合物（５０．０ｍｇ）より標記化合物（１３ｍｇ）を白色固体として得た。 <Step 5> N- (3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -1-methyl-4- (4-morpholinylsulfonyl) -2-piperazine Synthesis of Carboxamide By the method according to Example 68, the title compound (13 mg) was obtained as a white solid from the compound (50.0 mg) obtained in (Example 219) <Step 4>.
（実施例２２０）Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－メチルエチル）－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド
＜工程１＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－ベンジル－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド
　（実施例１８）に準ずる方法で、（実施例２１７）＜工程４＞で得られた化合物（０．２５ｇ）と４－（トリフルオロメトキシ）アニリン（０．１４ｍＬ）より標記化合物（６８．０ｍｇ）を白色固体として得た。 Example 220 N- [4- (trifluoromethoxy) phenyl] -1- (1-methylethyl) -4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide <Step 1> N- [ 4- (Trifluoromethoxy) phenyl] -1-benzyl-4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 217) <Step 4> The title compound (68.0 mg) was obtained as a white solid from the obtained compound (0.25 g) and 4- (trifluoromethoxy) aniline (0.14 mL).
＜工程２＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２２０）＜工程１＞で得られた化合物（６０．０ｍｇ）より標記化合物（３３．１ｍｇ）を白色固体として得た。 <Step 2> N- [4- (trifluoromethoxy) phenyl] -4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 26) In the same manner as in <Step 4>, (Example 220) The title compound (33.1 mg) was obtained as a white solid from the compound (60.0 mg) obtained in <Step 1>.
＜工程３＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－メチルエチル）－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミドの合成
　（実施例２２０）＜工程２＞で得られた化合物（２５．０ｍｇ）、アセトン（５μＬ）のメタノール－酢酸溶液（２．０ｍＬ、１：１）に、２－ピコリンボラン（９．２ｍｇ）を加え終夜撹拌した。反応溶液に水を入れ飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出し飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９０：１０～２０：８０）で精製して、標記化合物（１２．６ｍｇ）を無色アモルファスとして得た。 <Step 3> Synthesis of N- [4- (trifluoromethoxy) phenyl] -1- (1-methylethyl) -4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 220) < 2-picoline borane (9.2 mg) was added to a methanol-acetic acid solution (2.0 mL, 1: 1) of the compound obtained in step 2> (25.0 mg) and acetone (5 μL), and the mixture was stirred overnight. Water was added to the reaction solution, neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 90: 10 to 20:80) to give the title compound (12.6 mg). Was obtained as a colorless amorphous.
（実施例２２１）Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－アセチル－４－（１－ピペリジニルスルホニル）－２－ピペラジンカルボキシアミド
　（実施例６９）に準ずる方法で、（実施例２２０）＜工程２＞で得られた化合物（２５ｍｇより標記化合物（１６．８ｍｇ）を白色固体として得た。 (Example 221) N- [4- (trifluoromethoxy) phenyl] -1-acetyl-4- (1-piperidinylsulfonyl) -2-piperazinecarboxamide (Example 69) Example 220) The compound obtained in <Step 2> (from 25 mg of the title compound (16.8 mg) was obtained as a white solid.
（実施例２２２）Ｎ－[１－（１－ピペリジニルスルホニル）－ピペリジン－３－イル]－Ｎ’－［４－（トリフルオロメトキシ）フェニル］ウレア
　１－（１－ピペリジニルスルホニル）－３－ピペリジンアミン（１００．０ｍｇ）の塩化メチレン溶液（５．０ｍＬ）に、４－（トリフルオロメトキシ）フェニルイソシアネート（７３．２μＬ）を加え、室温で１８時間撹拌した。減圧下溶媒を留去し、ＬＣＭａｓｓにより分取精製することで標記化合物（１７．１ｍｇ）を白色固体として得た。 Example 222 N- [1- (1-piperidinylsulfonyl) -piperidin-3-yl] -N ′-[4- (trifluoromethoxy) phenyl] urea 1- (1-piperidinylsulfonyl) 4- (Trifluoromethoxy) phenyl isocyanate (73.2 μL) was added to a methylene chloride solution (5.0 mL) of -3-piperidineamine (100.0 mg), and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative LCMS to give the title compound (17.1 mg) as a white solid.
（実施例２２３）Ｎ－［１－（１－ピペリジニルスルホニル）－ピペリジン－３－イル]－４－（トリフルオロメトキシ）ベンズアミド
　（実施例１８）に準ずる方法で、１－（１－ピペリジニルスルホニル）－３－ピペリジンアミン（１００．０ｍｇ）より標記化合物（３８．３ｍｇ）白色固体として得た。 (Example 223) N- [1- (1-piperidinylsulfonyl) -piperidin-3-yl] -4- (trifluoromethoxy) benzamide (Example 18) The title compound (38.3 mg) was obtained as a white solid from peridinylsulfonyl) -3-piperidineamine (100.0 mg).
（実施例２２４）Ｎ－（２－メトキシフェニル）－３－［［（１－メチルエチル）スルホニル］アミノ］－ピペリジン－１－カルボキシアミド
＜工程１＞１－（ｔｅｒｔ－ブトキシカルボニル）－３－［［（１－メチルエチル）スルホニル］アミノ］－ピペリジンの合成
　１－（ｔｅｒｔ－ブトキシカルボニル）－３－ピペリジンアミン（０．５０ｇ）、トリエチルアミン（０．５２ｍＬ）の塩化メチレン溶液（５．０ｍＬ）に、室温でイソプロピルスルホニルクロリド（０．３３ｍＬ）を加え終夜撹拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝８０：２０～６６：３４）で精製し標記化合物（０．３２ｇ）を得た。
＜工程２＞３－［［（１－メチルエチル）スルホニル］アミノ］－ピペリジン・塩酸塩の合成
　（実施例１７２）＜工程２＞に準ずる方法で、（実施例２２４）＜工程１＞で合成した化合物（０．２１ｇ）を用いて標記粗化合物（０．１４ｇ）を得た。
＜工程３＞Ｎ－（２－メトキシフェニル）－３－［［（１－メチルエチル）スルホニル］アミノ］－ピペリジン－１－カルボキシアミドの合成
　（実施例２２２）に準ずる方法で、（実施例２２４）＜工程２＞で得られた化合物（６５．０ｍｇ）より標記化合物（１０．５ｍｇ）を無色油状物質として得た。 Example 224 N- (2-methoxyphenyl) -3-[[(1-methylethyl) sulfonyl] amino] -piperidine-1-carboxamide <Step 1> 1- (tert-Butoxycarbonyl) -3- Synthesis of [[(1-methylethyl) sulfonyl] amino] -piperidine 1- (tert-butoxycarbonyl) -3-piperidineamine (0.50 g), triethylamine (0.52 mL) in methylene chloride (5.0 mL) To the mixture, isopropylsulfonyl chloride (0.33 mL) was added at room temperature and stirred overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 80: 20 to 66:34) to obtain the title compound (0.32 g).
<Step 2> Synthesis of 3-[[(1-methylethyl) sulfonyl] amino] -piperidine hydrochloride (Example 172) In the same manner as in <Step 2>, in Example 224, synthesized in <Step 1> The title crude compound (0.14 g) was obtained using the obtained compound (0.21 g).
<Step 3> Synthesis of N- (2-methoxyphenyl) -3-[[(1-methylethyl) sulfonyl] amino] -piperidine-1-carboxamide (Example 224) ) The title compound (10.5 mg) was obtained as a colorless oil from the compound (65.0 mg) obtained in <Step 2>.
（実施例２２５）Ｎ－（２－メトキシフェニル）－３－［（１－ピペリジニルスルホニル）アミノ］－１－ピペリジンカルボキシアミド
　（実施例２２２）に準ずる方法で、Ｎ－（３－ピペリジニル）－１－ピペリジンスルホンアミド（７５．０ｍｇ）、２－メトキシフェニルイソシアナート（４６．０μＬ）より標記化合物（７．４ｍｇ）を無色アモルファスとして得た。 Example 225 N- (2-methoxyphenyl) -3-[(1-piperidinylsulfonyl) amino] -1-piperidinecarboxamide N- (3-piperidinyl) by a method similar to that in Example 222 The title compound (7.4 mg) was obtained as colorless amorphous from -1-piperidinesulfonamide (75.0 mg) and 2-methoxyphenyl isocyanate (46.0 μL).
（実施例２２６）Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－ピペリジニルスルホニル）－２－ピペリジンカルボキシアミド
＜工程１＞１－（１－ピペリジニルスルホニル）－２－ピペリジンカルボン酸エチルエステルの合成
　（実施例２５）＜工程１＞に準ずる方法で、２－ピペリジンカルボン酸エチルエステル（１．００ｇ）と１－ピペリジンスルホニルクロリド（１．４０ｇ）より、標記粗生成物（１．９０ｇ）を得た。
＜工程２＞１－（１－ピペリジニルスルホニル）－２－ピペリジンカルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２２６）＜工程１＞で得た化合物（１．９０ｇ）より標記化合物（１．６５ｇ）を白色固体として得た。
＜工程３＞Ｎ－［４－（トリフルオロメトキシ）フェニル］－１－（１－ピペリジニルスルホニル）－２－ピペリジンカルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２２６）＜工程２＞で得た化合物（１００．０ｍｇ）と４－（トリフルオロメトキシ）アニリン（６４．１ｍｇ）より標記化合物（１７．７ｍｇ）を無色油状物質として得た。 Example 226 N- [4- (trifluoromethoxy) phenyl] -1- (1-piperidinylsulfonyl) -2-piperidinecarboxamide <Step 1> 1- (1-piperidinylsulfonyl) -2 -Synthesis of piperidinecarboxylic acid ethyl ester (Example 25) In accordance with <Step 1>, the title crude product was obtained from 2-piperidinecarboxylic acid ethyl ester (1.00 g) and 1-piperidinesulfonyl chloride (1.40 g). The product (1.90 g) was obtained.
<Step 2> Synthesis of 1- (1-piperidinylsulfonyl) -2-piperidinecarboxylic acid (Example 25) A method similar to that in <Step 2> (Example 226) <Compound obtained in <Step 1> ( 1.90 g) gave the title compound (1.65 g) as a white solid.
<Step 3> Synthesis of N- [4- (trifluoromethoxy) phenyl] -1- (1-piperidinylsulfonyl) -2-piperidinecarboxamide (Example 226) The title compound (17.7 mg) was obtained as a colorless oil from the compound (100.0 mg) obtained in <Step 2> and 4- (trifluoromethoxy) aniline (64.1 mg).
（実施例２２７）Ｎ－（２－メトキシフェニル）－２－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－１Ｈ－イソインドリン－４－カルボキシアミド
＜工程１＞４－ブロモ－２－（１－ピペリジンスルホニル）－２，３－ジヒドロ－１Ｈ－イソインドールの合成
　欧州公開第３４３５６０号に記載された方法により合成した１－ブロモ－２，３－ビス（ブロモメチル）－ベンゼンの粗化合物（２．３０ｇ）、１－ピペリジンスルホンアミド（１．２１ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（２０．０ｍＬ）に、氷冷下６０％油状水素化ナトリウム（０．５９ｇ）を加え１時間撹拌した。反応溶液を室温まで昇温し、終夜撹拌した。反応溶液を氷水にあけ酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９０：１０～７５：２５）で精製して、標記粗化合物を得た。得られた粗化合物をジエチルエーテルでトリチュレートし、その母液を濃縮後、アミンシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９５：５～８０：２０）で精製し、標記化合物（０．４５ｇ）を白色固体として得た。 Example 227 N- (2-methoxyphenyl) -2- (1-piperidinylsulfonyl) -2,3-dihydro-1H-isoindoline-4-carboxamide <Step 1> 4-Bromo-2- Synthesis of (1-piperidinesulfonyl) -2,3-dihydro-1H-isoindole Crude compound of 1-bromo-2,3-bis (bromomethyl) -benzene synthesized by the method described in European Publication No. 343560 ( 2.30 g), 1-piperidinesulfonamide (1.21 g) in N, N-dimethylformamide (20.0 mL) was added with 60% oily sodium hydride (0.59 g) under ice cooling and stirred for 1 hour. . The reaction solution was warmed to room temperature and stirred overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 90: 10 to 75:25) to obtain the title crude compound. The obtained crude compound was triturated with diethyl ether, and the mother liquor was concentrated and purified by amine silica gel column chromatography (eluent; n-hexane: ethyl acetate = 95: 5 to 80:20) to give the title compound (0 .45 g) as a white solid.
＜工程２＞２－（１－ピペリジニルスルホニル）－２，３－ジヒドロ－１Ｈ－イソインドリン－４－カルボン酸の合成　
　（実施例２２７）＜工程１＞で得られた化合物（０．２８ｇ）のテトラヒドロフラン溶液（３．０ｍＬ）に、－７８℃でｎ－ブチルリチウムのヘキサン溶液（１．０４ｍＬ、１．６３Ｍ）を加え３０分撹拌した。反応溶液に、－７８℃ドライアイスの小片を加え１時間撹拌した後、室温まで昇温し２時間撹拌した。減圧下溶媒を留去し、１規定水酸化ナトリウム水溶液、酢酸エチルで逆抽出した後、水層を１規定塩酸で酸性にした。析出した白色固体を濾取し、水で洗浄した後、減圧乾燥して標記化合物（１４０ｍｇ）を白色固体として得た。 <Step 2> Synthesis of 2- (1-piperidinylsulfonyl) -2,3-dihydro-1H-isoindoline-4-carboxylic acid
Example 227 To a tetrahydrofuran solution (3.0 mL) of the compound (0.28 g) obtained in <Step 1> was added a hexane solution of n-butyllithium (1.04 mL, 1.63 M) at −78 ° C. The mixture was stirred for 30 minutes. A small piece of −78 ° C. dry ice was added to the reaction solution, and the mixture was stirred for 1 hour, then warmed to room temperature and stirred for 2 hours. After evaporating the solvent under reduced pressure and back-extracting with 1N aqueous sodium hydroxide and ethyl acetate, the aqueous layer was acidified with 1N hydrochloric acid. The precipitated white solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain the title compound (140 mg) as a white solid.
＜工程３＞Ｎ－（２－メトキシフェニル）－２－（１－ピペリジンスルホニル）－２，３－ジヒドロ－１Ｈ－イソインドリン－４－カルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２２７）＜工程２＞で得られた化合物（３０ｍｇ）、ｏ－アニシジン（１１．９ｍｇ）より標記化合物（８．３ｍｇ）を淡茶色固体として得た。 <Step 3> Synthesis of N- (2-methoxyphenyl) -2- (1-piperidinesulfonyl) -2,3-dihydro-1H-isoindoline-4-carboxamide (Example 18) Example 227) The title compound (8.3 mg) was obtained as a pale brown solid from the compound (30 mg) obtained in <Step 2> and o-anisidine (11.9 mg).
（実施例２２８）Ｎ－（２－メトキシフェニル）－２－（１－ピペリジニルスルホニル）－１Ｈ－インドール－４－カルボキシアミド
＜工程１＞１－ベンゼンスルホニル－４－ブロモインドールの合成
　４－ブロモインドール（３．０ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（１００ｍＬ）に、氷冷下で６０％油状水素化ナトリウム（０．９２ｇ）を加え３０分間撹拌した。そこに、ベンゼンスルホニルクロライド（２．４１ｍＬ）を加えた後、室温で終夜撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９０：１０～８０：２０）で精製して、標記化合物（２．１３ｇ）を白色固体として得た。 Example 228 N- (2-methoxyphenyl) -2- (1-piperidinylsulfonyl) -1H-indole-4-carboxamide <Step 1> Synthesis of 1-benzenesulfonyl-4-bromoindole 4- To a solution of bromoindole (3.0 g) in N, N-dimethylformamide (100 mL) was added 60% oily sodium hydride (0.92 g) under ice cooling, and the mixture was stirred for 30 minutes. Benzenesulfonyl chloride (2.41 mL) was added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, 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 = 90: 10 to 80:20) to give the title compound (2.13 g) as white. Obtained as a solid.
＜工程２＞１－ベンゼンスルホニル－４－ブロモ－２－（１－ピペリジニルスルホニル）インドールの合成
　ジイソプルピルアミン（０．５ｍＬ）のテトラヒドロフラン溶液（５．０ｍＬ）に－７８℃でｎ－ブチルリチウムのヘキサン溶液（２．１９ｍＬ、１．６３Ｍ）を加え、０℃まで昇温し３０分撹拌した。（実施例２２８）＜工程１＞で得られた化合物（１．０ｇ）のテトラヒドロフラン溶液（１０．０ｍＬ）に先に調製したＮ，Ｎ－ジイソプロピルリチウムアミドのテトラヒドロフラン－ヘキサン溶液を－７８℃で加え１時間撹拌した。そこに亜硫酸ガスを１０分かけてバブリングした後、室温までゆっくりと昇温し終夜撹拌した。溶媒を減圧下留去し塩化メチレン（１５．０ｍＬ）を加え、Ｎ－クロロスクシンイミド（０．４８ｇ）を加えた後、室温で３時間半撹拌した。水で反応を停止し、塩化メチレンで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し粗生成物を得た。得られた粗生成物の塩化メチレン溶液（１５．０ｍＬ）に室温でピペリジン（０．８８ｍＬ）を加え、１時間撹拌した。反応を水で停止し、塩化メチレンで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９０：１０～８０：２０）で精製して、標記化合物（０．５５ｇ）を白色固体として得た。 <Step 2> Synthesis of 1-benzenesulfonyl-4-bromo-2- (1-piperidinylsulfonyl) indole In a tetrahydrofuran solution (5.0 mL) of diisopropylpuramine (0.5 mL) at −78 ° C. -A hexane solution of butyllithium (2.19 mL, 1.63 M) was added, the temperature was raised to 0 ° C., and the mixture was stirred for 30 minutes. (Example 228) To a tetrahydrofuran solution (10.0 mL) of the compound (1.0 g) obtained in <Step 1>, a tetrahydrofuran-hexane solution of N, N-diisopropyllithium amide previously prepared was added at -78 ° C. Stir for 1 hour. Sulfurous acid gas was bubbled there over 10 minutes, and then the temperature was slowly raised to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, methylene chloride (15.0 mL) was added, N-chlorosuccinimide (0.48 g) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction was quenched with water, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. Piperidine (0.88 mL) was added to a methylene chloride solution (15.0 mL) of the obtained crude product at room temperature, and the mixture was stirred for 1 hour. The reaction was quenched with water, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 90: 10 to 80:20) to give the title compound (0.55 g). Obtained as a white solid.
＜工程３＞４－シアノ－２－（１－ピペリジニルスルホニル）インドールの合成
　（実施例２２８）＜工程２＞で得られた化合物（２００ｍｇ）のＮ－メチルピロリジノン溶液（２．０ｍＬ）にシアン化銅（７４ｍｇ）を加え、マイクロウェーブ反応装置で反応を行った（１８０℃、３０分）。反応溶液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝７０：３０～０：１００）で精製して、標記化合物（５５ｍｇ）を白色固体として得た。 <Step 3> Synthesis of 4-cyano-2- (1-piperidinylsulfonyl) indole (Example 228) To an N-methylpyrrolidinone solution (2.0 mL) of the compound (200 mg) obtained in <Step 2> Copper cyanide (74 mg) was added and the reaction was carried out in a microwave reactor (180 ° C., 30 minutes). Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 70: 30 to 0: 100) to give the title compound (55 mg) as a white solid. Got as.
＜工程４＞２－（１－ピペリジニルスルホニル）インドール－４－カルボン酸の合成
　（実施例２５）＜工程２＞に準ずる方法で、（実施例２２８）＜工程３＞で得られた化合物（５０．０ｍｇ）より標記化合物（４３．０ｍｇ）を白色固体として得た。 <Step 4> Synthesis of 2- (1-piperidinylsulfonyl) indole-4-carboxylic acid (Example 25) Compound obtained in (Step 228) <Step 3> by a method according to <Step 2> From 50.0 mg, the title compound (43.0 mg) was obtained as a white solid.
＜工程５＞Ｎ－（２－メトキシフェニル）－２－（１－ピペリジニルスルホニル）－１Ｈ－インドール－４－カルボキシアミドの合成
　（実施例１８）に準ずる方法で、（実施例２２８）＜工程４＞で得られた化合物（４０．０ｍｇ）、ｏ－アニシジン（１０．０μＬ）より標記化合物（２１．０ｍｇ）を白色固体として得た。 <Step 5> Synthesis of N- (2-methoxyphenyl) -2- (1-piperidinylsulfonyl) -1H-indole-4-carboxamide (Example 228) < The title compound (21.0 mg) was obtained as a white solid from the compound (40.0 mg) obtained in step 4> and o-anisidine (10.0 μL).
（実施例２２９）Ｎ－（２－メトキシフェニル）－１－メチル－２－（１－ピペリジニルスルホニル）－１Ｈ－インドール－４－カルボキシアミド
　（実施例８４）＜工程１＞に準ずる方法で、（実施例２２８）＜工程５＞で得られた化合物（１２．０ｍｇ）より、標記化合物（４．１ｍｇ）を白色固体として得た。 (Example 229) N- (2-methoxyphenyl) -1-methyl-2- (1-piperidinylsulfonyl) -1H-indole-4-carboxamide (Example 84) By a method according to <Step 1> (Example 228) The title compound (4.1 mg) was obtained as a white solid from the compound (12.0 mg) obtained in <Step 5>.
（実施例２３０）Ｎ－（２－メチル－５－ベンゾオキサゾリル）－２－クロロ－５－［［メチル（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞５－［メチル（１，１－ジメチルエチル）アミノ］スルホニル］－２－クロロ安息香酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、Ｎ－ｔｅｒｔ－ブチルメチルアミン（２．００ｍＬ）と２－クロロ－５－（クロロスルホニル）安息香酸（２．１３ｇ）より、標記化合物（０．４２ｇ）を白色固体として得た。 Example 230 N- (2-Methyl-5-benzoxazolyl) -2-chloro-5-[[methyl (1,1-dimethylethyl) amino] sulfonyl] benzamide <Step 1> 5- [Methyl Synthesis of (1,1-dimethylethyl) amino] sulfonyl] -2-chlorobenzoic acid (Example 25) N-tert-butylmethylamine (2.00 mL) and 2-chloro The title compound (0.42 g) was obtained as a white solid from -5- (chlorosulfonyl) benzoic acid (2.13 g).
＜工程２＞Ｎ－（２－メチル－５－ベンゾオキサゾリル）－２－クロロ－５－［［メチル（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、５－アミノ－２－メチルベンゾオキサゾール（３６．３ｍｇ）と（実施例２３０）＜工程１＞で得られた化合物（７５．０ｍｇ）より、標記化合物（８５．９ｍｇ）を白色固体として得た。 <Step 2> Synthesis of N- (2-methyl-5-benzoxazolyl) -2-chloro-5-[[methyl (1,1-dimethylethyl) amino] sulfonyl] benzamide (according to Example 18) The title compound (85.9 mg) was obtained as a white solid from 5-amino-2-methylbenzoxazole (36.3 mg) and the compound (75.0 mg) obtained in (Example 230) <Step 1>. Obtained.
（実施例２３１）Ｎ－［２－（１，１－ジメチルエチル）－５－ベンゾオキサゾリル）］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞Ｎ－（３－アミノ－４－ヒドロキシフェニル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成　
　（実施例１８）に準ずる方法で、２，４－ジアミノフェノール（０．３４ｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（０．５ｇ）より標記化合物（０．６０ｇ）を得た。 Example 231 N- [2- (1,1-dimethylethyl) -5-benzoxazolyl)]-2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide < Step 1> Synthesis of N- (3-amino-4-hydroxyphenyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide
The title compound was synthesized from 2,4-diaminophenol (0.34 g) and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid (0.5 g) according to the method of Example 18. (0.60 g) was obtained.
＜工程２＞Ｎ－（３－ピバロイルアミノ－４－ヒドロキシフェニル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１）＜工程１＞に準ずる方法で、（実施例２３１）＜工程１＞で得られた化合物（１００．０ｍｇ）とピバロイルクロリド（０．０３ｍＬ）より標記化合物（９１．０ｍｇ）を得た。 <Step 2> Synthesis of N- (3-pivaloylamino-4-hydroxyphenyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 1) In <Step 1> In the same manner, the title compound (91.0 mg) was obtained from the compound (100.0 mg) obtained in (Example 231) <Step 1> and pivaloyl chloride (0.03 mL).
＜工程３＞Ｎ－［２－（１，１－ジメチルエチル）－５－ベンゾオキサゾリル）］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２３１）＜工程２＞で得た化合物（９１ｍｇ）のキシレン溶液（２．０ｍＬ）に、室温でパラトルエンスルフォン酸ピリジニウム（１５．６ｍｇ）を加え、加熱還流下、１時間撹拌した。反応溶液に酢酸エチルを加え、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝５０：５０）で精製し、標記化合物（３７．０ｍｇ）を淡黄色固体として得た。 <Step 3> Synthesis of N- [2- (1,1-dimethylethyl) -5-benzoxazolyl)]-2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide Example 231 To a xylene solution (2.0 mL) of the compound (91 mg) obtained in <Step 2> was added pyridinium paratoluenesulfonate (15.6 mg) at room temperature, and the mixture was stirred for 1 hour with heating under reflux. Ethyl acetate was added to the reaction solution, 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 = 50: 50) to obtain the title compound (37.0 mg) as a pale yellow solid. .
（実施例２３２）Ｎ－［２－（トリフルオロメチル）－５－ベンゾオキサゾリル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞Ｎ－（３－トリフルオロアセチルアミノ－４－ヒドロキシフェニル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２３１）＜工程１＞で得られた化合物（１００．０ｍｇ）のテトラヒドロフラン溶液（２．０ｍＬ）に、トリフルオロ酢酸無水物（０．０３５ｍＬ）を加え、４時間撹拌した。反応溶液に酢酸エチルを加え、飽和重曹水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝４０：６０）で精製し、標記化合物（８２．０ｍｇ）を得た。 Example 232 N- [2- (trifluoromethyl) -5-benzoxazolyl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide <Step 1> N Synthesis of — (3-trifluoroacetylamino-4-hydroxyphenyl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 231) Obtained in <Step 1> To a tetrahydrofuran solution (2.0 mL) of the compound (100.0 mg) was added trifluoroacetic anhydride (0.035 mL), and the mixture was stirred for 4 hours. Ethyl acetate was added to the reaction solution, washed successively with saturated aqueous sodium hydrogen carbonate 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 = 40: 60) to obtain the title compound (82.0 mg).
＜工程２＞Ｎ－［２－（トリフルオロメチル）－５－ベンゾオキサゾリル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２３１）＜工程３＞に準ずる方法で、（実施例２３２）＜工程１＞で得られた化合物（８０．０ｍｇ）より標記化合物（４．６ｍｇ）を淡黄色固体として得た。 <Step 2> Synthesis of N- [2- (trifluoromethyl) -5-benzoxazolyl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 231) ) By the method according to <Step 3>, the title compound (4.6 mg) was obtained as a pale yellow solid from the compound (80.0 mg) obtained in (Example 232) <Step 1>.
（実施例２３３）Ｎ－［２－（１－ヒドロキシ－１－メチルエチル）－２－クロロ－５－ベンゾオキサゾリル）］－５－［［（１－メチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞Ｎ－（２－ヒドロキシ－５－ニトロフェニル）－２－ヒドロキシ－２－ジメチルアセトアミドの合成
　２－アミノ－４－ニトロフェノール（２．０ｇ）のキシレン溶液（２０．０ｍＬ）に２－メチル乳酸（２．０ｇ）を加え、加熱還流下、１２時間攪拌した。析出した固体をろ取し、乾燥することにより標記化合物（２．２ｇ）を褐色固体として得た。 Example 233 N- [2- (1-hydroxy-1-methylethyl) -2-chloro-5-benzoxazolyl)]-5-[[(1-methylethyl) amino] sulfonyl] benzamide < Step 1> Synthesis of N- (2-hydroxy-5-nitrophenyl) -2-hydroxy-2-dimethylacetamide 2-amino-4-nitrophenol (2.0 g) in a xylene solution (20.0 mL) Methyl lactic acid (2.0 g) was added, and the mixture was stirred for 12 hours with heating under reflux. The precipitated solid was collected by filtration and dried to obtain the title compound (2.2 g) as a brown solid.
＜工程２＞２－（１－ヒドロキシ－１－メチルエチル）－５－ニトロ－２－ベンゾオキサゾールの合成
　（実施例２３３）＜工程１＞で得られた化合物（１．０ｇ）のキシレン溶液（１５．０ｍＬ）にパラトルエンスルフォン酸ピリジニウム（０．３５ｇ）を加え、加熱還流下、１３時間攪拌した。ろ別後、ろ液を減圧下、濃縮することにより標記化合物（０．８９ｇ）を得た。 <Step 2> Synthesis of 2- (1-hydroxy-1-methylethyl) -5-nitro-2-benzoxazole (Example 233) A xylene solution of the compound (1.0 g) obtained in <Step 1> 15.0 mL) was added pyridinium paratoluenesulfonate (0.35 g), and the mixture was stirred for 13 hours under heating and reflux. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (0.89 g).
＜工程３＞５－アミノ－２－（１－ヒドロキシ－１－メチルエチル）－２－ベンゾオキサゾールの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２３３）＜工程２＞で得られた化合物（０．８０ｇ）より標記化合物（０．１８ｇ）を褐色固体として得た。 <Step 3> Synthesis of 5-amino-2- (1-hydroxy-1-methylethyl) -2-benzoxazole (Example 26) In the same manner as in <Step 4>, (Example 233) <Step 2> The title compound (0.18 g) was obtained as a brown solid from the compound (0.80 g) obtained in 1.
＜工程４＞Ｎ－［２－（１－ヒドロキシ－１－メチルエチル）－５－ベンゾオキサゾリル）］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２３３）＜工程３＞で得た化合物（６９．２ｍｇ）と２－クロロ－５－［［（１－メチルエチル）アミノ］スルホニル］安息香酸（０．１０ｇ）より標記化合物（０．１６ｇ）を無色アモルファスとして得た。 <Step 4> N- [2- (1-hydroxy-1-methylethyl) -5-benzoxazolyl)]-2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 233) The compound (69.2 mg) obtained in <Step 3> and 2-chloro-5-[[(1-methylethyl) amino] sulfonyl] benzoic acid were prepared according to the method of Example 18). The title compound (0.16 g) was obtained as a colorless amorphous form from the acid (0.10 g).
（実施例２３４）Ｎ－（３，４－ジヒドロ－２，２－ジメチル－４－メチル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞３，４－ジヒドロ－２，２－ジメチル－４－メチル－６－ニトロ－２Ｈ－１，４－ベンゾオキサジンの合成
　（実施例１２５）＜工程１＞で得られた化合物（０．１５ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（３ｍＬ）に、氷冷下で６０％油状水素化ナトリウム（０．０３５ｇ）を加え５分間撹拌した。そこに、よう化メチル（０．０６７ｍＬ）を加えた後、室温で終夜撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９０：１０）で精製して、標記化合物（０．１６ｇ）を橙色固体として得た。 Example 234 N- (3,4-dihydro-2,2-dimethyl-4-methyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1 -Dimethylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 3,4-dihydro-2,2-dimethyl-4-methyl-6-nitro-2H-1,4-benzoxazine (Example 125) <Step 60% oily sodium hydride (0.035 g) was added to an N, N-dimethylformamide solution (3 mL) of the compound obtained in 1> (0.15 g) under ice-cooling, and the mixture was stirred for 5 minutes. To this was added methyl iodide (0.067 mL), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, 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 = 90: 10) to obtain the title compound (0.16 g) as an orange solid. .
＜工程２＞６－アミノ－３，４－ジヒドロ－２，２－ジメチル－４－メチル－２Ｈ－１，４－ベンゾオキサジンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２３４）＜工程１＞で得られた化合物（０．１５ｇ）より標記化合物（０．１４ｇ）を紫色固体として得た。 <Step 2> Synthesis of 6-amino-3,4-dihydro-2,2-dimethyl-4-methyl-2H-1,4-benzoxazine (Example 26) Example 234) The title compound (0.14 g) was obtained as a purple solid from the compound (0.15 g) obtained in <Step 1>.
＜工程３＞Ｎ－（３，４－ジヒドロ－２，２－ジメチル－４－メチル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２３４）＜工程２＞で得た化合物（６５．９ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（０．１０ｇ）より標記化合物（０．１５ｇ）を淡黄色アモルファスとして得た。 <Step 3> N- (3,4-dihydro-2,2-dimethyl-4-methyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1- Synthesis of dimethylethyl) amino] sulfonyl] benzamide In the same manner as in Example 18, the compound (65.9 mg) obtained in (Example 234) <Step 2> and 2-chloro-5-[[(1, The title compound (0.15 g) was obtained as a pale yellow amorphous product from 1-dimethylethyl) amino] sulfonyl] benzoic acid (0.10 g).
（実施例２３５）Ｎ－［４－アミノカルボニル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞２，３－ジヒドロ－２，２－ジメチル－６－ニトロ－４－トリフルオロアセチル－４Ｈ－１，４－ベンゾオキサジンの合成
　（実施例１２５）＜工程１＞で得た化合物（２．５０ｇ）のジクロロメタン溶液（２０．０ｍＬ）に、氷冷下、トリエチルアミン（６．６９ｍＬ）及び無水トリフルオロ酢酸（３．６７ｍＬ）を加え、室温で２時間撹拌した。反応溶液に飽和重曹水を加え、ジクロロメタンで抽出し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣を酢酸エチルでトリチュレートし、標記化合物（２．８８ｇ）を得た。 Example 235 N- [4-aminocarbonyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1, 1-dimethylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 2,3-dihydro-2,2-dimethyl-6-nitro-4-trifluoroacetyl-4H-1,4-benzoxazine Example 125 ) To a dichloromethane solution (20.0 mL) of the compound (2.50 g) obtained in <Step 1>, triethylamine (6.69 mL) and trifluoroacetic anhydride (3.67 mL) were added under ice-cooling. Stir for hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate, 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 triturated with ethyl acetate to obtain the title compound (2.88 g).
＜工程２＞６－アミノ－２，３－ジヒドロ－２，２－ジメチル－４－トリフルオロアセチル－４Ｈ－１，４－ベンゾオキサジンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２３５）＜工程１＞で得られた化合物（２．８７ｇ）より標記化合物（２．６０ｇ）を黄色油状物質として得た。 <Step 2> Synthesis of 6-amino-2,3-dihydro-2,2-dimethyl-4-trifluoroacetyl-4H-1,4-benzoxazine (Example 26) In a method according to <Step 4>, Example 235 The title compound (2.60 g) was obtained as a yellow oil from the compound (2.87 g) obtained in <Step 1>.
＜工程３＞Ｎ－［３，４－ジヒドロ－２，２－ジメチル－４－トリフルオロアセチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２３５）＜工程２＞で得た化合物（１．３２ｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１．４０ｇ）より標記化合物（２．４４ｇ）を淡黄色アモルファスとして得た。 <Step 3> N- [3,4-dihydro-2,2-dimethyl-4-trifluoroacetyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1, Synthesis of 1-dimethylethyl) amino] sulfonyl] benzamide (Example 235) The compound (1.32 g) obtained in <Step 2> and 2-chloro-5-[[(( From 1,1-dimethylethyl) amino] sulfonyl] benzoic acid (1.40 g), the title compound (2.44 g) was obtained as a pale yellow amorphous.
＜工程４＞Ｎ－［３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２３５）＜工程３＞で得た化合物（２．４４ｇ）のメタノール－水（４：１）溶液（６０．０ｍＬ）に、炭酸カリウム（３．０８ｇ）を加え、終夜撹拌した。減圧下、反応液の溶媒を留去後、水を加え、ジクロロメタンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝５０：５０）で精製し、標記化合物（２．００ｇ）を淡黄色アモルファスとして得た。 <Step 4> N- [3,4-Dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1,1-dimethylethyl) amino Synthesis of Sulfonyl] benzamide (Example 235) To a methanol-water (4: 1) solution (60.0 mL) of the compound (2.44 g) obtained in <Step 3>, potassium carbonate (3.08 g) was added. And stirred overnight. The solvent of the reaction solution was distilled off under reduced pressure, water was added, extraction was performed with dichloromethane, and the organic layer was 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 = 50: 50) to obtain the title compound (2.00 g) as a pale yellow amorphous product. .
＜工程５＞Ｎ－［４－アミノカルボニル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２３５）＜工程４＞で得た化合物（０．１０ｇ）のテトラヒドロフラン溶液（２．０ｍＬ）に、トリエチルアミン（０．０４３ｍＬ）、ジメチルアミノピリジン（０．５４ｍｇ）、トリフォスゲン（２６．２６ｍｇ）を加え、室温で３時間撹拌後、さらにトリフォスゲン（２６．２６ｍｇ）加え、１時間攪拌した後、アンモニア水を加え、終夜攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝２０：８０）で精製し、標記化合物（０．１１ｇ）を無色アモルファスとして得た。 <Step 5> N- [4-aminocarbonyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[(1,1 Synthesis of —dimethylethyl) amino] sulfonyl] benzamide (Example 235) To a tetrahydrofuran solution (2.0 mL) of the compound (0.10 g) obtained in <Step 4> was added triethylamine (0.043 mL), dimethylaminopyridine ( 0.54 mg) and triphosgene (26.26 mg) were added, stirred at room temperature for 3 hours, further added triphosgene (26.26 mg), stirred for 1 hour, added with aqueous ammonia, and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 = 20: 80) to obtain the title compound (0.11 g) as a colorless amorphous.
（実施例２３６）Ｎ－（３，４－ジヒドロ－２，２－ジメチル－４－メチルスルホニル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例２３５）＜工程４＞で得た化合物（０．１０ｇ）のジクロロメタン溶液（２．０ｍＬ）に、トリエチルアミン（０．０６２ｍＬ）、メタンスルフォニルクロリド（０．０３４ｍＬ）を加え、、終夜攪拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝５０：５０）で精製し、標記化合物（９４．０ｍｇ）を淡褐色アモルファスとして得た。 Example 236 N- (3,4-dihydro-2,2-dimethyl-4-methylsulfonyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1, 1-dimethylethyl) amino] sulfonyl] benzamide (Example 235) To a dichloromethane solution (2.0 mL) of the compound (0.10 g) obtained in <Step 4>, triethylamine (0.062 mL), methanesulfonyl chloride (0 0.034 mL) was added and stirred overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 = 50: 50) to obtain the title compound (94.0 mg) as a light brown amorphous. .
（実施例２３７）Ｎ－（３，４－ジヒドロ－２，２－ジメチル－４－プロピオニル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例２３５）＜工程４＞で得た化合物（０．１０ｇ）のジクロロメタン溶液（２．０ｍＬ）に、ピリジン（０．０２７ｍＬ）、プロピオニルクロリド（０．０２９ｍＬ）を加え、、終夜攪拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝５０：５０）で精製し、標記化合物（０．１１ｇ）を無色アモルファスとして得た。 Example 237 N- (3,4-dihydro-2,2-dimethyl-4-propionyl-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1,1 -Dimethylethyl) amino] sulfonyl] benzamide (Example 235) To a dichloromethane solution (2.0 mL) of the compound (0.10 g) obtained in <Step 4> was added pyridine (0.027 mL) and propionyl chloride (0.029 mL). ) Was added and stirred overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 = 50: 50) to obtain the title compound (0.11 g) as a colorless amorphous substance.
（実施例２３８）Ｎ－［４－（２－ヒドロキシアセチル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞Ｎ－［４－（２－アセトキシアセチル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例２３５）＜工程４＞で得た化合物（０．１０ｇ）のジクロロメタン溶液（２．０ｍＬ）に、ピリジン（０．０２７ｍＬ）、アセトキシアセチルクロリド（０．０３６ｍＬ）を加え、、終夜攪拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝５０：５０）で精製し、標記化合物（０．１０６ｇ）を無色アモルファスとして得た。 Example 238 N- [4- (2-hydroxyacetyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5- [ [(1,1-Dimethylethyl) amino] sulfonyl] benzamide <Step 1> N- [4- (2-acetoxyacetyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine -6-yl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 235) A solution of the compound (0.10 g) obtained in <Step 4> in dichloromethane (2 To 0.0 mL), pyridine (0.027 mL) and acetoxyacetyl chloride (0.036 mL) were added and stirred overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 = 50: 50) to obtain the title compound (0.106 g) as a colorless amorphous.
＜工程２＞Ｎ－［４－（２－ヒドロキシアセチル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２３８）＜工程１＞で得た化合物（９０．０ｍｇ）のメタノール－水（４：１）溶液（３．０ｍＬ）に、炭酸カリウム（０．１１ｇ）を加え、終夜撹拌した。減圧下、反応液の溶媒を留去後、水を加え、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝５０：５０）で精製し、標記化合物（７９．３ｍｇ）を無色アモルファスとして得た。 <Step 2> N- [4- (2-hydroxyacetyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[ Synthesis of (1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 238) In a methanol-water (4: 1) solution (3.0 mL) of the compound (90.0 mg) obtained in <Step 1>, Potassium carbonate (0.11 g) was added and stirred overnight. The solvent of the reaction solution was distilled off under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and the organic layer was 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 = 50: 50) to obtain the title compound (79.3 mg) as a colorless amorphous.
（実施例２３９）Ｎ－［４－（２－アミノアセチル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞Ｎ－［４－（２－ブロモアセチル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例２３５）＜工程４＞で得た化合物（０．１７ｇ）のジクロロメタン溶液（３．０ｍＬ）に、ピリジン（０．０４４ｍＬ）、ブロモアセチルブロミド（０．０４８ｍＬ）を加え、、３時間攪拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝５０：５０）で精製し、標記化合物（０．１８９ｇ）を無色アモルファスとして得た。 Example 239 N- [4- (2-aminoacetyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5- [ [(1,1-Dimethylethyl) amino] sulfonyl] benzamide <Step 1> N- [4- (2-Bromoacetyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine -6-yl] -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 235) A solution of the compound (0.17 g) obtained in <Step 4> in dichloromethane (3 To 0.0 mL), pyridine (0.044 mL) and bromoacetyl bromide (0.048 mL) were added and stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was 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 = 50: 50) to obtain the title compound (0.189 g) as a colorless amorphous.
＜工程２＞Ｎ－［４－（２－アミノアセチル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２３９）＜工程１＞で得た化合物（９０．０ｍｇ）のテトラヒドロフラン溶液（１．１０ｍＬ）に、７規定アンモニア－メタノール溶液（０．８０ｍＬ）を加え、終夜撹拌した。減圧下、反応液の溶媒を留去後、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ジクロロメタン：メタノール＝９０：１０）で精製し、標記化合物（５３．５ｍｇ）を無色アモルファスとして得た。 <Step 2> N- [4- (2-aminoacetyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[ Synthesis of (1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 239) To a tetrahydrofuran solution (1.10 mL) of the compound (90.0 mg) obtained in <Step 1> was added a 7N ammonia-methanol solution ( 0.80 mL) was added and stirred overnight. After evaporating the solvent of the reaction solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; dichloromethane: methanol = 90: 10) to obtain the title compound (53.5 mg) as a colorless amorphous product. .
（実施例２４０）Ｎ－[４－（２－ピリジニル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル]－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞３，４－ジヒドロ－２，２－ジメチル－６－ニトロ－４－（２－ピリジニル）－２Ｈ－１，４－ベンゾオキサジンの合成
　（実施例１２５）＜工程１＞で得られた化合物（０．１０ｇ）をトルエン（２．０ｍＬ）に懸濁させ、アルゴン雰囲気下、２－ブロモピリジン（０．０５５ｍＬ）、トリス（ジベンジリデンアセトン）ジパラジウム（０．０１８ｇ）、１，３－ビス（ジフェニルフォスフィノ）プロパン（０．００８ｇ）、ｔ－ブトキシナトリウム（０．０６５ｇ）を加え、７０℃で５時間撹拌した。反応液にエーテルを加えた後、セライトろ過した。ろ液を水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝９０：１０）で精製して、標記化合物（０．０２１ｇ）を得た。 Example 240 N- [4- (2-pyridinyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[ (1,1-dimethylethyl) amino] sulfonyl] benzamide <Step 1> of 3,4-dihydro-2,2-dimethyl-6-nitro-4- (2-pyridinyl) -2H-1,4-benzoxazine Synthesis (Example 125) The compound (0.10 g) obtained in <Step 1> was suspended in toluene (2.0 mL), and 2-bromopyridine (0.055 mL), tris (dibenzylidene) was added under an argon atmosphere. Acetone) dipalladium (0.018 g), 1,3-bis (diphenylphosphino) propane (0.008 g) and sodium t-butoxy (0.065 g) were added, and the mixture was stirred at 70 ° C. for 5 hours. Ether was added to the reaction solution, followed by filtration through celite. The filtrate was washed successively with water and 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) to obtain the title compound (0.021 g).
＜工程２＞６－アミノ－３，４－ジヒドロ－２，２－ジメチル－４－（２－ピリジニル）－２Ｈ－１，４－ベンゾオキサジンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２４０）＜工程１＞で得られた化合物（３０．０ｍｇ）より標記化合物（１６．３ｍｇ）を無色油状物質として得た。 <Step 2> Synthesis of 6-amino-3,4-dihydro-2,2-dimethyl-4- (2-pyridinyl) -2H-1,4-benzoxazine (Example 26) Method according to <Step 4> (Example 240) The title compound (16.3 mg) was obtained as a colorless oil from the compound (30.0 mg) obtained in <Step 1>.
＜工程３＞Ｎ－[４－（２－ピリジニル）－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル]－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２４０）＜工程２＞で得た化合物（１６．０ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１８．３ｍｇ）より標記化合物（３２．８ｍｇ）を無色アモルファスとして得た。 <Step 3> N- [4- (2-pyridinyl) -3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl] -2-chloro-5-[[( Synthesis of 1,1-dimethylethyl) amino] sulfonyl] benzamide Using a method similar to that in Example 18, the compound (16.0 mg) obtained in (Example 240) <Step 2> and 2-chloro-5- [ The title compound (32.8 mg) was obtained as a colorless amorphous form from [(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (18.3 mg).
（実施例２４１）Ｎ－［２，２－ジメチルクロマン－４－オン－６－イル　）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、６－アミノ－２，２－ジメチルクロマン－４－オン（０．６６ｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１．０ｇ）より標記化合物（０．９２ｇ）を白色固体として得た。 Example 241 N- [2,2-dimethylchroman-4-one-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide (Example 18) 6-amino-2,2-dimethylchroman-4-one (0.66 g) and 2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (1. 0g) gave the title compound (0.92 g) as a white solid.
（実施例２４２）Ｎ－（３，４－ジヒドロ－４－ヒドロキシ－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例２４１）で得られた化合物（０．５２ｇ）のメタノール溶液（１０．０ｍＬ）に、水素化ホウ素ナトリウム（５１．７ｍｇ）を加え、３時間撹拌した。反応溶液に水を加えた後、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して、標記化合物（０．５３ｇ）を白色固体として得た。 Example 242 N- (3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl) -2-chloro-5-[[(1,1-dimethylethyl ) Amino] sulfonyl] benzamide Sodium borohydride (51.7 mg) was added to a methanol solution (10.0 mL) of the compound (0.52 g) obtained in Example 241 and stirred for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.53 g) as a white solid.
（実施例２４３）Ｎ－（２，２－ジメチルクロメン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例２４２）で得られた化合物（０．１１ｇ）及びＮ，Ｎ－ジイソプロピルエチルアミン（０．０９８ｍＬ）のジクロロメタン溶液（３．０ｍＬ）に、氷冷下メタンスルフォニルクロリド（０．０２２ｍＬ）を加え、２時間撹拌した。反応溶液に酢酸エチルを加え、飽和重曹水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去した。得られた残渣のトルエン溶液（３．０ｍＬ）に、１，８－ジアザビシクロ〔５，４，０〕ウンデカ‐７－エン（０．０４２ｍＬ）を加え、１００℃で１．５時間撹拌した。反応溶液に酢酸エチルを加え、飽和重曹水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝３４：６６）で精製し、標記化合物（０．０５９ｇ）を白色固体として得た。 Example 243 N- (2,2-dimethylchromen-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzamide obtained in Example 242 To a dichloromethane solution (3.0 mL) of the compound (0.11 g) and N, N-diisopropylethylamine (0.098 mL) was added methanesulfonyl chloride (0.022 mL) under ice cooling, and the mixture was stirred for 2 hours. Ethyl acetate was added to the reaction solution, 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. 1,8-Diazabicyclo [5,4,0] undec-7-ene (0.042 mL) was added to a toluene solution (3.0 mL) of the obtained residue, and the mixture was stirred at 100 ° C. for 1.5 hours. Ethyl acetate was added to the reaction solution, washed successively with saturated aqueous sodium hydrogen carbonate 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 = 34: 66) to obtain the title compound (0.059 g) as a white solid.
（実施例２４４）Ｎ－（４－アミノ－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞Ｎ－（３，４－ジヒドロ－４－ヒドロキシイミノ－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２４１）で得られた化合物（０．２０ｇ）のメタノール溶液（４．０ｍＬ）に、ヒドロキシアミン塩酸塩（８９．７ｍｇ）及び炭酸カリウム（０．２０ｇ）を加え、加熱還流下、３時間撹拌した。反応溶液に酢酸エチルを加え、水、飽和重曹水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝３４：６６）で精製し、標記化合物（０．１２ｇ）を白色固体として得た。 Example 244 N- (4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl) -2-chloro-5-[[(1,1-dimethylethyl ) Amino] sulfonyl] benzamide <Step 1> N- (3,4-dihydro-4-hydroxyimino-2,2-dimethyl-2H-1-benzopyran-6-yl) -2-chloro-5-[[( Synthesis of 1,1-dimethylethyl) amino] sulfonyl] benzamide To a methanol solution (4.0 mL) of the compound (0.20 g) obtained in Example 241) was added hydroxyamine hydrochloride (89.7 mg) and carbonic acid. Potassium (0.20 g) was added, and the mixture was stirred for 3 hours with heating under reflux. Ethyl acetate was added to the reaction solution, washed successively with water, saturated aqueous sodium hydrogen carbonate, and 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 = 34: 66) to obtain the title compound (0.12 g) as a white solid.
＜工程２＞Ｎ－（４－アミノ－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例２４４）＜工程１＞で得られた化合物（０．１０ｇ）の酢酸溶液（２．０ｍＬ）に、亜鉛（０．１１ｇ）を加え、加熱還流下、３時間撹拌した。反応溶液に酢酸エチルを加え、セライトろ過した。ろ液に飽和重曹水及び炭酸カリウムを加えた後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－ヘキサン：酢酸エチル＝１０：１）で精製し、標記化合物（０．０２６ｇ）を淡黄色固体として得た。 <Step 2> N- (4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl) -2-chloro-5-[[(1,1-dimethylethyl) Synthesis of Amino] sulfonyl] benzamide (Example 244) To an acetic acid solution (2.0 mL) of the compound (0.10 g) obtained in <Step 1>, zinc (0.11 g) was added and heated under reflux. Stir for hours. Ethyl acetate was added to the reaction solution and filtered through celite. A saturated aqueous sodium bicarbonate solution and potassium carbonate were added to the filtrate, followed by extraction with ethyl acetate. 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 = 10: 1) to obtain the title compound (0.026 g) as a pale yellow solid. .
（実施例２４５）Ｎ－（３，４－ジヒドロ－４－ジメチルアミノ－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例２４２）で得られた化合物（０．１０ｇ）及びＮ，Ｎ－ジイソプロピルエチルアミン（０．１５ｍＬ）のジクロロメタン溶液（３．０ｍＬ）に、氷冷下メタンスルフォニルクロリド（０．０３３ｍＬ）を加え、３時間撹拌した。続いて、ジメチルアミン塩酸塩（０．２６ｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．５６ｍＬ）を加え、終夜攪拌した。反応溶液に酢酸エチルを加え、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；酢酸エチル）で精製し、標記化合物（０．０２６ｇ）を淡黄色固体として得た。 Example 245 N- (3,4-Dihydro-4-dimethylamino-2,2-dimethyl-2H-1-benzopyran-6-yl) -2-chloro-5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] benzamide To a dichloromethane solution (3.0 mL) of the compound obtained in Example 242 (0.10 g) and N, N-diisopropylethylamine (0.15 mL) under ice-cooling, methanesulfonyl chloride was added. (0.033 mL) was added and stirred for 3 hours. Subsequently, dimethylamine hydrochloride (0.26 g) and N, N-diisopropylethylamine (0.56 mL) were added and stirred overnight. Ethyl acetate was added to the reaction solution, washed with water, 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) to obtain the title compound (0.026 g) as a pale yellow solid.
（実施例２４６）Ｎ－［３，４－ジヒドロ－４－（４－モルフォリニル）－２，２－ジメチル－２Ｈ－１－ベンゾピラン－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例２４５）と同様の方法により（実施例２４２）で得られた化合物（０．１０ｇ）及びモルフォリン（０．１９ｍＬ）から、標記化合物（０．０５３ｇ）を白色固体として得た。 Example 246 N- [3,4-dihydro-4- (4-morpholinyl) -2,2-dimethyl-2H-1-benzopyran-6-yl] -2-chloro-5-[[(1, 1-dimethylethyl) amino] sulfonyl] benzamide From the compound (0.10 g) and morpholine (0.19 mL) obtained in (Example 242) in the same manner as in Example 245, the title compound (0. 053 g) was obtained as a white solid.
（実施例２４７）Ｎ－［３，４－ジヒドロ－３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞１－（２，４－ジニトロフェノキシ）－１－シクロプロパンカルボン酸メチルの合成
　２，４－ジニトロフルオロベンセン（３．２ｇ）、１－ヒドロキシ－１－シクロプロパンカルボン酸メチル（２．０ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（５０．０ｍＬ）に、室温で炭酸カリウム（２．８６ｇ）を加え終夜撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をヘキサン、酢酸エチルで再沈殿させ、析出した固体を濾取、減圧乾燥し、標記化合物（３．３７ｇ）を黄色固体として得た。 Example 247 N- [3,4-dihydro-3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6-yl] -2-chloro-5-[[( 1,1-dimethylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of methyl 1- (2,4-dinitrophenoxy) -1-cyclopropanecarboxylate 2,4-dinitrofluorobenzene (3.2 g), 1 To a solution of methyl hydroxy-1-cyclopropanecarboxylate (2.0 g) in N, N-dimethylformamide (50.0 mL) was added potassium carbonate (2.86 g) at room temperature, and the mixture was stirred overnight. Water was added to the reaction solution, 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 reprecipitated with hexane and ethyl acetate, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (3.37 g) as a yellow solid.
＜工程２＞６－アミノ－スピロ［２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン］－３（４Ｈ）－オンの合成
　（実施例２４７）＜工程１＞で得られた化合物（３．３７ｇ）の酢酸エチル（７０．０ｍＬ）に、室温で１０％パラジウム－炭素（Ｐｄ／Ｃ）（３３７．０ｍｇ）を加え、水素ガス雰囲気下終夜撹拌した。反応溶液をセライト濾過し、減圧下溶媒を留去して得られた残渣に、酢酸（６．４ｍＬ）、メタノール（７０．０ｍＬ）を加え、１時間加熱還流した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え中和し、酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し標記化合物（２．０５ｇ）を淡茶色固体として得た。 <Step 2> Synthesis of 6-amino-spiro [2H-1,4-benzoxazin-2,1'-cyclopropane] -3 (4H) -one (Example 247) Compound obtained in <Step 1> 10% Palladium-carbon (Pd / C) (337.0 mg) was added to (3.37 g) of ethyl acetate (70.0 mL) at room temperature, and the mixture was stirred overnight under a hydrogen gas atmosphere. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure. Acetic acid (6.4 mL) and methanol (70.0 mL) were added to the resulting residue, and the mixture was heated to reflux for 1 hour. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, 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 (2.05 g) as a light brown solid.
＜工程３＞Ｎ－［３，４－ジヒドロ－３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、２－クロロ－５－［（１，１－ジメチルエチル）アミノ］スルホニル安息香酸（１００．０ｍｇ）と（実施例２４７）＜工程２＞で得られた化合物（６５．２ｍｇ）より、標記化合物（４１．１ｍｇ）を淡紫色固体として得た。 <Step 3> N- [3,4-dihydro-3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6-yl] -2-chloro-5-[[(1 , 1-Dimethylethyl) amino] sulfonyl] benzamide In the same manner as in Example 18, 2-chloro-5-[(1,1-dimethylethyl) amino] sulfonylbenzoic acid (100.0 mg) and ( Example 247) The title compound (41.1 mg) was obtained as a pale-purple solid from the compound (65.2 mg) obtained in <Step 2>.
（実施例２４８）Ｎ－［４－メチル－３，４－ジヒドロ－３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞６－アミノ－４－メチル－スピロ［２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン］－３（４Ｈ）－オンの合成
　（実施例８４）＜工程１＞に準ずる方法で、（実施例２４７）＜工程２＞で得られた化合物（１００．０ｍｇ）を用いて標記化合物（９５．３ｍｇ）を茶色固体として得た。 Example 248 N- [4-methyl-3,4-dihydro-3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6-yl] -2-chloro-5 -[[(1,1-Dimethylethyl) amino] sulfonyl] benzamide <Step 1> 6-Amino-4-methyl-spiro [2H-1,4-benzoxazine-2,1′-cyclopropane] -3 ( Synthesis of 4H) -one (Example 84) In the same manner as in <Step 1>, using the compound (100.0 mg) obtained in (Example 247) <Step 2>, the title compound (95.3 mg) was obtained. Obtained as a brown solid.
＜工程２＞Ｎ－［４－メチル－３，４－ジヒドロ－３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６－イル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、２－クロロ－５－［（１，１－ジメチルエチル）アミノ］スルホニル安息香酸（１３０．０ｍｇ）と（実施例２４８）＜工程１＞で得られた化合物（９１．０ｍｇ）より、標記化合物（９５．２ｍｇ）を白色固体として得た。 <Step 2> N- [4-Methyl-3,4-dihydro-3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6-yl] -2-chloro-5 Synthesis of [[(1,1-dimethylethyl) amino] sulfonyl] benzamide 2-Chloro-5-[(1,1-dimethylethyl) amino] sulfonylbenzoic acid (130. 0 mg) and (Example 248) From the compound (91.0 mg) obtained in <Step 1>, the title compound (95.2 mg) was obtained as a white solid.
（実施例２４９）Ｎ－（２，３，４，５－テトラヒドロ－４－オキソ－１，５－ベンゾオキサゼピン－７－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル]ベンズアミド
＜工程１＞２，３－ジヒドロ－７－ニトロ－１，５－ベンゾオキサゼピン－４（５Ｈ）－オンの合成
　６－ニトロクロマン－４－オン（４８０ｍｇ）のトルエン（１５．０ｍＬ）溶液に氷冷下、アジ化ナトリウム（６５０ｍｇ）、硫酸（５．０ｍＬ）を加えた後、室温で２０時間撹拌した。反応溶液の上澄みを除いた後、１規定水酸化ナトリウム水溶液を加え、反応液を中和した。有機層を酢酸エチルで抽出し、水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液；ｎ－へキサン：酢酸エチル＝８５：１５～５０：５０）で精製し、標記化合物（１３９ｍｇ）を得た。 Example 249 N- (2,3,4,5-tetrahydro-4-oxo-1,5-benzoxazepin-7-yl) -2-chloro-5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 2,3-dihydro-7-nitro-1,5-benzoxazepin-4 (5H) -one of 6-nitrochroman-4-one (480 mg) Sodium azide (650 mg) and sulfuric acid (5.0 mL) were added to a toluene (15.0 mL) solution under ice cooling, and the mixture was stirred at room temperature for 20 hours. After removing the supernatant of the reaction solution, 1N aqueous sodium hydroxide solution was added to neutralize the reaction solution. The organic layer was extracted with ethyl acetate, washed with water, 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 50:50) to obtain the title compound (139 mg).
＜工程２＞７－アミノ－２，３－ジヒドロ－１，５－ベンゾオキサゼピン－４（５Ｈ）－オンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２４９）＜工程１＞で得られた化合物（１３０ｍｇ）より標記化合物（１０６ｍｇ、９６％）を得た。 <Step 2> Synthesis of 7-amino-2,3-dihydro-1,5-benzoxazepin-4 (5H) -one (Example 26) In the same manner as in <Step 4>, (Example 249) The title compound (106 mg, 96%) was obtained from the compound (130 mg) obtained in <Step 1>.
＜工程３＞Ｎ－（２，３，４，５－テトラヒドロ－４－オキソ－１，５－ベンゾオキサゼピン－７－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル]ベンズアミドの合成
　（実施例１８）に準ずる方法で、２－クロロ－５－［（１，１－ジメチルエチル）アミノ］スルホニル安息香酸（６８．０ｍｇ）と、（実施例２４９）＜工程２＞で得られた化合物（５０．０ｍｇ）より標記化合物（１０．２ｍｇ）を白色固体として得た。 <Step 3> N- (2,3,4,5-Tetrahydro-4-oxo-1,5-benzoxazepin-7-yl) -2-chloro-5-[[(1,1-dimethylethyl ) Synthesis of amino] sulfonyl] benzamide 2-Chloro-5-[(1,1-dimethylethyl) amino] sulfonylbenzoic acid (68.0 mg) and (Example 249) according to the method of Example 18. The title compound (10.2 mg) was obtained as a white solid from the compound (50.0 mg) obtained in <Step 2>.
（実施例２５０）Ｎ－（２，３，４，５－テトラヒドロ－３，３－ジメチル－４－オキソ－１，５－ベンゾオキサゼピン－７－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞２，２－ジメチル－３－（２，４－ジニトロフェノキシ）プロピオン酸メチルの合成
　（実施例２４７）＜工程１＞に準ずる方法で、１－フルオロ－２，４－ジニトロベンゼン（２．０ｇ）、３－ヒドロキシ－２，２－ジメチルプロピオン酸メチル（１．４ｍＬ）より標記化合物（１．７ｇ）を得た。 Example 250 N- (2,3,4,5-tetrahydro-3,3-dimethyl-4-oxo-1,5-benzoxazepin-7-yl) -2-chloro-5-[[ (1,1-Dimethylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of methyl 2,2-dimethyl-3- (2,4-dinitrophenoxy) propionate (Example 247) Method according to <Step 1> The title compound (1.7 g) was obtained from 1-fluoro-2,4-dinitrobenzene (2.0 g) and methyl 3-hydroxy-2,2-dimethylpropionate (1.4 mL).
＜工程２＞７－アミノ－２，３－ジヒドロ－３，３－ジメチル－１，５－ベンゾオキサゼピン－４（５Ｈ）－オンの合成
　（実施例２５０）＜工程１＞で得られた化合物（１．７ｇ）の酢酸エチル（２０．０ｍＬ）溶液に、１０％パラジウム－炭素（Ｐｄ／Ｃ）（１５０ｍｇ）を加え、水素ガス雰囲気下室温で終夜撹拌した。反応溶液を濾過、溶媒を留去して得られた粗生成物に、メタノール（１０．０ｍＬ）溶液にナトリウムメトキシド（２８％メタノール溶液、１０ｍＬ）を加え、加熱還流下１０時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、標記化合物（４８５ｍｇ）を得た。 <Step 2> Synthesis of 7-amino-2,3-dihydro-3,3-dimethyl-1,5-benzoxazepin-4 (5H) -one (Example 250) obtained in <Step 1> To a solution of the compound (1.7 g) in ethyl acetate (20.0 mL) was added 10% palladium-carbon (Pd / C) (150 mg), and the mixture was stirred overnight at room temperature in a hydrogen gas atmosphere. The reaction solution was filtered, and the solvent was distilled off. To the crude product obtained, sodium methoxide (28% methanol solution, 10 mL) was added to a methanol (10.0 mL) solution, and the mixture was stirred with heating under reflux for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (485 mg).
＜工程３＞Ｎ－（２，３，４，５－テトラヒドロ－３，３－ジメチル－４－オキソ－１，５－ベンゾオキサゼピン－７－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、２－クロロ－５－［（１，１－ジメチルエチル）アミノ］スルホニル安息香酸（７５．０ｍｇ）、（実施例２５０）＜工程２＞で得られた化合物（６４．０ｍｇ）より標記化合物（２３．５ｍｇ）を白色固体として得た。 <Step 3> N- (2,3,4,5-tetrahydro-3,3-dimethyl-4-oxo-1,5-benzoxazepin-7-yl) -2-chloro-5-[[( Synthesis of 1,1-dimethylethyl) amino] sulfonyl] benzamide 2-chloro-5-[(1,1-dimethylethyl) amino] sulfonylbenzoic acid (75.0 mg) by a method according to Example 18 Example 250 The title compound (23.5 mg) was obtained as a white solid from the compound (64.0 mg) obtained in <Step 2>.
（実施例２５１）Ｎ－（１―メチル―３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞６－アミノ－１―メチル―３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドールの合成
　６－アミノ－３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール（０．１０ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（３ｍＬ）に、氷冷下で６０％油状水素化ナトリウム（０．０３４ｇ）を加え３０分間撹拌した。そこに、よう化メチル（０．０４２ｍＬ）を加えた後、室温で１時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をジエチルエーテルでトリチュレートして、標記化合物（０．０４ｇ）を淡褐色固体として得た。 Example 251 N- (1-methyl-3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1,1- Dimethylethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 6-amino-1-methyl-3,3-dimethyl-2,3-dihydro-2-oxo-1H-indole 6-amino-3,3-dimethyl To a solution of -2,3-dihydro-2-oxo-1H-indole (0.10 g) in N, N-dimethylformamide (3 mL) was added 60% oily sodium hydride (0.034 g) under ice-cooling. Stir for minutes. Methyl iodide (0.042 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, 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 triturated with diethyl ether to obtain the title compound (0.04 g) as a light brown solid.
＜工程２＞Ｎ－（１－メチル－３，３－ジメチル－２，３－ジヒドロ－２－オキソ－１Ｈ－インドール－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２５１）＜工程１＞で得た化合物（３９．１ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（６０．０ｍｇ）より標記化合物（６０．０ｍｇ）を白色固体として得た。 <Step 2> N- (1-Methyl-3,3-dimethyl-2,3-dihydro-2-oxo-1H-indol-6-yl) -2-chloro-5-[[(1,1-dimethyl Synthesis of ethyl) amino] sulfonyl] benzamide The compound (39.1 mg) obtained in (Example 251) <Step 1> and 2-chloro-5-[[(1,1 -Dimethylethyl) amino] sulfonyl] benzoic acid (60.0 mg) gave the title compound (60.0 mg) as a white solid.
（実施例２５２）Ｎ－（３，４－ジヒドロ－４－エチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－８－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、８―アミノ－４－エチル―３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン（３２．９ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（５０．０ｍｇ）より標記化合物（３８．０ｍｇ）を白色固体として得た。 Example 252 N- (3,4-dihydro-4-ethyl-3-oxo-2H-1,4-benzoxazin-8-yl) -2-chloro-5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] benzamide 8-amino-4-ethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (32.9 mg) and 2 in accordance with the method according to Example 18 The title compound (38.0 mg) was obtained as a white solid from -chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (50.0 mg).
（実施例２５３）Ｎ－［１－（１－メチルエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞２－［（１－メチルエチル）アミノ］－６－ニトロベンゾニトリルの合成
　２，６－ジニトロベンゾニトリル（５．０ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（２５．０ｍＬ）に、イソプロピルアミン（８．８２ｍｌ）を加え５０℃で１時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をヘキサンでトリチュレートし標記化合物（３．１１ｇ）を赤茶色固体として得た。 Example 253 N- [1- (1-methylethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 2-[(1-methylethyl) amino] -6-nitrobenzonitrile 2,6-Dinitrobenzonitrile (5.0 g) in N, N-dimethylformamide (25.0 mL) was added with isopropylamine (8.82 ml) and stirred at 50 ° C. for 1 hour. Water was added to the reaction solution, 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 residue was triturated with hexane to obtain the title compound (3.11 g) as a reddish brown solid.
＜工程２＞２－［（１－メチルエチル）アミノ］－６－ニトロベンジルアミンの合成
　水素化ホウ素ナトリウム（２．７７ｇ）のテトラヒドロフラン溶液（４０．０ｍＬ）に、氷冷下トリフルオロ酢酸（５．５９ｍＬ）を加え１５分撹拌した。そこに、（実施例２５３）＜工程１＞で得られた化合物（３．００ｇ）のテトラヒドロフラン溶液（３５．０ｍＬ）を加え、室温まで昇温した後、終夜撹拌した。反応溶液に０℃で１規定塩酸（１００．０ｍＬ）を加えた後、１規定水酸化ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し標記粗化合物（３．４１ｇ）を赤色油状物質として得た。 <Step 2> Synthesis of 2-[(1-methylethyl) amino] -6-nitrobenzylamine To a tetrahydrofuran solution (40.0 mL) of sodium borohydride (2.77 g) was added trifluoroacetic acid (5 .59 mL) was added and stirred for 15 minutes. A tetrahydrofuran solution (35.0 mL) of the compound (3.00 g) obtained in (Example 253) <Step 1> was added thereto, and the mixture was warmed to room temperature and stirred overnight. 1N Hydrochloric acid (100.0 mL) was added to the reaction solution at 0 ° C., neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title crude compound (3.41 g) as a red oily substance.
＜工程３＞１－（１－メチルエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－ニトロキナゾリンの合成
　（実施例８３）＜工程２＞に準ずる方法で、（実施例２５３）＜工程２＞で得られた化合物（３．０６ｇ）より標記化合物（２．２４ｇ）を橙色固体として得た。 <Step 3> Synthesis of 1- (1-methylethyl) -1,2,3,4-tetrahydro-2-oxo-5-nitroquinazoline (Example 83) In the same manner as in <Step 2>, (Example 253) The title compound (2.24 g) was obtained as an orange solid from the compound (3.06 g) obtained in <Step 2>.
＜工程４＞５－アミノ－（１－メチルエチル）－１，２，３，４－テトラヒドロ－２－オキソキナゾリンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２５３）＜工程３＞で得られた化合物（０．２０ｇ）より標記化合物（０．１７ｇ）を淡黄色固体として得た。 <Step 4> Synthesis of 5-amino- (1-methylethyl) -1,2,3,4-tetrahydro-2-oxoquinazoline (Example 26) In the same manner as in <Step 4>, (Example 253) The title compound (0.17 g) was obtained as a pale yellow solid from the compound (0.20 g) obtained in <Step 3>.
＜工程５＞Ｎ－［１－（１－メチルエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、２－クロロ－５－［（１，１－ジメチルエチル）アミノ］スルホニル安息香酸（７５．０ｍｇ）と（実施例２５３）＜工程４＞で得られた化合物（５２．８ｍｇ）より、標記化合物（４５．９ｍｇ）を白色固体として得た。 <Step 5> N- [1- (1-methylethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl ) Synthesis of Amino] sulfonyl] benzamide 2-Chloro-5-[(1,1-dimethylethyl) amino] sulfonylbenzoic acid (75.0 mg) and (Example 253) < The title compound (45.9 mg) was obtained as a white solid from the compound (52.8 mg) obtained in Step 4>.
（実施例２５４）Ｎ－［１－（２－ヒドロキシエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞２－［（２－ベンジルオキシエチル）アミノ］－６－ニトロベンゾニトリルの合成
　（実施例２５３）＜工程１＞に準ずる方法で、２,６－ジニトロベンゾニトリル（０．３５ｇ）と２－ベンジルオキシエチルアミン（０．８２ｇ）より標記化合物（０．４７ｇ）を黄色固体として得た。 Example 254 N- [1- (2-hydroxyethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 2-[(2-benzyloxyethyl) amino] -6-nitrobenzonitrile (Example 253) 2,6-dinitro by a method analogous to <Step 1> The title compound (0.47 g) was obtained as a yellow solid from benzonitrile (0.35 g) and 2-benzyloxyethylamine (0.82 g).
＜工程２＞２－［（２－ベンジルオキシエチル）アミノ］－６－ニトロベンジルアミンの合成
　（実施例２５３）＜工程２＞に準ずる方法で、（実施例２５４）＜工程１＞で得られた化合物（０．４７ｇ）より標記化合物（０．２７ｇ）を黄色油状物質として得た。 <Step 2> Synthesis of 2-[(2-benzyloxyethyl) amino] -6-nitrobenzylamine (Example 253) According to <Step 2>, obtained in (Example 254) <Step 1>. The title compound (0.27 g) was obtained as a yellow oil from the obtained compound (0.47 g).
＜工程３＞１－（２－ベンジルオキシエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－ニトロキナゾリンの合成
　（実施例８３）＜工程２＞に準ずる方法で、（実施例２５４）＜工程２＞で得られた化合物（０．２６ｇ）より標記化合物（０．１５ｇ）を黄色固体として得た。 <Step 3> Synthesis of 1- (2-benzyloxyethyl) -1,2,3,4-tetrahydro-2-oxo-5-nitroquinazoline (Example 83) In the same manner as in <Step 2>, Example 254) The title compound (0.15 g) was obtained as a yellow solid from the compound (0.26 g) obtained in <Step 2>.
＜工程４＞５－アミノ－１－（２－ヒドロキシエチル）－１，２，３，４－テトラヒドロ－２－オキソキナゾリンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２５４）＜工程３＞で得られた化合物（１４３．０ｍｇ）より標記化合物（８７．２ｍｇ）を黄色油状物質として得た。 <Step 4> Synthesis of 5-amino-1- (2-hydroxyethyl) -1,2,3,4-tetrahydro-2-oxoquinazoline (Example 26) In the same manner as in <Step 4>, (Example 254) The title compound (87.2 mg) was obtained as a yellow oily substance from the compound (143.0 mg) obtained in <Step 3>.
＜工程５＞Ｎ－［１－（２－ヒドロキシエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、２－クロロ－５－［（１，１－ジメチルエチル）アミノ］スルホニル安息香酸（６１．６ｍｇ）と（実施例２５４）＜工程４＞で得られた化合物（４３．９ｍｇ）より、標記化合物（３５．２ｍｇ）を白色固体として得た。 <Step 5> N- [1- (2-hydroxyethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl ) Synthesis of amino] sulfonyl] benzamide 2-Chloro-5-[(1,1-dimethylethyl) amino] sulfonylbenzoic acid (61.6 mg) and (Example 254) by the method according to Example 18. From the compound obtained in Step 4> (43.9 mg), the title compound (35.2 mg) was obtained as a white solid.
（実施例２５５）Ｎ－［１－（２－フルオロエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞２－［（２－フルオロエチル）アミノ］－６－ニトロベンゾニトリルの合成
　（実施例２５３）＜工程１＞に準ずる方法で、２,６－ジニトロベンゾニトリル（０．５０ｇ）と２－フルオロエチルアミン塩酸塩（１．０３ｇ）より標記化合物（０．２７ｇ）を黄色固体として得た。 Example 255 N- [1- (2-Fluoroethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] benzamide <Step 1> Synthesis of 2-[(2-fluoroethyl) amino] -6-nitrobenzonitrile (Example 253) 2,6-dinitrobenzoate according to the method of <Step 1> The title compound (0.27 g) was obtained as a yellow solid from nitrile (0.50 g) and 2-fluoroethylamine hydrochloride (1.03 g).
＜工程２＞２－［（２－フルオロエチル）アミノ］－６－ニトロベンゼンメタンアミンの合成
　（実施例２５３）＜工程２＞に準ずる方法で、（実施例２５５）＜工程１＞で得られた化合物（０．２７ｇ）より標記化合物（０．２１ｇ）を黄色油状物質として得た。 <Step 2> Synthesis of 2-[(2-fluoroethyl) amino] -6-nitrobenzenemethanamine (Example 253) According to <Step 2>, obtained in (Example 255) <Step 1> The title compound (0.21 g) was obtained as a yellow oil from the compound (0.27 g).
＜工程３＞１－（２－フルオロエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－ニトロキナゾリンの合成
　（実施例８３）＜工程２＞に準ずる方法で、（実施例２５５）＜工程２＞で得られた化合物（０．２０ｇ）より標記化合物（０．１５ｇ）を黄色固体として得た。 <Step 3> Synthesis of 1- (2-fluoroethyl) -1,2,3,4-tetrahydro-2-oxo-5-nitroquinazoline (Example 83) In the same manner as in <Step 2>, (Example 255) The title compound (0.15 g) was obtained as a yellow solid from the compound (0.20 g) obtained in <Step 2>.
＜工程４＞５－アミノ－１－（２－フルオロエチル）－１，２，３，４－テトラヒドロ－２－オキソキナゾリンの合成
　（実施例２６）＜工程４＞に準ずる方法で、（実施例２５５）＜工程３＞で得られた化合物（１４８．０ｍｇ）より標記化合物（１１４．６ｍｇ）を黄色固体として得た。 <Step 4> Synthesis of 5-amino-1- (2-fluoroethyl) -1,2,3,4-tetrahydro-2-oxoquinazoline (Example 26) In the same manner as in <Step 4>, (Example 255) The title compound (114.6 mg) was obtained as a yellow solid from the compound (148.0 mg) obtained in <Step 3>.
＜工程５＞Ｎ－［１－（２－フルオロエチル）－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、２－クロロ－５－［（１，１－ジメチルエチル）アミノ］スルホニル安息香酸（８０．２ｍｇ）と（実施例２５５）＜工程４＞で得られた化合物（５７．５ｍｇ）より、標記化合物（３３．３ｍｇ）を白色固体として得た。 <Step 5> N- [1- (2-Fluoroethyl) -1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl ) Synthesis of amino] sulfonyl] benzamide 2-Chloro-5-[(1,1-dimethylethyl) amino] sulfonylbenzoic acid (80.2 mg) and (Example 255) by the method according to Example 18. The title compound (33.3 mg) was obtained as a white solid from the compound (57.5 mg) obtained in Step 4>.
（実施例２５６）Ｎ－［１－エチル－３－メチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞５－アミノ－１－エチル－３－メチル－１，２，３，４－テトラヒドロ－２－オキソキナゾリンの合成
　（実施例８４）＜工程１＞に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した１，２，３，４－テトラヒドロ－５－アミノ－１－エチル－２－オキソキナゾリン（１００．０ｍｇ）より標記化合物（１０２．９ｍｇ）を茶色油状物質として得た。 Example 256 N- [1-ethyl-3-methyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl ) Amino] sulfonyl] benzamide <Step 1> Synthesis of 5-amino-1-ethyl-3-methyl-1,2,3,4-tetrahydro-2-oxoquinazoline (Example 84) Method according to <Step 1> From the 1,2,3,4-tetrahydro-5-amino-1-ethyl-2-oxoquinazoline (100.0 mg) synthesized according to the method described in the pamphlet of WO2008 / 091021, 102.9 mg) was obtained as a brown oil.
＜工程２＞Ｎ－［１－エチル－３－メチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル］－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、２－クロロ－５－［（１，１－ジメチルエチル）アミノ］スルホニル安息香酸（６１．７ｍｇ）と（実施例２５６）＜工程１＞で得られた化合物（４３．４ｍｇ）より、標記化合物（２７．０ｍｇ）を黄色油状物質として得た。 <Step 2> N- [1-ethyl-3-methyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl] -2-chloro-5-[[(1,1-dimethylethyl) Amino] sulfonyl] benzamide 2-chloro-5-[(1,1-dimethylethyl) amino] sulfonylbenzoic acid (61.7 mg) and (Example 256) <Step 1> according to a method similar to that in Example 18 The title compound (27.0 mg) was obtained as a yellow oil from the compound obtained in (43.4 mg).
（実施例２５７）Ｎ－（１－エチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド
＜工程１＞５－［（１，１－ジメチルエチル）アミノスルホニル］－２－（トリフルオロメチル）安息香酸の合成
　（実施例２５）＜工程１＞に準ずる方法で、（実施例１８８）＜工程２＞で得られた化合物（０．４０ｇ）より標記化合物（０．２９ｇ）を白色固体として得た。 Example 257 N- (1-ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -5-[[(1,1-dimethylethyl) amino] sulfonyl] -2- (Trifluoromethyl) benzamide <Step 1> Synthesis of 5-[(1,1-dimethylethyl) aminosulfonyl] -2- (trifluoromethyl) benzoic acid (Example 25) A method according to <Step 1> Example 188 The title compound (0.29 g) was obtained as a white solid from the compound (0.40 g) obtained in <Step 2>.
＜工程２＞Ｎ－（１－エチル－１，２，３，４－テトラヒドロ－２－オキソ－５－キナゾリニル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミドの合成
　（実施例１８）に準ずる方法で、国際公開第２００８／０９１０２１号のパンフレットに記載された方法に従い合成した１，２，３，４－テトラヒドロ－５－アミノ－１－エチル－２－オキソキナゾリン（２９．４ｍｇ）と（実施例２５７）＜工程１＞５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）安息香酸（５０．０ｍｇ）より、標記化合物（１１．６ｍｇ）を淡茶色固体として得た。 <Step 2> N- (1-ethyl-1,2,3,4-tetrahydro-2-oxo-5-quinazolinyl) -5-[[(1,1-dimethylethyl) amino] sulfonyl] -2- ( Synthesis of (trifluoromethyl) benzamide 1,2,3,4-tetrahydro-5-amino-1-synthesized according to the method described in the pamphlet of WO2008 / 091021 by the method according to Example 18 Ethyl-2-oxoquinazoline (29.4 mg) and (Example 257) <Step 1> 5-[[(1,1-dimethylethyl) amino] sulfonyl] -2- (trifluoromethyl) benzoic acid (50. 0 mg) gave the title compound (11.6 mg) as a light brown solid.
（実施例２５８）（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド
＜工程１＞アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オンの光学分割
　６－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（１４．０ｇ）を分取クロマトグラフィー（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＣＥＬ　ＯＪ－Ｈ　（５．０ｃｍ×２５ｃｍ）、溶出液；ｎ－ヘキサン：エタノール：ジエチルアミン＝６０：４０：０．１、流速：３５．０ｍＬ／分、ＵＶ：３２０ｎｍ検出）を用いて光学分割を行うことで標記化合物の各エナンチオマーを、第一分画（６．６ｇ、白色固体、＞９８％ｅｅ）、および第二分画（６．６ｇ、白色固体、＞９８％ｅｅ、）として得た。
　得られた化合物をキラルカラムクロマトグラフィー（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＯＪ－Ｈ　（０．４６ｃｍ×２５ｃｍ）、溶出液；ｎ－ヘキサン：エタノール＝５０：５０、流速：０．６ｍＬ／分、ＵＶ：２３７ｎｍ検出）を用いて分析した結果、第一分画（リテンションタイム２５．１分）が実施例（１３４）＜工程２＞で得られた（Ｓ）－６－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オンと一致した。従って第一分画をＳ体、第二分画（リテンションタイム３０．１分）をＲ体とした。 Example 258 (R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5-[[(1,1-dimethyl Ethyl) amino] sulfonyl] -2- (trifluoromethyl) benzamide <Step 1> Optical Resolution of Amino-2-methyl-2H-benzo [1,4] oxazin-3- (4H) -one 6-Amino-2 -Methyl-2H-benzo [1,4] oxazin-3- (4H) -one (14.0 g) was subjected to preparative chromatography (column: CHIRALCEL OJ-H (5.0 cm × 25 cm, manufactured by Daicel Chemical Industries, Ltd.) ), Eluent; n-hexane: ethanol: diethylamine = 60: 40: 0.1, flow rate: 35.0 mL / min, UV: 320 nm detection) to perform optical resolution, thereby The Chioma, first fraction (6.6 g, white solid,> 98% ee), and a second fraction was obtained (6.6 g, white solid,> 98% ee,) and.
The obtained compound was subjected to chiral column chromatography (column: CHIRALPAK OJ-H (0.46 cm × 25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent; n-hexane: ethanol = 50: 50, flow rate: 0.6 mL / min. , UV: 237 nm detection). As a result, the first fraction (retention time 25.1 minutes) was obtained in Example (134) <Step 2> (S) -6-amino-2-methyl Consistent with -2H-benzo [1,4] oxazin-3- (4H) -one. Therefore, the first fraction was designated as S, and the second fraction (retention time 30.1 minutes) as R.
＜工程２＞（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２５８）＜工程１＞で得られた（Ｒ）－６－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（２７．４ｍｇ）と５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）安息香酸（５０．０ｍｇ）より、標記化合物（４８．０ｍｇ）を白色固体として得た。 <Step 2> (R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5-[[(1,1-dimethylethyl ) Synthesis of amino] sulfonyl] -2- (trifluoromethyl) benzamide (R) -6-amino-2-methyl obtained in (Example 258) <Step 1> according to the method of (Example 18) -2H-benzo [1,4] oxazin-3- (4H) -one (27.4 mg) and 5-[[(1,1-dimethylethyl) amino] sulfonyl] -2- (trifluoromethyl) benzoic acid (50.0 mg) gave the title compound (48.0 mg) as a white solid.
（実施例２５９）Ｎ－（３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド
　（実施例１８）に準ずる方法で、６－アミノ－３，４－ジヒドロ－２，２－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン（２９．５ｍｇ）と５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）安息香酸（５０．０ｍｇ）より、標記化合物（２９．３ｍｇ）を白色固体として得た。 Example 259 N- (3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5-[[(1,1-dimethylethyl) Amino] sulfonyl] -2- (trifluoromethyl) benzamide 6-amino-3,4-dihydro-2,2-dimethyl-3-oxo-2H-1,4-benzo in a method analogous to Example 18 From oxazine (29.5 mg) and 5-[[(1,1-dimethylethyl) amino] sulfonyl] -2- (trifluoromethyl) benzoic acid (50.0 mg), the title compound (29.3 mg) was obtained as a white solid. Got as.
（実施例２６０）Ｎ－（４－アセチル－３，４－ジヒドロ－２，２－ジメチル－２Ｈ－１，４－ベンゾオキサジン－６－イル）－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド
　（実施例１８）に準ずる方法で、（実施例１２５）＜工程３＞で得られた化合物（３３．９ｍｇ）と５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）安息香酸（５０．０ｍｇ）より、標記化合物（１３．９ｍｇ）を淡黄色固体として得た。 Example 260 N- (4-acetyl-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-6-yl) -5-[[(1,1-dimethylethyl) Amino] sulfonyl] -2- (trifluoromethyl) benzamide (Example 18) In accordance with the method of Example 18, the compound (33.9 mg) obtained in <Step 3> and 5-[[(1, From 1-dimethylethyl) amino] sulfonyl] -2- (trifluoromethyl) benzoic acid (50.0 mg), the title compound (13.9 mg) was obtained as a pale yellow solid.
（実施例２６１）Ｎ－［３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６（４Ｈ）－イル］－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド
　（実施例１８）に準ずる方法で、（実施例２４７）＜工程２＞で得られた化合物（５８．５ｍｇ）と５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）安息香酸（１００．０ｍｇ）より、標記化合物（９２．０ｍｇ）を白色固体として得た。 Example 261 N- [3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6 (4H) -yl] -5-[[(1,1-dimethylethyl) Amino] sulfonyl] -2- (trifluoromethyl) benzamide (Example 247) (Example 247) The compound (58.5 mg) obtained in <Step 2> and 5-[[(1, 1-Dimethylethyl) amino] sulfonyl] -2- (trifluoromethyl) benzoic acid (100.0 mg) gave the title compound (92.0 mg) as a white solid.
（実施例２６２）Ｎ－［３，４－ジヒドロ－４－メチル－３－オキソスピロ（２Ｈ－１，４－ベンゾオキサジン－２，１’－シクロプロパン）－６－イル］－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）ベンズアミド
　（実施例８４）＜工程１＞に準ずる方法で、（実施例２４８）＜工程１＞で得られた化合物（１８．８ｍｇ）と５－［［（１，１－ジメチルエチル）アミノ］スルホニル］－２－（トリフルオロメチル）安息香酸（３０．０ｍｇ）より、標記化合物（３０．５ｍｇ）を白色固体として得た。 Example 262 N- [3,4-dihydro-4-methyl-3-oxospiro (2H-1,4-benzoxazine-2,1′-cyclopropane) -6-yl] -5-[[( 1,1-Dimethylethyl) amino] sulfonyl] -2- (trifluoromethyl) benzamide (Example 84) In the same manner as in <Step 1>, (Example 248) Compound (18) obtained in <Step 1> 8 mg) and 5-[[(1,1-dimethylethyl) amino] sulfonyl] -2- (trifluoromethyl) benzoic acid (30.0 mg), the title compound (30.5 mg) was obtained as a white solid. .
（実施例２６３）（Ｓ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
＜工程１＞アミノ－２，４－ジメチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オンの光学分割
　６－アミノ－２，４－ジメチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（１．５ｇ）を分取クロマトグラフィー（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＯＤ　（２．０ｃｍ×２５ｃｍ）、溶出液；ｎ－ヘキサン：エタノール：ジエチルアミン＝５０：５０、流速：１５．０ｍＬ／分、ＵＶ：２３７ｎｍ検出）を用いて光学分割を行うことで標記化合物の各エナンチオマーを、第一分画（４２０．０ｍｇ、白色固体、＞９８％ｅｅ）、および第二分画（４３０．０ｍｇ、白色固体、＞９８％ｅｅ、）として得た。 Example 263 (S) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[ (1,1-Dimethylethyl) amino] sulfonyl] benzamide <Step 1> Optical resolution of amino-2,4-dimethyl-2H-benzo [1,4] oxazin-3- (4H) -one 6-amino-2 , 4-dimethyl-2H-benzo [1,4] oxazin-3- (4H) -one (1.5 g) (column: CHIRALPAK OD (2.0 cm × 25 cm, manufactured by Daicel Chemical Industries, Ltd.) ), Eluent; n-hexane: ethanol: diethylamine = 50: 50, flow rate: 15.0 mL / min, UV: 237 nm detection) to carry out optical resolution to obtain each enantiomer of the title compound. First fraction (420.0 mg, white solid,> 98% ee), and a second fraction was obtained (430.0mg, white solid,> 98% ee,) and.
＜工程２＞（Ｓ）－アミノ－２，４－ジメチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オンの合成
　（実施例８４）＜工程１＞に準ずる方法で、（実施例１３４）＜工程２＞で得られた（Ｓ）－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（０．５０ｇ）、２－ヨードメタン（０．１９ｍＬ）より、標記化合物（０．３６ｇ）を淡黄色固体として得た。得られた化合物をキラルカラムクロマトグラフィー（カラム：（株）ダイセル化学工業製　ＣＨＩＲＡＬＰＡＫ　ＯＤ－Ｈ　（０．４６ｃｍ×２５ｃｍ）、溶出液；ｎ－ヘキサン：エタノール＝５０：５０、流速：０．６ｍＬ／分、ＵＶ：２３７ｎｍ検出）を用いて分析した結果、（実施例２６３）＜工程１＞で得られた第二分画と一致した。従って（実施例２６３）＜工程１＞の第一分画をＲ体、第二分画をＳ体とした。 <Step 2> Synthesis of (S) -amino-2,4-dimethyl-2H-benzo [1,4] oxazin-3- (4H) -one (Example 84) By a method according to <Step 1>, Example 134) (S) -Amino-2-methyl-2H-benzo [1,4] oxazin-3- (4H) -one (0.50 g) obtained in <Step 2>, 2-iodomethane (0 .19 mL) gave the title compound (0.36 g) as a pale yellow solid. The obtained compound was subjected to chiral column chromatography (column: CHIRALPAK OD-H (0.46 cm × 25 cm), manufactured by Daicel Chemical Industries, Ltd.), eluent; n-hexane: ethanol = 50: 50, flow rate: 0.6 mL / min , UV: 237 nm detection), and the result was consistent with the second fraction obtained in (Example 263) <Step 1>. Therefore, (Example 263) The first fraction in <Step 1> was designated as R-form and the second fraction as S-form.
＜工程３＞（Ｓ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミドの合成
　（実施例１８）に準ずる方法で、（実施例２６３）＜工程１＞で得られた（Ｓ）－６－アミノ－２，４－ジメチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（４６．４ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（７５．９ｍｇ）より、標記化合物（６９．４ｍｇ）を淡橙色固体固体として得た。 <Step 3> (S) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[( Synthesis of 1,1-dimethylethyl) amino] sulfonyl] benzamide (S) -6-amino-2,4-dimethyl obtained in (Example 263) <Step 1> by a method according to Example 18 -2H-benzo [1,4] oxazin-3- (4H) -one (46.4 mg) and 2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (75.9 mg ) Gave the title compound (69.4 mg) as a pale orange solid.
（実施例２６４）（Ｒ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、（実施例２６３）＜工程１＞で得られた（Ｒ）－６－アミノ－２，４－ジメチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（４８．９ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（７５．９ｍｇ）より、標記化合物（７４．３ｍｇ）を淡橙色固体として得た。 Example 264 (R) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[ (1,1-Dimethylethyl) amino] sulfonyl] benzamide (R) -6-amino-2,4-dimethyl-obtained in (Example 263) <Step 1> by a method analogous to Example 18 2H-benzo [1,4] oxazin-3- (4H) -one (48.9 mg) and 2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (75.9 mg) As a result, the title compound (74.3 mg) was obtained as a pale orange solid.
（実施例２６５）（Ｓ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド
　（実施例１８）に準ずる方法で、（実施例２６３）＜工程１＞で得られた（Ｓ）－６－アミノ－２，４－ジメチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（７５．４ｍｇ）と２－クロロ－５－（４－モルホリニルスルホニル）安息香酸（１００．０ｍｇ）より、標記化合物（１１７．３ｍｇ）を白色固体として得た。 Example 265 (S) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4 -Morpholinylsulfonyl) benzamide (S) -6-amino-2,4-dimethyl-2H-benzo [1, obtained in (Example 263) <Step 1> by a method analogous to Example 18) 4] From oxazin-3- (4H) -one (75.4 mg) and 2-chloro-5- (4-morpholinylsulfonyl) benzoic acid (100.0 mg), the title compound (117.3 mg) was obtained as a white solid. Got as.
（実施例２６６）（Ｒ）－Ｎ－（３，４－ジヒドロ－２，４－ジメチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－（４－モルホリニルスルホニル）ベンズアミド
　（実施例１８）に準ずる方法で、（実施例２６３）＜工程１＞で得られた（Ｒ）－６－アミノ－２，４－ジメチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（７５．４ｍｇ）と２－クロロ－５－（４－モルホリニルスルホニル）安息香酸（１００．０ｍｇ）より、標記化合物（１１８．９ｍｇ）を白色固体として得た。 Example 266 (R) -N- (3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5- (4 -Morpholinylsulfonyl) benzamide (R) -6-amino-2,4-dimethyl-2H-benzo [1, obtained in (Example 263) <Step 1> by a method analogous to Example 18 4] From oxazin-3- (4H) -one (75.4 mg) and 2-chloro-5- (4-morpholinylsulfonyl) benzoic acid (100.0 mg), the title compound (118.9 mg) was obtained as a white solid. Got as.
（実施例２６７）（Ｓ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、（実施例２５８）＜工程１＞で得られた（Ｓ）－６－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（６１．１ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（６３．０ｍｇ）を白色固体として得た。 Example 267 (S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 , 1-Dimethylethyl) amino] sulfonyl] benzamide (S) -6-amino-2-methyl-2H-benzo [benzoyl amide] obtained in (Example 258) <Step 1> according to the method of Example 18). The title compound was obtained from 1,4] oxazin-3- (4H) -one (61.1 mg) and 2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (100.0 mg). (63.0 mg) was obtained as a white solid.
（実施例２６８）（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、（実施例２５８）＜工程１＞で得られた（Ｒ）－６－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（６１．１ｍｇ）と２－クロロ－５－［［（１，１－ジメチルエチル）アミノ］スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（５７．０ｍｇ）を白色固体として得た。 Example 268 (R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[[(1 , 1-Dimethylethyl) amino] sulfonyl] benzamide (R) -6-amino-2-methyl-2H-benzo [benzoyl amide] obtained in (Example 258) <Step 1> by a method similar to Example 18). The title compound was obtained from 1,4] oxazin-3- (4H) -one (61.1 mg) and 2-chloro-5-[[(1,1-dimethylethyl) amino] sulfonyl] benzoic acid (100.0 mg). (57.0 mg) was obtained as a white solid.
（実施例２６９）（Ｓ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、（実施例２５８）＜工程１＞で得られた（Ｓ）－６－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（５８．７ｍｇ）と２－クロロ－５－［（シクロペンチルアミノ）スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（１０５．０ｍｇ）を白色固体として得た。 Example 269 (S) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclopentylamino) ) Sulfonyl] benzamide (S) -6-amino-2-methyl-2H-benzo [1,4] oxazine-3 obtained in (Example 258) <Step 1> by a method analogous to Example 18 The title compound (105.0 mg) was obtained as a white solid from-(4H) -one (58.7 mg) and 2-chloro-5-[(cyclopentylamino) sulfonyl] benzoic acid (100.0 mg).
（実施例２７０）（Ｒ）－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル）－２－クロロ－５－［（シクロペンチルアミノ）スルホニル］ベンズアミド
　（実施例１８）に準ずる方法で、（実施例２５８）＜工程１＞で得られた（Ｒ）－６－アミノ－２－メチル－２Ｈ－ベンゾ［１，４］オキサジン－３－（４Ｈ）－オン（５８．７ｍｇ）と２－クロロ－５－［（シクロペンチルアミノ）スルホニル］安息香酸（１００．０ｍｇ）より、標記化合物（１０９．０ｍｇ）を白色固体として得た。 Example 270 (R) -N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-chloro-5-[(cyclopentylamino) ) Sulfonyl] benzamide (R) -6-amino-2-methyl-2H-benzo [1,4] oxazine-3 obtained in (Example 258) <Step 1> by a method similar to that in Example 18 The title compound (109.0 mg) was obtained as a white solid from-(4H) -one (58.7 mg) and 2-chloro-5-[(cyclopentylamino) sulfonyl] benzoic acid (100.0 mg).
　上記の（実施例１）から（実施例２７０）で合成した最終化合物の構造を以下に示す。これら実施例最終化合物のＬＣ／ＭＳデータ及び代表化合物のＮＭＲデータ（無印：３００ＭＨz　ＮＭＲ、＊印：４００ＭＨz　ＮＭＲ）も以下の表に示す。また、各実施例で合成した中間体化合物の構造の一部、中間体化合物の一部のＬＣ／ＭＳデータ、中間体化合物の一部のＮＭＲデータも、以下の表に示す。なお中間体化合物については、例えば、実施例１＜工程１＞で得られた化合物を１‐１のように表記した。 The structure of the final compound synthesized in the above (Example 1) to (Example 270) is shown below. The LC / MS data of these final compounds of Examples and NMR data of representative compounds (no mark: 300 MHz NMR, * mark: 400 MHz NMR) are also shown in the following table. In addition, the following table also shows part of the structure of the intermediate compound synthesized in each example, LC / MS data of part of the intermediate compound, and part of NMR data of the intermediate compound. As for the intermediate compound, for example, the compound obtained in Example 1 <Step 1> is represented as 1-1.
Figure JPOXMLDOC01-appb-C000202
  
Figure JPOXMLDOC01-appb-C000202
  
Figure JPOXMLDOC01-appb-C000203
  
Figure JPOXMLDOC01-appb-C000203
  
Figure JPOXMLDOC01-appb-C000204
  
Figure JPOXMLDOC01-appb-C000204
  
Figure JPOXMLDOC01-appb-C000205
  
Figure JPOXMLDOC01-appb-C000205
  
Figure JPOXMLDOC01-appb-C000206
  
Figure JPOXMLDOC01-appb-C000206
  
Figure JPOXMLDOC01-appb-C000207
  
Figure JPOXMLDOC01-appb-C000207
  
Figure JPOXMLDOC01-appb-C000208
  
Figure JPOXMLDOC01-appb-C000208
  
Figure JPOXMLDOC01-appb-C000209
  
Figure JPOXMLDOC01-appb-C000209
  
Figure JPOXMLDOC01-appb-C000210
  
Figure JPOXMLDOC01-appb-C000210
  
Figure JPOXMLDOC01-appb-C000211
  
Figure JPOXMLDOC01-appb-C000211
  
Figure JPOXMLDOC01-appb-C000212
  
Figure JPOXMLDOC01-appb-C000212
  
Figure JPOXMLDOC01-appb-C000213
  
Figure JPOXMLDOC01-appb-C000213
  
Figure JPOXMLDOC01-appb-C000214
  
Figure JPOXMLDOC01-appb-C000214
  
Figure JPOXMLDOC01-appb-C000215
  
Figure JPOXMLDOC01-appb-C000215
  
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000218
  
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000218
  
Figure JPOXMLDOC01-appb-T000219
  
Figure JPOXMLDOC01-appb-T000220
  
Figure JPOXMLDOC01-appb-T000221
  
Figure JPOXMLDOC01-appb-T000219
  
Figure JPOXMLDOC01-appb-T000220
  
Figure JPOXMLDOC01-appb-T000221
  
Figure JPOXMLDOC01-appb-C000222
  
Figure JPOXMLDOC01-appb-C000222
  
Figure JPOXMLDOC01-appb-T000223
  
Figure JPOXMLDOC01-appb-T000223
  
Figure JPOXMLDOC01-appb-T000224
  
Figure JPOXMLDOC01-appb-T000224
  

Claims (14)

  1. 下記式（ＩＩＩ）－Ｂ
    Figure JPOXMLDOC01-appb-C000001
      
    　（式中、Ｒ５Ａ、Ｒ６Ａは、各々独立に、水素原子、Ｃ１～６の直鎖もしくは分枝鎖のアルキル基またはＣ３～８のシクロアルキル基を表し（但し、Ｒ５ＡまたはＲ６Ａの少なくとも１つは構成炭素原子数が３以上の基である）、Ｒ５Ａ、Ｒ６Ａはそれらが結合する窒素原子とともに４～６員の環状基を形成していてもよく、当該環状基はその環内の炭素原子１個が酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよいＣ１～６の直鎖もしくは分枝鎖のアルキル基で置換されていてもよい）で置き換えられていてもよく；
    Ｒ１７ＡはＣ１～６アルキル、ハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基を表し；
    Ｒ１８は水素原子を表し；
    ＷＡは、－ＣＯＮＲ７－、－ＮＲ８ＣＯ－または－ＮＲ９ＣＯＮＲ１０－（Ｒ７、Ｒ８、Ｒ９、Ｒ１０は、各々独立に水素原子またはＣ１～６アルキル基を表す）を表し；
    Ｒ１２は、水素原子、ハロゲン原子、保護されていてもよいヒドロキシル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルキル基、ＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４アルコキシル基、またはＲＣ群から任意に選ばれる基で置換されていてもよいＣ１～４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から任意に選ばれる基を表し；
    Ａａは－ＮＲ１３－、－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基を表し；
    Ｇａはメチレン基、カルボニル基またはスルホニル基を表し；
    Ｌ１ａは、－ＣＲ１５ＡＲ１５Ｂ－または酸素原子を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ１ａは酸素原子である）；
    Ｌ２ａは、単結合、－（ＣＲ１５ＣＲ１５Ｄ）ｕ－（ｕは１または２の整数）、酸素原子または－ＮＲ１６Ｂ－を表し（但し、Ａａが－ＣＲ１４ＡＲ１４Ｂ－またはカルボニル基である場合、Ｌ２ａは単結合または－（ＣＲ１５ＣＲ１５Ｄ）ｕ－である）；
    Ｒ１３、Ｒ１６Ｂは、各々独立に、水素原子またはＲＢ群から任意に選ばれる基を表し；
    Ｒ１４Ａ、Ｒ１４Ｂ、Ｒ１５Ａ、Ｒ１５Ｂ、Ｒ１５Ｃ、Ｒ１５Ｄは、各々独立に、水素原子、ハロゲン原子、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いＣ１～６アルキル基、－ＯＨ・－ＮＨ２・－ＣＯＯＨから任意に選ばれる基で置換されていても良いヘテロ環基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルコキシル基、ＲＣ群から任意に選ばれる基で置換されていても良いＣ１～６アルキル基でモノ－もしくはジ－置換されていても良いアミノ基または保護されていても良いヒドロキシル基から任意に選ばれる基を表し、
    Ｒ１５Ａ及びＲ１５Ｂ、またはＲ１５Ｃ及びＲ１５Ｄは、それらが結合する炭素原子とともに３～８員の環状基を形成してもよく、当該環状基は、その環内の炭素原子１個が、酸素原子、硫黄原子もしくは窒素原子（当該窒素原子は、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・ハロゲン化Ｃ１～６アルコキシルのいずれかで１～５個置換されていてもよい直鎖もしくは分枝鎖のＣ１～６のアルキル基で置換されていても良い）で置き換えられていてもよく、当該環状基はさらにＲＣ群から任意に選ばれる基で置換されていてもよく；
    Ａａ、Ｇａ、Ｌ１ａ及びＬ２ａを構成に含む環における破線は適宜単結合もしくは二重結合をとり（但し、当該環が芳香化しているものを除く）、
    Ａａ、Ｇａ、Ｌ１ａ及びＬ２ａを構成に含む環はＲＡ群から任意に選ばれる基でさらに１置換されていてもよく；
    以上のＲＡ群の置換基は、ハロゲン原子、オキソ、ニトロ、シアノ、
    Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
    （当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
    Ｃ３～８シクロアルキル、Ｃ６～１４アリール、へテロ環、
    保護されていてもよいヒドロキシル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、Ｃ６～１４アリールオキシ、ヘテロ環オキシ、
    メルカプト、Ｃ１～６アルキルチオ、Ｃ６～１４アリールチオ、ヘテロ環チオ、Ｃ１～６アルキルスルフィニル、Ｃ６～１４アリールスルフィニル、ヘテロ環スルフィニル、Ｃ１～６アルキルスルホニル、Ｃ６～１４アリールスルホニル、ヘテロ環スルホニル、スルファモイル（当該スルファモイルは、Ｃ１～６アルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、スルホ、
    アミノ（当該アミノは、Ｃ１～６アルキル・モノ／ジＣ１～６アルキルスルファモイル・モノ／ジＣ１～６アルキルカルバモイル・ホルミル・Ｃ２～７アルカノイル・Ｃ６～１４アリール・ヘテロ環・モノ／ジＣ６～１４アリールスルファモイル・モノ／ジヘテロ環スルファモイル・Ｃ６～１４アリールカルボニルもしくはヘテロ環カルボニルで置換されていてもよい）、
    ホルミル、Ｃ２～７アルカノイル、Ｃ６～１４アリールカルボニル、ヘテロ環カルボニル、
    保護されていてもよいカルボキシル、Ｃ１～６アルコキシカルボニル、Ｃ６～１４アリールオキシカルボニル、ヘテロ環オキシカルボニル、
    カルバモイル（当該カルバモイルは、Ｃ１～６アルキル、Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）
    から任意に選ばれる基を表し；
    以上のＲＢ群の置換基は、
    Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
    （当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイル・Ｃ３～８シクロアルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
    Ｃ３～８シクロアルキル、Ｃ６～１４アリール、へテロ環、
    Ｃ１～６アルキルスルホニル、Ｃ６～１４アリールスルホニル、ヘテロ環スルホニル、スルファモイル（当該スルファモイルは、Ｃ１～６アルキル・Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）、
    Ｃ２～７アルカノイル、Ｃ６～１４アリールカルボニル、ヘテロ環カルボニル、
    Ｃ１～６アルコキシカルボニル、Ｃ６～１４アリールオキシカルボニル、ヘテロ環オキシカルボニル、
    カルバモイル（当該カルバモイルは、Ｃ１～６アルキル、Ｃ６～１４アリールもしくはヘテロ環で置換されていてもよい）
    から任意に選ばれる基を表し；
    以上のＲＣ群の置換基は、ハロゲン原子、オキソ、ニトロ、シアノ、
    Ｃ１～６アルキル、Ｃ２～６アルケニル、Ｃ２～６アルキニル
    （当該Ｃ１～６アルキル・Ｃ２～６アルケニル・Ｃ２～６アルキニルは、ハロゲン原子・－ＯＨ・Ｃ１～６アルコキシル・Ｃ１～６アルキルチオ・Ｃ１～６アルキルスルフィニル・Ｃ１～６アルキルスルホニル・スルファモイル・モノ／ジＣ１～６アルキルスルファモイル・カルボキシル・Ｃ１～６アルコキシカルボニル・カルバモイル・モノ／ジＣ１～６アルキルカルバモイル・アミノ・モノ／ジＣ１～６アルキルアミノ・Ｃ２～７アルカノイルもしくはＣ３～８シクロアルキルで置換されていてもよい）、
    Ｃ３～８シクロアルキル、
    保護されていてもよいヒドロキシル、Ｃ１～６アルコキシル、Ｃ２～６アルケニルオキシ、Ｃ２～６アルキニルオキシ、ハロゲン化Ｃ１～６アルコキシル、
    メルカプト、Ｃ１～６アルキルチオ、Ｃ１～６アルキルスルフィニル、Ｃ１～６アルキルスルホニル、スルファモイル、モノ／ジＣ１～６アルキルスルファモイル、スルホ、
    アミノ（当該アミノは、Ｃ１～６アルキル・モノ／ジＣ１～６アルキルスルファモイル・モノ／ジＣ１～６アルキルカルバモイル・ホルミルもしくはＣ２～７アルカノイルで置換されていてもよい）、
    ホルミル、Ｃ２～７アルカノイル、
    保護されていてもよいカルボキシル、Ｃ１～６アルコキシカルボニル、
    カルバモイルもしくはモノ／ジＣ１～６アルキルカルバモイルから任意に選ばれる基を表す）
    で表される化合物（但し、５－［（シクロプロピルアミノ)スルホニル］-Ｎ-（３，４-ジヒドロ-３-オキソ-２Ｈ-１,４-ベンゾキサジン－６－イル)－２－メチル－ベンズアミド、
    Ｎ－（３，４-ジヒドロ－２－メチル-3-オキソ－２Ｈ－１，４－ベンゾキサジン－６－イル)－５－［［（１，１－ジメチルエチル)アミノ］スルホニル］－２－メチル－ベンズアミド、
    ２-クロロ－Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾキサジン－６－イル)－５－（１－ピペリジニルスルホニル)－ベンズアミド、
    Ｎ－（３，４－ジヒドロ－２－メチル－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－６－イル)－２－メチル－５－（１－ピペリジニルスルホニル)－ベンズアミド、
    ２－メチル－Ｎ－（６－クロロ－３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾキサジン－７－イル)－５－（１－ピペリジニルスルホニル)－ベンズアミド、
    Ｎ－（６－クロロ－３，４－ジヒドロ－３－オキソ－２Ｈ－１，４－ベンゾオキサジン－７－イル)－２－フルオロ－５－（４－モルホリニルスルホニル)－ベンズアミド、
     　Ｎ－（１－アセチル－２，３－ジヒドロ－１Ｈ－インドール－５－イル)－２－フルオロ－５－（４－モルホリニルスルホニル)－ベンズアミド、
    ５－［（シクロプロピルアミノ）スルホニル］－Ｎ－（５－エトキシ－２，３－ジヒドロ－２－メチル－６－ベンゾフラニル)－２－メチル－ベンズアミト゛、
    ２－クロロ－Ｎ－（２，３－ジヒドロ－５－ベンゾフラニル）－５－（１－ピペリジニルスルホニル)－ベンズアミド、
    ２，３－ジヒドロ－２－メチル－Ｎ－［２－メチル－５－（１－ピペリジニルスルホニル)フェニル］－１－（メチルスルホニル)－1H-インドール-5-カルボキサミド、
    １，２，３，４－テトラヒドロ－Ｎ－［２－メチル－５－（１－ピペリジンスルホニル)フェニル］－１－（メチルスルホニル)－６-キノリンカルボキサミド,
    及びＮ－（５－エトキシ－２，３－ジヒドロ－２－メチル－６－ベンゾフラニル)－２－メチル－５－（１－ピペリジンスルホニル)－ベンズアミドを除く）、またはその塩またはそれらの溶媒和物。     Formula (III) -B below
    Figure JPOXMLDOC01-appb-C000001
    (Wherein, R 5A, R 6A are each independently a hydrogen atom, a cycloalkyl group of C 1 ~ linear or branched alkyl group or a C 3 ~ 8 (where, R 5A or R 6A is a group having 3 or more carbon atoms), R 5A and R 6A may form a 4- to 6-membered cyclic group together with the nitrogen atom to which they are bonded, carbon atoms 1 oxygen atoms in the ring, a sulfur atom or a nitrogen atom (said nitrogen atom is from 1 to 5 or a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 alkoxy it may be replaced by may also) be substituted with a straight-chain or branched-chain alkyl group of pieces optionally substituted C 1 to 6;
    R 17A represents a group selected from C 1 ~ 6 alkyl, halogen atom or a halogenated C 1 ~ 6 alkyl;
    R 18 represents a hydrogen atom;
    W A is, -CONR 7 -, - NR 8 CO- or -NR 9 CONR 10 - (R 7 , R 8, R 9, R 10 represents a hydrogen atom or a C 1 ~ 6 alkyl group independently) Represents;
    R 12 is a hydrogen atom, a halogen atom, protected Also good hydroxyl groups, selected groups optionally substituted C 1 to 4 alkyl groups optionally selected from R C group, the R C groups optionally optionally substituted C 1 ~ 4 alkoxyl group or a group optionally substituted with chosen group which may C 1 to 4 alkyl groups of R C group, mono- - or di - may be substituted Represents a group arbitrarily selected from an amino group;
    A a represents —NR 13 —, —CR 14A R 14B — or a carbonyl group;
    G a represents a methylene group, a carbonyl group or a sulfonyl group;
    L 1a represents —CR 15A R 15B — or an oxygen atom (provided that when A a is —CR 14A R 14B — or a carbonyl group, L 1a is an oxygen atom);
    L 2a represents a single bond, — (CR 15C R 15D ) u— (u is an integer of 1 or 2), an oxygen atom or —NR 16B — (where A a is —CR 14A R 14B — or a carbonyl group L 2a is a single bond or — (CR 15C R 15D ) u—);
    R 13, R 16B are each independently, represent a group selected arbitrarily from a hydrogen atom or R B groups;
    R 14A , R 14B , R 15A , R 15B , R 15C , and R 15D may each independently be substituted with a group arbitrarily selected from a hydrogen atom, a halogen atom, and —OH · —NH 2 . —COOH. good C 1 ~ 6 alkyl group, -OH · -NH 2 · -COOH substituted with chosen groups arbitrarily from which may have heterocyclic group, may be substituted by a group selected arbitrarily from R C group may be an optionally substituted amino group or a protected - or di - C 1 ~ 6 alkoxy group, mono optionally substituted with chosen group which may have C 1 ~ 6 alkyl group from R C group Represents a group arbitrarily selected from a hydroxyl group,
    R 15A and R 15B , or R 15C and R 15D may form a 3- to 8-membered cyclic group together with the carbon atom to which they are bonded, and the cyclic group has one carbon atom in the ring, oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom, a halogen atom, -OH, C 1 ~ 6 alkoxy-halogenated C 1 ~ 6 or with 1-5 optionally substituted straight or alkoxyl substituted with an alkyl group of C 1 ~ 6 branched may be replaced by also good), the cyclic group may be further substituted by a group selected arbitrarily from R C groups;
    The broken line in the ring including A a , G a , L 1a and L 2a in the structure takes a single bond or a double bond as appropriate (except that the ring is aromatized),
    The ring comprising A a , G a , L 1a and L 2a as a constituent may be further substituted with one group arbitrarily selected from the group R A ;
    Or more substituents R A group, halogen atom, oxo, nitro, cyano,
    C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl, C 3 - 8 cycloalkyl, C 6 - 14 aryl or heteroaryl ring),
    C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl, heterocycle,
    Optionally protected hydroxyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy, C 6 ~ 14 aryloxy, heterocyclic oxy,
    Mercapto, C 1 ~ 6 alkylthio, C 6 ~ 14 arylthio, heterocyclic thio, C 1 ~ 6 alkylsulfinyl, C 6 ~ 14 arylsulfinyl, heterocyclic sulfinyl, C 1 ~ 6 alkylsulfonyl, C 6 ~ 14 arylsulfonyl, heterocyclic sulfonyl, sulfamoyl (the sulfamoyl may be substituted with C 1 ~ 6 alkyl · C 6 ~ 14 aryl or heterocyclic), sulfo,
    Amino (said amino, C 1 ~ 6 alkyl mono / di C 1 ~ 6 alkylsulfamoyl mono / di C 1 ~ 6 alkylcarbamoyl, formyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 aryl heterocycle mono / di C 6 ~ 14 may be substituted with an aryl sulfamoyl mono / diheterocyclic sulfamoyl-C 6 ~ 14 arylcarbonyl or heterocycle carbonyl),
    Formyl, C 2 ~ 7 alkanoyl, C 6 ~ 14 arylcarbonyl, heterocyclic carbonyl,
    Optionally protected carboxyl, C 1 ~ 6 alkoxycarbonyl, C 6 ~ 14 aryloxycarbonyl, heterocyclic oxycarbonyl,
    Carbamoyl (said carbamoyl, C 1 ~ 6 alkyl, optionally substituted with C 6 ~ 14 aryl or hetero ring)
    Represents a group arbitrarily selected from:
    Substituents of the above R B group,
    C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl, C 3 - 8 cycloalkyl, C 6 - 14 aryl or heteroaryl ring),
    C 3 ~ 8 cycloalkyl, C 6 ~ 14 aryl, heterocycle,
    C 1 ~ 6 alkylsulfonyl, C 6 ~ 14 arylsulfonyl, heterocyclic sulfonyl, sulfamoyl (the sulfamoyl may be substituted with C 1 ~ 6 alkyl · C 6 ~ 14 aryl or heterocycle),
    C 2 ~ 7 alkanoyl, C 6 ~ 14 arylcarbonyl, heterocyclic carbonyl,
    C 1 ~ 6 alkoxycarbonyl, C 6 ~ 14 aryloxycarbonyl, heterocyclic oxycarbonyl,
    Carbamoyl (said carbamoyl, C 1 ~ 6 alkyl, optionally substituted with C 6 ~ 14 aryl or hetero ring)
    Represents a group arbitrarily selected from:
    The substituents of the above RC group are halogen atoms, oxo, nitro, cyano,
    C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl (said C 1 ~ 6 alkyl, C 2 ~ 6 alkenyl, C 2 ~ 6 alkynyl, halogen atom, -OH, C 1 ~ 6 alkoxy C 1 ~ 6 alkylthio-C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkylsulfamoyl, carboxyl, C 1 ~ 6 alkoxycarbonyl, carbamoyl, mono / di C 1 1-6 may be substituted by an alkylcarbamoyl, amino mono / di C 1 - 6 alkylamino, C 2 - 7 alkanoyl or C 3 - 8 cycloalkyl),
    C 3 ~ 8 cycloalkyl,
    Optionally protected hydroxyl, C 1 ~ 6 alkoxy, C 2 ~ 6 alkenyloxy, C 2 ~ 6 alkynyloxy, halogenated C 1 ~ 6 alkoxy,
    Mercapto, C 1 ~ 6 alkylthio, C 1 ~ 6 alkylsulfinyl, C 1 ~ 6 alkylsulfonyl, sulfamoyl, mono / di C 1 ~ 6 alkyl sulfamoyl, sulfo,
    Amino (said amino may be substituted by C 1 ~ 6 alkyl mono / di C 1 ~ 6 alkylsulfamoyl mono / di C 1 ~ 6 alkylcarbamoyl, formyl or C 2 ~ 7 alkanoyl),
    Formyl, C 2 ~ 7 alkanoyl,
    Optionally carboxyl which may be protected, C 1 ~ 6 alkoxycarbonyl,
    Carbamoyl or mono / di-C 1 ~ 6 chosen group from alkylcarbamoyl optionally)
    Embedded image wherein 5-[(cyclopropylamino) sulfonyl] -N- (3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) -2-methyl-benzamide ,
    N- (3,4-Dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5-[[(1,1-dimethylethyl) amino] sulfonyl] -2-methyl -Benzamide,
    2-chloro-N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -5- (1-piperidinylsulfonyl) -benzamide,
    N- (3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazin-6-yl) -2-methyl-5- (1-piperidinylsulfonyl) -benzamide;
    2-methyl-N- (6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl) -5- (1-piperidinylsulfonyl) -benzamide,
    N- (6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-7-yl) -2-fluoro-5- (4-morpholinylsulfonyl) -benzamide,
    N- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -2-fluoro-5- (4-morpholinylsulfonyl) -benzamide,
    5-[(cyclopropylamino) sulfonyl] -N- (5-ethoxy-2,3-dihydro-2-methyl-6-benzofuranyl) -2-methyl-benzamido,
    2-chloro-N- (2,3-dihydro-5-benzofuranyl) -5- (1-piperidinylsulfonyl) -benzamide,
    2,3-dihydro-2-methyl-N- [2-methyl-5- (1-piperidinylsulfonyl) phenyl] -1- (methylsulfonyl) -1H-indole-5-carboxamide;
    1,2,3,4-tetrahydro-N- [2-methyl-5- (1-piperidinesulfonyl) phenyl] -1- (methylsulfonyl) -6-quinolinecarboxamide,
    And N- (5-ethoxy-2,3-dihydro-2-methyl-6-benzofuranyl) -2-methyl-5- (1-piperidinesulfonyl) -benzamide), or a salt thereof or a solvate thereof .
  2. 　前記式（ＩＩＩ）－Ｂにおいて、下記式（Ｅ１ａ）－ｂ部分の結合位置が、
    Figure JPOXMLDOC01-appb-C000002
      
    下記式（Ｅ１ａ－１）－ｂまたは（Ｅ１ａ－２）－ｂ
    Figure JPOXMLDOC01-appb-C000003
      
    であることを特徴とする、請求項１に記載の化合物、またはその塩、またはそれらの溶媒和物。     In the formula (III) -B, the bonding position of the following formula (E1a) -b moiety is
    Figure JPOXMLDOC01-appb-C000002
    The following formula (E1a-1) -b or (E1a-2) -b
    Figure JPOXMLDOC01-appb-C000003
    The compound according to claim 1, or a salt thereof, or a solvate thereof.
  3. 　前記式（Ｅ１ａ－１）－ｂおよび（Ｅ１ａ－２）－ｂが、以下に示される式から任意に選択される基であることを特徴とする、請求項１または２に記載の化合物、またはその塩、またはそれらの溶媒和物。
    Figure JPOXMLDOC01-appb-C000004
      
    Figure JPOXMLDOC01-appb-C000005
           The compound according to claim 1 or 2, wherein the formulas (E1a-1) -b and (E1a-2) -b are groups arbitrarily selected from the formulas shown below, or Its salts, or their solvates.
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
  4. 　前記式（ＩＩＩ）－Ｂにおいて、ＷＡが、－ＣＯＮＲ７－であることを特徴とする、請求項１ないし請求項３のいずれか１項に記載の化合物、またはその塩、またはそれらの溶媒和物。 In the formula (III) -B, W A is, -CONR 7 -, characterized in that a compound according to any one of claims 1 to 3 or a salt thereof, or their solvent, Japanese products.
  5. 　前記式（ＩＩＩ）－Ｂにおいて、－ＮＲ５ＡＲ６Ａが、以下の記載の式から任意に選ばれる基であることを特徴とする。請求項１ないし請求項４のいずれか１項に記載の化合物、またはその塩、またはそれらの溶媒和物。
    Figure JPOXMLDOC01-appb-C000006
           In the formula (III) -B, —NR 5A R 6A is a group arbitrarily selected from the following formulae. The compound of any one of Claims 1 thru | or 4, its salt, or those solvates.
    Figure JPOXMLDOC01-appb-C000006
  6. 　前記式（ＩＩＩ）－Ｂにおいて、Ｒ１７Ａがハロゲン原子またはハロゲン化Ｃ１～６アルキルから選ばれる基であることを特徴とする、請求項１ないし請求項５のいずれか１項に記載の化合物、またはその塩、またはそれらの溶媒和物。 In the formula (III) -B, wherein the R 17A is a group selected from a halogen atom or a halogenated C 1 ~ 6 alkyl, A compound according to any one of claims 1 to 5 Or a salt thereof, or a solvate thereof.
  7. 　前記式（ＩＩＩ）－Ｂにおいて、Ａａは－ＮＲ１３－であることを特徴とする、請求項１ないし請求項６に記載の化合物、またはその塩、またはそれらの溶媒和物。 In the formula (III) -B, A a is -NR 13 - characterized in that it is a compound according to claims 1 to 6 or a salt thereof, or a solvate thereof.
  8. 　請求項１ないし請求項７のいずれか１項に記載の化合物、または製薬学的に許容されるその塩、またはそれらの溶媒和物を少なくとも一つを有効成分として含有することを特徴とする、医薬組成物。 It contains at least one of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, Pharmaceutical composition.
  9. 　請求項１ないし請求項７のいずれか１項に記載の化合物、または製薬学的に許容されるその塩、またはそれらの溶媒和物を少なくとも一つを有効成分として含有することを特徴とする、長鎖脂肪酸伸長酵素（Ｅｌｏｖｌ６）阻害剤。 It contains at least one of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, Long chain fatty acid elongation enzyme (Elovl6) inhibitor.
  10. 　請求項１ないし請求項７のいずれか１項に記載の化合物、または製薬学的に許容されるその塩、またはそれらの溶媒和物を少なくとも一つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療剤。 It contains at least one of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, A preventive and / or therapeutic agent for NAFLD / NASH, diabetes, insulin resistance or obesity / obesity.
  11. 　請求項１ないし請求項７のいずれか１項に記載の化合物、または製薬学的に許容されるその塩、またはそれらの溶媒和物を少なくとも一つの有効量を患者に投与することを含む、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療方法。 8. A NAFLD comprising administering to a patient at least one effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for preventing and / or treating NASH, diabetes, insulin resistance or obesity / obesity.
  12. 　ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬品を製造するための、請求項１ないし請求項７に記載のいずれかの化合物、または製薬学的に許容されるその塩、またはそれらの溶媒和物の使用。 A compound according to any one of claims 1 to 7, or a pharmaceutically agent for producing a medicament for the prevention and / or treatment of NAFLD / NASH, diabetes, insulin resistance or obesity / obesity Use of an acceptable salt or solvate thereof.
  13. 　請求項１ないし請求項７のいずれか１項に記載の化合物、または製薬学的に許容されるその塩、またはそれらの溶媒和物を少なくとも一つを有効成分として含有することを特徴とする、ＮＡＦＬＤ・ＮＡＳＨ、糖尿病、インスリン抵抗性または肥満・肥満症の予防および／または治療のための医薬組成物。 It contains at least one of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, A pharmaceutical composition for preventing and / or treating NAFLD / NASH, diabetes, insulin resistance or obesity / obesity.
  14. 　請求項１ないし請求項７のいずれか１項に記載の化合物、または製薬学的に許容されるその塩、またはそれらの溶媒和物を少なくとも一つ、及び薬学的担体とともに、他の薬物の有効成分を含有していてもよい、医薬組成物。 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, together with a pharmaceutical carrier, and the efficacy of another drug A pharmaceutical composition which may contain an ingredient.
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