WO2013154163A1

WO2013154163A1 - Novel 5-aryl-1,2-thiazinane derivative

Info

Publication number: WO2013154163A1
Application number: PCT/JP2013/060953
Authority: WO
Inventors: 宗隆大河内
Original assignee: 持田製薬株式会社
Priority date: 2012-04-11
Filing date: 2013-04-11
Publication date: 2013-10-17

Abstract

Provided is a GPR40 activating agent comprising a novel compound of formula (I) which has a GPR40 agonist action, a salt or solvate thereof as an active ingredient, particularly an insulin secretion promoter, or an agent for prophylaxis and/or treatment of diabetes, obesity or the like. Ring A: C_5-7 cycloalkenyl, condensed aryl, condensed heteroaryl, or partially hydrogenated condensed heteroaryl, ring A': benzene, pyridine or pyrimidine, R¹, R³, R⁴: halogen, CN, C_1-6 alkyl or the like, R²: C_1-6 alkoxy or the like, R^5a, R^5b, R⁶, R^7a, R^7b: H, halogen, C_1-6 alkyl or the like, p: 0 to 4, q: 0 to 2, and r, s: 0 to 4.

Description

Novel 5-aryl-1,2-thiazinane derivatives

The present invention relates to a compound that regulates the function of GPR40 (G Protein-coupled Receptor 40), in particular, 5-aryl-1,1-dioxo-1,2-thiazinan-3-one represented by the formula (I) A compound having a group or a salt thereof or a solvate thereof, a pharmaceutical composition containing the compound as an active ingredient, or a prophylactic and / or therapeutic agent for a disease involving GPR40, particularly diabetes, or The present invention relates to an insulin secretagogue.

Diabetes is classified into type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (non-insulin-dependent diabetes), and borderline diabetes (impaired glucose tolerance), which can be regarded as a reserve army, has recently been regarded as important. Type 1 diabetes is characterized by little or no production of insulin, a blood glucose regulating hormone. Type 2 diabetes is characterized by peripheral insulin resistance and impaired insulin secretion. Borderline type diabetes is a disease state that shows impaired glucose tolerance (IGT) and fasting blood glucose abnormality (IFG), and is a disease that is at risk of progression to type 2 diabetes and diabetic complications.
Such diabetes develops due to multiple etiologies. In general, it is a disease characterized by high plasma glucose levels during fasting, postprandial or oral glucose tolerance tests, or chronic hyperglycemia. Chronic hyperglycemia control is important in clinical diabetes management and It is important for treatment. In particular, in type 2 diabetes and borderline diabetes, a decrease in insulin secretion from pancreatic β cells causes rapid postprandial hyperglycemia. In large-scale international clinical trials, it has been shown that suppression of such postprandial hyperglycemia in glucose intolerance is important not only for diabetes but also for suppression of the onset and progression of hypertension and cardiovascular disease ( JAMA, 290, 486-494 (2003) (non-patent document 1)). Based on these findings, a new diabetes treatment guideline (postprandial blood glucose level management guideline) was published by the International Diabetes Federation in 2007, and is intended to improve diabetes and reduce the risk of complications in patients with type 1 and type 2 diabetes. In addition, management of postprandial blood glucose levels is recommended as important. In fact, in α-glucosidase inhibitor (voglibose), an anti-diabetic post-hyperglycemic drug, the indication expansion for “suppression of type 2 diabetes in impaired glucose tolerance” has been approved in Japan. Is allowed to use. As described above, in recent years, the need for non-drug therapy and drug therapy targeting postprandial blood glucose management has been recognized in diabetes and borderline diabetes.
Treatment of diabetes is mainly dietary / exercise therapy, but if these cannot be improved, pharmacotherapy is required. There are various drugs for the prevention and treatment of diabetes, but as insulin secretion promoters, sulfonylureas (such as glibenclamide and glimepiride) and rapid insulin secretion promoters that stimulate insulin secretion by stimulating pancreatic β cells (Nateglinide, mitiglinide, etc.). However, these drugs are known to have side effects such as ineffective administration (primary ineffective / secondary ineffective) and hypoglycemia-inducing action. New insulin secretion promoters include GLP-1 (glucagon-like peptide 1) analogs (exenatide, liraglutide, etc.) that are hormones that promote glucose-responsive insulin secretion in pancreatic β cells, but administration by injection is required And the side effects of transient gastrointestinal tract disorders are known. DPP-IV (dipeptidyl peptidase IV) inhibitors (such as sitagliptin, vildagliptin, and alogliptin) that suppress endogenous GLP-1 degradation are also insulin secretagogues, but nasopharyngitis, headache, and infection are known as side effects It has been. α-glucosidase inhibitors (acarbose, voglibose, etc.) limit the rapid increase in postprandial blood glucose level by inhibiting the degradation and digestion of carbohydrates, but it is essential to take it immediately before meals. It is known that there are cases that cause severe liver damage. Biguanides (metformin, buformin, etc.) are insulin resistance improving agents that increase insulin sensitivity and improve hyperglycemia, but are known to induce side effects such as lactic acidosis, nausea and vomiting. Thiazolidinedione derivatives (pioglitazone, rosiglitazone, etc.) are peroxisome proliferator-activated receptors (PPAR) gamma agonists that increase insulin sensitivity in adipose tissue, liver and skeletal muscle, and improve chronic hyperglycemia It is known that it tends to cause edema, weight gain, and further liver damage, which is a serious side effect. Although the side effects of these drugs do not always occur, treatment satisfaction is still insufficient. Accordingly, an insulin secretion enhancer that suppresses postprandial hyperglycemia without inducing hypoglycemia, which is a drug with few problems and side effects, and particularly an orally administrable drug, with the conventional preventive / therapeutic agents as described above. It has been demanded.

Fatty acids play an important role in the use of insulin in the liver and skeletal muscle, glucose-responsive insulin secretion from the pancreas, and inflammation associated with fat accumulation in adipose tissue. It is known that there is a strong link between elevated plasma fatty acid levels and diabetes, metabolic syndrome, obesity and obesity.
GPR40 is one of G protein-coupled receptors, belongs to the Free Fatty Acids Receptor (FFAR) family, and is activated by C6-C22 saturated fatty acids and unsaturated fatty acids. GPR40 is highly expressed in pancreatic β cells and has been reported to be involved in insulin secretion by fatty acids (Nature, 422, 173-176 (2003) (Non-patent Document 2)). In recent years, non-fatty acid low molecular weight compounds having a GPR40 agonistic action have been found, and thiazolidinediones that are insulin sensitivity enhancers and MEDICA16 that is a lipid lowering drug have been reported to have agonistic actions. (Biochem. Biophys. Res. Comm., 301, 406-410 (2003) (non-patent document 3)).
In pancreatic islets of Langerhans isolated from GPR40 knockout mice, the glucose-responsive insulin secretion promoting action by fatty acids is attenuated as compared to normal mice. Therefore, a substance having a GPR40 agonistic action similar to fatty acid is expected to have an action to suppress postprandial hyperglycemia based on the glucose-responsive insulin secretion promoting action in the pancreas. Therefore, a substance having a GPR40 agonistic action is considered useful as a preventive / therapeutic agent for diabetes and borderline diabetes.

In recent years, research on compounds having GPR40 activating action as insulin secretagogues and diabetes treatments has been advanced. For example, as a technique related to a compound having a GPR40 agonistic action, WO 2004/041266 pamphlet (Patent Document 1), WO 2005/088661 pamphlet (Patent Document 2), WO 2007/123225 pamphlet (Patent Document 3), WO 2008/001931 pamphlet. (Patent Literature 4), WO 2009/054390 pamphlet (Patent Literature 5), WO 2009/054423 pamphlet (Patent Literature 6), WO 2005/063729 pamphlet (Patent Literature 7), WO 2008/130514 pamphlet (Patent Literature 8). Can be mentioned. However, there is no disclosure or suggestion of a compound having a 5-aryl-1,1-dioxo-1,2-thiazinan-3-one group.
As a technique related to a compound having a 5-aryl-3-isothiazolidinone ring, WO2005 / 035551 pamphlet (Patent Document 9) can be mentioned. There is no specific disclosure of a compound having a 5-aryl-1,1-dioxo-1,2-thiazinan-3-one ring, and in the compound of the patent document and the compound of the present invention, a linker site, etc. The basic structure is also different.
As a technique relating to a compound having a 5-aryl-1,1-dioxo-1,2-thiazinan-3-one ring, Synlett, 834-838 (2005) (Non-patent Document 4) can be mentioned. The basic skeleton is different from the compound, and there is no disclosure or suggestion of the GPR40 agonistic action as in the present invention.
Recently, it has a 3-hydroxy-5-arylisoxazole group or a 3-hydroxy-5-arylisothiazole group in WO2011 / 052756 pamphlet (patent document 10) and WO2011 / 078371 pamphlet (patent document 11). Compounds having GPR40 activating action have been reported.

Now, in drug development, it is required to satisfy strict criteria not only in the intended pharmacological activity but also in various aspects such as absorption, distribution, metabolism, and excretion. For example, drug interaction, desensitization or tolerance, digestive tract absorption after oral administration, transfer rate into the small intestine, absorption rate and first-pass effect, organ barrier, protein binding, induction and inhibition of drug metabolizing enzymes, excretion route and Various examination subjects are required in the body clearance, application method (application site, method, purpose) and the like, and it is difficult to find one that satisfies these.
Although there are a plurality of reported examples of compounds having a GPR40 agonistic action, they have not yet been put on the market. Even with this agonist, the above-mentioned comprehensive problems in drug development will always arise. More specifically, for example, hERG (human ether) which has low metabolic stability, makes systemic exposure difficult by oral administration, has poor pharmacokinetics such as absorbability and persistence, or has a risk of causing arrhythmia. -a-go-go related gene) channel inhibitory activity, drug metabolizing enzyme (eg, cytochrome P450, etc.) induction or inhibitory activity, or side effects caused by CNS due to translocation into the brain There is a problem of safety, and there is a demand for highly effective compounds that solve these problems as much as possible.
In addition, for GPR40 agonists, compounds with fewer problems and side effects as described above are required than conventional drugs used for the prevention or treatment of diabetes (especially type 2 diabetes or borderline diabetes) described above. -ing

WO2004 / 041266 pamphlet WO2005 / 088661 pamphlet WO2007 / 123225 pamphlet WO2008 / 001931 pamphlet WO2009 / 054390 pamphlet WO2009 / 054423 pamphlet WO2005 / 063729 pamphlet WO2008 / 130514 pamphlet WO2005 / 035551 pamphlet WO2011 / 052756 pamphlet WO2011 / 078371 pamphlet

In view of the above-described medical situation for diabetes, a prophylactic / therapeutic agent that activates GPR40 to promote insulin secretion, particularly glucose-responsive insulin secretion, and lower blood glucose level, particularly suppress postprandial hyperglycemia. It has been demanded.
In particular, GPR40 activators, insulin secretagogues, or diseases involving GPR40 that can be administered orally, are highly safe, highly effective, and highly selective for other FFAR families and similar receptors And / or therapeutic agents (especially preventive and / or therapeutic agents for diabetes and obesity).

In particular, there are issues to be addressed, such as the problems in the prior art described above. More specifically, as a prophylactic / therapeutic agent for diabetes, administration ineffective (primary ineffective / secondary ineffective) and side effects of hypoglycemia inducing action in sulfonylurea and rapid insulin secretagogue; Transient gastrointestinal tract disorders; nasopharyngitis and headaches with DPP-IV inhibitors, side effects of infections, etc .; side effects such as bloating and diarrhea with α-glucosidase inhibitors, and serious liver disorders; There are issues to be addressed, such as lactic acidosis in biguanides and side effects of nausea and vomiting; thiazolidinedione derivatives cause edema, weight gain, and severe liver damage. Furthermore, improved solubility, metabolic stability, improved absorption, improved pharmacokinetics, reduced hERG inhibitory action, reduced induction or inhibitory action of drug metabolizing enzymes (eg, cytochrome P450, etc.), reduced central migration There are issues to be addressed. Then, it overcomes at least one of these problems and can prevent orally administer drugs that can be orally administered to mammals including humans, particularly clinically convenient insulin secretion promoters and / or GPR40-related diseases. A therapeutic agent (particularly, a preventive and / or therapeutic agent for diabetes and obesity) is desired.

In order to solve the above-mentioned problems, the present inventors have conducted extensive research to obtain a compound that regulates the function of GPR40 that is highly safe and / or excellent in effectiveness. It was found that the 5-aryl-1,1-dioxo-1,2-thiazinan-3-one derivative represented by the above formula has a GPR40 agonistic action. The compound of the present invention has an excellent glucose-responsive insulin secretion-promoting action, and has a strong blood glucose elevation-inhibiting action during a glucose load.

The present invention relates to a compound having a 5-aryl-1,1-dioxo-1,2-thiazinan-3-one group represented by the formula (I) or a salt thereof or a solvate thereof, And a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
The compound of the present invention has a GPR40 agonistic action, or activates GPR40, thereby promoting insulin secretion, particularly glucose-responsive insulin secretion, and lowering blood sugar level, especially postprandial hyperglycemia. The pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally, and is used for insulin secretion promoters, GPR40-related diseases, particularly diabetes (especially type 2 diabetes or borderline diabetes), obesity / obesity Expected as a preventive and / or therapeutic agent.
In addition, the compound group of the present invention has good solubility, high metabolic stability, excellent oral absorbability, little hERG channel inhibitory action, and little central migration. It is highly useful because it also has at least one feature.

The present invention relates to a compound having a 5-aryl-1,1-dioxo-1,2-thiazinan-3-one group represented by the formula (I) represented by the following embodiment or a salt thereof, These solvates and pharmaceutical compositions characterized by containing them as active ingredients are GPR40 activators.

[Aspect of the Invention]
[1] Aspect of the present invention [1]
The first aspect of the present invention is:
Formula (I)

(In the formula, L represents 4- (3-hydroxy-3-methylbutoxy) -2,6-dimethylphenyl group and 4- (2-ethoxyethoxy) -2,6-dimethylphenyl group, and the following formula (A1 ), Formula (A2) and formula (A3)

(Wherein p represents an integer of 0 to 4; q represents an integer of 0 to 2 (provided that p + q is an integer of 0 to 5);
R ¹ is, each independently, a halogen atom, -OH, a cyano group, a substituent RI with 1-5 optionally substituted _C 1 _{to 6} alkyl groups, substituted one to five substituents RI which may _C 2 _{- 6} alkenyl group, which may be 1-5 substituted with a substituent RI _C 2 _{- 6} alkynyl group, a substituent RI with 1-5 optionally substituted _C 1 _{to 6} alkoxy group , _C 2 _{~ 7} alkanoyl group, -SH, _{^{group: -S (O) i R a}} (i is an integer of 0 to 2), group: ^-NR b ^{R c} and groups: optionally from -CONR ^d R ^e Represents a group selected by
R ² are each independently 1-5-substituted _C 1 _{- 6} alkoxyl group with a substituent M, substituted one to a group M 5-substituted _C 2 _{- 6} alkenyloxy group, 1 substituents M to five-substituted _C 2 _{- 6} alkynyloxy group, group: -CONR ^d R ^e1, aralkyloxy group, a heterocyclic oxy group (said heterocyclic group _is optionally at C 1 _{~ 6} alkyl group or oxo group 1-3 may be substituted), Hajime Tamaki (said heterocyclic group is optionally may be one to three substituents at C ₁ ~ ₆ alkyl group or oxo group), and heterocyclic carbonyl group (the heterocyclic carbonyl group may be optionally 1 to have three substituted with C ₁ ~ ₆ alkyl group or oxo group) represent a group chosen arbitrarily from;
Substituents M are each independently a halogen atom, -OH, C ₁ ~ ₆ alkoxy group, an aryl group (said aryl group is optionally may be 1-3 substituted with a halogen atom), a heterocyclic group (the heterocyclic group, _-OH, optionally may be one to three substituents at C 1 _{~ 6} alkyl group or oxo group), _{^{group: -S (O) i R a}} (i is 0-2 A group: —NR ^b R ^c , a group: —SO ₂ NR ^d R ^e and a group: —CONR ^d R ^e ;
Ring A represents a C ₅ ~ ₇ cycloalkyl group, condensed ring aryl group, condensed ring heteroaryl group or partially hydrogenated condensed heteroaryl group;
Ring A ′ represents a group arbitrarily selected from a benzene ring, a pyridine ring or a pyrimidine ring);
r and s each independently represents an integer of 0 to 4;
R ³ are each independently a halogen atom, -OH, a cyano group, a substituent RI with 1-5 optionally substituted _C 1 _{to 6} alkyl groups, substituted one to five substituents RI which may _C 2 _{- 6} alkenyl group, which may be 1-5 substituted with a substituent RI _C 2 _{- 6} alkynyl group, a substituent RI with 1-5 optionally substituted _C 1 _{to 6} alkoxy group , _C 2 _{~ 7} alkanoyl group, -SH, _{^{group: -S (O) i R a}} (i is an integer of 0 to 2), group: ^-NR b ^{R c} and groups: optionally from -CONR ^d R ^e Represents a group selected by
R ⁴ are each independently a halogen atom, a substituent RI with 1-5 optionally substituted _C 1 _{to 6} alkyl groups, optionally _C 2 _- it is 1-5 substituted with a substituent RI ₆ alkenyl group, the substituent RI in 1-5 optionally substituted C ₂ even though _2-6 alkynyl group, optionally from 1 to 5 substituents which may C ₁ to ₆ alkoxy group and a cyano group with substituents RI It represents a group ^selected; R ^{5a, R 5b} each independently represents a hydrogen atom, a halogen _atom, C 1 _{~ 6} alkyl _group, C 2 _{~ 6} alkenyl _group, C 2 _{~ 6} alkynyl _group, C 1 _{~ 6} alkoxy group And a group arbitrarily selected from a cyano group;
R ⁶ is a hydrogen atom, a halogen _atom, C 1 _{~ 6} alkyl group, a halogenated _C 1 _{~ 6} alkyl _group, C 2 _{~ 6} alkenyl _group, C 2 _{~ 6} alkynyl _group, C 1 _{~ 6} alkoxyl group, a halogenated C It represents _{_1-6} alkoxyl group, C ₂ ~ ₇ alkanoyl group and protected chosen arbitrarily from a carboxyl group which have groups;
R ^7a, ^{R 7b} are each independently a hydrogen atom, a halogen _atom, C 1 _{~ 6} alkyl group, a halogenated _C 1 _{~ 6} alkyl _group, C 2 _{~ 6} alkenyl _group, C 2 _{~ 6} alkynyl _{group, C} 1 ~ ₆ alkoxyl group, a halogenated C ₁ ~ ₆ alkoxy group and a group selected arbitrarily from a cyano group;

Or more substituents RI are the same or different from each other, a halogen atom, -OH, cyano _group, C 1 _{~ 6} alkoxy group (said _C 1 _{~ 6} alkoxy group, a halogen atom, _-OH, C 1 _{~ 6} alkoxy group , an aryl group (said aryl group may be optionally 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group is optionally 1 in C ₁ to ₆ alkyl group or oxo group 3 may be substituted), group: —S (O) _i R ^a (i represents an integer of 0 to 2), group: —SO ₂ NR ^d R ^e , group: —CONR ^d R ^e or group: ^-NR b ^{R c} optionally may be 1-5 substituted with) a group: ^-NR b ^{R c,} and a heterocyclic oxy group (the heterocyclic oxy _group, C 1 _{~ 6} alkyl group or oxo Optionally substituted with 1 to 3 groups Represents a group arbitrarily selected from:
R ^a _represents a C 1 _{~ 6} alkyl group or halogenated _C 1 _{~ 6} alkyl group;
R ^b, ^{R c} each independently represents a hydrogen _atom, C 1 _{~ 6} alkyl _group, a C 2 _{~ 7} alkanoyl groups and _C 1 _{~ 6} alkylsulfonyl optionally chosen group from ^group, R b, ^{R c} is 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, 1 or 2 carbon atoms in the ring are an oxygen atom, a sulfur atom and a nitrogen atom (the nitrogen atom). It represents may also be replaced by chosen atom or a carbonyl group arbitrarily from the may be) optionally substituted with C ₁ ~ ₆ alkyl group;
R ^d, ^{R e} are each independently a hydrogen atom or a _C 1 _{~ 6} alkyl group (said _C 1 _{~ 6} alkyl group is optionally 1-5 substituted by a halogen atom, -OH or _C 1 _{~ 6} alkoxy group It may be)
R ^e1 _is C 1 _{~ 6} alkyl group (said _C 1 _{~ 6} alkyl group, _-OH, C 1 _{- 6} alkoxyl group, an aryl group (said aryl group is optionally one to have three substituted by a halogen atom may be), a Hajime Tamaki (said heterocyclic group _is optionally may be one to three substituents at C 1 _{~ 6} alkyl group or oxo group), _{^{group: -S (O) i R a}} ( i represents an integer of 0 to 2), a group: —SO ₂ NR ^d R ^e , a group: —CONR ^d R ^e or a group: —NR ^b R ^c optionally substituted with 1 to 5) (However, 5- (4-((2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Excluding compounds that are))
Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt.

Below, each group in the said formula (I) of the said aspect [1] is demonstrated concretely.
In description of the compounds of the present invention, for example, "C ₁ ~ _6" indicates that the number of constituent carbon atoms is 1 to 6, unless otherwise indicated, a straight-chain, the carbon atoms of branched or cyclic group Represents a number. The number of constituent carbon atoms includes the total number of carbon atoms of a linear or branched group substituted with a cyclic group, or a group containing a cyclic group substituted with a linear or branched group. Accordingly, the chain group means “straight chain or branched chain having 1 to 6 carbon atoms”. Further, the cyclic group means “a cyclic group having 1 to 6 carbon atoms in the ring”. The group containing a chain group and a cyclic group means “a group having 1 to 6 total carbon atoms”.

The “alkyl group” represents a linear, branched or cyclic alkyl group. For example, as _"C 1 _{~ 6} alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert- pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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, Black, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-methylcyclopropyl, and the like.

The “alkenyl group” represents a linear, branched or cyclic alkenyl group. For example, as _"C 2 _{~ 6} alkenyl group" are vinyl, allyl, isopropenyl, 2-methylallyl, butenyl, pentenyl, isopentenyl, hexenyl, 1-cyclopropene-1-yl, 2-cyclopropene-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3- Examples include cyclohexen-1-yl, 2,4-cyclopentadien-1-yl, 2,5-cyclohexadien-1-yl, and the like. A cyclic alkenyl group is also referred to as a “cycloalkenyl group”. As the _"C 5 _{~ 7} cycloalkenyl group", 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1 Yl, 3-cyclohexen-1-yl, 1-cyclohepten-1-yl and the like.
The “alkynyl group” represents a linear, branched or cyclic alkynyl group. For example, as _"C 2 _{~ 6} alkynyl group", ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl and the like.

The "alkoxyl group", straight chain, represents a branched or cyclic alkoxyl group, the comprehensive RO- (R is C ₁ ~ ₆ alkyl group listed in above in C ₁ ~ ₆ alkoxy group Represents a group represented by: For example, _"C 1 _{~ 6} alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert- pentyloxy, 1- Methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1,1-dimethyl Butyloxy, 1,2-dimethylbutyloxy, 2,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,3-dimethylbutyloxy, 3,3-dimethylbutoxy, 1-ethylbutyloxy, 2- Ethyl butyloxy, 1,1, -Trimethylpropyloxy, 1,2,2-trimethylpropyloxy, 1-ethyl-1-methylpropyloxy, 1-ethyl-2-methylpropyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclo Examples include propylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy, 2-cyclobutylethoxy, 2-methylcyclopropyloxy and the like.

The “alkenyloxy group” is a group in which the “alkenyl group” is substituted with an oxygen atom, and represents a straight, branched or cyclic alkenyloxy group. For example, as the _"C 2 _{~ 6} alkenyloxy group", vinyloxy, allyloxy, isopropenyloxy, 2-methyl-allyloxy, butenyloxy, pentenyloxy, isopentenyl oxy, hexenyloxy, 1-cyclopropene-1-yloxy, 2- Cyclopropen-1-yloxy, 1-cyclobuten-1-yloxy, 1-cyclopenten-1-yloxy, 2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy, 1-cyclohexen-1-yloxy, 2-cyclohexene Examples include 1-yloxy, 3-cyclohexen-1-yloxy, 2,4-cyclopentadien-1-yloxy, 2,5-cyclohexadien-1-yloxy, and the like.
The “alkynyloxy group” is a group in which the “alkynyl group” is substituted with an oxygen atom, and represents a linear, branched or cyclic alkynyloxy group. For example, as "C ₂ ~ ₆ alkynyloxy group", ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, and the like.

The "aryl group", a monocyclic or condensed cyclic _C 6 _{~ 14} aryl group, e.g., phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, acenaphthyl and the like, or (1-, 2-, 4 -Or 5-) Partially hydrogenated condensed aryl groups such as indanyl, indenyl, tetrahydronaphthyl and the like. Here, the partially hydrogenated fused 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 ring part of the condensed ring or Either hydrogen atom in the hydrogenated part may be removed. For example, in the case of tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthalene (-1-yl, -2-yl, -3-yl, -4-yl, -5-yl, -6-yl,- 7-yl, -8-yl) and the like.

Examples of the “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) arbitrarily selected from N, O and S in addition to carbon atoms Alternatively, it means 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 7 ring members, such as pyrrolyl, furyl, thienyl, imidazolyl. , Pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 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, 4 1,2,4 thiadiazinyl, 6H-1,3,4-thiadiazinyl, 1,4 diazepinyl, 1,4-oxazepinyl and the like.

Further, the condensed heteroaryl group is preferably one having 8 to 14 ring members, which includes the 5- to 7-membered heterocycle and a monocyclic aryl group or monocyclic heteroaryl group. A monovalent group formed by removing an arbitrary hydrogen atom from a condensed ring formed by condensation is included. The arbitrary hydrogen atom may be removed from any condensed ring.
Specifically, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H -Benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl, 2,1,3-benzothiadiazinyl, chromenyl, isochromenyl, 4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, Quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl , Phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, thieno [3,2-c] pyridyl, thiazolo [5,4-c] pyridyl, pyrrolo [1,2-b] Pyridazinyl, pyrazolo [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, 1H-pyrazolo [3,4-b] pyridyl, 1,2, 4-triazolo [1,5-a] pyrimidinyl, dibenzofuranyl and the like.
Indolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, chromanyl, isochromanyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3, 4-dihydro-2H-1,4-benzothiazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxalinyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl, 1,3- Partially hydrogenated condensed heteroaryl groups such as benzodioxolyl, tetrahydrobenzoxazepinyl, tetrahydrobenzoazepinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridyl, etc. Also mentioned. Here, the partially hydrogenated condensed heteroaryl group and the like are preferably those having 8 to 14 ring members, which are a 5- to 7-membered heterocyclic ring, a monocyclic aryl group or a monocyclic heterocycle. In a condensed ring formed by condensation of an aryl group, it means a monovalent group formed by removing any hydrogen atom from a partially hydrogenated ring. The arbitrary hydrogen atom may be an aryl group, a hydrogen atom in the heterocyclic portion, or a hydrogen atom in the hydrogenated portion. For example, tetrahydroquinolyl includes 5,6,7,8-tetrahydroquinolyl or 1,2,3,4-tetrahydroquinolyl. These groups may be substituted depending on the position excluding any hydrogen atom, for example, 2-yl, 3-yl, -4-yl, -5-yl in the case of 5,6,7,8-tetrahydroquinolyl. Yl, -6-yl, -7-yl, -8-yl and the like, and 1,2,3,4-tetrahydroquinolyl, for example, -1-yl, -2-yl, -3 Examples include -yl, -4-yl, -5-yl, -6-yl, -7-yl, -8-yl and the like.

The “non-aromatic heterocyclic group” includes a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group such as aziridinyl, azetidinyl, oxiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, Pyrazolinyl, pyrazolidinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl (oxanyl), tetrahydrothiopyranyl, piperazinyl, dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxa And diazolinyl, oxadiazolidinyl, morpholinyl, thiomorpholinyl, quinuclidinyl, oxepanyl and the like, and a monovalent group formed by removing any hydrogen atom from the ring Meaning.
"Hajime Tamaki (said heterocyclic group may be optionally be 1-3, optionally substituted with C ₁ ~ ₆ alkyl group or oxo group)" is a, the groups listed in the "heterocyclic group" in addition, groups 1-3 the to the cyclic group "C ₁ ~ ₆ alkyl group" or oxo group is substituted at an arbitrary position thereof. For example, methyl pyrrolyl, methyl furyl, methyl thienyl, methyl imidazolyl, methyl pyrazolyl, methyl oxazolyl, methyl isoxazolyl, methyl thiazolyl, methyl isothiazolyl, methyl pyridyl, methyl pyrimidinyl, methyl aziridinyl, methyl azetidinyl, Methyloxiranyl, methyloxetanyl, methylthietanyl, methylpyrrolidinyl, methyltetrahydrofuryl, methylthiolanyl, methylpyrazolinyl, methylpyrazolidinyl, methylpiperidinyl, methyltetrahydropyranyl, methylpiperazinyl, methyl Oxazolinyl, methylisoxazolinyl, methyloxazolidinyl, methylisoxazolidinyl, methylthiazolinyl, methylisothiazolinyl, methylthiazolidinyl, methylisothiazolidinyl , Methyloxadiazolinyl, methyloxadiazolidinyl, methylmorpholinyl, methylthiomorpholinyl, methylquinuclidinyl, methyloxepanyl, oxopyrrolidinyl, 1,1-dioxidetetrahydrothiopyranyl, etc. Is mentioned.

"Aralkyl group" is a group which is substituted with an alkyl group of straight or branched chains of the "aryl group", "C ₁ ~ ₆ alkyl group", for example, benzyl, phenethyl, 3-phenylpropyl, 1 -Naphtylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 1-indanylmethyl, 2-indanylmethyl, 1,2,3,4-tetrahydronaphthalene- Examples include 1-ylmethyl, 1,2,3,4-tetrahydronaphthalen-2-ylmethyl and the like.

The “heterocyclic oxy group” is a group in which the “heterocyclic group” is substituted with an oxygen atom, and includes “heteroaryloxy group” or “non-aromatic heterocyclic oxy group”. Specific examples include groups in which the above-mentioned “heterocyclic group” is substituted with an oxygen atom.
The “heteroaryloxy group” is a group in which the “heteroaryl group” is substituted with an oxygen atom, and specifically includes a group in which the group listed in the “heteroaryl group” is substituted with an oxygen atom. For example, pyrrolyloxy, furyloxy, thienyloxy, imidazolyloxy, pyrazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, (2-, 3- or 4-) pyridyloxy, pyridazinyl Oxy, pyrimidinyloxy, pyrazinyloxy, indolyloxy, quinolyloxy, isoquinolyloxy, indolinyloxy, dihydrobenzofuranyloxy, chromanoxy, tetrahydroquinolyloxy, tetrahydroisoquinolyloxy, 1,4-benzodioxa Nyloxy, 1,3-benzodioxolyloxy and the like can be mentioned.

The “non-aromatic heterocyclic oxy group” is a group in which the “non-aromatic heterocyclic group” is substituted with an oxygen atom. Specifically, the groups listed in the “non-aromatic heterocyclic group” are oxygen atoms. And a substituted group. For example, a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic oxy group includes, for example, aziridinyloxy, azetidinyloxy, oxiranyloxy, oxetanyloxy, thietanyloxy, pyrrolidinyloxy, Tetrahydrofuryloxy, thiolanyloxy, pyrazolinyloxy, pyrazolidinyloxy, (1-, 2-, 3- or 4-) piperidinyloxy, dihydropyranyloxy, (2-, 3- or 4-) Tetrahydropyranyloxy ((2-, 3- or 4-) oxanyloxy), tetrahydrothiopyranyloxy, piperazinyloxy, dioxanyloxy, oxazolinyloxy, isoxazolinyloxy, oxazolidinini Ruoxy, isoxazolidinyloxy, thiazolinyloxy, isothiazolinyloxy Ci, thiazolidinyloxy, isothiazolidinyloxy, oxadiazolinyloxy, oxadiazolidinyloxy, morpholinyloxy, thiomorpholinyloxy, quinuclidinyloxy, oxepanyloxy, etc. It is done.
Examples of the “heterocyclic oxy group (the heterocyclic oxy group may be optionally substituted by 1 to 3 alkyl groups with ₁ to ₆ alkyl groups or oxo groups)” include the above-mentioned “heterocyclic oxy group”. was added to the group, groups in which one to three of the to the cyclic group "C ₁ ~ ₆ alkyl group" or oxo group is substituted at an arbitrary position thereof. Furthermore, the "Hajime Tamaki (said heterocyclic group may be optionally 1-3 substituted with C ₁ ~ ₆ alkyl group or oxo group)" can be also be expressed as substituted groups oxygen atom the specifically "heterocycle (the heterocyclic group, optionally 1 may be substituted to 3 to at C ₁ ~ ₆ alkyl group or oxo group)," the groups listed has been substituted with an oxygen atom Groups.

The “aralkyloxy group” is a group in which the “aralkyl group” is substituted with an oxygen atom, and specifically includes a group in which the group listed in the “aralkyl group” is substituted with an oxygen atom. For example, benzyloxy, phenethyloxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-naphthylmethoxy, 2- (1-naphthyl) ethoxy, 2- (2-naphthyl) ethoxy, 1-indanylmethoxy, 2-inda Examples include nylmethoxy, 1,2,3,4-tetrahydronaphthalen-1-ylmethoxy, 1,2,3,4-tetrahydronaphthalen-2-ylmethoxy and the like.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The "halogenated C ₁ ~ ₆ alkyl group" denotes a group wherein the above "C ₁ ~ ₆ alkyl group" is optionally substituted with one to five halogen atoms. For example, trifluoromethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl and the like can be mentioned.
The "halogenated C ₁ ~ ₆ alkoxy group" denotes a group wherein the above "C ₁ ~ ₆ alkoxy group" is optionally substituted with one to five halogen atoms. Examples thereof include trifluoromethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy and the like.

Examples of the protecting group for the “optionally protected carboxyl group” include alkyl ester protecting groups such as methyl, ethyl, tert-butyl, benzyl, diphenylmethyl and trityl, and silyl ester based groups such as trimethylsilyl and tert-butyldimethylsilyl. And protecting groups.
The _"C 2 _{~ 7} alkanoyl group", "linear _C 2 _{~ 7,} branched or cyclic alkylcarbonyl group" refers to, R-CO- (R is the _"C 1 _{~ 6} alkyl group" For example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, 2-methylcyclopropyl Examples include carbonyl and the like.

The “heterocyclic carbonyl group” means a “heterocyclic carbonyl group”, and a carbonyl group is added to the “heterocyclic group” (for example, a heteroaryl group, a saturated or unsaturated non-aromatic heterocyclic group, etc.). Bound groups such as pyrrolylcarbonyl, furylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-tria Zolylcarbonyl, 1,2,4-triazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl, 1,3,4-oxadiazolylcarbonyl, fraza Nylcarbonyl, 1,2,3-thiadiazolylcarbonyl, 1,2,4-thi Diazolylcarbonyl, 1,3,4-thiadiazolylcarbonyl, tetrazolylcarbonyl, pyridylcarbonyl, pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, 1,2,3-triazinylcarbonyl, 1, 2,4-triazinylcarbonyl, 1,3,5-triazinylcarbonyl, 2H-1,2,3-thiadiazinylcarbonyl, 4H-1,2,4-thiadiazinylcarbonyl, 6H-1, A carbonyl group to which a “monocyclic heteroaryl group” such as 3,4-thiadiazinylcarbonyl, 1,4-diazepinylcarbonyl, 1,4-oxazepinylcarbonyl and the like is bonded;
Indolylcarbonyl, isoindolylcarbonyl, benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothienylcarbonyl, benzoxazolylcarbonyl, 1,2-benzisoxazolylcarbonyl, benzothiazolyl Carbonyl, 1,2-benzisothiazolylcarbonyl, 1H-benzimidazolylcarbonyl, 1H-indazolylcarbonyl, 1H-benzotriazolylcarbonyl, 2,1,3-benzothiadiazinylcarbonyl, chromenylcarbonyl, iso Chromenylcarbonyl, 4H-1,4-benzooxazinylcarbonyl, 4H-1,4-benzothiazinylcarbonyl, quinolylcarbonyl, isoquinolylcarbonyl, cinnolinylcarbonyl, quinazolinylcarbonyl Quinoxalinylcarbonyl, phthalazinylcarbonyl, benzoxazepinylcarbonyl, benzoazepinylcarbonyl, benzodiazepinylcarbonyl, naphthyridinylcarbonyl, purinylcarbonyl, pteridinylcarbonyl, carbazolylcarbonyl, carbo Linylcarbonyl, acridinylcarbonyl, phenoxazinylcarbonyl, phenothiazinylcarbonyl, phenazinylcarbonyl, phenoxathinylcarbonyl, thianthrenylcarbonyl, phenanthridinylcarbonyl, phenanthrolinylcarbonyl, indolizinylcarbonyl , Thieno [3,2-c] pyridylcarbonyl, thiazolo [5,4-c] pyridylcarbonyl, pyrrolo [1,2-b] pyridazinylcarbonyl, pyrazolo [1,5-a] pyridylca Bonyl, 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, 1H-pyrazolo [3,4-b] pyridylcarbonyl, 1 , 2,4-Triazolo [1,5-a] pyrimidinylcarbonyl, indolinylcarbonyl, dihydrobenzofuranylcarbonyl, chromanylcarbonyl, tetrahydroquinolylcarbonyl, tetrahydroisoquinolylcarbonyl, 1,4-benzodioxanylcarbonyl , 1,3-benzodioxolylcarbonyl and the like may be partially hydrogenated “fused ring A carbonyl group to which a "heteroaryl group" is bonded, and aziridinylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl, piperidinylcarbonyl, tetrahydropyranylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl And a carbonyl group to which a “saturated or unsaturated non-aromatic heterocyclic group” is bonded.

The “non-aromatic heterocyclic carbonyl group” is a group in which the “heterocyclic group” of the “heterocyclic carbonyl group” is a “non-aromatic heterocyclic group”, that is, the “non-aromatic heterocyclic group” And a carbonyl group. Specific examples include a carbonyl group to which the “saturated or unsaturated non-aromatic heterocyclic group” mentioned in the above “heterocyclic carbonyl group” is bonded.

Group in: "group -S _(O) i ^{R a",} i is represents an integer of 0 to 2, and ^{R _a,} optionally selected from C 1 _{~ 6} alkyl group and a halogenated _C 1 _{~ 6} alkyl group Represents. When i is 0, "C ₁ ~ ₆ alkylthio group" or "halogenated C ₁ ~ ₆ alkylthio group", when i is 1, "C ₁ ~ ₆ alkylsulfinyl group" or "halogenated C ₁ ~ ₆ alkylsulfinyl group "is, i is the time of 2," _C 1 _{~ 6} alkylsulfonyl group "or" halogenated _C 1 _{~ 6} alkylsulfonyl group "and the like.
The "C ₁ ~ ₆ alkylthio group" means a straight chain, branched chain or cyclic alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec- Butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, 1-methylbutylthio, 2-methylbutylthio, 1,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, isohexyl Thio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 2,2-dimethylbutylthio, 1,3-dimethylbutyl Thio, 2,3-dimethylbutylthio, 3,3-dimethyl Rubutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio, 1-ethyl-2- Methylpropylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, 1-cyclopropylethylthio, 2-cyclopropylethylthio, 2-cyclobutylethylthio, Examples include 2-methylcyclopropylthio. The "halogenated C ₁ ~ ₆ alkylthio group" represents a group wherein the above "C ₁ ~ ₆ alkylthio group" are optionally substituted with 1-5 halogen atoms, for example, trifluoromethylthio and the like .
The "C ₁ ~ ₆ alkylsulfinyl group", straight chain C 1 -C 6 refers to branched or cyclic alkylsulfinyl group, for example methylsulfinyl, ethylsulfinyl, propyl sulfinyl, isopropyl-sulfinyl, cyclopropyl And sulfinyl, cyclopropylmethylsulfinyl, 2-methylcyclopropylsulfinyl and the like. The "halogenated C ₁ ~ ₆ alkylsulfinyl group" is a group wherein the above "C ₁ ~ ₆ alkylsulfinyl group" is optionally substituted with one to five halogen atoms, such as trifluoromethyl sulfinyl etc. Is mentioned.
The "C ₁ ~ ₆ alkylsulfonyl group", straight chain C 1 -C 6 refers to branched or cyclic alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropyl Examples include sulfonyl, cyclopropylmethylsulfonyl, 2-methylcyclopropylsulfonyl and the like. The "halogenated C ₁ ~ ₆ alkylsulfonyl group" is a group wherein the above "C ₁ ~ ₆ alkylsulfonyl group" is optionally substituted with one to five halogen atoms, for example, trifluoromethylsulfonyl and the like Is mentioned.

_In: "group -SO 2 ^NR d ^{R e} ', ^{R d} and ^{R e} are each independently a hydrogen atom or a _C 1 _{~ 6} alkyl group (said _C 1 _{~ 6} alkyl group, a halogen atom, -OH or C _{_1-6} alkoxyl optionally may be one to five substituents in group), one or two hydrogen atoms on the nitrogen atom of the sulfamoyl group is substituted with the "C _{_1-6} alkyl group" in addition to the sulfamoyl group _optionally, C 1 _{~ 6} alkyl group (said _C 1 _{~ 6} alkyl group, a halogen atom, is 1-5, optionally substituted with -OH or _C 1 _{~ 6} alkoxy group) in Means a substituted sulfamoyl group; Specifically, for example, sulfamoyl group, methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, cyclopropylsulfamoyl group, butylsulfamoyl group, isobutylsulfamoyl group Group, pentylsulfamoyl group, isopentylsulfamoyl group, hexylsulfamoyl group, isohexylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, dipropylsulfamoyl group, diisopropylsulfamoyl group Group, dibutylsulfamoyl group, dipentylsulfamoyl group, ethylmethylsulfamoyl group, methylpropylsulfamoyl group, ethylpropylsulfamoyl group, butylmethylsulfamoyl group, butylethylsulfamoyl group, butylpro Rusulfamoyl group, trifluoromethylsulfamoyl group, hydroxymethylsulfamoyl group, 2-hydroxyethylsulfamoyl group, 3-hydroxypropylsulfamoyl group, 3-hydroxybutylsulfamoyl group, 3-hydroxy-3 -Methylbutylsulfamoyl group, 2,3-dihydroxypropylsulfamoyl group, 3-hydroxy-2-hydroxymethylpropylsulfamoyl group, 3-hydroxy-2-hydroxymethyl-2methylpropylsulfamoyl group, Examples include 2-methoxyethylsulfamoyl group, 2-ethoxyethylsulfamoyl group, 2-methoxy-3-hydroxypropylsulfamoyl group and the like.

"Group: -CONR ^d R ^e" in, ^{R d} and ^{R e} are each independently a hydrogen atom or a _C 1 _{~ 6} alkyl group (said _C 1 _{~ 6} alkyl group, a halogen atom, -OH or _C 1 ~ ₆ represents an alkoxy group optionally may be 1-5 substituents in), even if one or two hydrogen atoms on the nitrogen atom of the carbamoyl group is substituted with the "C ₁ ~ ₆ alkyl group" in addition to a carbamoyl _group, C 1 _{~ 6} alkyl group (said _C 1 _{~ 6} alkyl group, a halogen atom, is 1-5, optionally substituted with -OH or _C 1 _{~ 6} alkoxy group) is substituted with Carbamoyl group. Specifically, for example, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, cyclopropylcarbamoyl group, butylcarbamoyl group, isobutylcarbamoyl group, pentylcarbamoyl group, isopentylcarbamoyl group, hexylcarbamoyl group , Isohexylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, dipropylcarbamoyl group, diisopropylcarbamoyl group, dibutylcarbamoyl group, dipentylcarbamoyl group, ethylmethylcarbamoyl group, methylpropylcarbamoyl group, ethylpropylcarbamoyl group, butylmethylcarbamoyl group , Butylethylcarbamoyl group, butylpropylcarbamoyl group, trifluoromethylcarbamo Group, hydroxymethylcarbamoyl group, 2-hydroxyethylcarbamoyl group, 3-hydroxypropylcarbamoyl group, 3-hydroxybutylcarbamoyl group, 3-hydroxy-3-methylbutylcarbamoyl group, 2,3-dihydroxypropylcarbamoyl group, 3 -Hydroxy-2-hydroxymethylpropylcarbamoyl group, 3-hydroxy-2-hydroxymethyl-2methylpropylcarbamoyl group, 2-methoxyethylcarbamoyl group, 2-ethoxyethylcarbamoyl group, 2-methoxy-3-hydroxypropylcarbamoyl group Etc.
"Group: -CONR ^d R ^e1" at, ^{R d} is a hydrogen atom or a _C 1 _{~ 6} alkyl group (said _C 1 _{~ 6} alkyl group, a halogen atom, optionally with -OH or _C 1 _{~ 6} alkoxyl group 1 represents ~ optionally substituted ^{five), R e1} _is, C 1 _{~ 6} alkyl group (said _C 1 _{~ 6} alkyl group, _-OH, C 1 _{- 6} alkoxyl group, an aryl group (said aryl group is optionally may be 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group is optionally may be one to three substituents at C ₁ ~ ₆ alkyl group or oxo group ), Group: —S (O) _i R ^a (i represents an integer of 0 to 2), group: —SO ₂ NR ^d R ^e , group: —CONR ^d R ^e or group: —NR ^b R ^c 1 to 5 are optionally substituted). That is, one of the hydrogen atoms on the nitrogen atom of the carbamoyl group, in addition to a carbamoyl group substituted with R ^e1, another of the hydrogen atoms on the nitrogen atom of the carbamoyl group, C ₁ ~ ₆ alkyl group (the C ₁ ~ ₆ alkyl group means a halogen atom, -OH or C ₁ ~ ₆ carbamoyl group substituted with an alkoxyl optionally may be one to five substituents in groups). Specifically, for example, hydroxymethylcarbamoyl group, 2-hydroxyethylcarbamoyl group, 3-hydroxypropylcarbamoyl group, 3-hydroxybutylcarbamoyl group, 3-hydroxy-3-methylbutylcarbamoyl group, 2,3-dihydroxypropylcarbamoyl group Group, 3-hydroxy-2-hydroxymethylpropylcarbamoyl group, 3-hydroxy-2-hydroxymethyl-2methylpropylcarbamoyl group, 2-methoxyethylcarbamoyl group, 2-ethoxyethylcarbamoyl group, 2-methoxy-3-hydroxy Propylcarbamoyl group, 3-methylsulfonyl-propylcarbamoyl group, 2- (morpholin-4-yl) ethylcarbamoyl group, 2- (4-methylpiperazin-1-yl) ethylcarbamoyl group, 2- (2 Oxopyrrolidin-1-yl) ethylcarbamoyl group, 3- (2-oxopyrrolidin-1-yl) propylcarbamoyl group, (5-oxopyrrolidin-2-yl) methylcarbamoyl group, 3- (2-oxooxazolidine-3 -Yl) propylcarbamoyl group, (3-methyloxetane-3-yl) methylcarbamoyl group, 3- (methylsulfonylamino) propylcarbamoyl group and the like.

"Group: ^-NR b ^{R c"} ^in, R b, and ^{R c,} each independently, a hydrogen _atom, C 1 _{~ 6} alkyl _group, optionally from C 2 _{~ 7} alkanoyl groups and _C 1 _{~ 6} alkylsulfonyl group R ^b and R ^c together with the nitrogen atom to which they are bonded may form a 3- to 8-membered cyclic group, in which one carbon atom in the ring is an oxygen atom , a sulfur atom and a nitrogen atom (said nitrogen atom, is may be substituted by C ₁ ~ ₆ alkyl group) may, be replaced by chosen atom or a carbonyl group optionally from. For example, "group: ^-NR b ^{R c"} as, amino, "mono / di _C 1 _{~ 6} alkylamino", _"C 2 _{~ 7} alkanoylamino" or _"C 1 _{~ 6} alkylsulfonylamino" and the like.

By "mono / di C ₁ ~ ₆ alkylamino" refers to one or two hydrogen atoms are linear, branched, or cyclic amino group substituted by a "C ₁ ~ ₆ alkyl group" of the amino group To do. Specifically, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, isopentylamino, hexylamino, isohexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino 1-cyclopropylmethylamino, 1-cyclobutylmethylamino, 1-cyclopentylmethylamino, 1-cyclohexylmethylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dipentylamino, ethylmethylamino, propyl Methylamino, propylethylamino, butylmethylamino, butylethylamino, butylpropylamino, N-cyclopropyl-N-methylamino, N- Cyclobutyl -N- methylamino, N- cyclopentyl -N- methylamino, N- cyclohexyl -N- methylamino, and the like.
The "halogenated mono / di C ₁ ~ ₆ alkylamino" represents a group wherein "mono / di C ₁ ~ ₆ alkylamino" are optionally substituted with 1-5 halogen atoms. For example, trifluoromethylamino and the like can be mentioned.

The "C ₂ ~ ₇ alkanoylamino", the hydrogen atoms of the amino group means a straight chain, branched chain or cyclic amino group substituted by "C ₂ ~ ₇ alkanoyl group". Specifically, acetamide, propionamide, butyramide, isobutylamide, barrelamide, isovaleramide, pivalamide, hexanamide, heptaneamide, cyclopropanecarboxamide, cyclobutanecarboxamide, cyclopentanecarboxamide, cyclohexanecarboxamide, 2-methylcyclopropanecarboxamide, etc. Is mentioned.
The "C ₁ ~ ₆ alkylsulfonylamino", the hydrogen atoms of the amino group means a straight-chain, substituted branched chain or cyclic alkylsulfonyl group an amino group having 1 to 6 carbon atoms. Specific examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, cyclopropylsulfonylamino, cyclopropylmethylsulfonylamino, 2-methylcyclopropylsulfonylamino and the like.

Specific examples of the 3- to 8-membered cyclic group in “R ^b and R ^c may form a 3- to 8-membered cyclic group together with the nitrogen atom to which they are bonded” include the above-mentioned “non-aromatic groups”. Of the 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group in “Aromatic heterocyclic group”, a hydrogen atom bonded to the nitrogen atom is removed from a ring containing a nitrogen atom in addition to the carbon atom 1 A valent cyclic group is meant. For example, aziridinyl, azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxadiazolinyl, oxadiazolinyl, oxadiazolinyl , Thiomorpholinyl, 2-oxopyrrolidinyl and the like. In R ^b and R ^c , the cyclic group as “when one carbon atom in the ring of the cyclic group is substituted with an oxygen atom, a sulfur atom, or a carbonyl group” means, among the cyclic groups, for example, Examples include oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, 2-oxopyrrolidinyl and the like.
R ^b, the cyclic group as "if the nitrogen atom is substituted with _C 1 _{~ 6} alkyl group" in ^{R c} is, for example, 4-methylpiperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-propylpiperazin-1-yl and the like can be mentioned.

The "substituent RI", halogen atom, -OH, cyano _group, C 1 _{~ 6} alkoxy group (said _C 1 _{~ 6} alkoxy group, a halogen atom, _-OH, C 1 _{~ 6} alkoxy group, an aryl group (said the aryl group may be optionally 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group is optionally one to have three substituted with C ₁ ~ ₆ alkyl group or oxo group Group: —S (O) _i R ^a (i represents an integer of 0 to 2), group: —SO ₂ NR ^d R ^e , group: —CONR ^d R ^e or group: —NR ^b optionally may be 1 to 5 substituents at R ^c), group: ^-NR b ^{R c,} and a heterocyclic oxy group (the heterocyclic oxy _group, 1 optionally with C 1 _{~ 6} alkyl group or oxo group ~ 3 may be substituted) Represents a group.
Here, R ^a , R ^d , R ^e , R ^b and R ^c are the above-mentioned “group: —S (O) _i R ^a ”, “group: —SO ₂ NR ^d R ^e ”, “group: —CONR”. ^d R ^e ”and“ group: —NR ^b R ^c ”have the same definitions as R ^a , R ^d , R ^e , R ^b and R ^c , respectively.

The "optionally 1-5 substituted with a substituent RI _C 1 _{~ 6} alkyl group", "halogen atom, -OH, cyano _group, C 1 _{~ 6} alkoxy group (said _C 1 _{~ 6} alkoxy group , halogen atom, -OH, C ₁ ~ ₆ alkoxy group, an aryl group (said aryl group is optionally may be 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group, C Optionally substituted with ₁ to ₆ alkyl groups or oxo groups), group: —S (O) _i R ^a (i represents an integer of 0 to 2), group: —NR ^b R ^c , group: —SO ₂ NR ^d R ^e or group: —CONR ^d R ^e optionally substituted 1 to 5), group: —NR ^b R ^c and heterocyclic oxy group (the hetero ring oxy group _is a C 1 _{~ 6} alkyl group or oxo group Optionally 1 to 3 may be substituted) to represent the selected one to five substituents which may C ₁ to ₆ alkyl group group "optionally Specific examples, include the following It is done.
For example, "1-5 optionally substituted C ₁ ~ ₆ alkyl group with a halogen atom", in addition to the "C ₁ ~ ₆ alkyl group", the alkyl group having 1 to 5 halogen atoms optionally substituted with are based in, that represents the "halogenated C ₁ ~ ₆ alkyl group". Specifically, in addition to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, for example, trifluoromethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl and the like can be mentioned.
For example, - the term "1-5 optionally substituted C ₁ ~ ₆ alkyl group OH", in addition to the "C ₁ ~ ₆ alkyl group", the alkyl group with 1-5 hydroxyl Represents an optionally substituted group, and there are a number of positional isomers at the substituted positions. Specifically, in addition to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxy-1-propyl, 2-hydroxy-1-propyl, 1-hydroxy-1-propyl, 2,3-dihydroxy-1-propyl, 1-hydroxy-1-methyl-1-ethyl, 2-hydroxy-1-methyl-1-ethyl, 4-hydroxy-1-butyl, 3-hydroxy-1-butyl, 2-hydroxy-1-butyl, 1-hydroxy-1-butyl, 3-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, 3-hydroxy-2-hydroxymethylpropyl, 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-hydroxy-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, 3-hydroxy-2-hydroxymethyl- 2-methylpropyl, 6-hydroxy-1-hexyl, 4- Dorokishi -1,1-dimethyl-1-butyl, 4-hydroxy-3,3-dimethyl-1-butyl, 2-hydroxy-cyclopropyl, 4-hydroxycyclohexyl, and the like.

For example, "1-5 optionally substituted _C 1 _{~ 6} alkyl group in _C 1 _{~ 6} alkoxy group" includes, in addition to the _"C 1 _{~ 6} alkyl group", the alkyl group is 1 to 5 It represents a number of said groups being optionally substituted by _"C 1 _{~ 6} alkoxy group", specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, in addition to the tert- butyl, e.g. , Methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl and the like.
For example, the "halogen atom with 1-5 substituents by ~ 1 which may C ₁ - ₆ alkoxy group optionally five optionally substituted C ₁ to ₆ alkyl group", the "C ₁ - ₆ alkyl in addition to the group "and the" C ₁ ~ ₆ alkoxy group with one to five substituents which may C ₁ ~ even if ₆ alkyl group ", said being optionally substituted with one to five halogen atoms" C ₁ ~ ₆ alkoxy group "denotes a group wherein the alkyl group is optionally 1-5 substituents, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, In addition to methoxymethyl, methoxyethyl, methoxypropyl, for example, trifluoromethoxymethyl, trifluoromethoxyethyl, trifluoromethoxypropyl and the like can be mentioned.
Further, the alkyl group is a halogen atom, -OH, cyano _group, C 1 _{~ 6} alkoxy group (said _C 1 _{~ 6} alkoxy group, a halogen atom, _-OH, C 1 _{~ 6} alkoxy group, an aryl group (said aryl group is optionally may be 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group may be 1-3, optionally substituted with C ₁ ~ ₆ alkyl group or oxo group Group): —S (O) _i R ^a (i represents an integer of 0 to 2), group: —NR ^b R ^c , group: —SO ₂ NR ^d R ^e or group: —CONR ^d R ^e in may be 1-5 optionally substituted), group: ^-NR b ^{R c,} and a heterocyclic oxy group (the heterocyclic oxy _group, C 1 _~ 1 _~ 3 optionally in ₆ alkyl or an oxo group 2 or more types that may be replaced) May be substituted with 2 to 5 groups arbitrarily selected from the above. For example, 2-hydroxy-3-methoxypropyl, 3-hydroxy-2-methoxypropyl, such as, such as one -OH and one _C 1 _{~ 6} alkyl group substituted with _C 1 _{~ 6} alkoxy group Can be mentioned.

Similarly, "1-5 optionally substituted _C 2 _{~ 6} alkenyl group with a substituent RI", in addition to the _"C 2 _{~ 6} alkenyl group", halogen atom, -OH, a cyano group, C ₁ ~ ₆ alkoxy group (said _C 1 _{~ 6} alkoxy group, a halogen atom, _-OH, C 1 _{~ 6} alkoxy group, an aryl group (said aryl group is optionally be optionally 1-3 substituted by a halogen atom may also), a Hajime Tamaki (said heterocyclic group _may be optionally 1-3 substituted with C 1 _{~ 6} alkyl group or oxo group), _{^{group: -S (O) i R a}} (i Represents an integer of 0 to 2), a group: —NR ^b R ^c , a group: —SO ₂ NR ^d R ^e or a group: —CONR ^d R ^e may be optionally substituted with 1 to 5), Group: —NR ^b R ^c and a heterocyclic oxy group (the heterocyclic group The alkoxy group, C ₁ ~ ₆ alkyl group or a group of the alkenyl group substituted by 1 to 3 selected arbitrarily from even may) have group optionally an oxo group is optionally 1-5 substituents To express. Specifically, in addition to vinyl, allyl, isopropenyl, 2-methylallyl, butenyl, pentenyl, hexenyl, for example, trifluorovinyl, 2-hydroxyvinyl, 2-methoxyvinyl, 2-trifluoromethoxyvinyl and the like can be mentioned. .
The "optionally 1-5 substituted with a substituent RI _C 2 _{~ 6} alkynyl group", in addition to the _"C 2 _{~ 6} alkynyl group", halogen atom, -OH, cyano _{group, C} 1 ~ ₆ alkoxyl group (said _C 1 _{~ 6} alkoxy group, a halogen atom, _-OH, C 1 _{~ 6} alkoxy group, an aryl group (said aryl group may be optionally 1-3 substituted with a halogen atom) , Hajime Tamaki (said heterocyclic group _may be optionally 1-3 substituted with C 1 _{~ 6} alkyl group or oxo group), _{^{group: -S (O) i R a}} (i is 0 ~ Represents an integer of 2), a group: —NR ^b R ^c , a group: —SO ₂ NR ^d R ^e or a group: —CONR ^d R ^e optionally substituted with 1 to 5), a group: NR ^b R ^c and a heterocyclic oxy group (the heterocyclic oxy group is Represents a group in which the alkynyl group in C ₁ to ₆ alkyl or a group chosen arbitrarily from even be) optionally 1 to have three are substituted with oxo group is optionally 1 to 5 substituents. Specifically, in addition to ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl, for example, fluoroethynyl, 2-hydroxyethynyl, 2-methoxyethynyl, 2-trifluoromethoxyethynyl and the like can be mentioned.

The "optionally 1-5 substituted with a substituent RI _C 1 _{~ 6} alkoxy group", in addition to the _"C 1 _{~ 6} alkoxy group", a halogen atom, -OH, cyano _{group, C} 1 ~ ₆ alkoxyl group (said _C 1 _{~ 6} alkoxy group, a halogen atom, _-OH, C 1 _{~ 6} alkoxy group, an aryl group (said aryl group may be optionally 1-3 substituted with a halogen atom) , Hajime Tamaki (said heterocyclic group _may be optionally 1-3 substituted with C 1 _{~ 6} alkyl group or oxo group), _{^{group: -S (O) i R a}} (i is 0 ~ Represents an integer of 2), a group: —NR ^b R ^c , a group: —SO ₂ NR ^d R ^e or a group: —CONR ^d R ^e , optionally substituted with 1 to 5 groups), a group: NR ^b R ^c and heterocyclic oxy group (the heterocyclic oxy Group represents a group in which the alkoxyl group in C ₁ to ₆ alkyl or a group chosen arbitrarily from even be) optionally 1 to have three are substituted with oxo group is optionally 1 to 5 substituents . Specifically, in addition to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, for example, trifluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 3-hydroxy Butoxy, 3-hydroxy-3-methylbutoxy, 2,3-dihydroxypropoxy, 3-hydroxy-2-hydroxymethylpropoxy, 3-hydroxy-2-hydroxymethyl-2methylpropoxy, 2-methoxyethoxy, 2-ethoxyethoxy 2-trifluoromethoxyethoxy, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-methoxypropoxy and the like.

In the compound of the formula (I), the 5-aryl-1,1-dioxo-1,2-thiazinan-3-one group may have proton tautomerism as shown in the following formula. The abundance ratio of this structure can vary depending on whether the compound represented by formula (I) is in a solid state or dissolved in a liquid. Tautomers generated by this structure are included in the formula (I).

That is, in the formula (I), for example, the following proton tautomers are assumed, and these tautomers are also included in the scope of the present compound.

For example, in the cyclic amide structure of the formula (I), when R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b are hydrogen atoms, the following tautomerism is assumed, and these tautomers Sexual forms are also included.

Note that the description of any particular tautomeric form in any structural formula in this specification is not intended to be limited to that type, but is intended to be representative of the entire tautomeric set. To do.
Specifically, for example, in the compound of Example 1, 5- (4-((4 ′-(3-hydroxy-3-methylbutoxy) -2 ′, 6′-dimethyl- [1,1′-biphenyl) ] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one If the compound name is 1,1-dioxide, its tautomer, 3-hydroxy-5- (4- ((4 '-(3-hydroxy-3-methylbutoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -5,6-dihydro-4H- 1,2-thiazine 1,1-dioxide is also the compound of Example 1.

[1-1] In the compound of the formula (I) of the embodiment [1], r is preferably 0 or 1, more preferably 0. If r is 1, 1-position of the bond position of the methylene linker portion in the benzene ring R ³ is attached, when the 3-position to the bonding position of L, and preferably the bonding position of R ³ is 2-position.
[1-2] In the compound of the formula (I) of the embodiment [1], each R ³ is preferably independently a halogen atom, or C _1- ₄ alkyl group or the like is good C ₁ ~ ₄ alkoxyl group which may be 1-5 substituted with a halogen atom,. More specifically, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy and the like. More preferably, a fluorine atom, methyl, ethyl, methoxy, and ethoxy are mentioned. In the formula (A3), R ³ is preferably a group other than tert-butyl.

[1-3] In the compound of the formula (I) of the embodiment [1], s is preferably 0 or 1, more preferably 0.
[1-4] In the compound of the formula (I) of the embodiment [1], R ⁴ is preferably each independently C ₁ optionally substituted with 1 to 5 halogen atoms and substituents RI. _1-4 alkyl group, a substituent RI with 1-5 optionally substituted C ₁ to ₄ alkoxy groups (more substituents RI are the same or different from each other, represent the same definitions as described above substituents RI) Or a cyano group is mentioned.
[1-4-a] More preferably, ^{R 4} is a halogen atom, 1-5 optionally substituted _C 1 _{to 4} alkyl groups with a halogen atom, be 1-5 substituted by a halogen atom It includes optionally _C 1 _{~ 4} alkoxyl group or a cyano group, more specifically, ^{R 4} is fluorine atom, chlorine atom, bromine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert -Butyl, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, cyano and the like.

[1-5] In the compound of formula (I) of the embodiment ^[1], R ^{5a, R 5b} is preferably independently a hydrogen atom, halogen atom or _C 1 _{~ 4} alkyl group, More specifically, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl and the like can be mentioned.
[1-5-a] One of R ^5a and R ^5b is more preferably a hydrogen atom, and still more preferably, both R ^5a and R ^5b are hydrogen atoms.

[1-6] In the compound of formula (I) of the embodiment [1], ^{R 6} is preferably a hydrogen atom, a halogen _atom, C 1 _{~ 4} alkyl groups, halogenated _C 1 _{~ 4} alkyl groups, C _{_2-5} alkanoyl group or a carboxyl group, more preferably a hydrogen atom or a _C 1 _{~ 4} alkyl group. More specifically, R ⁶ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, acetyl, carboxyl, etc. It is. More preferably, R ⁶ is a hydrogen atom.

[1-7] In the compound of formula (I) of the embodiment ^[1], R ^{7a, R 7b} are preferably each independently represent a hydrogen atom, a halogen _atom, C 1 _{~ 4} alkyl group, a halogenated C Examples thereof include ₁ to ₄ alkyl groups and cyano groups. Specifically, R ^7a and R ^7b are a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, cyano, etc. It is.
[1-7-a] One of R ^7a and R ^7b is more preferably a hydrogen atom, and still more preferably, both R ^7a and R ^7b are hydrogen atoms.

[1-8] In the compound of the formula (I) of the embodiment [1], it is preferable that R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are all hydrogen atoms. That is, a compound having a 1,1-dioxo-1,2-thiazinan-3-one group is preferable.

[1-9] In the compound of the formula (I) of the embodiment [1], L is a 4- (3-hydroxy-3-methylbutoxy) -2,6-dimethylphenyl group, 4- (2-ethoxy Ethoxy) -2,6-dimethylphenyl group, the following formula (A1), formula (A2) or formula (A3)

(Wherein, p, q, ring A, ring A ′, R ¹ and R ^{2 have} the same definitions as in formula (I)).
[1-9-a] In the formula (A1) or (A2) as L, q is preferably 0 or 1, and q is more preferably 0. That is, the following formula (A1a) or formula (A2a)

(Wherein, each definition of p, R ¹ , ring A and ring A ′ is the same as that in formula (I)).
In [1-9-b] Formula as L (A1) or formula (A2), ^{R 2} preferably each _{independently,} C 1 _{~ 6} alkoxy group (said alkoxy group is -OH, _{C 1} _1-6 alkoxyl group, non-aromatic Hajime Tamaki (said heterocyclic group, _-OH, optionally may be one to two substituents at C 1 _{- 4} alkyl group or oxo group), group: -S ( O) _i R ^a (i represents an integer of 0 to 2), group: —NR ^b2 R ^c2 , group: —SO ₂ NR ^d R ^e and group: —CONR ^d R ^e A group: —CONR ^d3 R ^e3 , an aralkyloxy group, a non-aromatic heterocyclic oxy group (the heterocyclic oxy group may be optionally substituted with one or two oxo groups) Good) or a non-aromatic heterocyclic carbonyl group (the hetero Ring carbonyl group may be optionally 1-2 substituted with oxo group) can be ^mentioned; R ^{b2, R c2} are each independently a hydrogen _atom, C 1 _{~ 6} alkyl _group, C 2 _{~ 7} represents a group selected arbitrarily from alkanoyl group and a C ₁ ~ ₆ alkylsulfonyl group, R ^b2, R ^c2 may form a cyclic group having 3 to 8-membered together with the nitrogen atom to which they are attached, said cyclic group , Part 1 carbon atoms in the ring may be replaced with a carbonyl group, ^{a; R d3} represents a hydrogen atom or a _C 1 _{~ 4} alkyl ^{group, R e3} _is C 1 _{~ 6} alkyl group ( the _C 1 _{- 6} alkyl group, _-OH, C 1 _{- 6} alkoxyl group, non-aromatic Hajime Tamaki (said heterocyclic group _is optionally one to be two substituted with C 1 _{- 4} alkyl group or oxo group And group: Represents a _{^{S (O) i R a (}} i represents an integer of 0-2) is 1-5 substituents in chosen group optionally from).
More preferably [1-9-b-1], R 2 _is, C 1 _{~ 6} alkoxy group (said alkoxy group, -OH, methoxy, ethoxy, 4-hydroxy-1,1-dioxidotetrahydro--2H- Thiopyran-4-yl, 3-methyloxetane-3-yl, methylsulfonyl, ethylsulfonyl, —NH ₂ , acetylamino, methylsulfonylamino, 2-oxo-1-pyrrolidinyl, 5-oxo-2-pyrrolidinyl, sulfamoyl, 1 to 5 groups optionally substituted from methylsulfamoyl, dimethylsulfamoyl, carbamoyl, methylcarbamoyl and dimethylcarbamoyl), a group: —CONR ^d4 R ^e4 (R ^d4 represents a hydrogen atom or C represents _{_1-4} alkyl ^{group, R e4} _is, C 1 _{~ 6} alkyl group (said _{C 1} ₆ alkyl group represents -OH, methoxy, ethoxy, 3-methyl-oxetane-3-yl, a is 1-5 optionally substituted with a group selected arbitrarily from methylsulfonyl and ethylsulfonyl)), benzyloxy, ( 1,1-dioxidetetrahydro-2H-thiopyran-4-yl) oxy or (pyrrolidin-1-yl) carbonyl. The substitution number of substituents in _C 1 _{~ 6} alkyl group as _C 1 _{~ 6} alkoxy group or ^{R e4} as R ² are particularly preferably 1-2.

More specifically, R ² represents 2-hydroxyethoxy, 3-hydroxypropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy, 2,3-dihydroxypropoxy, (2R) -2,3-dihydroxy Propoxy, (2S) -2,3-dihydroxypropoxy, (3S) -3-hydroxybutoxy, (3R) -3-hydroxybutoxy, 3-hydroxy-2-hydroxymethylpropoxy, 3-hydroxy-2-hydroxymethyl- 2-methylpropoxy, 2-ethoxyethoxy, (4-hydroxy-1,1-dioxidetetrahydro-2H-thiopyran-4-yl) methoxy, (3-methyloxetane-3-yl) methoxy, 2-methylsulfonyl- Ethoxy, 3-methylsulfonyl-propoxy, 2-ethylsulfonyl -Ethoxy, 3-ethylsulfonyl-propoxy, 2-aminoethoxy, 3-aminopropoxy, 2-acetylamino-ethoxy, 3-acetylamino-propoxy, 2-methylsulfonylamino-ethoxy, 3-methylsulfonylamino-propoxy, 2- (2-oxo-1-pyrrolidinyl) ethoxy, 3- (2-oxo-1-pyrrolidinyl) propoxy, (5-oxo-2-pyrrolidinyl) methoxy, 2-sulfamoyl-ethoxy, 3-sulfamoyl-propoxy, 2 -Methylsulfamoyl-ethoxy, 3-methylsulfamoyl-propoxy, 2-dimethylsulfamoyl-ethoxy, 3-dimethylsulfamoyl-propoxy, 2-carbamoyl-ethoxy, 3-carbamoyl-propoxy, 2-methyl Carbamoyl-etoki 3-methylcarbamoyl-propoxy, 2-dimethylcarbamoyl-ethoxy, 3-dimethylcarbamoyl-propoxy, N- (2-hydroxyethyl) carbamoyl, N- (2-methoxyethyl) carbamoyl, N- (2-hydroxyethyl) -N-methylcarbamoyl, N- (2-methoxyethyl) -N-methylcarbamoyl, N- (2-methylsulfonyl-ethyl) carbamoyl, N- (2-methylsulfonyl-ethyl) -N-methylcarbamoyl, (1 , 1-dioxidetetrahydro-2H-thiopyran-4-yl) oxy, benzyloxy, (pyrrolidin-1-yl) carbonyl and the like.
[1-9-b-2] The bonding position of R ² in the formula (A2) is preferably the 3rd or 4th position when the bonding position with the oxygen atom in the ring A ′ is the 1st position.
In formula (A1) or formula (A1a) as [1-9-c] L, ring _A, C 5 _{~ 7} cycloalkyl group, condensed ring aryl group, condensed ring heteroaryl group or partially hydrogenated Represents a condensed fused heteroaryl group. More specifically, as L, the following formula (A1a) -1 or formula (A1a) -2

(In the formula, R ^{1 has} the same definition as in formula (I); p1a represents an integer of 0 to 4; p1b and p1c represent an integer of 0 to 3 (provided that p1b + p1c represents 0 to 4) Ring A1 represents a cyclohexene ring; ring A2 represents a 5- to 6-membered aryl group or heterocyclic group).
[1-9-c-1] In the formula (A1) or (A1a), the ring A is more preferably cyclohexene, naphthalene, indole or dihydrobenzofuran. Specific examples include those represented by the formula (A1a) -1 and those represented by the formula (A1a) -2 in which the ring A2 is benzene, pyrrole or 2,3-dihydrofuran. More preferably, in formula (A1) or (A1a), ring A is 1-cyclohexen-1-yl, naphthalen-1-yl, 1H-indol-4-yl or 2,3-dihydrobenzofuran-7-yl. It is.
[1-9-d] In formula (A2), formula (A3) or formula (A2a) as L, ring A ′ represents a benzene ring, a pyridine ring or a pyrimidine ring, and ring A ′ is benzene or pyridine. Preferred is benzene, pyridin-3-yl or pyridin-4-yl. In the formula (A2) or (A2a), the ring A ′ is more preferably benzene or pyridin-4-yl. In formula (A3), ring A ′ is more preferably benzene or pyridin-3-yl.

[1-9-e] In formula (A1), formula (A2), formula (A3), formula (A1a) or formula (A2a) as L, p is preferably an integer of 0 to 3. P + q is preferably an integer of 0 to 4, more preferably an integer of 0 to 3.
In Formula (A1) or Formula (A1a), p is more preferably 0 or 1. In formula (A1a) -1, p1a is preferably 0 or 1, more preferably 0. In formula (A1a) -2, p1b is 0 or 1, p1c is 0 or 1, p1b + p1c is preferably 0 or 1, and more preferably p1b is 0.
In Formula (A2) or Formula (A2a), p is more preferably 0 or 1.
In the formula (A3), p is more preferably an integer of 1 to 3.

[1-9-f] In the above formula (A1), formula (A2), formula (A3), formula (A1a), formula (A2a), formula (A1a) -1 or formula (A1a) -2 as L , ^{R 1} is preferably independently a halogen atom, a cyano _group, C 1 _{~ 4} alkyl group (said _C 1 _{~ 4} alkyl groups, one to five with a group selected arbitrarily from a halogen atom and -OH optionally _{substituted),} C 2 _{~ 4} alkenyl _group, C 1 _{~ 4} alkoxyl group (said _C 1 _{~ 4} alkoxyl group may be one to five substituted with a halogen _atom), C 2 _{~ 5} alkanoyl group, _{^{groups: -S (O) i R a}} (R a represents _C 1 _{~ 4} alkyl group), ^{^{^{group: -CONR d R e (R d}}} , R e are each independently a hydrogen atom or a C _{_1-4} represents an alkyl group) or a ^group: -NR ^{^b R} c (R ^b , R ^c together with the nitrogen atom to which they are attached form a 3- to 8-membered cyclic group, in which one or two carbon atoms in the ring are formed from an oxygen atom, a sulfur atom and a nitrogen atom. Optionally substituted with an optionally selected atom or carbonyl group).
[1-9-f-1] More preferably, ^{R 1,} each independently, a halogen atom, a cyano _group, C 1 _{~ 4} alkyl group (said _C 1 _{~ 4} alkyl group, optionally halogen atom and -OH selected may be one to have five substituted with _{groups) to,} C 2 _{- 3} alkenyl or _C 1 _{to 4} alkoxy group (said _C 1 _{~ 4} alkoxyl groups, is 1-5 substituted by a halogen atom and may _be), C 2 _{~ 3} alkanoyl group, _{^{groups: -S (O) i R a}} (R a represents _C 1 _{~ 2} alkyl group), ^{^{^{group: -CONR d R e (R d}}} , R e are each independently a hydrogen atom or represents a _C 1 _{~ 2} alkyl group) or a ^{^{^{group: -NR b R c (R b}}} , R c forms a 3-6 membered cyclic group together with the nitrogen atom to which they are attached The cyclic group has 1 carbon atom in the ring. The two are an oxygen atom, it may be replaced by a nitrogen atom or a carbonyl group).
[1-9-f-2] More preferably, ^{R 1} is, each independently, a halogen atom, a cyano group, 1-5 optionally substituted _C 1 _{to 4} alkyl groups with a halogen atom or a halogen atom, in a 1-5 optionally substituted C ₁ ~ ₄ alkoxyl group.
More specifically, fluorine atom, chlorine atom, bromine atom, cyano, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, methoxy , Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclopropylmethoxy, trifluoromethoxy, trifluoroethoxy, vinyl, acetyl, methylsulfonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1-piperidinyl 4-morpholinyl, 2-oxooxazolidin-3-yl and the like. More preferably, a fluorine atom, a chlorine atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy are mentioned.
In formula (A1), formula (A1a), formula (A1a) -1 or formula (A1a) -2, R ¹ is particularly preferably methyl.
In formula (A2) or formula (A2a), R ¹ is particularly preferably cyano or methoxy.
In the formula (A3), R ¹ is particularly preferably each independently a fluorine atom, a chlorine atom, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy. In Formula (A3), at least one R ¹ is preferably a group other than methyl.

[1-9-g] In the above formula (A1), formula (A2), formula (A3), formula (A1a), formula (A2a), formula (A1a) -1 or formula (A1a) -2 as L , P, p1a, p1b, p1c, q, ring A, ring A1, ring A2, ring A ′, R ² and R ¹ are preferably selected from the above-described embodiments [1-9-a], [1-9-b ], [1-9-b-1], [1-9-b-2], [1-9-c], [1-9-c-1], [1-9-d], [1 This is the same as the preferred embodiment described in [-9-e], [1-9-f] or [1-9-f-1]. Further, by combining each of these embodiments and preferred embodiments thereof with the definition of substituents as appropriate, the above formula (A1), formula (A2), formula (A3), formula (A1a), formula (A2a), A preferred embodiment of L represented by formula (A1a) -1 or formula (A1a) -2 can be arbitrarily formed.

[1-9-g-1] Specifically, in the formula (A1a) as L, ring A is cyclohexene, naphthalene, indole or dihydrobenzofuran, p is 0 or 1, and R ¹ is a halogen atom , cyano group, C ₁ ~ ₄ alkyl group which may be 1-5 substituted with a halogen atom or one optionally be 1-5 substituted by a halogen atom is also good C ₁ ~ ₄ alkoxyl groups, is, L It is mentioned as a preferable aspect of. More preferably, ring A is cyclohexene, naphthalene, indol or dihydrobenzofuran, p is 0 or 1, ^{R 1} is _C 1 _{~ 4} alkyl group. More specific examples of the formula (A1a) include 1-cyclohexen-1-yl, naphthalen-1-yl, 1-methyl-1H-indol-4-yl and 2,3-dihydrobenzofuran-7-yl. It is done.

[1-9-g-2] In the formula (A2a) as L, ring A ′ is a benzene ring or a pyridine ring, p is 0 or 1, R ¹ is a halogen atom, a cyano group or a halogen atom. 1-5 optionally substituted C ₁ to ₄ alkyl groups or those optionally be 1-5 substituted by a halogen atom is also good C ₁ ~ ₄ alkoxyl group, it may be mentioned as a preferred embodiment of L. More preferably, Ring A 'is a benzene ring or a pyridine ring, p is 0 or 1, R ¹ is a cyano group or a C ₁ ~ ₄ alkoxyl group. More preferably, Ring A 'is a benzene ring or pyridine-4-yl, p is 0 or 1, ^{R 1} is a cyano group or a _C 1 _{~ 4} alkoxyl group. Specific examples of the formula (A2a) include phenoxy, (2-, 3- or 4-) fluorophenoxy, (2-, 3- or 4-) chlorophenoxy, (2-, 3- or 4-) cyanophenoxy. , (2-, 3- or 4-) methoxyphenoxy, (2-, 3- or 4-) trifluoromethoxyphenoxy, (2-, 3- or 4-) methylphenoxy, (2-, 3- or 4) -) Trifluoromethylphenoxy, (2-, 3- or 4-) pyridyloxy, (2-, 4-, 5- or 6-) chloropyridin-3-yloxy, (2- or 3-) chloropyridine- 4-yloxy, (3-, 4-, 5- or 6-) cyanopyridin-2-yloxy, (2-, 4-, 5- or 6-) cyanopyridin-3-yloxy, 2- or 3-) cyanopyridin-4-yloxy, (2-, 4-, 5- or 6-) methoxypyridin-3-yloxy, (2- or 3-) methoxypyridin-4-yloxy (2-, 4-, 5- or 6-) methylpyridin-3-yloxy, (2- or 3-) methylpyridin-4-yloxy, 6-methoxy- (2-, 4- or 5-) methylpyridin-3-yloxy Etc. More specifically, phenoxy, (2-, 3- or 4-) cyanophenoxy, (2-, 3- or 4-) methoxyphenoxy, (2-, 3- or 4-) pyridyloxy, (3- , 4-, 5- or 6-) cyanopyridin-2-yloxy, (2-, 4-, 5- or 6-) cyanopyridin-3-yloxy, (2- or 3-) cyanopyridin-4-yloxy , (2-, 4-, 5- or 6-) methoxypyridin-3-yloxy or (2- or 3-) methoxypyridin-4-yloxy.

[1-9-g-3] In the formula (A3) as L, the ring A ′ is a benzene ring or a pyridine ring, p is an integer of 1 to 3, and each R ¹ is independently a halogen atom. , cyano group, C ₁ ~ ₄ alkyl group which may be 1-5 substituted with a halogen atom or one optionally be 1-5 substituted by a halogen atom is also good C ₁ ~ ₄ alkoxyl groups, is, L It is mentioned as a preferable aspect of. More preferably, ring A ′ is a benzene ring or a pyridine ring, p is an integer of 1 to 3, and each R ¹ is independently substituted with 1 to 5 halogen atoms or halogen atoms. C ₁ - ₄ alkyl group or 1-5 optionally substituted _C 1 _{to 4} alkoxy groups with a halogen atom,. More preferably, ring A ′ is a benzene ring or a pyridine ring, p is an integer of 1 to 3, and each R ¹ is independently substituted with 1 to 5 halogen atoms or halogen atoms. a C ₁ - ₄ alkyl group or 1-5 optionally substituted C ₁ to ₄ alkoxy groups with a halogen atom,, R ¹ is at least one of which is a group other than methyl. More specifically, as formula (A3), (2-, 3- or 4-) fluorophenyl, (2-, 3- or 4-) chlorophenyl, (2,6-, 2,5-, 2,4 -, 2,3-, 3,4- or 3,5-) difluorophenyl, (2,6-, 2,5-, 2,4-, 2,3-, 3,4- or 3,5- ) Dichlorophenyl, 4-chloro-2-fluorophenyl, (2-, 3- or 4-) methoxyphenyl, (2-, 3- or 4-) ethoxyphenyl, (2-, 3- or 4-) propoxyphenyl , (2-, 3- or 4-) isopropoxyphenyl, (2-, 3- or 4-) trifluoromethoxyphenyl, (2-, 3- or 4-) ethylphenyl, (2-, 3- or 4-) propylphenyl, (2-, 3- also Or 4-) isopropylphenyl, (2-, 3- or 4-) isobutylphenyl, (2-, 3- or 4-) tert-butylphenyl, (2-, 3- or 4-) trifluoromethylphenyl , (2,6-, 2,5-, 2,4-, 2,3-, 3,4- or 3,5-) dimethoxyphenyl, (2,6-, 2,5-, 2,4- , 2,3-, 3,4- or 3,5-) ditrifluoromethylphenyl, (4- or 5-) fluoro- (2- or 3-) methylphenyl, (2- or 3-) fluoro- ( 4- or 5-) methylphenyl, (4- or 5-) chloro-2-methylphenyl, 2-chloro- (4- or 5-) methylphenyl, (4- or 5-) fluoro-2-trifluoro Methylphenyl, (4 Or 5-) chloro-2-trifluoromethylphenyl, 2-fluoro- (4- or 5-) trifluoromethylphenyl, 2-chloro- (4- or 5-) trifluoromethylphenyl, (4- or 5 -) Fluoro- (2- or 3-) methoxyphenyl, 2-fluoro- (3-, 4- or 5-) methoxyphenyl, (4- or 5-) chloro- (2- or 3-) methoxyphenyl, 2-chloro- (3-, 4- or 5-) methoxyphenyl, 3-chloro-4-methoxyphenyl, (4- or 5-) fluoro-2-ethoxyphenyl, (4- or 5-) chloro-2 -Ethoxyphenyl, (2- or 3-) fluoro-4-ethoxyphenyl, (2- or 3-) chloro-4-ethoxyphenyl, 2- Methyl- (4- or 5-) trifluoromethylphenyl, 2-methoxy- (4- or 5-) methylphenyl, (4- or 5-) methoxy-2-methylphenyl, 4-methoxy- (2,6 -, 2,5- or 2,3-) dimethylphenyl, (2-, 4-, 5- or 6-) fluoropyridin-3-yl, (2-, 4-, 5- or 6-) chloropyridine -3-yl, (3-, 4-, 5- or 6-) methoxypyridin-2-yl, (2-, 4-, 5- or 6-) methoxypyridin-3-yl, (2- or 3 -) Methoxypyridin-4-yl, (2-, 4-, 5- or 6-) ethoxypyridin-3-yl, (2-, 4-, 5- or 6-) trifluoromethylpyridin-3-yl , (2,4-, 2,5--2 6-, 4,5-, 4,6- or 5,6-) dimethoxypyridin-3-yl, 6-isopropyl- (2-, 4- or 5-) chloropyridin-3-yl, 6-methoxy- (2-, 4- or 5-) methylpyridin-3-yl and the like.

[1-10] In the compound of the formula (I) of the embodiment [1], as a preferable compound, a compound in which L is the formula (A1), that is, the following formula (I) -1

(Wherein, p, q, r, s, ring A, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are defined in the above-mentioned embodiment [1]. And compounds represented by the formula (I) and the formula (A1) described above.
More specifically, preferred embodiments of p, q, r, s, ring A, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are the aforementioned embodiments. This is the same as the preferred embodiment described in [1-1] to [1-9] or any of the sub-embodiments thereof. In addition, the formula (A1), the formula (A1a), the formula (A1a) according to any one of the above embodiments [1-9], [1-9-a], [1-9-c], or any of their subembodiments -1, a preferred embodiment of the partial structure of the formula (I) -1 corresponding to the formula (A1a) -2 is the above-described embodiments [1-9], [1-9-a], [1-9-c] Or it is the same as the description in any one of those submodes.

[1-10-1] In the compound of the formula (I) -1 in the embodiment [1-10], a preferable compound is that q is 0, and R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b Are both hydrogen atoms.
[1-10-2] Among the compounds of formula (I) -1 of the embodiment [1-10], preferred compounds are those of the following formula (I) -1a

(Wherein p, r, s and ring A are defined as in formula (I) in the above embodiment [1]; each of R ^1-1 independently represents a halogen atom, a cyano group, or a halogen atom. in is 1 to 5 substituents which may _C 1 _{- 4} alkyl group optionally or 1-5 substituted _C 1 optionally _1-4 alkoxyl group with a halogen ^{atom,; R 3-1} are each independently , halogen atom, a 1-5 optionally substituted C ₁ - ₄ alkyl group optionally or 1-5 substituted C ₁ optionally _1-4 alkoxyl group with a halogen atom, a halogen atom; R ^{4- 1} are each independently a halogen atom, 1-5 optionally substituted C ₁ to ₄ alkyl groups with a halogen atom, a halogen atom with one to five optionally substituted C ₁ ~ ₄ alkoxyl group or A cyano group)
More specifically, preferred embodiments of p, r, s and ring A are any of the above-described embodiments [1-1], [1-3], [1-9-c], and [1-9-e]. This is the same as the preferred embodiment described above. In addition, the formula (A1a), the formula (A1a) -1, or any one of the sub-embodiments [1-9-a], [1-9-c], [1-9-g], Preferred embodiments of the partial structure of the formula (I) -1a corresponding to the formula (A1a) -2 are the above-mentioned embodiments [1-9-a], [1-9-c], [1-9-g] or It is the same as the description of any of those sub-embodiments.
In formula (I) -1a, p is preferably 0 or 1. In the formula (I) -1a, r is preferably 0 or 1, more preferably 0. In formula (I) -1a, s is preferably 0 or 1, more preferably 0. In formula (I) -1a, ring A is preferably cyclohexene, naphthalene, indole or dihydrobenzofuran, more preferably ring A is 1-cyclohexen-1-yl, naphthalen-1-yl, 1H-indole- 4-yl or 2,3-dihydrobenzofuran-7-yl.
Specific examples of R ^1-1 include the specific groups of R ¹ described in the above embodiment [1-9-f-2]. R ^1-1 is preferably 1 to 5 amino optionally substituted C ₁ to ₄ alkyl groups with a halogen atom, more preferably a C ₁ - ₄ alkyl group, and specific examples thereof include methyl . Specific examples of R ^3-1 include the specific group of R ³ described in the above embodiment [1-2]. Specific examples of R ^4-1 include the above-described embodiment [1- And specific groups for R ⁴ described in 4-a].
As formula (I) -1a, preferably, p is 0 or 1, r and s are 0, and ring A is cyclohexene, naphthalene, indole or dihydrobenzofuran.
The group corresponding to the formula (A1a) in the formula (I) -1a, that is, the ring A substituted with (R ^1-1 ) _p is preferably the one described in the above embodiment [1-9-g-1]. Specific examples include 1-cyclohexen-1-yl, naphthalen-1-yl, 1-methyl-1H-indol-4-yl and 2,3-dihydrobenzofuran-7-yl.

[1-11] In the compound of the formula (I) of the embodiment [1], as a preferable compound, a compound in which L is the formula (A2), that is, the following formula (I) -2

(Wherein, p, q, r, s, ring A ′, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are defined in the above-mentioned embodiment [1]. And the compound represented by the formula (I) and the formula (A2) described in (1).
More specifically, preferred embodiments of p, q, r, s, ring A ′, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are as described above. The same as the preferred embodiments described in the embodiments [1-1] to [1-9] or any of the sub-embodiments thereof. In addition, the partial structure of the formula (I) -2 corresponding to the formula (A2) or the formula (A2a) according to any one of the above embodiments [1-9], [1-9-a] or a sub-embodiment thereof Preferred embodiments of are the same as those described in the above embodiments [1-9], [1-9-a], or any of their sub-embodiments.

[1-11-1] In the compound of the formula (I) -2 of the embodiment [1-11], a preferable compound is q and R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are preferred. Are both hydrogen atoms.
[1-11-2] Among the compounds of formula (I) -2 of the embodiment [1-11], preferred compounds are those of the following formula (I) -2a

(Wherein p, r, s and ring A ′ are as defined in the formula (I) described in the above embodiment [1]; each of R ^1-2 independently represents a halogen atom, a cyano group, a halogen atom, There 1-5 an optionally substituted _C 1 _{- 4} alkyl group or 1 to 5 amino optionally substituted _C 1 _{to 4} alkoxy groups with a halogen atom, in ^{atom; R 3-2} are each independently to, a halogen atom, 1-5 optionally substituted C ₁ - ₄ alkyl group optionally or 1-5 substituted C ₁ optionally _1-4 alkoxyl group with a halogen atom, a halogen atom; R ^{4 -2,} each independently, a halogen atom, a halogen atom with one to five substituents which may C ₁ to ₄ alkyl groups, one to five substituents which may C ₁ to ₄ alkoxy groups with a halogen atom Or a cyano group) .
More specifically, preferred embodiments of p, r, s, and ring A ′ are the same as those of the above embodiments [1-1], [1-3], [1-9-d], and [1-9-e]. This is the same as the preferred embodiment described in any one. Also, preferred embodiments of the partial structure of the formula (I) -2a corresponding to the formula (A2a) described in the above embodiments [1-9-a], [1-9-g] or any of their sub-embodiments Is the same as described in any one of the above-mentioned embodiments [1-9-a], [1-9-g] or sub-embodiments thereof.
In formula (I) -2a, p is preferably 0 or 1. In the formula (I) -2a, r is preferably 0 or 1, more preferably 0. In the formula (I) -2a, s is preferably 0 or 1, more preferably 0. As Formula (I) -2a, ring A ′ is preferably benzene or pyridine, more preferably ring A ′ is benzene or pyridin-4-yl.
Specific examples of R ^1-2 include the specific groups of R ¹ described in the above embodiment [1-9-f-2]. R ^1-2 is preferably 1-5 substituents which may C ₁ to ₄ alkoxy groups with a cyano group or a halogen atom, more preferably a cyano group, or a C ₁ - ₄ alkoxy group, specifically Includes cyano or methoxy. Specific groups for R ^3-2 include the specific groups for R ³ described in the above embodiment [1-2], and specific groups for R ^4-2 include those described in the above embodiment [1- And specific groups for R ⁴ described in 4-a].
As formula (I) -2a, preferably, p is 0 or 1, r and s are 0, and ring A ′ is a benzene ring or a pyridine ring.
The group corresponding to the formula (A2a) in the formula (I) -2a, that is, the ring A ′ substituted with (R ^1-2 ) _p is preferably the one described in the above embodiment [1-9-g-2] Specific examples include phenyl, (2-, 3- or 4-) cyanophenyl, (2- or 3-) methoxypyridin-4-yl, and the like.

[1-12] In the compound of the formula (I) of the embodiment [1], as a preferable compound, a compound in which L is the formula (A3), that is, the following formula (I) -3

(Wherein p, r, s, ring A ′, R ¹ , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are defined in the formula (1) I) and the same as formula (A3) except that 5- (4-((2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2 -Thiazinan-3-one 1,1-dioxide and 5- (4-((6- (tert-butyl) -2'-fluoro-5'-methoxy- [1,1'-biphenyl] -3-yl) Methoxy) phenyl) -1,2-thiazinan-3-one, except for the compound that is 1,1-dioxide))).
More specifically, preferred embodiments of p, r, s, ring A ′, R ¹ , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are the above-described embodiments [1-1 ] To [1-9] or the preferred embodiments described in any of the sub-embodiments thereof. In addition, a preferred embodiment of the partial structure of the formula (I) -3 corresponding to the formula (A3) according to the above embodiment [1-9] or any of its subembodiments is the above embodiment [1-9] or It is the same as the description of any of those sub-embodiments.

[1-12-1] In the compound of the formula (I) -3 of the embodiment [1-12], a preferable compound is that R ^5a , R ^5b , R ⁶ , R ^7a and R ^7b are all hydrogen atoms. A compound.
[1-12-2] Among the compounds of the formula (I) -3 of the embodiment [1-12], preferred compounds are those of the following formula (I) -3a

(Wherein p, r, s and ring A ′ are as defined in the formula (I) described in the above embodiment [1]; each of R ^1-3 independently represents a halogen atom, a cyano group, a halogen atom, There 1-5 an optionally substituted _C 1 _{- 4} alkyl group or 1 to 5 amino optionally substituted _C 1 _{to 4} alkoxy groups with a halogen atom, in ^{atom; R 3-3} are each independently to, a halogen atom, 1-5 optionally substituted C ₁ - ₄ alkyl group optionally or 1-5 substituted C ₁ optionally _1-4 alkoxyl group with a halogen atom, a halogen atom; R ^{4 -3} are each independently a halogen atom, a halogen atom with one to five substituents which may C ₁ to ₄ alkyl groups, one to five substituents which may C ₁ to ₄ alkoxy groups with a halogen atom Or a cyano group (provided that 5- (4-((2 ', 6'-Dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide and 5- (4-((6- ( tert-butyl) -2'-fluoro-5'-methoxy- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Is a compound represented by
More specifically, preferred embodiments of p, r, s, and ring A ′ are the same as those of the above embodiments [1-1], [1-3], [1-9-d], and [1-9-e]. This is the same as the preferred embodiment described in any one. In addition, a preferred embodiment of the partial structure of the formula (I) -3a corresponding to the formula (A3) described in the above embodiments [1-9], [1-9-g] or any of the sub-embodiments thereof, This is the same as the description in any one of the above embodiments [1-9], [1-9-g] or their sub embodiments.
In the formula (I) -3a, p is preferably an integer of 1 to 3. In the formula (I) -3a, r is preferably 0 or 1, more preferably 0. In formula (I) -3a, s is preferably 0 or 1, more preferably 0. As Formula (I) -3a, ring A ′ is preferably benzene or pyridine, more preferably ring A ′ is benzene or pyridin-3-yl.
Specific examples of R ^1-3 include the specific groups of R ¹ described in the above embodiment [1-9-f-2]. R ^1-3 is preferably, independently, halogen atom, be 1-5 substituents with one to five substituents are C ₁ optionally _1-4 alkyl group or a halogen atom with a halogen atom C ₁ to ₄ alkoxyl groups, and specific examples thereof include fluorine atom, chlorine atom, methyl, ethyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy. At least one R ^1-3 is preferably a group other than methyl. Specific examples of R ^3-3 include the specific group of R ³ described in the above embodiment [1-2], and R ^3-3 is preferably a group other than tert-butyl. Specific groups for R ^4-3 include the specific groups for R ⁴ described in the above embodiment [1-4-a].
In formula (I) -3a, preferably, p is an integer of 1 to 3, r and s are 0, and ring A ′ is a benzene ring or a pyridine ring.
The group corresponding to the formula (A3) in the formula (I) -3a, that is, the ring A ′ substituted with (R ^1-3 ) _p is preferably the one described in the above embodiment [1-9-g-3] Specifically, (2-, 3- or 4-) fluorophenyl, (2-, 3- or 4-) chlorophenyl, (2,6-, 2,5-, 2,4-, 2,3-, 3,4- or 3,5-) difluorophenyl, (2,6-, 2,5-, 2,4-, 2,3-, 3,4- or 3,5-) dichlorophenyl , (2-, 3- or 4-) methoxyphenyl, (2-, 3- or 4-) trifluoromethoxyphenyl, (2-, 3- or 4-) ethylphenyl, (2-, 3- or 4) -) Trifluoromethylphenyl, (4- or 5-) chloro-2-methylpheny 2-chloro- (4- or 5-) methylphenyl, 2-fluoro- (4- or 5-) trifluoromethylphenyl, 2-chloro- (3-, 4- or 5-) methoxyphenyl, 3 -Chloro-4-methoxyphenyl, (4- or 5-) fluoro-2-ethoxyphenyl, 2-methyl- (4- or 5-) trifluoromethylphenyl, (4- or 5-) methoxy-2-methyl Examples include phenyl, 4-methoxy- (2,6-, 2,5- or 2,3-) dimethylphenyl, (2-, 4-, 5- or 6-) ethoxypyridin-3-yl and the like.

[1-13] As described above, each of the embodiments [1-1] to [1-12] of the present invention or the sub-embodiments thereof, and preferred embodiments thereof, and further, by appropriately combining the definitions of substituents, A preferred embodiment of the compound represented by the formula (I) of [1] can be arbitrarily formed.

[1-14] Preferred examples of the compound of the formula (I) of the embodiment [1] include the following.
5- (4-((4 '-(3-hydroxy-3-methylbutoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2 -Thiazinan-3-one 1,1-dioxide (Example 1);
5- (4-((4′-fluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 2);
5- (4-((4 '-(2-ethoxyethoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinane-3 -One 1,1-dioxide (Example 3);
5- (4-((2′-chloro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 4);
5- (4-((2'-methyl-4 '-(trifluoromethyl)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 5);
5- (4-((4′-Chloro-2′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 6);
5- (4-((2′-chloro-4′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 7);
5- (4-((4′-methoxy-2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1 -Dioxide (Example 8);
5- (4-((2 ′, 6′-Dichloro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Examples) 9);
5- (4-((3- (2,3-dihydrobenzofuran-7-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 10);
5- (4-((3- (1-methyl-1H-indol-4-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 11);
5- (4-((2'-Chloro-4'-methoxy- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 12);
5- (4-((2 '-(trifluoromethyl)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Example 13);
5- (4-((2 ′, 3 ′, 4 ′, 5′-tetrahydro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 14);
5- (4-((3′-fluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 15);
5- (4-((4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 16);
5- (4-((2 '-(trifluoromethoxy)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Example 17);
5- (4-((2′-fluoro-5 ′-(trifluoromethyl)-[1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 18);
5- (4-((3′-chloro-4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 19);
5- (4-((3- (naphthalen-1-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 20);
5- (4-((2'-ethoxy-5'-fluoro- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 21);
5- (4-((4′-methoxy-2′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 22);
5- (4-((2′-ethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 23);
5- (4-((3 ′, 5′-difluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Examples) 24);
5- (4-((3- (2-ethoxypyridin-3-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 25);
5- (4-((3-phenoxybenzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 26);
3- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile (Example 27);
4- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile (Example 28), and 5- (4- ((3-((2-Methoxypyridin-4-yl) oxy) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 29)
Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt, or an optical of the compound An isomer, or a pharmaceutically acceptable salt of the isomer, or a pharmaceutically acceptable solvate of the isomer or a pharmaceutically acceptable solvate of the salt.

[1-14-1] The compound of formula (I) -1 or formula (I) -1a described in the above embodiment [1-10] or [1-10-2], or a subembodiment thereof Among the compounds, the following are exemplified as preferred compounds.
5- (4-((3- (2,3-dihydrobenzofuran-7-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 10);
5- (4-((3- (1-methyl-1H-indol-4-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 11);
5- (4-((2 ′, 3 ′, 4 ′, 5′-tetrahydro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 14), and 5- (4-((3- (naphthalen-1-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 20)
Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt, or an optical of the compound An isomer, or a pharmaceutically acceptable salt of the isomer, or a pharmaceutically acceptable solvate of the isomer or a pharmaceutically acceptable solvate of the salt.

[1-14-2] The compound of formula (I) -2 or formula (I) -2a described in the above embodiment [1-11] or [1-11-2], or a subembodiment thereof Among the compounds, the following are exemplified as preferred compounds.
5- (4-((3-phenoxybenzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 26);
3- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile (Example 27);
4- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile (Example 28), and 5- (4- ((3-((2-Methoxypyridin-4-yl) oxy) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 29)
Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt, or an optical of the compound An isomer, or a pharmaceutically acceptable salt of the isomer, or a pharmaceutically acceptable solvate of the isomer or a pharmaceutically acceptable solvate of the salt.

[1-14-3] The compound of formula (I) -3 or formula (I) -3a described in the above embodiment [1-12] or [1-12-2], or a subembodiment thereof Among the compounds, the following are exemplified as preferred compounds.
5- (4-((4′-fluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 2);
5- (4-((2′-chloro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 4);
5- (4-((2'-methyl-4 '-(trifluoromethyl)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 5);
5- (4-((4′-Chloro-2′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 6);
5- (4-((2′-chloro-4′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 7);
5- (4-((4′-methoxy-2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1 -Dioxide (Example 8);
5- (4-((2 ′, 6′-Dichloro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Examples) 9);
5- (4-((2'-Chloro-4'-methoxy- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 12);
5- (4-((2 '-(trifluoromethyl)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Example 13);
5- (4-((3′-fluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 15);
5- (4-((4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 16);
5- (4-((2 '-(trifluoromethoxy)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Example 17);
5- (4-((2′-fluoro-5 ′-(trifluoromethyl)-[1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 18);
5- (4-((3′-chloro-4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 19);
5- (4-((2'-ethoxy-5'-fluoro- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 21);
5- (4-((4′-methoxy-2′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 22);
5- (4-((2′-ethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 23);
5- (4-((3 ′, 5′-difluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Examples) 24), and 5- (4-((3- (2-Ethoxypyridin-3-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 25)
Or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt, or an optical of the compound An isomer, or a pharmaceutically acceptable salt of the isomer, or a pharmaceutically acceptable solvate of the isomer or a pharmaceutically acceptable solvate of the salt.

[2] A second aspect of the present invention is a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound, or the A pharmaceutical composition comprising a pharmaceutically acceptable solvate of a salt.

[3] A third aspect of the present invention is the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound, or the A prophylactic and / or therapeutic agent for a disease involving GPR40, comprising at least one pharmaceutically acceptable solvate of a salt as an active ingredient.

[3-1] Specifically, the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt Diabetes [more specifically, type 1 diabetes (insulin-dependent diabetes), type 2 diabetes (insulin non-insulin), characterized by containing at least one pharmaceutically acceptable solvate as an active ingredient Dependent diabetes) or borderline diabetes (any or all of impaired glucose tolerance (IGT) and / or fasting glycemia (IFG))], or a prophylactic and / or therapeutic agent for each disease such as obesity and obesity It is. An example is the onset inhibitor of type 2 diabetes in impaired glucose tolerance. Sulfonylurea drugs are also examples of therapeutic agents for secondary ineffective diabetes. Sufficient blood glucose lowering effects cannot be obtained even by administration of sulfonylurea drugs (glibenclamide, glimepiride, etc.) or rapid insulin secretion promoters (mitiglinide, etc.) ( Ineffective administration) Insulin secretion effect and blood glucose lowering effect can be obtained even in diabetic patients.
In addition, in relation to blood glucose level and disease, 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. . Borderline diabetes (also referred to as impaired glucose tolerance) 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, and / or a 75 gOGTT 2 hour value is 140 mg / dl or more and 200 mg / dl. This refers to abnormal glucose tolerance (IGT) that is less than dl.
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.
“Obesity” is defined by the Japanese Society of Obesity as “a medical condition that is associated with or is expected 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.

[4] A fourth aspect of the present invention is the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound, or the An insulin secretagogue comprising at least one pharmaceutically acceptable solvate of a salt as an active ingredient.

[5] A fifth aspect of the present invention is the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of the compound, or the A GPR40 activator comprising one or more pharmaceutically acceptable solvates of a salt.

In the second to fifth embodiments and preferred embodiments thereof, more preferred substituents in the formula (I) or combinations thereof are in accordance with the explanation described in the first embodiment.

In each of the embodiments described in [1] to [5] of the present invention, when the GPR40 agonistic action is measured by a method appropriately selected (for example, Pharmacological Experimental Example 1 (agonist action on human-derived GPR40) described later) It is preferable to use a compound having an EC ₅₀ value of 3 μM or less, more preferably 1 μM or less, still more preferably 300 nM or less, particularly preferably 100 nM or less.

In the embodiment of the present invention, the “therapeutic agent” is intended to include not only treatment of a disease or symptom but also improvement of the disease or symptom.
In all of the above embodiments, when the term “compound” is used, “a pharmaceutically acceptable salt thereof” is also referred to. Further, 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. Further, the compound of the formula (I) may have axial asymmetry due to steric hindrance, and isomers generated by axial asymmetry (axial chirality) are also included in the formula (I). 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.

When the compound of the present invention is a salt, examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. And the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. And salts with ethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt), In the case where the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
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.
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 simultaneously form both an acid addition salt and a base salt, depending on the side chain substituent.

When the compound of the present invention has isomers such as tautomers, optical isomers, stereoisomers, positional isomers, and rotational isomers, either one of the isomers or a mixture is included in the compound of the present invention. Is included. Furthermore, when an optical isomer exists in the compound of the present invention, an optical isomer resolved from a racemate is also encompassed in the compound of the present invention.
The compound of the present invention may be in the form of a crystal, and a single crystal form or a mixture of crystal forms is included in the compound of the present invention.
The compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid. The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
The compound of the present invention may be a solvate (for example, hydrate etc.) or a solvate, and both are included in the compound of the present invention.
A compound labeled or substituted with an isotope (eg, ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I, etc.) is also encompassed in the compound of the present invention. The compound of the present invention labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in Positron Emission Tomography (PET), and is useful in fields such as medical diagnosis.

[Method for producing compound of the present invention]
Below, the manufacturing method of the compound represented by Formula (I) of this invention is demonstrated.
The compounds represented by the formula (I) of the present invention, salts thereof and solvates thereof can be produced by a combination of known general chemical production methods, and typical production methods are described below. To do.
Ring A, ring A ′, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ^7a , R ^7b , p, q, r, in each formula of the following production methods Unless otherwise specified, the definitions of s and L are the same as the definitions of Formula (I), Formula (A1), Formula (A2), and Formula (A3) described in the above embodiment.
The definition of P ¹ in the production method is a protecting group for an amino group (—NH ₂ ) and an imino group (—NH—) unless otherwise specified.
The definition of P ² in the production method is a protecting group for an alcohol group (including a phenol group) unless otherwise specified.
The definition of P ³ in the production method is a protecting group for —SO ₂ NHCO— group unless otherwise specified.
Definition of R 'in the manufacturing process, unless otherwise indicated, are H or C ₁ ~ ₆ alkyl group.
Unless otherwise specified, W ¹ and W ² in the production method are defined as follows. When W ¹ is a hydroxyl group, a halogen atom, or a trifluoromethanesulfonyloxy group, W ² is a boronic acid, boronic acid ester, or trifluoroborate salt. And when W ¹ is a boronic acid, boronic acid ester, or trifluoroborate salt, W ² is a hydroxyl group, a halogen atom, or a trifluoromethanesulfonyloxy group. In addition, the compound which has applicable boronic acid, boronic acid ester, or a trifluoroborate salt is marketed, or can be easily obtained from a commercial item by a general organic chemistry manufacturing method.
The definition of X ₁ in the production method is a halogen atom, methanesulfonyloxy, p-toluenesulfonyloxy unless otherwise specified.
Definition of _{X 2} in the manufacturing process, unless otherwise specified, a chlorine atom, OH, ONa, is OK.
The definition of Hal in the production method is a halogen atom unless otherwise specified.
The definition of * in the production method represents an asymmetric center.

In each of the following production methods, each raw material compound used for the production of formula (I) may form a salt, and examples of such a salt include the same salts as those of formula (I). .
Each raw material compound used in the production of formula (I) can be used in the next reaction as a reaction liquid or as a crude product, but can also be isolated from a reaction mixture according to a conventional method. It can be easily purified by known means, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
Examples of the solvent used for the recrystallization include water; alcohols such as methanol, ethanol, 2-propanol and butanol; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; n-hexane, cyclohexane and heptane. Hydrocarbons such as benzene, toluene, xylene, etc .; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; chloroform Halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; nitriles such as acetonitrile; ketones such as acetone and diphenyl ketone; esters such as methyl acetate and ethyl acetate; sulfoxides such as dimethyl sulfoxide; , Trifluoroacetic acid, methanesulfo Acid, organic acids such as p- toluenesulfonic acid; and the like. These solvents can be used alone, or two or more kinds of solvents can be mixed at an appropriate ratio, for example, a ratio of 1: 1 to 1:10. Moreover, when the compound in a formula is marketed, a commercial item can also be used as it is, and what was manufactured by the method known per se or a method according to it can also be used.

Moreover, in each reaction of the manufacturing method of a compound represented by the formula (I) of this invention and each reaction of a raw material compound synthesis | combination, as a substituent, a hydroxyl group (alcoholic hydroxyl group, phenolic hydroxyl group, heterocyclic hydroxyl group etc.), an amino group When there is a reactive group such as a carboxyl group or a thiol group, these groups can be appropriately protected in each reaction step, and the protective group can be removed at an appropriate stage.
Examples of the protective group for the hydroxyl group (alcoholic hydroxyl group, phenolic hydroxyl group, heterocyclic hydroxyl group, etc.) include, for example, methyl group (Me group), ethyl group (Et group), n-propyl group (n-Pr group), isopropyl A C _1-6 alkyl group represented by a group (i-Pr group), n-butyl group (n-Bu group), tert-butyl group (tert-Bu group), etc .; methoxymethyl group (MOM group), methoxy Alkoxyalkyl groups typified by ethoxymethyl group (MEM group), tetrahydropyranyl group (THP group), etc .; arylmethyl typified by benzyl group (Bn group), triphenylmethyl group (trityl group, Tr group), etc. group; a trimethylsilyl group _(Me 3 Si group), triethylsilyl group _(Et 3 Si group), t-butyldimethylsilyl group _{_{(t-Bu (CH 3)}} 2 Si group), t Silyl group represented by butyldiphenylsilyl group _{(t-Bu (Ph) 2} Si group); an acetyl group (Ac group), an ethylcarbonyl group (EtCO group), alkanoyl typified by a pivaloyl group (Piv group) Group: C _7-10 aralkyl-carbonyl group represented by benzylcarbonyl group (BnCO group), etc .; aroyl group represented by benzoyl group (Bz group), etc .; methoxycarbonyl group (CH ₃ OCO group), ethoxycarbonyl group (CH ₃ CH ₂ OCO group), alkoxycarbonyl group represented by t-butoxycarbonyl group (t-BuOCO group, Boc group) and the like; arylmethoxycarbonyl group represented by benzyloxycarbonyl group (BnOCO group) and the like Is used.
Examples of the protecting group for the amino group (—NH ₂ group) or imino group (—NH— group) include acetyl group (Ac group), ethylcarbonyl group (EtCO group), pivaloyl group (Piv group) and the like. Alkanoyl group; methoxycarbonyl group (CH ₃ OCO group), ethoxycarbonyl group, (CH ₃ CH ₂ OCO group), ethoxycarbonyl group (CH ₃ CH ₂ OCO group), t-butoxycarbonyl group (t-BuOCO group) , Boc group) and the like; allyloxycarbonyl group (Alloc group); fluorenylmethoxycarbonyl group (Fmoc group); phenyloxycarbonyl group (PhOCO group); benzyloxycarbonyl group (BnOCO group, Z group), paramethoxybenzyloxycarbonyl group (p-CH ₃ OPh) Arylmethoxycarbonyl group represented by CH ₂ OCO group), paranitrobenzyloxycarbonyl group (p-NO ₂ PhCH ₂ OCO group), etc .; benzyl group (Bn group), triphenylmethyl group (trityl group, Tr group) An arylmethyl group represented by benzoyl group (Bz group) or the like; a C _7-10 aralkyl-carbonyl group represented by benzylcarbonyl group (BnCO group) or the like; a methanesulfonyl group (CH ₃ SO ₂ group, Ms group), benzenesulfonyl group (Bs group), p-toluenesulfonyl group (p-Ts group), nitrobenzenesulfonyl group (nosyl group, Ns group), 2,4-dinitrobenzenesulfonyl group (DNs) Sulfonyl group typified by a group); 2- (trimethylsilyl) ethoxymethyl group ((CH ₃ )) ₃ SiCH ₂ CH ₂ OCH ₂ group, SEM group); phthaloyl group (Pht group); N, N-dimethylaminomethylene group ((CH ₃ ) ₂ NCH ₂ group) and the like.
Examples of the protective group for the carboxyl group include methyl group (Me group), ethyl group (Et group), n-propyl group (n-Pr group), isopropyl group (i-Pr group), n-butyl group (n- C _1-6 alkyl group, allyl group (allyl group); phenyl group (Ph group); benzyl group (Bn group), triphenylmethyl, typified by Bu group), tert-butyl group (tert-Bu group), etc. An arylmethyl group represented by a group (Ph ₃ C group); or a trimethylsilyl group (Me ₃ Si group), a triethylsilyl group (Et ₃ Si group), a t-butyldimethylsilyl group (t-Bu (CH ₃ )) ₂ Si group), a silyl group represented by t-butyldiphenylsilyl group (t-Bu (Ph) ₂ Si group) and the like are used.
Examples of the protecting group for the thiol group include methyl group (Me group), ethyl group (Et group), n-propyl group (n-Pr group), isopropyl group (i-Pr group), n-butyl group ( n 1 -Bu group), C _1-6 alkyl group represented by tert-butyl group (tert-Bu group), etc .; benzyl group (Bn group), represented by triphenylmethyl group (Ph ₃ C group), etc. An arylmethyl group; an alkanoyl group typified by an acetyl group (Ac group), an ethylcarbonyl group (EtCO group), a pivaloyl group (Piv group), etc .; an aroyl group typified by a benzoyl group (Bz group), etc. are used. .

Examples of the method for removing the protecting group include an alkanoyl group represented by an acetyl group (Ac group), an ethylcarbonyl group (EtCO group), a pivaloyl group (Piv group), and the like; a methoxycarbonyl group (CH ₃ OCO group), Alkoxycarbonyl groups or benzoyl groups typified by ethoxycarbonyl group, (CH ₃ CH ₂ OCO group), ethoxycarbonyl group (CH ₃ CH ₂ OCO group), t-butoxycarbonyl group (t-BuOCO group, Boc group), etc. An acyl-type protecting group such as an aroyl group represented by (Bz group) is hydrolyzed by using an appropriate base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. Can be deprotected.
Alkoxyalkyl-type protecting groups represented by methoxymethyl group (MOM group), methoxyethoxymethyl group (MEM group), tetrahydropyranyl group (THP group), etc .; t-butoxycarbonyl group (tBuOCO group) or paramethoxybenzyloxy Substituted methoxycarbonyl-type protecting groups such as carbonyl groups (p-CH ₃ OPhCH ₂ OCO groups), trimethylsilyl groups (Me ₃ Si groups), triethylsilyl groups (Et ₃ Si groups), t-butyldimethylsilyl groups (t Silyl-type protecting groups such as —Bu (CH ₃ ) ₂ Si group) can be selected from suitable acids such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or combinations thereof. Can be deprotected. The silyl-type protecting group described above can also be deprotected with an appropriate fluorine ion (F ⁻ ) generating reagent such as tetrabutylammonium fluoride and hydrogen fluoride.
Arylmethoxycarbonyl typified by benzyloxycarbonyl group (BnOCO group), paramethoxybenzyloxycarbonyl group (p-CH ₃ OPhCH ₂ OCO group), paranitrobenzyloxycarbonyl group (p-NO ₂ PhCH ₂ OCO group) and the like The arylmethyl group represented by the group and benzyl group (Bn group) can be deprotected by hydrogenolysis using a palladium carbon catalyst. The benzyl group can also be deprotected by Birch reduction using metallic sodium in liquid ammonia.
The triphenylmethyl group (Ph ₃ C group) can be deprotected with a suitable acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or combinations thereof. In addition, deprotection can also be achieved by Birch reduction using metallic sodium or hydrogenolysis using a palladium carbon catalyst in liquid ammonia.
Depending on the type of sulfonyl group, in the case of a methanesulfonyl group (Ms group), sodium amalgam (Na-Hg) and HBr-AcOH can be used to form a p-toluenesulfonyl group (Ts group) and a benzenesulfonyl group (Bs group). In the case of 2,4-dinitrobenzenesulfonyl group (DNs group) with a sodium anthreneide and sodium naphthalenide separately prepared at a low temperature of −78 ° C., and in the case of a nitrobenzenesulfonyl group (nosyl group, Ns group) with a thiol. In this case, it can be deprotected with thioglycolic acid / triethylamine.

The method for introducing / removing the protecting group shown here 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, 4th edition, 2007, John Wiley & Sons].

The reaction conditions in the production method described below are as follows unless otherwise specified. The reaction temperature is in the range from −78 ° C. to the temperature at which the solvent is refluxed. When the temperature is not described, it is room temperature (0 to 35 ° C.), and the reaction time is the time for which the reaction proceeds sufficiently. .
In addition, each step in the production method can be performed without solvent or by dissolving or suspending the raw material compound in a solvent not involved in an appropriate reaction before the reaction.
Specific examples of the solvent not involved in the reaction include water; saturated hydrocarbon solvents such as cyclohexane and hexane; aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene; methanol, ethanol, 1-propanol, 2 Alcohol solvents such as -propanol, tert-butyl alcohol, 2-methoxyethanol; N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), 1, Polar amide solvents such as 3-dimethyl-2-imidazolidinone (DMI); sulfoxide solvents such as dimethyl sulfoxide (DMSO); nitrile solvents such as acetonitrile and propionitrile; diethyl ether, diisopropyl ether, diphenyl ether, tetrahydro Ether solvents such as lofrane, 1,4-dioxane, 1,2-dimethoxyethane; ester solvents such as methyl acetate, ethyl acetate, butyl acetate; ketone solvents such as acetone, methyl ethyl ketone; dichloromethane, chloroform, carbon tetrachloride Halogenated hydrocarbon solvents such as 1,2-dichloroethane; basic solvents such as triethylamine, N, N-diisopropylethylamine, pyridine, lutidine, N, N-dialkylaniline; acid anhydrides such as acetic anhydride; formic acid, Organic acids such as acetic acid, propionic acid, trifluoroacetic acid and methanesulfonic acid; and inorganic acids such as hydrochloric acid and sulfuric acid. One kind of these solvents may be used alone, or two or more kinds of solvents may be mixed and used at an appropriate ratio by appropriately selecting depending on the reaction conditions.
Specific examples of the base (or deoxidizer) used in the production method of the compound of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and carbonate. Inorganic bases such as cesium, calcium carbonate, sodium bicarbonate; triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), N, N-dimethylaniline, N -Methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), 1,4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU Organic bases such as imidazole; sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide and other metal alkoxides; alkali metal hydrides such as sodium hydride and potassium hydride; sodium amide, lithium diisopropylamide ( Metal amides such as LDA), lithium hexamethyldisilazide (LHMDS), potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NaHMDS); methyllithium, n-butyllithium, sec-butyllithium, and organic lithium reagents such as tert-butyllithium.
Examples of the acid or acid catalyst used in the production method of the compound of the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and phosphoric acid; acetic acid, trifluoroacetic acid (TFA), Organic acids such as oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid (CSA); boron trifluoride ether complex ( BF ₃ · Et ₂ O), zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, and other Lewis acids.
However, it is not necessarily limited to those described above.

The salt of the formula (I) of the present invention is prepared according to a method known per se. For example, when the formula (I) is a basic compound, an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid Mineral acids) or formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. By adding an acid, or when formula (I) is an acidic compound, ammonia, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N-diisopropylethylamine, N, N′-dibenzylethylenediamine, N, N— It can be produced by adding an organic base such as dialkylaniline or an inorganic base such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate.

When there are geometric isomers (geometric isomers), configuration isomers (configurational isomers), stereoisomers (diastereomers), conformers (conformers), etc., in the formula (I) of the present invention Each can be isolated by known means. When the formula (I) is an optically active substance, the racemate may be separated into a (+) form, a (−) form [(D) form, (L) form] by a conventional optical resolution means. it can.
When formula (I) of the present invention contains optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, these are also included as formula (I) and known per se. Each can be obtained as a single product by the synthesis method and the separation method.
For example, as the optical resolution method, a method known per se, for example, (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like are used.
(1) Fractionation recrystallization method: After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. A method for obtaining a free optically pure compound. Examples of the optical resolution agent include (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine, There are cinchonine, (−)-cinchonidine, brucine and the like.
(2) Diastereomer method: An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , HPLC (High Performance Liquid Chromatography, etc.) etc., and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. To obtain a simple optical isomer. For example, when the compound of formula (I) has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], (−)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when a carboxyl group is present in the formula (I), an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted into an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
(3) Chiral column method: A method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to HPLC on a chiral column (optical isomer separation column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as Daicel's CHIRAL series, and water, various buffers (eg, phosphate buffer), organic solvents (eg, ethanol, methanol, The optical isomers can be separated by development using isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution. In addition, for example, in the case of gas chromatography, separation can be performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

Necessary starting materials are commercially available, or can be easily obtained from commercially available products by general organic chemical production methods.

The production method will be described below, but the present invention is not limited to this method.

The compound represented by the formula (I) of the present invention can be produced using the compound represented by the formula (AI) as a starting material.

(Production method A) <however, in the formula ^(I), a ^{R 5b = H, R 7b =} H, R 6 = H, C 1 ~ 6 alkyl group, a halogenated _C 1 _{~ 6} alkyl group, _{C 2} to _6. alkenyl or _C 2 _{- 6} alkynyl group>

<Step 1>
Using a compound represented by the formula (AI) and a compound represented by the formula (A-II), methods known in the literature, for example, “Journal of the American Chemical Society”, 132 ( 2) 436-437, 2010 ”, in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate or the like in the reaction with a polar solvent such as N, N-dimethylformamide or acetonitrile. The compound represented by the formula (A-III) can be produced by performing the reaction in a solvent not involved or in a mixed solvent thereof at a temperature at which the solvent is refluxed from −78 ° C.
<Step 2>
Using a compound represented by the formula (A-III) and a sulfonamide derivative represented by the formula (A-IV), a method known in the literature, for example, “Synlett, pages 5, 834-838, 2005” In the presence of a base such as lithium hexamethyldisilazane (LHMDS), tert-butoxypotassium (t-BuOK), sodium hydride (NaH), diethyl chlorophosphate, etc. In a solvent that does not participate in the reaction such as an ether solvent such as toluene, an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as N, N-dimethylformamide, or a mixed solvent thereof, a solvent from −78 ° C. The compound represented by the formula (AV) can be produced by carrying out the reaction at a temperature at which is refluxed.
<Step 3>
Using a compound represented by the formula (AV) and a malonic acid derivative represented by the formula (A-VI), methods known in the literature, for example, “Heterocyclic Communications”, 3 (1), 19 In the presence of bases such as sodium hydride (NaH), tert-butoxypotassium (t-BuOK), sodium methoxide (NaOMe), sodium ethoxide (NaOEt) In an ether solvent such as diethyl ether or tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene or benzene, or a polar solvent such as N, N-dimethylformamide, or a mixed solvent thereof. The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C., and the formula (A Can be prepared a compound represented by VII).
<Step 4>
According to a method known in the literature, for example, the method described in “Chemical & Pharmaceutical Bulletin, 33 (12), pages 5316-5327, 1985”, the formula (A-VII) In the presence or absence of sodium chloride, a compound represented by a solvent such as water, dimethyl sulfoxide, N, N-dimethylformamide or the like, which is not involved in the reaction, or a mixed solvent thereof, from 0 ° C. to the solvent The compound represented by the formula (A-VIII) can be produced by performing the reaction at a temperature at which is refluxed.
<Step 5>
Using a compound represented by the formula (A-VIII), a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition”, 4th edition, 2007, John Willie and In accordance with the method described in the book of John Wiley & Sons, Green et al., The P ¹ group was deprotected by reacting in a method corresponding to the type of the protecting group P ¹ . A compound represented by the formula (A-IX) can be produced.
<Step 6>
Using a compound represented by the formula (A-IX), a method known in the literature, for example, a method described in “Organic Letters, 7 (22), pages 5067-5069, 2005” is used. Similarly, in the presence of a base such as sodium methoxide (NaOMe) or sodium ethoxide (NaOEt), in a solvent that does not participate in the reaction such as methanol or ethanol, or in a mixed solvent thereof, at a temperature at which the solvent is refluxed from 0 ° C. By performing the reaction, a compound represented by the formula (AX) can be produced.

<Step 7>
<Step 7-1> (In Formula (I), L = 4- (3-hydroxy-3-methylbutoxy) -2,6-dimethylphenyl group, 4- (2-ethoxyethoxy) -2,6-dimethyl) Phenyl group, in the case of formula (A1) or formula (A3))
A compound represented by the formula (AX) and a compound represented by the formula (A1) -W or a compound represented by the formula (A2) -W [in the case of L = formula (A1), the formula (A1)- When a compound represented by W is used and L = formula (A3), a compound represented by formula (A2) -W where q = 0 is used, and L = 4- (3-hydroxy-3-methylbutoxy ) -2,6-dimethylphenyl group or 4- (2-ethoxyethoxy) -2,6-dimethylphenyl group, p, q, R ¹ , R ² and ring A ′ are the corresponding formulas (A2) A compound represented by -W is used. However, when W ₁ is a halogen atom or a trifluoromethanesulfonyloxy group, W ₂ is a boronic acid, boronic acid ester, or trifluoroborate salt, and W ₁ and W ₂ may be reversed. , Methods known in the literature, for example, “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI -Organic synthesis using metals—327-352, 2004, Maruzen”, and “Journal of Medicinal Chemistry” (Journal) of Medicinal Chemistry), 48 (20), pages 6326-6339, 2005 ”, palladium (II) acetate (Pd (OAc) ₂ ), tetrakistriphenylphosphine palladium (Pd (PPh ₃ ₄ ), Tris (dibenzylideneacetone) diparadiu ((Dba) ₃ Pd ₂ ), bis (dibenzylideneacetone) palladium ((dba) ₂ Pd), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (Pd (dppf) Cl ₂ ) palladium catalyst such as triphenylphosphine, tris (tert-butyl) phosphine, tris (o-tolyl) phosphine, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′ , 4 ′, 6′-triisopropylbiphenyl and the like, and in the presence of organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, potassium carbonate, cesium carbonate, toluene, xylene, N, N-dimethylformamide, N, N-dimethyl Using a solvent that does not participate in the reaction, such as cetamide, dimethoxyethane, acetonitrile (acetonitrile / water), tetrahydrofuran (tetrahydrofuran / water), or a mixed solvent thereof, the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. A compound represented by I) can be produced. Moreover, it can manufacture by the same method using tetramethylammonium chloride, tetrabutylammonium chloride, etc. instead of a phosphine-type reagent.
<Step 7-2> (In Formula (I), L = Formula (A2))
Using a compound represented by the formula (AX) and a compound represented by the formula (A2) -W, a method known in the literature, for example, “Tetrahedron Letters, 44, 3863-3865, 2003” In accordance with the method described in the formula (A2) -W [wherein W ₁ is a hydroxyl group, W ₂ is a boronic acid, a boronic acid ester, or a trifluoroborate salt, and , W ₁ and W ₂ may be reversed] in the presence of a copper catalyst such as copper (II) acetate and copper (II) trifluoroacetate, and a base such as triethylamine, N, N-diisopropylethylamine and pyridine Lower solvent such as dichloromethane, 1,4-dioxane, tetrahydrofuran, N, N-dimethylformamide, etc., or a mixture thereof With medium, carrying out the reaction at a temperature at which the solvent refluxes from 0 ° C., it is possible to produce a compound of formula (I).

(Production method B) <where, in the formula ^{(I), R 5b = H} , an ^{R 7b} = H>

<Step 1>
Using the compound represented by the formula (A-VIII) and the compound represented by the formula (A1) -W or the formula (A2) -W, (Production Method A) <Step 7-1> or <Step 7-2> The compound represented by the formula (BI) can be produced by performing the reaction in the same manner as described above.
<Step 2>
The compound represented by the formula (BI) can be produced by reacting the compound represented by the formula (BI) in the same manner as in (Production Method A) <Step 5>.
<Step 3>
A compound represented by the formula (I) can be produced by reacting the compound represented by the formula (B-II) in the same manner as in (Production Method A) <Step 6>.

(Production Method C) <However, in the formula (I), R ^5a or / and R ^5b ≠ H, R ^7b = H>

<Step 1>
Using the compound represented by the formula (AV) and the compound represented by the formula (CI), the reaction is carried out in the same manner as in (Production Method A) <Step 3>. In the formula (C-II) The compounds represented can be produced.
<Step 2>
A compound represented by the formula (C-II) can be produced by reacting the compound represented by the formula (C-II) in the same manner as in (Production Method A) <Step 4>.
<Step 3>
Using a compound represented by the formula (C-III) and an alkyl halide represented by, for example, R ^5a X ₁ or R ^5b X ₁ , a known method such as “Experimental Chemistry Course 5th Edition 16 Synthesis IV Carboxylic acid / amino acid / peptide, page 1-70, 2005, Maruzen ”, etc., according to the method described in sodium methoxide, sodium ethoxide, sodium hydride, lithium hydroxide, sodium hydroxide, water In the presence of a base such as potassium oxide, lithium carbonate, sodium carbonate, or potassium carbonate, a solvent that does not participate in the reaction, such as water, methanol, ethanol, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, or a mixed solvent thereof The reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C., and the compound represented by the formula (C-IV) is used. It is possible to manufacture things.
<Step 4>
Using the compound represented by the formula (C-IV), deprotection can be carried out in the same manner as in (Production Method A) <Step 5> to produce the compound represented by the formula (CV). .
<Step 5>
The compound represented by the formula (CV) can be produced by reacting the compound represented by the formula (CV) in the same manner as in (Production Method A) <Step 6>.
<Step 6>
Using the compound represented by the formula (C-VI) and the compound represented by the formula (A1) -W or the formula (A2) -W, (Production Method A) <Step 7-1> or <Step 7-2> The compound represented by the formula (I) can be produced by performing the reaction in the same manner as described above.

(Production method D) <however, in the formula ^(I), a ^{R 5b = H, R 7b =} H, R 6 = H, C 1 ~ 6 alkyl group, a halogenated _C 1 _{~ 6} alkyl group, _{C 2} to _6. alkenyl or _C 2 _{- 6} alkynyl group>

<Step 1>
Using a compound represented by the formula (AI), a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition”, 4th edition, 2007, John Willy and Sands (John Wiley & Sons), in accordance with the method described in textbooks of green (Greene) et al ", by reacting a method according to the type of the protecting group the protecting group ^{P 2,} phenol group ^{P 2} A compound of formula (DI) protected with a group can be prepared.
<Step 2>
Using the compound represented by the formula (DI) and the compound represented by the formula (A-IV), the reaction is carried out in the same manner as in (Production Method A) <Step 2>, and in the formula (D-II) The compounds represented can be produced.
<Step 3>
Using the compound represented by the formula (D-II) and the compound represented by the formula (A-VI), the reaction is carried out in the same manner as in (Production Method A) <Step 3>, and in the formula (D-III) The compounds represented can be produced.
<Step 4>
A compound represented by the formula (D-IV) can be produced by reacting the compound represented by the formula (D-III) in the same manner as in (Production Method A) <Step 4>.
<Step 5>
Using the compound represented by the formula (D-IV), deprotection can be carried out in the same manner as in (Production Method A) <Step 5> to produce the compound represented by the formula (DV). .
<Step 6>
A compound represented by the formula (D-V) can be produced by reacting the compound represented by the formula (D-V) in the same manner as in (Production Method A) <Step 6>.
<Step 7>
Using a compound represented by the formula (D-VI), a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition”, 4th edition, 2007, John Willy and Sands (John Wiley & Sons),
According to the method described in the book of Green et al., The —SO ₂ —NH—CO— group is converted to a P ³ group by reacting the protecting group P ³ with a method according to the type of the protecting group. A compound represented by the formula (D-VII) protected with can be produced.
<Step 8>
Using the compound represented by the formula (D-VII), deprotection can be carried out in the same manner as in (Production Method A) <Step 5> to produce the compound represented by the formula (D-VIII). .
<Step 9>
Using the compound represented by the formula (D-VIII) and the compound represented by the formula (D-IX), the reaction is carried out in the same manner as in (Production Method A) <Step 1>, followed by (Production Method A) The protecting group P ³ can be deprotected in the same manner as in <Step 5> to produce a compound represented by the formula (I).

(Production method E) <Production method of formula (D-IX) [where L = formula (A1)] in (production method D)>

<Step 1 and Step 2>
Using a compound represented by formula (A1) -W and a compound represented by formula (EI), or a compound represented by formula (A1) -W ₁ and a compound represented by formula (E-II), (Production Method A) The compound represented by the formula (E-III) can be produced by reacting in the same manner as in <Step 7-1>.
<Step 3>
(X ₁ = in case of halogen: chlorine)
Using a compound represented by the formula (E-III), it is described in literature known methods, for example, “Bioorganic & Medicinal Chemistry, 17 (10), 3604-3617, 2009” and the like. In accordance with the above method, thionyl chloride, phosphorus oxychloride, pentachloride in a solvent that does not participate in the reaction, such as halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, and aromatic hydrocarbon solvents such as toluene and benzene. The compound represented by the formula (D-IX) -A1 can be produced by reacting in the presence of a chlorinating agent such as phosphorus and hydrogen chloride at a temperature at which the solvent is refluxed from 0 ° C.
(When X ₁ = halogen: bromine)
Using a compound represented by the formula (E-III), it is described in a method known in the literature, for example, “European Journal of Medicinal Chemistry, 40 (6), 563-581, 2005”. In a solvent that does not participate in the reaction, such as halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ether solvents such as diethyl ether, and aromatic hydrocarbon solvents such as toluene and benzene, The compound represented by the formula (D-IX) -A1 can be produced by reacting in the presence of a chlorinating agent such as phosphorus bromide and hydrogen bromide at a temperature at which the solvent is refluxed from 0 ° C. Further, according to the method described in the pamphlet of WO 2005/026120, in the presence of triphenylphosphine and carbon tetrabromide in a solvent not involved in the reaction such as a halogen-based solvent such as dichloromethane, chloroform, 1,2-dichloroethane, By reacting at a temperature at which the solvent is refluxed from 0 ° C., the compound represented by the formula (D-IX) -A1 can be produced.
(X ₁ = in the case of halogen: iodine)
Using a compound represented by the formula (E-III), it is described in literature known methods such as “Bioorganic & Medicinal Chemistry, 13 (15), 4740-4749, 2005”. In a solvent that does not participate in the reaction, such as halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ether solvents such as diethyl ether, aromatic hydrocarbon solvents such as toluene and benzene, The compound represented by the formula (D-IX) -A1 can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C. in the presence of an iodinating agent such as hydrofluoric acid.
(When X ₁ = Methanesulfonyl group or p-toluenesulfonyl group)
Using a compound represented by the formula (E-III) and a sulfonylating agent such as methanesulfonyl chloride, methanesulfonic anhydride, tosyl chloride or tosylic anhydride, 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 ”, etc., halogen solvents such as dichloromethane and chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane and the like Ether solvents, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as acetonitrile, and the like, triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, In the presence of a base such as saturated aqueous sodium bicarbonate solution. Alternatively, the compound represented by the formula (D-IX) -A1 can be produced by reacting at a temperature at which the solvent is refluxed from 0 ° C. in the absence.

(Production method F) <(Production method D) in formula (D-IX) [where L = 4- (3-hydroxy-3-methylbutoxy) -2,6-dimethylphenyl group, 4- (2- Ethoxyethoxy) -2,6-dimethylphenyl group or formula (A3)]

<Step 1 and Step 2>
Compounds represented by formula (A2) a compound represented by -W and formula (F-I), or with a compound represented by the formula (A2) a compound represented by -W ₁ and formula (F-II), (Production Method A) The compound represented by the formula (F-III) can be produced by reacting in the same manner as in <Step 7-1> [in the case of L = formula (A3), q = 0 And a compound represented by the formula (A2) -W or the formula (A2) -W ₁ is used, and L = 4- (3-hydroxy-3-methylbutoxy) -2,6-dimethylphenyl group or 4- ( In the case of the 2-ethoxyethoxy) -2,6-dimethylphenyl group, p, q, R ¹ , R ² , and ring A ′ are the corresponding formulas (A2) -W or (A2) -W ₁ Is used].
<Step 3>
A compound represented by the formula (D-IX) -A3 can be produced by reacting the compound represented by the formula (F-III) in the same manner as in (Production Method E) <Step 3>. it can.

(Production Method G) <Production Method of Formula (D-IX) [where L = Formula (A2)] in (Production Method D)>

<Step 1 and Step 2>
Using a compound represented by the formula (A2) -W and a compound represented by the formula (GI), or a compound represented by the formula (A2) -W ₁ and a compound represented by the formula (G-II), (Production Method A) The compound represented by the formula (G-III) can be produced by performing the reaction in the same manner as in <Step 7-2>.
<Step 3>
(When R ′ = alkyl group)
A method known in the literature using a compound represented by the formula (G-III), for example, “Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, pp. 234-245, 1992, Maruzen In the presence of a reducing agent such as diisobutylaluminum hydride (DIBAH), lithium aluminum hydride (LAH), lithium borohydride, lithium triethoxyaluminum hydride, and the like. Using a solvent that does not participate in the reaction, such as an ether solvent such as 1,2-dimethoxyethane, 1,4-dioxane, the reaction is performed at a temperature at which the solvent refluxes from 0 ° C., and is represented by the formula (G-IV) Compounds can be produced.
(When R ′ = OH group)
A method known in the literature using a compound represented by the formula (G-III), for example, “Experimental Chemistry Course 4th Edition 26 Organic Synthesis VIII Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, pp. 234-245, 1992, Maruzen In the presence of a reducing agent such as lithium aluminum hydride (LAH), borane-tetrahydrofuran (BH ₃ · THF), borane-dimethyl sulfide (BH ₃ · Me ₂ S), and the like. , Tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane and the like, a solvent that does not participate in the reaction, such as an ether solvent, is reacted at a temperature at which the solvent is refluxed from 0 ° C., and is represented by the formula (G-IV) The compounds represented can be produced.
<Step 4>
A compound represented by the formula (D-IX) -A2 can be produced by reacting the compound represented by the formula (G-IV) in the same manner as in (Production Method E) <Step 3>. it can.

(Production Method H) <In the (Production Method G), another production method of the formula (G-IV)>

<Step 1 and Step 2>
Compounds represented by formula (A2) a compound represented by -W and formula (H-I), or with a compound represented by the formula (A2) a compound represented by -W ₁ and formula (H-II), (Production Method A) The compound represented by the formula (H-III) can be produced by carrying out the reaction in the same manner as in <Step 7-2>.
<Step 3>
Using the compound represented by the formula (H-III), deprotection can be carried out in the same manner as in (Production Method A) <Step 5> to produce the compound represented by the formula (G-IV). .

In (Method I) <proviso that said formula ^{(I), R 6 = H} , C 1 ~ 6 alkyl group, a halogenated _C 1 _{~ 6} alkyl _group, with C 2 _{~ 6} alkenyl or _C 2 _{~ 6} alkynyl group Yes>

<Step 1>
Using the compound represented by the formula (II), the phenol group is protected in the same manner as in (Production Method D) <Step 1> to produce the compound represented by the formula (II-II). Can do.
<Step 2>
According to methods known in the literature, for example, methods described in “Journal of Organic Chemistry, 49 (16), 2922-2925, 1984”, etc., ethers such as diethyl ether and tetrahydrofuran A nucleophilic species is prepared by reacting a compound represented by the formula (I-II) with a base such as n-butyllithium or a Grignard reagent in a solvent that does not participate in the reaction such as a system solvent, and then a trifluorodiethyl ether complex (BF ₃ ) Et ₂ O) and the like and an ethylene oxide derivative represented by the formula (I-III) are added, and the reaction is carried out at a temperature at which the solvent is refluxed from −78 ° C. to represent the formula (I-IV). Compounds can be made.
<Step 3>
Using compounds of formula (I-IV), it is described in literature known methods such as “Experimental Chemistry Course 5th edition 13 Synthesis of organic compounds I Hydrocarbons / halides, pages 374-420, 2004, Maruzen”, etc. The solvent is refluxed from 0 ° C. using a solvent inert to the reaction such as diethyl ether and 1,4-dioxane or a mixed solvent thereof in the presence of a halogenating agent such as phosphorus tribromide. The compound represented by the formula (IV) can be produced by carrying out the reaction at a temperature at which
<Step 4>
Using a compound represented by the formula (IV), it was described in literature known methods such as “Justus Liebigs Annalen der Chemie, 586, 158-164, 1954”. According to the method, in the presence of a sulfur reagent such as sodium sulfite, potassium sulfite, sodium disulfite, thiourea, etc., in an alcoholic solvent such as methanol, ethanol, or a solvent not involved in the reaction such as water, or in a mixed solvent thereof The compound represented by the formula (I-VI) can be produced by conducting the reaction at a temperature at which the solvent is refluxed from 0 ° C.
<Step 5>
Using a compound represented by the formula (I-IV) and thioacetic acid, according to a method known in the literature, for example, a method described in “Organic Reaction, 42, 1992” or the like, triphenyl In the presence of organic phosphorus compounds such as phosphine and azo compounds such as azodicarboxylic acid esters and azodicarboxylic acid amides, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, aromatics such as toluene and benzene It was obtained by conducting the reaction at a temperature at which the solvent refluxed from 0 ° C. in a solvent that does not participate in the reaction such as a hydrocarbon solvent, or a polar solvent such as N, N-dimethylformamide, dimethyl sulfoxide, or the like. Compounds can be prepared by methods known in the literature, eg, “Canadian In accordance with a method described in Canadian of Chemistry, 62 (3), pages 610-614, 1984, etc., a compound of formula (I-VI) is obtained by reacting with chlorine in an acetic acid solvent. The compound represented by these can be manufactured.

<Step 6>
[In the case of X ₂ = OH or salt of ONa, OK, etc.]
A method known in the literature using a compound represented by the formula (I-VI), for example, a method described in “Organic Letters, 7 (22), pages 5067-5069, 2005”, etc. In the presence of a chlorinating agent such as phosphorus pentachloride, in a solvent that does not participate in the reaction such as methylene chloride, N, N-dimethylformamide, or a mixed solvent thereof at a temperature at which the solvent is refluxed from 0 ° C. By carrying out the reaction, the compound represented by the formula (I-VII) can be produced by further reacting the resulting sulfonyl chloride compound with ammonia (water).
[When X ₂ = Cl]
Using compounds represented by the formula (I-VI), described in literature known methods such as “Experimental Chemistry Course 4th Edition 22 Organic Synthesis IV Acids / Amino Acids / Peptides, 191-309, 1992, Maruzen” In accordance with the method described above, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as acetonitrile, etc. Ammonia (gas, water) in the presence or absence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, saturated aqueous sodium hydrogen carbonate, By reacting at a temperature at which the solvent refluxes from 0 ° C., it is represented by the formula (I-VII) Compounds can be produced.
<Step 7>
Using a compound represented by the formula (I-VII), a method known in the literature, for example, “Protective Groups in Organic Synthesis 4th Edition”, 4th edition, 2007, John Willie and Sands (John Wiley & Sons)
In accordance with the method described in the book of Green et al., The compound (I-) protected with the P ¹ group is reacted with the protecting group P ¹ according to the type of the protecting group. VIII) can be prepared.
<Step 8>
Using a compound represented by the formula (I-VIII), it is described in literature known methods such as “Journal of Organic Chemistry, 57 (10), 2967-2970, 1992”. <The reaction is carried out using 2-bromopropanedioic acid-1,3-diethyl ester as a brominating agent at a temperature at which the solvent is refluxed from 0 ° C.> or “Experimental Chemistry Course 5th edition 13 Synthesis of organic compounds” I. Hydrocarbons / halides, 374-420, 2004, Maruzen, etc. <N-chlorosuccinimide, N-bromosuccinimide and other halogenating agents and α, α'-azobisisobutyronitrile In the presence of (AIBN), a solvent inert to the reaction such as carbon tetrachloride and chloroform, or these Using mixed solvent, that solvent from 0 ℃ performs the reaction in accordance with> the reaction is carried out at a temperature of refluxing, it is possible to produce a compound represented by the formula (I-IX).
<Step 9>
Using a compound represented by the formula (I-IX) and a silyl enolate represented by the formula (IX), a method known in the literature, for example, “Tetrahedron, 65 (28), 5462- In the presence of indium bromide (InBr ₃ ), the solvent is refluxed from 0 ° C. in a solvent not involved in the reaction, such as dichloromethane, n-hexane, benzene, toluene, and the like. The compound represented by the formula (I-XI) can be produced by reacting at a temperature at which the reaction is performed.
<Step 10>
Using the compound represented by the formula (I-XI), deprotection can be carried out in the same manner as in (Production Method A) <Step 5> to produce the compound represented by the formula (I-XII). .
<Step 11>
A compound represented by the formula (I-XIII) can be produced by reacting the compound represented by the formula (I-XII) in the same manner as in (Production Method A) <Step 6>.
<Step 12>
Using the compound represented by the formula (I-XIII), protecting the —SO ₂ NHCO— group in the same manner as in (Production Method D) <Step 7>, and then the compound represented by the formula (I-XIV) Can be manufactured.
<Step 13>
Using the compound represented by the formula (I-XIV), deprotection can be carried out in the same manner as in (Production Method D) <Step 8> to produce the compound represented by the formula (I-XV). .
<Step 14>
Using the compound represented by the formula (I-XV), alkylation and deprotection are carried out in the same manner as in (Production Method D) <Step 9> to produce the compound represented by the formula (I) -chiral. be able to.

[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. Especially for use in prevention / delay / treatment of GPR40 agonist-mediated condition, especially diabetes (type 1 diabetes, type 2 diabetes, borderline diabetes (abnormal glucose tolerance (IGT) and / or fasting glycemic abnormality (IFG))), insulin It is used in at least one disease selected from the group consisting of resistance, hyperinsulinemia, obesity / obesity, or various diseases caused or related thereto.
For example, as an insulin sensitizer / diabetic drug, 1) PPARγ agonist (specifically, pioglitazone, rosiglitazone, troglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, etc.), 2) biguanide (specific) Specifically, metformin, buformin, phenformin, etc.), 3) sulfonylurea agents (specifically, tolbutamide, acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, glimepiride, glipentide, glyquidone, glicoramide, tolazamide, etc. 4) Fast-acting insulin secretagogues (specifically nateglinide, mitiglinide, repaglinide, etc.) 5) α-glucosidase inhibitors (specifically acarbose, voglibose, miglitol, camiglibose, adiposis) 6) Insulin or insulin derivatives (specifically, insulin zinc suspension, insulin lispro, insulin aspart, regular insulin, NPH insulin, insulin glargine, insulin detemir, etc.) Mixed insulin, etc.), 7) GLP-1 or GLP-1 receptor agonist (specifically exenatide, liraglutide, lixisenatide, taspoglutide, albiglutide, duraglutide, etc.), 8) DPP-IV inhibitor (specifically Sitagliptin, vildagliptin, alogliptin, saxagliptin, linagliptin, teneligliptin, anagliptin, SYR-472, NVP-DPP-728, etc.), 9) α2 antagonist (specifically, midaglyzo 10) SGLT2 inhibitors (specifically, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, canagliflozin, luceogliflozin, etc.), etc. . Also included are combinations of the above two or more components (specifically, pioglitazone / metformin, pioglitazone / glimepiride, mitiglinide / voglibose, alogliptin / pioglitazone, alogliptin / metformin, etc.).
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 Fibrates, gemfibrozil, KRP-101, etc.), 10) PPARδ agonists, 11) LXR agonists, 12) FXR agonists (specifically, INT-747, etc.), 13) MTTP inhibitors, 14) squalene eposidase Inhibitors, 15) bile acid absorption inhibitors (specifically, cholestyramine, colestipol, etc.) and the like.
Other examples include anti-obesity drugs. Specifically, 1) CB-1 receptor antagonist (specifically, rimonabant, SR-147778, BAY-6-25520, 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.
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, improvement of lifestyle habits by weight control, exercise therapy, diet therapy, radiation therapy, and the like.
Diseases involving GPR40 other than diabetes and obesity can be used in combination with drugs used in the respective fields.
Preferably, the concomitant agent is a PPARγ agonist (more preferably pioglitazone, rosiglitazone), a biguanide agent (more preferably metformin, buformin), a sulfonylurea agent (more preferably glibenclamide, gliclazide, glimepiride), a fast-acting insulin secretagogue Agents (more preferably nateglinide, mitiglinide, repaglinide), α-glucosidase inhibitors (more preferably acarbose, voglibose, miglitol), insulin or insulin derivatives, GLP-1 or GLP-1 receptor agonists (more preferably exenatide, liraglutide) ), DPP-IV inhibitors (more preferably sitagliptin, vildagliptin, alogliptin, saxagliptin, linagliptin, teneligliptin; more preferably sitag Liptin, vildagliptin, alogliptin, linagliptin) and the like.
By using in combination with existing drugs for the above-mentioned 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 said drug is not limited to the said disease, and the drug used together is not limited to the compound illustrated above.
When the compound of the present invention is used in combination with a drug used in combination, it may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or administered at different times.

[Formulation of the preventive / therapeutic agent of the present invention]
The medicament of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the present invention only needs to contain at least one compound represented by the formula (I) or the formula (II) 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, paraoxybenzoate), 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 al) Coal, xanthan gum), dispersants, antioxidants (eg; ascorbic acid, butylhydroxyanisole (BHA), propyl gallate, dl-α-tocopherol), buffers, preservatives (eg; parabens, 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 Various dosage forms can be combined with the compounds of the invention as appropriate. That.

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

[Pharmacological experiment example]
Hereinafter, the present invention will be described in detail with reference to experimental examples, but the present invention is not limited thereto.
The following pharmacological examples 1-8 provide methods for testing the effectiveness of the compounds of the present invention.

Pharmacological experiment example 1: Agonist action on human-derived GPR40 The agonist action of the test compound was determined using a CHO cell line stably expressing human-derived GPR40. This cell line was seeded in a clear bottom 96-well plate at 2 × 10 ⁴ cells / 100 μL / well, and ham F− containing 10% fetal bovine serum, 100 U / mL penicillin, 0.1 mg / mL streptomycin, 400 μg / mL geneticin. Twelve media were used and cultured overnight in a CO ₂ incubator. Calcium-4 assay kit (Molecular Device) was used as a fluorescent calcium indicator reagent. 1 mL of 77 mg / mL probenecid (Invitrogen) was added to 100 mL of the calcium indicator reagent solution, and a solution (loading solution) mixed with an equal amount of 20 mM HEPES-containing Hanks balanced salt solution (HBSS) was prepared. 200 μL of the loading solution was added to the cells from which the culture solution was removed, and the cells were cultured in a CO ₂ incubator for 1 hour. The test compound was diluted with 20 mM HEPES-containing HBSS, and 50 μL each was added to the cells, and the change in Ca ²⁺ concentration was measured with an intracellular ion analyzer. The EC ₅₀ value of the test compound was calculated from the dose response curve of changes in fluorescence intensity. The EC ₅₀ values are the compounds of the present invention of less than 0.3 [mu] M as A, also _{The EC 50} values are the present compounds of less than · 3 [mu] M 0.3 [mu] M as B, shown in Table 1.

Pharmacological Experiment Example 2: Oral Glucose Tolerance Test Male C57BL / 6J mice or SD rats fasted overnight are used to examine the blood glucose increase inhibitory effect of the test compound after glucose loading. The test compound is suspended in a solvent (for example, 0.5% carboxymethyl cellulose) and administered orally before glucose loading. The control group receives only the solvent. Blood collection is performed before compound administration (pre-collection), immediately after glucose administration, immediately after glucose loading, after glucose loading, 15, 30, 60, and 120 minutes, and the blood glucose level is measured with the collected blood. A preferred compound of the present invention has an action to suppress an increase in blood glucose by oral administration at a dose of 0.3 to 10 mg / kg.

Pharmacological Experiment Example 3: Solubility Test (1) DMSO Precipitation Solubility (Kinetic Solubility)
A 10 mM DMSO solution of the compound of the present invention is added to 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) Crystal solubility (Thermodynamic Solubility)
The compound of the present invention is added to water at 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, a 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.

Pharmacological experiment example 4: Metabolic stability test Liver microsome solution (human, mouse or rat; XenoTech), NADPH generating solution (β-NADP, Glucose-6- Phosphate, G-6-PDH (Y), water containing MgCl ₂ ). The solution is incubated at 37 ° C. for 20 minutes and then quenched with acetonitrile. Similarly, sampling is performed at a predetermined time during incubation, and the reaction is stopped. These reaction solutions are centrifuged through a filter plate (MultiScreenHTS-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, the compound concentration in the control is set to 100%, and the residual ratio of the compound in each reaction solution is calculated. These residual rates are plotted against time, and metabolic clearance CL (μL / mg / min) is calculated from the slope of the obtained regression line.

Pharmacological Experiment Example 5 hERG Inhibition Test by Patch Clamp Method The effect on hERG (human ether-a-go-related gene) channels 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 a decrease rate (inhibition 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 (ventricular tachycardia, sudden death, etc.) is shown.

Pharmacological experiment example 6: Pharmacokinetics test (cassette PK)
The compound of the present invention was orally administered to 7- or 8-week-old male C57BL / 6J Jcl mice or SD rats at a dose of 1 mg / kg (administration solvent: DMSO: Tween 80: ultrapure water = 1: 1: 8, 10 mL / kg). Dosage once. After administration, blood is collected from the abdominal vena cava after 0.25, 0.5, 1 and 2 hours in the case of mice, and from the jugular vein after 0.5, 1, 2, and 4 hours in the case of rats. 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. Similarly, a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added was measured, and a calibration curve was prepared. The plasma concentration (μg / mL) is calculated, and the maximum plasma concentration is defined as Cmax (μg / mL).

Pharmacological experiment example 7: 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 abnormalities are observed, indicating the safety of the compound of the present invention.
Pharmacological Experiment Example 8: Brain penetration test
The compound of the present invention is orally administered at a dose of 1 mg / kg to male SD rats of 7 to 9 weeks old fasted overnight the day before (administration solvent is 0.5% carboxymethylcellulose aqueous solution, 10 mL / kg). Blood is collected and cerebral cortex is collected from the jugular vein 1 hour after administration. Using blood plasma obtained by centrifugation (3000 rpm, 15 minutes, 4 ° C.), the test compound in plasma is measured by high performance liquid chromatogram / mass spectrometry. Similarly, a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added was measured, and a calibration curve was prepared. The plasma concentration (μg / mL) is calculated.
The cerebral cortex is homogenized by adding water, then methanol is added, and the supernatant obtained by stirring and centrifuging (14000 rpm, 10 minutes, 4 ° C.) is used for high-performance liquid chromatogram / mass spectrometry. Measure test compounds in cerebral cortex. Similarly, a standard solution to which a known concentration of a test compound (0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 μg / mL) was added was measured, and a calibration curve was prepared. The cerebral cortex concentration (μg / mL) is calculated.
From the measured plasma concentration (μg / mL) and cerebral cortex concentration (μg / mL), the rate of transfer of the test compound into the brain (hereinafter B / P ratio) is calculated. B / P ratio is a good and usually used parameter for evaluating the degree of transfer into the brain. Therefore, for example, by comparing the B / P ratio of the test compound with other compounds, it is possible to compare the degree of migration into the brain.

From the above results, the compound of the present invention was shown to have an excellent GPR40 agonistic action, and showed a blood glucose elevation inhibitory action in a single oral glucose tolerance test using normal mice or rats. In addition, no abnormality is observed in the safety test, indicating the low toxicity of the present invention.
Furthermore, it was confirmed that the compound of the present invention is good in at least one of the above-described tests, such as solubility, metabolic stability, pharmacokinetics, avoidance of hERG channel inhibitory action, and ability to enter the brain. The
Therefore, the compound of the present invention is expected to be used as a GPR40 agonist for an agent for promoting insulin secretion, a preventive and / or therapeutic agent for diabetes (especially type 2 diabetes or borderline diabetes) and obesity / obesity.

[Formulation example]
The following are examples of the pharmaceutical composition of the present invention.
Formulation Example 1 Compound of Tablet Example 2 100 g
137g of lactose
Crystalline cellulose 30g
Hydroxypropylcellulose 15g
Carboxymethyl starch sodium 15g
Magnesium stearate 3g
The ingredients are weighed and mixed uniformly. This mixture is compressed into tablets having a weight of 150 mg.

Formulation Example 2 Film-coated hydroxypropylmethylcellulose 9g
Macrogol 6000 1g
Titanium oxide 2g
After weighing the above components, hydroxypropylmethylcellulose and macrogol 6000 are dissolved in water and titanium oxide is dispersed. This liquid is film-coated on 300 g of the tablet of Preparation Example 1 to obtain film-coated tablets.

Formulation Example 3 Capsule Example 6 Compound 50g
Lactose 435g
Magnesium stearate 15g
The 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 form a capsule.

Formulation Example 4 Capsule Example 8 Compound 100g
Lactose 63g
Corn starch 25g
Hydroxypropylcellulose 10g
Talc 2g
After weighing the above components, the compound of Example 8, 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 Powder Example 11 Compound 200g
790 g of lactose
Magnesium stearate 10g
After weighing each of the above components, they are mixed uniformly to make a 20% powder.

Formulation Example 6 Granules, Fine Granules Compound of Example 13 100 g
Lactose 200g
Crystalline cellulose 100g
Partially pregelatinized starch 50g
Hydroxypropylcellulose 50g
After weighing the above components, the compound of Example 13, 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.

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-ECX400 (JEOL JNM-ECX400) FT-NMR (manufactured by JEOL Ltd.), Geol JNM-ECX300 (JEOL JNM-ECX300) FT-NMR (JEOL) (Made by Co., Ltd.) was used. For LC / MS, a Waters FractionLynx MS system (manufactured by Waters) was used. The mobile phase is methanol: 0.05% acetic acid aqueous solution = 1: 9 (0 min) to 10: 0 (5 min) to 10: 0 (7 min), or methanol: 0.05% aqueous trifluoroacetic acid = 1. : Gradient conditions of 9 (0 minutes) to 10: 0 (5 minutes) to 10: 0 (7 minutes) were used. For UPLC / MS, a Waters UPLC-ZQ MS system (manufactured by Waters) was used, the column was manufactured by Shiseido, MGIII-H (2.1 mm × 5 cm, 3 μm), and the mobile phase was methanol: 0.05% trifluoroacetic acid. Gradient conditions of aqueous solution = 5: 95 (0 minute) to 100: 0 (1 minute) to 100: 0 (2 minutes) were used. For the preparative system, gradient conditions appropriately changed depending on the compound were used.

(Reference Example 1)
Synthesis of N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) methanesulfonamide Sodium hydride (4.6 g) was added to DMF (35 ml), and methanesulfonamide (5.0 g) in DMF (15 ml) The solution was added dropwise. (2- (Chlorotrimethoxy) ethyl) trimethylsilane (18.6 ml) was added and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, 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) to obtain the title compound (7.4 g) as a colorless oil.
(Reference Example 2)
Synthesis of 4- (4- (5,5-dimethyl-1,3,2-dioxaborin-2-yl) -3,5-dimethylphenoxy) -2-methylbutan-2-ol <Step 1> 4- (4 -Bromo-3,5-dimethylphenoxy) -2-methylbutan-2-ol Synthesis 3-hydroxy-3-methylbutyl 4-methyl synthesized according to the method described in [WO2009 / 066763 Pamphlet Example 308] A mixed solution of benzene sulfonate (4.24 g), 4-bromo-3,5-dimethylphenol (3.0 g), potassium carbonate (3.09 g), N, N-dimethylformamide (15 mL) at 80 ° C. Stir for 3 hours. Ethyl acetate (200 mL) and water (100 mL) were added to the reaction solution, followed by liquid separation and extraction. The organic layer was washed successively with water (50 mL) and saturated brine (50 mL), 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 70:30). The solvent was evaporated under reduced pressure to give the title compound ( 3.9 g) was obtained.
<Step 2> Synthesis of 4- (4- (5,5-dimethyl-1,3,2-dioxaborin-2-yl) -3,5-dimethylphenoxy) -2-methylbutan-2-ol (Reference Example 2) ) To a solution of the compound (3.90 g) obtained in <Step 1> and bis (neopentylglycolate) diboron (3.7 g) in 1,4-dioxane (39 mL), potassium acetate (4.0 g), [ 1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (0.55 g) was added, and after deaeration, the mixture was heated to reflux for 16 hours. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL), washed with saturated brine (100 mL), 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 70:30) to obtain the title compound (2.7 g). .

Example 1
5- (4-((4 '-(3-hydroxy-3-methylbutoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2 Of 2-thiazinan-3-one 1,1-dioxide <Step 1> (E) -2- (4-((3-Bromobenzyl) oxy) phenyl) -N, N-bis ((2- (trimethylsilyl) Synthesis of Ethoxy) methyl) ethenesulfonamide A THF solution of the compound (13.4 g) of Reference Example 1 was replaced with nitrogen, cooled to −43 ° C., and 1M-lithium hexamethyldisilazane (83 ml) was added dropwise. And stirred for 50 minutes. Diethyl chlorophosphonate (6.0 ml) was added dropwise, and the mixture was stirred as it was for 90 minutes. Then, a solution of 4-((3-bromobenzyl) oxy) benzaldehyde (11 g) in THF (60 ml) was slowly added dropwise and stirred as it was for 30 minutes. The mixture was ice-cooled, further stirred for 1 hour, returned to room temperature, and further stirred for 1 hour. 0.5M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and half 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 = 95: 5 to 90:10), and the solvent was distilled off under reduced pressure to obtain The obtained solid was washed with hexane to obtain the title compound (16 g) as a white solid.
<Step 2> Dimethyl 2- (1- (4-((3-bromobenzyl) oxy) phenyl) -2- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) ethyl) malonate Synthesis To a solution of dimethyl malonate (7.6 ml) in THF (60 ml), 28% sodium methoxide-methanol solution (13 g) was added at room temperature and stirred for 10 minutes, and then (Example 1) <Step 1> A solution of the compound (16 g) in THF (100 ml) was added, and the mixture was heated to reflux for 18 hours. 0.5M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, washed with half-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 = 95: 5 to 75:25) to give the title compound (22 g) as a colorless oil. It was.
<Step 3> Synthesis of methyl 3- (4-((3-bromobenzyl) oxy) phenyl) -4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) butanoate (Example 1) ) Sodium chloride (2.7 g) and water (2.1 ml) were added to a DMF (220 ml) solution of the compound of step 2 (22 g), and the mixture was heated to reflux for 9 hours. Water and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, washed with a water-saturated brine mixture, 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 = 95: 5 to 85:15) to obtain the title compound (12 g) as a colorless oil. It was.
<Step 4> Synthesis of methyl 3- (4-((3-bromobenzyl) oxy) phenyl) -4-sulfamoylbutanoate (Example 1) Acetic acid of compound (5.0 g) in <Step 3> Water (25 ml) was added to the (50 ml) solution, and the mixture was heated and stirred at 83 degrees for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, washed with half-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 45:55) to give the title compound (1.8 g) as a colorless oil. Got as.
<Step 5> Synthesis of 5- (4-((3-bromobenzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 1) <Step 4> compound (1 0.5 g) in methanol (40 ml) was added 28% sodium methoxide in methanol (0.85 g) at room temperature and stirred for 2 hours. 0.5M hydrochloric acid was added to the reaction solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.1 g) as a white solid.
<Step 6> 5- (4-((4 ′-(3-hydroxy-3-methylbutoxy) -2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) Synthesis of -1,2-thiazinan-3-one 1,1-dioxide (Example 1) Compound obtained in <Step 5> (50 mg), compound obtained in (Reference Example 2) (43 mg), acetic acid Palladium (2.7 mg), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (XPhos; 11.6 mg), potassium carbonate (67 mg), 1,4-dioxane (1.0 mL), A mixed solvent of water (0.5 mL) was heated to reflux for 2 hours. 0.5M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with half saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by LC / MS to obtain the title compound (28 mg) as a white solid.

The following compounds of (Example 2) to (Example 25) were obtained in (Example 1) <Step 5> in the same manner as (Example 1) <Step 6> or a method analogous thereto. Synthesized using the compounds and the corresponding substituted boronic esters or boronic acids respectively. The corresponding boronic acid ester or boronic acid used was commercially available, or was synthesized by a method similar to (Reference Example 2) or a method analogous thereto. Specifically, in (Example 3), 2-bromo-5- (2-ethoxyethoxy) -1,3-synthesized according to the method described in [WO 2005/063729 Pamphlet Reference Example 31]. Boronate ester (2- (4- (2-ethoxyethoxy) -2,6-dimethylphenyl) -5,5-dimethyl-1 was prepared using dimethylbenzene according to the method of Reference Example 2 <Step 2>. , 3,2-dioxaborinane).

(Example 2)
5- (4-((4'-Fluoro- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 3)
5- (4-((4 '-(2-ethoxyethoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinane-3 -One 1,1-dioxide (Example 4)
5- (4-((2'-Chloro- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 5)
5- (4-((2'-methyl-4 '-(trifluoromethyl)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 6)
5- (4-((4′-Chloro-2′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 7)
5- (4-((2′-chloro-4′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 8)
5- (4-((4′-methoxy-2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1 Dioxide (Example 9)
5- (4-((2 ′, 6′-Dichloro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Examples) 10)
5- (4-((3- (2,3-dihydrobenzofuran-7-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 11)
5- (4-((3- (1-Methyl-1H-indol-4-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 12)
5- (4-((2'-Chloro-4'-methoxy- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 13)
5- (4-((2 '-(trifluoromethyl)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Example 14)
5- (4-((2 ′, 3 ′, 4 ′, 5′-tetrahydro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 15)
5- (4-((3'-Fluoro- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 16)
5- (4-((4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 17)
5- (4-((2 '-(trifluoromethoxy)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Example 18)
5- (4-((2′-fluoro-5 ′-(trifluoromethyl)-[1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide (Example 19)
5- (4-((3′-chloro-4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 20)
5- (4-((3- (Naphthalen-1-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 21)
5- (4-((2'-ethoxy-5'-fluoro- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 22)
5- (4-((4′-methoxy-2′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 23)
5- (4-((2'-Ethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 24)
5- (4-((3 ′, 5′-difluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Examples) 25)
5- (4-((3- (2-Ethoxypyridin-3-yl) benzyl) oxy) phenyl) -1,2-thiazin-3-one 1,1-dioxide

(Example 26)
Synthesis of 5- (4-((3-phenoxybenzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide <Step 1> Methyl 4- (N, N-bis ((2- Synthesis of (Trimethylsilyl) ethoxy) methyl) sulfamoyl) -3- (4-((3- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl) benzyl) oxy) phenyl) butanoate (Examples) 1) To a solution of the compound (0.3 g) obtained in <Step 3> and bis (neopentylglycolate) diboron (0.12 g) in 1,4-dioxane (4.3 mL), potassium acetate (0.13 g) ), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane adduct (17 mg) was added, and after degassing, the mixture was heated to reflux for 2 hours. The reaction mixture was filtered through celite, water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 9: 1 to 0: 100) to obtain the title compound (0.29 g). .
<Step 2> Trifluoro (3-((4- (1- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) -4-methoxy-4-oxobutan-2-yl) phenoxy) Synthesis of methyl) phenyl) borate potassium salt (Example 26) To a solution of the compound (0.1 g) obtained in <Step 1> in methanol (1.0 mL) and water (0.2 ml), potassium dihydrofluoride ( 21 mg) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction solution under reduced pressure to obtain the title compound (0.10 g).
<Step 3> Synthesis of methyl 4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) -3- (4-((3-phenoxybenzyl) oxy) phenyl) butanoate (Example 26) ) To a solution of the compound obtained in <Step 2> (0.30 g) in methylene chloride (18 mL), phenol (46 mg), copper (II) acetate (82 mg), triethylamine (0.29 mL), molecular sieves 4A (0 .30 g) was added and stirred at room temperature for 2 days under an oxygen atmosphere. Further, copper (II) acetate (82 mg) and triethylamine (0.29 mL) were added, and the mixture was stirred at room temperature for 1 day. 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 purified by silica gel column chromatography to obtain the title compound (0.12 g).
<Step 4> Synthesis of methyl 3- (4-((3-phenoxybenzyl) oxy) phenyl) -4-sulfamoylbutanoate (Example 1) According to the method of <Step 4> (Example 26) The title compound (42 mg) was obtained as a colorless oil using the compound (0.15 g) obtained in <Step 3>.
<Step 5> Synthesis of 5- (4-((3-phenoxybenzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide (Example 1) According to the method of <Step 5> Example 26 Using the compound (40 mg) obtained in <Step 4>, the title compound (20 mg) was obtained as a white solid.

(Example 27)
Synthesis of 3- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile <Step 1> Methyl 3- (4- Synthesis of ((3- (3-cyanophenoxy) benzyl) oxy) phenyl) -4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) butanoate Example 26 <Step 3> According to the method of Example 26, the title compound (0.14 g) was obtained as a colorless oil using the compound (0.30 g) obtained in <Step 2>.
<Step 2> Synthesis of methyl 3- (4-((3- (3-cyanophenoxy) benzyl) oxy) phenyl) -4-sulfamoylbutanoate (Example 1) According to the method of <Step 4> Example 27 Using the compound (0.15 g) obtained in <Step 1>, the title compound (45 mg) was obtained as a colorless oil.
<Step 3> Synthesis of 3- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile (Example 1) < According to the method of Step 5>, the title compound (32 mg) was obtained as a white solid using the compound (40 mg) obtained in (Example 27) <Step 2>.

(Example 28)
Synthesis of 4- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile <Step 1> Methyl 3- (4- Synthesis of ((3- (4-Cyanophenoxy) benzyl) oxy) phenyl) -4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) butanoate Example 26 <Step 3> According to the method of Example 26, the title compound (0.14 g) was obtained as a colorless oil using the compound (0.30 g) obtained in <Step 2>.
<Step 2> Synthesis of methyl 3- (4-((3- (4-cyanophenoxy) benzyl) oxy) phenyl) -4-sulfamoylbutanoate (Example 1) According to the method of <Step 4> Example 28 Using the compound (0.15 g) obtained in <Step 1>, the title compound (38 mg) was obtained as a colorless oil.
<Step 3> Synthesis of 4- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile (Example 1) < According to the method of Step 5>, the title compound (31 mg) was obtained as a white solid using the compound (40 mg) obtained in (Example 28) <Step 2>.

(Example 29)
Synthesis of 5- (4-((3-((2-methoxypyridin-4-yl) oxy) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide <Step 1> methyl Synthesis of 4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) -3- (4-((3-hydroxybenzyl) oxy) phenyl) butanoate In acetone (5 ml) under ice-cooling Sodium bicarbonate (1.1 g) was added and OXONE (1.0 g) was added slowly. Further, acetone (40 ml) was added and stirred for 30 minutes, and then a solution of the compound (0.50 g) obtained in Example 26 <Step 1> in acetone (5 ml) was added and stirred for 1.5 hours. . A 10% aqueous sodium hydrogen sulfate solution was added, water was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.39 g).
<Step 2> Methyl 4- (N, N-bis ((2- (trimethylsilyl) ethoxy) methyl) sulfamoyl) -3- (4-((3-((2-methoxypyridin-4-yl) oxy) benzyl )) Synthesis of oxy) phenyl) butanoate (Example 26) According to the method of <Step 3>, the compound (28 mg) obtained in (Example 29) <Step 1> and (6-methoxypyridin-4-yl) ) Boronic acid (8.0 mg) was used to give the title compound (12 mg) as a colorless oil.
<Step 3> Synthesis of methyl 3- (4-((3-((2-methoxypyridin-4-yl) oxy) benzyl) oxy) phenyl) -4-sulfamoylbutanoate (Example 1) < According to the method of Step 4>, the title compound (5 mg) was obtained as a colorless oil using the compound (11 mg) obtained in (Example 29) <Step 2>.
<Step 4> Synthesis of 5- (4-((3-((2-methoxypyridin-4-yl) oxy) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide ( Example 1) According to the method of <Step 5>, the title compound (1.6 mg) was obtained as a white solid using the compound (4.0 mg) obtained in (Example 29) <Step 3>. .

The structure of the final compound synthesized in (Example 1) to (Example 29) is shown in the following figures (Structural Formulas 1 and 2). The LC / MS data and NMR data (400 MHz NMR) of these final compounds are also shown in the following tables (Tables 2 and 5). In addition, the structures of the intermediate compounds and reference example compounds synthesized in each Example are shown in the following figures (Structural Formulas 3 and 4). LC / MS data of the intermediate compounds and reference example compounds, NMR data of the intermediate compounds ( 400 MHz NMR) is also shown in the following tables (Tables 3, 4 and 6). As for the intermediate compound, for example, the compound obtained in (Example 1) <Step 1> is represented as (Example 1-1).

Claims

Formula (I)

(In the formula, L represents 4- (3-hydroxy-3-methylbutoxy) -2,6-dimethylphenyl group and 4- (2-ethoxyethoxy) -2,6-dimethylphenyl group, and the following formula (A1 ), Formula (A2) and formula (A3)

(Wherein p represents an integer of 0 to 4; q represents an integer of 0 to 2 (provided that p + q is an integer of 0 to 5);
R 1 is, each independently, a halogen atom, -OH, a cyano group, a substituent RI with 1-5 optionally substituted C 1 to 6 alkyl groups, substituted one to five substituents RI which may C 2 - 6 alkenyl group, which may be 1-5 substituted with a substituent RI C 2 - 6 alkynyl group, a substituent RI with 1-5 optionally substituted C 1 to 6 alkoxy group , C 2 ~ 7 alkanoyl group, -SH, group: -S (O) i R a (i is an integer of 0 to 2), group: -NR b R c and groups: optionally from -CONR d R e Represents a group selected by
R 2 are each independently 1-5-substituted C 1 - 6 alkoxyl group with a substituent M, substituted one to a group M 5-substituted C 2 - 6 alkenyloxy group, 1 substituents M to five-substituted C 2 - 6 alkynyloxy group, group: -CONR d R e1, aralkyloxy group, a heterocyclic oxy group (said heterocyclic group is optionally at C 1 ~ 6 alkyl group or oxo group 1-3 may be substituted), Hajime Tamaki (said heterocyclic group is optionally may be one to three substituents at C 1 ~ 6 alkyl group or oxo group), and heterocyclic carbonyl group (the heterocyclic carbonyl group may be optionally 1 to have three substituted with C 1 ~ 6 alkyl group or oxo group) represent a group chosen arbitrarily from;
Substituents M are each independently a halogen atom, -OH, C 1 ~ 6 alkoxy group, an aryl group (said aryl group is optionally may be 1-3 substituted with a halogen atom), a heterocyclic group (the heterocyclic group, -OH, optionally may be one to three substituents at C 1 ~ 6 alkyl group or oxo group), group: -S (O) i R a (i is 0-2 A group: —NR b R c , a group: —SO 2 NR d R e and a group: —CONR d R e ;
Ring A represents a C 5 ~ 7 cycloalkyl group, condensed ring aryl group, condensed ring heteroaryl group or partially hydrogenated condensed heteroaryl group;
Ring A ′ represents a benzene ring, a pyridine ring or a pyrimidine ring)
Represents a group arbitrarily selected from:
r and s each independently represents an integer of 0 to 4;
R 3 are each independently a halogen atom, -OH, a cyano group, a substituent RI with 1-5 optionally substituted C 1 to 6 alkyl groups, substituted one to five substituents RI which may C 2 - 6 alkenyl group, which may be 1-5 substituted with a substituent RI C 2 - 6 alkynyl group, a substituent RI with 1-5 optionally substituted C 1 to 6 alkoxy group , C 2 ~ 7 alkanoyl group, -SH, group: -S (O) i R a (i is an integer of 0 to 2), group: -NR b R c and groups: optionally from -CONR d R e Represents a group selected by
R 4 are each independently a halogen atom, a substituent RI with 1-5 optionally substituted C 1 to 6 alkyl groups, optionally C 2 - it is 1-5 substituted with a substituent RI 6 alkenyl group, the substituent RI in 1-5 optionally substituted C 2 even though 2-6 alkynyl group, optionally from 1 to 5 substituents which may C 1 to 6 alkoxy group and a cyano group with substituents RI It represents a group selected; R 5a, R 5b each independently represents a hydrogen atom, a halogen atom, C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxy group And a group arbitrarily selected from a cyano group;
R 6 is a hydrogen atom, a halogen atom, C 1 ~ 6 alkyl group, a halogenated C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxyl group, a halogenated C It represents 1-6 alkoxyl group, C 2 ~ 7 alkanoyl group and protected chosen arbitrarily from a carboxyl group which have groups;
R 7a, R 7b are each independently a hydrogen atom, a halogen atom, C 1 ~ 6 alkyl group, a halogenated C 1 ~ 6 alkyl group, C 2 ~ 6 alkenyl group, C 2 ~ 6 alkynyl group, C 1 ~ 6 alkoxyl group, a halogenated C 1 ~ 6 alkoxy group and a group selected arbitrarily from a cyano group;
Or more substituents RI are the same or different from each other, a halogen atom, -OH, cyano group, C 1 ~ 6 alkoxy group (said C 1 ~ 6 alkoxy group, a halogen atom, -OH, C 1 ~ 6 alkoxy group , an aryl group (said aryl group may be optionally 1-3 substituted with a halogen atom), a Hajime Tamaki (said heterocyclic group is optionally 1 in C 1 to 6 alkyl group or oxo group 3 may be substituted), group: —S (O) i R a (i represents an integer of 0 to 2), group: —SO 2 NR d R e , group: —CONR d R e or group: -NR b R c optionally may be 1-5 substituted with) a group: -NR b R c, and a heterocyclic oxy group (the heterocyclic oxy group, C 1 ~ 6 alkyl group or oxo Optionally substituted with 1 to 3 groups Represents a group arbitrarily selected from:
R a represents a C 1 ~ 6 alkyl group or halogenated C 1 ~ 6 alkyl group;
R b, R c each independently represents a hydrogen atom, C 1 ~ 6 alkyl group, a C 2 ~ 7 alkanoyl groups and C 1 ~ 6 alkylsulfonyl optionally chosen group from group, R b, R c is 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, 1 or 2 carbon atoms in the ring are an oxygen atom, a sulfur atom and a nitrogen atom (the nitrogen atom). It represents may also be replaced by chosen atom or a carbonyl group arbitrarily from the may be) optionally substituted with C 1 ~ 6 alkyl group;
R d, R e are each independently a hydrogen atom or a C 1 ~ 6 alkyl group (said C 1 ~ 6 alkyl group is optionally 1-5 substituted by a halogen atom, -OH or C 1 ~ 6 alkoxy group It may be)
R e1 is C 1 ~ 6 alkyl group (said C 1 ~ 6 alkyl group, -OH, C 1 - 6 alkoxyl group, an aryl group (said aryl group is optionally one to have three substituted by a halogen atom may be), a Hajime Tamaki (said heterocyclic group is optionally may be one to three substituents at C 1 ~ 6 alkyl group or oxo group), group: -S (O) i R a ( i represents an integer of 0 to 2), a group: —SO 2 NR d R e , a group: —CONR d R e or a group: —NR b R c optionally substituted with 1 to 5) (However, 5- (4-((2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide Excluding compounds that are))
Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt.
Formula (I) -1a

Wherein p, r, s and ring A are as defined in the above formula (I);
R 1-1 are each independently a halogen atom, a cyano group, it may be one to five substituents with one to five substituents on these C 1 ~ 4 alkyl group or a halogen atom, a halogen atom It is a C 1 ~ 4 alkoxyl group;
R 3-1 are each independently a halogen atom, a halogen atom with one to five substituents on these C 1 - 4 alkyl group or a halogen atom with one to five substituents which may C 1 to, 4 alkoxyl groups;
R 4-1 are each independently a halogen atom, a C 1 ~ be 1-5 substituted with a halogen atom 4 alkyl group, 1-5 optionally substituted C 1 ~ 4 with a halogen atom An alkoxyl group or a cyano group)
Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. .
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1, r and s are 0, and ring A is cyclohexene, naphthalene, indole or dihydrobenzofuran, or A pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt.
Formula (I) -2a

(Wherein p, r, s and ring A ′ are defined as in the above formula (I);
R 1-2 are each independently a halogen atom, a cyano group, it may be one to five substituents with one to five substituents on these C 1 ~ 4 alkyl group or a halogen atom, a halogen atom It is a C 1 ~ 4 alkoxyl group;
R 3-2 are each independently a halogen atom, a halogen atom with one to five substituents on these C 1 - 4 alkyl group or a halogen atom with one to five substituents which may C 1 to, 4 alkoxyl groups;
R 4-2 are each independently a halogen atom, a C 1 ~ be 1-5 substituted with a halogen atom 4 alkyl group, 1-5 optionally substituted C 1 ~ 4 with a halogen atom An alkoxyl group or a cyano group)
Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. .
The compound according to claim 4, wherein p is 0 or 1, r and s are 0, and ring A 'is a benzene ring or a pyridine ring, or a pharmaceutically acceptable salt thereof, or of the compound A pharmaceutically acceptable solvate or a pharmaceutically acceptable solvate of the salt.
Formula (I) -3a

(Wherein p, r, s and ring A ′ are defined as in the above formula (I);
R 1-3 are each independently a halogen atom, a cyano group, it may be one to five substituents with one to five substituents on these C 1 ~ 4 alkyl group or a halogen atom, a halogen atom It is a C 1 ~ 4 alkoxyl group;
R 3-3 are each independently a halogen atom, a halogen atom with one to five substituents on these C 1 - 4 alkyl group or a halogen atom with one to five substituents which may C 1 to, 4 alkoxyl groups;
R 4-3 are each independently a halogen atom, a C 1 ~ be 1-5 substituted with a halogen atom 4 alkyl group, 1-5 optionally substituted C 1 ~ 4 with a halogen atom An alkoxyl group or a cyano group (provided that 5- (4-((2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinane-3 -One 1,1-dioxide and 5- (4-((6- (tert-butyl) -2'-fluoro-5'-methoxy- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one, except for compounds that are 1,1-dioxide))
Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. .
7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein p is an integer of 1 to 3, r and s are 0, and ring A ′ is a benzene ring or a pyridine ring, or A pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt.
The following compound groups:
5- (4-((4 '-(3-hydroxy-3-methylbutoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2 -Thiazinan-3-one 1,1-dioxide;
5- (4-((4′-fluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((4 '-(2-ethoxyethoxy) -2', 6'-dimethyl- [1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinane-3 -One 1,1-dioxide;
5- (4-((2′-chloro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((2'-methyl-4 '-(trifluoromethyl)-[1,1'-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide;
5- (4-((4′-chloro-2′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((2′-chloro-4′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((4′-methoxy-2 ′, 6′-dimethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1 -Dioxide;
5- (4-((2 ′, 6′-dichloro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((3- (2,3-dihydrobenzofuran-7-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((3- (1-methyl-1H-indol-4-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((2′-chloro-4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((2 ′-(trifluoromethyl)-[1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((2 ′, 3 ′, 4 ′, 5′-tetrahydro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide;
5- (4-((3′-fluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((2 ′-(trifluoromethoxy)-[1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((2′-fluoro-5 ′-(trifluoromethyl)-[1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazin-3-one 1, 1-dioxide;
5- (4-((3′-chloro-4′-methoxy- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((3- (naphthalen-1-yl) benzyl) oxy) phenyl) -1,2-thiazin-3-one 1,1-dioxide;
5- (4-((2′-ethoxy-5′-fluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((4′-methoxy-2′-methyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((2′-ethyl- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((3 ′, 5′-difluoro- [1,1′-biphenyl] -3-yl) methoxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((3- (2-ethoxypyridin-3-yl) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
5- (4-((3-phenoxybenzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide;
3- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile;
4- (3-((4- (1,1-dioxide-3-oxo-1,2-thiazinan-5-yl) phenoxy) methyl) phenoxy) benzonitrile, and 5- (4-((3- ( A compound selected from (2-methoxypyridin-4-yl) oxy) benzyl) oxy) phenyl) -1,2-thiazinan-3-one 1,1-dioxide, or a pharmaceutically acceptable salt thereof, or A pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt, and an optical isomer of the compound, or a pharmaceutically acceptable salt of the isomer, Or a pharmaceutically acceptable solvate of the isomer or a pharmaceutically acceptable solvate of the salt.
The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable salt of the salt. A pharmaceutical composition containing a solvate.
The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable salt of the salt. A prophylactic and / or therapeutic agent for a disease involving GPR40, comprising at least one solvate as an active ingredient.
The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable salt of the salt. An insulin secretagogue comprising at least one solvate as an active ingredient.
The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable salt of the salt. A GPR40 activator comprising one or more solvates.
The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable salt of the salt. Solvates, and PPARγ agonists, biguanides, sulfonylureas, fast-acting insulin secretagogues, α-glucosidase inhibitors, insulin or insulin derivatives, GLP-1 and GLP-1 receptor agonists, DPP-IV Inhibitors, α2 antagonists, SGLT2 inhibitors, ω3 fatty acids, HMG-CoA reductase inhibitors, HMG-CoA synthetase inhibitors, cholesterol absorption inhibitors, acyl-CoA / cholesterol acyltransferase (ACAT) inhibitors, CETP inhibitor, squalene synthase inhibitor, antioxidant, PPARα agonist, PPARδ agonist, LXR agonist, FXR agonist, MTTP inhibitor, squalene eposidase inhibitor, bile acid absorption inhibitor, CB-1 receptor antagonist, monoamine reuptake inhibitor, serotonin reuptake inhibitor, lipase inhibitor, neuropeptide Y (NPY) A pharmaceutical composition comprising one or more compounds selected from the group consisting of a receptor antagonist, a peptide YY (PYY) receptor antagonist, and an adrenergic β3 receptor agonist.
The pharmaceutical composition according to claim 13, wherein the DPP-IV inhibitor is a compound selected from sitagliptin, vildagliptin, alogliptin, saxagliptin, linagliptin or teneligliptin or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to claim 13, wherein the DPP-IV inhibitor is sitagliptin or a pharmaceutically acceptable salt thereof.