RU2803743C2 - Dihydropyrazolopyrazinone derivative with mgat-2 inhibitory activity - Google Patents

Abstract

FIELD: organic chemistry; pharmaceuticals.

SUBSTANCE: group of inventions relates to compounds with inhibitory activity against monoacylglycerin acyl transferase 2 (MGAT2). A compound represented by formula (I) is disclosed, wherein R¹ is hydrogen; R^2a and R^2b together with the adjacent carbon atom form ring B; ring B is represented by the formula: where each R⁶ is independently halogen, C1-C4 alkyloxy optionally substituted with substituent(s) selected from the group consisting of halogen, C1-C4 alkyloxy and phenyl, and n is 1 or 2; R^3a is hydrogen; R^3b is hydrogen; R^4a is a group represented by the formula: where L³ is a single bond or C1-C4 alkylene optionally substituted with halogen, R⁷ is halogen, sulfamoyl optionally substituted with C1-C4 alkyl, C1-C4 alkyloxy optionally substituted with halogen, C1-C4 alkylsulfonyl, aromatic heterocyclyl which is 5-membered monocyclic group containing two heteroatoms selected from O and N, a non-aromatic heterocyclyl which is a 4-membered monocyclic group containing one heteroatom selected from S and optionally substituted with oxo, or a group represented by the formula: -S(= O)(=NR^N)-R^S1, R^N is hydrogen and R^S1 is C1-C4 alkyl; and R^4b is C1-C6 alkyl optionally substituted with substituent group α, phenyl optionally substituted with substituent group β, or pyridyl optionally substituted with substituent β, substituent group α is halogen and cyclopropanyl, and substituent group β is halogen, cyano, C1-C4 alkyl, haloC1-C4 alkyl, hydroxyalkyl, C1-C4 alkyloxy, haloC1-C4 alkyloxy, cyclopropanyl, cyclopropanyloxy, C1-C4 alkylsulfonyl, or a pharmaceutically acceptable salt thereof. In addition, specific compounds are disclosed, a pharmaceutical composition having MGAT2 inhibitory activity containing the above compound or a pharmaceutically acceptable salt thereof, and a method of treating or preventing an MGAT2-associated disease, comprising administering the above compound.

EFFECT: group of inventions provides effective treatment of MGAT2-associated disease.

18 cl, 24 tbl, 13 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001]

The present invention relates to a compound having monoacylglycerol acyl transferase 2 (hereinafter referred to as “MGAT2”) inhibitory activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.

PREREQUISITES FOR CREATION OF THE INVENTION

[0002]

Obesity is defined as an excessively high amount of body fat or fatty tissue compared to lean body mass and is considered a major risk factor for health problems. Body mass index (BMI) is a simple ratio of weight to height that is commonly used to classify overweight and obesity in adult (age 15 years and older) populations and individuals. It is defined as the ratio of mass in kilograms to height in meters squared (kg/ ^m2 ). The World Health Organization defines "overweight" as a BMI of 25 kg/ ^m2 or more and "obesity" as a BMI of 30 kg/ ^m2 or more. On the other hand, the Japan Obesity Society defines “obesity” as a BMI of 25 kg/ ^m2 or more. This is because the number of obesity-related disorders, including diabetes and dyslipidemia, increases with BMI, and at a BMI of 25 kg/m ² the average number of obesity-related disorders is 1.0 or more. The World Health Organization reported that in 2005, approximately 1600 million and at least 400 million people worldwide were overweight and obese, respectively. Obesity is usually caused by consuming more calories than are used in physical activity and daily life. The number of obese people has increased due to the consumption of more foods high in fat and/or sugar, and it is estimated that 700 million people or more will be diagnosed with obesity worldwide in 2015. For the treatment of obesity, diet therapy, exercise therapy, drug therapy, etc. are used. Drug therapy uses drugs including orlistat, mazindol and sibutramine. However, they fall short in two aspects: effectiveness and side effects.

One of the causes of obesity is excessive consumption of neutral fat. Neutral fat (triglycerol) consumed in food is broken down by pancreatic lipase in the gastrointestinal tract into 2-monoacylglycerol and free fatty acids, which are absorbed by the epithelial cells of the small intestine. The acyl group is transferred from free fatty acids to 2-monoacylglycerol by the action of monoacylglycerol acyltransferase (MGAT). The resulting diacylglycerol is further converted to neutral fat by the action of diacylglycerol acyltransferase (DGAT).

Three isoforms of MGAT have been identified, namely MGAT1, MGAT2 and MGAT3. Among them, MGAT2 and MGAT3 are highly expressed in the small intestine and are thought to be involved in the process of fat absorption in the small intestine.

It was reported that in an experiment with MGAT2 knockout mice, it was demonstrated that a high-fat diet increases the expression of MGAT2 in the small intestine with an increase in MGAT activity (Non-Patent Document 1). In addition, MGAT2 knockout mice were found to reduce high-fat diet-induced weight gain, suppress the induction of insulin resistance, reduce elevated blood cholesterol levels, prevent fatty liver transformation, etc., and increase energy expenditure (non-patent document 2).

Although compounds having MGAT2 inhibitory activity have been previously reported (Patent Documents 1-19, Non-Patent Documents 3-13), the compounds of the present invention described below have not been disclosed.

REFERENCES TO BACKGROUND ART

Patent documents

[0003]

[Patent Document 1] International Publication WO 2010/095767 A

[Patent Document 2] International Publication WO 2012/091010 A

[Patent Document 3] International Publication WO 2012/124744 A

[Patent Document 4] International Publication WO 2013/082345 A

[Patent Document 5] International Publication WO 2013/112323 A

[Patent Document 6] International Publication WO 2013/116065 A

[Patent Document 7] International Publication WO 2013/116075 A

[Patent Document 8] International Publication WO 2014/074365 A

[Patent Document 9] International Publication WO 2014/133134 A

[Patent Document 10] International Publication WO 2014/193884 A

[Patent Document 11] JP 2014-5245 A

[Patent Document 12] JP 2014-9165 A

[Patent Document 13] International Publication WO 2015/112465 A

[Patent Document 14] International Publication WO 2015/129845 A

[Patent Document 15] International Publication WO 2015/134699 A

[Patent Document 16] International Publication WO 2015/134701 A

[Patent Document 17] International Publication WO 2015/191681 A

[Patent Document 18] International Publication WO 2016/121782 A

[Patent Document 19] International Publication WO 2017/069224 A

Non-patent documents

[0004]

[Non-Patent Document 1] Journal of Biological Chemistry (2004), 279, 18878-18886

[Non-Patent Document 2] Nature Medicine (2009), 15, (4), 442-446

[Non-Patent Document 3] Bioorganic & Medicinal Chemistry Letter (2013), 23, 2721-2726

[Non-Patent Document 4] Med. Chem. Commun (2013), 4, 1305-1311

[Non-Patent Document 5] Bioorganic & Medicinal Chemistry Letter (2015), 23, 5922-5931

[Non-Patent Document 6] Bioorganic & Medicinal Chemistry Letter (2015), 23, 4544-4560

[Non-Patent Document 7] Journal of Lipid Research 2015, 56, 747-753

[Non-Patent Document 8] European Journal of Pharmacology, 2015, 758, 72-81

[Non-Patent Document 9] Journal of Medicinal Chemistry (2015), 58, 3892-3909

[Non-Patent Document 10] HETEROCYCLES 2016, 92, 470-484

[Non-Patent Document 11] Chemical and Pharmaceutical Bulletin, 2016, 64, 228-238

[Non-Patent Document 12] European Journal of Pharmacology, 2016, 791, 569-577

[Non-Patent Document 13] Analytical Biochemistry, 2016, 501, 48-55

SUMMARY OF THE INVENTION

Problems to be solved by the present invention

[0005]

The object of the present invention is to provide a compound having inhibitory activity against MGAT2, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.

Means for solving the problem

[0006]

The inventors of the present invention have carried out extensive research and succeeded in synthesizing more advanced compounds having inhibitory activity against MGAT2. The present invention includes the following:

[0007]

[1] The compound represented by formula (I):

Where

R ¹ is hydrogen, hydroxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbo cyclyl, substituted or unsubstituted aromatic heterocyclyl , substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxy carbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl;

R ^2a is a group represented by the formula:

wherein ring C is an aromatic carbocycle, an aromatic heterocycle, a non-aromatic carbocycle, or a non-aromatic heterocycle;

each R ⁵ independently represents halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl , substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl yl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl , substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , a group represented by formula: -LS(=O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(= NR ^N ) ₂ -R ^S1 , and

m is equal to an integer from 1 to 5,

R ^2b is hydrogen, cyano, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkylsulfonyl, or

R ^2a and R ^2b together with the adjacent carbon atom can form a B ring,

ring B is a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;

R ^3a is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted substituted non-aromatic heterocyclyl , substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, for substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl,

R ^3b is hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted substituted non-aromatic heterocyclyl , substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, for substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl,

R ^3a and R ^3b together with an adjacent carbon atom may form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle, or

R ^2b and R ^3b together with adjacent carbon atoms may form a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;

R ^4a is a group represented by the formula:

L ³ represents a single bond or a substituted or unsubstituted alkylene,

R ⁷ is hydrogen, halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio , sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted not aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbon yloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbo cyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, group represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , group represented by the formula: -LS( =O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ - R ^S1 ,

provided that if L ³ represents a single bond, then R ⁷ does not represent hydrogen or halogen,

R ^4b is halogen, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted, aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic car bocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy , substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl , substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, group represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , group represented by the formula: -LS (=O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 ,

each L independently represents a single bond, alkylene or C(=O),

each R ^S1 and R ^S2 independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, or

^RS1 and ^RS2 bonded to the same sulfur atom can, together with the sulfur atom, form a substituted or unsubstituted non-aromatic heterocycle;

each R ^N is independently hydrogen, cyano, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic ical heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, or substituted or unsubstituted non-aromatic heterocyclylcarbonyl,

or a pharmaceutically acceptable salt thereof.

[2]

A compound or a pharmaceutically acceptable salt thereof as defined in [1], wherein ring B is represented by any of the formulas:

Where

B ¹ represents CR ^11a R ^11b , NR ^11c , O or S,

B ² represents CR ^12a R ^12b , NR ^12c , O or S,

B ³ represents CR ^13a R ^13b , NR ^13c , O or S,

B ⁴ is CR ^14a R ^14b , NR ^14c , O or S, and

B ⁵ is CR ^15a R ^15b , NR ^15c , O or S,

Each R ^11A , R ^12A , R ^13A , R ^14A , and R ^15A independently represents hydrogen, halogen, hydroxy, cyano, carboxy, replaced or unnoticed by carbamoil, replaced or unnoticed by thiocarbamil, replaced or unnoticed amidino, replaced or unnoticed amino, replaced or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkyl carbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy , substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, for substituted or unsubstituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -LN=S( =O)(-R ^S1 )-R ^S2 , group represented by the formula: -LS(=O)(=NR ^N )-R ^S1 , group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 ,

R ^11b , R ^12b , R ^13b , R ^14b and R ^15b are each independently hydrogen, halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcar bonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfine yl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy , substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl anyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted substituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -LN=S(= O)(-R ^S1 )-R ^S2 , group represented by the formula: -LS(=O)(=NR ^N )-R ^S1 , group represented by the formula: -N=S(=NR ^N )(-R ^S1 ) -R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 ,

R ^11c , R ^12c , R ^13c , R ^14c , and R ^15c are each independently hydrogen, cyano, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkene ylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocycle yl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted substituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulf anyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl ,

or R ^11a and R ^12a , R ^12a and R ^13a , R ^13a and R ^14a , and/or R ^14a and R ^15a together with adjacent carbon atoms can form a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted non-aromatic carbocycle, a substituted or unsubstituted aromatic heterocycle, or substituted or unsubstituted non-aromatic heterocycle,

and/or R ^11c and R ^12a , R ^11c and R ^12c , R ^12c and R ^11a , R ^{12c and R 13a, R 12c and R 13c} , R ^13c and R ^12a , R ^13c and R ^14a , R ^13c and R ^14c , R ^14c and R ^13a , R ^14c and R ^15a , R ^14c and R ^15c , and/or R ^15c and R ^14a together with adjacent atoms can form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle,

and/or R ^11a and R ^13a , R ^11a and R ^13c , R ^11a and R ^14a , R ^11a and R ^14c , R ^11a and R ^15a , R ^11a and R ^15c , R ^11c and R ^13a , R ^11c and R ^13c , R ^11c and R ^14a , R ^11c and R ^14c , R ^11c and R ^15a , R ^11c and R ^15c , R ^12a and R ^14a , R ^12a and R ^14c , R ^12a and R ^15a , R ^12a and R ^15c , R ^12c and R ^14a , R ^12c and R ^14c , R ^12c and ^{R 15a} , R 12c and R ^15c , R ^13a and R ^15a , R ^13a and R ^15c , R ^13c and R ^15a , and/or R ^13c and R ^15c together can form a C2-C4 bridge, optionally containing heteroatom(s),

and/or R ^11b and R ^12b , R ^11b and R ^12c , R ^11c and R ^12b , R ^{11c and R 12c, R 12b and R 13b} , R ^12b and R ^13c , R ^12c and R ^13b , R ^12c and R ^13c , R ^13b and R ^14b , R ^13b and R ^14c , R ^13c and R ^14b , R ^13c and R ^14c , R ^14b and R ^15b , R ^14b and R ^15c , R ^14c and R ^15b , and/or R ^14c and R ^15c together can form a bond, and

the meanings of other symbols are described in paragraph [1].

[3]

A compound or a pharmaceutically acceptable salt thereof as defined in [1] or [2], wherein ring B is represented by any of the formulas:

Where

B ¹ represents C, CR ^11a or N,

B ² represents C, CR ^12a or N,

B ³ represents CR ^13a R ^13b , NR ^13c , O or S,

B ⁴ is CR ^14a R ^14b , NR ^14c , O or S,

B ⁵ is CR ^15a R ^15b , NR ^15c , O or S,

Each R ^11A , R ^12A , R ^13A , R ^14A , and R ^15A independently represents hydrogen, halogen, hydroxy, cyano, carboxy, replaced or unnoticed by carbamoil, replaced or unnoticed by thiocarbamil, replaced or unnoticed amidino, replaced or unnoticed amino, replaced or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkyl carbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy , substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, for substituted or unsubstituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -LN=S( =O)(-R ^S1 )-R ^S2 , group represented by the formula: -LS(=O)(=NR ^N )-R ^S1 , group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 ,

each R ^13b , R ^14b , and R ^15b independently represents hydrogen, halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted ny or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alk enylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfone yl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic hetero cyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted substituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocycle ilsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, group, represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , a group represented by the formula: -LS(=O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 ,

R ^13c , R ^14c , and R ^15c are each independently hydrogen, cyano, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidium but, pentafluorothio, sulfo , substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl yl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl , substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted ny or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclyl sulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted substituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl,

and/or R ^11a and R ^13a , R ^11a and R ^13c , R ^11a and R ^14a , R ^11a and R ^14c , R ^11a and R ^15a , R ^11a and R ^15c , R ^12a and R ^14a , R ^12a and R ^14c , R ^12a and R ^15a , R ^12a and R ^15c , R ^13a and R ^15a , R ^13a and R ^15c , R ^13c and R ^15a , and/or R ^13c and R ^15c together may form a C2-C4 bridging bond, optionally containing heteroatom(s),

and/or R ^11a and R ^12a , R ^12a and R ^13b , R ^12a and R ^13c , R ^13b and R ^14b , R ^13b and R ^14c , R ^13c and R ^14b , R ^13c and R ^14c , R ^14b and R ^15b , R ^14b and R ^15c , R ^14c and R ^15b , and/or R ^14c and R ^15c together can form a bond,

ring D is an aromatic carbocycle, non-aromatic carbocycle, aromatic heterocycle or non-aromatic heterocycle,

each R ⁶ independently represents halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl , substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl yl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl , substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , a group represented by formula: -LS(=O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(= NR ^N ) ₂ -R ^S1 ,

n is an integer from 1 to 4, and

the meanings of other symbols are described in paragraph [1].

[4]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein ring B is represented by any of the formulas:

where the values of B ³ , B ⁴ , B ⁵ , R ⁶ and n are described in paragraph [3].

[5]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein ring B is represented by any of the formulas:

where the values of R ⁶ , R ^13a , R ^13b , R ^14a , R ^14b , R ^15a , R ^15b and n are described in paragraph [3].

[6]

A compound or a pharmaceutically acceptable salt thereof as defined in [3] or [4], wherein each ^R6 is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted carbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted non aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl.

[7]

A compound or a pharmaceutically acceptable salt thereof according to any one of [3] to [5], wherein each R ⁶ independently represents a halogen or a substituted or unsubstituted alkyloxy.

[8]

A compound or a pharmaceutically acceptable salt thereof according to any one of [3] to [5], wherein ring B is represented by any of the formulas:

where each R ⁶ independently represents a substituted or unsubstituted alkyloxy, and the meanings of R ^13a , R ^13b , R ^14a , R ^14b , R ^15a and R ^15b are described in paragraph [3].

[9]

A compound or a pharmaceutically acceptable salt thereof according to any one of [3] to [5], wherein ring B is represented by any of the formulas:

wherein each ^R6 is independently halogen or substituted or unsubstituted alkyloxy, and the meanings of ^R13a , ^R13b , ^R14a , ^R14b , ^R15a and ^R15b are described in paragraph [3].

[10]

A compound or a pharmaceutically acceptable salt thereof as defined in [1], wherein ring C is an aromatic carbocycle or an aromatic heterocycle.

[eleven]

A compound or a pharmaceutically acceptable salt thereof as defined in [1] or [10], wherein each ^R5 is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted carbamoyl , substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted non aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, and

m is equal to 1-3.

[12]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1], [10] and [11], wherein R ^2b is substituted or unsubstituted alkyl.

[13]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [12], wherein R ^4a is a group represented by the formula:

Where

the values of L ³ and R ⁷ are described in paragraph [1].

[14]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [13], wherein L ³ represents a substituted or unsubstituted alkylene.

[15]

A compound or a pharmaceutically acceptable salt thereof as defined in [14], wherein R ⁷ is halogen, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or a group represented by the formula: -LS( =O)(=NR ^N )-R ^S1 .

[16]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [13], wherein L ³ represents a single bond.

[17]

A compound or a pharmaceutically acceptable salt thereof as defined in [16], wherein R ⁷ is a substituted or unsubstituted aromatic heterocyclyl, or a substituted or unsubstituted non-aromatic heterocyclyl.

[18]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [17], wherein R ^4b is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclyl, or a substituted or unsubstituted aromatic heterocyclyl.

[19]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [18], wherein R ^3a and R ^3b are each hydrogen.

[20]

A compound or a pharmaceutically acceptable salt thereof according to paragraph [1], selected from the group consisting of compounds I-6, I-13, I-14, I-20, I-33, I-46, I-58, I -61, I-66, I-79, I-126, I-130, I-133, I-137 and I-142.

[20-1]

A compound or a pharmaceutically acceptable salt thereof according to paragraph [1], selected from the group consisting of compounds I-123, I-124, I-136, I-139, I-141, I-143, I-145 and I -147.

[20-2]

A compound or a pharmaceutically acceptable salt thereof according to paragraph [1], selected from the group consisting of compounds I-151 and I-153.

[21]

A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [20] and [20-1] to [20-2].

[22]

Pharmaceutical composition according to paragraph [21], which has inhibitory activity against MGAT2.

[23]

Pharmaceutical composition according to paragraph [21] or [22] for use in the treatment or prevention of MGAT2-associated disease.

[24]

Pharmaceutical composition according to paragraph [23] for use in the treatment or prevention of obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyper-VLDL-triglyceridemia, hyperlipoacidemia, diabetes mellitus or arteriosclerosis.

[25]

A method for treating or preventing an MGAT2-associated disease, comprising administering a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [20] and [20-1] to [20-2].

[26]

A compound or a pharmaceutically acceptable salt thereof according to any one of [1]-[20] and [20-1]-[20-2] for the treatment or prevention of an MGAT2-associated disease.

[27]

Use of a compound according to any one of [1] to [20] and [20-1] to [20-2], or a pharmaceutically acceptable salt thereof, for the treatment or prevention of an MGAT2-associated disease.

[0008]

[1']

The compound represented by formula (I):

Where

R ¹ represents hydrogen;

R ^2a and R ^2b together with the adjacent carbon atom form ring B,

ring B is represented by the formula:

wherein each ^R6 is independently halogen or substituted or unsubstituted alkyloxy, and

n is 1 or 2;

R ^3a represents hydrogen;

R ^3b represents hydrogen;

R ^4a is a group represented by the formula:

Where

L ³ represents a single bond or a substituted or unsubstituted alkylene,

R ⁷ represents halogen, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or a group represented by a group represented by the formula: -S(=O)(= NR ^N )-R ^S1 ,

R ^N represents hydrogen, and

R ^S1 represents substituted or unsubstituted alkyl; And

R ^4b represents substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted aromatic heterocyclyl,

or a pharmaceutically acceptable salt thereof.

[2']

A compound or a pharmaceutically acceptable salt thereof according to paragraph [1'], wherein ring B is represented by any of the formulas:

where each R ⁶ independently represents substituted or unsubstituted alkyloxy.

[3']

A compound or a pharmaceutically acceptable salt thereof according to paragraph [1'], wherein ring B is represented by any of the formulas:

wherein each R ⁶ independently represents halogen or substituted or unsubstituted alkyloxy.

[4']

A compound or a pharmaceutically acceptable salt thereof according to any of paragraphs [1']-[3'], wherein L ³ represents a substituted or unsubstituted alkylene.

[5']

A compound or a pharmaceutically acceptable salt thereof according to paragraph [4'], wherein R ⁷ represents a halogen, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or a group represented by the formula: -S(=O)( =NR ^N )-R ^S1 .

[6']

A compound or a pharmaceutically acceptable salt thereof according to any one of [1']-[3'], wherein L ³ represents a single bond.

[7']

A compound or a pharmaceutically acceptable salt thereof as defined in [6'], wherein R ⁷ is a substituted or unsubstituted aromatic heterocyclyl, or a substituted or unsubstituted non-aromatic heterocyclyl.

[8']

A compound or a pharmaceutically acceptable salt thereof according to paragraph [1'], selected from the group consisting of compounds I-6, I-13, I-14, I-20, I-33, I-46, I-58, I-61, I-66, I-79, I-126, I-130, I-133, I-137 and I-142.

[8'-1]

A compound or a pharmaceutically acceptable salt thereof according to paragraph [1'], selected from the group consisting of compounds I-123, I-124, I-136, I-139, I-141, I-143, I-145 and I-147.

[8'-2]

A compound or a pharmaceutically acceptable salt thereof according to paragraph [1'], selected from the group consisting of compounds I-151 and I-153.

[9']

A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof according to any of paragraphs [1']-[8'] and [8'-1]-[8'-2].

[10']

The pharmaceutical composition according to paragraph [9’], which has inhibitory activity against MGAT2.

[eleven']

Pharmaceutical composition according to paragraph [9’] or [10’] for use in the treatment or prevention of MGAT2-associated disease.

[12']

Pharmaceutical composition according to paragraph [11’] for use in the treatment or prevention of obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyper-VLDL-triglyceridemia, hyperlipoacidemia, diabetes mellitus or arteriosclerosis.

[13']

A method of treating or preventing an MGAT2-associated disease, comprising administering a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1']-[8'] and [8'-1]-[8'-2].

[14']

A compound or a pharmaceutically acceptable salt thereof according to any of paragraphs [1']-[8'] and [8'-1]-[8'-2] for the treatment or prevention of MGAT2-associated disease.

[15']

Use of a compound according to any one of [1']-[8'] and [8'-1]-[8'-2] or a pharmaceutically acceptable salt thereof for the treatment or prevention of an MGAT2-associated disease.

EFFECT OF THE PRESENT INVENTION

[0009]

The compound of the present invention has MGAT2 inhibitory activity and is useful as a prophylactic and/or therapeutic agent for, for example, obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyper-VLDL-triglyceridemia, hyperlipoacidemia, diabetes mellitus or arteriosclerosis.

OPTION FOR IMPLEMENTATION OF THE INVENTION

[0010]

The following explains the terms used in the present description. Unless otherwise noted, each term has the same meaning when used alone or with other terms.

The term “consisting of” means containing only the specified components.

The term “comprising” means not limited to the specified components without excluding undescribed features.

[0011]

The term "halogen" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Particularly, a fluorine atom and a chlorine atom are preferred.

[0012]

The term "alkyl" includes a C1-C15, preferably a C1-C10, more preferably a C1-C6, and more preferably a C1-C4 straight or branched hydrocarbon group. Examples include methyl, ethyl, n- propyl, isopropyl, n -butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n- hexyl, isohexyl, n- heptyl, isoheptyl, n- octyl, isooctyl, n- nonyl and n- decyl.

A preferred embodiment of "alkyl" is methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, or n- pentyl. A more preferred embodiment is methyl, ethyl, n- propyl, isopropyl or tert-butyl.

[0013]

The term "alkenyl" includes a C2-C15, preferably C2-C10, more preferably a C2-C6, and even more preferably a C2-C4, straight or branched hydrocarbon group containing one or more double bonds at any of the positions. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.

A preferred embodiment of "alkenyl" is vinyl, allyl, propenyl, isopropenyl or butenyl.

[0014]

The term "alkynyl" includes a C2-C10, preferably C2-C8, more preferably C2-C6, and even more preferably a C2-C4, straight or branched hydrocarbon group containing one or more triple bonds at any of the positions. In addition, it may contain double bond(s) in any of the positions. For example, the term includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, nonynyl, decynyl, and the like.

A preferred embodiment of "alkynyl" is ethynyl, propynyl, butynyl or pentynyl.

[0015]

The term "alkylene" includes a C1-C15, preferably a C1-C10, more preferably a C1-C6, and more preferably a C1-C4 straight or branched divalent hydrocarbon group. Examples include methylene, ethylene, propylene, tetramethylene, pentamethylene and hexamethylene.

[0016]

The term "aromatic carbocyclyl" means a cyclic aromatic hydrocarbon group that is monocyclic or polycyclic containing two or more rings. Examples include phenyl, naphthyl, anthryl and phenanthryl.

A preferred embodiment of the "aromatic carbocyclyl" is phenyl.

[0017]

The term "non-aromatic carbocyclyl" means a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group that is monocyclic or polycyclic containing two or more rings. A "non-aromatic carbocyclyl" which is polycyclic, containing two or more rings, includes a fused ring group in which a non-aromatic carbocyclyl, which is monocyclic or polycyclic, containing two or more rings, is fused to a ring of the above-described "aromatic carbocyclyl".

In addition, examples of "non-aromatic carbocyclyl" also include a group containing a bridged bond or a group to form the following spiro ring:

The non-aromatic carbocyclyl, which is monocyclic, is preferably a C3-C16 carbocyclyl, more preferably a C3-C12 carbocyclyl, and more preferably a C4-C8 carbocyclyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclohexadienyl.

The non-aromatic carbocyclyl, which is polycyclic containing two or more rings, is preferably a C8-C20 carbocyclyl and more preferably a C8-C16 carbocyclyl. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl and fluorenyl.

[0018]

The term "aromatic carbocycle" includes a cyclic aromatic hydrocarbon that is monocyclic or polycyclic, containing two or more rings. Examples include the benzene ring, naphthalene ring, anthracene ring, and phenanthrene ring.

An embodiment of the "aromatic carbocycle" is a benzene ring and a naphthalene ring. Another embodiment thereof includes a benzene ring.

The term "non-aromatic carbocycle" includes a cyclic saturated hydrocarbon or a cyclic unsaturated non-aromatic hydrocarbon that is monocyclic or polycyclic containing two or more rings. A "non-aromatic carbocycle", which is polycyclic, containing two or more rings, includes a fused ring, wherein a non-aromatic carbocycle, which is monocyclic or polycyclic, containing two or more rings, is fused to a ring of the above-described "aromatic carbocycle".

In addition, examples of a "non-aromatic carbocycle" also include a ring containing a bridged bond or a ring to form the following spiro ring:

The non-aromatic carbocycle, which is monocyclic, is preferably a C3-C16 carbocycle, more preferably a C3-C12 carbocycle, and more preferably a C3-C8 carbocycle. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclohexadiene.

The non-aromatic carbocyclyl, which is polycyclic containing two or more rings, is preferably a C8-C20 carbocycle and more preferably a C8-C16 carbocycle. Examples include indane, indene, acenaphthene, tetrahydronaphthalene and fluorene.

[0019]

The term "aromatic heterocyclyl" means an aromatic cyclyl which is monocyclic or polycyclic, containing two or more rings, containing one or more identical or different heteroatoms independently selected from O, S and N. "Aromatic heterocyclyl" which is polycyclic, containing two or more rings, includes a fused ring group in which an aromatic heterocyclyl, which is monocyclic or polycyclic containing two or more rings, is fused to a ring of the above-described "aromatic carbocyclyl".

An aromatic heterocyclyl that is monocyclic is preferably a 5-8 membered ring and more preferably a 5-6 membered ring. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl.

The aromatic heterocyclyl, which is bicyclic, is preferably an 8-10 membered ring and more preferably a 9 or 10 membered ring. Examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothia diazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl and thiazolopyridyl.

Examples of an aromatic heterocyclyl that is polycyclic containing three or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl and dibenzofuryl.

[0020]

The term "non-aromatic heterocyclyl" means a non-aromatic cyclyl which is monocyclic or polycyclic, containing two or more rings, containing one or more identical or different heteroatoms independently selected from O, S and N. Non-aromatic heterocyclyl which is polycyclic, containing two or more rings, includes a fused ring group in which a non-aromatic heterocyclyl, which is monocyclic or polycyclic containing two or more rings, is fused to a ring of the above-described "aromatic carbocyclyl", "non-aromatic carbocyclyl" and/or "aromatic heterocyclyl", and includes a fused ring a group in which a ring of the above-described "aromatic heterocyclyl" is fused with the above-described "non-aromatic carbocyclyl" which is monocyclic or polycyclic containing two or more rings.

In addition, examples of "non-aromatic heterocyclyl" also include a group containing a bridged bond or a group to form the following spiro ring:

A non-aromatic heterocyclyl that is monocyclic is preferably 3-8 membered and more preferably 5-6 membered. Examples include dioxanil, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazodidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, di hydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanil, dioxazinyl, aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thiinyl and thiazinyl.

A non-aromatic heterocyclyl that is polycyclic containing two or more rings is preferably 8-20 membered and more preferably 8-10 membered. Examples include indolinyl, isoindolinyl, chromanyl and isochromanil.

[0021]

The term "aromatic heterocycle" includes an aromatic ring that is monocyclic or polycyclic, containing two or more rings, containing one or more identical or different heteroatoms independently selected from O, S and N.

An "aromatic heterocycle" that is polycyclic, containing two or more rings, includes a fused ring in which an aromatic heterocycle, which is monocyclic or polycyclic, containing two or more rings, is fused to a ring of the above-described "aromatic carbocycle".

An aromatic heterocycle that is monocyclic is preferably a 5-8 membered ring, and more preferably a 5- or 6-membered ring. Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole and thiadiazole.

An aromatic heterocycle that is bicyclic is preferably 8-10 membered and more preferably 9 or 10 membered. Examples include indole, isoindole, indazole, indolysine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridine, oxazolopyridine and thiazolopyridine.

An aromatic heterocycle that is polycyclic containing three or more rings is preferably an 11 to 26 membered ring, and more preferably a 13 or 14 membered ring. Examples include carbazole, acridine, xanthene, phenothiazine, phenoxathiine, phenoxazine, and dibenzofuran.

The term "non-aromatic heterocycle" includes a cyclic non-aromatic ring that is monocyclic or polycyclic, containing two or more rings, containing one or more identical or different heteroatoms independently selected from an oxygen atom, a sulfur atom and a nitrogen atom.

A "non-aromatic heterocycle", which is polycyclic, containing two or more rings, includes a fused ring in which a non-aromatic heterocycle, which is monocyclic or polycyclic, containing two or more rings, is fused with a ring of the above-described "aromatic carbocycle", "non-aromatic carbocycle" and/or an “aromatic heterocycle”.

In addition, the term "non-aromatic heterocycle" also includes a ring containing a bridged bond or a ring to form the following spiro ring:

The non-aromatic heterocycle which is monocyclic is preferably a 3-8 membered ring and more preferably a 5 or 6 membered ring. Examples include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, di hydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxole, oxepane, thiolane, thiine and thiazine.

A non-aromatic heterocycle that is polycyclic containing two or more rings is preferably 8-20 membered and more preferably 8-10 membered. Examples include indoline, isoindoline, chromane and isochromane.

[0022]

Substituents "substituted carbamoyl", "substituted thiocarbamoyl", "substituted amidino", "substituted amino", "substituted ureido", "substituted guanidino", "substituted sulfamoyl", "substituted alkyl", "substituted alkenyl", "substituted alkynyl" , "substituted alkylene", "substituted alkyloxy", "substituted alkenyloxy", "substituted alkylcarbonyloxy", "substituted alkenylcarbonyloxy", "substituted alkylcarbonyl", "substituted alkenylcarbonyl", "substituted alkyloxycarbonyl", "substituted alkenyloxycarbonyl", "substituted alkylsulfanyl" , "substituted alkenylsulfanyl", "substituted alkylsulfinyl", "substituted alkenylsulfinyl", "substituted alkylsulfonyl" and "substituted alkenylsulfonyl" include the substituents presented below. The carbon atom or nitrogen atom at any position(s) may be bonded to one or more groups selected from the following substituents.

Group of substituents: halogen, hydroxy, cyano, formyl, formyloxy, thioformyl, carboxy, thiocarboxy, dithiocarboxy, carbamoyl, thiocarbamoyl, amidino, amino, hydroxyamino, azido, hydradino, ureido, guanidino, pentafluorothio, thiol, sulfino, sulfo, sulfamoyl, trialkyl Silil , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, haloalkyloxyalkyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycar bonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl , alkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylaminosulfonyl, monoalkenylaminosulfonyl, monoalkynylaminosulfonyl, dialkylaminosulfonyl, dialkenylaminosulfonyl, dialkynylaminosulfonyl, monoalkylamino, monoalkenylamino, monoalkynylamino, dialkylamino, dialkenylamino, dial kynylamino, monoalkylcarbonylamino, monoalkenylcarbonylamino, monoalkynylcarbonylamino, dialkenylcarbonylamino, dialkynylcarbonylamino, monoalkyloxycarbonylamino, monoalkenyloxycarbonylamino, monoalkynyloxycarbonylamino, dialkyloxycarbonylamino , dialkenyloxycarbonylamino, dialkynyloxycarbonylamino, monoalkylsulfonylamino, monoalkenylsulfonylamino, monoalkynylsulfonylamino, dialkylsulfonylamino, dialkenylsulfonylamino, dialkynylsulfonylamino, monoalkylcarbamoyl, monoalkenylcarbamoyl, monoalkynylcarbamoyl, dialkylcarbamoyl, dial kenylcarbamoyl, dialkynylcarbamoyl, monoalkyloxycarbamoyl, monoalkenyloxycarbamoyl, monoalkynyloxycarbamoyl, dialkyloxycarbamoyl, dialkenyloxycarbamoyl, dialkynyloxycarbamoyl, monoalkylcarbonylcarbamoyl, monoalkenylcarbonylcarbamoyl, monoalkynylcarbonylcarbamoyl, monoalkyloxycarbonylcarbamoyl yl, monoalkenyloxycarbonylcarbamoyl , monoalkynyloxycarbonylcarbamoyl, monoalkylsulfonylcarbamoyl, monoalkenylsulfonylcarbamoyl, monoalkynylsulfonylcarbamoyl, monoalkylsulfamoyl, monoalkenylsulfamoyl, monoalkynylsulfamoyl, dialkylsulfamoyl, dialkenylsulfamoyl, dialkynylsulfamoyl, monoalkyloxysulfamoyl, monoalkenyloxysulfame oil, monoalkynyloxysulfamoyl, dialkyloxysulfamoyl, dialkenyloxysulfamoyl, dialkynyloxysulfamoyl, monoalkylcarbonylsulfamoyl, monoalkenylcarbonylsulfamoyl, monoalkynylcarbonylsulfamoyl, monoalkyloxycarbonylsulfamoyl, monoalkenyloxycarbonylsulfamoyl, monoalkynyloxycarbonylsulfamoyl, monoalkylsulf onylsulfamoyl, monoalkenylsulfonylsulfamoyl, monoalkynylsulfonylsulfamoyl , aromatic carbocyclyl, optionally substituted with a group A substituent, non-aromatic carbocyclyl, optionally substituted with a group A substituent, aromatic heterocyclyl, optionally substituted with a group A substituent, non-aromatic heterocyclyl, optionally substituted with a group A substituent, aromatic carbocyclyloxy, optionally substituted with a group A substituent, non-aromatic carbocyclyloxy, optional Floster by the deputy group A, aromatic heterocylox, not necessarily replaced by the deputy group A, non -aromatic heterocylox, not necessarily replaced by the deputy group A, aromatic carbocylcarbonyloxy, not necessarily replaced by the deputy group A, non -aromatic carbocylcarbonyloxy, not necessarily replaced by the deputy group A, aromatic heterocylcarbonyloxy, which is not necessarily denied by the deputy group A, non-aromatic heterocyclylcarbonyloxy, optionally substituted with a group A substituent, aromatic carbocyclylcarbonyl, optionally substituted with a group A substituent, non-aromatic carbocyclylcarbonyl, optionally substituted with a group A substituent, aromatic heterocyclylcarbonyl, optionally substituted with a group A substituent, non-aromatic heterocyclylcarbonyl, optionally substituted with a group A substituent, aromatic carbocycle yloxycarbonyl, optionally substituted a group A substituent, non-aromatic carbocyclyloxycarbonyl, optionally substituted with a group A substituent, aromatic heterocyclyloxycarbonyl, optionally substituted with a group A substituent, non-aromatic heterocyclyloxycarbonyl, optionally substituted with a group A substituent, aromatic carbocyclylsulfanyl, optionally substituted with a group A substituent, non-aromatic carbocyclylsulfanyl, optionally substituted with a group A substituent Group A agent, aromatic heterocyclylsulfanyl, optionally substituted with a group A substituent, non-aromatic heterocyclylsulfanyl, optionally substituted with a group A substituent, aromatic carbocyclylsulfinyl, optionally substituted with a group A substituent, non-aromatic carbocyclylsulfinyl, optionally substituted with a group A substituent, aromatic heterocyclylsulfinyl, optionally substituted with a group A substituent, non-aromatic heterocyclylsulfinyl , optionally substituted by a substituent group A, aromatic carbocyclylsulfonyl, optionally substituted with a group A substituent, non-aromatic carbocyclylsulfonyl, optionally substituted with a group A substituent, aromatic heterocyclylsulfonyl, optionally substituted with a group A substituent, non-aromatic heterocyclylsulfonyl, optionally substituted with a group A substituent, aromatic carbocyclylalkyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkyl , optionally substituted with a group A substituent, aromatic heterocyclylalkyl, optionally substituted with a group A substituent, non-aromatic heterocyclylalkyl, optionally substituted with a group A substituent, aromatic carbocyclylalkyloxy, optionally substituted with a group A substituent, non-aromatic carbocyclylalkyloxy, optionally substituted with a group A substituent, aromatic heterocyclylalkyloxy, optionally substituted group deputy A, non-aromatic heterocyclylalkyloxy, optionally substituted with a group A substituent, aromatic carbocyclylalkylcarbonyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylcarbonyl, optionally substituted with a group A substituent, aromatic heterocyclylalkylcarbonyl, optionally substituted with a group A substituent, non-aromatic heterocyclylalkylcarbonyl, optionally with substituted with group A, aromatic carbocyclylalkyloxycarbonyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkyloxycarbonyl, aromatic heterocyclylalkyloxycarbonyl, optionally substituted with a group A substituent, non-aromatic heterocyclylalkyloxycarbonyl, optionally substituted with a group A substituent, aromatic carbocyclylalkylsulfanyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylsulfanyl , optionally substituted with a group A substituent, aromatic heterocyclylalkylsulfanyl, optionally substituted a group A substituent, non-aromatic heterocyclylalkylsulfanyl, optionally substituted with a group A substituent, aromatic carbocyclylalkylsulfinyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylsulfinyl, optionally substituted with a group A substituent, aromatic heterocyclylalkylsulfinyl, optionally substituted with a group A substituent, non-aromatic heterocyclylalkylsulfanyl inyl, optionally substituted with a group A substituent, aromatic carbocyclylalkylsulfonyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylsulfonyl, optionally substituted with a group A substituent, aromatic heterocyclylalkylsulfonyl, optionally substituted with a group A substituent, non-aromatic heterocyclylalkylsulfonyl, optionally substituted with a group A substituent, aromatic carbocyclylalkylamino, optionally substituted with a group A substituent group A, non-aromatic carbocyclylalkylamino, optionally substituted with a substituent group A, aromatic heterocyclylalkylamino, optionally substituted with a group A substituent, non-aromatic heterocyclylalkylamino, optionally substituted with a group A substituent, aromatic carbocyclylalkylcarbonylamino, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylcarbonylamino, optionally substituted with a group A substituent, aromatic heterocyclylalkylcarbonylamino, non necessarily substituted with a group A substituent, non-aromatic heterocyclylalkylcarbonylamino , optionally substituted with a group A substituent, aromatic carbocyclylalkyloxycarbonylamino, optionally substituted with a group A substituent, non-aromatic carbocyclylalkyloxycarbonylamino, optionally substituted with a group A substituent, aromatic heterocyclylalkyloxycarbonylamino, optionally substituted with a group A substituent, non-aromatic heterocyclylalkyloxycarbonylamino, optionally substituted substituted with a group A substituent, aromatic carbocyclylalkylsulfonylamino, optionally substituted with a group substituent A, non-aromatic carbocyclylalkylsulfonylamino, optionally substituted with a Group A substituent, aromatic heterocyclyloxyalkylamino, optionally substituted with a Group A substituent, non-aromatic heterocyclyloxyalkylsulfonylamino, optionally substituted with a Group A substituent, aromatic carbocyclyloxyalkylamino, optionally substituted with a Group A substituent, non-aromatic carbocyclyloxyal kylamino, optionally substituted with a group A substituent, aromatic heterocyclyloxyalkylamino, optionally substituted with a group A substituent, and non-aromatic heterocyclyloxyalkylamino, optionally substituted with a group A substituent.

The term "optionally substituted by a group A substituent" means that a carbon atom, a nitrogen atom or a sulfur atom at any position may be bonded to one or more groups selected from the group A substituents.

Group A substituent: oxo, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, haloalkyloxy, alkyloxycarbonylalkyl, monoalkylamino, dialkylamino, aromatic carbocyclyl, aromatic heterocyclyl and aromatic carbocyclyloxy.

Hereinafter, the same applies to the term “optionally substituted by a group B substituent.”

Group B substituent: halogen, alkyl and haloalkyl.

[0023]

Ring substituents of “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle” or “non-aromatic heterocycle” in “substituted non-aromatic carbocycle”, “substituted non-aromatic heterocycle”, “substituted aromatic carbocyclyl”, “substituted non-aromatic carbocyclyl”, “substituted aromatic” heterocyclyl", "substituted non-aromatic heterocyclyl", "substituted aromatic carbocyclyloxy", "substituted non-aromatic carbocyclyloxy", "substituted aromatic heterocyclyloxy", "substituted non-aromatic heterocyclyloxy", "substituted aromatic carbocyclylcarbonyloxy", "substituted non-aromatic carbocyclylcarbonyloxy", "substituted aromatic heterocyclylcarbonyl" oxy" , "substituted non-aromatic heterocyclylcarbonyloxy", "substituted aromatic carbocyclylcarbonyl", "substituted non-aromatic carbocyclylcarbonyl", "substituted aromatic heterocyclylcarbonyl", "substituted non-aromatic heterocyclylcarbonyl", "substituted aromatic carbocyclyloxycarbonyl", "substituted non-aromatic carbocyclyloxycarbonyl", "substituted pure aromatic heterocyclyloxycarbonyl", " substituted non-aromatic heterocyclyloxycarbonyl", "substituted aromatic carbocyclylsulfanyl", "substituted non-aromatic carbocyclylsulfanyl", "substituted aromatic heterocyclylsulfanyl", "substituted non-aromatic heterocyclylsulfanyl", "substituted aromatic carbocyclylsulfanyl", "substituted non-aromatic carbocyclylsulfanyl", "substituted aromatic hetero cyclylsulfinyl", "substituted non-aromatic heterocyclylsulfinyl", "substituted aromatic carbocyclylsulfonyl", "substituted non-aromatic carbocyclylsulfonyl", "substituted aromatic heterocyclylsulfonyl" and "substituted non-aromatic heterocyclylsulfonyl" include the substituents set forth below. An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.

Substituents: oxo, halogen, hydroxy, cyano, formyl, formyloxy, thioformyl, carboxy, thiocarboxy, dithiocarboxy, carbamoyl, thiocarbamoyl, amidino, amino, hydroxyamino, imino, hydroxyimino, azide, hydrazino, ureido, guanidino, pentafluorothio, thiol, sulfino, sulfo, sulfamoyl, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, haloalkenyloxy, haloalkynyloxy, alkyloxyalkyloxy, haloalkyloxyalkyloxy, hydroxyalkyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylaminosulfonyl, monoalkenylaminosulfonyl, monoalkynylaminosulfonyl, dialkylaminosulfonyl, dialkenylaminosulfonyl, dialkynylaminosulfonyl, monoalkylam ino, monoalkenylamino, monoalkynylamino, monohaloalkylamino, dialkylamino, dialkenylamino, dialkynylamino, monoalkylcarbonylamino, monoalkenylcarbonylamino, monoalkynylcarbonylamino, monohaloalkylcarbonylamino, dialkylcarbonylamino, dialkenylcarbonylamino, dialkynylcarbonylamino, monoalkyloxycarbonylamino, monoalkenyloxycarbonylamino, monoalkynyloxycarbonylamino, dialkyloxycarbonylamino, dialkenyloxycarbonylamino, dialkynyloxycarbonylamino, monoalkylsulfonylamino, monoalkenyl sulfonylamino, monoalkynylsulfonylamino, dialkylsulfonylamino, dialkenylsulfonylamino, dialkynylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, monoalkylcarbamoyl, monoalkenylcarbamoyl, monoalkynylcarbamoyl, dialkylcarbamoyl, dialkenylcarbamoyl, dialkynylcarbamoyl, monoalkyloxycarbamoyl, monoalkenyloxycarbamoyl, monoalkynyloxycarbamoyl, dialkyloxycarbamoyl, dialkenyloxycarbamoyl, dialkynyloxycarbamoyl, monoalkylcarbonylcarbamoyl, monoalkenylcarbonylcarbamoyl, monoalkynylcarbonylcarbamoyl , monoalkyloxycarbonylcarbamoyl, monoalkenyloxycarbonylcarbamoyl, monoalkynyloxycarbonylcarbamoyl, monoalkylsulfonylcarbamoyl, monoalkenylsulfonylcarbamoyl, monoalkynylsulfonylcarbamoyl, monoalkylsulfamoyl, monoalkenylsulfamoyl, monoalkynylsulfamoyl, dialkylsulfamoyl, dialkenylsulfamoyl, dial kinylsulfamoyl, monoalkyloxysulfamoyl, monoalkenyloxysulfamoyl, monoalkynyloxysulfamoyl, dialkyloxysulfamoyl, dialkenyloxysulfamoyl, dialkynyloxysulfamoyl, monoalkylcarbonylsulfamoyl, monoalkenylcarbonylsulfamoyl, monoalkynylcarbonylsulfamoyl, monoalkyloxycarbonylsulfamoyl, monoalkenyloxycarbonylsulfamoyl, monoalkynyloxycarbonylsulfame oil, monoalkylsulfonylsulfamoyl, monoalkenylsulfonylsulfamoyl, monoalkynylsulfonylsulfamoyl, aromatic carbocyclyl, optionally substituted with a group A substituent, non-aromatic carbocyclyl, optionally substituted with a group A substituent, aromatic heterocyclyl, optional substituted with a group A substituent, non-aromatic heterocyclyl, optionally substituted with a group A substituent, aromatic carbocyclyloxy, optionally substituted with a group A substituent, non-aromatic carbocyclyloxy, optionally substituted with a group A substituent, aromatic heterocyclyloxy, optionally substituted with a group A substituent, non-aromatic heterocyclyloxy, optionally substituted with a group A substituent, aromatic carbocyclylcarbonyloxy, optionally substituted with a group A substituent, non-aromatic carbocyclylcarbonyloxy, optionally substituted with a group A substituent, aromatic heterocyclylcarbonyloxy, optionally substituted with a group A substituent, non-aromatic heterocyclylcarbonyloxy, optionally substituted with a group A substituent, aromatic carbocyclylcarbonyl, optionally substituted with a group A substituent, non-aromatic tic carbocyclylcarbonyl, optionally substituted a group A substituent, an aromatic heterocyclylcarbonyl optionally substituted with a group A substituent, a non-aromatic heterocyclylcarbonyl optionally substituted with a group A substituent, an aromatic carbocyclyloxycarbonyl optionally substituted with a group A substituent, a non-aromatic carbocyclyloxycarbonyl optionally substituted with a group A substituent, an aromatic heterocyclyloxycarbonyl optionally substituted with a group A substituent, non-aromatic heterocyclyloxycarbonyl, optionally substituted with a group A substituent, aromatic carbocyclylsulfanyl, optionally substituted with a group A substituent, non-aromatic carbocyclylsulfanyl, optionally substituted with a group A substituent, aromatic heterocyclylsulfanyl, optionally substituted with a group A substituent, non-aromatic heterocyclylsulfanyl, optionally substituted with a group A substituent, aromatic carbocyclylsulfanyl, optionally substituted by a substituent group A, non-aromatic carbocyclylsulfinyl, optionally substituted with a group A substituent, aromatic heterocyclylsulfinyl, optionally substituted with a group A substituent, non-aromatic heterocyclylsulfinyl, optionally substituted with a group A substituent, aromatic carbocyclylsulfonyl, optionally substituted with a group A substituent, non-aromatic carbocyclylsulfonyl, optionally substituted with a group A substituent, aromatic heterocyclylsulfonyl , optionally substituted with a group A substituent, non-aromatic heterocyclylsulfonyl, optionally substituted with a group A substituent, aromatic carbocyclylamino, optionally substituted with a group A substituent, non-aromatic carbocyclylamino, optionally substituted with a group A substituent, aromatic heterocyclylamino, optionally substituted with a group A substituent, non-aromatic heterocyclylamino, optionally substituted with a group A substituent leader of the group A, aromatic carbocyclylalkyl, optionally substituted with a Group A substituent, non-aromatic carbocyclylalkyl, optionally substituted with a Group A substituent, aromatic heterocyclylalkyl, optionally substituted with a Group A substituent, non-aromatic heterocyclylalkyl, optionally substituted with a Group A substituent, aromatic carbocyclylalkyloxy, optionally substituted with a Group A substituent, non-aromatic carbocyclylalkyloxy, optionally substituted with a group A substituent, aromatic heterocyclylalkyloxy, optionally substituted with a group A substituent, non-aromatic heterocyclylalkyloxy, optionally substituted with a group A substituent, aromatic carbocyclylalkylcarbonyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylcarbonyl, optionally substituted with a group A substituent, aromatic heterocyclylalkylcarbonyl sludge optionally substituted with a group A substituent , non-aromatic heterocyclylalkyloxycarbonyl, optionally substituted with a Group A substituent, aromatic carbocyclylalkyloxycarbonyl, optionally substituted with a Group A substituent, non-aromatic carbocyclylalkyloxycarbonyl, aromatic heterocyclylalkyloxycarbonyl, optionally substituted with a Group A substituent, non-aromatic heterocyclylalkyloxycarbonyl, optionally substituted with a Group A substituent group A, aromatic carbocyclylalkylsulfanyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylsulfanyl, optionally substituted with a Group A substituent, aromatic heterocyclylalkylsulfanyl, optionally substituted with a Group A substituent, non-aromatic heterocyclylalkylsulfanyl, optionally substituted with a Group A substituent, aromatic carbocyclylalkylsulfinyl, optionally substituted with a Group A substituent, non-aromatic carbocyclylalkylsulfinyl, optionally substituted with a Group A substituent group A substituent, aromatic heterocyclylalkylsulfinyl, optionally substituted with a substituent group A, non-aromatic heterocyclylalkylsulfinyl, optionally substituted with a group A substituent, aromatic carbocyclylalkylsulfonyl, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylsulfonyl, optionally substituted with a group A substituent, aromatic heterocyclylalkylsulfonyl, optionally substituted with a group A substituent, non-aromatic heterocyclylalkylsulfonyl, optionally substituted with a group A substituent, aromatic carbocyclylalkylamino , optionally substituted with a group A substituent, non-aromatic carbocyclylalkylamino, optionally substituted with a group A substituent, aromatic heterocyclylalkylamino, optionally substituted with a group A substituent, non-aromatic heterocyclylalkylamino, optionally substituted with a group A substituent, aromatic carbocyclylalkylamino, optionally substituted with a group A substituent, non-aromatic carbocycle ylalkylcarbonylamino, optionally substituted with a group substituent A, aromatic heterocyclylalkylcarbonylamino, optionally substituted with a Group A substituent, non-aromatic heterocyclylalkylcarbonylamino, optionally substituted with a Group A substituent, aromatic carbocyclylalkyloxycarbonylamino, optionally substituted with a Group A substituent, non-aromatic carbocyclylalkyloxycarbonylamino, optionally substituted with a Group A substituent, aromatic heterocyclylal kyloxycarbonylamino, optionally substituted with a group A substituent, non-aromatic heterocyclylalkyloxycarbonylamino, optionally substituted with a group A substituent, aromatic carbocyclylalkylsulfonylamino, optionally substituted with a group A substituent, non-aromatic carbocyclylalkylsulfonylamino, optionally substituted with a group A substituent, aromatic heterocyclylalkylsulfonylamino, optionally substituted with a group A substituent, non-aromatic heterocyclylalkylsulfonylamino, optionally substituted with a group substituent A, aromatic carbocyclyloxyalkylamino, optionally substituted with a group A substituent , non-aromatic carbocyclyloxyalkylamino optionally substituted with a group A substituent, aromatic heterocyclyloxyalkylamino optionally substituted with a group A substituent and non-aromatic heterocyclyloxyalkylamino optionally substituted with a group A substituent.

[0024]

Embodiments and preferred embodiments of each substituent in the compound represented by formula (I) are presented below. The following compounds containing possible combinations of embodiments of each substituent are preferred.

[0025]

R ¹ includes hydrogen, hydroxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocycle yl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl yl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl.

A preferred embodiment of R ¹ is hydrogen or hydroxy.

A more preferred embodiment of R ¹ is hydrogen.

Examples of the substituent when R ¹ is unsubstituted include halogen, hydroxy, amino, alkyl, monoalkylamino, dialkylamino, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl or non-aromatic heterocyclyl.

[0026]

In a preferred embodiment, R ^2a and R ^2b together with the adjacent carbon atom form a B ring.

As another embodiment of R ^2a and R ^2b , the following embodiments are also preferred,

R ^2a is a group represented by the formula:

, And

R ^2b is hydrogen, cyano, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkylsulfonyl.

A more preferred embodiment of R ^2b is hydrogen or substituted or unsubstituted alkyl.

A particularly preferred embodiment of R ^2b is substituted or unsubstituted alkyl, and alkyl and haloalkyl are particularly preferred.

Examples of the substituent when R ^2b is unsubstituted include halogen.

[0027]

Ring B includes a substituted or unsubstituted non-aromatic carbocycle, or a substituted or unsubstituted non-aromatic heterocycle.

A preferred embodiment of ring B is the group represented by the formula:

.

A more preferred embodiment of ring B is the group represented by the formula:

.

A particularly preferred embodiment of ring B is the group represented by the formula:

.

Another preferred embodiment of ring B is the group represented by the formula:

and more preferably includes a group represented by the formula:

Another preferred embodiment of ring B is the group represented by the formula:

more preferably includes a group represented by the formula:

and especially more preferably includes the group represented by the formula:

Another preferred embodiment of ring B is the group represented by the formula:

more preferably includes a group represented by the formula:

Another preferred embodiment of ring B is the group represented by the formula:

more preferably includes a group represented by the formula:

[0028]

According to another aspect, B is a group represented by the formula:

[0029]

Ring D includes an aromatic carbocycle, a non-aromatic carbocycle, an aromatic heterocycle, or a non-aromatic heterocycle.

A preferred embodiment of the D ring is an aromatic carbocycle.

[0030]

B ¹ includes CR ^11a R ^11b , NR ^11c , O or S.

A preferred embodiment of B ¹ is CR ^11a R ^11b .

A more preferred embodiment of B ¹ is C.

[0031]

B ² includes CR ^12a R ^12b , NR ^12c , O or S.

A preferred embodiment of B ² is CR ^12a R ^12b .

A more preferred embodiment of B ² is C.

[0032]

B ³ includes CR ^13a R ^13b , NR ^13c , O or S.

A preferred embodiment of B ³ is CR ^13a R ^13b or O.

A specific embodiment of B ³ is, for example, CH ₂ and O.

[0033]

B ⁴ includes CR ^14a R ^14b , NR ^14c , O or S.

A preferred embodiment of B ⁴ is CR ^14a R ^14b .

A particular preferred embodiment of B ⁴ is CH ₂ or CF ₂ .

[0034]

B ⁵ includes CR ^15a R ^15b , NR ^15c , O or S.

A preferred embodiment of B ⁵ is CR ^15a R ^15b .

A particular preferred embodiment of B ⁵ is CH ₂ .

[0035]

provided that three or more identical atoms of any of N, O, and S in -B ¹ -B ² -B ³ -B ⁴ - or -B ¹ -B ² -B ³ -B ⁴ -B ⁵ - not connected in series like -OOOO-, -SSSS-, etc.

[0036]

each R ^11a , R ^12a , R ^13a , R ^14a and R ^15a independently represents hydrogen, halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcar bonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfine yl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy , substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl anyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted substituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -LN=S(= O)(-R ^S1 )-R ^S2 , group represented by the formula: -LS(=O)(=NR ^N )-R ^S1 , group represented by the formula: -N=S(=NR ^N )(-R ^S1 ) -R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 .

In this document, each group represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , a group represented by the formula: -LS(=O)(=NR ^N )-R ^S1 , a group represented by formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , and the group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 is characterized by the following structures:

A preferred embodiment of each of R ^11a , R ^12a , R ^13a , R ^14a and R ^15a is independently hydrogen, halogen, or substituted or unsubstituted alkyl.

A more preferred embodiment of each of R ^11a , R ^12a , R ^13a , R ^14a and R ^15a is independently hydrogen or halogen.

When R ^11a , R ^12a , R ^13a , R ^14a and R ^15a are substituted, each substituent is independently halogen, hydroxy, amino, alkyl, monoalkylamino, dialkylamino, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl or non-aromatic heterocyclyl .

[0037]

R ^11b , R ^12b , R ^13b , R ^14b and R ^15b are each independently hydrogen, halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkyl car bonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfine yl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy , substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl anyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted substituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -LN=S(= O)(-R ^S1 )-R ^S2 , group represented by the formula: -LS(=O)(=NR ^N )-R ^S1 , group represented by the formula: -N=S(=NR ^N )(-R ^S1 ) -R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 .

A preferred embodiment of each of R ^11b , R ^12b , R ^13b , R ^14b and R ^15b is independently hydrogen or halogen.

When R ^11b , R ^12b , R ^13b , R ^14b and R ^15b are substituted, each substituent is independently halogen, hydroxy, amino, alkyl, monoalkylamino, dialkylamino, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl or non-aromatic heterocyclyl .

[0038]

Each R ^11c , R ^12c , R ^13c , R ^14c and R ^15c independently includes hydrogen, cyano, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted ny or unsubstituted guanidino , pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted substituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-ar omatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted substituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocycle ylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl.

A preferred embodiment of each of R ^11c , R ^12c , R ^13c , R ^14c and R ^15c is independently hydrogen, halogen, or substituted or unsubstituted alkyl.

A more preferred embodiment of R ^11c , R ^12c , R ^13c , R ^14c and R ^15c is hydrogen.

When R ^11c , R ^12c , R ^13c , R ^14c and R ^15c are substituted, each substituent is independently halogen, hydroxy, amino, alkyl, monoalkylamino, dialkylamino, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl or non-aromatic heterocyclyl .

[0039]

R ^11a and R ^12a , R ^12a and R ^13a , R ^13a and R ^14a , and/or R ^14a and R ^15a , together with adjacent carbon atoms, can form a substituted or unsubstituted aromatic carbocycle, a substituted or unsubstituted non-aromatic carbocycle, a substituted or unsubstituted aromatic heterocycle , or a substituted or unsubstituted non-aromatic heterocycle,

and/or R ^11c and R ^12a , R ^11c and R ^12c , R ^12c and R ^11a , R ^12c and R ^13a , R ^12c and R ^13c , R ^13c and R ^12a , R ^13c and R ^14a , R ^13c and R ^14c , R ^14c and R ^13a , R ^14c and R ^15a , R ^14c and R ^15c , and/or R ^15c and R ^14a together with adjacent atoms can form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted non-aromatic heterocycle,

and/or R ^11a and R ^13a , R ^11a and R ^13c , R ^11a and R ^14a , R ^11a and R ^14c , R ^11a and R ^15a , R ^11a and R ^15c , R ^11c and R ^13a , R ^11c and R ^13c , R ^11c and R ^14a , R ^11c and R ^14c , R ^11c and R ^15a , R ^11c and R ^15c , R ^12a and R ^14a , R ^12a and R ^14c , R ^12a and R ^15a , R ^12a and R ^15c , R ^12c and R ^14a , R ^12c and R ^14c , R ^12c and ^{R 15a} , R 12c and R ^15c , R ^13a and R ^15a , R ^13a and R ^15c , R ^13c and R ^15a , and/or R ^13c and R ^15c together can form a C2-C4 bridge, optionally containing heteroatom(s),

and/or R ^11b and R ^12b , R ^11b and R ^12c , R ^11c and R ^12b , R ^{11c and R 12c, R 12b and R 13b} , R ^12b and R ^13c , R ^12c and R ^13b , R ^12c and R ^13c , R ^13b and R ^14b , R ^13b and R ^14c , R ^13c and R ^14b , R ^13c and R ^14c , R ^14b and R ^15b , R ^14b and R ^15c , R ^14c and R ^15b , and/or R ^14c and R ^15c together can form a bond.

[0040]

n includes an integer from 1 to 4.

A preferred embodiment of n is an integer between 1 and 3.

A more preferred embodiment of n is 1 or 2.

[0041]

each R ^S1 and R ^S2 independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, or R ^S1 and R ^S2 related to with the same sulfur atom, can, together with the sulfur atom, form a substituted or unsubstituted non-aromatic heterocycle.

In a preferred embodiment, R ^S1 and R ^S2 are each independently hydrogen or substituted or unsubstituted alkyl.

A more preferred embodiment of R ^S1 and R ^S2 is hydrogen.

Examples of the substituent when ^RS1 and ^RS2 are substituted each independently include halogen, hydroxy, amino, alkyl, alkyloxy, monoalkylamino, dialkylamino, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl or non-aromatic heterocyclyl.

[0042]

Each R ^N independently includes, cyano, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, or substituted or unsubstituted non-aromatic heterocyclylcarbonyl.

The preferred embodiment of each R ^N is independently hydrogen or substituted or unsubstituted alkyl.

A more preferred embodiment of each R ^N is independently substituted or unsubstituted alkyl.

When each ^RN is substituted, examples of the substituent independently include halogen, hydroxy, amino, alkyl, alkyloxy, monoalkylamino, dialkylamino, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl or non-aromatic heterocyclyl.

[0043]

Each L independently includes a single bond, alkylene, or C(=O).

The preferred embodiment of each L is independently a single bond or alkylene.

A more preferred embodiment of L is a single bond.

[0044]

m includes an integer from 1 to 5.

A preferred embodiment of m is an integer from 1 to 3.

A more preferred embodiment of m is 1 or 2.

[0045]

Ring C includes an aromatic carbocycle, an aromatic heterocycle, a non-aromatic carbocycle, or a non-aromatic heterocycle.

A preferred embodiment of the C ring is an aromatic carbocycle or an aromatic heterocycle.

A more preferred embodiment of the C ring is benzene, naphthalene, indane, pyridine, pyrimidine, pyrazole, piperidine, piperazine, benzodioxole, benzothiophene or thiazole.

A more preferred embodiment of the C ring is benzene or pyridine.

A particularly preferred embodiment of the C ring is benzene.

[0046]

Each R ⁵ independently includes halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocycle yl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted substituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl , substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, group represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , group represented by the formula : -LS(=O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 .

A preferred embodiment of each R ⁵ is independently halogen, cyano, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyloxy, or substituted or unsubstituted non-aromatic heterocyclyloxy.

A more preferred embodiment of each R ⁵ is independently halogen, cyano, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted ny non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyloxy, or substituted or unsubstituted non-aromatic heterocyclyloxy.

An even more preferred embodiment of each R ⁵ is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted displaced non-aromatic carbocyclyloxy, or substituted or unsubstituted non-aromatic heterocyclyloxy.

A particularly preferred embodiment of R ⁵ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl.

When R ⁵ is unsubstituted, examples of the substituent include halogen, alkyl, haloalkyl, cyanoalkyl, alkyloxyalkyl, haloalkylcarbonyl, non-aromatic carbocyclyl, non-aromatic heterocyclyl, non-aromatic carbocyclyl alkyl, aromatic heterocyclyl alkyl or non-aromatic heterocyclyl alkyl.

[0047]

R ^3a includes hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted substituted non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted substituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl.

A preferred embodiment of R ^3a is hydrogen.

When R ^3a is unsubstituted, examples of the substituent include halogen, hydroxy, amino, alkyl, monoalkylamino, dialkylamino, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl or non-aromatic heterocyclyl.

[0048]

R ^3b includes hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted substituted non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted substituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl.

A preferred embodiment of R ^3b is hydrogen.

When R ^3b is unsubstituted, examples of the substituent include halogen, hydroxy, amino, alkyl, monoalkylamino, dialkylamino, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl or non-aromatic heterocyclyl.

[0049]

R ^4a includes the group represented by the formula:

A more preferred embodiment of R ^4a is

[0050]

R ^4b includes halogen, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted not aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbon yloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbo cyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, group represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , group represented by the formula: -LS( =O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ - R ^S1 .

A preferred embodiment of R ^4b is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl.

A more preferred embodiment of R ^4b is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted aromatic heterocyclyl.

When R ^4b is unsubstituted, examples of the substituent include halogen, hydroxy, cyano, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkyloxy, haloalkyloxy, alkylsulfonyl, dialkylamino, aromatic carbocyclyl optionally substituted with a group B substituent, non-aromatic carbocyclyl optionally substituted with a substituent group B, an aromatic heterocyclyl optionally substituted with a group B substituent, and a non-aromatic heterocyclyl optionally substituted with a group B substituent.

When R ^4b is unsubstituted, preferred substituents include halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, haloalkyloxy, alkylsulfonyl, aromatic carbocyclyl optionally substituted with a group B substituent, non-aromatic carbocyclyl optionally substituted with a group B substituent, aromatic heterocyclyl, optionally substituted with a group B substituent, non-aromatic heterocyclyloxy, optionally substituted with a group B substituent, aromatic carbocyclyloxy, optionally substituted with a group B substituent, non-aromatic carbocyclyloxy, optionally substituted with a group B substituent, aromatic heterocyclyloxy, optionally substituted with a group B substituent, and non-aromatic heterocyclyloxy, optionally substituted with a group B substituent B.

[0051]

L ³ includes a single bond or a substituted or unsubstituted alkylene.

A preferred embodiment of L ³ is a single bond, unsubstituted alkylene or alkylene substituted with halogen.

A particular preferred embodiment of L ³ is a single bond, methylene, or a group represented by the formula:

[0052]

R ⁷ includes hydrogen, halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic car bocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl , substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy , substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl bonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfonyl , substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -N=S(=O)(-R ^S1 )-R ^S2 , a group represented by the formula: -S(= O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(=NR ^N ) ₂ -R ^S1 .

A preferred embodiment of R ⁷ is halogen, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or a group represented by the formula: -S(=O)(=NR ^N )-R ^S1 .

When R ⁷ is unsubstituted, examples of the substituent include oxo, halogen, cyano, hydroxy, alkyl, haloalkyl, alkyloxy, haloalkyloxy, hydroxyalkyl, alkylcarbonyl or alkylsulfonyl.

[0053]

Each of R ⁶ independently includes halogen, hydroxy, cyano, carboxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl , substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclylcarbonyloxy, substituted or unsubstituted aromatic heterocyclylcarbonyloxy, substituted or unsubstituted non-aromatic heterocyclylcarbonyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl yl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl , substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, a group represented by the formula: -LN=S(=O)(-R ^S1 )-R ^S2 , a group represented by formula: -LS(=O)(=NR ^N )-R ^S1 , a group represented by the formula: -N=S(=NR ^N )(-R ^S1 )-R ^S2 , or a group represented by the formula: -S(= NR ^N ) ₂ -R ^S1 .

A preferred embodiment of each R ⁶ is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted not aromatic carbocyclyl , substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyl sulfonyl, or substituted or unsubstituted non-aromatic heterocyclyl sulfone ill.

A more preferred embodiment of each R ⁶ is independently halogen, or substituted or unsubstituted alkyloxy.

A more preferred embodiment of each R ⁶ is independently halogen or haloalkyloxy.

When R ⁶ is unsubstituted, examples of the substituent include halogen, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkyloxy, haloalkyloxy, alkyloxyalkyl, haloalkylcarbonyl, alkyloxycarbonylalkyl, aromatic carbocyclyl optionally substituted with a group B substituent, non-aromatic carbocyclyl optionally substituted with a substituent Group B , aromatic heterocyclyl, optionally substituted with a group B substituent, non-aromatic heterocyclyl, optionally substituted with a group B substituent, aromatic carbocyclyloxy, optionally substituted with a group B substituent, non-aromatic carbocyclyloxy, optionally substituted with a group B substituent, aromatic heterocyclyloxy, optionally substituted with a group B substituent, and non-aromatic heterocyclyloxy, optionally substituted with a group B substituent.

[0054]

Each R ¹⁶ independently includes hydrogen, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted amino, substituted or unsubstituted ureido, substituted or unsubstituted guanidino, pentafluorothio, sulfo, substituted or unsubstituted substituted sulfamoyl, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted ny alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkylsulfinyl , substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocycle yl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocycle ylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocycle ilsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, etc. p.

A preferred embodiment of R ¹⁶ is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted substituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted an aromatic heterocyclylcarbonyl, or a substituted or unsubstituted non-aromatic heterocyclylcarbonyl.

A preferred embodiment of R ¹⁶ is substituted or unsubstituted alkyl, aromatic carbocyclyl optionally substituted with a group B substituent, non-aromatic carbocyclyl optionally substituted with a group B substituent, aromatic heterocyclyl optionally substituted with a group B substituent, non-aromatic heterocyclyl optionally substituted with a group B substituent, aromatic carbocyclylcarbonyl, optionally substituted with a group B substituent, a non-aromatic carbocyclylcarbonyl optionally substituted with a group B substituent, an aromatic heterocyclylcarbonyl optionally substituted with a group B substituent, or a non-aromatic heterocyclylcarbonyl optionally substituted with a group B substituent.

A particularly preferred embodiment of R ¹⁶ is an aromatic carbocyclyl, optionally substituted with a group B substituent.

When R ¹⁶ is unsubstituted, examples of the substituent include halogen, alkyl, haloalkyl, aromatic carbocyclyl optionally substituted with a group B substituent, non-aromatic carbocyclyl optionally substituted with a group B substituent, aromatic heterocyclyl optionally substituted with a group B substituent, and non-aromatic heterocyclyl optionally substituted with a group B substituent.

[0055]

A characteristic feature of the compound of the present invention is that it has MGAT2 inhibitory activity through conversion to the dihydropyrazolopyrazinone derivative represented by formula (I). Moreover, another characteristic is that the dihydropyrazolopyrazinone derivative represented by formula (I) has a structure in which a pyrazole ring is fused with a dihydropyrazinone ring, an enone structure can be avoided, and toxicity can be suppressed. In addition, a characteristic feature of the dihydropyrazolopyrazinone derivative represented by formula (I) is that it has high solubility and metabolic stability, and high stability in acidic solution.

[0056]

The compounds represented by formula (I) are not limited to specific isomers, but include all possible isomers (eg, keto-enol isomers, imine-enamine isomers, diastereoisomers, enantiomers, rotamers, etc.), racemates and mixtures thereof.

[0057]

One or more hydrogen, carbon and/or other atoms in the compounds represented by formula (I) may be replaced by isotopes of hydrogen, carbon and/or other atoms, respectively. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P , ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ³⁶ Cl, respectively. The compounds represented by formula (I) also include those substituted with the indicated isotopes. The isotope-substituted compounds are useful as drugs and include all radiolabeled compounds represented by formula (I). “Method of radioactive isotope labeling” for the production of “radiolabeled compounds” is covered by the present invention, and “radiolabeled compounds” are useful for studies of the pharmacokinetics of a metabolizable compound, for binding assays and/or as diagnostic agents.

[0058]

The radiolabeled compounds represented by formula (I) can be prepared using methods well known in the art. For example, a tritium-labeled compound represented by formula (I) can be prepared by introducing tritium into a certain compound represented by formula (I) through a catalytic dehalogenation reaction using tritium. This method involves reacting an appropriately halogen-substituted precursor of the compound represented by formula (I) with tritium gas in the presence of a suitable catalyst such as Pd/C, in the presence or absence of a base. For another suitable method for preparing a tritium-labeled compound, see Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)." ^{The 14} C-labeled compound can be prepared by using a starting material containing ¹⁴ C.

[0059]

Pharmaceutically acceptable salts of the compounds represented by formula (I) include, for example, salts of the compounds represented by formula (I) with an alkali metal (eg, lithium, sodium, potassium, etc.), alkaline earth metal ( e.g. calcium, barium, etc.), magnesium, transition metal (e.g. zinc, iron, etc.), ammonium, organic bases (e.g. trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine , meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) or amino acids, or salts with inorganic acids (for example, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, and etc.) or organic acids (for example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). Primarily included are salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, and the like. Said salts can be prepared by conventional methods.

[0060]

The compounds represented by formula (I) according to the present invention, or pharmaceutically acceptable salts thereof, can form a solvate (eg, hydrate), co-crystal and/or crystal polymorph. The present invention also covers such various solvates, cocrystals and crystalline polymorphs. A “solvate” may be a solvate in which any number of solvent molecules (eg, water molecules, etc.) are in coordination with the compounds represented by formula (I). If the compounds represented by formula (I) or their pharmaceutically acceptable salts are allowed to settle in the atmosphere, the compounds may absorb water, resulting in the addition of the absorbed water and the formation of hydrates. By recrystallization of the compounds represented by formula (I) or pharmaceutically acceptable salts thereof, a crystalline polymorph can be obtained. The term "co-crystal" means that the compounds represented by formula (I), or salts thereof, and a countermolecule are present in the same crystal lattice, and a co-crystal with any number of countermolecules can be formed.

[0061]

The compounds represented by formula (I) according to the present invention, or a pharmaceutically acceptable salt thereof, can form prodrugs. The present invention also covers such various prodrugs. Prodrugs are derivatives of compounds of the present invention that contain chemically or metabolically degradable groups, and compounds that are converted to pharmaceutically active compounds of the present invention by solvolysis or under physiological conditions in vivo . Prodrugs include compounds that are converted to the compounds represented by formula (I) by enzymatic oxidation, reduction, hydrolysis, and the like. under physiological conditions and in vivo , compounds which are converted to the compounds represented by formula (I) by hydrolysis by gastric juice, etc., etc. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs themselves may have some activity.

[0062]

If the compounds represented by formula (I) or a pharmaceutically acceptable salt thereof contain hydroxy group(s), the prodrugs include acyloxy derivatives and sulfonyloxy derivatives, which are prepared, for example, by reacting the hydroxy group(s) containing compounds with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride and a mixed anhydride or with a condensing agent. Examples include CH ₃ COO-, C ₂ H ₅ COO-, tert-BuCOO-, C ₁₅ H ₃₁ COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH ₂ CH ₂ COO-, CH ₃ CH(NH ₂ )COO-, CH ₂ N(CH ₃ ) ₂ COO-, CH ₃ SO ₃ -, CH ₃ CH ₂ SO ₃ -, CF ₃ SO ₃ -, CH ₂ FSO ₃ -, CF ₃ CH ₂ SO ₃ -, pair - CH ₃ O-PhSO ₃ -, PhSO ₃ - and para- CH ₃ PhSO ₃ -.

[0063]

(Production method of the compound of the present invention)

For example, the compound represented by formula (I) according to the present invention can be prepared according to the general procedure described below. During extraction, purification and other operations, any method usually used for this in organochemical experiments can be used.

The compound of the present invention can be synthesized in accordance with a method known in the art.

[0064]

(General technique)

The compound represented by formula (I) according to the present invention (a17 below) can be produced, for example, according to the following production method.

where the meaning of each symbol is described above.

Stage A-1

Compound a2 can be prepared by reacting Compound a1 with tert-butylsulfinamide with tetraisopropoxytitanium, tetraethoxyethane, etc.

The reaction temperature is from 20°C to 120°C and preferably from 70°C to 100°C.

The reaction time is from 1 hour to 12 hours and preferably from 3 hours to 6 hours.

As the reaction solvent, examples are tetrahydrofuran, 2-methyltetrahydrofuran and toluene.

Stage A-2

After the reaction is carried out, a base such as lithium diisopropylamide or lithium hexamethyldisilazide and compound a3, optionally titanium triisopropoxide, etc. are added and Compound a2 is reacted to obtain Compound a4.

As R in Compound a3, examples are methyl, ethyl and tert-butyl.

The reaction temperature for the reaction between a base such as lithium diisopropylamide or lithium hexamethyldisilazide and ester a3 and subsequent reaction with Compound a2 is -78°C to -20°C.

The reaction time between the base and ester a3 is from 30 minutes to 2 hours, and the subsequent reaction time with Compound a2 is from 1 to 5 hours.

As the reaction solvent, examples are tetrahydrofuran and diethyl ether.

Stage A-3

Compound a5 can be prepared by reacting Compound a4 with an acid or Lewis acid, followed by reacting it with Boc ₂ O in the presence of a base.

As an acid, examples are hydrochloric acid in ethyl acetate, hydrochloric acid in methanol, hydrochloric acid in dioxane, sulfuric acid, formic acid and trifluoroacetic acid. Examples of Lewis acid include trimethylsiliodide, BBr ₃ , AlCl ₃ and BF ₃ ∙(Et ₂ O). Relative to compound a4, 1 to 10 molar equivalents of acid or Lewis acid can be used.

As the base, examples include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine and triethylamine, and relative to compound a4, 3 to 15 molar equivalents of base can be used.

The reaction temperature is from 0°C to 60°C and preferably from 0°C to 20°C.

The reaction time is from 0.5 hour to 24 hours and preferably from 6 hours to 18 hours.

As the reaction solvent, examples include methanol, ethanol, water, acetone, acetonitrile and DMF, and these solvents can be used alone or in combination.

Stage A-4

Compound a5 can be prepared by reacting Compound a6 with a reducing agent.

As a reducing agent, examples are lithium borohydride and lithium aluminum hydride. Regarding compound a5, 1 to 10 molar equivalents of reducing agent can be used.

The reaction temperature is from 0°C to the sublimation temperature, preferably from 20°C to the sublimation temperature.

The reaction time is from 0.2 hour to 48 hours and preferably from 1 hour to 24 hours.

As the reaction solvent, examples include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, dichloromethane and water, and these reaction solvents can be used alone or in combination.

Stage A-5

Compound a7 can be prepared by reacting Compound a6 with an oxidizing agent such as 2-iodoxybenzoic acid or Dess-Martin periodinane.

The reaction temperature is from -10°C to 50°C and preferably from 0°C to 30°C.

The reaction time is from 1 hour to 24 hours and preferably from 5 hours to 20 hours.

Dimethyl sulfoxide, etc. can be used as the reaction solvent.

Stage A-6

Compound a8 can be prepared by reacting Compound a7 with osmium tetroxide, 4-methylmorpholine, 4-methylmorpholine-N-oxide, sodium periodate, etc.

The reaction temperature is from -10°C to 50°C and preferably from 0°C to 30°C.

The reaction time is from 1 hour to 24 hours and preferably from 5 hours to 20 hours.

A mixed solvent of acetone and water, etc. can be used as the reaction solvent.

Stage A-7

Compound a10 can be prepared by reacting Compound a8 with nucleophile a9.

Examples of nucleophile a9 include lithium reagent such as methyllithium, ethyl lithium, etc., Grignard reagent such as methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium iodide, etc., and a metal salt reagent mixed thereof, and relative to Compound a8, 1 to 5 molar equivalents may be used.

The reaction temperature is from -78°C to the sublimation temperature of the solvent, preferably from -45°C to 0°C.

The reaction time is from 0.5 to 24 hours, preferably from 1 hour to 6 hours.

As the reaction solvent, tetrahydrofuran, hexane, diethyl ether, methyl tert-butyl ether, toluene, dichloromethane and methanol are exemplified, and these reaction solvents can be used alone or in combination.

Nucleophile a9 can be prepared by lithiation of a halide with an alkyl lithium such as n- butyllithium.

The reaction solvent is not particularly limited as long as it is not a solvent such as tetrahydrofuran and dioxane that does not react with alkyllithium. The lithiation temperature is preferably from about -78°C to 0°C.

The compound where R ^3b is hydrogen can be prepared by reacting with a reducing agent such as sodium borohydride, lithium borohydride or lithium aluminum hydride in place of nucleophile a9.

Stage A-8

Compound a11 can be prepared by reacting Compound a10 with thionyl chloride and a base.

As a base, examples include pyridine, triethylamine and diisopropylethylamine, and relative to Compound a10, 1 to 5 molar equivalents can be used.

The reaction temperature is from -10°C to 50°C and preferably from 0°C to 30°C.

The reaction time is from 1 hour to 24 hours and preferably from 5 hours to 10 hours.

Acetonitrile, dioxane, tetrahydrofuran, DMF, etc. can be used as the reaction solvent.

Stage A-9

Compound a12 can be prepared by reacting Compound a11 with ruthenium chloride hydrate, sodium periodate, etc.

The reaction temperature is from -10°C to 50°C and preferably from 0°C to 30°C.

The reaction time is from 1 hour to 24 hours and preferably from 5 hours to 20 hours.

As the reaction solvent, a mixed solvent of ethyl acetate and water, etc. can be used.

Stage A-10

Compound a14 can be prepared by reacting Compound a12, Compound a13 and a base.

As the base, examples include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine and triethylamine, and relative to Compound a13, 1 to 5 molar equivalents of the base can be used.

The reaction temperature is from 0°C to 150°C and preferably from 50°C to 100°C.

The reaction time is from 0.5 hour to 24 hours and preferably from 1 hour to 5 hours.

As the reaction solvent, examples include methanol, ethanol, acetonitrile and DMF, and these reaction solvents can be used alone or in combination.

Stage A-11

Compound a15 can be prepared by reacting Compound a14 with a base.

As a base, examples include sodium hydroxide, potassium hydroxide and sodium hydride, and with respect to Compound a14, 1 to 5 molar equivalents can be used.

The reaction temperature is from 0°C to 100°C and preferably from 0°C to 30°C.

The reaction time is from 0.5 hour to 24 hours and preferably from 1 hour to 5 hours.

As the reaction solvent, examples include methanol, ethanol, acetonitrile, water and DMF, and these reaction solvents can be used alone or in combination.

Stage A-12

Compound a16 can be prepared by reacting Compound a15 with an acid or Lewis acid.

As an acid, examples are hydrochloric acid in ethyl acetate, hydrochloric acid in methanol, hydrochloric acid in dioxane, sulfuric acid, formic acid and trifluoroacetic acid. Examples of Lewis acid include trimethylsilyl iodide, BBr ₃ , AlCl ₃ and BF ₃ ∙ (Et ₂ O). Regarding Compound a15, from 1 to 50 molar equivalents of acid or Lewis acid can be used.

The reaction temperature is from 0°C to 60°C and preferably from 0°C to 20°C.

The reaction time is from 0.5 hour to 24 hours and preferably from 6 hours to 18 hours.

As the reaction solvent, examples include ethyl acetate, methanol, ethanol, water, acetonitrile, acetonitrile and DMF, and these reaction solvents can be used alone or in combination.

Stage A-13

Compound a17 can be prepared by reacting Compound a16 with a condensing agent and a base.

As a condensing agent, examples include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and HATU. Regarding Compound a16, 1 to 5 molar equivalents of condensing agent can be used.

As a base, examples include triethylamine and diisopropylethylamine, and relative to Compound a16, 1 to 5 molar equivalents can be used.

The reaction temperature is from -20°C to 60°C and preferably from 0°C to 30°C.

The reaction time is from 0.1 hour to 24 hours and preferably from 1 hour to 5 hours.

As the reaction solvent, examples are DMF, DMA, NMP, tetrahydrofuran, dioxane, dichloromethane and acetonitrile, and these reaction solvents can be used alone or in combination.

[0065]

The compounds of the present invention have MGAT2 inhibitory activity and are useful as a prophylactic and/or therapeutic agent for, for example, obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyper-VLDL-triglyceridemia, hyperlipoacidemia, diabetes mellitus or arteriosclerosis.

The compounds of the present invention not only have MGAT2 inhibitory activity, but are also useful as a drug, and have any or all of the following superiority features:

a) the presence of high metabolic stability,

b) display of high solubility,

c) presence of a reduced risk of phototoxicity,

d) presence of a reduced risk of hepatotoxicity,

e) presence of a reduced risk of renal toxicity,

f) presence of a reduced risk of cardiovascular toxicity,

g) presence of a reduced risk of gastrointestinal disorders,

h) presence of a reduced risk of drug interactions,

i) the presence of high oral absorption,

j) the presence of low clearance,

k) presence of high distribution in the target tissue,

l) the presence of intense enzymatic activity,

m) reduced induction of a drug-metabolizing enzyme,

n) the presence of pronounced effectiveness,

o) the presence of high selectivity of inhibitory activity against MGAT2 and

p) the presence of high chemical stability.

[0066]

The pharmaceutical composition according to the present invention can be administered orally or parenterally. Methods of parenteral administration include dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, inner ear, or vaginal.

[0067]

In the case of oral administration, any commonly used forms may be prepared and administered, such as oral solid formulations (eg, tablets, powders, granules, capsules, pills or films) and oral liquid formulations (eg, suspension, emulsion) , elixir, syrup, lemonade, alcohol solution, flavored water, extract, decoction or tincture). The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, buccal tablets, chewable tablets or orally dispersible tablets. Powders and granules can be in the form of dry syrup. The capsules may be soft capsules, microcapsules or sustained release capsules.

[0068]

In the case of parenteral administration, any commonly used forms may preferably be administered, such as injections, droppers and topical preparations (eg, eye drops, nasal drops, ear drops, aerosols, inhalations, lotion, infusion, liniment, mouthwash cavities, enema, ointment, plaster, jelly, cream, patch, hot compress, topical powder or suppository). Injections can be emulsions of the oil/water, water/oil, oil/water/oil, water/oil/water, etc. type emulsions.

[0069]

The pharmaceutical composition can be prepared by mixing an effective amount of a compound of the present invention with various pharmaceutical additives suitable for the formulation, such as fillers, binders, disintegrants, lubricants and diluents. In addition, the pharmaceutical composition can be adapted for pediatric patients, geriatric patients, serious cases or surgical procedures by appropriately changing the effective amount of the compound of the present invention, the composition and/or various pharmaceutical additives. Pediatric pharmaceutical compositions are preferably administered to patients under 12 or 15 years of age. In addition, pediatric pharmaceutical compositions can be administered to patients aged less than 27 days after birth, from 28 days to 23 months after birth, from 2 to 11 years, from 12 to 16 years, or 18 years. Geriatric pharmaceutical compositions are preferably administered to patients aged 65 years and older.

[0070]

Although the dosage of the pharmaceutical composition according to the present invention should be determined taking into account the age and body weight of the patient, the type and severity of diseases, route of administration, etc., the usual oral dosage is from 0.05 to 100, and preferably from 0 ,1 to 10 mg/kg per day. For parenteral administration, although the dosage varies greatly depending on the route of administration, the usual dosage is from 0.005 to 10 mg/kg per day, and preferably from 0.01 to 1 mg/kg per day. The dosage can be administered once or in several portions throughout the day.

[0071]

The dosage for co-administered drugs may be suitably selected based on the clinical dose. The formulation ratio of the compounds of the present invention and the co-administered drugs can be suitably selected depending on the subject to be treated, the route of administration, the disease to be treated, symptoms, drug combination, and the like. For administration to humans, for example, 1 part by weight of the compounds of the present invention can be used in combination with 0.01 to 100 parts by weight of co-administered drugs.

[0072]

The pharmaceutical composition of the present invention is also effective in obesity (however, only if both type 2 diabetes and dyslipidemia are present and the BMI is 25 kg/m ² or more, even in the presence of diet/exercise therapy).

[0073]

The pharmaceutical composition according to the present invention is also effective in severe obesity, for which the effect of previously applied diet and exercise therapy is insufficient.

[0074]

The pharmaceutical composition according to the present invention can be used in combination with other anti-obesity agent(s) (a pharmaceutical composition containing compounds having an anti-obesity effect or a medical agent for obesity or for weight control in obesity). For example, for the prevention and/or treatment of obesity or for weight control in obesity, combination treatment with a pharmaceutical composition containing a compound having an anti-obesity effect and a compound of the present invention can be used. Combination treatment of a pharmaceutical composition containing a compound of the present invention and a pharmaceutical composition(s) containing a compound having an anti-obesity effect can be used for the prevention and/or treatment of obesity or for weight control in obesity. In addition, the treatment method by administering the pharmaceutical composition according to the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.

[0075]

In the present description, the meanings of each abbreviation are as follows:

Boc: tert-butoxycarbonyl

DMA: Dimethylacetamide

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et: ethyl

HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

NMP: N-methylpyrrolidone

[0076]

The present invention will be described in more detail with reference to, but without limitation, the following Examples and Test Examples.

Presents the NMR spectra of the compound of the present invention and its intermediate. The NMR analysis done in each Example was performed at 400 MHz and measured using deuterated chloroform (CDCl ₃ ) or dimethyl sulfoxide (d6-DMSO).

[Example 1]

[0077]

Stage 1

Synthesis of Compound 2

(R)-2-Methylpropane-2-sulfinamide (631 mg, 5.21 mmol) was dissolved in toluene (2.5 ml) and tetraethoxytitanium (0.654 ml, 3.12 mmol) was added. Thereafter, known compound 1 (384 mg, 2.08 mmol) was dissolved in toluene (2.5 ml) and added. The mixture was stirred at 100°C for 3 hours. Then, at room temperature, an aqueous solution of citric acid and ethyl acetate were added to it, the insoluble substance was filtered, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 2 (428 mg, 72% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.32 (s, 9H), 3.31-3.38 (m, 1H), 3.45-3.52 (m, 1H), 4.27-4 .33 (m, 1H), 4.36-4.41 (m, 1H), 6.43-6.49 (m, 2H).

Stage 2

Synthesis of Compound 3

To a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (2.23 ml, 2.23 mmol) at -78°C, tetrahydrofuran (1 ml) and methyl acetate (0.178 ml, 2.23 mmol) were added and stirred for 1 hour. Thereafter, a 1 M solution of titanium triisopropoxide-chloride in hexane (2.98 mL, 2.98 mmol) was added dropwise at -78°C and the mixture was stirred for 30 minutes. Compound 2 (428 mg, 1.49 mmol) was then dissolved in tetrahydrofuran (1 ml), added dropwise at -78°C, and the mixture was stirred for 4 hours. After this, a 10% aqueous solution of citric acid and Rochelle salt were added, the mixture was heated to room temperature and stirred for 12 hours. Then, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate, water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 3 (305 mg, 57% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.22 (s, 9H), 2.19-2.27 (m, 1H), 2.45-2.49 (m, 1H), 2.74 (d , J=15.9 Hz, 1H), 3.40 (d, J=15.9 Hz, 1H), 3.70 (s, 3H), 4.19-4.24 (m, 1H), 4 .51-4.57 (m, 1H), 5.02 (s, 1H), 6.36-6.47 (m, 2H).

Stage 3

Synthesis of Compound 4

Compound 3 (2.31 g, 6.40 mmol) was dissolved in methanol (18.5 ml), a 4 mol/L solution of hydrogen chloride in dioxane (3.20 ml, 12.8 mmol) was added and the mixture was stirred at room temperature for 1 hour and 15 minutes. The mixture was diluted with water (9.3 ml), sodium hydrogen carbonate (1.61 g, 19.2 mmol) and di-tert-butyl dicarbonate (2.79 g, 12.8 mmol) were added, and the mixture was further stirred at room temperature in within 18 hours. The reaction solution was concentrated under reduced pressure and azeotropically dehydrated with ethyl acetate, then diluted with ethyl acetate, and the insoluble material was filtered. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, silica gel) to give Compound 4 (1.85 g, 96.1% purity, 78% yield). ¹ H-NMR (CDCl ₃ ) δ: 6.42-6.33 (2H, m), 5.50 (1H, s), 4.27-4.13 (2H, m), 3.64 (3H , s), 3.37-3.30 (1H, m), 3.04 (1H, d, J=14.6 Hz), 2.91-2.82 (1H, m), 2.27- 2.18 (1H, m), 1.38 (9H, br s).

Stage 4

Synthesis of Compound 5

Compound 4 (1.85 g, 4.97 mmol) was dissolved in tetrahydrofuran (9.3 ml), a 1 mol/L solution of lithium borohydride in tetrahydrofuran (2.50 ml, 2.50 mmol) was added at -78°C. and stirred the mixture at room temperature for 18.5 hours. Ice was added to the reaction solution, 2 mol/L aqueous hydrochloric acid was added to adjust to pH 4, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in dimethyl sulfoxide (9.1 ml), 2-iodoxybenzoic acid (2.09 g, 7.46 mmol) was added and the mixture was stirred at room temperature for 19.5 hours. Thereafter, further 2-iodoxybenzoic acid (0.418 g, 1.41 mmol) was added and the mixture was stirred for 4 hours. Ethyl acetate and water were added to the reaction solution, the precipitated solid was filtered off, the organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, silica gel) to give Compound 5 (1.70 g, 94.4% purity, 99% yield). ¹ H-NMR (CDCl ₃ ) δ: 9.65 (1H, sq, J=1.7 Hz), 6.45-6.36 (2H, m), 5.03 (1H, s), 4, 23 (1H, tt, J=11.3, 4.0 Hz), 4.18 (1H, td, J=11.3, 2.3 Hz), 3.59-3.51 (1H, m) , 3.34 (1H, dt, J=17.1, 1.7 Hz), 2.96-2.88 (1H, m), 2.19 (1H, ddd, J=14.2, 10, 9, 4.1 Hz), 1.42 (9H, s).

Stage 5

Synthesis of Compound 6

Compound 5 (1.70 g, 4.89 mmol) was dissolved in acetone (30 ml) and water (3 ml), 5% microencapsulated osmium tetroxide (0.889 g, 0.245 mmol), 4-methylmorpholine (1.24 g, 12.2 mmol), 4-methylmorpholine-N-oxide (1.15 g, 9.79 mmol) and sodium periodate (6.07 g, 24.5 mmol), and stirred the mixture at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate and water, then sodium thiosulfate pentahydrate (6.07 g, 24.5 mmol) was added, the insoluble material was filtered off, the organic layer was washed with water, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in methanol (12 ml), sodium borohydride (93.0 mg, 2.45 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, diluted with water, 2 mol/L aqueous hydrochloric acid was added to adjust to pH 4, and extracted with ethyl acetate. The organic layer was washed with water, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, silica gel) to give Compound 6 (1.06 g, 68% yield). ¹ H-NMR (CDCl ₃ ) δ: 6.43-6.37 (2H, m), 5.17 (1H, s), 4.49-4.44 (1H, m), 4.28-4 .14 (3H, m), 3.70 (1H, dd, J=11.4, 10.1 Hz), 2.51-2.36 (2H, m), 1.42 (9H, s).

Stage 6

Synthesis of Compound 7

A solution of Compound 6 (1.05 g, 3.32 mmol) in acetonitrile (12 ml) at -50°C was added dropwise to a solution of thionyl chloride (1.22 g, 10.3 mmol) in acetonitrile (10 ml). The mixture was stirred at the same temperature for 1 hour and then pyridine (1.05 g, 23.3 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and then extracted with ethyl acetate and washed with water. Thereafter, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, silica gel) to obtain Compound 7 (1.09 g, purity 91.2%, yield 83%) as a diastereomeric mixture mixtures with a ratio of 92.6:7.4. Both diastereoisomers were used in the next step without separation.

Stage 7

Synthesis of Compound 8

Compound 7 (1.08 g, 2.73 mmol) was dissolved in ethyl acetate (10 ml) and water (10 ml), and ruthenium chloride hydrate (3.0 mg, 0.01 mmol) and sodium periodate were added at 0°C (642 mg, 3.00 mmol). The mixture was stirred at room temperature for 2 hours. At room temperature, water (10 ml) was added, ruthenium chloride hydrate (2.1 mg, 0.01 mmol) and sodium periodate (117 mg, 0.546 mmol) were added, and the mixture was further stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate and washed with water, and then filtered through a column packed with dry silica gel. The filtrate was concentrated under reduced pressure and then powdered with hexane-ethyl acetate to give Compound 8 (873 mg, 85% yield). ¹ H-NMR (DMSO-D ₆ ) δ: 6.93 (1H, ddd, J=11.4, 9.2, 2.7 Hz), 6.72 (1H, dt, J=10.1, 2.0 Hz), 5.09 (1H, d, J=10.2 Hz), 4.63 (1H, dd, J=10.2, 1.0 Hz), 4.42 (1H, ddd, J=12.2, 4.0, 2.6 Hz), 4.22 (1H, td, J=12.4, 2.0 Hz), 2.47-2.32 (2H, m), 1 .22 (9H, s).

Stage 8

Synthesis of Compound 10

Compound 9 (110 mg, 0.439 mmol) was dissolved in DMF (4 ml), potassium carbonate (60.6 mg, 0.439 mmol) was added and the mixture was heated to 100°C. Compound 8 (151 mg, 0.399 mmol) was added to the mixture, and the mixture was stirred at 100°C for 40 minutes. The mixture was diluted with water and then extracted with ethyl acetate and washed with water. Thereafter, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, silica gel) to obtain Compound 10 (151 mg, purity 96.3%, yield 67%). ¹ H-NMR (CDCl ₃ ) δ: 8.42 (1H, d, J=2.8 Hz), 8.01-7.95 (1H, m), 7.46 (1H, td, J=8 .5, 2.8 Hz), 6.84 (1H, s), 6.44-6.32 (2H, m), 5.87 (2H, s), 5.15-4.86 (2H, m), 4.44-4.19 (4H, m), 2.68-2.91 (1H, m), 1.90-1.81 (1H, m), 1.42 (3H, t, J=7.2 Hz), 1.32 (9H, br. s).

Stage 9

Synthesis of Compound 11

Compound 10 (150 mg, 0.439 mmol) was dissolved in DMF (4 ml), 60% sodium hydride (42.3 mg, 1.06 mmol) was added, the mixture was stirred at room temperature for 1 hour and diluted with ice. Then, 1 mol/L aqueous hydrochloric acid was added to the mixture to adjust to pH 4, and extracted with ethyl acetate. After washing with water, the solvent was concentrated under reduced pressure, and 4 mol/L hydrogen chloride in dioxane (4 mL, 16.0 mmol) was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and diluted with DMF (6 ml), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (151 mg, 0.398 mmol) and triethylamine (0.257) were added ml, 1.86 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was added with water, extracted with ethyl acetate and washed with water. Thereafter, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate, silica gel) to obtain Compound 11 (59.5 mg, purity 97.4%, yield 55%). ¹ H-NMR (CDCl ₃ ) δ: 8.43 (1H, d, J=2.9 Hz), 7.96 (1H, d, J=8.9, 4.5 Hz), 7.45 ( 1H, td, J=8.6, 2.9 Hz), 6.54-6.49 (2H, m), 5.75 (1H, s), 5.68 (2H, s), 4.77 (1H, d, J=13.1 Hz), 4.29-4.19 (3H, m), 2.37-2.21 (2H, m).

Stage 10

Synthesis Compound (I-119)

Compound 11 (30.8 mg, 0.075 mmol) and 2-(methylsulfonyl)-acetic acid (20.6 mg, 0.149 mmol) were dissolved in tetrahydrofuran (4 ml), O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (56.8 mg, 0.149 mmol) and triethylamine (0.041 ml, 0.299 mmol), and stirred the mixture at room temperature for 2 hours. The mixture was added with water, extracted with ethyl acetate and washed with water. Thereafter, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol, aminosilica gel) to obtain Compound I-119 (35.4 mg, purity 97.0%, yield 88%). ¹ H-NMR (DMSO-D ₆ ) δ: 10.07 (1H, s), 8.97 (1H, s), 8.56 (1H, d, J=2.8 Hz), 7.89 ( 1H, dd, J=8.8, 4.6 Hz), 7.77 (1H, td, J=8.8, 2.8 Hz), 6.91 (1H, dd, J=11.0, 9.2, 2.2 Hz), 6.74-6.70 (1H, m), 4.76 (1H, d, J=13.6 Hz), 4.71 (1H, d, J=13 .6 Hz), 4.39-4.19 (3H, m), 3.17 (3H, s), 2.25-2.19 (1H, m), 2.10-2.02 (1H, m).

[Example 2]

[0078]

Stage 1

Synthesis of Compound 9

To ethanol (20 ml) at 0°C was added 60% sodium hydride (314 mg, 7.86 mmol), after stirring the mixture for 10 min, the known Compound 12 (1.00 g, 7.15 mmol) was added dropwise and 88.3% ethyl diazoacetate (1.02 g, 7.86 mmol), and the mixture was stirred at room temperature for 5 hours. 2 mol/L aqueous hydrochloric acid was added to the reaction solution at 0°C to adjust to pH 8.6, and extracted with ethyl acetate. After washing with water, most of the solvent was evaporated under reduced pressure, and the residue was ground into powder with hexane-ethyl acetate to give Compound 9 (1.49 g, 84% yield). ¹ H-NMR (CDCl ₃ ) δ: 8.42 (1H, d, J=3.0 Hz), 8.02 (1H, dd, J=8.8, 4.5 Hz), 7.46 ( 1H, td, J=8.5, 3.0 Hz), 5.66 (2H, br. s), 4.42 (2H, kv, J=7.2 Hz), 1.43 (3H, t , J=7.2 Hz).

[0079]

Subsequent compounds were synthesized in a similar manner. The physical details of the connections are presented below.

In the tables, "RT" means retention time (in minutes) as measured by LC/MS, "MS" means mass (M+H) as determined by LC/MS, and "LCMS Method" means any from the subsequent measurement conditions using the LC/MS method.

[Measurement conditions A]

Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 µm, 2.1 x 50 mm i.d.) (Waters)

Flow rate: 0.55ml/min

UV detection wavelength: 254 nm

Mobile phase: [A] is 0.1% formic acid in water, and [B] is 0.1% formic acid in acetonitrile.

Gradient: run a linear gradient from 5% to 100% solvent [B] over 3 min, followed by 100% solvent [B] for 0.5 min.

[Measurement conditions B]

Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 µm, 2.1 x 50 mm i.d.) (Waters)

Flow rate: 0.8ml/min

UV detection wavelength: 254 nm

Mobile phase: [A] is 0.1% formic acid in water, and [B] is 0.1% formic acid in acetonitrile.

Gradient: Run a linear gradient from 5% to 100% solvent [B] over 3.5 min, followed by 100% solvent [B] for 0.5 min.

[Measurement conditions C]

Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 µm, 2.1 x 50 mm i.d.) (Waters)

Flow rate: 0.8ml/min

UV detection wavelength: 254 nm

Mobile phase: [A] is 0.1% formic acid in water, and [B] is 0.1% formic acid in acetonitrile.

Gradient: Run a linear gradient from 5% to 100% solvent [B] over 3.5 min, followed by 100% solvent [B] for 0.5 min.

[Measurement conditions D]

Column: Shim-pack XR-ODS (2.2 µm, i.d. 3.0×50 mm) (Shimadzu)

Flow rate: 1.6ml/min

UV detection wavelength: 254 nm

Mobile phase: [A] is 0.1% formic acid in water, and [B] is 0.1% formic acid in acetonitrile.

Gradient: run a linear gradient from 10% to 100% solvent [B] over 3 min, followed by 100% solvent [B] for 0.5 min.

[0080]

[Table 1]

[0081]

[Table 2]

[0082]

[Table 3]

[0083]

[Table 4]

[0084]

[Table 5]

[0085]

[Table 6]

[0086]

[Table 7]

[0087]

[Table 8]

[0088]

[Table 9]

[0089]

[Table 10]

[0090]

[Table 11]

[0091]

[Table 12]

[0092]

[Table 13]

[0093]

[Table 14]

[0094]

[Table 15]

[0095]

[Table 16]

[0096]

[Table 17]

[0097]

[Table 18]

[0098]

[Table 19]

[0099]

[Table 20]

[0100]

[Table 21]

[0101]

[Table 22]

[0102]

In compounds I-54 and I-55, the asymmetric carbon atom in the parent nucleus is a mixture of R/S=1/1.

In compounds I-62 and I-63, the stereochemistry of the parent nucleus is unique, but the absolute configuration is not defined.

In compounds I-72, I-105, I-106 and I-107, the stereochemistry of sulfoximine is unique, but the absolute configuration is not defined.

In compounds I-73, I-108 and I-112, the stereochemistry of sulfoximine is a mixture of R/S=1/1.

[0103]

[Table 23]

[0104]

Biological test examples for the compounds of the present invention are described below.

The compound represented by formula (I) according to the present invention may have MGAT2 inhibitory activity and may inhibit MGAT2.

More specifically, in the evaluation method described below, the IC ₅₀ value is preferably 100 nM or less, more preferably 50 nM or less, and even more preferably 10 nM or less.

[0105]

Preparation Example 1: Preparation of Recombinant Human MGAT2

The full-length human MGAT2 gene, to which a Flag tag was added at the N-terminus, was inserted into pFastBac (manufactured by Invitrogen). Recombinant baculovirus was prepared according to the protocol for the Bac-to-Bac baculovirus expression system (manufactured by Invitrogen) and infected Sf-9 cells. Cells were collected and sonicated, and then the membrane fraction was collected by centrifugation. The membrane fraction was subjected to Western blotting with anti-Flag antibodies to confirm expression, and the membrane fraction was used as a solution of recombinant human MGAT2 enzyme.

[0106]

Test Case 1: Measurement of inhibitory activity against human MGAT2

Each of the DMSO solutions of the compounds of the present invention was aliquoted into 0.2 μl and placed in a 384-well polystyrene microplate manufactured by Corning Incorporated, and 5 μl of an enzyme solution prepared with assay buffer (100 mmol/L phosphate buffer) was added thereto. pH 7.4) containing 2 mmol/L DTT) and 5 μl of substrate solution (100 mmol/L phosphate buffer (pH 7.4), 30 μmol/L 2-oleoylglycerol, 10 μmol/L oleoyl-CoA) obtained the mixture was stirred, centrifuged and incubated in a humid chamber at room temperature for 1 hour. After the enzymatic reaction, 50 μL of quenching solution (containing 0.2 μmol/L Diolein-d5, 0.4% formic acid and 50% isopropanol) containing internal standard (IS) was added to stop the reaction, and the final mixture was placed in the production plate Shimadzu GLC Ltd., and then mixed and centrifuged, and measured on RapidFire360 and Agilent 6550 Q-TOF mass spectrometers with electrospray ionization. Diolein as the reaction product (P) of 2-oleioylglycerol as substrate and the ammonium ion adduct IS was determined, and the peak intensity ratio P/IS was calculated by peak height to evaluate the inhibitory activity. The inhibitory activity values without/with enzyme addition were defined as Control(+)/Control(-), respectively, and the corresponding inhibition (in %) was determined as 0% inhibition and 100% inhibition. Inhibitory activity was calculated using the formula below using TIBCO Spotfire (manufactured by TIBCO Software Inc.):

Inhibitory activity (in%) = [1 - {Sample -Control(-)}/{Control(+) - Control(-)}] * 100,

where Sample means the intensity peak ratio P/IS upon addition of the compound of the present invention.

The results of the inhibitory activity of the compounds according to the present invention are presented in the following table. The IC ₅₀ (nM) values in the tables indicate the concentration demonstrating 50% enzyme inhibition.

[0107]

[Table 24]

[0108]

Test Case 2: Metabolic Stability Test

Using commercially available pooled human liver microsomes, the compound of the present invention was reacted for a fixed time, the remaining fraction was calculated by comparing the reacted sample and the unreacted sample, thereby assessing the extent of metabolism of the compound of the present invention.

[0109]

The reaction (oxidation reaction) was carried out at 37°C for 0 minutes or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 ml buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride , 10 mmol/l magnesium chloride) containing 0.5 mg protein/ml human liver microsomes. After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol/acetonitrile (1/1 (v/v)), mixed and centrifuged at 3000 rpm. within 15 minutes. The compound of the present invention in the supernatant was quantified by LC/MS/MS, and the amount of the compound of the present invention remaining after the reaction was calculated, taking the amount of the compound at time 0 minutes as 100%.

Result

The following table shows the residual fraction values for a test compound concentration of 0.5 µmol/L.

Compound I-6: 92.4%

Compound I-13: 76%

Compound I-14: 103%

Compound I-20: 74.5%

Compound I-33: 98.5%

Compound I-46: 78.1%

Compound I-58: 88.4%

Compound I-61: 95.6%

Compound I-66: 105%

Compound I-79: 77.2%

Compound I-126: 100%

Compound I-130: 94.8%

Compound I-137: 101%

Compound I-141: 99.4%

Compound I-142: 106%

Compound I-147: 89.8%

Compound I-151: 104%

[0110]

Test Case 3: Solubility Test

The solubility of the compound of the present invention was determined under the conditions of adding 1% DMSO. A 10 mmol/L solution of the compound in DMSO was prepared, and 6 μL of a solution of the compound of the present invention was added to 594 μL of artificial intestinal juice pH 6.8 (118 ml of 0.2 mol/L NaOH test solution and water was added to 250 ml of 0. 2 mol/l potassium dihydrogen phosphate test solution to obtain 1000 ml). The mixture was left to settle for 16 hours at a temperature of 25°C, and the mixture was vacuum filtered. The filtrate was diluted two-fold with methanol/water (1/1 (v/v)), and the concentration of the compound in the filtrate was measured by HPLC or LC/MS/MS using the absolute value calibration plot method. If necessary, the dilution concentration and dilution solvent were changed.

Result

Compound I-6: > 50 µmol/l

Compound I-14: 41.8 µmol/L

Compound I-46: > 50 µmol/l

Compound I-58: > 50 µmol/l

Compound I-66: > 50 µmol/l

Compound I-79: > 50 µmol/l

Compound I-126: > 50 µmol/l

Compound I-130: > 50 µmol/l

Compound I-137: > 50 µmol/l

Compound I-141: 48.9 µmol/L

Compound I-142: > 50 µmol/l

Compound I-147: > 50 µmol/l

Compound I-151: > 50 µmol/l

[0111]

Test Case 4: Phototoxicity Test

The erythrocyte photohemolysis test (Wolfgang JW Pepe et al., ATLA29, 145-162, 2001), which is an evaluation method using the effect on biomembranes and photoperoxidation as indicators, was performed as an in vitro phototoxicity test. In this method, a solution of the compound of the present invention was prepared with dimethyl sulfoxide as a medium, to which a solution of sheep red blood cells was added at a ratio of 2.5% (v/v) relative to the prepared solution, and the resulting mixed solution was used (concentration: from 0 .1 to 0.0008%). The mixed solution was added to two microplates, one of the prepared microplates was irradiated with UVA and UVB light (10 J/ ^cm2 , 290 to 400 nm) using an ultraviolet fluorescent lamp (GL20SE lamp, SANKYO DENKI Co., Ltd., and FL20S lamp -BLB, Panasonic Corporation), and were centrifuged together with the microplate, which was not irradiated with light, and then the absorbance of the supernatant was measured (540 nm or 630 nm). To determine two indicators (effect on biomembranes and photoperoxidation) for assessing phototoxicity, the optical density value of the medium was subtracted from the optical density value obtained for the compound according to the present invention in each of the cases with and without light irradiation, and the values thus calculated were used in subsequent calculations . In relation to the effect on biomembranes, the degree of photohemolysis was determined by the difference in optical density values (540 nm) in the case of light irradiation and without light irradiation, and in relation to photoperoxidation, the difference in optical density values (630 nm) in the case of light irradiation and without irradiation was determined light. When calculating the degree of photohemolysis, the optical density (540 nm) obtained from a 2.5% (v/v) solution of sheep red blood cells subjected to forced hemolysis with distilled water was taken as 100% degree of hemolysis and used as a reference point. The result was considered (-) if the degree of photohemolysis was less than 10% and the difference in absorbance values at 630 nm was less than 0.05. The result was considered (+) if the degree of photohemolysis was 10% or more and the difference in absorbance values at 630 nm was 0.05 or more.

[0112]

Test Case 5: Cytotoxicity Test

To evaluate the cytotoxicity of the compound of the present invention, cells after treatment with the compound were automatically counted using a Toxinsight Cell Image Analyzer (Thermo Fisher Scientific).

HepG2 cells (derived from human liver malignant cells) were seeded in a 384-well plate at 60,000 cells/ml, and compound solution was added to each well after 24 hours. The solution of the compound was a solution of the compound of the present invention in DMSO (made 5 times a 2-fold dilution from a maximum concentration of 50 μmol/L to a minimum concentration of approximately 3.1 μmol/L), and a solution consisting of DMSO alone was used as negative control, and camptothecin solution was used as a positive control. A solution of the compound of the present invention in DMSO, a negative control solution or a positive control solution was added to each well. After 71 hours, Hoechst 33342 diluted in Dulbecco's phosphate buffered saline (D-PBS) was added to each well to a final concentration of 1 μg/ml, and nuclear staining was performed in an incubator at 37°C and 5% CO ₂ for 1 hour. After staining, the result was fixed with 4% paraformaldehyde in a CO ₂ incubator at 37°C for 20 minutes. Finally, wells were washed three times with D-PBS, and fluorescence-emitting nuclei in each well were counted using Toxinsight (Thermo Fisher Scientific). Four wells were allocated per concentration, and the mean and standard deviation (SD) for the number of nuclei (the number of cells for which no toxicity was detected) in the four wells were calculated. Comparisons were made with the negative control group, and the compound exposure concentration (IC ₅₀ ) at which the mean was reduced to less than 50% of the negative control mean was calculated. A lower IC ₅₀ value was assessed as a higher risk of cytotoxicity.

[0113]

Test Case 6: Anti-Obesity Test

The anti-obesity effect of the compound of the present invention was tested using C57BL/6j mice (DIO mice) fed a high-fat diet (TestDiet; 58Y1).

Five-week-old male C57BL/6j mice were purchased (CLEA Japan, Inc.) and raised on a high-fat diet on 12-hour light/night cycles for 4 weeks to generate DIO mice. Medium (0.5% HPMC) was administered twice daily, starting 3 weeks before compound administration. Randomization was used to allocate groups (n=7) based on body weight and changes in food intake during the run-in period. Forced oral administration of test compound or medium (0.5% HPMC) was carried out twice daily from days 1 to 28. Body weight and food intake were measured every day. On day 28, an autopsy was performed and epididymal fat mass was measured and biochemical analysis of the collected blood was performed.

[0114]

Test Case 7: CYP Inhibition Test

Using commercially available mixed human liver microsomes and using 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methylhydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) as markers. As typical reactions of metabolism of substrates of the main five forms of human CYP enzyme (CYP1A2, 2C9, 2C19, 2D6, 3A4), the degree of inhibition of the produced amount of each metabolite by the compound of the present invention was assessed.

The reaction conditions were as follows: substrate - 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenytoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L l terfenedine (CYP3A4); reaction time - 15 minutes; reaction temperature - 37°C; enzyme - mixed human liver microsomes, 0.2 mg protein/ml; the concentration of the compound according to the present invention is 1, 5, 10, 20 µmol/l (four points).

Every five kinds of substrates, human liver microsomes or a compound of the present invention in 50 mmol/L Hepes buffer as a reaction solution were added to a 96-well plate in the composition described above, and NADPH was added as a cofactor to initiate metabolic reactions. After incubation at 37°C for 15 minutes, methanol/acetonitrile (1/1 v/v) was added to stop the reaction. After centrifugation at 3000 rpm. within 15 minutes, resorufin (CYP1A2 metabolite) was quantified in the supernatant by multichannel fluorescence counter or LC/MS/MS, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4'-hydroxide (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) was quantified by LC/MS/MS.

Adding only DMSO, which is a solvent to dissolve the drug, into the reaction system was taken as control (100%). Residual activity (%) was calculated. The IC ₅₀ value was calculated according to the inverse logistic model using concentration and degree of inhibition.

Result

Compound I-6: five types > 20 µmol/L

Compound I-14: five types > 20 µmol/L

Compound I-20: five types > 20 µmol/L

Compound I-33: five types > 20 µmol/L

Compound I-46: five types > 20 µmol/L

Compound I-58: five types > 20 µmol/L

Compound I-66: five types > 20 µmol/L

Compound I-126: five types > 20 µmol/L

Compound I-130: five types > 20 µmol/L

Compound I-141: five types > 20 µmol/L

Compound I-142: five types > 20 µmol/L

Compound I-147: five types > 20 µmol/L

Compound I-151: five types > 20 µmol/L

[0115]

Test Case 8: Bioavailability Test (BA)

Materials and Methods for Oral Absorption Experiments

(1) Animals: SD mice or rats were used.

(2) Housing conditions: SD mice or rats were allowed to freely consume solid food and sterilized tap water.

(3) Dosing and grouping conditions: Oral administration and intravenous administration were carried out at a predetermined dosage. Dividing into groups was carried out as follows (dosage varied for compound).

Oral administration: from 1 to 30 mg/kg (n=2-3)

Intravenous administration: from 0.5 to 10 mg/kg (n=2-3)

(4) Preparation of the administration solution: Oral administration was carried out in the form of a suspension or solution. Intravenous administration was carried out after solubilization.

(5) Route of administration: Oral administration was carried out forcefully into the stomach through an oral tube. Intravenous administration was carried out through the tail vein or femoral vein using syringes with a needle.

(6) Evaluation parameters: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured by LC/MS/MS.

(7) Statistical analysis: Taking into account the change in plasma concentration of the compound of the present invention, the area under the plasma concentration-time curve (AUC) was calculated using the WinNonlin (registered trademark) nonlinear least squares analysis program, and calculated from AUC bioavailability of the compound of the present invention in the oral administration group and in the intravenous administration group.

Result

Compound I-6: 55.1%

Compound I-20: 63.4%

Compound I-33: 60.5%

Compound I-46: 53.1%

Compound I-58: 88.2%

Compound I-137: 49%

Compound I-141: 67%

Compound I-142: 66.2%

[0116]

Test Case 9: CYP3A4 Irreversible Inhibition (MBI) Test (MDZ)

The MBI CYP3A4 (MDZ) test is a test to investigate the potential of irreversible inhibition of CYP3A4 to enhance the degree of inhibition of the metabolic response caused by the compound of the present invention. CYP3A4 inhibition was assessed using mixed human liver microsomes in the midazolam 1-hydroxylation reaction (MDZ) as a response marker.

The reaction conditions were as follows: substrate - 10 μmol/L MDZ; pre-reaction time - 0 or 30 minutes; interaction time with the substrate - 2 minutes; reaction temperature - 37°C; protein content in mixed human liver microsomes: during the preliminary reaction - 0.5 mg/ml, during the reaction time - 0.05 mg/ml (with a 10-fold dilution); the concentration of the compound according to the present invention during the preliminary reaction is 1, 5, 10, 20 μmol/l (four points).

Mixed human liver microsomes and a solution of the compound of the present invention in K-Pi buffer (pH 7.4) as a pre-reaction solution were added to a 96-well plate in the pre-reaction composition. A portion of the pre-reaction solution was transferred to another 96-well plate and diluted with 1/10 K-Pi buffer containing the substrate. To initiate the reaction, NADPH was added as a co-factor for the marker reaction (option without pre-reaction). After a predetermined reaction time, methanol/acetonitrile (1/1, v/v) was added to stop the reaction. In addition, NADPH was added to the remaining pre-reaction solution to initiate the pre-reaction (pre-reaction option). After a predetermined pre-reaction time, the portion was transferred to another plate and diluted with 1/10 K-Pi buffer containing the substrate to initiate the reaction, as a marker reaction. After a predetermined reaction time, a methanol/acetonitrile solution (1/1, v/v) was added to stop the reaction. The plate in which each representative reaction was carried out was centrifuged at 3000 rpm. for 15 minutes and then quantified 1-hydroxylated midazolam in the supernatant by LC/MS/MS.

The sample with DMSO added to the reaction system as a solvent instead of a solution to dissolve the compound of the present invention was taken as the control (100%). Residual activity (%) was calculated for each concentration of the compound of the present invention in comparison with the control, and the IC value was calculated according to the inverse logistic model using the concentration and the degree of inhibition. The ratio [IC for preincubation for 0 minutes/IC for preincubation for 30 minutes] was defined as the value of the biased IC, and the example where the value of the biased IC was 1.5 or more was considered "positive", and the example when the value of the biased An IC of 1.0 or less was considered “negative.”

Result

Connection I-6: negative

Connection I-14: negative

Connection I-20: negative

Connection I-46: negative

Connection I-58: negative

Connection I-66: negative

Connection I-126: negative

Connection I-130: negative

Connection I-147: negative

Connection I-151: negative

[0117]

Test Case 10: Powder Solubility Test

An appropriate amount of the compound of the present invention is placed in suitable containers. To each container, 200 μl of JP-1 solution was added independently (water was added to 2.0 g of sodium chloride and 7.0 ml of hydrochloric acid to reach 1000 ml), 200 μl of JP-2 solution (500 ml of water was added to 500 ml of phosphate buffer (pH 6.8)) or 20 mmol/L sodium taurocholate (TCA)/JP-2 solution (JP-2 solution was added to 1.08 g TCA to reach 100 ml). When the entire amount was dissolved after adding the test reagent, the compound of the present invention was added accordingly. After sealing and shaking at 37°C for 1 hour, the solution was filtered and 100 μL of methanol was added to 100 μL of each filtrate to dilute it twofold. If necessary, the degree of dilution and the dilution solvent were changed. After checking for the absence of bubbles and sediment, the container was sealed and mixed by shaking. The compound of the present invention was measured by HPLC using the absolute value calibration graph method.

Compound I-46: solution JP-2: 8.64 µmol/L

[0118]

Test Case 11: Ames Fluctuation Test

The mutagenicity of the compound of the present invention was assessed.

20 μl of frozen rat typhus bacilli ( Salmonella typhimurium strain TA98, strain TA100) were added to 10 ml of liquid nutrient medium (2.5% Oxoid No. 2 nutrient broth) and cultured, then stirred at 37°C for 10 hours. To remove the culture solution, 8.0 ml of the bacterial solution of the TA98 strain was centrifuged (2000 rpm, 10 minutes). Bacteria were suspended in 8.0 ml of Micro F buffer (K ₂ HPO ₄ : 3.5 g/l, KH ₂ PO ₄ : 1 g/l, (NH ₄ ) ₂ SO ₄ : 1 g/l, trisodium citrate dihydrate: 0.25 g/l, MgSO ₄ 7H ₂ O: 0.1 g/l), the suspension was added to 120 ml of exposure medium (Micro F buffer containing 8 μg/ml biotin, 0.2 μg/mg histidine, 8 mg/ml glucose). To prepare the test bacterial solution, strain TA100 was added to 120 ml of exposure medium in an amount of 3.1 ml of bacterial solution. Mix 12 μl of each solution of a compound of the present invention (several 2-3-fold dilutions of the maximum dose of 50 mg/ml) in DMSO, DMSO as a negative control, and 50 μg/ml solution of 4-nitroquinoline-1-oxide in DMSO for strain TA98, 0.25 μg/ml solution of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide in DMSO for strain TA100 in the absence of metabolic activation, 40 μg/ml solution of 2-aminoanthracene in DMSO for strain TA98, 20 µg/ml solution of 2-aminoanthracene in DMSO for strain TA100 under metabolic activation conditions, as a positive control, and 588 µl test bacterial solution (mixed solution of 498 µl test bacterial solution and 90 µl mixture S9 under activation conditions metabolism), and this mixture was cultured with stirring at a temperature of 37°C for 90 minutes. 230 μl of a bacterial solution treated with a compound according to the present invention was mixed with 1150 μl of indicator medium (Micro F buffer containing 8 μg/ml biotin, 0.2 μg/ml histidine, 8 mg/ml glucose, 37.5 μg/ml bromocresol red), every 50 μl was transferred to a microplate of 48 wells per dose, and subjected to stationary cultivation at 37°C for 3 days. Because a well containing a bacterium that has acquired the ability to proliferate through mutation of the gene for the enzyme that synthesizes the amino acid (histidine) changes color from red to yellow due to a change in pH, wells with proliferating bacteria that did not change color to yellow in 48 wells per dose were counted , and were evaluated in comparison with a negative control group. (-) and (+) indicate negative and positive mutagenicity, respectively.

Connection I-33: (-)

[0119]

Test Case 12: Test with hERG

To evaluate the risk of electrocardiogram QT prolongation by a compound of the present invention, using CHO cells expressing the human potassium channel alpha subunit gene (hERG), the effects of the compound of the present invention on delayed rectifier potassium current ( _IKr ), which plays an important role in the process, were examined. ventricular repolarization.

After fixing the cell to a membrane potential of -80 mV by patch-clamping in a whole-cell configuration using an automatic patch-clamp system (QPatch; Sophion Bioscience A/S), I _Kr induced by exposure to a leakage potential of -50 mV was recorded, followed by depolarizing pulse stimulation at +20 mV for 2 seconds, followed by repolarizing pulse stimulation at -50 mV for 2 seconds. After stabilization of the generated current, the cell was treated at room temperature for 10 minutes with an extracellular solution (NaCl: 145 mmol/L, KCl: 4 mmol/L, _CaCl2 : 2 mmol/L, _MgCl2 : 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazinethanesulfonic acid): 10 mmol/L, pH 7.4), in which the compound of the present invention was dissolved at the target concentration. Based on the I _Kr recording results, the absolute value of the peak trace current was measured using analytical software (Falster Patch; Sophion Bioscience A/S) based on the membrane resting potential current value. In addition, to evaluate the effect of the compound of the present invention on I _Kr , the inhibition (%) of the peak trace current by the compound of the present invention was calculated in comparison with the peak trace current after treatment with the vehicle.

Result

Inhibition (%) is presented for 10 μmol/L test compound.

Compound I-20: 27.8%

Compound I-33: 21.3%

Compound I-66: 14.6%

Compound I-79: 25.5%

Compound I-14: 25.5%

Compound I-126: 14.2%

Compound I-130: 15.4%

Compound I-137: 23.6%

Compound I-141: 14.0%

Compound I-142: 10.6%

Compound I-147: 21.6%

Compound I-151: 25.8%

[0120]

Test Case 13: Solution Stability Test

The compound of the present invention (0.4 mg) was weighed into a 4 ml screw cap vial, and 2 ml of various media with pH 1 (0.1 N aq. HCl + 30% MeCN), pH 7 (pH 7 phosphate buffer ( 100 mM + 30% MeCN) or pH 9 (pH 9 carbonate buffer (100 mM + 30% MeCN), respectively. Complete dissolution was confirmed. In the absence of dissolution, filtration was carried out on a 0.45-μm filter. The solution or filtrate was placed in a vial for HPLC The sample cooler for HPLC was set at 40°C and the analysis sequence was set in which sample collection and HPLC analysis were performed at 0, 3, 6, 9, 12, 15 and 18 hours. % value of the peak area of the product at the 0 h point.

Result

Residual content of compound I-3 at 40°C, 18 h: 100.2% at pH 1, 100.9% at pH 7, 100.2% at pH 9

[0121]

EXAMPLE OF COMPOSITION

The compound of the present invention may be administered as a pharmaceutical composition by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in nasal or suppository form. Pharmaceutical compositions containing a compound of the present invention in free base form or in pharmaceutically acceptable salt form, in combination with at least one pharmaceutically acceptable carrier or diluent, can be prepared in conventional manner by mixing, granulating or coating methods. For example, oral compositions may be tablets, granules or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients. Injectable compositions may be solutions or suspensions, may be sterilized, and may contain preservatives, stabilizers, buffers, and the like.

INDUSTRIAL APPLICABILITY

[0122]

Since the compounds of the present invention have MGAT2 inhibitory activity, they are useful as a drug for MGAT2-mediated diseases, including obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyper-VLDL-triglyceridemia, hyperlipoacidemia, diabetes mellitus or arteriosclerosis.

Claims (56)

1. The compound represented by formula (I): Where R ¹ represents hydrogen; R ^2a and R ^2b together with the adjacent carbon atom form ring B; ring B is represented by the formula: wherein each R ⁶ independently represents halogen, C1-C4 alkyloxy, optionally substituted with substituent(s) selected from the group consisting of halogen, C1-C4 alkyloxy and phenyl, and n is 1 or 2; R ^3a represents hydrogen; R ^3b represents hydrogen; R ^4a is a group represented by the formula: Where L ³ represents a single bond or C1-C4alkylene, optionally substituted with halogen, R ⁷ represents halogen, sulfamoyl, optionally substituted with C1-C4 alkyl, C1-C4 alkyloxy, optionally substituted with halogen, C1-C4 alkylsulfonyl, aromatic heterocyclyl, which is a 5-membered monocyclic group containing two heteroatoms selected from O and N, non-aromatic heterocyclyl, which is a 4-membered monocyclic group containing one heteroatom selected from S and optionally substituted with oxo, or a group represented by the formula: -S(=O)(= ^NRN )-R ^S1 , R ^N represents hydrogen, and R ^S1 represents C1-C4alkyl; And R ^4b is C1-C6alkyl, optionally substituted with α, phenyl, optionally substituted with β, or pyridyl, optionally substituted with β, the substituent group α is halogen and cyclopropanyl, and substituent group β represents halogen, cyano, C1-C4alkyl, halogenC1-C4alkyl, hydroxyalkyl, C1-C4alkyloxy, halogenC1-C4alkyloxy, cyclopropanyl, cyclopropanyloxy, C1-C4alkylsulfonyl, or a pharmaceutically acceptable salt thereof. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is represented by any of the formulas: wherein each R ⁶ is each independently C1-C4 alkyloxy, optionally substituted with a substituent selected from the group consisting of halogen, C1-C4 alkyloxy and phenyl. 3. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is represented by any of the formulas: wherein each R ⁶ independently represents halogen or C1-C4 alkyloxy, optionally substituted with a substituent selected from the group consisting of halogen, C1-C4 alkyloxy and phenyl. 4. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-3, where L ³ represents C1-C4alkylene, optionally substituted with halogen, R ⁷ represents halogen, sulfamoyl, optionally substituted with C1-C4 alkyl, C1-C4 alkyloxy, optionally substituted with halogen, C1-C4 alkylsulfonyl, or a group represented by the formula: -S(=O)(=NR ^N )-R ^S1 . 5. The compound or its pharmaceutically acceptable salt according to claim 1, where L ³ represents a single bond, R ⁷ is an aromatic heterocyclyl which is a 5-membered monocyclic group containing two heteroatoms selected from O and N, or a non-aromatic heterocyclyl which is a 4-membered monocyclic group containing one heteroatom selected from S and optionally substituted oxo group. 6. The compound or its pharmaceutically acceptable salt according to claim 1, where L ³ represents C1-C4 alkylene, optionally substituted with halogen, R ⁷ represents halogen or C1-C4 alkylsulfonyl. 7. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound is selected from the group consisting of compounds I-6, I-13, I-14, I-20, I-33, I-46, I-58, I-61, I-66, I-79, I-123, I-124, I-126, I-130, I-133, I-136, I-137, I-139, I-141, I- 142, I-143, I-145, I-147, I-121, I-129, I-131 and I-138: . 8. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound is selected from the group consisting of compounds I-151 and I-153: . 9. A compound or a pharmaceutically acceptable salt thereof, where the compound is represented by the formula: . 10. A compound or a pharmaceutically acceptable salt thereof, where the compound is represented by the formula: . 11. A compound or a pharmaceutically acceptable salt thereof, where the compound is represented by the formula: . 12. A compound or a pharmaceutically acceptable salt thereof, where the compound is represented by the formula: . 13. A compound or a pharmaceutically acceptable salt thereof, where the compound is represented by the formula: . 14. A compound or a pharmaceutically acceptable salt thereof, where the compound is represented by the formula: . 15. A pharmaceutical composition having inhibitory activity against MGAT2, containing an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims. 1-14. 16. A method of treating or preventing an MGAT2-associated disease, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims. 1-14. 17. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-14 for the treatment or prevention of MGAT2-associated disease. 18. The compound or its pharmaceutically acceptable salt according to any one of paragraphs. 1-14 for the treatment or prevention of obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyper-VLDL-triglyceridemia, hyperlipoacidemia, diabetes mellitus or arteriosclerosis.