Dihydropyridopyrazinon derivatives with MGAT2 inhibitory activity

Abstract

To provide a compound having MGAT2 inhibitory activity. 【Solution】To provide a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. JPEG2026046943000033.jpg3544 [Wherein, R 1 is hydrogen, and R 2a is of the formula: JPEG2026046943000034.jpg1834 (Wherein, ring C is an aromatic heterocyclic ring or the like, R 5 is halogen or the like, and n is an integer of 0 to 3), R 2b is alkyl or the like, R 3a is hydrogen, R 3b is hydrogen, R 4a is cyano or the like, R 4b is alkyl or the like which may be substituted with substituent group α, and substituent group α is halogen or the like.]

Description

[Technical Field]

[0001] The present invention relates to a compound having a monoacylglycerol acyltransferase 2 (hereinafter also referred to as MGAT2) inhibitory effect, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. [Background technology]

[0002] Obesity is defined as a condition in which excess fat or adipose tissue is accumulated in the body relative to lean body mass, and is recognized as a major risk factor for health problems. Body Mass Index (BMI) is a simple index of height-to-weight ratio commonly used to classify a group or individual of adults (15 years and older) as overweight or obese. Weight (kg / m²) is calculated by dividing height (in meters) by the square of the height. 2 ) is defined as 25 kg / m². The World Health Organization defines BMI as 25 kg / m². 2 The above is considered "overweight," 30 kg / m². 2 The above is defined as "obesity." On the other hand, the Japan Society for the Study of Obesity defines a BMI of 25 kg / m² as obese. 2 The above is defined as "obesity." This is because the number of obesity-related diseases, including diabetes and dyslipidemia, increases with BMI, and the average BMI for the number of these diseases is 25 kg / m². 2This is because the ratio exceeds 1.0. A 2022 survey by the World Health Organization estimated that approximately 2.5 billion people worldwide are overweight, and at least 890 million are obese (Non-Patent Literature 1). Obesity is mainly caused by an increase in the ratio of calorie intake to expenditure in physical activity and daily life. The number of obese people has increased in recent years due to the increased consumption of high-fat, high-sugar foods, and the World Obesity Union's World Obesity Atlas 2023 predicts that by 2035, more than 4 billion people worldwide, more than half of the world's population, will be classified as overweight or obese. Furthermore, the global economic impact of overweight and obesity is projected to reach US$4.32 trillion annually by 2035 if preventive and treatment measures are not improved. Treatments for these conditions include diet therapy, exercise therapy, and drug therapy. Drug therapy includes semaglutide, tylzepatide, liraglutide, Saxenda, Contrev, and phentermine, but none are satisfactory in terms of efficacy, side effects, or healthcare costs. In particular, GLP-1 receptor agonists such as semaglutide and tilzepatide, which have been approved by the FDA in recent years, have been shown in clinical trials to have a weight-loss effect of approximately 15-20% per year with weekly subcutaneous injections. On the other hand, these drugs have side effects such as gastrointestinal disorders, requiring gradual dose increases over several months, and are very expensive, raising concerns about the burden on healthcare costs. One cause of obesity is excessive intake of triglycerides. Triglycerides ingested through diet are broken down into 2-monoacylglycerol and free fatty acids by pancreatic lipase in the digestive tract and absorbed by small intestinal epithelial cells. Monoacylglycerol acyltransferase (MGAT) transfers the acyl group of free fatty acids to 2-monoacylglycerol. The resulting diacylglycerol is further converted into triglycerides by diacylglycerol acyltransferase (DGAT). Three isoforms of MGAT have been identified: MGAT1, MGAT2, and MGAT3. Of these, MGAT2 and MGAT3 are highly expressed in the small intestine and are thought to be involved in fat absorption in the small intestine. Experiments using MGAT2 knockout mice have reported that a high-fat diet enhances MGAT2 expression in the small intestine and increases MGAT activity (Non-Patent Literature 2). Furthermore, in MGAT2 knockout mice, suppression of weight gain, suppression of insulin resistance induction, suppression of elevated blood cholesterol, suppression of fatty liver formation, and increased energy expenditure have been observed in mice fed a high-fat diet (Non-Patent Literature 3). Although compounds with MGAT2 inhibitory activity have been reported to date (Patent Documents 1-24, Non-Patent Documents 4-14), none of them disclose the compound of the present invention shown below. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2010 / 095767 [Patent Document 2] International Publication No. 2012 / 091010 [Patent Document 3] International Publication No. 2012 / 124744 [Patent Document 4] International Publication No. 2013 / 082345 [Patent Document 5] International Publication No. 2013 / 112323 [Patent Document 6] International Publication No. 2013 / 116065 [Patent Document 7] International Publication No. 2013 / 116075 [Patent Document 8] International Publication No. 2014 / 074365 [Patent Document 9] International Publication No. 2014 / 133134 [Patent Document 10] International Publication No. 2014 / 193884 [Patent Document 11] Japanese Patent Publication No. 2014-5245 [Patent Document 12] Japanese Patent Publication No. 2014-9165 [Patent Document 13] International Publication No. 2015 / 112465 [Patent Document 14] International Publication No. 2015 / 129845 [Patent Document 15] International Publication No. 2015 / 134699 [Patent Document 16] International Publication No. 2015 / 134701 [Patent Document 17] International Publication No. 2015 / 191681 [Patent Document 18] International Publication No. 2016 / 121782 [Patent Document 19] International Publication No. 2017 / 069224 [Patent Document 20] International Publication No. 2019 / 013311 [Patent Document 21] International Publication No. 2019 / 013312 [Patent Document 22] Patent application No. 2020-02515 [Patent Document 23] International Publication No. 2020 / 145369 [Patent Document 24] Patent application No. 2021-113901 [Non-patent literature]

[0004] [Non-Patent Document 1] "Obesity and overweight", World Health Organization, 1 March 2024. [Non-Patent Document 2] Journal of Biological Chemistry (2004), 279, 18878-18886 [Non-Patent Document 3] Nature Medicine (2009), 15, (4), 442-446 [Non-Patent Document 4] Bioorganic & Medicinal Chemistry Letter (2013), 23, 2721-2726 [Non-Patent Document 5] Med. Chem. Commun (2013), 4, 1305-1311 [Non-Patent Document 6] Bioorganic & Medicinal Chemistry Letter (2015), 23, 5922-5931 [Non-Patent Document 7] Bioorganic & Medicinal Chemistry Letter (2015), 23, 4544-4560 [Non-Patent Document 8] Journal of Lipid Research 2015, 56, 747-753 [Non-Patent Document 9] European Journal of Pharmacology, 2015, 758, 72-81 [Non-Patent Document 10] Journal of Medicinal Chemistry (2015), 58, 3892-3909 [Non-Patent Document 11] HETEROCYCLES 2016, 92, 470-484 [Non-Patent Document 12] Chemical and Pharmaceutical Bulletin, 2016, 64, 228-238 [Non-Patent Document 13] European Journal of Pharmacology, 2016, 791, 569-577 [Non-Patent Document 14] Analytical Biochemistry, 2016, 501, 48-55 [Overview of the project] [Problems that the invention aims to solve]

[0005] The object of the present invention is to provide compounds having MGAT2 inhibitory activity or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them. [Means for solving the problem]

[0006] As a result of diligent research, the inventors have succeeded in synthesizing an excellent compound that exhibits MGAT2 inhibitory activity. In other words, the present invention relates to the following:

[0007] [1] Equation (I): [ka] (In the formula, R 1 is hydrogen; R 2a The formula is: [ka] (In the formula, ring C is either an aromatic heterocycle or a non-aromatic heterocycle, R 5 Each of these is independently a halogen, cyano, haloalkylamino, haloalkylcarbonylamino, a non-aromatic carbocyclic amino that may be substituted with substituent group γ, a non-aromatic heterocyclic amino that may be substituted with substituent group γ, alkyl, haloalkyl, a non-aromatic carbocyclic alkyl that may be substituted with substituent group γ, a non-aromatic heterocyclic alkyl that may be substituted with substituent group γ, alkyloxy, haloalkyloxy, haloalkyloxyalkyloxy, a non-aromatic carbocyclic alkyloxy that may be substituted with substituent group γ, a non-aromatic heterocyclic alkyloxy that may be substituted with substituent group γ, an aromatic carbocyclic group that may be substituted with substituent group γ, a non-aromatic carbocyclic group that may be substituted with substituent group γ, an aromatic heterocyclic group that may be substituted with substituent group γ, a non-aromatic heterocyclic group that may be substituted with substituent group γ, a non-aromatic carbocyclic oxy that may be substituted with substituent group γ, or a non-aromatic heterocyclic oxy that may be substituted with substituent group γ. Replacement group γ: halogen, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, alkyloxycarbonylalkyl, aromatic carbocyclic group, aromatic heterocyclic group, aromatic carbocyclic oxy and aromatic heterocyclic oxy, n is an integer from 0 to 3), R 2b is alkyl, or haloalkyl, or R 2a and R 2b may together with adjacent carbon atoms form ring B, Ring B has the formula:

Chemical formula

[10] The pharmaceutical composition according to [9], which has MGAT2 inhibitory activity.

[11] Use of any of the compounds described in [1] to [8], or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic or prophylactic agent for diseases involving MGAT2. [Effects of the Invention]

[0008] The compounds according to the present invention have MGAT2 inhibitory activity and are useful as prophylactic and / or therapeutic agents for obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDL cholesterolemia, hyperfatty acidemia, diabetes mellitus, or arteriosclerosis. [Modes for carrying out the invention]

[0009] The meanings of the terms used in this specification are explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "includes" means that it is not limited to constituent elements and does not exclude any elements that are not listed.

[0010] "Halogen" includes fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms. Fluorine atoms and chlorine atoms are particularly preferred.

[0011] "Alkyl" refers to linear or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. 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, n-decyl, and the like. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0012] "Alkenyl" refers to a linear or branched hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, and the like. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl.

[0013] "Alkylene" refers to a linear or branched divalent hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples include methylene, ethylene, propylene, tetramethylene, pentamethylene, and hexamethylene.

[0014] An "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group consisting of one or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0015] "Aromatic carbocyclic ring" refers to a ring derived from the "aromatic carbocyclic group" described above.

[0016] "Non-aromatic carbocyclic group" refers to a monocyclic or bicyclic or multicyclic cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group. A "non-aromatic carbocyclic group" with two or more rings also includes a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group to which the rings in the above-mentioned "aromatic carbocyclic group" are fused. Furthermore, "non-aromatic carbocyclic groups" also include groups that are bridging or that form a spiro ring, as described below. [ka] The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and even more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. The non-aromatic carbocyclic group with two or more rings preferably has 8 to 20 carbon atoms, and more preferably 8 to 16 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0017] "Non-aromatic carbon ring" refers to a ring derived from the "non-aromatic carbon ring group" described above.

[0018] An "aromatic heterocyclic group" refers to a monocyclic or bicyclic or multicyclic aromatic heterocyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N within the ring. A bicyclic or multicyclic aromatic heterocyclic group also includes those in which a ring from the above-mentioned "aromatic carbocyclic group" is fused to a monocyclic or bicyclic or multicyclic aromatic heterocyclic group. The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. The bicyclic aromatic heterocyclic group is preferably 8 to 10 members, more preferably 9 or 10 members. Examples include indolyl, isoindolyl, indazolyl, indolidinyl, quinolinyl, isoquinolinyl, synnolinyl, phthalazinyl, quinazolinyl, naphthylidinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, and the like. Examples of 9-membered aromatic heterocyclic groups include indolyl, isoindolyl, indazolyl, indolidinyl, prinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, oxazolopyridyl, and thiazolopyridyl. Examples of 10-membered aromatic heterocyclic groups include quinolinyl, isoquinolinyl, synnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, and pyrazinopyridazinyl. Examples of aromatic heterocyclic groups with three or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

[0019] The term "aromatic heterocyclic ring" refers to a ring derived from the "aromatic heterocyclic group" described above.

[0020] "Non-aromatic heterocyclic group" means a monocyclic or bicyclic or multicyclic non-aromatic heterocyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N within the ring. A bicyclic or multicyclic non-aromatic heterocyclic group includes a monocyclic or bicyclic or multicyclic non-aromatic heterocyclic group fused with the respective rings of the above-mentioned "aromatic carbocyclic group," "non-aromatic carbocyclic group," and / or "aromatic heterocyclic group," as well as a monocyclic or bicyclic or multicyclic non-aromatic carbocyclic group fused with the rings of the above-mentioned "aromatic heterocyclic group." Furthermore, "non-aromatic heterocyclic groups" also include groups that form bridges or spiro rings, as described below. [ka] The monocyclic non-aromatic heterocyclic group is preferably 3 to 8-membered, and more preferably 5 or 6-membered. Examples include dioxanil, thiranil, oxyranil, oxetanil, oxathiolanil, azetidinil, thianil, thiazolidinil, pyrrolidinil, pyrrolidinil, imidazolidinil, imidazolinil, pyrazolidinil, pyrazolidinil, piperidyl, piperazinil, morpholinil, morpholino, thiomorpholinil, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranil, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinil, hexahydroazepinil, tetrahydrodiazepinil, tetrahydropyridazinil, hexahydropyrimidinil, dioxolanil, dioxazinil, azilidinil, dioxolinil, oxepanil, thioranil, thiranil, thiadinil, etc. The non-aromatic heterocyclic group with two or more rings preferably has 8 to 20 members, and more preferably 8 to 10 members. Examples include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0021] A "non-aromatic heterocyclic ring" refers to a ring derived from the "non-aromatic heterocyclic group" described above.

[0022] In this specification, "may be substituted with substituent group α" means "may be substituted with one or more groups selected from substituent group α." The same applies to substituent groups β, γ, ε, and δ.

[0023] The embodiments and preferred embodiments of each substituent in the compound represented by formula (I) are shown below. Compounds with possible combinations of each substituent embodiment shown below are preferred.

[0024] R 2a and R 2b In a preferred embodiment, the carbon atoms combine with adjacent carbon atoms to form ring B. R 2a and R 2b Another preferred embodiment is the following: R 2a The formula is: [ka] And, R 2b It is alkyl or haloalkyl. R 2b A more preferred embodiment is a haloalkyl.

[0025] Ring B is given by equation: [ka] These are some examples. A preferred embodiment of ring B is given by formula: [ka] These are some examples. A more preferred embodiment of ring B is given by formula: [ka] include the following. As another aspect of ring B, the formula:

Chemical formula

[0026] B 3 includes CR 13a R 13b NR 13c O, S, S=O, S(=O)2 or Se. B 3 Preferably includes CR 13a R 13b S, S=O, S(=O)2 or Se. B 3 Preferably specific examples include, for example, CH2 or S. However, when B 3 is CR 13a R 13b m is an integer from 1 to 3, and when B 3 is O and m is 1, n is 0.

[0027] B 4 includes CR 14a R 14b include the following. B 4 Preferably specific examples include CH2 or CF2.

[0028] B 5 includes CR 15a R 15b include the following. B 5 Preferably specific examples include CH2 or CF2.

[0029] R 13a R 14a and R 15a each independently include hydrogen, halogen, or alkyl. R 13a R14a and R 15a Preferred embodiments include, independently, hydrogen and halogen. R 13a , R 14a and R 15a A more preferred embodiment is hydrogen.

[0030] R 13b , R 14b and R 15b These can be independently hydrogen, halogen, or alkyl. R 13b , R 14b and R 15b Preferred embodiments include hydrogen or halogen. R 13b , R 14b and R 15b A more preferred embodiment is hydrogen.

[0031] R 13c Examples include hydrogen or alkyl groups.

[0032] n can be an integer between 0 and 3. A preferred form of n is an integer between 1 and 3. A more preferred embodiment of n is 1 or 2.

[0033] m can be an integer between 0 and 3. A preferred form of m is an integer between 1 and 3. A more preferred embodiment of m is 1 or 2.

[0034] Examples of ring C include aromatic heterocycles and non-aromatic heterocycles. Preferred embodiments of ring C include a 5- or 6-membered aromatic heterocycle or a 4- to 10-membered non-aromatic heterocycle. A more preferred embodiment of ring C is pyridine.

[0035] R 5These include, independently, halogens, cyanos, haloalkylaminos, haloalkylcarbonylaminos, non-aromatic carbocyclic aminos which may be substituted with substituent group γ, non-aromatic heterocyclic aminos which may be substituted with substituent group γ, alkyls, haloalkyls, non-aromatic carbocyclic alkyls which may be substituted with substituent group γ, non-aromatic heterocyclic alkyls which may be substituted with substituent group γ, alkyloxys, haloalkyloxys, haloalkyloxyalkyloxys, non-aromatic carbocyclic alkyloxys which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxys which may be substituted with substituent group γ, aromatic carbocyclic groups which may be substituted with substituent group γ, non-aromatic carbocyclic groups which may be substituted with substituent group γ, aromatic heterocyclic groups which may be substituted with substituent group γ, non-aromatic heterocyclic groups which may be substituted with substituent group γ, non-aromatic carbocyclic oxys which may be substituted with substituent group γ, or non-aromatic heterocyclic oxys which may be substituted with substituent group γ. The substituent group γ includes halogens, alkyls, haloalkyls, hydroxyalkyls, alkyloxys, alkyloxycarbonylalkyls, aromatic carbocyclic groups, aromatic heterocyclic groups, aromatic carbocyclic oxys, and aromatic heterocyclic oxys. R 5 Preferred embodiments include, independently, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, alkyloxyalkyloxy, or haloalkyloxyalkyloxy. R 5 More preferred embodiments include, independently, halogens, alkyls, haloalkyls, alkyloxys, or haloalkyloxys.

[0036] R 4a For example, Cyano, formula: [ka] These are some examples. R 4a A preferred embodiment is, [ka] These are some examples.

[0037] R 4b Examples include alkyl groups which may be substituted with substituent group α, aromatic carbocyclic groups which may be substituted with substituent group β, non-aromatic carbocyclic groups which may be substituted with substituent group β, aromatic heterocyclic groups which may be substituted with substituent group β, or non-aromatic heterocyclic groups which may be substituted with substituent group β. The substituent group α is an aromatic carbocyclic group which may be substituted with halogen, cyano, hydroxy, alkyloxy, haloalkyloxy, alkylamino, substituent group δ, a non-aromatic carbocyclic group which may be substituted with substituent group δ, an aromatic heterocyclic group which may be substituted with substituent group δ, and a non-aromatic heterocyclic group which may be substituted with substituent group δ. The substituent group β consists of halogens, cyano, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkyloxy, haloalkyloxy, alkylsulfonyl, and cyclopropanyl. The substituent group δ consists of halogens, alkyls, haloalkyls, and hydroxyalkyls. R 4b Preferred embodiments include alkyl groups which may be substituted with substituent group α, six-membered aromatic carbocyclic groups which may be substituted with substituent group β, or five-membered or six-membered aromatic heterocyclic groups which may be substituted with substituent group β. The substituent group α: halogen, cyano, and cyclopropanyl, The substituent group β consists of halogens, cyano, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, haloalkyloxy, alkylsulfonyl, and cyclopropanyl.

[0038] L 3 Examples include single bonds, alkylenes, or haloalkylenes. L 3 Another form of this is alkylene or haloalkylene. L 3 Another form is a single bond.

[0039] R 7 Examples include hydrogen, halogen, hydroxy, cyano, alkylamino, alkylcarbonyl, alkylcarbonylamino, carbamoyl, alkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkyloxy, haloalkyloxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkyloxyalkylsulfonyl, aromatic carbocyclic groups that may be substituted with substituent group ε, non-aromatic carbocyclic groups that may be substituted with substituent group ε, aromatic heterocyclic groups that may be substituted with substituent group ε, non-aromatic heterocyclic groups that may be substituted with substituent group ε, aromatic carbocyclic sulfonyl groups that may be substituted with substituent group ε, non-aromatic carbocyclic sulfonyl groups that may be substituted with substituent group ε, non-aromatic carbocyclic alkylsulfonyl groups that may be substituted with substituent group ε, formula: -N=S(=O)(-R S1 )-R S2 , or formula: -S(=O)(=NR N )-R S1 These are some examples.

[0040] L 3 and R 7 As for L 3 However, these are alkylenes or haloalkylenes. R 7 However, hydrogen, halogen, sulfamoyl, alkylsulfamoyl, alkyloxy, haloalkyloxy, alkylsulfonyl, or formula: -S(=O)(=NR N )-R S1 One example of this is the configuration in which the following characteristics are observed.

[0041] R S1 and R S2 These can be independently identified as hydrogen, alkyl, or haloalkyl. R S1 and R S2 Preferred embodiments include alkyl groups, each independently. R NExamples include hydrogen, alkyl, or haloalkyl. R N A preferred embodiment is hydrogen.

[0042] R 6 These include, independently, halogens, cyanos, haloalkylaminos, haloalkylcarbonylaminos, non-aromatic carbocyclic aminos which may be substituted with substituent group γ, non-aromatic heterocyclic aminos which may be substituted with substituent group γ, alkyls, haloalkyls, non-aromatic carbocyclic alkyls which may be substituted with substituent group γ, non-aromatic heterocyclic alkyls which may be substituted with substituent group γ, alkyloxys, haloalkyloxys, haloalkyloxyalkyloxys, non-aromatic carbocyclic alkyloxys which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxys which may be substituted with substituent group γ, aromatic carbocyclic groups which may be substituted with substituent group γ, non-aromatic carbocyclic groups which may be substituted with substituent group γ, aromatic heterocyclic groups which may be substituted with substituent group γ, non-aromatic heterocyclic groups which may be substituted with substituent group γ, non-aromatic carbocyclic oxys which may be substituted with substituent group γ, or non-aromatic heterocyclic oxys which may be substituted with substituent group γ. The substituent group γ includes halogens, alkyls, haloalkyls, hydroxyalkyls, alkyloxys, alkyloxycarbonylalkyls, aromatic carbocyclic groups, aromatic heterocyclic groups, aromatic carbocyclic oxys, and aromatic heterocyclic oxys. R 6 Preferred embodiments include, independently, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, alkyloxyalkyloxy, or haloalkyloxyalkyloxy. R 6 More preferred embodiments include, independently, halogens, alkyls, haloalkyls, alkyloxys, or haloalkyloxys.

[0043] A key feature of the compound according to the present invention is that it exhibits MGAT2 inhibitory activity even when the spiro ring bound to the dihydropyridone skeleton shown in formula (I) is changed in various ways. Another feature is that the R bound to the dihydropyridone skeleton shown in formula (I) 2a The key point is that it retains its MGAT2 inhibitory effect even when the compound is changed to a heterocyclic ring.

[0044] The compound represented by formula (I) is not limited to a specific isomer, but includes all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates, or mixtures thereof.

[0045] One or more hydrogen, carbon, and / or other atoms in the compound represented by formula (I) may be substituted with isotopes of hydrogen, carbon, and / or other atoms, respectively. Examples of such isotopes are, 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 Like Cl, it includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. Compounds represented by formula (I) also include compounds substituted with such isotopes. Compounds substituted with such isotopes are also useful as pharmaceuticals. Compounds represented by formula (I) include all radiolabeled compounds substituted with radioisotopes contained in said isotope. The present invention also includes a "radiolabeling method" for producing said "radiolabeled compounds," said "radiolabeled compounds" are useful as tools for metabolic pharmacokinetic studies, binding assays, and / or diagnostics.

[0046] Radiolabeled compounds of the compound represented by formula (I) can be prepared by methods well known in the art. For example, tritium-labeled compounds represented by formula (I) can be prepared by introducing tritium into a specific compound represented by formula (I) through a catalytic dehalogenation reaction using tritium. This method involves reacting a appropriately halogenated precursor of the compound represented by formula (I) with tritium gas in the presence or absence of a suitable catalyst, such as Pd / C, or a base. For other suitable methods for preparing tritium-labeled compounds, see "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds are 14 It can be prepared by using a raw material containing carbon.

[0047] Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, the compound represented by formula (I) and alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyramide, methylamine, diethylamine, diethanol Examples include salts of lysine, picoline, quinoline, etc., with amino acids, or salts of inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., 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.). In particular, salts of hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, and methanesulfonic acid are examples. These salts can be formed by commonly used methods.

[0048] The present invention includes the following embodiments. (i) The compound represented by formula (I) of the present invention may form salts or cocrystals. (ii) The compound represented by formula (I) of the present invention also includes solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (iii) Pharmaceutically acceptable salts of the compound represented by formula (I) of the present invention also include solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (iv) The cocrystals of the compound represented by formula (I) of the present invention also include solvates (e.g., hydrates, etc.) and / or crystalline polymorphs. (v) The “solvate” may be coordinated with any number of solvent molecules (e.g., water molecules) to the compound represented by formula (I). (vi) When a compound represented by formula (I), a pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention, or a cocrystal of the compound represented by formula (I) of the present invention is left in the air, it may absorb moisture, resulting in the adhesion of adsorbed water or the formation of hydrates. (vii) Compounds represented by formula (I), pharmaceutically acceptable salts of compounds represented by formula (I) of the present invention, or cocrystals of compounds represented by formula (I) of the present invention may be mutually transformed by recrystallization. (viii) A pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention is a salt comprising the compound represented by formula (I) and a counter molecule or counter ion, the two being connected by an ionic bond. (ix) The cocrystal of the compound represented by formula (I) of the present invention means that the compound represented by formula (I) and the counter molecule exist in the same crystal lattice, and may contain any number of counter molecules. (x) Cocrystals are distinguished from salts in that the compound represented by formula (I) remains essentially uncharged or neutral. (xi) Cocrystals are distinguished from solvates (e.g., hydrates) in that the counter molecule is not water or a solvent. Generally, salts are thought to involve proton transfer between the compound and the counter molecule; however, it is known that in some cases, proton transfer may not be complete. This state is not a true salt and is sometimes called a cocrystal. It is also known that proton transfer can change continuously with temperature. Accordingly, as used herein, "a pharmaceutically acceptable salt of the compound represented by formula (I)" includes cocrystals and refers to a pharmaceutically acceptable salt or cocrystal of the compound represented by formula (I).

[0049] (xii) The compound represented by formula (I) of the present invention may be amorphous. (xiii) The pharmaceutically acceptable salt of the compound represented by formula (I) of the present invention may be amorphous.

[0050] The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also encompasses various such prodrugs. A prodrug is a derivative of the compound of the present invention having a group that can be chemically or metabolically degraded, and which becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed, etc., under physiological conditions in vivo to be converted to the compound represented by formula (I), compounds that are hydrolyzed by gastric acid, etc., to be converted to the compound represented by formula (I), etc. Methods for selecting and producing a suitable prodrug derivative are described, for example, in “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may be active themselves.

[0051] If the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, examples of prodrugs include acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride, and a mixed anhydride, or by reacting them with a condensing agent. For example, CH3COO-, C2H5COO-, tert-BuCOO-, C 15 H 31 Examples include COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3-, and p-CH3PhSO3-.

[0052] (Method for producing the compound of the present invention) The compound represented by formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, etc., can be carried out using the same procedures as those performed in ordinary organic chemistry experiments. The compounds of the present invention can be synthesized with reference to methods known in the art. [ka] (In the formula, X1 is chlorine, bromine, iodine, trifluoromethanesulfonate, etc.; X2 is chlorine, bromine, iodine; and other symbols have the same meaning as above.) Process A-1 Compound a2 can be obtained by reacting compound a1 with tert-butylsulfinamide and tetraisopropoxytitanium or tetraethoxyethane. The reaction temperature is 20°C to 120°C, preferably 70°C to 100°C. The reaction time is 1 to 12 hours, preferably 3 to 6 hours. Examples of reaction solvents include tetrahydrofuran and 2-methyltetrahydrofuran. Process A-2 By reacting diisopropylamine with n-butyllithium, lithium diisopropylamide is prepared, which is then reacted with ester a3, and finally titanium chloride triisopropoxide is added and reacted with compound a2 to obtain compound a4. The reaction temperature during the preparation of lithium diisopropylamide is -78°C to -20°C, and the subsequent reactions with ester a3 and compound a2 are also at -78°C to -20°C. The reaction times are 30 minutes to 1 hour for the preparation of diisopropylamide, 30 minutes to 2 hours for the reaction between diisopropylamide and ester a3, and 1 to 5 hours for the subsequent reaction with compound a2. Examples of reaction solvents include tetrahydrofuran and diethyl ether. Furthermore, by performing reactions such as alkylation in succession, R 2 This allows for the synthesis of compounds such as alkyl groups. Process A-3 Compound a5 can be obtained by reacting compound a4 with an acid or a Lewis acid. Examples of acids include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, and trifluoroacetic acid. Examples of Lewis acids include trimethylsilyl iodide, BBr3, AlCl3, and BF3·(Et2O), which can be used in amounts of 1 to 10 molar equivalents relative to compound a4. The reaction temperature is 0°C to 60°C, preferably 0°C to 20°C. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. Examples of reaction solvents include methanol, ethanol, water, acetone, acetonitrile, and DMF, which can be used individually or in combination. Process A-4 Compound a6 can be obtained by reacting compound a5 with a carboxylic acid chloride in the presence of a base. Examples of bases include pyridine, DIEA, potassium carbonate, sodium bicarbonate, sodium hydride, and sodium hydroxide. The reaction temperature is 0°C to 150°C, preferably 20°C to 100°C. The reaction time is 0.5 hours to 120 hours, preferably 1 hour to 72 hours. Examples of reaction solvents include acetonitrile, tetrahydrofuran, toluene, and dichloromethane. Process A-5 Compound a7 can be obtained by reacting compound a6 with a base. Examples of bases include piperidine, pyrrolidine, triethylamine, diisopropylethylamine, sodium methoxide, and sodium ethoxide. The reaction temperature is between 0°C and 100°C. The reaction time is 1 to 10 hours. Examples of reaction solvents include methanol, ethanol, and tetrahydrofuran. Process A-6 Compound a8 can be obtained by reacting compound a7 with a halogenating agent and a base. By using halogenating agents such as oxalyl dichloride, thionyl chloride, phosphorus oxychloride, and carbon tetrabromide-triphenylphosphine, compounds in which X1 is a chlorine atom can be obtained, and 1 to 5 molar equivalents can be used relative to compound a7. Furthermore, by treating the compound with trifluoromethanesulfonic anhydride instead of a halogenating agent, a compound in which X1 is trifluoromethanesulfonate can be obtained. Further treatment with an iodinating agent such as sodium iodide can yield a compound in which X1 is an iodine atom. In addition, by treating the compound with a brominating agent, a compound in which X1 is a bromine atom can be obtained. Examples of bases include triethylamine, diisopropylethylamine, pyridine, and 2,6-lutidine. The reaction temperature is between -50°C and 100°C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours. As reaction solvents, acetonitrile, tetrahydrofuran, toluene, dichloromethane, dichloroethane, etc., can be used. Process A-7 Compound a10 can be obtained by reacting compound a8 with compound a9 and a base. Examples of bases include triethylamine, diisopropylethylamine, sodium bicarbonate, cesium carbonate, and potassium carbonate. The reaction temperature is between 0°C and 100°C. The reaction time is 1 to 10 hours. Examples of reaction solvents include methanol, ethanol, and tetrahydrofuran. Process A-8 Compound a11 can be obtained by reacting compound a10 with a halogenating agent such as copper chloride or copper bromide, an acid, and an aqueous solution such as sodium nitrite. Examples of acids include hydrochloric acid and acetic acid. The reaction temperature is between 0°C and 100°C. The reaction time is 1 to 10 hours. Process A-9 Compound (I) can be obtained by reacting compound a11 with a boronic acid, a boronic acid ester, or a trialkyl stannane in the presence of a metal catalyst and a base. Examples of metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-tert-butylphosphine)palladium, which can be used in amounts of 0.001 to 0.5 molar equivalents relative to compound a4. Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, and potassium hydrogen phosphate, and can be used in amounts of 1 to 10 molar equivalents relative to compound a4. Boronic acid, boronic acid ester, or trialkyl stannane can be used in amounts of 1 to 10 molar equivalents relative to compound a4. The reaction temperature is 20°C to the reflux temperature of the solvent, and in some cases, under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of reaction solvents include tetrahydrofuran, toluene, DMF, dioxane, and water, which can be used individually or in combination. Furthermore, by reacting compound a11 with an amine, imine, or potassium cyanide, R 4a Compound (I) having an amine, imine, or cyanide can be synthesized. Also, R 4a If the compound is a carbonylamino acid, sulfonylamino acid, etc., it can be synthesized by adding various functional groups to compound a10.

[0053] The following compounds can be synthesized using the method described above. [ka]

[0054] The compounds according to the present invention have MGAT2 inhibitory activity and are useful as preventive or therapeutic agents for obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDL cholesterolemia, hyperfatty acidemia, diabetes mellitus, arteriosclerosis, and the like. The compounds of the present invention possess not only MGAT2 inhibitory activity but also pharmaceutical utility, and have any or all of the following excellent characteristics. a) High metabolic stability. b) It exhibits high solubility. c) There is little concern about phototoxicity. d) There is little concern about hepatotoxicity. e) There is little concern about nephrotoxicity. f) There is little concern about toxicity to the cardiovascular system. g) There is little concern about gastrointestinal disorders. h) There is little concern about drug interactions. i) It has high oral absorption. j) The clearance is small. k) High transferability to target tissues l) The enzyme activity is strong. m) Less induction of drug-metabolizing enzymes. n) It has a strong medicinal effect. o) High selectivity for MGAT2 inhibition. p) High chemical stability.

[0055] The pharmaceutical composition of the present invention can be administered orally or parenterally. Parenteral administration methods include transdermal, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, ophthalmic, ophthalmic, and vaginal administration.

[0056] For oral administration, the drug may be prepared and administered in any of the commonly used dosage forms, such as oral solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.) or oral liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, lemonades, alcoholic preparations, aromatic preparations, extracts, decoctions, tinctures, etc.), according to conventional methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0057] For parenteral administration, any commonly used dosage form such as injections, infusions, or topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injectables, ointments, gargles, enemas, ointments, plasters, jellies, creams, patches, poultices, topical powders, suppositories, etc.) can be suitably administered. Injectable preparations may also be emulsions of O / W, W / O, O / W / O, W / O / W type, etc.

[0058] A pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, as needed. Furthermore, by appropriately changing the effective amount of the compound of the present invention, the dosage form, and / or the various pharmaceutical additives, the pharmaceutical composition can be prepared for use in children, the elderly, critically ill patients, or for surgical use. The pediatric pharmaceutical composition is preferably administered to patients under 12 or 15 years of age. The pediatric pharmaceutical composition can also be administered to patients under 27 days postpartum, 28 days to 23 months postpartum, 2 to 11 years of age, or 12 to 16 or 18 years of age. The elderly pharmaceutical composition is preferably administered to patients 65 years of age or older.

[0059] The dosage of the pharmaceutical composition of the present invention should preferably be determined considering the patient's age, weight, type and severity of the disease, route of administration, etc. However, when administered orally, it is usually 0.05 to 100 mg / kg / day, preferably within the range of 0.1 to 10 mg / kg / day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 10 mg / kg / day, preferably within the range of 0.01 to 1 mg / kg / day. This can be administered once or several times a day.

[0060] The compound of the present invention may be used in combination with other anti-obesity drugs (pharmaceutical compositions containing compounds having anti-obesity effects, drugs that can be used for obesity or weight management in obesity) (such anti-obesity drugs include approved drugs and drugs under development or to be developed in the future) (hereinafter referred to as "combination drugs") for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the timing of administration of the compound of the present invention and the combination drugs is not limited, and they may be administered to the target patient simultaneously or with a time difference. Furthermore, the compound of the present invention and the combination drugs may be administered as two or more formulations containing their respective active ingredients, or as a single formulation containing their active ingredients. For example, a pharmaceutical composition containing a compound having anti-obesity effects can be used in combination with the compound of the present invention for the prevention and / or treatment of obesity and weight management in obese individuals. Furthermore, a pharmaceutical composition containing the compound of the present invention can be used in combination with a pharmaceutical composition containing a compound having anti-obesity effects for the prevention and / or treatment of obesity and weight management in obese individuals. In addition, the administration therapy of the pharmaceutical composition of the present invention can be used in combination with dietary therapy, drug therapy, exercise, etc.

[0061] The dosage of the concomitant drug can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the target recipient, route of administration, target disease, symptoms, combination, etc. For example, if the target recipient is a human, 0.01 to 100 parts by weight of the concomitant drug may be used for every 1 part by weight of the compound of the present invention.

[0062] The pharmaceutical composition of the present invention is for obesity (however, for those who have both type 2 diabetes and dyslipidemia, and whose BMI is 25 kg / m² despite dietary therapy and exercise therapy). 2 It is also effective in the above cases only.

[0063] The pharmaceutical composition of the present invention is also effective for severe obesity in cases where the effects of previously applied dietary therapy and exercise therapy are insufficient.

[0064] (Examples) The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited thereto.

[0065] The abbreviations used herein have the following meanings: AlCl3: Aluminum chloride BBr3: Boron tribromide BF3·(Et2O): Boron trifluoride diethyl ether complex Cbz: Benzyloxycarbonyl CbzCl: Benzyl chloroformate DIEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide HATU:O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HCl: Hydrochloric acid LHMDS: Lithium bis(trimethylsilyl)amide NaOH: Sodium hydroxide TBAB: Tetrabutylammonium bromide THF: Tetrahydrofuran Ti(OEt)4: Titanium (IV) Ethoxide

[0066] (Method for identifying compounds) NMR analysis of the results obtained in each example was performed at 400 MHz using DMSO-d6 and CDCl3. Note that when presenting NMR data, not all measured peaks may be listed. In this specification, "MS(ESI):m / z" refers to the molecular mass observed by LC / MS (liquid chromatography / mass spectrometry). The measurement conditions for LC / MS are listed below, but are not limited to these conditions. Unless otherwise specified, MS(ESI):m / z refers to [M+H]. + It represents. (Measurement condition 1) Column: ACQUITY UPLC(registered trademark) BEH C18 (1.7μm id2.1x50mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid. Gradient: A linear gradient was applied from 5% to 100% solvent [B] over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. (Measurement condition 2) Column: ACQUITY UPLC(registered trademark) BEH C18 (1.7μm id2.1x50mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: A linear gradient was performed from 5% to 100% solvent [B] over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes. Reference Example 1

[0067] [ka] To a solution of Compound 1 (9.6 g, 32 mmol) in THF (100 ml), a 1.6 M n-butyllithium hexane solution (1.26 ml, 38 mmol) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. 2,2,2-trifluoro-N-methoxy-N-methylacetamide (4.72 ml, 38 mmol) was added at -78°C, and the mixture was stirred at the same temperature for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture at -78°C, and after raising the temperature to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was removed by reduced pressure distillation, and the resulting residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate) to obtain Compound 2 (4.0 g, yield 41%). 1H NMR (400MHz, DMSO-d6): 3.14 (2H, t, J=8.56Hz), 3.80 (2H, t, J=8.80Hz), 4.29 (2H, q, J=9.62Hz), 6.82 (1H, d, J=8.31Hz), 7.69 (1H, s), 7.81 (1H, d, J=8.80Hz).Reference example 2

[0068] [ka] Process 1 A mixture of compound 4 (300 mg, 2.32 mmol), compound 3 (0.38 ml, 4.18 mmol), and trifluoromethanesulfonic acid (21 µl, 0.232 mmol) was heated and stirred at 100°C for 13 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 5 (390 mg, yield 78%). MS(ESI): m / z=216 Process 2 To a solution of compound 5 (390 mg, 1.81 mmol) in acetone (4 ml), an aqueous solution of sodium carbonate (423 mg, 3.99 mmol) (2 ml) and CbzCl (0.283 ml, 1.99 mmol) were added and the mixture was stirred at room temperature for 3 hours. Sodium carbonate (423 mg, 3.99 mmol) and CbzCl (0.283 ml, 1.99 mmol) were added and the mixture was stirred at room temperature for a further 8 hours. After filtering off the solid, it was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was removed by reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 6 (606 mg, yield 96%). MS(ESI): m / z = 372[M+Na] Process 3 Compound 6 (580 mg, 1.66 mmol) was dissolved in methanol (6 ml), to which 8 N NaOH aqueous solution (0.415 ml, 3.32 mmol) was added and the mixture was stirred at room temperature for 5 hours. After adjusting the pH to approximately 2 with 2 N HCl aqueous solution, methanol was removed by distillation under reduced pressure. Compound 7 (471 mg, yield 85%) was obtained by suspension purification with water added to the residue. MS(ESI): m / z = 334 [M - H]

[0069] Process 4 To a solution of compound 7 (419 mg, 1.25 mmol) in dichloromethane (8 ml), oxalyl chloride (0.131 ml, 1.5 mmol) and DMF (4.9 µl, 0.062 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Aluminum chloride (500 mg, 3.75 mmol) was added to the reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was added dropwise to ice-cooled water, and saturated sodium bicarbonate solution was added to adjust the pH to approximately 8. Insoluble materials were filtered through Celite and extracted with dichloromethane. The organic layer was dried over sodium sulfate. The solvent was removed by reduced pressure distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 8 (129 mg, yield 56%). MS(ESI): m / z=184 Process 5 To a solution of compound 8 (129 mg, 0.704 mmol) in acetone (2 ml), an aqueous solution of sodium carbonate (492 mg, 4.65 mmol) (1 ml) and CbzCl (0.33 ml, 2.33 mmol) were added, and the mixture was stirred at room temperature to 50°C for 18 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate and chloroform-ethyl acetate) to obtain compound 9 (197 mg, yield 88%). MS(ESI): m / z=318 [Examples]

[0070] [ka] Process 1 Compound 10 (609 mg, 4.25 mmol) and TBAB (137 mg, 0.425 mmol) were dissolved in 6 ml of 2 N HCl aqueous solution, compound 3 (613 mg, 8.51 mmol) was added, and the mixture was heated under reflux at 100°C for 5 hours. An 8 N NaOH aqueous solution was added to the reaction mixture to adjust the pH to approximately 5, and then the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 11 (896 mg, 98% yield). MS(ESI): m / z=216 Process 2 Compound 11 (940 mg, 4.37 mmol) was dissolved in dichloromethane (10 ml), and oxalyl chloride (0.459 ml, 5.24 mmol) and DMF (0.017 ml, 0.218 mmol) were added under ice cooling, and the mixture was stirred at room temperature. After 1.5 hours, aluminum chloride (1.75 g, 13.10 mmol) was added under ice cooling, and the mixture was heated under reflux for 1 hour. Another 1.75 g of aluminum chloride (13.10 mmol) was added to the reaction mixture under ice cooling, and the mixture was heated under reflux for 37 hours. After ice cooling, the reaction mixture was added dropwise to water under ice cooling and extracted with chloroform. The organic layer was dried over sodium sulfate. The solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 12 (748 mg, yield 87%). MS(ESI): m / z=198 Process 3 To a solution of compound 12 (300 mg, 1.52 mmol) in THF (3 ml), Ti(OEt)4 (1.27 ml, 6.09 mmol) and (R)-2-methylpropane-2-sulfinamide (277 mg, 2.282 mmol) were added and heated and stirred in a sealed container at 80°C for 24 hours. Water and ethyl acetate were added and stirred, and insoluble matter was removed by Celite filtration. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, and then dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 13 (213 mg, yield 47%). MS(ESI): m / z=301

[0071] Process 4 To a 1M LHMDS THF solution (1.398 ml, 1.398 mmol), a THF (0.5 ml) solution of t-butyl acetate (0.187 ml, 1.398 mmol) was added at -60°C and the mixture was stirred at -60°C for 1 hour. A 1M chlorotitanium triisopropoxide n-hexane solution (1.398 ml, 1.398 mmol) was added to the reaction mixture and the mixture was stirred at -60°C for 30 minutes. A THF (2 ml) solution of compound 13 (210 mg, 0.699 mmol) was added to the reaction mixture at -60°C and the mixture was stirred at the same temperature for 3 hours. A saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture and stirred, then filtered by Celite to remove insoluble matter. The organic layer was washed with a saturated ammonium chloride aqueous solution and saturated brine, and then dried over sodium sulfate. The solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). The obtained crude solid was purified by suspension with hexane under ice cooling to obtain compound 14 (196 mg, yield 67%). MS(ESI): m / z=417 Process 5 Compound 14 (190 mg, 0.456 mmol) was dissolved in methanol (2 ml), to which 4N dioxane hydrochloride solution (0.171 ml, 0.684 mmol) was added and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, and then dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain compound 15 (142 mg, 99% yield). MS(ESI): m / z = 296 (fragment) Process 6 Compound 15 (140 mg, 0.448 mmol) was dissolved in THF (2 ml) and 2-cyanoacetic acid (45.7 mg, 0.538 mmol), HATU (205 mg, 0.538 mmol), and triethylamine (0.155 ml, 1.12 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the compound was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 16 (149 mg, yield 88%). MS(ESI): m / z=380

[0072] Process 7 To a solution of compound 16 (147 mg, 0.387 mmol) in THF (3 ml), a 1 M sodium methoxide methanol solution (0.775 ml, 0.775 mmol) was added and the mixture was stirred at 50°C for 2 hours. A 2 N HCl aqueous solution was added to the reaction mixture to adjust the pH to approximately 4, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting crude solid was purified by suspension over diethyl ether to obtain compound 17 (106 mg, 90% yield). MS(ESI): m / z=306 Process 8 A mixed suspension of compound 17 (103 mg, 0.337 mmol) in ethyl acetate (1 ml) and 1,2-dichloroethane (1 ml) was added with DMF (0.031 ml, 0.404 mmol) and phosphorus oxychloride (0.04 ml, 0.438 mmol), and stirred at 40 °C for 6 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 18 (94.6 mg, yield 87%). MS(ESI): m / z = 324 Step 9 A suspension of compound 18 (50 mg, 0.154 mmol), sodium hydrogen carbonate (32.4 mg, 0.386 mmol) and 2 - hydrazinyl - 5 - methylpyridine hydrochloride (29.6 mg, 0.185 mmol) in ethanol (1 ml) was stirred in a sealed container at 80 °C for 4 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 19 (63 mg, yield 99%). MS(ESI): m / z = 411 Step 10 To a suspension of 2-methanesulfonylacetic acid (63.6 mg, 0.46 mmol) in dichloromethane (1 ml), oxalyl chloride (0.04 ml, 0.46 mmol) and DMF (1.2 µl, 0.015 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. To a solution of compound 19 (63 mg, 0.153 mmol) in dichloromethane (1 ml), pyridine (0.037 ml, 0.46 mmol) and the above-prepared acid chloride solution were added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, and then dried over sodium sulfate. The solvent was removed by vacuum distillation, and the resulting residue was purified by aminosilica gel column chromatography (chloroform-methanol) and silica gel column chromatography (chloroform-methanol). The resulting crude product was solidified with ethanol under ice cooling to obtain compound I-006 (24 mg, yield 30%). MS(ESI): m / z=531

[0073] The following compounds were synthesized according to the general synthesis methods and the methods described in the examples above.

[0074] [Table 1]

[0075] The physical data for each compound is shown below. In the table, "MS" represents "MS(ESI):m / z". [Table 2] [Table 3]

[0076] Examples of biological tests of 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 only needs to inhibit MGAT2. Specifically, in the evaluation method described below, IC50 is preferably 100 nM or less, more preferably 50 nM or less, and even more preferably 10 nM or less.

[0077] Preparation Example 1: Preparation of recombinant human MGAT2 The full-length human MGAT2 gene, with a flag tag added to the N-terminus, was inserted into pFastBac (Invitrogen). Recombinant baculoviruses were generated according to the Bac-to-Bac baculovirus expression system protocol (Invitrogen) and used to infect Sf-9 cells. After sonication of the harvested cells, the membrane fraction was collected by centrifugation. Expression was confirmed by Western blotting analysis using an anti-flag antibody, and recombinant human MGAT2 enzyme solution was prepared.

[0078] Test Example 1: Measurement of Human MGAT2 Inhibitory Activity To Corning polystyrene 384-well microplates, each containing 0.2 μL of DMSO solution of the compound of the present invention, 5 μL of enzyme solution prepared with assay buffer (100 mmol / L phosphate buffer (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) were added. After stirring and centrifugation, the mixtures were incubated in a humidified chamber at room temperature for 1 hour. After the enzymatic reaction, the reaction was stopped by adding 50 μL of a stop solution containing an Internal Standard (IS) (containing 0.2 μmol / L Diolein-d5, 0.4% formic acid, and 50% isopropanol). After sealing the solution onto a Shimadzu GLC plate, the mixture was stirred and centrifuged, and measurements were performed using electrospray ionization with RapidFire360 and Agilent 6550 Q-TOF mass spectrometers. The reaction product (P) Diolein of the substrate 2-Oleoylglycerol and the ammonium adduct ions of IS were detected, and the peak intensity ratio P / IS was calculated using the peak height to evaluate the inhibitory activity. Inhibitory activity was defined as Control(+) / Control(-) with and without enzyme addition, respectively, with inhibition rates of 0% and 100% inhibition, respectively. The peak intensity ratio P / IS when the inventive compound was added was used as the sample, and the calculation was performed using TIBCO Spotfire (TIBCO Software) with the following formula. Inhibitory activity (%) = [1 - {Sample - Control (-)} / {Control (+) - Control (-)}] * 100 The inhibitory activity results for each compound of the present invention are shown in the following table. 50 (nM) indicates the concentration that exhibits 50% enzyme inhibition.

[0079] [Table 4]

[0080] Test Example 2: CYP Inhibition Test Using commercially available pooled human liver microsomes, the degree to which the production of each metabolite is inhibited by the compound of the present invention is evaluated, using as indicators the typical substrate metabolic reactions of the major human CYP5 isoforms (CYP1A2, 2C9, 2C19, 2D6, 3A4): O-deethylation of 7-ethoxyresorphin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4).

[0081] The reaction conditions were as follows: Substrates: 0.5 μmol / L ethoxyresorphin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time: 15 minutes; reaction temperature: 37°C; enzyme: 0.2 mg of pooled human liver microsome protein / mL; concentrations of the compound of the present invention: 1, 5, 10, 20 μmol / L (4 points).

[0082] Add each of the five substrates, human liver microsomes, and the compound of the present invention to a 96-well plate in the above composition in 50 mmol / L Hepes buffer, and add the coenzyme NADPH to initiate the target metabolic reaction. After reacting at 37°C for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, resolphin (CYP1A2 metabolite) in the supernatant is quantified by a fluorescent multilabel counter or LC / MS / MS, and tolbutamide hydroxylated (CYP2C9 metabolite), mephenytoin 4' hydroxylated (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS. Note that the dilution concentration and dilution solvent may be changed as needed. The compounds of the present invention can be tested essentially as described above.

[0083] Only DMSO, the solvent in which the compound was dissolved instead of the compound of the present invention, was added to the reaction solution as a control (100%), and the residual activity (%) was calculated. Using the concentration and the inhibition rate, IC 50 was calculated by inverse estimation using a logistic model.

[0084] Test Example 2-2: CYP3A4 (MDZ) MBI Test Regarding the CYP3A4 inhibition of the compound of the present invention, this is a test for evaluating the mechanism-based inhibition (MBI) ability from the enhancement of the inhibitory effect caused by the metabolic reaction of the compound of the present invention. Using pooled human liver microsomes, CYP3A4 inhibition is evaluated using the 1-hydroxylation reaction of midazolam (MDZ) as an index.

[0085] The reaction conditions are as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolism reaction time, 2 minutes; reaction temperature, 37°C; pooled human liver microsomes, 0.5 mg / mL at pre-reaction, 0.05 mg / mL (10-fold dilution) during reaction; concentration of the compound of the present invention at pre-reaction, 0.83, 5, 10, 20 μmol / L (4 points).

[0086] In a 96-well plate, pooled human liver microsomes and the compound solution of the present invention are added to K-Pi buffer (pH 7.4) as a pre-reaction solution in the composition described above. A portion of this solution is transferred to another 96-well plate with K-Pi buffer containing the substrate to a 1 / 10 dilution, and the coenzyme NADPH is added to initiate the indicator reaction (Preincubation 0 min). After a predetermined reaction time, the reaction is stopped by adding methanol / acetonitrile = 1 / 1 (V / V) solution. NADPH is also added to the remaining pre-reaction solution to initiate the pre-reaction (Preincubation 30 min). After a predetermined reaction time, a portion of this solution is transferred to another plate with K-Pi buffer containing the substrate to a 1 / 10 dilution, and the indicator reaction is started. After a predetermined reaction time, the reaction is stopped by adding methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifugation of each plate in which the indicator reaction was performed at 3000 rpm for 15 minutes, 1-midazolam hydroxylated in the supernatant is quantified by LC / MS / MS. Note that the dilution concentration and dilution solvent may be changed as needed. The compounds of the present invention can be tested essentially as described above.

[0087] A control (100%) is obtained by adding only DMSO, the solvent in which the compound of the present invention is dissolved, to the reaction solution instead of the compound of the present invention. The residual activity (%) is calculated when the compound of the present invention is added at each concentration, and the IC is calculated by inverse estimation using a logistic model with the concentration and inhibition rate. The IC at preincubation 0 min / IC at preincubation 30 min is taken as the Shifted IC value. If the Shifted IC is 1.5 or higher, it is considered positive, and if the Shifted IC is 1.0 or lower, it is considered negative.

[0088] Test Example 3: BA Test Materials and methods for the study of oral absorption (1) Animals used: Mice or rats will be used. (2) Rearing conditions: Mice or rats will be given free access to solid feed and sterilized tap water. (3) Dosage and group setting: Administer orally and intravenously at the prescribed dosage. Groups are set as follows: (Dosage may vary depending on the compound) Oral administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3) Intravenous administration: 1-30 μmol / kg or 0.5-10 mg / kg (n=2-3) (4) Preparation of administration solution: Oral administration should be given as a solution or suspension. Intravenous administration should be given after solubilization. (5) Method of administration: Oral administration is performed by forcibly administering the drug into the stomach using an oral tube. Intravenous administration is performed by administering the drug into the tail vein using a syringe fitted with a needle. (6) Evaluation items: Blood samples are collected over time, and the concentration of the compound of the present invention in the plasma is measured using LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) is calculated for the plasma concentration profile of the compound of the present invention using moment analysis, and the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio and AUC ratio between the oral administration group and the intravenous administration group. Note that the dilution concentration and dilution solvent may be changed as needed. The compounds of the present invention can be tested essentially as described above.

[0089] Test Example 4: Metabolic Stability Test The compound of the present invention is reacted with commercially available pooled human liver microsomes for a certain period of time, and the residual rate is calculated by comparing the reacted sample with the unreacted sample to evaluate the extent to which the compound of the present invention is metabolized in the liver.

[0090] The reaction is carried out at 37°C for 0 or 30 minutes (oxidative reaction) in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg / mL of human liver microsome protein in the presence of 1 mmol / L NADPH. After the reaction, half the volume of the reaction solution is added to a methanol / acetonitrile = 1 / 1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant is quantified by LC / MS / MS or solid-phase extraction (SPE) / MS, and the ratio of the amount of the compound of the present invention at 0 minutes of reaction to the amount of the compound after the reaction is expressed as the residual rate. Note that the hydrolysis reaction is carried out in the absence of NADPH, and the glucuronidation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same procedure is performed thereafter. Dilution concentrations and dilution solvents may be changed as needed. The compounds of the present invention can be tested essentially as described above.

[0091] Test Example 5: Solubility Test The solubility of the compound of the present invention is determined under conditions of 1% DMSO addition. A 10 mmol / L compound solution is prepared with DMSO. 2 μL of the compound solution is added to 198 μL of JP-1 solution and JP-2 solution, respectively. After shaking at room temperature for 1 hour, the mixture is filtered by suction. The filtrate is diluted 10 or 100 times with methanol / water = 1 / 1 (V / V) or acetonitrile / methanol / water = 1 / 1 / 2 (V / V / V), and the concentration in the filtrate is measured using LC / MS or solid-phase extraction (SPE) / MS by absolute calibration curve. The dilution concentration and dilution solvent may be changed as needed.

[0092] The composition of JP-1 solution is as follows: Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make a total volume of 1000 mL. The composition of JP-2 solution is as follows: Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL of solution, and add 1 volume of water to this solution. The compounds of the present invention can be tested essentially as described above.

[0093] Test Example 6: Photolysis Test The compound of the present invention is dissolved at the desired concentration and mixed on a microplate with a 0.1-0.0008% red blood cell suspension (2.5 v / v%) prepared from defibrillated sheep blood. The mixture is then irradiated with UVA and UVB light (10 J / cm²) using an ultraviolet fluorescent lamp (GL20SE lamp, Sankyo Electric and FL20S-BLB lamp, Panasonic). 2 Perform photoirradiation at 290-400 nm. Collect the mixed solution after light irradiation and centrifuge it. After centrifugation, collect the supernatant and transfer it to a microplate, then measure the absorbance of the supernatant (540 or 630 nm) and make a judgment based on the absorbance. The absorbance at 540 and 630 nm will be used as indicators of biological membrane damage (photolysis rate %) and lipid membrane peroxidation (methemoglobin production), respectively. If the photolysis rate is less than 10% and the change in absorbance at 630 nm is less than 0.05, it will be classified as (-), and if the photolysis rate is 10% or more or the change in absorbance at 630 nm is 0.05 or more, it will be classified as (+). The compounds of the present invention can be tested essentially as described above.

[0094] Test Example 7: Cytotoxicity Test The cytotoxicity of the compound of the present invention is evaluated by automatically measuring the number of cells after exposure to the compound using a cell image analyzer called Toxinsight (Thermofisher Scientific). HepG2 cells (derived from human liver cancer cells) are seeded in a 384-well plate at a concentration of 60,000 cells / mL, and a compound solution is added to each well after 24 hours. The compound solution used is a DMSO solution containing the compound of the present invention (with a maximum concentration of 50 μmol / L and five stepwise dilutions using a 2x common ratio, with a minimum concentration of approximately 3.1 μmol / L), a DMSO-only solution as a negative control, and a camptothecin solution as a positive control. The DMSO solution of the compound of the present invention, the negative control solution, or the positive control solution is added to each well. After 71 hours, Hoechst 33342 solution diluted with Dulbecco's phosphate buffer (D-PBS) to a final concentration of 1 μg / mL is added to each well, and the nuclei are stained for 1 hour in a 37°C, 5% CO2 incubator. After staining, the cells are fixed with 4% paraformaldehyde for 20 minutes in a 37°C, CO2 incubator. Finally, after washing three times with D-PBS, the number of fluorescently colored nuclei in each well is measured using Toxinsight (Thermofisher Scientific). Four wells are prepared for each concentration, and the mean and variability (SD) of the number of nuclei (number of cells without damage) in the four wells are calculated. The compound exposure concentration (IC) at which the mean value decreases by more than 50% from the mean value of the negative control group is compared with the negative control group. 50 ) calculates IC 50 A smaller value indicates a higher risk of cytotoxicity. The compounds of the present invention can be tested essentially as described above.

[0095] Test Example 8: Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. 20 μL of cryopreserved Salmonella typhimurium strains TA98 and TA100 were inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and cultured at 37°C for 10 hours with shaking. For strain TA98, 7.70-8.00 mL of the bacterial suspension was centrifuged (2000 × g, 10 minutes) to remove the culture medium. The bacteria are suspended in the same volume of Micro F buffer (K2HPO4: 3.5 g / L, KH2PO4: 1 g / L, (NH4)2SO4: 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO4·7H2O: 0.1 g / L) as the bacterial suspension used for centrifugation, and added to 120 mL of Exposure medium (Micro F buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL). For strain TA100, 3.10-3.42 mL of the bacterial suspension is added to 120-130 mL of Exposure medium to prepare the test bacterial suspension. 12 μL of the compound of the present invention in DMSO solution (several step dilutions at a common ratio of 2 to 3 times from the maximum dose of 50 mg / mL), DMSO as a negative control, and 12 μL of the positive control in which 50 μg / mL of 4-nitroquinoline-1-oxide DMSO solution is used for TA98 strain and 0.25 μg / mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution is used for TA100 strain under non-metabolic activation conditions, and 12 μL of each in which 40 μg / mL of 2-aminoanthracene DMSO solution is used for TA98 strain and 20 μg / mL of 2-aminoanthracene DMSO solution is used for TA100 strain are mixed with 588 μL of the test bacterial suspension (a mixture of 498 μL of the test bacterial suspension and 90 μL of S9 mix under metabolic activation conditions) and cultured with shaking at 37°C for 90 minutes. 460 μL of bacterial suspension exposed to the compound of the present invention is mixed with 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, and bromocresol purple: 37.5 μg / mL), dispensed into 48-well microplates in 50 μL portions, and incubated statically at 37°C for 3 days.Wells containing bacteria that have acquired the ability to proliferate due to mutations in the amino acid (histidine) synthase gene change color from purple to yellow in response to pH changes. Therefore, the number of wells in 48 wells that have turned yellow due to bacterial growth is counted per dose and evaluated by comparing with the negative control group. Mutagenicity is indicated as (-) for negative results and (+) for positive results. Note that the dilution concentration and dilution solvent may be changed as needed. The compounds of the present invention can be tested essentially as described above.

[0096] Test Example 9: hERG Test To evaluate the risk of QT interval prolongation on an electrocardiogram using the compounds of the present invention, CHO cells expressing human ether-a-go-go related gene (hERG) channels were used to evaluate delayed rectification K, which plays an important role in the ventricular repolarization process. + Current (I Kr The effects of the present invention compound on ) will be investigated. Using a fully automated patch clamp system (QPatch; Sophion Bioscience A / S), the whole-cell patch clamp method was used to maintain cells at a membrane potential of -80mV, apply a leakage potential of -50mV, then apply a depolarizing stimulus of +20mV for 2 seconds, followed by a repolarizing stimulus of -50mV for 2 seconds, which induced I Kr Record the results. Using an extracellular solution of dimethyl sulfoxide adjusted to 0.1% (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-piperazineethanesulfonic acid): 10 mmol / L, pH=7.4) as a medium, apply the extracellular solution containing the medium and the compound of the present invention dissolved at the desired concentration to cells for at least 7 minutes under room temperature conditions. The obtained I KrThen, using analysis software (QPatch Assay software; Sophion Bioscience A / S), the absolute value of the maximum tail current is measured based on the current value at the retaining membrane potential. Furthermore, the maximum tail current after application of the compound of the present invention is calculated as the inhibition rate relative to the maximum tail current after application of the medium, and the I of the compound of the present invention is determined. Kr Evaluate the impact on [the substance]. Note that the dilution concentration and dilution solvent may be changed as needed. The compounds of the present invention can be tested essentially as described above.

[0097] Test Example 10: Ames Test The mutagenicity of the compounds of the present invention was evaluated using the Ames test with Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and Escherichia coli strain WP2uvrA as test strains. 0.1 mL of a DMSO solution of the compounds of the present invention was mixed with 0.5 mL of S9mix under metabolic activation conditions, or with 0.5 mL of phosphate buffer and 0.1 mL of test bacterial suspension under non-metabolic activation conditions. This mixture was then overlaid on a minimum glucose agar plate with 2 mL of soft agar containing histidine and biotin, or tryptophan. The same procedure was performed simultaneously for a negative control (DMSO) and a positive control (2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene). After incubation at 37°C for 48 hours, the revertant colonies that appeared were counted and evaluated in comparison to the negative control group. A positive result (+) was determined if the number of revertant colonies increased in a concentration-dependent manner and was more than twice the number of colonies in the negative control group. The dilution concentration and solvent may be changed as needed. The compounds of the present invention can be tested essentially as described above.

[0098] Test Example 11: Anti-obesity effect test The anti-obesity effects of the compounds in the examples will be investigated in C57BL / 6j mice (DIO mice) fed a high-fat diet (TestDiet;58Y1). Five-week-old male C57BL / 6j mice (Nihon CREA) were purchased and reared for four weeks under a 12-hour light-dark cycle on a high-fat diet to create DIO mice. Starting three weeks prior to compound administration, the medium (0.5% HPMC) was administered twice daily. Randomization was performed based on changes in body weight and food intake during the acclimatization period (n=7). From Day 1 to Day 28, the example compound or medium (0.5% HPMC) was administered orally twice daily. Body weight and food intake were measured daily. On Day 28, dissection was performed, epididymal fat weight was measured, and biochemical tests were conducted on collected blood. The compounds of the present invention can be tested essentially as described above.

[0099] Examples of formulations The formulation examples shown below are for illustrative purposes only and are not intended to limit the scope of the invention in any way. The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, particularly enterally, for example, orally, for example, in the form of tablets or capsules; parenterally, for example, in the form of injection solutions or suspensions; topically, for example, in the form of lotions, gels, ointments or creams; or intranasally or in the form of suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of pharmaceutically acceptable salts, together with at least one pharmaceutically acceptable carrier or diluent, can be produced by conventional methods such as mixing, granulation or coating. For example, oral compositions may be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and the active ingredient, etc. Injectable compositions may be solutions or suspensions, may be sterile, and may contain preservatives, stabilizers, buffers, etc. [Industrial applicability]

[0100] Since the compound of the present invention has MGAT2 inhibitory activity, it is useful as a pharmaceutical for diseases involving MGAT2, such as obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDL cholesterolemia, hyperfatty acidemia, diabetes mellitus, and arteriosclerosis.

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, R １ is hydrogen; R ２ａ The formula is: 【Chemistry 2】 (In the formula, ring C is an aromatic heterocycle or a non-aromatic heterocycle, R ５ Each of these is independently a halogen, cyano, haloalkylamino, haloalkylcarbonylamino, a non-aromatic carbocyclic amino that may be substituted with substituent group γ, a non-aromatic heterocyclic amino that may be substituted with substituent group γ, alkyl, haloalkyl, a non-aromatic carbocyclic alkyl that may be substituted with substituent group γ, a non-aromatic heterocyclic alkyl that may be substituted with substituent group γ, alkyloxy, haloalkyloxy, haloalkyloxyalkyloxy, a non-aromatic carbocyclic alkyloxy that may be substituted with substituent group γ, a non-aromatic heterocyclic alkyloxy that may be substituted with substituent group γ, an aromatic carbocyclic group that may be substituted with substituent group γ, a non-aromatic carbocyclic group that may be substituted with substituent group γ, an aromatic heterocyclic group that may be substituted with substituent group γ, a non-aromatic heterocyclic group that may be substituted with substituent group γ, a non-aromatic carbocyclic oxy that may be substituted with substituent group γ, or a non-aromatic heterocyclic oxy that may be substituted with substituent group γ. The substituent group γ consists of halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkyloxy groups, alkyloxycarbonylalkyl groups, aromatic carbocyclic groups, aromatic heterocyclic groups, aromatic carbocyclic oxy groups, and aromatic heterocyclic oxy groups. n is an integer between 0 and 3. R ２ｂ is alkyl, or haloalkyl, or R ２ａ and R ２ｂ It may also form ring B together with an adjacent carbon atom. Ring B is given by equation: 【Transformation 3】 (In the formula, B ３ is CR １３ａ R １３ｂ NR １３ｃ O, S, S=O, S(=O) ２ or Se, and B ４ CR １４ａ R １４ｂ And, B ５ CR １５ａ R １５ｂ And, R １３ａ , R １４ａ and R １５ａ Each of these is independently hydrogen, halogen, or alkyl. R １３ｂ , R １４ｂ and R １５ｂ Each of these is independently hydrogen, halogen, or alkyl. R １３ｃ is hydrogen or alkyl, R ６ Each of these is independently a halogen, cyano, haloalkylamino, haloalkylcarbonylamino, a non-aromatic carbocyclic amino that may be substituted with substituent group γ, a non-aromatic heterocyclic amino that may be substituted with substituent group γ, alkyl, haloalkyl, a non-aromatic carbocyclic alkyl that may be substituted with substituent group γ, a non-aromatic heterocyclic alkyl that may be substituted with substituent group γ, alkyloxy, haloalkyloxy, haloalkyloxyalkyloxy, a non-aromatic carbocyclic alkyloxy that may be substituted with substituent group γ, a non-aromatic heterocyclic alkyloxy that may be substituted with substituent group γ, an aromatic carbocyclic group that may be substituted with substituent group γ, a non-aromatic carbocyclic group that may be substituted with substituent group γ, an aromatic heterocyclic group that may be substituted with substituent group γ, a non-aromatic heterocyclic group that may be substituted with substituent group γ, a non-aromatic carbocyclic oxy that may be substituted with substituent group γ, or a non-aromatic heterocyclic oxy that may be substituted with substituent group γ. m is an integer between 0 and 3. n and the substituent group γ are equivalent to those described above; R ３ａ It is hydrogen, R ３ｂ is hydrogen; R ４ａ is cyano, formula: 【Chemistry 4】 And; L ３ These are single bonds, alkylenes, or haloalkylenes. R ７ This includes hydrogen, halogen, hydroxy, cyano, alkylamino, alkylcarbonyl, alkylcarbonylamino, carbamoyl, alkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkyloxy, haloalkyloxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkyloxyalkylsulfonyl, aromatic carbocyclic groups which may be substituted with substituent group ε, non-aromatic carbocyclic groups which may be substituted with substituent group ε, aromatic heterocyclic groups which may be substituted with substituent group ε, non-aromatic heterocyclic groups which may be substituted with substituent group ε, aromatic carbocyclic sulfonyl which may be substituted with substituent group ε, non-aromatic carbocyclic sulfonyl which may be substituted with substituent group ε, formula: -N=S(=O)(-R Ｓ１ )-R Ｓ２ , or formula: -S (=O) (=N-R Ｎ )-R Ｓ１ And, The substituent group ε consists of halogens, hydroxy, cyano, oxo, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, and alkylsulfonyl; R ４ｂ is an alkyl group which may be substituted with substituent group α, an aromatic carbocyclic group which may be substituted with substituent group β, a non-aromatic carbocyclic group which may be substituted with substituent group β, an aromatic heterocyclic group which may be substituted with substituent group β, or a non-aromatic heterocyclic group which may be substituted with substituent group β. The substituent group α is an aromatic carbocyclic group which may be substituted with halogen, cyano, hydroxy, alkyloxy, haloalkyloxy, alkylamino, substituent group δ, a non-aromatic carbocyclic group which may be substituted with substituent group δ, an aromatic heterocyclic group which may be substituted with substituent group δ, and a non-aromatic heterocyclic group which may be substituted with substituent group δ. The substituent group β consists of halogens, cyano, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkyloxy, haloalkyloxy, alkylsulfonyl, and cyclopropanyl. Substituent group δ: halogen, alkyl, haloalkyl, and hydroxyalkyl, R Ｓ１ and R Ｓ２ Each of these is independently hydrogen, alkyl, or haloalkyl. R Ｎ is hydrogen, alkyl, or haloalkyl; however, B ３ However, CR １３ａ R １３ｂ In this case, m is an integer from 1 to 3. B ３ A compound represented by (where m is 0, and when m is 1, n is 0), or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is one of the following formulas. 【Transformation 5】 (In the formula, R １３ａ , R １３ｂ , R １３ｃ , R １４ａ , R １４ｂ , R １５ａ , R １５ｂ , R ６ (and n are the same as in claim 1)

3. R ２ａ However, the formula is: 【Transformation 6】 (In the formula, ring C is a 5-membered or 6-membered aromatic heterocycle or a 4- to 10-membered non-aromatic heterocycle) R ５ (and n is the same as in claim 1), R ２ｂ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is a haloalkyl.

4. R ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each is independently a halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, alkyloxyalkyloxy, or haloalkyloxyalkyloxy.

5. R ５ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein each is independently a halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, alkyloxyalkyloxy, or haloalkyloxyalkyloxy.

6. R ４ａ but, 【Transformation 7】 (In the formula, L ３ and R ７ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein (the latter is equivalent to claim 1).

7. L ３ However, these are alkylenes or haloalkylenes. R ７ However, hydrogen, halogen, sulfamoyl, alkylsulfamoyl, alkyloxy, haloalkyloxy, alkylsulfonyl, or formula: -S(=O)(=N-R Ｎ )-R Ｓ１ The compound according to claim 6, or a pharmaceutically acceptable salt thereof.

8. R ４ｂ However, it is an alkyl group which may be substituted with substituent group α, a six-membered aromatic carbocyclic group which may be substituted with substituent group β, or a five-membered or six-membered aromatic heterocyclic group which may be substituted with substituent group β. The substituent group α consists of halogens, cyanos, and cyclopropanyls. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the substituent group β is halogen, cyano, alkyl, haloalkyl, hydroxyalkyl, alkyloxy, haloalkyloxy, alkylsulfonyl, and cyclopropanyl.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9, having MGAT2 inhibitory activity.

11. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic or prophylactic agent for diseases involving MGAT2.

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