WO2025127097A1 - Medicine for treating steatotic liver diseases - Google Patents

Abstract

Provided is a pharmaceutical composition for treating and/or preventing steatotic liver diseases, particularly non-alcoholic fatty liver diseases, which has an excellent MGAT2 inhibitory effect and does not involve adverse side effects such as hemostatic abnormality, hepatic and renal disorders or embryonic lethality. The pharmaceutical composition contains a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.　Formula (I): (wherein: R^2a and R^2b together, in conjunction with the adjacent carbon atom, form a ring B; the ring B is represented by any one of the formulae shown in the middle part of FIG. 1 (wherein R⁶'s each independently represent a halogen atom or the like); R^4a is represented by the formula shown in the lower part of FIG. 1 (wherein L³ represents an alkylene group, and R⁷ represents an alkylsulfonyl group); R^4b represents an alkyl group which may be substituted by a group α substituent, or the like; the group α substituent is a halogen atom, or the like; and a group β substituent is a halogen atom, or the like.)

Description

Medicine for treating fatty liver disease

The present invention relates to a new pharmaceutical composition for treating and/or preventing fatty liver disease, particularly non-alcoholic fatty liver disease.

Liver disease is a leading cause of death worldwide. Liver disease can be caused by infection, injury, exposure to drugs or toxic compounds, alcohol, impurities in food, and abnormal accumulation of normal substances in the blood, autoimmune processes, genetic defects (such as hemochromatosis), or unknown cause(s). Liver disease is commonly classified as acute or chronic based on the duration of the disease.
Fatty liver disease (SLD) is a general term for diseases in which accumulation of neutral fat in the liver causes liver damage. A case in which 30% or more of hepatocytes in liver tissue contain lipid droplets is called fatty liver.
Fatty liver is a state where neutral fat accumulates in the liver, and since the accumulation of fat in the liver is a non-progressive (reversible) change, the accumulation of fat in the liver returns to normal when the cause is removed. However, if the accumulation of fat progresses and liver dysfunction occurs, it may develop into cirrhosis or liver cancer. Alcoholic steatohepatitis (ASH), which is caused by drinking alcohol, is a typical example of fatty liver.
On the other hand, fatty liver can occur even in people who consume very little alcohol, and this condition is called nonalcoholic fatty liver disease (NAFLD). The most severe form of NAFLD is called nonalcoholic steatohepatitis (NASH). NASH is considered to be an important cause of cirrhosis and liver cancer.
The histological findings of alcoholic and non-alcoholic hepatitis are similar, and common mechanisms of onset, such as oxidative stress in the liver, are being studied.
According to the American Liver Association, more than 20% of the population has NAFLD. If left untreated, NAFLD can progress to NASH, which causes serious adverse effects. Furthermore, if untreated, NASH can lead to liver fibrosis, cirrhosis, liver failure, or hepatocellular carcinoma. An estimated 16 million adults in the United States have NASH, and roughly 50% have advanced liver fibrosis (bridging fibrosis or cirrhosis) associated with NASH. NASH is currently the leading cause of hepatocellular carcinoma in the United States and the second most common indication for liver transplantation after hepatitis C. NASH is characterized by the presence of steatosis, as well as other characteristics including hepatocellular degeneration (balloon, Mallory hyaline), inflammatory cell infiltration, and the development of progressive fibrosis.
There are no currently approved therapies for the treatment of NASH or that reduce fibrosis and/or steatosis in NASH patients. Thus, there remains a need to provide new effective agents for treating liver disease or symptoms of liver disease.

Patent Document 1 describes a method for treating and/or preventing NASH and/or primary biliary cirrhosis, which comprises administering a pharmaceutical composition containing eicosapentaenoic acid or a derivative thereof to a subject in need thereof. It has been reported that obeticholic acid, a semisynthetic bile acid and an agonist for the nuclear receptor FXR (farnesoid X receptor), has been applied for in Europe and the United States for the treatment of fibrosis caused by NASH.

In monoacylglycerol acyltransferase 2 (hereinafter also referred to as MGAT2) knockout mice, it has been confirmed that high-fat diet-induced weight gain, insulin resistance, blood cholesterol elevation, fatty liver formation, and energy consumption are suppressed (Non-Patent Document 1). In addition, it has been reported that compounds having MGAT2 inhibitory activity (JTP-103237, BMS-963272 ) improve fatty liver in high sucrose-loaded model mice and improve liver fibrosis in NASH model mice (Non-Patent Documents 2 and 3). Furthermore, it has been reported that expression of MGAT2 is increased in the liver of NAFLD patients (Non-Patent Document 4).
Based on these findings, it is expected that MGAT2 inhibitors are promising therapeutic agents for fatty liver diseases including NASH, but no drug that shows efficacy in humans has yet been developed (Non-Patent Document 5).

で示される化合物が記載されている。
　また特許文献５～６には、ＭＧＡＴ２阻害剤である式：

で示される化合物が記載されている。
　しかしながら、これら特許文献２～６には非アルコール性脂肪肝疾患の治療及び／又は予防に有効であることは記載されていない。 Patent documents 2 to 4 disclose MGAT2 inhibitors of the formula:

The compound represented by the formula:
Furthermore, Patent Documents 5 and 6 disclose MGAT2 inhibitors of the formula:

The compound represented by the formula:
However, Patent Documents 2 to 6 do not disclose that they are effective in treating and/or preventing non-alcoholic fatty liver disease.

US Patent Publication No. 2014/187633 International Publication No. 2019013311 International Publication No. 2019013312 Patent Application No. 2020-02515 International Publication No. 2020145369 Patent application No. 2021-113901

Nature Medicine volume 15, pages442-446 (2009) Journal of Pharmacological Sciences 128 (2015) 150e157 Cell Metabolism 34, 1732-1748, 2022 Journal of Lipid Research Volume 53, 2012, p990-999 J. Med. Chem. 2018, 61, 9879-9888

The object of the present invention is to provide a pharmaceutical composition for the treatment and/or prevention of fatty liver disease, particularly non-alcoholic fatty liver disease, which has excellent MGAT2 inhibitory activity and is free of side effects such as hemostatic abnormalities, liver damage, renal damage, or embryonic lethality.

As a result of extensive investigations to solve the above problems, the present inventors discovered that, among the compounds having MGAT2 inhibitory activity described in Patent Documents 2 to 4, certain compounds are effective in treating and/or preventing non-alcoholic fatty liver disease and are free of side effects such as hemostatic abnormalities, liver damage, renal damage, or embryonic lethality, and thus completed the present invention. The present invention relates to the following.

（式中、
　Ｒ^２ａ及びＲ^２ｂは、隣接する炭素原子と一緒になって、環Ｂを形成し；
　環Ｂは、式：

（式中、Ｒ^６は、それぞれ独立して、ハロゲン、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、又はシクロプロパニルである）であり；
　Ｒ^４ａは、式：

（式中、
　Ｌ^３は、アルキレンであり、
　Ｒ^７は、アルキルスルフォニルである）であり；
　Ｒ^４ｂは、置換基群αで置換されていてもよいアルキル、置換基群βで置換されていてもよいフェニル基、又は置換基群βで置換されていてもよい５～６員の芳香族複素環式基であり；
　置換基群αは、ハロゲン、ハロアルキルオキシ、及びシクロプロパニルであり、
　置換基群βは、ハロゲン、シアノ、アルキル、ハロアルキル、及びシクロプロパニルである）で示される化合物又はその製薬上許容される塩を含有する、脂肪性肝疾患を治療及び／又は予防するための、医薬組成物。
［２］Ｒ^６が、それぞれ独立して、ハロゲン、ハロアルキル、又はハロアルキルオキシであり、
Ｒ^４ａが、式：

であり、
Ｒ^４ｂが、ハロアルキルオキシアルキル、ハロゲンで置換されていてもよいフェニル基、又は置換基群βで置換されていてもよい５～６員の芳香族複素環式基であり、
　置換基群βは、ハロゲン及びアルキルである、［１］記載の医薬組成物。
［３］環Ｂが、式：

（式中、各記号は［１］又は［２］と同意義）
である、［１］又は［２］記載の医薬組成物。
［４］化合物Ｉ－８、Ｉ－２３、Ｉ－３４、Ｉ－１９０、Ｉ－２１２、Ｉ－２３６、Ｉ－２５３、Ｉ－２７５、Ｉ－２７６、ＩＩ－９３、ＩＩ－１０３、ＩＩ－１２１、ＩＩ－１５１、ＩＩ－１６８、ＩＩ－１７４、ＩＩ－２０３、ＩＩ－２２５、ＩＩ－２３３及びＩＩ－２９５からなる群から選択される化合物又はその製薬上許容される塩を含有する、［１］記載の医薬組成物。
［５］化合物Ｉ－２３６、Ｉ－２５３、Ｉ－２７５、ＩＩ－１０３、ＩＩ－１２１、ＩＩ－１７４、ＩＩ－２０３、ＩＩ－２２５及びＩＩ－２３３からなる群から選択される化合物又はその製薬上許容される塩を含有する、［１］記載の医薬組成物。
［６］前記脂肪性肝疾患が非アルコール性脂肪肝疾患（ＮＡＦＬＤ）である、［１］記載の医薬組成物。
［７］前記脂肪性肝疾患が代謝機能障害関連脂肪性肝疾患（ＭＡＳＬＤ）、成因不明脂肪性肝疾患（Ｃｒｙｐｔｏｇｅｎｉｃ　ＳＬＤ）又は特定成因脂肪性肝疾患（Ｓｐｅｃｉｆｉｃ　ａｅｔｉｏｌｏｇｙ　ＳＬＤ）である、［１］記載の医薬組成物。
［８］前記脂肪性肝疾患が非アルコール性脂肪肝炎（ＮＡＳＨ）である、［１］記載の医薬組成物。
［９］前記脂肪性肝疾患が代謝機能障害関連脂肪肝炎（ＭＡＳＨ）である、［１］記載の医薬組成物。
［１０］前記脂肪性肝疾患がＮＡＳＨ又はＭＡＳＨによって引き起こされる肝線維症である、［１］記載の医薬組成物。
［１１］前記脂肪性肝疾患がＮＡＳＨ又はＭＡＳＨによって引き起こされる肝硬変である、［１］記載の医薬組成物。
［１２］前記脂肪性肝疾患がＮＡＳＨ又はＭＡＳＨによって引き起こされる肝細胞癌（ＨＣＣ）である、［１］記載の医薬組成物。
［１３］前記医薬組成物の投与によって、止血異常、肝障害、腎障害及び胚致死性の少なくとも１つの副作用を伴わない、［１］記載の医薬組成物。
［１４］身体質量指数（ＢＭＩ）が２５ｋｇ／ｍ^２未満である対象における脂肪性肝疾患を治療及び／又は予防するための、［１］～［１３］のいずれかに記載の医薬組成物。
［１５］脂肪性肝疾患を治療及び／又は予防するための、［１］～［１４］のいずれかに記載の医薬組成物であって、有効量の化合物が対象に投与される、医薬組成物。
［１６］前記化合物の有効量が１日あたり０．５ｍｇ～１００ｍｇの範囲である、［１５］記載の医薬組成物。
［１７］前記化合物の有効量が１日あたり１ｍｇ～５０ｍｇの範囲である、［１６］記載の医薬組成物。
［１８］前記化合物の有効量が１日あたり３ｍｇ～３０ｍｇの範囲である、［１７］記載の医薬組成物。
［１９］脂肪性肝疾患の治療及び／又は予防方法であって、式：

（式中、
　Ｒ^２ａ及びＲ^２ｂは、隣接する炭素原子と一緒になって、環Ｂを形成し；
　環Ｂは、式：

（式中、Ｒ^６は、それぞれ独立して、ハロゲン、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、又はシクロプロパニルである）であり；
　Ｒ^４ａは、式：

（式中、
　Ｌ^３は、アルキレンであり、
　Ｒ^７は、アルキルスルフォニルである）であり；
　Ｒ^４ｂは、置換基群αで置換されていてもよいアルキル、置換基群βで置換されていてもよいフェニル基、又は置換基群βで置換されていてもよい５～６員の芳香族複素環式基であり；
　置換基群αは、ハロゲン、ハロアルキルオキシ、及びシクロプロパニルであり、
　置換基群βは、ハロゲン、シアノ、アルキル、ハロアルキル、及びシクロプロパニルである）で示される化合物又はその製薬上許容される塩の有効量を、脂肪性肝疾患の治療及び／又は予防を必要とする個体に投与する工程を含む、脂肪性肝疾患の治療及び／又は予防方法。
［２０］脂肪性肝疾患の治療及び／又は予防用医薬を製造するための、式：

（式中、
　Ｒ^２ａ及びＲ^２ｂは、隣接する炭素原子と一緒になって、環Ｂを形成し；
　環Ｂは、式：

（式中、Ｒ^６は、それぞれ独立して、ハロゲン、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、又はシクロプロパニルである）であり；
　Ｒ^４ａは、式：

（式中、
　Ｌ^３は、アルキレンであり、
　Ｒ^７は、アルキルスルフォニルである）であり；
　Ｒ^４ｂは、置換基群αで置換されていてもよいアルキル、置換基群βで置換されていてもよいフェニル基、又は置換基群βで置換されていてもよい５～６員の芳香族複素環式基であり；
　置換基群αは、ハロゲン、ハロアルキルオキシ、及びシクロプロパニルであり、
　置換基群βは、ハロゲン、シアノ、アルキル、ハロアルキル、及びシクロプロパニルである）で示される化合物又はその製薬上許容される塩の使用。
［２１］脂肪性肝疾患を治療及び／又は予防するための、式：

（式中、
　Ｒ^２ａ及びＲ^２ｂは、隣接する炭素原子と一緒になって、環Ｂを形成し；
　環Ｂは、式：

（式中、Ｒ^６は、それぞれ独立して、ハロゲン、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、又はシクロプロパニルである）であり；
　Ｒ^４ａは、式：

（式中、
　Ｌ^３は、アルキレンであり、
　Ｒ^７は、アルキルスルフォニルである）であり；
　Ｒ^４ｂは、置換基群αで置換されていてもよいアルキル、置換基群βで置換されていてもよいフェニル基、又は置換基群βで置換されていてもよい５～６員の芳香族複素環式基であり；
　置換基群αは、ハロゲン、ハロアルキルオキシ、及びシクロプロパニルであり、
　置換基群βは、ハロゲン、シアノ、アルキル、ハロアルキル、及びシクロプロパニルである）で示される化合物又はその製薬上許容される塩。 [1] Formula (I):

(In the formula,
R ^2a and R ^2b together with adjacent carbon atoms form ring B;
Ring B is of the formula:

wherein each ^R6 is independently halogen, haloalkyl, alkyloxy, haloalkyloxy, or cyclopropanyl;
R ^4a is a group represented by the formula:

(In the formula,
^L3 is alkylene;
R ⁷ is alkylsulfonyl;
R ^4b is an alkyl group optionally substituted with substituent group α, a phenyl group optionally substituted with substituent group β, or a 5- to 6-membered aromatic heterocyclic group optionally substituted with substituent group β;
Substituent group α is halogen, haloalkyloxy, and cyclopropanyl;
A pharmaceutical composition for treating and/or preventing fatty liver disease, comprising a compound represented by the formula (I) or a pharma- ceutically acceptable salt thereof, wherein substituent group β is halogen, cyano, alkyl, haloalkyl, and cyclopropanyl.
[2] Each R ⁶ is independently halogen, haloalkyl, or haloalkyloxy;
R ^4a is a group represented by the formula:

and
R ^4b is a haloalkyloxyalkyl, a phenyl group optionally substituted with halogen, or a 5- to 6-membered aromatic heterocyclic group optionally substituted with substituent group β,
The pharmaceutical composition according to [1], wherein the substituent group β is halogen and alkyl.
[3] Ring B is represented by the formula:

(In the formula, each symbol has the same meaning as [1] or [2].)
The pharmaceutical composition according to [1] or [2],
[4] The pharmaceutical composition according to [1], which contains a compound selected from the group consisting of compounds I-8, I-23, I-34, I-190, I-212, I-236, I-253, I-275, I-276, II-93, II-103, II-121, II-151, II-168, II-174, II-203, II-225, II-233 and II-295, or a pharma- ceutical acceptable salt thereof.
[5] The pharmaceutical composition according to [1], which contains a compound selected from the group consisting of compounds I-236, I-253, I-275, II-103, II-121, II-174, II-203, II-225 and II-233, or a pharma- ceutical acceptable salt thereof.
[6] The pharmaceutical composition according to [1], wherein the fatty liver disease is nonalcoholic fatty liver disease (NAFLD).
[7] The pharmaceutical composition according to [1], wherein the fatty liver disease is metabolic dysfunction-associated fatty liver disease (MASLD), cryptogenic fatty liver disease (Cryptogenic SLD) or specific aetiology fatty liver disease (Specific aetiology SLD).
[8] The pharmaceutical composition according to [1], wherein the fatty liver disease is nonalcoholic steatohepatitis (NASH).
[9] The pharmaceutical composition according to [1], wherein the fatty liver disease is metabolic dysfunction-associated steatohepatitis (MASH).
[10] The pharmaceutical composition according to [1], wherein the fatty liver disease is hepatic fibrosis caused by NASH or MASH.
[11] The pharmaceutical composition according to [1], wherein the fatty liver disease is cirrhosis caused by NASH or MASH.
[12] The pharmaceutical composition according to [1], wherein the fatty liver disease is hepatocellular carcinoma (HCC) caused by NASH or MASH.
[13] The pharmaceutical composition according to [1], wherein administration of the pharmaceutical composition does not result in at least one side effect of hemostatic abnormalities, liver damage, kidney damage, and embryonic lethality.
[14] The pharmaceutical composition according to any one of [1] to [13], for treating and/or preventing fatty liver disease in a subject having a body mass index (BMI) of less than 25 kg/ ^m2 .
[15] The pharmaceutical composition according to any one of [1] to [14] for treating and/or preventing fatty liver disease, wherein an effective amount of the compound is administered to a subject.
[16] The pharmaceutical composition according to [15], wherein the effective amount of the compound is in the range of 0.5 mg to 100 mg per day.
[17] The pharmaceutical composition according to [16], wherein the effective amount of the compound is in the range of 1 mg to 50 mg per day.
[18] The pharmaceutical composition according to [17], wherein the effective amount of the compound is in the range of 3 mg to 30 mg per day.
[19] A method for treating and/or preventing fatty liver disease, comprising administering to a patient having the formula:

(In the formula,
R ^2a and R ^2b together with adjacent carbon atoms form ring B;
Ring B is of the formula:

wherein each ^R6 is independently halogen, haloalkyl, alkyloxy, haloalkyloxy, or cyclopropanyl;
R ^4a is a group represented by the formula:

(In the formula,
^L3 is alkylene;
R ⁷ is alkylsulfonyl;
R ^4b is an alkyl group optionally substituted with substituent group α, a phenyl group optionally substituted with substituent group β, or a 5- to 6-membered aromatic heterocyclic group optionally substituted with substituent group β;
Substituent group α is halogen, haloalkyloxy, and cyclopropanyl;
and R 1 is an integer from 1 to 3. The present invention relates to a method for treating and/or preventing fatty liver disease, the method comprising the step of administering an effective amount of a compound represented by the formula:
[20] A compound according to the formula:

(In the formula,
R ^2a and R ^2b together with adjacent carbon atoms form ring B;
Ring B is of the formula:

wherein each ^R6 is independently halogen, haloalkyl, alkyloxy, haloalkyloxy, or cyclopropanyl;
R ^4a is a group represented by the formula:

(In the formula,
^L3 is alkylene;
R ⁷ is alkylsulfonyl;
R ^4b is an alkyl group optionally substituted with substituent group α, a phenyl group optionally substituted with substituent group β, or a 5- to 6-membered aromatic heterocyclic group optionally substituted with substituent group β;
Substituent group α is halogen, haloalkyloxy, and cyclopropanyl;
Substituent group β is halogen, cyano, alkyl, haloalkyl, and cyclopropanyl, or a pharma- ceutically acceptable salt thereof.
[21] A compound of the formula:

(In the formula,
R ^2a and R ^2b together with adjacent carbon atoms form ring B;
Ring B is of the formula:

wherein each ^R6 is independently halogen, haloalkyl, alkyloxy, haloalkyloxy, or cyclopropanyl;
R ^4a is a group represented by the formula:

(In the formula,
^L3 is alkylene;
R ⁷ is alkylsulfonyl;
R ^4b is an alkyl group optionally substituted with substituent group α, a phenyl group optionally substituted with substituent group β, or a 5- to 6-membered aromatic heterocyclic group optionally substituted with substituent group β;
Substituent group α is halogen, haloalkyloxy, and cyclopropanyl;
Substituent group β is halogen, cyano, alkyl, haloalkyl, and cyclopropanyl, or a pharma- ceutically acceptable salt thereof.

The pharmaceutical composition of the present invention has an excellent effect of being effective in treating and/or preventing fatty liver disease, particularly non-alcoholic fatty liver disease. In addition, it has a high level of safety, being free from at least one of the side effects of hemostatic abnormalities, liver damage, renal damage, and embryonic lethality.

1 shows the intracellular fat accumulation content in HepG2 cells after overnight treatment with compounds II-203, II-121 and BMS-963272. 1 shows the intracellular ATP content when compounds II-203, II-121 and BMS-963272 were treated in HepG2 cells for 48 hours. 4 shows LDH activity in the culture supernatant of HepG2 cells treated with compounds II-203, II-121 and BMS-963272 for 24 hours.

The meaning of each term used in this specification will be 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 "comprising" is meant to be open ended and does not exclude unrecited elements.
Hereinafter, the present invention will be described with reference to the embodiments. Throughout this specification, it should be understood that the singular expression includes the plural concept unless otherwise specified. Therefore, it should be understood that the singular article (for example, in the case of English, "a", "an", "the", etc.) includes the plural concept unless otherwise specified.
In addition, it should be understood that the terms used in this specification are used in the same sense as commonly used in the above field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, the present specification (including definitions) shall prevail.

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

The term "alkyl" includes straight-chain 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, and n-decyl.
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.

"Alkylene" includes straight-chain or branched divalent 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 methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, and hexamethylene.

The term "aromatic heterocyclic group" means a monocyclic or bicyclic or more aromatic cyclic group having one or more identical or different heteroatoms selected from O, S and N in the ring.
The aromatic heterocyclic group having two or more rings also includes a monocyclic or bicyclic or more ring aromatic heterocyclic group condensed with a ring in the above-mentioned "aromatic carbocyclic group", and the bond may be on any of the rings.
The monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
The bicyclic aromatic heterocyclic group is preferably an 8- to 10-membered ring, more preferably an 9- or 10-membered ring, and examples thereof include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, and the like.
The aromatic heterocyclic group having three or more rings is preferably a group having 13 to 15 members, and examples thereof include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.

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 group β.

Fatty liver disease (SLD) is a general term for diseases in which triglycerides accumulate in the liver, causing liver damage. In the past, it was believed that alcohol was often the cause, but recently it has become more common among obese people who do not drink alcohol. Liver damage characterized by fatty deposits in the liver similar to alcoholic liver disease in liver tissue findings, even in cases where there is no clear history of drinking, is called non-alcoholic fatty liver disease (NAFLD).

NAFLD is a condition characterized by the presence of fatty liver tissue or imaging findings, after exclusion of other liver diseases such as alcoholic liver disease. NAFLD is characterized by the accumulation of fat in hepatocytes and is often associated with some aspects of the metabolic syndrome (e.g., type 2 diabetes mellitus, insulin resistance, hyperlipidemia, hypertension). The frequency of this disease is becoming increasingly common due to the consumption of carbohydrate-rich and high-fat diets. A subset of patients with NAFLD develops nonalcoholic steatohepatitis (NASH).

NASH, a subtype of fatty liver disease, is a more severe form of NAFLD. It is characterized by macrovesicular steatosis, balloon degeneration of liver cells, and/or inflammation that ultimately leads to scarring of the liver (i.e., fibrosis). Patients diagnosed with NASH progress to advanced stages of liver fibrosis and ultimately cirrhosis. The current treatment for end-stage cirrhotic NASH patients is liver transplantation.

NAFLD as defined above includes metabolic dysfunction-associated fatty liver disease (MASLD), cryptogenic fatty liver disease (Cryptogenic SLD), and specific aetiology fatty liver disease (Specific Aetiology SLD).

Metabolic dysfunction-associated fatty liver disease (MASLD) refers to a disease that, in addition to fatty liver, meets one or more of the following criteria: obesity, impaired glucose tolerance, hypertension, hypertriglyceridemia, and low HDL cholesterol. Examples of the criteria include those described in J Hepatol, 2023; 79 (6): 1542-56.

Cryptogenic fatty liver disease (Cryptogenic SLD) refers to a disease among the NAFLD/NASH defined above that does not meet any of the criteria for obesity, impaired glucose tolerance, hypertension, hypertriglyceridemia, or hypo-HDL cholesterol. Examples of the criteria include those described in J Hepatol, 2023; 79 (6): 1542-56.

Specific aetiology fatty liver disease (SLD) refers to fatty liver disease that is not accompanied by metabolic dysfunction and is caused by specific drugs or other factors.

As defined above, NASH includes metabolic dysfunction-associated steatohepatitis (MASH). Thus, a subset of patients with NAFLD or MASLD may develop MASH.

Metabolic dysfunction-associated steatohepatitis (MASH) refers to the MASLD defined above in which ballooning and Mallory-Denk bodies are histologically observed.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, that occurs in most types of chronic liver disease. Advanced liver fibrosis leads to cirrhosis, liver failure, and portal hypertension, often requiring liver transplantation.

As liver fibrosis progresses, liver cells become surrounded by fibrosis, resulting in liver cirrhosis. As liver cirrhosis progresses, symptoms such as edema, ascites, and jaundice appear, and if gastrointestinal lesions such as esophageal and gastric varices occur at the same time, vomiting of blood may occur. In addition, as liver fibrosis progresses, the risk of developing liver cancer increases.

Hepatocellular carcinoma is the most common cancer originating from the liver and usually occurs in patients with severe scarring of the liver (cirrhosis). Patients with advanced liver fibrosis and cirrhosis are reported to develop liver cancer within five years at a rate of 5-30%.

Alcoholic liver disease (ALD) encompasses a wide range of diseases, including alcoholic fatty liver (AFL), alcoholic steatohepatis (ASH), severe alcoholic hepatitis (SAH), alcoholic liver fibrosis, and liver cirrhosis.
Since the compound according to the present invention has an excellent MGAT2 inhibitory effect, it is also useful as a therapeutic and/or preventive agent for ALD.

In the specification, Body Mass Index (BMI) refers to a simple index of weight to height commonly used to classify adult (15 years or older) populations or individuals as overweight or obese, and is weight in kilograms divided by height in meters squared (kg/ ^m2 ). It is particularly effective in subjects with a BMI of less than 25 kg/ ^m2 , although it is also effective in subjects with a BMI of 25 kg/ ^m2 or more.

As the compound represented by formula (I), the following compounds or pharma- ceutically acceptable salts thereof are particularly preferred.

The compounds used in the present invention are not limited to specific isomers, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.

One or more hydrogen, carbon and/or other atoms of the compounds used in the present invention may be replaced with isotopes of hydrogen, carbon and/or other atoms, respectively. Examples of such isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as ^2H , ^3H , ^{11C , 13C, 14C, 15N, 18O , 17O , 31P , 32P ,} 35S, ^18F , ^123I and ^36Cl . The compounds used in the present invention also include compounds replaced with such isotopes. The isotope-substituted compounds are also useful as pharmaceuticals, and include all isotopes and radiolabeled compounds of the compounds used in the present invention. The "radiolabeling method" for producing the "radiolabel" is also included in the present invention, and the "radiolabel" is useful as a research and/or diagnostic tool in metabolism pharmacokinetic studies and binding assays.

Radiolabeled compounds used in the present invention can be prepared by methods well known in the art. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a particular compound of formula (I) by catalytic dehalogenation using tritium. This method involves reacting a precursor of a compound of formula (I) in which the halogen is appropriately substituted with tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". ¹⁴ C-labeled compounds can be prepared by using a raw material having ¹⁴ C carbon.

Pharmaceutically acceptable salts of the compounds used in the present invention include, for example, salts of the compounds used in the present invention with 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, pyridine, pyridine, etc.), and the like. Examples of the salts include salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and amino acids, and salts with 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, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

The compound or its pharma- ceutically acceptable salt used in the present invention may form a solvate (e.g., hydrate, etc.), co-crystal, and/or crystalline polymorph, and the present invention includes such various solvates, co-crystals, and crystalline polymorphs. A "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) to the compound used in the present invention. When the compound or its pharma- ceutically acceptable salt used in the present invention is left in the air, it may absorb moisture, and adsorbed water may adhere to it, or a hydrate may be formed. In addition, the compound or its pharma- ceutically acceptable salt used in the present invention may form a crystalline polymorph by recrystallizing it. A "co-crystal" means that the compound or salt used in the present invention and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.

The compounds or pharma- ceutically acceptable salts thereof used in the present invention may form prodrugs, and the present invention also includes such various prodrugs. Prodrugs are derivatives of the compounds of the present invention having a group that can be decomposed chemically or metabolically, and are compounds that become the pharma- ceutically active compounds of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compounds of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in the living body, and compounds that are converted to the compounds of formula (I) by hydrolysis by gastric acid, etc. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs may themselves have activity.

The compound according to the present invention has an excellent MGAT2 inhibitory effect, and is therefore useful as a therapeutic and/or preventive agent for fatty liver disease, particularly non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease is not limited to non-alcoholic steatohepatitis (NASH), and is also useful as a therapeutic and/or preventive agent for liver fibrosis, liver cirrhosis, or hepatocellular carcinoma (HCC) caused by NASH.
Furthermore, the compound according to the present invention has pharmaceutical utility and preferably has one or more of the following excellent characteristics:
a) It has a weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.).
b) It exhibits favorable pharmacokinetics, such as high bioavailability and moderate clearance.
c) High metabolic stability.
d) It does not exhibit irreversible inhibitory effects on CYP enzymes (e.g., CYP3A4) within the concentration range of the measurement conditions described herein.
e) It is not mutagenic.
f) Lower cardiovascular risk.
g) It exhibits high solubility.
h) It is free of at least one of the side effects of hemostatic abnormalities, liver damage, renal damage, and embryonic lethality.

The pharmaceutical composition of the present invention can be administered either orally or parenterally. Parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

　In the case of oral administration, the drug may be prepared and administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic preparations, extracts, decoctions, tinctures, etc.), in accordance with the usual methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, 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.

In the case of parenteral administration, any of the commonly used dosage forms such as injections, drops, topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, topical powders, suppositories, etc.) can be suitably administered. Injections may be emulsions such as O/W, W/O, O/W/O, and W/O/W types.

A pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrants, lubricants, etc., as necessary. Furthermore, the pharmaceutical composition can be prepared as a pharmaceutical composition for children, elderly people, seriously ill patients, or surgical patients by appropriately changing the effective amount of the compound of the present invention, the dosage form, and/or various pharmaceutical additives. For example, a pharmaceutical composition for children can be administered to newborns (less than 4 weeks after birth), infants (4 weeks to less than 1 year after birth), toddlers (1 year to less than 7 years), children (7 years to less than 15 years), or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be administered to patients aged 65 years or older.

The dosage of the compound according to the present invention is preferably determined taking into consideration the age and weight of the patient, the type and severity of the disease, the route of administration, etc., but typically, in the case of oral administration, about 0.5 mg to 100 mg, preferably about 1 mg to 50 mg, and more preferably about 3 mg to 30 mg per day for adults, which may be administered in divided doses if necessary. In the case of children, about 0.5 to 100 mg may be administered per day. In the case of parenteral administration, about 0.1 mg to 100 mg, preferably about 0.5 mg to 50 mg, or about 1 mg to 30 mg, is administered per day for adults. This may be administered once or in divided doses several times a day.

（式中、各記号は前記と同意義である。）で示される化合物又はその製薬上許容される塩は、該化合物の作用の増強又は該化合物の投与量の低減等を目的として、抗肥満作用を有する薬剤、血糖値をコントロールするための薬剤、血中のコレステロール及び／又はトリグリセライドをコントロールするための薬剤、及び血圧をコントロールするための薬剤からなる群から選択される少なくとも１つの薬剤と組み合わせて用いることができる。 The formula of the present invention:

(wherein each symbol has the same meaning as defined above) or a pharma- ceutically acceptable salt thereof can be used in combination with at least one drug selected from the group consisting of drugs having anti-obesity action, drugs for controlling blood glucose level, drugs for controlling blood cholesterol and/or triglyceride, and drugs for controlling blood pressure, for the purpose of enhancing the action of the compound or reducing the dose of the compound, etc.

The "at least one drug selected from the group consisting of drugs having an anti-obesity effect, drugs for controlling blood glucose levels, drugs for controlling blood cholesterol and/or triglycerides, and drugs for controlling blood pressure" is not limited to those on the market or under development, but examples of those on the market or under development include orlistat, cetilistat, phentermine, mazindol, benzphetamine, amfepramone, methamphetamine, phentermine hydrochloride/topiramate, naltrexone hydrochloride/bupropion hydrochloride, liraglutide, semaglutide, setomelanotide (s etmelanotide, RM-493), metreleptin, topiramate, naltrexone, bupropion, acarbose, voglibose, miglitol, ipragliflozin, dapagliflozin, remogliflozin, KGT-1075, luseogliflozin, tofogliflozin, canagliflozin, empagliflozin, ertugliflozin, bexagliflozin, enavogliflozin, henagliflozin, janagliflozin, sotagliflozin, insulin Aspart, insulin lispro, insulin glulisine, biosynthetic human neutral insulin, human insulin, biosynthetic human isophane insulin, human isophane insulin, intermediate-acting insulin lispro, insulin detemir, insulin glargine, insulin Degludec, glibenclamide, gliclazide, glimepiride, glipizide, gliquidone, nateglinide, mitiglinide calcium hydrate, repaglinide, metformin hydrochloride, buformin hydrochloride, pioglitazone hydrochloride, rosiglitazone, lobeglitazone, sitagliptin phosphate, vildagliptin, alogliptin benzoate, linagliptin, teneligliptin hydrobromide, anagliptin, saxagliptin, trelagliptin succinate, omarigliptin, gemigliptin, evogliptin in), lixisenatide, exenatide, dulaglutide, tirzepatide, imeglimin, sitagliptin phosphate/ipragliflozin, pioglitazone hydrochloride/metformin, pioglitazone hydrochloride/glimepiride, teneligliptin hydrobromide/canagliflozin, alogliptin benzoate/pioglitazone hydrochloride, alogliptin benzoate/metformin hydrochloride, vildagliptin/metformin hydrochloride, mitiglinide calcium/voglibose, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, lovastatin, clinofibrate, clofibrate acetaminophen, bezafibrate, fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, colestimide, cholestyramine, colesevelam hydrochloride, colestipol, ezetimibe, brobucol, nicomol, tocopherol nicotinate, niceritrol, ethyl icosapentate, omega-3 fatty acid ethyl ester, evolocumab, alirocumab, nifedipine, amlodipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nilvadipine, barnidipine, felodipine, bendipine, manidipine, azelnidipine, aranidipine, ziltipine Azem, tolchlormethiazide, benzylhydrochlorothiazide, hydrochlorothiazide, meicran, invadamide, tripamide, mefruside, furosemide, triamterene, spinolactone, eplerenone, tolvaptan, torasemide, hydrochlorothiazide, bumetanide, chlortalidone, isosorbide, metolazone, losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan, azilsartan, captopril, enalapril, alacepril, delapril, cilazapril, lisinopril, bena Zepril, imidapril, temocapril, quinapril, trandolapril, perindopril erbumine, urapidil, terazosin, brazosin, doxazosin, bunazosin, atenolol, bisobrolol, metoprolol, acebutolol, celiprolol, propranolol, nadolol, nipradilol, carteolol, pindolol, nebivolol, carvedilol, labetalol, sotalol, landiolol, arotinolol, amosulalol, arotinolol, carvedilol, labetalol, bevantolol, clonidine, guanabenz, methyldopa, reserpine, hydralazine, nitroprusside, aliskiren, kalizinogena azepam, alprostadil alfadex, dihydroergotoxine, doxazosin, urapidil, hydralazine, prazosin, moxonidine, guanfacine, rilmenidine, amlodipine/atorvastatin, losartan/hydrochlorothiazide, valsartan/hydrochlorothiazide, candesartan/hydrochlorothiazide, telmisartan/hydrochlorothiazide, irbesartan/trichlorthiazide, valsartan/amlodipine, olmesartan/azelnidipine, candesartan/amlodipine, telmisartan/amlodipine, irbesartan /Amlodipine, Valsartan/Cilnidipine, Azilsartan/Amlodipine, Tirzepatide, SCO-094, Efinopegdutide (HM12525A), BI-456906, DD01, NN-9423, LY-3437943, Danuglipron, PF07081532, LY -3502970, RGT-075, efpeglenatide, exenatide, noiglutide, GMA105, HM-15136, noliglycopeptide (SHR-20004), carbetocin (LV-101), PYY-1 562 (NNC0165-1562), PYY-1875 (NNC0165-1875), cotadutide/AM833 (NN9838, NNC-01740833), cotadutide (cotadutide, MEDI0382), LY3305677, pegapamodutide ide, LY2944876, OPK88003), NGM395, YH34160, CT-388, CT-868, SCO-267, SCO-792, diazoxide, tesofensine, namodenoson, ERX1000, AMG133, ASC41, Xla1, HDV Biotin, EMP16, metoprolol/tesofensine, RZL-012, CB4211, BI1356225, AMG171, NO-13065, bardoxolone methyl, HSG4112, YHC2129, YHC2134, KTX-0200, obeticholic acid, cilofexor (GS-9674), tropifexor (LJN452) , EDP-305, EYP-001, resmetirom, VK-2809, cenicriviroc, saroglitazar, lanifibranor, selonsertib, PF-06835919, pegbelfermin, efrugxifermin, Aldafermin, aramcol, MK-3655, MSDC-0602K, belapectin, firsocostat (GS-0976), PF-05221304, ervogastat, ION-224, AXA-1125, HU-6, MET-409, MET-642, TERN-101, TERN-501, LPC Examples of such drugs include N-1144, denifanstate, fluxifermin, leronlimab, pegozafermin, rencofilstat, retatrutide, tipelukast, S-237648, and S-723595. Furthermore, when these drugs do not form a salt, their pharma- ceutically acceptable salts are also included, and when they form a salt, they may form other pharma- ceutically acceptable salts.
Preferably, orlistat, cetilistat, phentermine, mazindol, benzphetamine, amfepramone, methamphetamine, phentermine hydrochloride/topiramate, naltrexone hydrochloride/bupropion hydrochloride, liraglutide, semaglutide, setmelanotide (RM-493), metreleptin, topiramate, naltrexone, bupropion, tirze Patide, SCO-094, efinopegdutide (HM12525A), BI-456906, DD01, NN-9423, LY-3437943, danuglipron, PF07081532, LY-3502970, RGT-075, efpeglenatide, exenatide, neuglutide, GMA105, H M-15136, noliglycopeptide (SHR-20004), carbetocin (LV-101), PYY-1562 (NNC0165-1562), PYY-1875 (NNC0165-1875), cotadutide/AM833 (NN9838, NNC-01740833), cotadutide (MEDI0 382), LY3305677, pegapamodutide (LY2944876, OPK88003), NGM395, YH34160, CT-388, CT-868, SCO-267, SCO-792, diazoxide, tesofensine, namodenoson, ERX1000, AMG133, ASC41, Xla1, HDV Biotin, EMP16, metoprolol/tesofensine, RZL-012, CB4211, BI1356225, AMG171, NO-13065, bardoxolone methyl, HSG4112, YHC2129, YHC2134, KTX-0200, S-237648, S-723595, and the like.
More preferred examples include liraglutide, semaglutide, tirzepatide, BI-456906, danugliplon, PF07081532, LY-3502970, RGT-075, S-237648, and S-723595.

The administration timing of the compound of the present invention and the concomitant drug used in combination as described above is not limited, and they may be administered to the subject simultaneously or consecutively, or may be administered with a time lag. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more types of preparations containing the respective active ingredients, or as a single preparation containing those active ingredients.

The dosage of the concomitant drug can be appropriately selected based on the dose used clinically. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these. Furthermore, changes may be made within the scope of the present invention. The compound names given in the following examples and comparative examples do not necessarily conform to the IUPAC nomenclature.

　市販化合物から、特許文献２に記載の方法に従い、化合物ＩＩ－１２１を合成した。
¹H-NMR(CDCl₃) δ: 2.09-2.18(m, 2H), 2.29-2.36(m, 2H), 3.03(d, J=16.3 Hz, 1H), 3.21(s, 3H), 3.31(d, J=16.3 Hz, 1H), 3.99-4.35(m, 10H), 5.92(s, 1H), 6.40(d, J=2.4 Hz, 1H), 6.60(dd, J=8.8, 2.4 Hz, 1H), 7.41(d, J=8.8 Hz, 1H), 9.56(s, 1H). (Synthesis Example 1) Compound II-121

Compound II-121 was synthesized from a commercially available compound according to the method described in Patent Document 2.
¹ H-NMR(CDCl ₃ ) δ: 2.09-2.18(m, 2H), 2.29-2.36(m, 2H), 3.03(d, J=16.3 Hz, 1H), 3.21(s, 3H), 3.31(d, J=16.3 Hz, 1H), 3.99-4.35(m, 10H), 5.92(s, 1H), 6.40(d, J=2.4 Hz, 1H), 6.60(dd, J=8.8, 2.4 Hz, 1H), 7.41(d, J=8.8 Hz, 1H), 9.56(s, 1H).

The following compounds were synthesized from commercially available compounds according to the methods described in Patent Documents 2 to 4.

The physical data of each compound is shown below.
In the table, "MS" indicates the mass (M+H) measured by LC/MS.
[Measurement condition A]
Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id2.1x50 mm) (Waters)
Flow rate: 0.8 mL/min UV detection wavelength: 254 nm
Mobile phase: [A] was an aqueous solution containing 0.1% formic acid; [B] was an acetonitrile solution containing 0.1% formic acid. A linear gradient of 5%-100% solvent [B] was performed over 3.5 minutes, followed by maintaining 100% solvent [B] for 0.5 minutes.
[Measurement condition B]
Column: Shim-pack XR-ODS (2.2 μm id50x3.0 mm) (Shimadzu)
Flow rate: 1.6 mL/min UV detection wavelength: 254 nm;
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 of 10%-100% solvent [B] was performed over 3 minutes, and 100% solvent [B] was maintained for 0.5 minutes.
[Measurement conditions C]
Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id2.1x50 mm) (Waters)
Flow rate: 0.55 mL/min UV detection wavelength: 254 nm
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 of 5%-100% solvent [B] was performed over 3 minutes, and 100% solvent [B] was maintained for 0.5 minutes.

The NMR analysis obtained in each example was performed at 300 MHz using DMSO-d ₆ and CDCl ₃ .

Test Example 1: Measurement of human MGAT2 inhibitory activity To a 384-well polystyrene microplate manufactured by Corning Incorporated, into which 0.2 μL of a DMSO solution of each compound according to the present invention had been dispensed, 5 μL of an enzyme solution prepared with an assay buffer (100 mmol/L phosphate buffer (pH 7.4) containing 2 mmol/L DTT) and 5 μL of a substrate solution (100 mmol/L phosphate buffer (pH 7.4), 30 μmol/L 2-Oleoylglycerol, 10 μmol/L Oleoyl-CoA) were added, stirred and centrifuged, and then incubated in a humidified box at room temperature for 1 hour. After the enzyme reaction, the reaction was stopped by adding 50 μL of a stop solution (containing 0.2 μmol/L Diolein-d5, 0.4% formic acid and 50% isopropanol) containing an internal standard (IS), and the mixture was sealed on a Shimadzu GLC plate, stirred and centrifuged, and then measured by electrospray ionization using a RapidFire360 and an Agilent 6550 Q-TOF mass spectrometer. The reaction product (P) Diolein of the substrate 2-oleoylglycerol and the ammonium adduct ion of IS were detected, and the peak intensity ratio P/IS was calculated using the peak height to evaluate the inhibitory activity. The inhibitory activity was calculated using TIBCO Spotfire (TIBCO Software) according to the following formula, with and without the addition of enzyme defined as Control (+)/Control (-), the inhibition rate was 0% and 100%, respectively, and the peak intensity ratio P/IS when the compound according to the present invention was added was taken as Sample.
Inhibitory activity (%) = [1-{Sample-Control(-)} / {Control(+)-Control(-)}] * 100
The inhibitory activity results of each compound according to the present invention are shown in the following table, in which IC ₅₀ (nM) indicates the concentration exhibiting 50% enzyme inhibition.

Test Example 2: Verification of the effect on hepatic fat accumulation in high-fat diet-fed obese mice Five-week-old male C57BL/6J mice were fed a high-fat diet (TestDiet; 58Y1) for 4 weeks to prepare high-fat diet-fed obese mice. From 3 weeks before compound administration, the vehicle (0.5% HPMC) was administered twice a day. Randomization was performed according to changes in body weight and food intake during this habituation administration period, and grouping was performed. From Day 0 to Day 35 or Day 88, 0.5% HPMC was administered by forced oral administration (hereinafter, control group), or the compound according to the present invention was administered by forced oral administration (hereinafter, II-121 and II-203 administration groups). After the end of repeated oral administration, plasma and liver were collected, and liver weight and hepatic neutral fat content were measured. In addition, plasma liver damage markers and liver fibrosis-related gene expression analysis were performed.
(result)
At the time of dissection, the reduction rates of liver weight, hepatic neutral fat, plasma liver damage markers, and hepatic fibrosis-related gene expression compared to the control group were as follows. From these results, the degree of hepatic fat accumulation and NASH pathology markers in the liver were evaluated, and it was confirmed that the compound according to the present invention suppressed hepatic fat accumulation and NASH pathology marker levels.

Test Example 3: Verification of effects on hepatic fat accumulation and hepatotoxicity using in vitro hepatic cell line The in vitro hepatic fat accumulation inhibitory effects and cytotoxic effects of the compounds and/or agents according to the present invention were verified using human hepatic cell line HepG2 cells.
PBS, the compound according to the present invention, or BMS-963272 was added to HepG2 cells at 10 or 30 μM, and the accumulation of intracellular lipid droplets after overnight culture was evaluated.
(result)
The results are shown in Figure 1. The compound II-121 and II-203 treatment groups inhibited lipid droplet accumulation in a concentration-dependent manner compared to the PBS treatment group. On the other hand, the BMS-963272 treatment group did not show a significant lipid droplet accumulation inhibitory effect.

Next, the cytotoxicity of the compounds according to the present invention was evaluated using HepG2 cells.
Cytotoxicity was evaluated by adding each compound (12.5-100 μM) and culturing for 48 hours, and then measuring the intracellular ATP content as the cell viability and LDH activity in the culture supernatant as the cell death evaluation.
(result)
The results are shown in Figures 2 and 3. Compound II-203 (100 μM) reduced the intracellular ATP content by about 5%, but no change was observed in the LDH activity in the culture supernatant. Similarly, compound II-121 (100 μM) reduced the intracellular ATP content by about 7%, but no change was observed in the LDH activity in the culture supernatant. On the other hand, BMS-963272 (100 μM) reduced the intracellular ATP content by about 67%, and increased the LDH activity in the culture supernatant by about 9 times. These results suggest that BMS-963272 has stronger cytotoxicity than compounds II-203 and II-121.

Test Example 4: Verification of the effect on the progression of liver fibrosis in mice fed a high-fat, choline-deficient, methionine-reduced diet Seven-week-old male C57BL/6J mice were fed a high-fat, choline-deficient, methionine-reduced diet (RESEARCH DIETS, A06071302), and from 4 weeks after feeding, the mice were orally administered a vehicle (0.5% methylcellulose solution) (hereinafter, referred to as the control group) or the compound according to the present invention suspended in a 0.5% methylcellulose solution at a dose of 3 to 30 mg/kg/10 ml once a day for 8 weeks. After the end of the oral administration, the liver was harvested, and the hydroxyproline content in the liver was measured.
(result)
The reduction rates of hydroxyproline content in the liver at the time of dissection relative to the control group were as follows: From these results, the degree of progression of fibrosis in the liver was evaluated, and inhibition of fibrosis progression by the compound according to the present invention was confirmed.

Test Example 5: Evaluation of toxicity by repeated administration for four days in rats The toxicity of the compounds and/or drugs according to the present invention was evaluated in Crl:CD (SD) rats.
Six-week-old male Crl:CD (SD) rats were administered the compound according to the present invention or BMS-963272 by gavage once a day for 4 days, and general observations, body weight and food intake measurements, hematology and blood chemistry tests, and pathological tests were performed.
(result)
In the groups administered with compounds II-121 and II-203, no toxicity was observed up to the maximum dose of 500 mg/kg/day. On the other hand, in the group administered with BMS-963272 , prolongation of blood coagulation time and elevation of hepatic biliary system injury markers were observed at doses of 500 and 1000 mg/kg/day, and liver injury, kidney injury, deterioration of general condition, and reduction in body weight/food intake were observed at the dose of 1000 mg/kg/day.

Test Example 6: Metabolic stability test Commercially available pooled human liver microsomes were reacted with the compound of the present invention for a certain period of time, and the remaining rate was calculated by comparing the reacted sample with the unreacted sample, to evaluate the degree to which the compound of the present invention was metabolized in the liver.

The mixture was reacted in 0.2 mL of a buffer solution (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes in the presence of 1 mmol/L NADPH at 37°C for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a 1/1 (v/v) methanol/acetonitrile solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant was quantified by LC/MS/MS, and the remaining amount of the compound of the present invention after the reaction was calculated by assuming the amount of the compound at 0 minutes of reaction as 100%.
(Results) The residual rate at a compound concentration of 0.5 μmol/L is shown.

Test Example 7: Solubility Test The solubility of the compound according to the present invention was determined under the condition of adding 1% DMSO. A 10 mmol/L compound solution was prepared in DMSO, and 6 μL of the compound solution according to the present invention was added to 594 μL of pH 6.8 artificial intestinal fluid (250 mL of 0.2 mol/L potassium dihydrogen phosphate test solution, 118 mL of 0.2 mol/L NaOH test solution, and water were added to make 1000 mL). After standing at 25° C. for 16 hours, the mixture was filtered by suction. The filtrate was diluted 2-fold with methanol/water = 1/1 (V/V), and the concentration in the filtrate was measured using HPLC or LC/MS/MS by the absolute calibration curve method.
(result)

Test Example 8: Phototoxicity test As an in vitro phototoxicity test, a red blood cell photohemolysis test (Wolfgang JW Pepe et al., ATLA29, 145-162, 2001), which is an evaluation method using the effect on biological membranes and photoperoxidation as indicators, was performed. In this method, a mixed solution (concentration: 0.1 to 0.0008%) was used in which 2.5% (v/v) sheep red blood cell solution was added to a preparation solution of the compound according to the present invention using dimethyl sulfoxide as a medium. Two microplates containing this mixture were prepared, and one microplate was irradiated with UVA and UVB light (10 J/cm ² , 290-400 nm) using an ultraviolet fluorescent lamp (GL20SE lamp, Sankyo Electric and FL20S-BLB lamp, Panasonic), and centrifuged together with the microplate that was not irradiated, and the absorbance of the supernatant (540 nm or 630 nm) was measured. In order to determine two indices used in determining phototoxicity (action on biomembranes and photoperoxidation), the absorbance obtained from the compound according to the present invention was subtracted from the absorbance in the medium for each of the light-irradiated and non-irradiated cases, and the values were used in the following calculations. Regarding the action on biomembranes, the photohemolysis rate was calculated from the difference between the absorbance (540 nm) of the light-irradiated and non-irradiated cases, and regarding photoperoxidation, the change in absorbance (630 nm) of the light-irradiated and non-irradiated cases was calculated. In calculating the rate of photohemolysis, the absorbance (540 nm) obtained from a 2.5% (v/v) sheep red blood cell solution subjected to forced hemolysis using distilled water was used as the standard for the rate of photohemolysis of 100%. When the rate of photohemolysis was less than 10% and the change in absorbance at 630 nm was less than 0.05, it was marked as (-), and when the rate of photohemolysis was 10% or more and the change in absorbance at 630 nm was 0.05 or more, it was marked as (+).
(result)
Compound I-34: (-)

Test Example 9: Cytotoxicity test Using a cell image analyzer Toxinsight (Thermofisher Scientific), the number of cells after exposure to the compound was automatically measured to evaluate the cytotoxicity of the compound according to the present invention.
HepG2 cells (derived from human hepatoma cells) were seeded in a 384-well plate at 60,000 cells/mL, and after 24 hours, a compound solution was added to each well. As the compound solution, a DMSO solution containing the compound of the present invention (maximum concentration set at 50 μmol/L, diluted five times with a common ratio of 2 times, minimum concentration was about 3.1 μmol/L), a solution of DMSO only as a negative control, and a camptothecin solution as a positive control were used. A DMSO solution of the compound of the present invention, a negative control solution, or a positive control solution was added to each well. After 71 hours, a Hoechst 33342 solution diluted with Dulbecco's phosphate buffer (D-PBS) to a final concentration of 1 μg/mL was added to each well, and the nuclei were stained for 1 hour in a 37°C, 5% _CO2 incubator. After staining, the cells were fixed with 4% paraformaldehyde for 20 minutes in a 37°C _CO2 incubator. Finally, after washing three times with D-PBS, the number of fluorescent nuclei per well was counted using Toxinsight (Thermofisher Scientific). Four wells were set up per concentration, and the average and variance (SD) of the number of nuclei (number of cells in which no damage was observed) in the four wells were calculated. The compound exposure concentration (IC50) at which the average value was reduced by 50% or more from the average value of the negative control was calculated in comparison with the _negative control group. It was determined that the smaller the _IC50 value, the higher the risk of cytotoxicity.

Test Example 10: CYP inhibition test Using commercially available pooled human liver microsomes, the extent to which the production amount of each metabolite was inhibited by the compound of the present invention was evaluated using as indicators the O-deethylation of 7-ethoxyresorufin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) as typical substrate metabolic reactions of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4).
The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenytoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human liver microsome, 0.2 mg protein/mL; compound of the present invention concentration, 1, 5, 10, 20 μmol/L (4 points).
Five kinds of substrates, human liver microsomes, and the compound according to the present invention were added to a 50 mmol/L Hepes buffer solution in a 96-well plate in the above composition as a reaction solution, and NADPH, a coenzyme, was added to start the metabolic reaction as an indicator. After reacting at 37°C for 15 minutes, the reaction was stopped by adding a methanol/acetonitrile = 1/1 (V/V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugal supernatant was quantified by a fluorescent multi-label counter or LC/MS/MS, and tolbutamide hydroxylated form (CYP2C9 metabolite), mephenytoin 4' hydroxylated form (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol form (CYP3A4 metabolite) were quantified by LC/MS/MS.
A reaction system in which only DMSO, the solvent in which the drug was dissolved, was added was used as a control (100%). The remaining activity (%) was calculated, and the _IC50 was calculated by inverse estimation using a logistic model using the concentration and inhibition rate.
(result)
Compound II-103: 5 species >20 μmol/L

Test Example 11: BA Test: Examination of oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats were used.
(2) Rearing conditions: Mice or SD rats were allowed to freely consume solid food and sterilized tap water.
(3) Dosage and grouping: Oral and intravenous administration was performed at a predetermined dose. The groups were set up as follows. (Dosages were changed for each compound.)
Oral administration: 1-30 mg/kg (n=2-3)
Intravenous administration: 0.5-10 mg/kg (n=2-3)
(4) Preparation of administration liquid: For oral administration, the compound was administered as a solution or suspension. For intravenous administration, the compound was administered in a solubilized form.
(5) Method of administration: Oral administration was performed by forcibly administering the compound into the stomach using an oral probe, whereas intravenous administration was performed by administering the compound into the tail vein or femoral vein using a syringe with an injection needle.
(6) Evaluation item: Blood samples were collected over time, and the plasma concentration of the compound according to the present invention was measured using LC/MS/MS.
(7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound according to the present invention was calculated using the nonlinear least squares program WinNonlin (registered trademark) for the plasma concentration transition of the compound according to the present invention, and the bioavailability (BA) of the compound according to the present invention was calculated from the AUC of the oral administration group and the intravenous administration group.

Test Example 12: CYP3A4 (MDZ) MBI Test This is a test to evaluate the mechanism based inhibition (MBI) ability of the compound of the present invention from the enhancement by metabolic reaction regarding CYP3A4 inhibition. CYP3A4 inhibition was evaluated using pooled human liver microsomes with the 1-hydroxylation reaction of midazolam (MDZ) as an index.
The reaction conditions were as follows: substrate, 10 μmol/L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37° C.; pooled human liver microsomes, 0.5 mg/mL at pre-reaction and 0.05 mg/mL (at 10-fold dilution) at reaction; concentration of the compound according to the present invention at pre-reaction, 1, 5, 10, and 20 μmol/L (4 points).
Pooled human liver microsomes and a compound solution according to the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above pre-reaction composition, and a portion of the solution was transferred to another 96-well plate so as to be diluted 1/10 with the substrate and K-Pi buffer, and a coenzyme, NADPH, was added to start the reaction using the indicator (no pre-reaction). After a predetermined reaction time, the reaction was stopped by adding a methanol/acetonitrile = 1/1 (V/V) solution. NADPH was also added to the remaining pre-reaction solution to start the pre-reaction (with pre-reaction). After a predetermined reaction time, a portion of the solution was transferred to another plate so as to be diluted 1/10 with the substrate and K-Pi buffer, and a reaction using the indicator was started. After a predetermined reaction time, the reaction was stopped by adding a methanol/acetonitrile = 1/1 (V/V) solution. The plates in which the respective indicator reactions were performed were centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the centrifugal supernatant was quantified by LC/MS/MS.
The reaction system was treated as a control (100%) with only DMSO, the solvent in which the compound according to the present invention was dissolved, and the residual activity (%) was calculated when the compound according to the present invention was added at each concentration. The IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The IC at 0 min preincubation/IC at 30 min preincubation was used as the Shifted IC value, and if the Shifted IC was 1.5 or more, it was considered positive, and if the Shifted IC was 1.0 or less, it was considered negative.
(result)
Compound II-103: Negative

Test Example 13: Powder solubility test An appropriate amount of the compound according to the present invention was placed in an appropriate container, and 200 μL of JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid, and water added to make 1000 mL), JP-2 solution (500 mL of water added to 500 mL of phosphate buffer solution at pH 6.8), and 20 mmol/L sodium taurocholate (TCA)/JP-2 solution (1.08 g of TCA and JP-2 solution added to make 100 mL) were added to each container. If the entire amount was dissolved after the addition of the test solution, the compound according to the present invention was appropriately added. The container was sealed and shaken at 37° C. for 1 hour, and then filtered, and 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution ratio was changed as necessary. The container was checked for the presence of bubbles and precipitates, and then sealed and shaken. The compound according to the present invention was quantified using HPLC by the absolute calibration curve method.

Test Example 14: Fluctuation Ames test The mutagenicity of the compound according to the present invention was evaluated.
20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and pre-cultured with shaking for 10 hours at 37° C. For the TA98 strain, 8.0 mL of the bacterial solution was centrifuged (2000×g, 10 minutes) to remove the culture medium. The bacteria were suspended in 8.0 mL of Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L) 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). TA100 strain was added to 120 mL of Exposure medium per 3.1 mL of bacterial solution to prepare a test bacterial solution. The compound DMSO solution according to the present invention (diluted in several stages at a common ratio of 2 to 3 times from the maximum dose of 50 mg / mL), DMSO as a negative control, 50 μg / mL 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain as a positive control under non-metabolic activation conditions, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for the TA100 strain, 40 μg / mL 2-aminoanthracene DMSO solution for the TA98 strain under metabolic activation conditions, 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain were mixed with 12 μL each and 588 μL of test bacteria solution (a mixture of 498 μL of test bacteria solution and 90 μL of S9 mix under metabolic activation conditions), and cultured with shaking at 37 ° C. for 90 minutes. 230 μL of the bacterial solution exposed to the compound according to the present invention was mixed with 1150 μL of Indicator medium (MicroF buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, bromocresol purple: 37.5 μg/mL), and 50 μL was dispensed into 48 wells/dose of a microplate, and cultured at 37° C. for 3 days. Since wells containing bacteria that have acquired the ability to grow due to mutation of the amino acid (histidine) synthase gene change color from purple to yellow due to pH change, the number of wells that have grown yellow in the 48 wells per dose were counted and evaluated in comparison with the negative control group. Negative mutagenicity is indicated as (-), and positive mutagenicity is indicated as (+).

Test Example 15: hERG Test For the purpose of evaluating the risk of electrocardiogram QT interval prolongation of the compound according to the present invention, the effect of the compound according to the present invention on delayed rectifier K ⁺ current (I _Kr ), which plays an important role in the ventricular repolarization process, was investigated using CHO cells expressing human ether-a-go-go related gene (hERG) channel.
Using a fully automated patch clamp system (QPatch; Sophion Bioscience A/S), the cells were held at a membrane potential of -80 mV by the whole-cell patch clamp method, and a leak potential of -50 mV was applied, followed by a depolarizing stimulus of +20 mV for 2 seconds and a repolarizing stimulus of -50 mV for 2 seconds. The I _Kr evoked by this was recorded. After the generated current became stable, an extracellular solution containing the compound according to the present invention dissolved at a desired concentration (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCl ₂ : 2 mmol/L, MgCl ₂ : 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4) was applied to the cells at room temperature for 10 minutes. From the obtained I _Kr , the absolute value of the maximum tail current was measured based on the current value at the resting membrane potential using analysis software (Falster Patch; Sophion Bioscience A/S). Furthermore, the inhibition rate relative to the maximum tail current before application of the compound according to the present invention was calculated to evaluate the effect of the compound according to the present invention on I _Kr .
(Results) The inhibition rate at a compound concentration of 10 μmol/L is shown.
Compound I-253: 6.9%

Test Example 16: Reproductive and developmental toxicity test The embryo-fetal developmental toxicity of the compound according to the present invention was evaluated in Crl:CD (SD) rats.
The compound of the present invention was administered by gavage once a day to 10-14 week old female Crl:CD (SD) rats for 12 days from 6 to 17 days of pregnancy, and then cesarean section was performed on 21 days of pregnancy. The general condition of the dams was observed, and the weight and food intake were measured, and necropsy and luteal count were examined. In addition, the viability and sex of the embryos and fetuses were confirmed, and the weight and placenta were measured, and external and placental visual examinations were performed, and internal organs and skeletons were examined.
(result)
In the II-203 administration group, no toxicity was observed up to a dose of 1000 mg/kg/day.

The formulation examples shown below are merely illustrative 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, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injection solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in the form of intranasal or suppositories. Pharmaceutical compositions containing the compounds of the present invention in free form or in the form of a pharma-ceutically acceptable salt together with at least one pharma-ceutically acceptable carrier or diluent can be prepared by conventional mixing, granulation or coating methods. For example, oral compositions can be tablets, granules, or capsules containing excipients, disintegrants, binders, lubricants, etc., and active ingredients, etc. In addition, injectable compositions can be solutions or suspensions, which may be sterilized and may contain preservatives, stabilizers, buffers, etc.

The method for treating and/or preventing non-alcoholic fatty liver disease of the present invention and the pharmaceutical composition for treatment therewith are believed to show excellent therapeutic effects by administering a predetermined amount of the active ingredient, the compound represented by formula (I) or a pharma- ceutical acceptable salt thereof, to a patient with non-alcoholic fatty liver disease. Furthermore, the administration of the compound represented by formula (I) or a pharma-ceutical acceptable salt thereof does not cause side effects such as hemostatic abnormalities, liver damage, kidney damage, or embryonic lethality, and can be applied extremely safely and is suitable for long-term administration, so the method for treating and/or preventing and the pharmaceutical composition for treatment of the present invention are extremely excellent.

Claims (13)

formula:

(In the formula,
R ^2a and R ^2b together with adjacent carbon atoms form ring B;
Ring B is of the formula:

wherein each ^R6 is independently halogen, haloalkyl, alkyloxy, haloalkyloxy, or cyclopropanyl;
R ^4a is a group represented by the formula:

(In the formula,
^L3 is alkylene;
R ⁷ is alkylsulfonyl;
R ^4b is an alkyl group optionally substituted with substituent group α, a phenyl group optionally substituted with substituent group β, or a 5- to 6-membered aromatic heterocyclic group optionally substituted with substituent group β;
Substituent group α is halogen, haloalkyloxy, and cyclopropanyl;
A pharmaceutical composition for treating and/or preventing fatty liver disease, comprising a compound represented by the formula (I) or a pharma- ceutically acceptable salt thereof, wherein substituent group β is halogen, cyano, alkyl, haloalkyl, and cyclopropanyl. R ⁶ is independently halogen, haloalkyl, or haloalkyloxy;
R ^4a is a group represented by the formula:

and
R ^4b is a haloalkyloxyalkyl, a phenyl group optionally substituted with halogen, or a 5- to 6-membered aromatic heterocyclic group optionally substituted with substituent group β,
The pharmaceutical composition according to claim 1 , wherein the substituent group β is halogen and alkyl. Ring B is of the formula:

(In the formula, each symbol has the same meaning as in claim 1 or 2.)
The pharmaceutical composition according to claim 1 or 2, The pharmaceutical composition according to claim 1, comprising a compound selected from the group consisting of compounds I-8, I-23, I-34, I-190, I-212, I-236, I-253, I-275, I-276, II-93, II-103, II-121, II-151, II-168, II-174, II-203, II-225, II-233 and II-295, or a pharma- ceutical acceptable salt thereof. The pharmaceutical composition according to claim 1, which contains a compound selected from the group consisting of compounds I-236, I-253, I-275, II-103, II-121, II-174, II-203, II-225 and II-233, or a pharma- ceutical acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein the fatty liver disease is nonalcoholic fatty liver disease (NAFLD). The pharmaceutical composition according to claim 1, wherein the fatty liver disease is metabolic dysfunction-associated fatty liver disease (MASLD), cryptogenic fatty liver disease (Cryptogenic SLD), or specific aetiology fatty liver disease (Specific Aetiology SLD). The pharmaceutical composition according to claim 1, wherein the fatty liver disease is nonalcoholic steatohepatitis (NASH). The pharmaceutical composition according to claim 1, wherein the fatty liver disease is metabolic dysfunction-associated steatohepatitis (MASH). The pharmaceutical composition according to claim 1, wherein the fatty liver disease is hepatic fibrosis caused by NASH or MASH. The pharmaceutical composition according to claim 1, wherein the fatty liver disease is cirrhosis caused by NASH or MASH. The pharmaceutical composition according to claim 1, wherein the fatty liver disease is hepatocellular carcinoma (HCC) caused by NASH or MASH. The pharmaceutical composition according to claim 1, wherein administration of the pharmaceutical composition does not result in at least one of hemostatic abnormalities, liver damage, kidney damage, and embryonic lethality.

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