KR20200076318A - A pharmaceutical composition comprising benzoxazepine derivatives for preventing or treating obesity - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating obesity containing a benzoxazepine derivative compound, wherein the compound has excellent activity on a TGR5 receptor promoting GLP-1 secretion compared to lithocholic acid used as an existing TGR5 receptor agonist, thereby being able to be usefully used as a composition for preventing or treating obesity.

Description

A pharmaceutical composition comprising benzoxazepine derivatives for preventing or treating obesity}

The present invention relates to a pharmaceutical composition for preventing or treating obesity comprising a benzooxazepine derivative compound.

Recently, as the rapid industrialization, income level improvement, and lifestyle patterns such as eating habits and eating habits have been rapidly westernized, various adult disease patients, such as cancer, diabetes, cardiovascular disease, and obesity, are rapidly increasing.

In general, obesity (obesity) is a type of disease that is consumed and consumed among energy consumed and converted into triglycerides, which is mainly accumulated in fat cells (adipocytes) of the abdomen and subcutaneous tissues. mass index) 25㎏ / m ² refers to the above, in the case of women over 30㎏ / m ^2.

Obesity is a complex syndrome caused by various causes such as genetic, nutritional, environmental, and social factors. Although obesity itself is a disease that interferes with everyday life, obesity rather than the meaning of the disease itself causes various complications. There is even more seriousness of the problem.

Due to obesity, hyperlipidemia, which increases the amount of cholesterol or triglycerides in the blood, causes hyperlipidemia, which can develop into fatal diseases such as hypertension, cardiovascular disease and stroke, and peripheral tissues (Kelley, DE et al., Diabetes, 49( 5), 677-683, 2000) and increase in triglyceride accumulation in abdominal adipose tissue (Kelley, DE et al., Am J Physiol Endocrinol Metab., 278(5), E941-948, 2000) Since it may cause type 2 diabetes, long-term care and treatment are absolutely necessary. Also, in the case of Asians, obesity management is more important than the Westerners because the body mass index is at least abdominal obesity, which makes it more susceptible to complications from arterial-related diseases such as hypertension, diabetes, and hyperlipidemia.

GLP-1 (glucagon like peptide-1) is a peptide hormone consisting of 30 amino acids. GLP-1 secreted from enteroendocrine cells by activating Takeda G-protein-coupled receptor 5 (TGR5) stimulates glucose-dependent insulin secretion in the pancreas, promotes insulin gene expression, promotes pancreatic beta-cell proliferation and survival Effects, glucagon secretion inhibitory effect, blood sugar lowering, etc. are involved in showing the treatment effect of diabetes. In addition, it is known to slow down the rate of emptying the stomach, suppress appetite, improve satiety, and suppress food intake, and thus has an effect of treating obesity (Seino, Y. et al., J Diabetes Investig., 1(1-2), 8-23, 2010)

As a receptor that promotes secretion of GLP-1, GPBAR1 (G protein-coupled bile acid receptor 1 or TGR5) is typical, which is present in cell membranes such as liver, skeletal muscle, intestine, brown adipose tissue, and monocytes. GCR (G protein-coupled receptor) (Londregan, AT et al., Bioorg Med Chem Lett., 23(5), 1407-1411, 2013).

Bile acids and bile acid derivatives act as a TGR5 agonist in combination with TGR5. When TGR5 is activated, the concentration of intracellular cAMP is increased to increase the activity of protein kinase A (PKA). Activation of PKA plays an important role in the regulation of metabolism and glucose and energy homeostasis specifically for tissues in which TGR5 exists. That is, when TGR5 is activated, secretion of GLP-1 is increased from intestinal endocrine cells, and when TGR5 present in the cell membrane of hepatocytes is activated, production of eNOS (endothelial nitric oxide synthase) and NO (nitric oxide) is increased in hepatocytes, When TGR5 present in the cell membrane of brown adipose tissue and skeletal muscle tissue is activated, D2 (type 2 iodothyronine deiodinase) is activated in brown adipose tissue and skeletal muscle tissue to treat diabetes and obesity (Katsuma, S. et al ., Biochem Biophys Res Commun., 329(1), 386-390, 2005; Kietel, V. et al., Hepatology, 45(3), 695-704, 2007; Brufau, G. et al., Nutr Metab (Lond)., 7, 73, 2010).

TGR5 can be divided into two types: steroidal and nonsteroidal agonists. The steroidal agonist is lycoholic amide (International Publication No. 2008-009407), and the non-steroidal agonist is naturally derived compounds (International Publication No. 2009-146772), especially the oxazepine compound And has been known to act selectively on receptors (European Publication No. 01591120).

Thus, the present inventors were able to complete the present invention by confirming that the benzooxazepine derivative compound represented by Chemical Formula 1 has excellent TGR5 agonist activity in the process of studying the activity of the TGR5 agonist involved in promoting secretion of GLP-1. . In particular, as a compound for the treatment of obesity by confirming that the TGR5 agonist activity is improved than the existing compound, by selecting a benzooxazepine as a basic structure and using a phenylcarboxylic acid derivative or a heterocyclic compound and an amide-bonded compound as the compound represented by Formula 1 It was found that it can be useful.

On the other hand, as a prior art related to a composition for preventing or treating obesity containing a benzoxazepine derivative compound, prior art [Wilson, JE et al., Bioorg Med Chem Lett., 26(12), 2947-2951, 2016] Antidiabetic activity of oxazepine derivatives was disclosed, and Korean Patent Registration No. 10-1608927 discloses the use of benzooxazepine derivatives for the treatment of various diseases including cardiovascular diseases and diabetes, and International Publication No. 2010-118208 There have been disclosed anti-cancer compositions of benzoxazepine derivatives. However, there has been no previous report stating that the benzooxazepine derivative compound represented by Formula 1, as in the present invention, has excellent TGR5 receptor activity that promotes GLP-1 secretion and can be used as a composition for the treatment of obesity.

Korean Registered Patent No. 10-1608927, fused benzooxazepine as an ion channel modulator, registered on March 29, 2016. Published European Patent No. 01591120, RECEPTOR AGONISTS, published on 02/02/2005. International Publication No. 2010-118208, BENZOXAZEPIN-4- (5H) -YL DERIVATIVES AND THEIR USE TO TREAT CANCER, published on October 14, 2010. Published International Patent No. 2009-146772, NEW TERPENES AND MACROCYCLES, published on December 10, 2009. International Publication No. 2008-009407, CHOLANIC ACID AMIDES, published on January 24, 2008.

Brufau, G. et al., Plasma bile acids are not associated with energy metabolism in humans, Nutr Metab (Lond)., 7, 73, 2010. Katsuma, S. et al., Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1, Biochem Biophys Res Commun., 329(1), 386-390, 2005. Kelley, D. E. et al., Fuel selection in human skeletal muscle in insulin resistance: a reexamination, Diabetes, 49(5), 677-683, 2000. Kelley, D. E. et al., Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance, Am J Physiol Endocrinol Metab., 278(5), E941-948, 2000. Kietel, V. et al., The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells, Hepatology, 45(3), 695-704, 2007. Londregan, AT et al., Discovery of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as potent agonists of TGR5 via sequential combinatorial libraries, Bioorg Med Chem Lett., 23(5), 1407-1411 , 2013. Seino, Y. et al., GIP and GLP-1, the two incretin hormones: Similarities and differences, J Diabetes Investig., 1(1-2), 8-23, 2010. Wilson, JE et al., Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes, Bioorg Med Chem Lett., 26(12), 2947 -2951, 2016.

An object of the present invention is to provide a pharmaceutical composition for preventing or treating obesity comprising a benzoxazepine derivative compound.

The present invention relates to a pharmaceutical composition for the prevention or treatment of obesity comprising a compound represented by the following formula (1), its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In Chemical Formula 1,

X and Y are carbon or nitrogen;

R is substituted or unsubstituted C ₄ -C ₆ aryl, substituted or unsubstituted C ₄ -C ₁₀ heteroaryl,

At this time, the substituted aryl and heteroaryl is one selected from the group consisting of hydrogen, halogen, nitro, cyano, amino, hydroxy, trihalogenmethyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy Substituted with the above substituents;

n is an integer of 0 or 1; to be.

The following terms in the present invention have the following meanings unless otherwise indicated. Any term not defined has a meaning understood in the art.

“Halogen” in the present invention means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

The term "alkyl" used in the present invention means a single-bonded straight-chain or branched-chain hydrocarbon group. Examples are methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, and the like.

The term "alkoxy" used in the present invention means an oxygen group to which a single-bonded straight-chain or branched-chain saturated hydrocarbon is bonded. Examples include methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy, and the like.

The term "aryl" used in the present invention refers to an aromatic substituent having at least one ring having a covalent py electron system, for example, phenyl, benzyl, naphthyl and the like.

The term "heteroaryl" refers to an aromatic cyclic compound containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, pyrrolyl, furanyl, pyridine And work, pyrimidinyl, and pyranyl.

In the present invention, the pharmaceutically acceptable salt means a salt or complex of Formula 1 having desirable biological activity. Examples of such salts include, but are not limited to, inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) Acid addition salts formed by] and acetic acid, oxalic acid, tartari acid, succinic acid, malic acid, fumaric acid, maleic acid ), ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene Salts formed with organic acids such as disulfonic acid (naphthalene disulfonic acid), and poly-galacturonic acid (poly-galacturonic acid). The compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carbohydrate Boxylates (e.g. benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandelate) And diphenyl acetate). The compound of Formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates that can be prepared by conventional methods.

In addition, the compounds of the present invention may contain one or more asymmetric carbon atoms, and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.

More specifically exemplifying the compound of Formula 1 of the present invention,

(2,4-difluorophenyl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (compound One);

(4-chlorophenyl)(7-pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (Compound 2);

(2-fluorophenyl)(7-pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (Compound 3);

(2,6-difluorophenyl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (compound 4);

Furan-3-yl(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone (Compound 5);

(6-Bromopyridin-3-yl)(7-(pyridin-4-yl)2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (compound 6);

(6-Chloropyridin-3-yl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (compound 7);

(2-Chloro-6-fluorophenyl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone ( Compound 8);

2-(3,4-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 9);

2-(3,4-difluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl )Ethanone (Compound 10);

2-(4-chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone ( Compound 11);

2-(3-chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone ( Compound 12);

2-(2-fluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 13);

2-(2-chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone ( Compound 14);

2-(4-fluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 15);

1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-(4-(trifluoromethyl) Phenyl)ethanone (Compound 16);

2-(3-Bromophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl-ethanone (Compound 17);

2-(3-bromo-4-fluorophenyl)-1-(7-)pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) -Yl)ethanone (Compound 18);

2-(4-chloro-3-fluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- Work)ethanone (Compound 19);

2-(benzo[d][1,3]dioxol-5-yl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine -4(5H)-yl)ethanone (Compound 20);

2-(4-Nitrophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 21);

2-(3-Nitrophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 22);

2-(pyridin-2-yl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 23);

2-(pyridin-3-yl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 24);

2-(pyridin-4-yl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 25);

2-(3,5-bis(trifluoromethyl)phenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4( 5H)-yl)ethanone (Compound 26);

2-(2,6-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 27);

1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-(3-thiopheny)ethanone ) (Compound 28);

2-(3,5-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 29);

(8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][ 1,4]oxazepine-4(5H)-yl)methanone (Compound 30);

2-(3,4-dichlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 31);

2-(4-chlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone ( Compound 32);

2-(3-chlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone ( Compound 33);

2-(2-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 34);

2-(2-chlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone ( Compound 35);

2-(4-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 36);

1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-(4-(trifluoromethyl) Phenyl)ethanone (Compound 37);

2-(3-Bromophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 38);

2-(3-Bromo-4-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) -Yl)ethanone (Compound 39);

2-(4-Chloro-3-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- Work)ethanone (Compound 40);

2-(4-Nitrophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 41);

2-(3-Nitrophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 42);

2-(3,5-bis(trifluoromethyl)phenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4( 5H)-yl)ethanone (Compound 43);

2-(2,6-dichlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 44);

2-(3,5-dichlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 45);

2-(3,5-difluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl )Ethanone (Compound 46);

2-(3-fluoro-4-hydroxyphenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) -Yl)ethanone (Compound 47);

2-(2-Chloro-4-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- Work)ethanone (Compound 48); And

2-(3-chloro-4-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- Work)ethanone (Compound 49); It is selected from the group consisting of.

In addition, the compound represented by Formula 1 of the present invention is synthesized by a coupling reaction between an amine and a carboxylic acid as shown in Reaction Schemes 1 and 2 below, but a compound represented by Formula 1 is prepared according to a conventional method in the art. If possible, it is included in the present invention without limitation.

[Scheme 1]

[Scheme 2]

In Reaction Scheme 1, X in Formula (4) is a protecting group for amines, such as F-moc, carboxybenzyl group, p-methoxybenzyl carbonyl group, tert-butoxycarbonyl group, and Y in Formula (5) Hydroxy (boronic acid), alkoxy (boronate) groups, and the like.

Catalysts used in carbon-carbon bonding reactions to synthesize materials of formulas (2A) and (2B) palladium chloride, tris(dibenzylideneacetone)dipalladium(0), palladium acetate, tetrakis(triphenylphosphine) )Palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), etc., and the base is Na ₂ CO ₃ , Ba(OH) ₂ , K ₃ PO ₄ , K ₂ CO ₃ , KF, Cs ₂ CO ₃ and the like. As the reaction temperature, it is possible to proceed at 50 to 120°C, but preferably at 70 to 90°C. The reaction time can proceed from 1 to 12 hours, but preferably proceeds for 3 to 5 hours.

In addition, R and n in Reaction Scheme 2 are as defined in Chemical Formula 1.

The amide bond reaction according to Reaction Scheme 2 is a benzoxazepine compound represented by Formulas (2A) and (2B) dissolved in a solvent and an aryl carboxylic acid compound represented by Formula (3) (eg, a phenylacetic acid derivative) or hetero The aryl carboxylic acid compound is stirred together under a stream of nitrogen, and then a base is slowly added thereto, and then an amide binding reagent is added to obtain a compound represented by the formulas (1A) and (1B).

The solvent that can be used for the amide bond reaction according to Reaction Scheme 2 is not particularly limited as long as it is a conventional organic solvent that does not inhibit the reaction, but preferably tetrahydrofuran, dichloromethane, or chloroform.

As the base, alkylamines such as triethylamine and diisopropylethylamine, and Na ₂ CO ₃ and K ₂ CO ₃ may be used, and the base is used in an amount of 1 to 5 equivalents based on the reactants, preferably 4 equivalents Use

Amide-binding reagents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b] pyridinium 3-oxide hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, etc. can be used, and amide The binding reagent is used in an amount of 1 to 5 equivalents, preferably 1.5 equivalents.

It is possible to proceed from 0 to 50°C as the reaction temperature, and it is possible to proceed from 1 to 12 hours as the reaction time, but preferably from 3 to 5 hours.

After the reaction is completed, a compound represented by the above formulas (1A) and (1B) is obtained using conventional separation methods such as tube chromatography.

In addition, the present invention is characterized in that the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof increases the activity for the TGR5 receptor.

The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier. “Pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not cause an allergic or similar reaction, such as gastrointestinal disorders, dizziness, etc., when administered to humans. In addition, the composition may be formulated and used in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., according to a conventional method.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto. When formulated, it is prepared using diluents or excipients such as fillers, stabilizers, binders, disintegrants, surfactants, etc., which are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in the compounds of the present invention, for example starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose and hypromellose. Also, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As the non-aqueous solvent and suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used. To formulate a formulation for parenteral administration, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized and/or an auxiliary agent such as a preservative, stabilizer, hydrating agent or emulsifying accelerator, salt for controlling osmotic pressure, and/or buffer, And other therapeutically useful substances, mixed with water to prepare a solution or suspension, which can be prepared in ampoules or vials.

The pharmaceutical composition provides a pharmaceutical composition comprising the compound of Formula 1 and excipients. The compound may be added in an amount of preferably 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight relative to the total weight of the total composition.

The pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to various mammals, such as rats, livestock, and humans. Any mode of administration can be envisaged, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura or cerebrovascular injection. The dosage is the age, gender, weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the time of administration, the route of administration, the absorption, distribution and excretion rate of the drug, the type of other drug used and the prescriber's It will depend on the judgment. Dosage determination based on these factors is within the level of those skilled in the art, and the dosage is generally in the range of 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. The administration may be administered once a day, or may be divided into several times. The above dosage does not limit the scope of the present invention in any way.

The present invention relates to a pharmaceutical composition for preventing or treating obesity comprising a benzoxazepine derivative compound, wherein the compound has superior activity to the TGR5 receptor that promotes GLP-1 secretion than lithocholic acid used as a conventional TGR5 receptor agonist. Therefore, it can be usefully used as a composition for preventing or treating obesity.

Hereinafter, a preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the contents introduced herein are thorough and complete, and are provided to sufficiently convey the spirit of the present invention to those skilled in the art.

<Example 1. Preparation of benzooxazepine derivative compound>

The structures of the benzoxazepine derivative compounds 1 to 49 of the present invention are shown in Table 1 below, and the physicochemical data of the preparation process and compounds are as follows.

Benzooxazepine skeleton


Phenylacetic acid derivatives

Compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9 Compound 31

Compound 10

Compound 11 Compound 32

Compound 12 Compound 33

Compound 13 Compound 34

Compound 14 Compound 35

Compound 15 Compound 36

Compound 16 Compound 37

Compound 17 Compound 38

Compound 18 Compound 39

Compound 19 Compound 40

Compound 20

Compound 21 Compound 41

Compound 22 Compound 42

Compound 23

Compound 24

Compound 25

Compound 26 Compound 43

Compound 27 Compound 44

Compound 28

Compound 29 Compound 45

Compound 30

Compound 46

Compound 47

Compound 48

Compound 49

Compound 1. (2,4- Difluorophenyl )(7-(pyridin-4-yl)-2,3- Dihydrobenzo[f][1,4]oxazepine -4(5H)-yl)methanone

7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (30mg, 0.13mmol, 1 eq.) dissolved in dichloromethane 1.5ml Then, N,N-diisopropylethylamine (113.2 µl, 0.65 mmol, 5 eq.) and 2,4-difluorobenzoyl chloride (17.20 µl, 0.14 mmol, 1.1 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 1 (33.4 mg, yield 70.12%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.76-3.78(t, 1H), 4.12-4.27(m, 3H), 4.48(s, 1H), 4.90(s, 1H), 6.78-6.97(m, 1H) , 6.92-6.97(m, 1H), 7.14-7.23(1H), 7.30-7.32(d, J=6.25Hz, 1H), 7.34-7.40(m, 1H), 7.50-7.55(m, 2H), 7.73 -7.74 (d, J=2.34 Hz, 1H), 8.64-8.66 (m, 2H);

ESI-MS m/z calcd for C ₂₁ H ₁₆ F ₂ N ₂ O ₂ [M+H] ⁺ 367.3, found 366.12.

Compound 2. (4-chlorophenyl)(7-pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone

7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.22mmol, 1 eq.) dissolved in dichloromethane 1.5ml Then, N,N-diisopropylethylamine (192.47 µl, 1.11 mmol, 5 eq.) and 4-chlorobenzoyl chloride (30.89 µl, 0.24 mmol, 1.1 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 2 (59.6 mg, yield 73.92%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.85(s, 1H), 4.10-4.15(m, 3H), 4.30(s, 1H), 4.53(s, 1H), 4.87(s, 1H), 6.90(s , 1H), 7.17(s, 1H), 7.30-7.40(m, 5H), 7.52-7.55(dd, J=8.20, 2.34Hz, 2H), 8.66(s, 1H);

ESI-MS m/z calcd for C ₂₁ H ₁₇ ClN ₂ O ₂ [M+H] ⁺ 365.2, found 364.10.

Compound 3. (2-fluorophenyl)(7-pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone

7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.22mmol, 1 eq.) dissolved in dichloromethane 1.5ml Then, N,N-diisopropylethylamine (192.47 µl, 1.11 mmol, 5 eq.) and 2-fluorobenzoyl chloride (29.01 µl, 0.24 mmol, 1.1 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 3 (49.4 mg, yield 64.16%) was obtained through purification using tube chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.76-3.78(t, 1H), 4.10-4.27(m, 3H), 4.48(s, 1H), 4.92(s, 1H), 6.71-6.72(d, 1H) , 7.07-7.12(t, 1H), 7.14-7.22(m, 2H), 7.29-7.31(m, 1H), 7.34-7.44(m, 1H), 7.48-7.55(m, 2H), 8.56-8.69( dd, J=14.74, 5.77 Hz, 2H);

ESI-MS m/z calcd for C ₂₁ H ₁₇ FN ₂ O ₂ [M+H] ⁺ 363.3, found 348.13.

Compound 4. (2,6-difluorophenyl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methane On

7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.22mmol, 1 eq.) dissolved in dichloromethane 1.5ml Then, N,N-diisopropylethylamine (192.47 µl, 1.11 mmol, 5 eq.) and 2,6-difluorobenzoyl chloride (17.61 µl. 24 mmol, 1.1 eq.) were added in this order, followed by reaction for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 4 (80.3 mg, yield 99.18%) was obtained through purification using tube chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.75-3.77(t, 1H), 4.12-4.14(t, 1H), 4.22-4.26(m, 2H), 4.47(s, 1H), 4.92(s, 1H) , 6.92-7.00(ddd, J=14.36, 7.62, 7.32Hz, 2H), 7.15-7.19(dd, J=8.40, 6.45Hz, 1H), 7.30-7.31(d, J=5.86Hz, 1H), 7.34 -7.38 (m, 1H), 7.44-7.50 (m, 1H), 7.52-7.55 (m, 2H), 8.65-8.66 (m, 2H);

ESI-MS m/z calcd for C ₂₁ H ₁₆ F ₂ N ₂ O ₂ [M+H] ⁺ 367.2, found 366.12.

Compound 5. Furan-3-yl(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), furan-3-carboxylic acid (31.94mg, 0.28mmol, 1.5equivalent) and coupling reagent 1-ethyl-3-( 3-dimethylaminopropyl)carbodiimide (54.63mg, 0.28mmol, 1.5 eq.) and hydrooxylbenzotriazole (37.65mg, 0.28mmol, 1.5eq.) After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 5 (55 mg, yield 90%) was obtained through purification using a column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 4.10(br.s., 2H), 4.22(br.s., 2H), 4.80(br.s., 2H), 6.55(s, 1H), 7.14-7.16 (d, J=8.20 Hz, 1H), 4.47-4.53 (m, 5H), 7.67 (s, 1H), 8.64-8.65 (d, J=5.86 Hz, 2H);

ESI-MS m/z calcd for C ₁₉ H ₁₆ N ₂ O ₃ [M+H] ⁺ 320.1, found 321.12.

Compound 6. (6-Bromopyridin-3-yl)(7-(pyridin-4-yl)2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methane On

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 6-bromonic acid (57.57mg, 0.28mmol, 1.5equivalent) and coupling reagent 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.) and hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 6 (64.8 mg, yield 83%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.87 (br.s., 1H), 4.08-4.15 (m, 2H), 4.30 (br.s., 1H), 4.53 (br.s., 1H), 4.87 (br.s., 1H), 8.92 (br.s., 1H), 7.15-7.19 (m, 1H), 7.39-7.41 (m, 2H), 7.52-7.54 (m, 2H), 7.68-7.71( m, 1H), 8.40-8.41 (d, J=4.30 Hz, 1H), 8.63-8.65 (d, J=5.86 Hz, 2H);

ESI-MS m/z calcd for C ₂₀ H ₁₆ BrN ₃ O ₂ [M+H] ⁺ 411.1, found 409.04.

Compound 7. (6-Chloropyridin-3-yl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methane On

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 6-clonicic acid (44.90mg, 0.28mmol, 1.5equivalent) and coupling reagent 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.) and hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was removed, and compound 7 (62.5 mg, yield 89.9%) was obtained through purification using a tube chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.87 (br.s., 1H), 4.09-4.16 (m, 2H), 4.31 (br.s., 1H), 4.53 (br.s., 1H), 4.88 (br.s., 1H), 6.92 (br.s., 1H), 7.15-7.21 (m, 1H), 7.41-7.49 (m, 1H), 7.53-7.57 (m, 4H), 8.30-8.40( m, 1H), 8.65-8.66 (d, J=5.86 Hz, 2H);

ESI-MS m/z calcd for C ₂₀ H ₁₆ ClN ₃ O ₂ [M+H] ⁺ 367.1, found 365.09.

Compound 8. (2-Chloro-6-fluorophenyl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Methanol

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 2-chloro-6-fluorobenzoic acid (49.75mg, 0.28mmol, 1.5equivalent) and coupling reagent 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.) and hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was removed, and compound 8 (65.4 mg, yield 90%) was obtained through purification using tube chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.69-3.71(t, 1H), 4.23-4.26(m, 2H), 4.43(s, 1H), 4.89-4.99(m, 1H), 5.30(s, 1H) , 7.02-7.09(m, 1H), 7.15-7.18(m, 1H), 7.21-7.24(m, 1H), 7.29-7.32(m, 2H), 7.41-7.45(m, 1H), 7.49-7.56( m, 2H), 8.61-8.66 (dd, J=14.45, 6.25 Hz, 2H).

Compound 9. 2-(3,4-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) -Sun) Ethanon

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent) and then coupling with 2-(3,4-dichlorophenyl)acetic acid (58.44mg, 0.28mmol, 1.5equivalent) Reagent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.), hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) Reacted. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 9 (70.5 mg, yield 89.7%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.66(s, 1H), 3.79(s, 1H), 3.88-3.90(t, J=4.69Hz, 1H), 4.05-4.10(m, 2H), 4.18-4.21 (m, 1H), 4.64(s,1H), 4.75(s,1H), 7.00-7.04(dt, J=8.20Hz, 1H), 7.10-7.18(m, 1H), 7.24-7.26(dd, 1H ), 7.28-7.31(m, 1H), 7.35-7.37(d, J=0.73Hz, 1H), 7.41-7.43(dd, J=4.76, 1.28Hz, 1H), 7.49-53(m, 2H), 8.62-8.68 (m, 2H);

ESI-MS m/z calcd for C ₂₂ H ₁₈ C _l2 N ₂ O ₂ [M+H] ⁺ 405.1, found 412.07.

Compound 10. 2-(3,4-difluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H )-Sun)ethanone

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent) and then couple with 2-(3,4-difluorophenyl)acetic acid (49.06mg, 0.28mmol, 1.5equivalent) Ring reagent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq), hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq) in this order, and then 3 Time reaction. After completion of the reaction, extraction with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was removed, and compound 10 (68.7 mg, yield 95%) was obtained through purification using a column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.65(s, 1H), 3.76(s, 1H), 3.87-3.88(d, J=4.69Hz, 1H), 4.02-4.09(m, 2H), 4.17-4.20 (d, J=4.69Hz, 1H), 4.63(s, 1H), 4.73(s, 1H), 6.87-6.89(m, 1H), 6.98-7.11(m, 2H), 7.15-7.18(d, 1H) ), 7.43-7.45 (d, 1H), 7.48-7.54 (m, 2H), 7.62-7.63 (d, 1H), 8.61-8.67 (m, 2H);

ESI-MS m/z calcd for C ₂₂ H ₁₈ F ₂ N ₂ O ₂ [M+H] ⁺ 389.1, found 387.6

Compound 11. 2-(4-Chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethane

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 2-(4-chlorophenyl)acetic acid (48.62mg, 0.28mmol, 1.5equivalent) and coupling reagent 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.) and hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 11 (65.7 mg, yield 91.2%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.69(s, 1H), 3.81(s, 1H), 3.88(m, 1H), 4.02-4.04(dd, J=5.22, 3.75Hz, 1H), 4.06-4.08 (d, J=4.76Hz, 1H), 4.19-4.21(t, J=2.29Hz, 1H), 4.62(s, 1H), 4.75(s, 1H), 7.05-7.07(m, 1H), 7.09- 7.11(d, J=8.24Hz, 1H), 7.13-7.16(m, 1H), 7.18-7.19(m, 1H), 7.21-7.23(m, 1H), 7.41-7.42(dd, J=4.58, 1.65 Hz, 1H), 7.48-7.53 (m, 2H), 7.65 (d, J=2.20 Hz, 1H), 8.63-8.68 (m, 2H);

ESI-MS m/z calcd for C ₂₂ H ₁₉ C _l N ₂ O ₂ [M+H] ⁺ 365.2, found 364.10.

Compound 12. 2-(3-chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl) Ethane

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 2-(3-chlorophenyl)acetic acid (48.62mg, 0.28mmol, 1.5equivalent) and coupling reagent 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.) and hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 12 (65.9 mg, yield 91.5%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.68(s, 1H), 3.80(s, 1H), 3.85-3.87(t, 1H), 4.01-4.03(m, 1H), 4.04-4.06(m, 1H) , 4.17-4.19(t, 1H), 4.61(s, 1H), 4.72(s, 1H), 7.03-7.08(m, 1H), 7.10(m,1H), 7.13-7.16(m, 2H), 7.20 -7.21 (m, 1H), 7.42-7.44 (d, J=6.25 Hz, 1H), 7.47-7.51 (m, 2H), 8.61-8.66 (dd, 2H);

ESI-MS m/z calcd for C ₂₂ H ₁₉ C _l N ₂ O ₂ [M+H] ⁺ 379.3, found 378.11.

Compound 13. 2-(2-fluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl )Ethanone

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After dissolving with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4 eq.) and then adding 2-(2-fluorophenyl)acetic acid (43.93mg, 0.28mmol, 1.5 eq.) and coupling reagent 1 -Ethyl-3-(3-dimethylaminopropyl) carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.), hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) . After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 13 (52.7 mg, yield 76.5%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.72(s, 1H), 3.84(s, 1H), 4.05-4.08(q, J=4.27Hz, 1H), 4.17-4.20(m, 1H), 4.63(s , 1H), 4.74(s, 1H), 7.02-7.07(m, 1H), 7.08-7.11(m, 1H), 7.16-7.18(m, 1H), 7.21-7.25(m, 1H), 7.43-7.48 (m, 2H), 7.50-7.54 (m, 1H), 7.64-7.65 (d, J=2.38 Hz, 1H), 8.62-8.68 (m, 2H);

ESI-MS m/z calcd for C ₂₂ H ₁₉ FN ₂ O ₂ [M+H] ⁺ 371.1, found 362.14.

Compound 14. 2-(2-chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethane

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 2-(2-chlorophenyl)acetic acid (48.62mg, 0.28mmol, 1.5equivalent) and coupling reagent 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.) and hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was removed, and compound 14 (60.4 mg, yield 83.9%) was obtained through purification using a column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.82(s, 1H), 3.91-3.95(m, 2H), 4.07-4.09(t, 2H), 4.81-4.20(m, 1H), 4.61(s, 1H) , 4.76(s, 1H), 7.09-7.11(d, J=8.20Hz, 1H), 7.13-7.24(m, 4H), 7.32-7.36(m, 1H), 7.42(d, J=2.34 Hz, 1H ), 7.44-7.46 (d, J=6.25 Hz, 1H), 7.48-7.53 (m, 2H), 7.64 (d, J=2.34 Hz, 1H), 8.61-8.66 (m, 2H);

ESI-MS m/z calcd for C ₂₂ H ₁₉ C _l N ₂ O ₂ [M+H] ⁺ 379.3, found 378.11.

Compound 15. 2-(4-fluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl )Ethanone

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 2-(4-fluorophenyl)acetic acid (43.93mg, 0.28mmol, 1.5equivalent) and coupling reagent 1 -Ethyl-3-(3-dimethylaminopropyl) carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.), hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) . After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 15 (65.7 mg, yield 95.4%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.69(s, 1H), 3.80(s, 1H), 3.87-3.89(t, 1H), 3.98-4.00(t, 1H), 4.05-4.07(t, 1H) , 4.18-4.21(t, 1H), 4.63(s, 1H), 4.74(s, 1H), 6.93-7.00(m, 2H), 7.12-7.18(m, 3H), 7.42-7.44(d, J= 6.23 Hz, 1H), 7.49-7.54 (m, 2H), 7.65-7.66 (d, J=2.20 Hz, 1H), 8.63-8.68 (dd, 2H);

ESI-MS m/z calcd for C ₂₂ H ₁₉ FN ₂ O ₂ [M+H] ⁺ 363.4, found 362.14.

Compound 16. 1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-2-(4-(trifluoro Romethyl)phenyl)ethanone

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 2-(4-(trifluoromethyl)phenyl)acetic acid (58.18.mg, 0.28mmol, 1.5equivalent) And coupling reagent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.), hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) After reacting for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 16 (68.1 mg, yield 86.9%) was obtained through purification using tube chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.77(s, 1H), 3.88-3.91(m, 2H), 4.05-4.09(m, 2H), 4.19-4.22(m, 1H), 4.64(s, 1H) , 4.75(s, 1H), 7.10-7.19(m, 1H), 7.30-7.34(t, 2H), 7.42-7.43(d, 1H), 7.48-7.55(m, 4H), 7.57-7.65(d, 1H), 8.63-8.68 (m, 2H).

Compound 26. 2-(3,5-bis(trifluoromethyl)phenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine -4(5H)-day)ethanone

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4 eq), 2-(3,5-bis(trifluoromethyl)phenyl)acetic acid (77.56mg, 0.28mmol, 1.5 Equivalent) and coupling reagent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63mg, 0.28mmol, 1.5equivalent), hydrooxylbenzotriazole (37.65mg, 0.28mmol, 1.5equivalent) After addition, the reaction was performed for 3 hours. After completion of the reaction, extraction with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was removed, and compound 26 (80.1 mg, yield 87.7%) was obtained through purification using a column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.82(s, 1H), 3.94-3.96(m, 2H), 4.07-4.09(m, 1H), 4.15-4.17(m, 1H), 4.19-4.21(m, 1H), 4.70(s, 1H), 4.76(s, 1H), 7.10-7.20(m, 1H), 7.28-7.29(m, 1H), 7.40-7.42(d, 1H), 7.47-7.52(m, 1H), 7.58 (s, 1H), 7.61-7.66 (t, 2H), 7.76 (s, 1H), 8.60-8.65 (dd, 2H);

ESI-MS m/z calcd for C ₂₃ H ₁₉ F ₃ N ₂ O ₂ [M+H] ⁺ 413.2, found 412.14.

Compound 27. 2-(2,6-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) -Sun) Ethanon

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent) and then coupling with 2-(2,6-dichlorophenyl)acetic acid (58.44mg, 0.28mmol, 1.5equivalent) Reagent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.), hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) Reacted. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 27 (68.3 mg, yield 86.9%) was obtained through purification using tube chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 4.00(s, 1H), 4.05-4.07(m, 2H), 4.15-4.18(m, 2H), 4.27-4.30(m, 1H), 4.75-4.76(m, 2H), 7.08-7.14 (m, 1H), 7.19-7.22 (m, 1H), 7.24-7.28 (m, 2H), 7.31-7.33 (d, 1H), 7.47-7.50 (m, 2H), 7.54- 7.58 (m, 1H), 8.59-8.65 (m, 2H);

ESI-MS m/z calcd for C ₂₂ H ₁₈ C _l2 N ₂ O ₂ [M+H] ⁺ 413.3, found 412.07.

Compound 28. 1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)-2-(3-thiophene )Ethanone)

2 ml of tetrahydrofuran (THF) in 7-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (50mg, 0.19mmol, 1 eq) After melting with N,N-diisopropylethylamine (0.13ml, 0.76mmol, 4equivalent), 2-thiophenine-2-acetic acid (40.52mg, 0.28mmol, 1.5equivalent) and coupling reagent 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide (54.63 mg, 0.28 mmol, 1.5 eq.) and hydrooxyl benzotriazole (37.65 mg, 0.28 mmol, 1.5 eq.) were added in order, followed by reaction for 3 hours. After completion of the reaction, extraction was performed with ethyl acetate, and the organic layer was dried over magnesium sulfate, and then the solvent was removed. Compound 28 (60.8 mg, yield 91.32%) was obtained through purification using column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ 3.72(s, 1H), 3.82(s, 1H), 3.85-3.87(m, 1H), 3.93-3.95(m, 1H), 4.04-4.06(m, 1H) , 4.17-4.19(m, 1H), 4.62(s, 1H), 4.72(s, 1H), 6.91-6.99(m, 1H), 7.04(s, 1H), 7.07-7.16(m, 1H), 7.22 -7.26(m, 1H), 7.43-7.45(d, J=6.25Hz, 1H), 7.47-7.52(m, 2H), 7.65-7.66(d, J=2.34, 1H), 8.62-8.66(dd, J=12.11, 5.86 Hz, 2H).

ESI-MS m/z calcd for C ₂₀ H ₁₈ N ₂ O ₂ S [M+H] ⁺ 350.1, found 351.11.

<Experimental Example 1. Confirmation of TGR5 receptor activity>

It was measured using the stability report screening cell line (CHO/CREB-luc/TGR5) to confirm the TGR5 receptor binding ability and receptor activity, which are the receptors that promote the secretion of GLP-1. Cells were maintained at 37° C. in a 5% CO ₂ incubator in HAM F12 medium supplemented with 10%, 200 μg/ml hygromycin and 300 μg/ml G418.

For the TGR5 receptor agonist screening experiment, cells were cultured on 384-white plates at a density of 12,000 cells and stabilized overnight. Cells were then stimulated by changing the medium to F-12 containing the test compound at the indicated concentration for 5 hours. Prior to analysis, 1X lysis buffer was prepared from 5X lysis buffer and equilibrated to room temperature. After D-PBS washing, 1X lysis buffer was shaken appropriately and treated for 5 minutes. Subsequently, 20 μl of the luminase material was added to each well, and luminescence was measured using Fusion alpha (PerkinElmer). The activity (%) value was calculated from the comparative sample luminescence rate of 10 μM of lithocholic acid (CAS no. 434-13-9). The results of TGR5 receptor activity of the compounds of the present invention measured from the above process are shown in Table 2 below.

Compound number Efficacy
(%-control @10μM) EC ₅₀ (μM) Compound 1 9.7 - Compound 2 7.0 - Compound 3 4.5 - Compound 4 29.8 - Compound 5 8.1 - Compound 6 4.0 - Compound 7 8.2 - Compound 8 3.2 - Compound 9 231.6 0.62 Compound 10 86.3 2.22 Compound 11 109.8 2.41 Compound 12 198.2 0.38 Compound 13 179.4 1.22 Compound 14 185.8 0.85 Compound 15 76.5 2.63 Compound 16 164.8 1.56 Compound 26 95.0 3.55 Compound 27 14.1 - Compound 28 5.0 - Control
(Litocholic acid) - 11.09

Looking at Table 2, it can be seen that the compounds of the present invention have improved TGR5 receptor activity than lithocholic acid used as a conventional TGR5 receptor agonist. In particular, in the case of compounds 9, 11, 12, 13, 14 and 16, the TGR5 receptor activity It has been found that it is remarkably high and can be usefully used as a composition for treating obesity.

<Formulation Example 1. Preparation of tablets>

Compound 9(2-(3,4-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4( 5H)-yl)ethanone) 20g were mixed with 175.9g of lactose, 180g of potato starch and 32g of colloidal silicic acid, respectively. After adding 10% gelatin solution to this mixture, it was ground and passed through a 14 mesh sieve. This mixture was dried, and a mixture obtained by adding potato starch 160g, talc 50g, and magnesium stearate 5g was purified.

<Formulation Example 2. Preparation of capsules>

Compound 9(2-(3,4-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4( 5H)-day)ethanone) 100mg, cornstarch 100mg, lactose 100mg, and magnesium stearate 2mg are mixed and the above ingredients are mixed according to a conventional capsule preparation method and filled into a gelatin capsule to obtain a capsule. It was prepared.

< Formulation example 3. Preparation of injections>

Compound 9(2-(3,4-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4( 5H)-yl)ethanone) 1 g, sodium chloride 0.6 g and ascorbic acid 0.1 g were dissolved in distilled water to make 100 ml. The solution was put in a bottle and sterilized by heating at 20°C for 30 minutes.

Claims (4)

A pharmaceutical composition for preventing or treating obesity comprising the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In Chemical Formula 1,
X and Y are carbon or nitrogen;
R is substituted or unsubstituted C ₄ -C ₆ aryl, substituted or unsubstituted C ₄ -C ₁₀ heteroaryl,
At this time, the substituted aryl and heteroaryl is one selected from the group consisting of hydrogen, halogen, nitro, cyano, amino, hydroxy, trihalogenmethyl, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy Substituted with the above substituents;
n is an integer of 0 or 1; to be. According to claim 1,
The compound of Formula 1
(2,4-difluorophenyl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (compound One);
(4-chlorophenyl)(7-pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (Compound 2);
(2-fluorophenyl)(7-pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (Compound 3);
(2,6-difluorophenyl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (compound 4);
Furan-3-yl(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone (Compound 5);
(6-Bromopyridin-3-yl)(7-(pyridin-4-yl)2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (compound 6);
(6-Chloropyridin-3-yl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone (compound 7);
(2-Chloro-6-fluorophenyl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)methanone ( Compound 8);
2-(3,4-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 9);
2-(3,4-difluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl )Ethanone (Compound 10);
2-(4-chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone ( Compound 11);
2-(3-chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone ( Compound 12);
2-(2-fluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 13);
2-(2-chlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone ( Compound 14);
2-(4-fluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 15);
1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-(4-(trifluoromethyl) Phenyl)ethanone (Compound 16);
2-(3-Bromophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl-ethanone (Compound 17);
2-(3-bromo-4-fluorophenyl)-1-(7-)pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) -Yl)ethanone (Compound 18);
2-(4-chloro-3-fluorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- Work)ethanone (Compound 19);
2-(benzo[d][1,3]dioxol-5-yl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine -4(5H)-yl)ethanone (Compound 20);
2-(4-Nitrophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 21);
2-(3-Nitrophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 22);
2-(pyridin-2-yl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 23);
2-(pyridin-3-yl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 24);
2-(pyridin-4-yl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 25);
2-(3,5-bis(trifluoromethyl)phenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4( 5H)-yl)ethanone (Compound 26);
2-(2,6-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 27);
1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-(3-thiopheny)ethanone ) (Compound 28);
2-(3,5-dichlorophenyl)-1-(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 29);
(8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)(7-(pyridin-4-yl)-2,3-dihydrobenzo[f][ 1,4]oxazepine-4(5H)-yl)methanone (Compound 30);
2-(3,4-dichlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 31);
2-(4-chlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone ( Compound 32);
2-(3-chlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone ( Compound 33);
2-(2-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 34);
2-(2-chlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethanone ( Compound 35);
2-(4-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 36);
1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-(4-(trifluoromethyl) Phenyl)ethanone (Compound 37);
2-(3-Bromophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 38);
2-(3-Bromo-4-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) -Yl)ethanone (Compound 39);
2-(4-Chloro-3-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- Work)ethanone (Compound 40);
2-(4-Nitrophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 41);
2-(3-Nitrophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl)ethanone (Compound 42);
2-(3,5-bis(trifluoromethyl)phenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4( 5H)-yl)ethanone (Compound 43);
2-(2,6-dichlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 44);
2-(3,5-dichlorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl) Ethanone (Compound 45);
2-(3,5-difluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-yl )Ethanone (Compound 46);
2-(3-fluoro-4-hydroxyphenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H) -Yl)ethanone (Compound 47);
2-(2-Chloro-4-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- Work)ethanone (Compound 48); And
2-(3-chloro-4-fluorophenyl)-1-(7-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- Work)ethanone (Compound 49);
Pharmaceutical composition for preventing or treating obesity, characterized in that it is selected from the group consisting of. According to claim 1,
The compound is a pharmaceutical composition for preventing or treating obesity, characterized in that it increases the activity on the TGR5 receptor. According to claim 1,
The composition is a pharmaceutical composition for preventing or treating obesity, characterized in that it is formulated into a pharmaceutical dosage form by adding a pharmaceutically acceptable carrier, excipient or diluent.