BR112016030599B1 - NEW AMINOALKYLBENZOTIAZEPINE DERIVATIVES AND THEIR USES - Google Patents

Abstract

NEW AMINOALKYLBENZOTHIAZEPINE DERIVATIVES AND THEIR USES. The present invention relates to a new aminoalkylbenzothiazepine derivative or a pharmaceutically acceptable salt thereof, and to a pharmaceutical composition for the prevention or treatment of constipation which comprises the same as an active ingredient.

Description

[001] [Technical Field]

[002] The present invention relates to a new aminoalkylbenzothiazepine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for the prevention or treatment of constipation which comprises the same as an active ingredient.

[003] [State of the Prior Art]

[004] Constipation is a common digestive disease, with a prevalence rate of about 16% in Korea. It occurs more frequently in women than in men and the prevalence rate is higher in older people, namely around 30% to 40%. Due to the discomfort and serious consequences in everyday life, constipation has been rated as the second most important reason for absence from work in Western countries and some victims of constipation report a serious deterioration in their quality of life.

[005] Currently, stimulant laxatives and stool softeners are widely used in the treatment of constipation. Stimulant laxatives prevent the absorption of water in the large intestine and stimulate its movement, with SennaTM and BisacodilTM widely used. In addition, laxatives increase the absorption of water by the stool by reducing its surface tension, with DocusateTM being a representative example of a laxative. However, these stimulant laxatives and stool softeners only provide temporary effects and may develop resistance, so they are not recommended for long-term use.

[006] On the other hand, bile acid is produced in the liver from cholesterol, stored in the gallbladder, and excreted into the small intestine to help with the digestion of nutrients, such as vitamins and lipids, after meals. About 90% of bile acid is reabsorbed by the liver during its transport to the lower part of the small intestine. Inhibition of bile acid reabsorption by a drug promotes the passage of bile acid into the large intestine and induces water secretion within the large intestine as well as bowel movements, and is therefore useful for the prevention and treatment of constipation ( American Journal of Gastroenterology, 2011, 106: 2154-2163).

[007] [Disclosure]

[008] [Technical Problem]

[009] When trying to develop a new compound to be used in the prevention and treatment of constipation, the inventors of the present invention found that a series of aminoalkylbenzothiazepine derivatives could effectively inhibit the reabsorption of bile acid, thus being useful for the prevention and treatment constipation, and thus concluded the present invention.

[010] [Technical Solution]

[011] In one aspect, the present invention provides a compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof:

[012] [Formula 1]

[013] in which

[014] R1 is hydroxy, carboxy, or hydroxysulfonyl(C1-4 alkyl);

[015] R2 and R3 are each independently hydrogen, C1-4 alkyl, hydroxy(C1-4 alkyl), carbamoyl(C1-4 alkyl), carboxy, carboxy(C1-4 alkyl), (C5-10 heteroaryl )(C1-4 alkyl), or (C5-10 aryl)(C1-4 alkyl), or R2 and R3, together with the respective carbon atom to which they are attached, form C3-7 cycloalkylene;

[016] R4 is hydrogen or carboxy(C1-4 alkyl);

[017] R5 is hydrogen, halogen, (C1-4 alkyl)thio, (C1-4 alkyl)amino, or di(C1-4 alkyl)amino;

[018] R6 and R7 are each independently C1-6 alkyl;

[019] R8 and R9 are each independently hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, halogen, nitro, cyano, amino, (C1-4 alkyl)amino, di(C1-4 alkyl)amino , acetamido, formyl, C1-4 alkanoyl, carboxy, carbamoyl, (C1-4 alkyl)carbamoyl, di(C1-4 alkyl)carbamoyl, carbamoyloxy, (C1-4 alkyl)carbamoyloxy, di(C1-4 alkyl)carbamoyloxy, (C1-4alkyl)sulfonyloxy, sulfamoyloxy, (C1-4alkyl)sulfamoyloxy, or di(C1-4alkyl)sulfamoyloxy;

[020] Q is C5-10 aryl or C5-10 heteroaryl; It is

[021] n is an integer from 0 to 3.

[022] Preferably, in previous Formula 1,

[023] R1 is hydroxy, carboxy, or hydroxysulfonyl(C1-4 alkyl);

[024] R2 and R3 are each, independently, hydrogen, C1-4 alkyl, hydroxy(C1-4 alkyl), carbamoyl(C1-4 alkyl), carboxy, carboxy(C1-4 alkyl), or (C5-heteroaryl) 10)(C1-4 alkyl), or R2 and R3, together with the respective carbon atom to which they are attached, form C3-7 cycloalkylene;

[025] R4 is hydrogen or carboxy(C1-4 alkyl);

[026] R5 is (C1-4 alkyl)thio;

[027] R6 and R7 are each independently C1-6 alkyl;

[028] R8 and R9 are each independently hydrogen, hydroxy, halogen, or C1-4 alkoxy;

[029] Q is C5-10 aryl; It is

[030] n is an integer from 0 to 3.

[031] Preferably, in Formula 1 above, R1 may be hydroxy, carboxy, or hydroxysulfonylmethyl.

[032] Preferably, in Formula 1 above, R 2 and R 3 may each independently be hydrogen, carboxy, methyl, isobutyl, carbamoylmethyl, carboxymethyl, carboxyethyl, hydroxymethyl, imidazolylmethyl, indolylmethyl, or ethyl, or R2 and R3, together with the respective carbon atom to which they are attached, they can form cyclopropylene.

[033] Preferably, in Formula 1 above, R4 may be hydrogen, carboxymethyl, or carboxyethyl.

[034] Preferably, in Formula 1 above, R5 may be methylthio, ethylthio, or dimethylamino.

[035] Preferably, in Formula 1 above, R6 and R7 may both be butyl or both ethyl.

[036] Preferably, in the above Formula 1, R8 and R9 may each independently be hydrogen, hydroxy, methoxy, methyl, ethyl, fluorine, chlorine, nitro, cyano, amino, methylamino, ethylamino, dimethylamino, acetyl, carboxy , carbamoyl, methylcarbamoyl, dimethylcarbamoyl, carbamoyloxy, methylcarbamoyloxy, dimethylcarbamoyloxy, methylsulfonyloxy, sulfamoyloxy, methylsulfamoyloxy, or dimethylsulfamoyloxy.

[037] Preferably, in Formula 1 above, Q may be phenyl, pyridinyl, pyrimidinyl, or thiophenyl. According to Formula 1 above, Q can be phenyl, pyridinyl, pyrimidinyl or thiophenyl, substituted with R8 and R9. In Q above, the positions of substituents R8 and R9 are not defined, but they can be on mutually different atoms, and hydrogen can be bonded to positions other than these positions. Therefore, when both R8 and R9 are hydrogen, Q may refer to unsubstituted phenyl, pyridinyl, pyrimidinyl or thiophenyl groups.

[038] More preferably, the compound can be:

[039] 1. 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)acetic;

[040] 2. 3-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)propanoic;

[041] 3. 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)succinic;

[042] 3. acid (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)propanoic;

[043] 4. 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)pentanedioic acid;

[044] 5. 4-amino-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)-4-oxobutanoyl;

[045] 6. (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)propanoic;

[046] 7. 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)-2-methylpropanoic;

[047] 8. (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)-3-(1H-imidazol-4-yl)propanoic acid;

[048] 9. (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)-3-(1H-indol-2-yl)propanoic acid;

[049] 10. (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)-4-methylpentanoyl;

[050] 11. (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)pentanedioic acid;

[051] 12. (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic;

[052] 13. 3-((carboxymethyl)((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)propanoic acid;

[053] 14. 3-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)pentanedioic acid;

[054] 15. 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)-2-oxoacetic;

[055] 16. 1-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- carboxylic 8-yl)methyl)amino)cyclopropane;

[056] 17. 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)-2-oxoethanesulfonic acid;

[057] 18. 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)acetic;

[058] 19. 2-(((3,3-dibutyl-5-(4-hydroxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)acetic;

[059] 20. 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)acetic;

[060] 21. 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)acetic;

[061] 22. 2-(((3,3-dibutyl-5-(3-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)acetic;

[062] 23. 2-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b) acid ][1,4]thiazepine-8-yl)methyl)amino)acetic;

[063] 24. 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid;

[064] 25. 1-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b) acid carboxylic][1,4]thiazepine-8-yl)methyl)amino)cyclopropane;

[065] 26. 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid;

[066] 27. (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b) acid ][1,4]thiazepine-8-yl)methyl)amino)propanoic acid;

[067] 28. (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b) acid ][1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic acid; It is

[068] 29. 1-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1, 4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid.

[069] In addition, the compound of the present invention may be present in the form of a pharmaceutically acceptable salt thereof. For the salt, acid addition salts formed by pharmaceutically acceptable free acids may be useful. As used herein, the term "pharmaceutically acceptable salt" refers to any addition salt, organic or inorganic, of the foregoing compounds, which exhibits effective action at a concentration that is relatively non-toxic and harmless to patients, and adverse effects associated with the salt do not deteriorate the advantageous effects of the compounds represented by Formula 1.

[070] Acid addition salts can be prepared by a conventional method, for example, dissolving the compounds in an excess amount of aqueous acid solution, followed by precipitation of the salt in a water-miscible organic solvent, for example, methanol , ethanol, acetone, or acetonitrile. An equimolar amount of a compound and the acid or alcohol (e.g. glycol monomethyl ether) in water is heated and then the mixture is dried by evaporation, or the precipitated salt can be filtered off with suction.

[071] In addition, a pharmaceutically acceptable metal salt can be prepared using a base. Alkali metal salts or alkaline earth metal salts can be prepared, for example, by dissolving the compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering undissolved salts of the compound, evaporation and drying of the filtrate.

[072] The pharmaceutically acceptable salt of the present invention, unless otherwise indicated, may include a salt of the acidic or basic group that may be present in the compound of Formula 1, and may be prepared by an art-known method of preparing salts.

[073] In addition, the compounds of the present invention have an asymmetric carbon center in the main structure and in the substituent group thereof, and thus may be present as R or S isomers, racemates, mixtures of stereoisomers, and individual stereoisomers, and all these isomers and mixtures thereof are within the scope of the present invention.

[074] For example, the compounds of the present invention can be synthesized from aminoalkoxybenzenethiol and 3-bromo-2-(mono or di)alkylpropanoic acid by a series of reactions shown in Reaction Scheme 1 below. However, the Reaction Scheme shown below is for illustrative purposes only and is not limited to the method of preparing the compounds of the present invention, and any method known in the art can be used or adapted accordingly for use.

[075] [Reaction Scheme 1]

[076] The substituents in the above reaction scheme are the same as previously defined.

[077] Specifically, Step 1 refers to the preparation of a compound represented by Formula 4 by reacting aminoalkoxybenzenethiol (for example, aminomethoxybenzenethiol), which is a compound represented by Formula 2, and a 3-bromo-2 acid derivative -(mono- or di)alkylpropanoic acid (eg, 3-bromo-2,2-dibutylpropanoic acid, also known as 2-bromomethyl-2-butylhexanoate), which is a compound represented by Formula 3. Preferably, the reaction in Step 1 can be carried out in the presence of potassium hydroxide, and water can be used as a solvent, but is not limited to them.

[078] Step 2 refers to cyclization to form benzothiazepine, in which a derivative of 3,3-dialkyl-8-alkoxy-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)- One represented by Formula 5 is prepared by reacting a compound represented by Formula 4, prepared in Step 1, with HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 - b]pyridinium-3-oxide). Preferably, dichloromethane can be used as the solvent in Step 2, but is not limited to it.

[079] Step 3 refers to the introduction of a bromo group in the form of a reactive substituent group, in which a derivative of 7-bromo-3,3-dialkyl-8-alkoxy-2,3-dihydrobenzo[b] [1,4]thiazepine-4(5H)-one represented by Formula 6 is prepared by reacting a compound represented by Formula 5, prepared in Step 2, with N-bromosuccinimide. Preferably, dichloromethane can be used as the solvent in Step 3, but is not limited to it. N-halo-succinimide, including other halogen atoms, can be used in place of N-bromosuccinimide. For the halogen atom, any one that can provide a substituent capable of exhibiting sufficient reactivity in a subsequent substitution reaction can be used without limitation.

[080] Step 4 refers to the introduction of a substituent group on a nitrogen atom of the thiazepine ring, which can be carried out by reacting a compound represented by Formula 6, prepared in Step 3, with an iodinated compound represented by Formula 7. Preferably, the reaction of Step 4 can be carried out in the presence of Cul, and xylene can be used as a solvent, but is not limited to them.

[081] Step 5 refers to the removal of a ketone group from the thiazepine ring by a reduction reaction, and LiAlH4 can be used as a reducing agent, but is not limited to it, and any reducing agent capable of converting - (C=O)- to -CH2- by selectively reducing the ketone group on the thiazepine ring can be used without limitation. Preferably, diethyl ether can be used as the solvent in Step 5, but is not limited thereto.

[082] Step 6 relates to the preparation of a derivative of thiazepine dioxide by oxidation with osmium tetroxide, and a mixed solvent of tetrahydrofuran and t-butanol can be preferably used as a solvent in Step 6, but is not limited thereto .

[083] Step 7 refers to the conversion of the alkoxy group of a benzo ring into a hydroxyl group with the simultaneous introduction of a substituent group R5 in the position, in which a reactive halogen is replaced by a substitution reaction, and a salt of metal, for example, an alkali metal salt (M-R5; M being an alkali metal) of the substituent group to be introduced can be used as a reagent for the substitution reaction. Preferably, dimethylformamide (DMF) can be used as the solvent in step 7, but is not limited thereto.

[084] Step 8 refers to the conversion of the hydroxy group of a benzo ring into trifluoromethanesulfonate (triflate; OTf), which is a good leaving group, and trifluoromethanesulfonic anhydride (TfO2) can be used as a reagent for the introduction of OTf . Preferably, dichloromethane can be used as the solvent in Step 8, but is not limited to it.

[085] Step 9 refers to the introduction of a cyano group as a precursor of an aminomethyl group, in which an OTf group is replaced with a CN group by reaction of a compound represented by Formula 13, which is introduced with the group OTf is prepared in Step 8 with zinc cyanide. Preferably, the reaction of Step 9 can be carried out in the presence of palladium, and dimethylformamide can be used as a solvent, but is not limited to them.

[086] Step 10 refers to the conversion of a cyano group into a formyl group by reacting the compound into which the cyano group is introduced in Step 9 with diisobutylaluminum hydride (DIBAL-H). Preferably, dichloromethane can be used as the solvent in Step 10, but is not limited to it.

[087] Step 11 refers to obtaining a title compound by a condensation reaction between a compound represented by Formula 15, prepared in Step 10, and an amine derivative. Preferably, the reaction in Step 11 can be carried out in the presence of sodium triacetoxyborohydride (NaB(OAc)3H) and dichloroethane can be used as a solvent, but is not limited to them.

[088] In another aspect, the present invention provides a pharmaceutical composition for preventing or treating constipation which comprises the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[089] As used herein, the term "prevention" refers to any action that results in the suppression or delay of the onset, propagation and recurrence of constipation due to the administration of the pharmaceutical composition according to the present invention, and the term " treatment" refers to any action that results in the amelioration of the symptoms of the disease(s) or the beneficial change resulting from the administration of the composition according to the present invention.

[090] The pharmaceutical composition of the present invention may comprise the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient, and may also further comprise a pharmaceutically acceptable carrier, diluent, or excipient.

[091] The composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat disease, at a reasonable benefit/risk ratio, applicable to medical treatment, without causing any adverse effects, and the term "administration " refers to the introduction of a predetermined substance into a patient by a specific suitable method.

[092] As used herein, the term "therapeutically effective amount", which was used in relation to active ingredients, refers to the amount of aminoalkylbenzothiazepine derivatives or their pharmaceutically acceptable salts that is effective for the prevention or treatment of disease(s) in question.

[093] In addition to the aminoalkylbenzothiazepine derivatives or their pharmaceutically acceptable salts, the pharmaceutical composition of the present invention may also comprise other known drug(s) conventionally used in the prevention or treatment of the disease(s) as active ingredient(s) , depending on the disease(s) to be prevented or treated.

[094] [Advantageous Effects]

[095] The novel aminoalkylbenzothiazepine derivatives of the present invention can inhibit bile acid reabsorption and therefore allow bile acid to pass into the large intestine, thereby inducing the secretion of water within the large intestine and promoting bowel movements thick. These results indicate that the compounds of the present invention can be effectively used in the treatment and prevention of constipation.

[096] [Best Mode]

[097] Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these examples are for illustrative purposes only and the invention is not limited thereto.

[098] Several methods of preparing the starting materials for the synthesis of the compounds of the present invention are known and, if available on the market, the starting materials can be purchased from suppliers. Examples of reagent suppliers include, but are not limited to, Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, and DaeJung. Furthermore, all commercially available materials were used without further purification unless otherwise noted.

[099] First, the compounds used in the synthesis of the Examples were prepared as described in the Preparation Examples. The Preparation Examples are exemplary embodiments of Reaction Scheme 1, and can be suitably adapted corresponding to the structures of the compounds of the Examples.

[100] Preparation Example 1: Preparation of 3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8 1,1-dioxide - carbaldehyde

[101] Step 1) Preparation of 2-(((2-amino-5-methoxyphenyl)thio)methyl)-2-butylhexanoic acid

[102] 6-Methoxybenzo[d]thiazol-2-amine (25 g, 139.7 mmol) was added to 250 ml of 30% potassium hydroxide and stirred at 140°C for 18 hours. The reaction mixture was monitored by TLC to confirm the formation of 2-amino-5-methoxybenzenethiol, and cooled to room temperature. Then 2-bromomethyl-2-butylhexanoate (44.6 g, 167.7 mmol) was added and stirred at room temperature for about 17 hours. Saturated ammonium chloride solution and dichloromethane were added, stirred for 10 minutes, the dichloromethane layer was extracted, and the whole process was repeated three times. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated compound thus obtained was charged with methyl t-butyl ether and a 6N HCl solution in order to extract an ester phase, and then concentrated again. The concentrated compound was a brown solid. Add hexane, shake and filter to give 25 g of an ivory solid, 51% yield.

[103] Step 2) Preparation of 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one

[104] 2-(((2-Amino-5-methoxyphenyl)thio)methyl)-2-butylhexanoic acid (25 g, 71.78 mmol) obtained in Step 1) was added to 900 ml of dichloromethane and cooled to -40 °C. When the temperature reached -40 °C, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (41 g, 107.68 mmol; HATU) and stirred for about 10 minutes. Then diisopropylamine (58.15 ml, 358.9 mmol) was slowly added dropwise. At the end of the diisopropylamine addition, the mixture was stirred for about 5 hours. Saturated ammonium chloride solution was added and the dichloromethane phase was extracted. The entire process was repeated three times. The extracted dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 23 g of 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4 ]thiazepine-4(5H)-one. The compound thus obtained was charged with 480 ml of dichloromethane and cooled to 0°C. After cooling, N-bromosuccinimide (14.51 g, 81.54 mmol) was added slowly and stirred for about 4 hours. Then a saturated ammonium chloride solution was added and the dichloromethane phase was extracted. The extracted dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated. To the concentrated compound, 200 ml of a mixture of hexane and ethyl acetate (hexane:ethyl acetate = 30: 1) was added, and 200 ml of hexane was further added with stirring. The resulting solid was filtered, yielding 14 g of 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one as the compound of the title, with a yield of 50%.

[105] 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 6.99 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 3.78 (s, 3H), 2.97 (s, 2H), 1.78-1.85 ( m, 2H), 1.55-1.62 (m, 2H), 1.18-1.30 (m, 8H), 0.87 (t, J = 6.8 Hz, 6H).

[106] Step 3) Preparation of 3,3-dibutyl-8-hydroxy-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide

[107] At 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one (5.77 g, 14.44 mmol) obtained in Step 2) added iodobenzene (50 mL), copper iodide (0.55 g, 2.89 mmol), potassium carbonate (4 g, 28.9 mmol), and tris[2-(2- methoxyethoxy)ethyl]amine (0.5 ml, 1.44 mmol), and the mixture was stirred at room temperature for about 5 minutes and refluxed at 190°C for 17 hours. The resulting mixture was cooled to room temperature, filtered through silica, and washed with hexane to remove iodobenzene. The compound retained on the silica was eluted with ethyl acetate and dichloromethane, and the recovered solution was concentrated to give 5.8 g of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3 -dihydrobenzo[b][1,4]thiazepine-4(5H)-one. Lithium aluminum hydride (1.4 g, 36.88 mmol) was added to a 500 mL round bottom flask dried under vacuum. Diethyl ether (150 ml) was added, cooled to -10 °C and then anhydrous sulfate (1 ml, 18.44 mmol) was added slowly dropwise. 7-Bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one was dissolved in diethyl ether and added dropwise to the reaction flask. The resulting mixture was stirred at room temperature for 2 hours, and charged with saturated ammonium chloride solution to extract the diethyl ether layer. The extract was dried with anhydrous magnesium sulfate, filtered and concentrated, obtaining 5 g of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepine. The compound thus obtained (5 g, 10.98 mmol) was charged with 75 ml of a mixed solvent (tetrahydrofuran:t-butanol = 1: 1), osmium tetroxide (0.07 g, 0.27 mmol), and N-methylmorpholine-N-oxide (3.96 g, 32.94 mmol), and stirred at room temperature for 12 hours. Saturated ammonium chloride solution and dichloromethane were added to extract the dichloromethane layer, and the extract was concentrated to yield 3.55 g of 7-bromo-3,3-dibutyl-8-methoxy-5-dioxide. -phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine as an ivory solid. The compound thus obtained (3.55 g, 7.18 mmol) was charged with dimethylformamide (100 ml), sodium thiomethoxide (5.032 g, 71.79 mmol), and sodium borohydride (5.43 g, 143.6 mmol). mmol), and stirred at 60°C for 15 hours. A saturated ammonium chloride solution and t-butyl methyl ether were added to extract the ether layer, and this was concentrated. The concentrated compound was charged with hexane and the solid was filtered to give 2.7 g of 3,3-dibutyl-8-hydroxy-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[ b][1,4]thiazepine, with a yield of 84%.

[108] 1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.16 (t, J = 8 Hz, 2H), 6.92 (d, J = 8 Hz, 2H), 6 .84 (t, J = 6.8 Hz, 1H), 6.67 (s, 1H), 3.61 (s, 2H), 3.07 (s, 2H), 2.15 (s, 3H) , 1.28-1.44 (m, 4H), 1.97-1.19 (m, 8H), 0.74 (t, J = 6.8 Hz).

[109] Step 4) Preparation of 3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8 trifluoromethanesulfonate -ilo

[110] 3,3-Dibutyl-8-hydroxy-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide (2.7 g, 5.98 mmol) obtained in Step 3) was charged with dichloromethane (30 mL) and pyridine (0.63 mL, 7.77 mmol), and cooled to 0 °C. Trifluoromethanesulfonic anhydride (1.3 ml, 7.77 mmol) was added slowly dropwise and stirred at room temperature for 5 hours. Saturated ammonium chloride solution was added to extract the dichloromethane layer, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by column chromatography on silica using a mixture of solvents (hexane:ethyl acetate = 8:1). As a result, 2.96 g of 3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4] trifluoromethanesulfonate were obtained thiazepine-8-yl in 86% yield.

[111] 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 7.2 Hz, 1H), 6.46 (s, 1H), 3.89 (s, 2H), 3.26 (s, 2H), 2.13 ( s, 3H), 1.48-1.85 (m, 2H), 1.35-1.42 (m, 2H), 1.01-1.20 (m, 8H), 0.74 (t, 2H). J = 6.8 Hz).

[112] Step 5) Preparation of 3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbonitrile dioxide

[113]

[114] 3,3-Dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl trifluoromethanesulfonate (2.96 g , 5.12 mmol) obtained in Step 4) was charged with dimethylformamide (60 mL), zinc dust (0.034 g, 0.512 mmol), zinc cyanide (0.66 g, 5.632 mmol), tris(dibenzylideneacetone)dipalladium (0. 47 g, 0.51 mmol), and 1,1-bis(diphenylphosphino)ferrocene (0.34 g, 0.614 mmol), and stirred at 80 °C for 20 hours. The resulting mixture was cooled to room temperature, and saturated ammonium chloride solution and ethyl acetate were added to extract the ethyl acetate layer. The extracted ethyl acetate phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated compound was purified by silica column chromatography using a mixture of solvents (hexane:ethyl acetate = 6:1) to obtain 1 g of the title compound in 50% yield.

[115] 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.24-7.31 (m, 3H), 6.26 (s, 1H), 4.02 (s, 2H), 3.30 (s, 2H), 2.11 (s, 3H), 1.261.58 (m, 4H), 0.83-1 .19 (m, 8H), 0.74 (t, J = 6.8 Hz).

[116] Step 6) Preparation of 3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbaldehyde dioxide

[117] 3,3-Dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbonitrile dioxide (1 g, 2.1 mmol) obtained in Step 5) was charged with dichloromethane, cooled to 0 °C and 5 ml of diisobutylaluminum hydride (DIBAL-H) was added slowly dropwise. The resulting mixture was warmed to room temperature and stirred for 1 hour. Then, the mixture was again cooled to 0 °C, distilled water, ethyl acetate, and potassium sodium tartrate were added, and stirred for 30 minutes. After extracting the ethyl acetate layer, it was dried with anhydrous magnesium sulfate, filtered and concentrated. The concentrated compound was purified by column chromatography on silica using a mixture of solvents (hexane:ethyl acetate = 4:1), to obtain 600 mg of the title compound in 63% yield.

[118] 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.37 (s, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.26- 7.30 (m, 3H), 6.27 (s, 1H), 4.08 (s, 2H), 3.34 (s, 2H), 0.881.40 (m, 12H), 0.77 (t , J = 6.8 Hz).

[119] Example 1: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)acetic

[120] 3,3-Dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbaldehyde dioxide (31 mg, 0.067 mmol) obtained from Preparation Example 1 was added to 2 ml of dichloroethane, ethylglycine methyl ester hydrochloride (11 mg, 0.088 mmol) was added and stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (28 mg, 0.131 mmol) was added and stirred at room temperature for 17 hours. At the end of the reaction, an extraction was performed by adding dichloromethane and distilled water, drying with anhydrous magnesium sulfate, filtering and concentrating under reduced pressure. The filtrate was purified by PTLC (dichloromethane:methanol = 50:1) to obtain 20.5 mg of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2, Ethyl 3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetate in 57% yield.

[121] The compound thus obtained (20.5 mg, 0.038 mmol) was added to 3 ml of a mixed solution (tetrahydrofuran: methanol: distilled water = 1: 1: 1), lithium hydroxide (16 mg, 0.40 mmol), and stirred at room temperature for 12 hours. At the end of the reaction, ethyl acetate and 1N HCl were added for extraction, the extract was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane:methanol = 20:1), yielding 10 mg of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2, 3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid as the title compound (yield: 44%).

[122] 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 6.47 (s, 1H), 4.46 (s, 2H), 3.733.93 (m, 4H), 3.33 ( s, 2H), 2.15 (s, 3H), 1.47-1.52 (m, 2H), 1.33-1.39 (m, 2H), 1.08-1.15 (m, 4H), 1.00-1.03 (m, 4H), 0.78 (t, J = 6.8 Hz, 6H).

[123] Example 2: Preparation of 3-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)propanoic

[124] The title compound was synthesized similarly to Example 1, except that ethyl 3-aminopropanoate was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 65%).

[125] 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.38-7.34 (m, 2H), 7.26 7.22 (m, 2H), 7.17- 6.97 (m, 1H), 6.46 (s, 1H), 4.35 (s, 2H), 3.88 (s, 2H), 3.26 (s, 4H), 2.93 (s , 2H), 2.15 (s, 3H), 1.60-1.46 (m, 2H), 1.40-1.29 (m, 2H), 1.14-0.99 (m, 8H ), 0.81-0.74 (m, 6H).

[126] Example 3: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)succinic

[127] The title compound was synthesized similarly to Example 1, except that diethyl aspartate was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 52%).

[128] 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.34 (s, 3H), 7.24 (s, 1H), 7.12 (s, 1H), 6, 46 (s, 1H), 4.62-4.35 (m, 2H), 4.02-3.88 (m, 2H), 3.50-3.10 (m, 5H), 2.17 ( s, 3H), 1.66-1.35 (m, 4H), 1.22-0.89 (m, 8H), 0.75 (s, 6H).

[129] Example 4: Preparation of (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b]) acid [1,4]thiazepine-8-yl)methyl)amino)propanoic

[130] The title compound was synthesized similarly to Example 1, except that alanine diethyl ester was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 61%).

[131] 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.32 (s, 2H), 7.16-7.12 (m, 3H), 6.45 (s, 1H ), 4.24-4.19 (m, 2H), 3.81 (s, 2H), 3.52 (s, 1H), 3.27 (s, 2H), 2.09 (s, 3H) , 1.52-1.42 (m, 5H), 1.41-1.25 (m, 2H), 1.24-0.92 (m, 8H), 0.88-0.65 (m, 6H).

[132] Example 5: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)pentanedioic acid

[133] The title compound was synthesized similarly to Example 1, except that glutamine diethyl ester was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 36%).

[134] 1H NMR (400 MHz, CDCl3 δ 7.74 (s, 1H), 7.35-7.33 (m, 2H), 7.19 7.18 (m, 2H), 7.12-7 .09 (m, 1H), 6.43 (s, 1H), 4.97 (d, J = 14 Hz, 1H), 4.17 (d, J = 15.2 Hz, 1H), 3.85 (s, 3H), 3.26 (s, 2H), 1.21-0.96 (m, 8H), 0.82-0.76 (m, 6H).

[135] Example 6: Preparation of 4-amino-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepine-8-yl)methyl)amino)-4-oxobutanoyl

[136] The title compound was synthesized similarly to Example 1, except that arginine diethyl ester was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 23%).

[137] MS: 576.25 [M + H] +.

[138] Example 7: Preparation of (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b]) acid [1,4]thiazepine-8-yl)methyl)amino)propanoic

[139] Compound Example 1, except that alanine diethyl ester was used as reagent instead of glycine ethyl ester hydrochloride (yield: 56%).

[140] 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.19-7.26 (m, 2H), 7.08 7.10 (m, 3H), 6.38 ( s, 1H), 4.03-7.09 (m, 2H), 3.76 (s, 2H), 3.41 (s, 1H), 3.20 (s, 2H), 2.89-2 .99 (m, 1H), 2.02 (s, 3H), 1.43 (s, 3H), 1.29-1.36 (m, 2H), 1.18-1.23 (m, 2H ), 0.81-1.08 (m, 8H), 0.69-0.7 (m, 6H).

[141] Example 8: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)-2-methylpropanoic

[142] The title compound was synthesized similarly to Example 1, except that ethyl 2-amino-2-methylpropanoate was used as the reagent instead of ethylglycine methyl ester hydrochloride (yield: 57%).

[143] 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.33 (t, J = 7.6 Hz, 2H), [2] 7-7.18 (m, 2H) , 7.11-7.12 (m, 1H), 6.48 (s, 1H), 3.96 (s, 2H), 3.81 (s, 2H), 3.21 (s, 2H), 2.14 (s, 3H), 1.53 (s, 6H), 1.25-1.34 (m, 4H), 0.85-1.14 (m, 8H), 0.76 (t, J = 6.8 Hz, 6H).

[144] Example 9: Preparation of acid (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepine-8-yl)methyl)amino)-3-(1H-imidazol-4-yl)propanoic

[145] The title compound was synthesized similarly to Example 1, except that histidine ethyl ester was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 43%).

[146] 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.54 (s, 1H), 7.28-7.30 (m, 2H), 7.04-7.11 (m, 3H), 6.78 (s, 1H), 6.38 (s, 1H), 3.78 (s, 4H), 3.41-4.11 (m, 2H), 3.18 ( s, 2H), 2.94-2.98 (m, 1H), 1.86 (s, 3H), 1.27-1.43 (m, 4H), 0.82-1.10 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H).

[147] Example 10: Preparation of acid (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepine-8-yl)methyl)amino)-3-(1H-indol-2-yl)propanoic

[148] The title compound was synthesized similarly to Example 1, except that tryptophan ethyl ester was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 37%).

[149] MS: 648.29 [M + H] +.

[150] Example 11: Preparation of acid (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepine-8-yl)methyl)amino)-4-methylpentanoyl

[151] The title compound was synthesized similarly to Example 1, except that leucine ethyl ester was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 58%).

[152] MS: 575.29 [M + H] +.

[153] Example 12: Preparation of acid (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid

[154] The title compound was synthesized similarly to Example 1, except that glutamine diethyl ester was used as the reagent instead of glycine ethyl ester hydrochloride (yield: 25%).

[155] MS: 591.27 [M + H] +.

[156] Example 13: Preparation of acid (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b] [1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic

[157] The title compound was synthesized similarly to Example 1, except that serine diethyl ester was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 45%).

[158] MS: 549.25 [M + H] +.

[159] Example 14: Preparation of 3-((carboxymethyl)((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][ 1,4]thiazepine-8-yl)methyl)amino)propanoic

[160] The title compound was synthesized similarly to Example 1, except that 3-((2-ethoxy-2-oxoethyl)amino)propanoate was used as the reagent instead of glycine methyl ester hydrochloride (yield: 49%).

[161] 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.34-7.43 (m, 2H), 7.27 (s, 2H), 7.12-7.16 (m, 1H), 6.45 (s, 1H), 4.60-4.72 (m, 2H), 4.48-4.59 (m, 2H), 4.004.13 (m, 2H), 3.34 (s, 2H), 3.12-3.23 (m, 2H), 2.14 (s, 3H), 1.36-1.60 (m, 4H), 1.24-1, 30 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H).

[162] Example 15: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-

[163] The title compound was synthesized similarly to Example 1, except that diethyl 2,2'-azanediyldiacetate was used as the reagent instead of glycine ethyl ester hydrochloride (yield: 41%).

[164] 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.10 (t, J = 6.8 Hz, 1H), 6.48 (s, 1H), 4.47 (s, 2H), 4.03 (s, 1H), 3.85 ( m, 2H), 3.29 (s, 2H), 3.06-3.17 (m, 4H), 2.16 (s, 3H), 1.35-1.46 (m, 4H), 1 .23-1.32 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H).

[165] Example 16: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid

[166] 3,3-Dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbonitrile dioxide (160 mg, 0.350 mmol) obtained from Step 5) of Preparation Example 1 was dissolved in 5 ml of a mixed solution (dichloromethane:diethyl ether = 3:2). The resulting mixture was cooled to 0 °C, lithium aluminum hydride (66 mg, 1.752 mmol) was added in divided amounts, and stirred at room temperature for 12 hours. At the end of the reaction, diethyl ether and distilled water were added for extraction, the extract was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane:methanol = 50:1) yielding 40 mg of 8-aminomethyl-3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzoyl dioxide [b][1,4]thiazepine (yield: 25%).

[167] The compound thus obtained (0.023 g, 0.05 mmol) was added to 5 ml of dichloromethane, triethylamine (0.01 ml, 0.1 mmol) and 4-dimethylaminopyridine (0.003 g) were added and stirred. at room temperature for 10 minutes. The reaction solution was cooled to 0°C, ethyl 2-chloro-2-oxoacetate was slowly added, and stirred at room temperature for 18 hours. A solution of ammonium chloride and dichloromethane were added thereto to extract the dichloromethane layer. The extracted dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated. To the concentrated compound (0.02 g) was added tetrahydrofuran (1 ml), methanol (1 ml), distilled water (1 ml), and lithium hydroxide (0.03 g), and stirred at room temperature for 12 hours. Then, 6N HCl and dichloromethane were added for extraction followed by concentration, and the concentrated compound was purified by PTLC (dichloromethane:methanol = 13:1), obtaining 0.015 g of 2-(((3.3 -dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic as the title compound (yield: 78%).

[168] 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.25-7.33 (m, 2H), 6.97 7.11 (m, 3H), 6.50 ( s, 1H), 3.72-4.40 (m, 2H), 3.19 (s, 2H), 2.50-2.68 (m, 2H), 2.06 (s, 3H), 1 .27-1.43 (m, 4H), 0.93-1.20 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H).

[169] Example 17: Preparation of 1-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic

[170] The title compound was synthesized similarly to Example 1, except that ethyl 1-aminocyclopropanecarboxylate was used as a reagent instead of glycine ethyl ester hydrochloride (yield: 52%).

[171] 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.42-7.35 (m, 2H), 7.21 7.15 (m, 2H), 7.13- 7.12 (m, 1H), 6.49 (s, 1H), 4.53 (s, 2H), 3.88 (s, 2H), 3.24 (s, 2H), 2.04 (s , 3H), 1.68-1.61 (m, 2H), 1.55-1.48 (m, 2H), 1.21-0.92 (m, 12H), 0.78-0.71 (m , 6H).

[172] Example 18: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4) acid ]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic

[173] 8-Aminomethyl-3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide was prepared in the same manner as in Example 16 The compound (40 mg, 0.087 mmol) was dissolved in 4 ml of dichloromethane. The resulting mixture was cooled to 0 °C, triethylamine (36 µl, 0.260 mmol) was added slowly dropwise and stirred for 10 minutes. Bromoacetyl chloride (15 µL, 0.174 mmol) was added slowly dropwise and stirred at room temperature for 16 hours. At the end of the reaction, dichloromethane and an ammonium chloride solution were added for extraction, and the extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane:methanol = 30:1), yielding 25 mg of ((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4, 5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)acetamide (yield: 50%).

[174] The compound thus obtained (25 mg, 0.043 mmol) was dissolved in 3 ml of a mixed solution (ethanol: distilled water = 1: 1). Sodium sulfite (271 mg, 2.149 mmol) was added and stirred at 80°C for 17 hours. At the end of the reaction, the resulting product was cooled to room temperature. Ethyl acetate and distilled water were added for extraction, the extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane:methanol = 10:1), yielding 12.5 mg of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl- 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid (yield: 50%).

[175] MS: 583.20 [M + H] +.

[176] Example 19: Preparation of 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b] acid) [1,4]thiazepine-8-yl)methyl)amino)acetic

[177] The title compound was synthesized similarly to Example 1, except that 1-iodo-4-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene (yield: 64%).

[178] 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.13-7.15 (m, 2H), 6.80 6.89 (m, 2H), 6.31 ( s, 1H), 4.22 (s, 2H), 3.70-3.81 (m, 5H), 3.42 (s, 2H), 3.21 (s, 2H), 2.08 (s , 3H), 1.30-1.55 (m, 4H), 0.86-1.06 (m, 8H), 0.71-0.76 (m, 6H).

[179] Example 20: Preparation of 2-(((3,3-dibutyl-5-(4-hydroxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b] acid) [1,4]thiazepine-8-yl)methyl)amino)acetic

[180] The title compound was synthesized similarly to Example 1, except that 4-iodophenol was used in Step 3 of Preparation Example 1 instead of iodobenzene (yield: 37%).

[181] 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8 Hz, 2H) , 6.43 (s, 1H), 4.30 (s, 2H), 3.89-3.93 (m, 4H), 3.30-3.36 (m, 2H), 2.21 (s , 3H), 1.40-1.61 (m, 4H), 1.20-1.29 (m, 8H), 0.81 (t, J = 6.8 Hz, 6H).

[182] Example 21: Preparation of 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b] acid) [1,4]thiazepine-8-yl)methyl)amino)acetic

[183] The title compound was synthesized similarly to Example 1, except that 1-iodo-3-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene (yield: 47%).

[184] 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.27-7.23 (m, 1H), 6.78 6.67 (m, 2H), 6.66- 6.57 (m, 1H), 6.54 (s, 1H), 4.20 (s, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 3.42 (s , 2H), 3.29 (s, 2H), 1.53-1.47 (m, 2H), 1.43-1.32 (m, 2H), 1.24-1.04 (m, 8H ), 0.88-0.78 (m, 6H).

[185] Example 22: Preparation of 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b] acid) [1,4]thiazepine-8-yl)methyl)amino)acetic

[186] The title compound was synthesized similarly to Example 1, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[187] 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.17-7.20 (m, 2H), 7.03 (t, J = 8.4 Hz, 2H), 6.40 (s, 1H), 4.16 (s, 2H), 3.70 (s, 2H), 3.33 (s, 2H), 3.21 (s, 2H), 2.08 (s , 3H), 1.37-1.46 (m, 4H), 0.82-1.06 (m, 8H), 0.77 (t, J = 6.8 Hz, 6H).

[188] Example 23: Preparation of 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b] acid) [1,4]thiazepine-8-yl)methyl)amino)acetic

[189] The title compound was synthesized similarly to Example 1, except that 1-fluoro-3-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[190] 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.23-7.13 (m, 1H), 6.89 6.83 (m, 2H), 6.75- 6.71 (m, 1H), 6.65 (s, 1H), 4.27 (s, 2H), 3.73 (s, 2H), 3.52 (s, 2H), 3.26 (s , 2H), 2.20 (s, 3H), 1.57-1.46 (m, 2H), 1.43-1.33 (m, 2H), 1.26-1.07 (m, 8H ), 0.86-0.78 (m, 6H).

[191] Example 24: Preparation of 2-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic

[192] The title compound was synthesized similarly to Example 1, except that 2-fluoro-4-iodo-1-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[193] 1H NMR (400 MHz, CDCl3) δ 8.10 (brs, 1H), 6.70-6.90 (brs, 3H), 193.1-50 (brs, 1H), 3.90-4.20 (brs, 2H ), 3.30-3.89 (brs, 3H), 3.55-3.29 (brs, 2H), 3.45-2.95 (m, 4H), 1.98-2.22 (brs, 3H), 1.23-1.49 ( m, 4H), 0.73-1.24 (8H), 0.73 (brs, 6H).

[194] Example 25: Preparation of 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b] acid) [1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic

[195] The title compound was synthesized similarly to Example 18, except that 1-iodo-4-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[196] 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.09-6.94 (m, 2H), 6.82 6.64 (m, 2H), 6.27 ( s, 1H), 3.80-3.63 (m, 7H), 3.12 (s, 2H), 2.43 (s, 2H), 1.97 (s, 3H), 1.52-1 .27 (m, 4H), 1.07-0.88 (m, 8H), 0.82-0.78 (m, 6H).

[197] Example 26: Preparation of 1-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5- carboxylic tetrahydrobenzo[b][1,4]thiazepine-8-yl)amino)cyclopropane

[198] The title compound was synthesized similarly to Example 17, except that 2-fluoro-4-iodo-1-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[199] 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 6.98-6.82 (m, 3H), 6.48 (s, 1H), 3.97 (s, 2H ), 3.88 (s, 3H), 3.70 (s, 2H), 3.19 (s, 2H), 2.17 (s, 3H), 1.51-1.32 (m, 4H) , 1.20-0.94 (m, 8H), 0.81-0.78 (m, 6H).

[200] Example 27: Preparation of 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b] acid) [1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid

[201] The title compound was synthesized similarly to Example 16, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[202] 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.10 (br s, 2H), 6.95 (br s, 2H), 6.42 (s, 1H), 4, 22-4.36 (m, 2H), 3.66-3.97 (m, 2H), 3.19-3.47 (m, 2H), 2.07 (s, 3H), 1.30-1, 33 (m, 4H), 0.88-1.12 (m, 8H), 0.75-0.83 (m, 3H).

[203] Example 28: Preparation of acid (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic

[204] The title compound was synthesized similarly to Example 4, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[205] 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.10 (br s, 2H), 6.95 (br s, 2H), 6.42 (s, 1H), 4, 22-4.36 (m, 2H), 3.66-3.97 (m, 2H), 3.19-3.47 (m, 2H), 2.07 (s, 3H), 1.30-1, 33 (m, 4H), 0.88-1.12 (m, 8H), 0.75-0.83 (m, 3H).

[206] Example 29: Preparation of acid (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5- tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic

[207] The title compound was synthesized similarly to Example 13, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[208] 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.17 (br s, 2H), 6.95 (br s, 2H), 6.51 (s, 1H), 4, 36 (br s, 2H), 3.95 (br s, 2H), 6.63 (br s, 2H), 3.46 (s, 1H), 3.26 (brs, 2H), 2.01 (s, 3H), 1.25-1.43 (m, 4H), 0.70-0.87 (m, 8H), 0.59-0.67 (m, 3H).

[209] Example 30: Preparation of 1-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b] acid) [1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic

[210] The title compound was synthesized similarly to Example 17, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[211] 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.17-7.14 (m, 2H), 7.09 7.02 (m, 2H), 6.42 ( s, 1H), 4.11 (s, 2H), 3.77 (s, 2H), 3.22 (s, 2H), 2.15 (s, 3H), 1.68-1.46 (m , 4H), 1.40-1.30 (m, 4H), 1.21-0.92 (m, 8H), 0.88-0.76 (m, 6H).

[212] Test Example 1: Fecal excretion time and efficacy assessment

[213] Eight week old SD mice were purchased and allowed to adapt to breeding conditions under 12 hour lighting at 24°C for 7 days. Rats were fasted for 16 hours prior to the test day, and on the test day were orally administered a vehicle (0.5% methylcellulose) and a test material, which were prepared at a concentration of 0 .2 mg/ml and at a dose of 5 mg/kg, respectively. Thirty minutes after administration, rats fed 3 g of a barium-containing diet were placed in a metabolism cage and observed for 10 hours in order to record the time required for barium to be eliminated in the feces of each rat after it had passed through of the intestines. In addition, the percentage of rats that excreted feces containing barium within 10 hours was calculated. The results are shown in Table 1 below.

[214] [Table 1]

[215] Fecal excretion time:

[216] A: 301 - 400 min, B: 401 - 500 min, C: 501 - 590 min, D: 591 - 600 min

[217] Percentage of rats that excreted faeces within 10 hours (%):

[218] A: 76 - 100%, B: 50 - 75%, C: <50%

[219] The reduction in faecal excretion time and the increase in the percentage of rats that excreted faeces within 10 hours are closely related to relief in constipation symptoms. As can be seen from Table 1, the test rats administered the compounds of the present invention excreted feces within a reduced period of time and, in addition, a significantly higher percentage of the number of rats exhibited fecal excretion within 10 hours than compared to control rats administered a methylcellulose vehicle, which is known to prevent constipation by controlling bowel functions. Furthermore, when the administration dose of the compounds of the present invention was reduced from a level of 1/5 to 1/50, the consequent effects were still equal to or better than those of vehicle administration. This suggests that the compounds of the present invention can effectively prevent or treat constipation.

Claims (13)

1. Compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof: [Formula 1] characterized in that R1 is hydroxy, carboxy, or hydroxysulfonyl(C1-4 alkyl); R2 and R3 are each, independently, hydrogen, C1-4 alkyl, hydroxy(C1-4 alkyl), carbamoyl(C1-4 alkyl), carboxy, carboxy(C1-4 alkyl), (C5-10 heteroaryl)(C1-4 alkyl) C1-4), or (C5-10 aryl)(C1-4 alkyl), or R2 and R3, together with the respective carbon atom to which they are attached, form C3-7 cycloalkylene; R4 is hydrogen or carboxy(C1-4 alkyl); R5 is hydrogen, halogen, (C1-4 alkyl)thio, (C1-4 alkyl)amino, or di(C1-4 alkyl)amino; R6 and R7 are each independently C1-6 alkyl; R8 and R9 are each independently hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, halogen, nitro, cyano, amino, (C1-4 alkyl)amino, di(C1-4 alkyl)amino, acetamido, formyl, C1-4 alkanoyl, carboxy, carbamoyl, (C1-4 alkyl)carbamoyl, di(C1-4 alkyl)carbamoyl, carbamoyloxy, (C1-4 alkyl)carbamoyloxy, di(C1-4 alkyl)carbamoyloxy, (C1 alkyl) -4)sulfonyloxy, sulfamoyloxy, (C1-4alkyl)sulfamoyloxy, or di(C1-4alkyl)sulfamoyloxy; Q is C5-10 aryl or C5-10 heteroaryl; and en be an integer from 0 to 3. Compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R 1 is hydroxy, carboxy, or hydroxysulfonyl(C 1-4 alkyl); R2 and R3 are each independently hydrogen, C1-4 alkyl, hydroxy(C1-4 alkyl), carbamoyl(C1-4 alkyl), carboxy, carboxy(C1-4 alkyl), or (C5-10 heteroaryl)( C1-4 alkyl), or R2 and R3, together with the respective carbon atom to which they are attached, form C3-7 cycloalkylene; R4 is hydrogen or carboxy(C1-4 alkyl); R5 is (C1-4 alkyl)thio; R6 and R7 are each independently C1-6 alkyl; R8 and R9 are each independently hydrogen, hydroxy, halogen, or C1-4 alkoxy; Q is C5-10 aryl; and n being an integer from 0 to 3. Compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that RI is hydroxy, carboxy, or hydroxysulfonylmethyl. 4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R 2 and R 3 are each independently hydrogen, carboxy, methyl, isobutyl, carbamoylmethyl, carboxymethyl, carboxyethyl, hydroxymethyl, imidazolylmethyl, indolylmethyl, or ethyl, or R2 and R3 together with the respective carbon atom to which they are attached form cyclopropylene. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R4 is hydrogen, carboxymethyl, or carboxyethyl. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R5 is methylthio, ethylthio, or dimethylamino. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R6 and R7 are both butyl or both ethyl. 8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R8 and R9 are each, independently, hydrogen, hydroxy, methoxy, methyl, ethyl, fluorine, chlorine, nitro, cyano, amino, methylamino, ethylamino , dimethylamino, acetyl, carboxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, carbamoyloxy, methylcarbamoyloxy, dimethylcarbamoyloxy, methylsulfonyloxy, sulfamoyloxy, methylsulfamoyloxy, or dimethylsulfamoyloxy. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that Q is phenyl, pyridinyl, pyrimidinyl, or thiophenyl. 10. Compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound is selected from the group consisting of: 1) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide) -5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic; 2) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl acid) )methyl)amino)propanoic; 3) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl acid )methyl)amino)succinic; 4) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)propanoic; 5) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl acid) )methyl)amino)pentanedioic acid; 6) 4-amino-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid -8-yl)methyl)amino)-4-oxobutanoic; 7) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)propanoic; 8) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl acid) )methyl)amino)-2-methylpropanoic; 9) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)-3-(1H-imidazol-4-yl)propanoic acid; 10) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)-3-(1H-indol-2-yl)propanoic; 11) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)-4-methylpentanoic; 12) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine) acid -8-yl)methyl)amino)pentanedioic acid; 13) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)-3-hydroxypropanoic; 14) 3-((carboxymethyl)((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine- 8-yl)methyl)amino)propanoic; 15) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl acid) )methyl)amino)pentanedioic acid; 16) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl acid) )methyl)amino)-2-oxoacetic; 17) 1-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl acid) )methyl)amino)cyclopropanecarboxylic acid; 18) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl acid) )methyl)amino)-2-oxoethanesulfonic acid; 19) 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)acetic; 20) 2-(((3,3-dibutyl-5-(4-hydroxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)acetic; 21) 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)acetic; 22) 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)acetic; 23) 2-(((3,3-dibutyl-5-(3-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)acetic; 24) 2-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1) acid ,4]thiazepine-8-yl)methyl)amino)acetic acid; 25) 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)-2-oxoethanesulfonic acid; 26) 1-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1) acid carboxylic ,4]thiazepine-8-yl)methyl)amino)cyclopropane; 27) 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine acid) -8-yl)methyl)amino)-2-oxoacetic; 28) (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1) acid ,4]thiazepine-8-yl)methyl)amino)propanoic acid; 29) (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1) acid ,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic acid; and 30) 1-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxide-2,3,4,5-tetrahydrobenzo[b][1,4] acid) thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid. Compound according to any one of claims 1 to 10, characterized in that it is for preventing or treating constipation. 12. Pharmaceutical composition for the prevention or treatment of constipation, characterized in that it comprises a compound as defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable vehicle, diluent or excipient. Pharmaceutical composition according to claim 12, characterized in that it is for preventing or treating constipation.