KR20220100795A - Novel tryptophan hydroxylase inhibitors and use thereof - Google Patents

Abstract

The present invention relates to a novel oxadiazole phenylalanine derivative and medicinal use thereof. The novel tryptophan hydroxylase inhibitor of the present invention and the pharmaceutical composition containing the same suppress the synthesis of serotonin in the peripheral nervous system by inhibiting the activity of tryptophan hydroxylase 1.

Description

Novel tryptophan hydroxylase inhibitors and use thereof

The present invention relates to novel oxadiazole phenylalanine derivatives and medicinal uses thereof.

Obesity refers to an abnormal or excessive accumulation of adipose tissue in the body. Obesity can be caused by excessive intake of nutrients relative to energy expenditure over a long period of time. A simple index for measuring obesity is body mass index (BMI), which is defined as weight/height squared (kg/m ² ). According to the World Health Organization, adults with a BMI of 30 or more are classified as overweight and obese. In addition, obesity has been classified as a disease since 2013, and may cause complications such as type 2 diabetes, cardiovascular disease, high blood pressure, stroke, colorectal cancer, breast cancer, and ovarian cancer.

The treatment methods for obesity include diet, exercise, drug treatment, and surgical methods. Specifically, the drug used for drug treatment can be classified into an anti-obesity agent acting on the central nerve and an anti-obesity agent acting on the peripheral nerve. Existing obesity treatment is a treatment that suppresses appetite by suppressing serotonin present in the central nervous system. However, serotonin, present in the central nervous system, can affect mood, sleep and memory in addition to appetite. On the other hand, side effects such as headache, agitation, tension, and depression have been reported for existing anti-obesity drugs acting on the central nervous system.

Serotonin is a monoamine-based compound that acts on the central nervous system and the peripheral nervous system, and its synthesis starts from tryptophan, an amino acid, and the synthesis proceeds in the order of hydroxylation and decarboxylation of tryptophan. In this process, tryptophan hydroxlase (TPH) may act as a rate-regulating enzyme. This suggests that the synthesis of serotonin can be inhibited by inhibiting tryptophan hydroxylase.

This serotonin does not pass through the blood brain barrier (BBB), and is synthesized in the central nervous system and the peripheral nervous system, respectively. There are two isoforms of tryptophan hydroxylase. Of these, tryptophan hydroxylase 1 (TPH1) is mainly expressed in peripheral tissues, and tryptophan hydroxylase 2 (TPH2) is a neurotransmitter in the intestine and central nervous system. expressed in cells. Since the serotonin cannot cross the blood-brain barrier (BBB), the peripheral serotonin system is functionally distinct from the central serotonin system. In the peripheral nervous system, serotonin plays an important role in the metabolic regulation of peripheral tissues.

Specifically, when serotonin is excessively secreted from peripheral tissues, it interferes with the activity of brown fat cells that burn energy. Therefore, inhibiting the synthesis of serotonin present in the peripheral nervous system can activate the metabolism of peripheral tissues. have.

Crane, J. D. et al., Nature Medicine, 2015, 21(2): 166-172.

One object of the present invention is to provide a novel oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a composition for inhibiting tryptophan hydroxylase comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for preventing or treating a metabolic disease comprising administering the pharmaceutical composition to an individual in need thereof.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, comprising the oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for preventing or treating cancer, comprising administering the pharmaceutical composition to an individual in need thereof.

Each description and embodiment disclosed in the present invention is also applicable to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be said that the scope of the present invention is limited by the specific descriptions described below.

In addition, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Also, such equivalents are intended to be encompassed by the present invention.

In addition, throughout the specification of the present invention, when a part "includes" a certain component, it does not exclude other components unless otherwise stated, but may further include other components. it means.

Hereinafter, the present invention will be described in more detail.

A first aspect of the present invention provides a compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

n is an integer from 0 to 2,

R ₁ is hydroxy, amino, C _1-6 alkoxy, hydroxy-C _1-4 alkoxy, or hydroxy-amino,

R ₂ To R ₆ are each independently hydrogen, hydroxy, nitro, cyano, halo, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-4 alkylamino, di( C _1-4 alkyl)amino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonylamino, C _6-10 arylcarbonylamino, C _6-14 aryl, C _6-10 aryl-C _1-4 alkyl, C _6-10 aryl-C _1-4 alkoxy, C _1-4 alkoxy-C _6-10 aryl, or

R ₃ and R ₄ are linked to each other to C _3-14 heterocyclyl, or form C _5-14 heteroaryl;

wherein said aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C _1-4 alkoxy, or C _1-4 haloalkyl.

For example, in Formula 1, n may be 0 or 1, but is not limited thereto.

For example, in Formula 1, R ₁ may be hydroxy, amino, ethoxy, hydroxyethoxy, or hydroxyamino, but is not limited thereto.

For example, in Formula 1, R ₂ may be hydrogen, phenyl, hydroxyphenyl, or methoxyphenyl, but is not limited thereto.

For example, in Formula 1, R ₃ may be hydrogen, bromo, nitro, methoxy, phenyl, hydroxyphenyl, or methoxyphenyl, but is not limited thereto.

For example, in Formula 1, R ₄ is hydrogen, hydroxy, nitro, cyano, fluoro, bromo, iodo, methoxy, ethoxy, acetyl, methylcarbonylamino, phenylcarbonylamino, phenylmethoxy , phenylmethyl, dimethylamino, trifluoromethyl, or trifluoromethoxy, but is not limited thereto.

Alternatively, R ₃ and R ₄ may be connected to each other to form dioxolanyl, dioxanyl, pyrazolyl, pyrroline, or benzofuranyl, but is not limited thereto.

For example, in Formula 1, R ₅ and R ₆ may both be hydrogen, but is not limited thereto.

Specifically, the compound is

1. (S)-2-amino-3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-( 4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

2. (S)-2-amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

3. (S)-2-amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

4. (S)-2-amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

5. (S)-2-amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

6. (S)-2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

7. (S)-2-amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

8. (S)-2-amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

9. (S)-2-amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

10. (S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

11. (S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

12. (S)-2-amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

13. (S)-3-(4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S)-3- (4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),

14. (S)-2-amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2- amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

15. (S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

16. (S)-2-amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

17. (S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

18. (S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

19. (S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

20. (S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

21. (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),

22. (S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanamide ((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide),

23. (S)-2-Amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanamide ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl )propanamide),

24. (S)-Ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole-3- yl)phenyl)propanoate ((S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3- yl)phenyl)propanoate),

25. (S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

26. (S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),

27. (S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

28. (S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),

29. (S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

30. (S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

31. (S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),

32. (S)-3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S) -3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),

33. (S)-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S) )-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),

34. (S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadia zol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1, 2,4-oxadiazol-3-yl)phenyl)propanoic acid),

35. (S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl) Phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl) phenyl) propanoic acid),

36. (S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propane acid ((S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

37. (S)-2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

38. (S)-2-amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2- amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

39. (S)-2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

40. (S)-3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S)- 3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),

41. (S)-2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)- 2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),

42. (S)-2-Amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadia zol-3-yl)phenyl)propanamide ((S)-2-amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2, 4-oxadiazol-3-yl)phenyl)propanamide), or

43. (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)-N-(2-hydroxyethoxy)propanamide ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1, 2,4-oxadiazol-3-yl)phenyl)-N-(2-hydroxyethoxy)propanamide), but is not limited thereto.

For example, the compound of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid value formed by a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" refers to a concentration having an effective action that is relatively non-toxic and harmless to a patient. any and all organic or inorganic addition salts.

Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and an acid or alcohol (eg glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.

At this time, organic acids and inorganic acids can be used as free acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid as organic acids (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , but not limited to these.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate. , dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like, and preparation of salts known in the art It can be prepared through a method.

The oxadiazole phenylalanine derivative or salt of an isomer thereof of the present invention is a pharmaceutically acceptable salt, if it is an oxadiazole phenylalanine derivative or a salt of an isomer thereof that exhibits pharmacological activity equivalent to that of the oxadiazole phenylalanine derivative or an isomer thereof. All are available without restrictions.

In addition, the compounds of the present invention include, without limitation, pharmaceutically acceptable salts thereof, as well as solvates such as possible hydrates and all possible stereoisomers that can be prepared therefrom. Solvates and stereoisomers of the compounds can be prepared from the compounds of the present invention using methods known in the art.

Furthermore, the compounds of the present invention may be prepared in crystalline or amorphous form, and when prepared in crystalline form, may optionally be hydrated or solvated. In the present invention, not only stoichiometric hydrates of the above compounds, but also compounds containing various amounts of water may be included. Solvates of the compounds of the present invention include both stoichiometric and non-stoichiometric solvates.

A second aspect of the present invention is a first step of synthesizing a compound represented by Formula 4 by reacting a compound represented by Formula 2 with a compound represented by Formula 3; and a second step of converting the compound represented by Formula 4 obtained from the previous step into the compound represented by Formula 1; provides a method for preparing a compound represented by Formula 1, including:

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

In Formulas 1 to 4,

n is an integer from 0 to 2,

R ₁ is hydroxy, amino, C _1-6 alkoxy, hydroxy-C _1-4 alkoxy, or hydroxy-amino,

R ₂ To R ₆ are each independently hydrogen, hydroxy, nitro, cyano, halo, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-4 alkylamino, di( C _1-4 alkyl)amino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonylamino, C _6-10 arylcarbonylamino, C _6-14 aryl, C _6-10 aryl-C _1-4 alkyl, C _6-10 aryl-C _1-4 alkoxy, C _1-4 alkoxy-C _6-10 aryl, or

R ₃ and R ₄ are linked to each other to C _3-14 heterocyclyl, or form C _5-14 heteroaryl;

R ₂ ' to R ₆ ' are each the same as R ₂ to R ₆ or a precursor thereof,

wherein said aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C _1-4 alkoxy, or C _1-4 haloalkyl.

As used herein, the term "pharmaceutically acceptable salt" is as described above.

For example, in the reaction of the first step, the reactant is reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (hydroxybenzotriazole; HOBt), and N,N-diisopropylethylamine (N,N-diisopropylethylamine; DIPEA) in the presence of 10 to 35 ℃ reacted for 12 to 24 hours, the obtained product was refluxed for 12 to 24 hours can be performed, but is not limited thereto. The reaction may be performed on a solution dissolved in an organic solvent, and the solvents used in each reaction may be the same or different from each other. For example, a material produced as an intermediate may be isolated and/or purified and used in a subsequent reaction, or may be used in a subsequent reaction as a crude product without additional treatment. For example, in one embodiment of the present invention, the product obtained by reacting with EDCI, HOBt, and DIPEA in a dichloromethane solution is isolated and purified to obtain a white solid, and then it is dissolved in 1,4-dioxane to carry out the reaction did. However, this is only an example of a synthesis method, and the scope of the present invention is not limited thereto.

For example, in the compound represented by Formula 2, a compound including a substituent bonded to R ₂ ' to R ₆ ' through an aryl group is a boronic acid derivative of R ₂ ' to R ₆ ', in which a halogen is It may be prepared by reaction with a substituted derivative of the compound of Formula 2, but is not limited thereto.

The reaction may be performed similarly to the series of reactions exemplified below, but is not limited thereto. The reaction exemplified below is a synthesis example for a compound having a specific substituent, and the scope of the present invention is not limited thereto.

[Step a1]

[Step a2]

[Step a3]

For example, the compound represented by Formula 3 may be prepared from (S)-2-amino-3-(4-cyanophenyl)propanoic acid, but is not limited thereto.

The reaction may be performed similarly to the series of reactions exemplified below, but is not limited thereto. The reaction exemplified below is a synthesis example for a compound having a specific substituent, and the scope of the present invention is not limited thereto.

[Step b1]

[Step b2]

[Step b3]

The compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof may be prepared through a series of reactions exemplified by Scheme 1 or 2 below, but is not limited thereto:

[Scheme 1]

[Scheme 2]

.

.

Schemes 1 and 2 are only specific examples of the preparation method, and the scope of the present invention is not limited thereto.

A third aspect of the present invention provides a composition for inhibiting tryptophan hydroxylase, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

A fourth aspect of the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

A fifth aspect of the present invention provides a method for preventing or treating a metabolic disease, comprising administering the pharmaceutical composition of the fourth aspect to an individual in need thereof.

A sixth aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound of the first aspect, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

A seventh aspect of the present invention provides a method for preventing or treating cancer, comprising administering the pharmaceutical composition of the sixth aspect to an individual in need thereof.

As used herein, the term "prevention" refers to any action that inhibits or delays the occurrence, spread, and recurrence of metabolic or cancer diseases by administration of the composition of the present invention, and "treatment" refers to any action by administration of the composition of the present invention. It refers to any action that improves or beneficially changes the symptoms of the above disease.

The pharmaceutical composition of the present invention can prevent or treat diseases related thereto by inhibiting the activity of tryptophan hydroxylase. Specifically, the pharmaceutical composition of the present invention can activate metabolism by inhibiting the activity of tryptophan hydroxylase, in particular, TPH1, thereby inhibiting serotonin synthesis in the peripheral nervous system. Therefore, the pharmaceutical composition of the present invention can exhibit the effect of suppressing weight gain without stimulating the brain or suppressing appetite through the above mechanism. On the other hand, serotonin is known to promote the progression of cancer diseases by various mechanisms. As described above, inhibition of serotonin expression through inhibition of TPH1 activity prevents or treats cancer diseases by inhibiting the promotion of cancer diseases by serotonin. can

As used herein, the term "tryptophan hydroxylase" refers to an enzyme involved in the synthesis of serotonin (5-hydroxytryptamine; 5-HT), a monoamine neurotransmitter, which hydroxylates tryptophan to 5 -Can produce hydroxytryptophan. The tryptophan hydroxylase, together with tyrosine hydroxylase and phenylalanine hydroxylase, constitute a family of biopterin-dependent aromatic amino acid hydroxylases. There are two distinct TPH genes, TPH1 and TPH2 , in humans as well as other mammals, which are present on chromosomes 11 and 12 and encode two other different homologous enzymes, TPH1 and TPH2, respectively. For example, TPH1 is expressed in tissues that express serotonin in the periphery (eg, skin, gut and pineal gland, etc.) but is also expressed in the central nervous system, whereas TPH2 is exclusively expressed in neuronal cell types. It is the predominant isoform in the central nervous system.

For example, metabolic diseases that can be prevented or treated with the pharmaceutical composition of the present invention may be obesity, hypertension, arteriosclerosis, diabetes, insulin resistance, hepatic steatosis, fatty liver disease, dyslipidemia, and the like.

For example, cancer diseases that can be prevented or treated by the pharmaceutical composition of the present invention include colorectal cancer, colon cancer, cholangiocarcinoma, bile duct carcinoma, lung cancer, gastric cancer. , breast cancer, pancreatic cancer, urinary bladder cancer, prostate cancer, ovarian cancer, placental cancer, choriocarcinoma, squamous epithelium Esophageal squamous cell cancer, glioblastomas, melanomas, renal carcinomas, cervical squamous cell carcinomas, hepatocellular carcinomas, and cervical intraepithelial tumors (cervical intraepithelial neoplasia), etc.

However, diseases that can be prevented or treated using the pharmaceutical composition of the present invention are not limited thereto, and any disease capable of exhibiting a preventive or therapeutic effect by inhibiting tryptophan hydroxylase activity may be included in the scope of the present invention.

Preferably, the pharmaceutical composition according to the present invention contains, as an active ingredient, the compound represented by Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 75% by weight based on the total weight of the composition, more preferably may be contained in an amount of 1 to 50% by weight.

The composition of the present invention may further include a pharmaceutically acceptable carrier, diluent, or excipient, and may include powders, granules, tablets, capsules, suspensions, emulsions, syrups, It can be formulated and used in various forms such as oral dosage forms such as aerosols, injections of sterile injection solutions, etc., and can be administered orally or administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like. Examples of suitable carriers, excipients or diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, and cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition, the composition of the present invention may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a fragrance, an emulsifier, a preservative, and the like.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. are mixed and formulated. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

Liquid formulations for oral use may include suspensions, solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents, may be included. can

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. The suppositories are Witepsol, Macrogol, and Twin61. Cacao butter, laurin fat, glycerogelatin, etc. may be used. On the other hand, the injection may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, and the like.

At this time, 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 a disease at a reasonable benefit/risk ratio applicable to medical treatment and not to cause side effects, and the effective dose level depends on the patient's health condition, disease type, severity, drug activity, sensitivity to drug, administration method, administration time, administration route and excretion rate, duration of treatment, factors including drugs used in combination or concomitantly, and other factors well known in the medical field. can The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.

For example, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and thus the dosage is not intended to limit the scope of the present invention in any way.

Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 100 mg per kg of body weight, preferably 5 to 60 mg, is administered daily or every other day, or 1 It can be administered in divided doses 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.

As used herein, the term "individual" means monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, It means all animals, including cats, dogs, mice, mice, rabbits, or guinea pigs, and by administering the pharmaceutical composition of the present invention to an individual, the disease can be effectively prevented or treated. The pharmaceutical composition of the present invention may be administered in parallel with a conventional therapeutic agent.

The term "administration" of the present invention means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. have. Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, may be administered intrarectally, but is not limited thereto. In addition, the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell. Preferred administration modes and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like. For injections, aqueous solvents such as physiological saline solution and Ringer's solution, vegetable oil, higher fatty acid esters (eg, ethyl oleate), and non-aqueous solvents such as alcohols (eg, ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) Stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, to inhibit microbial growth Pharmaceutical carriers such as preservatives (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.

The term "therapeutically effective amount" used in combination with an active ingredient in the present invention means an amount of an oxadiazole phenylalanine derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof effective for preventing or treating a target disease.

The pharmaceutical composition of the present invention may be used for the prevention or treatment of known diseases other than oxadiazole phenylalanine derivatives, isomers thereof, or pharmaceutically acceptable salts thereof as an active ingredient, depending on the type of disease to be prevented or treated. It may further include a known drug used. For example, when used for the prevention or treatment of cancer diseases, as an active ingredient, an oxadiazole phenylalanine derivative, an isomer thereof, or a known drug in addition to a pharmaceutically acceptable salt thereof may be additionally included, and the treatment of these diseases It can be used in combination with other treatments known for

The novel tryptophan hydroxylase inhibitor of the present invention and a pharmaceutical composition comprising the same inhibit the synthesis of serotonin in the peripheral nervous system by inhibiting the activity of tryptophan hydroxylase 1. Therefore, it does not stimulate the central nervous system and activates the metabolic activity of peripheral tissues, so it can be usefully used for the prevention or treatment of metabolic diseases.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Preparation Example 1: (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole-3 Preparation of -yl)phenyl)propanoic acid hydrochloride

Step 1-1: Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid

(S)-2-amino-3-(4-cyanophenyl)propanoic acid (3.0 g, 15.773 mmol) and sodium hydrogen carbonate (3.98 g, 47.32 mmol) were dissolved in 20 mL of 1,4-dioxane. The reaction mixture was cooled to 0 °C and 1,4-dioxane (200 mL) in di-tert-butyl dicarbonate (5.16 g, 23.66 mmol) was slowly added dropwise to the reaction mixture at 0 °C over 1 hour. The reaction mixture was allowed to reach room temperature and stirred for 18 h. After completion of the reaction, the solvent was removed in vacuo, and 5% KHSO ₄ aqueous solution was added to the residue, followed by extraction with ethyl acetate. The organic phase of the extract was washed with brine and dried over anhydrous sodium sulfate. The dried extract was concentrated in vacuo and filtered to beige (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (3.31 g, 70%) by filtration. obtained as a solid.

Step 1-2: Preparation of ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate

The obtained (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid (3.31 g, 11.40 mmol) and potassium carbonate (3.15 g, 22.80 mmol) It was sequentially added to a solution in DMF (10 mL) at 0 °C. To this mixture was added iodoethane (1.1 mL, 13.68 mmol) slowly and the reaction mixture was allowed to reach room temperature and stirred for 16 h. After completion of the reaction, water was added to the resulting mixture, followed by extraction with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The reaction mixture was purified by column chromatography to give ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate (3.42 g, 94%) as a white solid. was obtained with

Step 1-3: Preparation of (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(N'-hydroxycarbamimidoyl)phenyl)propanoate

Ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoate (2.5 g, 7.85 mmol), hydroxylamine hydrochloride (1.64 g, 23.56 mmol) and triethylamine (5.48 mL, 39.26 mmol) was dissolved in ethanol (20 mL) and stirred under reflux for 2 hours. After the reaction mixture was cooled to room temperature, the volume was reduced by evaporation, water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The product was purified by silica gel column chromatography with ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(N-hydroxycarbamiimidoyl)phenyl)propanoate (2.49 g , 90%) as a white solid.

Step 1-4: Preparation of methyl 4'-hydroxy-6-methoxybiphenyl-3-carboxylate

Methyl 3-bromo-4-methoxybenzoate (3.9 g, 15.91 mmol), (4-hydroxyphenyl)boronic acid (2.41 g, 17.51 mmol), tetrakis(tri 2M potassium carbonate solution (6.60 g, 47.74 mmol) was added dropwise to a solution of phenylphosphine) palladium (0) (919.49 mg, 0.80 mmol), followed by stirring at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, the mixture was extracted with ethyl acetate and water. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography to obtain methyl 4'-hydroxy-6-methoxybiphenyl-3-carboxylate (2.875 g, 70%) as a white solid.

Step 1-5: Preparation of 4'-hydroxy-6-methoxybiphenyl-3-carboxylic acid

To a solution of methyl 4'-hydroxy-6-methoxybiphenyl-3-carboxylate (2.88 g, 11.13 mmol) in 20 mL of THF, 2M sodium hydroxide solution was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the reaction, THF was removed from the mixture under vacuum, and acidified to pH 2 with 1 N hydrochloric acid. Then, additionally 50 mL of water was added to the mixture, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography to obtain 4'-hydroxy-6-methoxybiphenyl-3-carboxylic acid as a white solid (1.83 g, 67%).

Step 1-6: Preparation of 4'-acetoxy-6-methoxybiphenyl-3-carboxylic acid

A mixture of 4'-hydroxy-6-methoxybiphenyl-3-carboxylic acid (1.83 g, 7.49 mmol) and pyridine (4.83 mL, 59.94 mmol) in dichloromethane (20 mL) was cooled to 0 °C. and acetyl chloride (3.73 mL, 52.45 mmol) was added dropwise. The reaction mixture was allowed to reach room temperature and stirred for 18 h. After completion of the reaction, the mixture was extracted with dichloromethane and water. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography to obtain 4'-acetoxy-6-methoxybiphenyl-3-carboxylic acid as a white solid (1.185 g, 55%).

Step 1-7: (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamiimidoyl)phenyl)-2-(tert-butoxy Preparation of carbonylamino) propanoate

4′-acetoxy-6-methoxybiphenyl-3-carboxylic acid (1.185 g, 4.139 mmol), (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(N) '-Hydroxycarbamimidoyl) phenyl) propanoate (1.75 g, 4.97 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; EDCI, 1.98 g, 10.35 mmol), hydroxybenzotriazole hydrate (HOBt, 950.78 mg, 6.21 mmol) and N,N-diisopropylethylamine (N,N-diisopropylethylamine; DIPEA, 2.50 mL, 14.49 mmol) was dissolved in dichloromethane (20 mL) and stirred at room temperature for 18 hours. After the reaction, the mixture was diluted with water and extracted with dichloromethane. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamiimidoyl)phenyl)-2 -(tert-butoxycarbonylamino)propanoate (2.45 g, 96%) was obtained as a white solid.

Step 1-8: (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-(tert-butoxy Preparation of carbonylamino) propanoate

(S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-(tert-butoxycarbonylamino)prop Panoate (2.45 g, 3.96 mmol) was dissolved in 1,4-dioxane (10 mL) and the reaction mixture was refluxed for 18 h. After the reaction mixture was cooled to room temperature, the residue was extracted with ethyl acetate and water, and dried over anhydrous sodium sulfate. The reaction mixture was purified by column chromatography (S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)-2-( tert-butoxycarbonylamino)propanoate (1.94 g, 78%) was obtained as a white solid.

Step 1-9: (S)-2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1, Preparation of 2,4-oxadiazol-3-yl)phenyl)propanoic acid

(S)-ethyl 3-(4-(N'-(4'-acetoxy-6-methoxybiphenylcarbonyloxy)carbamimidoyl)phenyl)- in 50 mL of THF/water (3:1) To a solution of 2-(tert-butoxycarbonylamino)propanoate (1.94 g, 3.23 mmol), an aqueous solution of sodium hydroxide (50.27 mg, 1.26 mmol) was added. The mixture was stirred with acid hydrochloride at ambient temperature for 24 hours. After the reaction, THF was removed from the mixture under vacuum, and acidified to pH 4 with 1 N hydrochloric acid. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography (S)-2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3) -yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (1.58 g, 92%) was obtained as a white solid.

Step 1-10: (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- Preparation of 3-yl)phenyl)propanoic acid hydrochloride

(S)-2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1 in 10 mL of ethyl acetate To a solution in which ,2,4-oxadiazol-3-yl)phenyl)propanoic acid (600 mg, 1.13 mmol) was added, 5 mL of 4.0 M HCl in 1,4-dioxane solution was added dropwise. After that, the mixture was stirred for 12 hours. After the reaction was completed, the mixture was concentrated to a minimum volume and the concentrate was collected by filtration (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl) )-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride (510 mg, 97%) was obtained as a white solid.

Preparation 2: (S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- Preparation of 3-yl)phenyl)propanoate hydrochloride

Step 2-1: (S)-Ethyl 2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1 Preparation of ,2,4-oxadiazol-3-yl)phenyl)propanoate

(S)-ethyl 3-(4-(5-(4'-acetoxy-6-methoxy-biphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)- 2-((tert-butoxycarbonyl)amino)propanoate (130 mg, 0.22 mmol) and sodium hydrogen carbonate (181.51 mg, 2.16 mmol) were dissolved in ethanol (5 mL) and stirred at room temperature for 18 hours. . After the reaction, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography (S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-) 3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate (100 mg, 83%) was obtained as a white solid.

Step 2-2: (S)-Ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole Preparation of -3-yl)phenyl)propanoate hydrochloride

(S)-ethyl 2-(tert-butoxycarbonylamino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)- in 5 mL of ethyl acetate To a solution in which 1,2,4-oxadiazol-3-yl)phenyl)propanoate (100 mg, 0.18 mmol) was added, 5 mL of 4.0 M HCl in 1,4-dioxane solution was added dropwise. After that, the mixture was stirred for 12 hours. After the reaction, the mixture was concentrated to a minimum volume, and the concentrate was collected by filtration, (S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3- yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate hydrochloride (83 mg, 94%) was obtained as a white solid.

Preparation 3: (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole-3 Preparation of -yl)phenyl)propanamide hydrochloride

Step 3-1: (S)-tert-Butyl 1-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxa Preparation of diazol-3-yl)phenyl)-1-oxopropan-2-ylcarbamate

(S)-2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4 -oxadiazol-3-yl)phenyl)propanoic acid (250 mg, 0.47 mmol), EDCI (270.47 mg, 1.411 mmol) and HOBt (144.04 mg, 0.94 mmol) were dissolved in THF (5 mL) and stirred at room temperature. After 0.5 h, ammonium hydroxide (80.09 mg, 4.703 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. After the reaction was completed, the solvent was removed in vacuo, and the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer of the extract was washed with brine, dried over sodium sulfate, and then concentrated. The concentrated material was purified by column chromatography (S)-tert-butyl 1-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1 ,2,4-oxadiazol-3-yl)phenyl)-1-oxopropan-2-ylcarbamate (87 mg, 35%) was obtained as a white solid.

Step 3-2: (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- Preparation of 3-yl)phenyl)propanamide hydrochloride

(S)-tert-Butyl 1-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4- in 5 mL of ethyl acetate To a solution in which oxadiazol-3-yl)phenyl)-1-oxopropan-2-ylcarbamate (87 mg, 0.16 mmol) was added, 5 mL of 4.0 M HCl in 1,4-dioxane solution was added dropwise. After that, the mixture was stirred for 12 hours. After the reaction was completed, the mixture was concentrated to a minimum volume and the concentrate was collected by filtration (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl) )-1,2,4-oxadiazol-3-yl)phenyl)propanamide hydrochloride (68 mg, 89%) was obtained as a white solid.

A total of 43 compounds (Examples 1 to 43) were prepared in a manner similar to Preparation Examples 1 to 3, and the chemical structural formulas and compound names of the synthesized compounds are shown in Table 1 below.

Example chemical structural formula compound name One

(S)-2-amino-3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 2

(S)-2-amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 3

(S)-2-amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 4

(S)-2-amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 5

(S)-2-amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 6

(S)-2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 7

(S)-2-amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 8

(S)-2-amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 9

(S)-2-amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 10

(S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 11

(S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 12

(S)-2-amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 13

(S)-3-(4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid hydrochloride 14

(S)-2-amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 15

(S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 16

(S)-2-amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 17

(S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 18

(S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 19

(S)-2-amino-3-(4-(5-(4′,6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 20

(S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 21

(S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid hydrochloride 22

(S)-2-amino-3-(4-(5-(4′,6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide hydrochloride 23

(S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanamide hydrochloride 24

(S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl) Phenyl)propanoate hydrochloride 25

(S)-2-amino-3-(4-(5-(3′,6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 26

(S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid hydrochloride 27

(S)-2-amino-3-(4-(5-(2′,6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 28

(S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid hydrochloride 29

(S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 30

(S)-2-amino-3-(4-(5-(4′,5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 31

(S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid hydrochloride 32

(S)-3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid hydrochloride 33

(S)-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid hydrochloride 34

(S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadiazole- 3-yl)phenyl)propanoic acid hydrochloride 35

(S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid hydrochloride 36

(S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 37

(S)-2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 38

(S)-2-amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 39

(S)-2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 40

(S)-3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid hydrochloride 41

(S)-2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid hydrochloride 42

(S)-2-amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole- 3-yl)phenyl)propanamide hydrochloride 43

(S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl )-N-(2-hydroxyethoxy)propanamide hydrochloride

Experimental Example 1: Identification of the synthesized compound

The compounds of Examples 1 to 43 synthesized through Preparation Examples were identified by analysis by nuclear magnetic resonance (NMR) or liquid chromatography-mass spectrometry (LC-MS). The results measured for each compound are shown in Table 2 below.

Example LCMS or NMR One ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.48 (s, 3H), 8.20 (d, J = 7.3 Hz, 2H), 8.06 (d, J = 7.9 Hz, 2H), 7.77-7.66 (m, 3H), 7.52 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.24 (d, J = 6.1 Hz, 2H) 2 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (s, 3H), 8.14 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 9.2 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.89 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H) 3 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.47 (s, 3H), 8.06 (d, J = 8.2 Hz, 2H), 7.77 (dt, J = 7.7, 1.1 Hz, 1H), 7.66 (q, J = 1.3 Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.32 (ddd, J = 8.3, 2.7, 0.8 Hz, 1H), 4.22 ( t, J = 6.6 Hz, 1H), 3.89 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H) 4 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.69 (s, 1H), 8.47 (s, 3H), 8.02 (d, J = 8.7 Hz, 4H), 7.50 (d, J = 7.8 Hz, 2H) , 7.02 (d, J = 8.7 Hz, 2H), 4.20 (t, J = 5.5 Hz, 1H), 3.22 (d, J = 5.5 Hz, 2H) 5 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.46 (s, 3H), 8.12 (d, J = 8.5 Hz, 2H), 8.04 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 4.22 (t, J = 5.3 Hz, 1H), 4.16 (q, J = 6.9 Hz, 2H), 3.23 (d, J = 5.8 Hz) , 2H), 1.37 (t, J = 6.9 Hz, 3H) 6 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.48 (s, 3H), 8.05 (d, J = 8.2 Hz, 2H), 7.80 (dd, J = 8.5, 2.1 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 1H), 4.22 (t, J = 6.4 Hz, 1H), 3.90 (s, 3H) , 3.89 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H) 7 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.46 (s, 3H), 8.24-8.29 (m, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.51-7.56 (m, 4H), 4.24 (t, J = 6.5 Hz, 1H), 3.23 (d, J = 6.6 Hz, 2H) 8 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.48 (s, 2H), 8.12 (dt, J = 8.9, 2.1 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.89 (dt, J = 9.0, 2.1 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 4.23 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 9 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (s, 3H), 8.06 (t, J = 7.6 Hz, 4H), 7.94 (d, J = 6.9 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 4.24 (t, J = 5.9 Hz, 1H), 3.22 (d, J = 5.7 Hz, 2H) 10 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.48 (s, 3H), 8.40 (d, J = 8.2 Hz, 2H), 8.06 (t, J = 7.9 Hz, 4H), 7.53 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 11 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.48 (s, 3H), 8.33 (dt, J = 9.6, 2.4 Hz, 2H), 8.06 (d, J = 8.5 Hz, 2H), 7.67 (dd, J = 9.2, 0.9 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 12 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.46 (s, 3H), 8.26 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 4.21 (t, J = 6.1 Hz, 1H), 3.23 (d, J = 6.1 Hz, 2H) 13 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.46 (s, 3H), 8.26 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 4.21 (t, J = 6.1 Hz, 1H), 3.23 (d, J = 6.1 Hz, 2H) 14 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.54 (s, 23H), 8.49 (dd, J = 6.9, 2.3 Hz, 2H), 8.44 (dd, J = 6.9, 2.3 Hz, 2H), 8.07 ( d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.25 (d, J = 6.5 Hz, 2H) 15 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.99 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.47 (s, 3H), 8.44 (dd, J = 8.9, 2.1 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 1H) , 4.06 (s, 3H), 3.23 (d, J = 6.4 Hz, 2H) 16 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.42 (s, 3H), 7.93 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.31 (dt, J = 9.5, 2.5 Hz, 2H), 6.93 (dt, J = 9.5, 2.5 Hz, 2H), 4.36 (s, 2H), 4.20 (t, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.20 ( d, J = 6.4 Hz, 2H) 17 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.47 (s, 3H), 8.33 (d, J = 2.1 Hz, 1H), 8.19 (dd, J = 8.9, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.9 Hz, 1H), 4.24 (t, J = 6.4 Hz, 1H), 3.99 (s, 3H) , 3.23 (d, J = 6.4 Hz, 2H) 18 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (s, 3H), 8.19 (dd, J = 8.5, 2.1 Hz, 1H), 8.03-8.06 (m, 3H), 7.55 (d, J = 7.0) Hz, 2H), 7.46-7.51 (m, 4H), 7.39-7.42 (m, 2H), 4.23 (t, J = 6.3 Hz, 1H), 3.90 (s, 3H), 3.22 (d, J = 6.4 Hz) , 2H) 19 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.46 (s, 3H), 8.15 (dd, J = 8.8, 2.3 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 2.3 Hz, 1H), 7.48-7.51 (m, 4H), 7.37 (d, J = 9.2 Hz, 1H), 7.03 (dt, J = 9.4, 2.6 Hz, 2H), 4.23 (t, J = 6.5) Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.22 (d, J = 6.5 Hz, 2H) 20 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (s, 3H), 8.35 (t, J = 1.7 Hz, 1H), 8.12 (dt, J = 8.1, 1.3 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 8.00 (dq, J = 7.9, 1.0 Hz, 1H), 7.71-7.76 (m, 3H), 7.53 (d, J = 8.0 Hz, 2H), 7.09 (dt, J = 9.5) , 2.5 Hz, 2H), 4.24 (t, J = 6.3 Hz, 1H), 3.23 (d, J = 6.5 Hz, 2H) 21 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 8.44 (s, 3H), 8.12 (dd, J = 8.5, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.38 (dt, J = 9.2, 2.3 Hz, 2H), 7.35 (d, J = 8.9 Hz, 1H), 6.86 (dt, J = 9.2, 2.3 Hz, 2H), 4.23 (t, J = 6.4 Hz, 1H), 3.89 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H) 22 LCMS [M+H] 445.18 23 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 8.23 (s, 3H), 8.13 (dd, J = 8.5, 2.3 Hz, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.38 (dt, J = 8.4, 2.8) Hz, 2H), 7.35 (d, J = 8.7 Hz, 1H), 6.86 (dt, J = 8.4, 2.8 Hz, 2H), 4.02 (t, J = 6.9 Hz, 1H), 3.89 (s, 3H), 3.20 (dd, J = 13.7, 6.0 Hz, 1H), 3.10 (dd, J = 13.9, 7.4 Hz, 1H) 24 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 8.59 (s, 3H), 8.13 (dd, J = 8.8, 2.3 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.37-7.40 (dt, J = 8.4, 3.2 Hz, 2H), 7.35 (d, J = 9.2) Hz, 1H), 6.86 (dt, J = 8.4, 3.2 Hz, 2H), 4.34 (t, J = 6.7 Hz, 1H), 4.10-4.20 (m, 2H), 3.90 (s, 3H), 3.28 (dd , J = 13.9, 5.9 Hz, 1H), 3.17 (dd, J = 13.9, 7.8 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H) 25 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (s, 3H), 8.19 (dd, J = 8.7, 2.3 Hz, 1H), 8.03-8.06 (m, 3H), 7.50 (d, J = 8.2) Hz, 2H), 7.37-7.40 (m, 2H), 7.09-7.11 (m, 2H), 6.98 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H), 4.23 (t, J = 6.4 Hz, 1H) , 3.90 (s, 3H), 3.80 (s, 3H), 3.22 (d, J = 6.4 Hz, 2H) 26 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.56 (s, 1H), 8.17 (s, 2H), 8.16 (dd, J = 8.7, 1.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 2H), 7.99 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H) , 6.94-6.95 (m, J = 2.1 Hz, 2H), 6.80 (dd, J = 8.0, 2.1 Hz, 1H), 4.11 (t, J = 5.5 Hz, 1H), 3.90 (s, 3H), 3.22 ( dd, J = 14.7, 6.4 Hz, 1H), 3.16 (dd, J = J = 14.7, 6.4 Hz, 1H) 27 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (s, 3H), 8.18 (dd, J = 8.7, 2.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.37-7.42 (m, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.22 (dd, J = 7.5, 1.7) Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.03 (td, J = 7.5, 0.9 Hz, 1H), 4.23 (t, J = 6.4 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.16-3.25 (m, 2H) 28 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.46 (s, 1H), 8.35 (s, 2H), 8.14 (dd, J = 8.7, 2.3 Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 2.3 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.20 (td, J = 7.8, 1.5 Hz, 1H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.85 (td, J = 7.4, 1.1 Hz, 1H), 4.08 (t, J = 6.2) Hz, 1H), 3.84 (s, 3H), 3.23 (dd, J = 14.2, 6.0 Hz, 1H), 3.16 (dd, J = 14.2, 6.0 Hz, 1H) 29 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44 (s, 3H), 8.07 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.39-7.43 (m, 3H), 7.30-7.33 (m, 2H), 7.21 (dd, J = 8.9, 2.7 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 4.14 (t, J = 6.0 Hz, 1H), 3.92 (s, 3H), 3.15-3.23 (m, 2H) 30 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.38 (s, 3H), 8.03 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.23 (dt, J = 9.4, 2.5 Hz, 2H), 7.17 (dd, J = 8.7, 2.6 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.97 (dt, J = 9.5, 2.6 Hz, 2H), 4.17 (t, J = 6.4 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.15-3.24 (m, 2H) 31 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.70 (s, 1H), 8.42 (s, 2H), 7.98 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H) , 7.45 (d, J = 8.2 Hz, 2H), 7.13 (dd, J = 8.7, 2.7 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 2.3 Hz, 1H) , 6.77 (d, J = 8.2 Hz, 2H), 3.89 (s, 3H), 3.86 (t, J = 6.1 Hz, 1H), 3.21 (dd, J = 14.7, 5.0 Hz, 1H), 3.08 (dd, J = 14.7, 5.0 Hz, 1H) 32 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.92 (s, 1H), 11.72 (s, 1H), 8.49 (s, 3H), 8.47 (d, J = 1.5 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.91 (dd, J = 8.5, 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 2.7 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 6.68 (t, J = 2.1 Hz, 1H), 4.26 (t, J = 5.2 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 33 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.73 (s, 1H), 8.47 (s, 3H), 8.35 (s, 1H), 8.13 (dd, J = 8.9, 0.6 Hz, 1H), 8.08 ( d, J = 8.2 Hz, 2H), 7.81 (dd, J = 8.9, 0.6 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 4.27 (q, J = 5.4 Hz, 1H), 3.24 ( d, J = 6.4 Hz, 2H) 34 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.43 (s, 3H), 8.03 (d, J = 8.2 Hz, 2H), 7.68 (dd, J = 8.5, 2.1 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H), 4.34-4.38 (m, 4H), 4.23 (t, J = 6.4 Hz, 1H), 3.16-3.26 (m, 2H) 35 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.47 (s, 3H), 8.03 (d, J = 8.4 Hz, 2H), 7.78 (dd, J = 8.2, 1.7 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 1H), 6.21 (s, 2H), 4.23 (t, J = 6.5 Hz, 1H) , 3.22 (d, J = 6.5 Hz, 2H) 36 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.06 (d, J = 1.5 Hz, 1H), 8.49 (s, 3H), 8.41 (d, J = 7.3 Hz, 1H), 8.35 (dd, J = 8.7, 2.0 Hz, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63 (td, J = 7.8, 1.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.48-7.52 (m, 1H), 4.25 (t, J = 6.4 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H) 37 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 8.02 (d, J = 8.2 Hz, 2H), 7.96 (dt, J = 9.7, 2.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H) ), 6.87 (dt, J = 9.8, 2.3 Hz, 2H), 4.23 (q, J = 5.5 Hz, 1H), 3.24 (d, J = 6.4 Hz, 2H), 3.05 (s, 6H) 38 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 8.47 (s, 2H), 8.11 (dd, J = 6.6, 1.7 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.52 (dd , J = 8.4, 6.6 Hz, 4H), 7.34-7.27 (m, 4H), 7.24-7.19 (m, 1H), 4.24 (t, J = 6.4 Hz, 1H), 4.08 (s, 2H), 3.23 ( d, J = 6.4 Hz, 2H) 39 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 8.45 (s, 2H), 8.14 (dt, J = 9.6, 2.4 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.52-7.48 (m, 4H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 1H), 7.29 (dt, J = 9.6, 2.4 Hz, 2H), 5.25 (s, 2H), 4.24 (t, J) = 6.6 Hz, 1H), 3.22 (d, J = 6.4 Hz, 2H) 40 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ10.52 (s, 1H), 8.45 (s, 3H), 8.13 (dd, J = 7.0, 1.8 Hz, 2H), 8.04 (d, J = 8.2) Hz, 2H), 7.88 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.4 Hz, 1H), 3.23 (d, J = 6.7 Hz, 2H), 2.12 (s, 3H) 41 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 10.71 (s, 1H), 8.40 (s, 2H), 8.19 (d, J = 8.9 Hz, 2H), 8.12-8.10 (m, 2H), 8.05 (d, J = 8.2 Hz, 2H), 8.00-7.98 (m, 2H), 7.65-7.61 (m, 1H), 7.58-7.54 (m, 2H), 7.51 (d, J = 8.5 Hz, 2H), 4.24 (t, J = 6.6 Hz, 1H), 3.21 (d, J = 4.9 Hz, 2H) 42 ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 11.05 (s, 1H), 9.63 (s, 1H), 9.27 (s, 1H), 8.36 (s, 2H), 8.13 (dd, J = 8.5, 2.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.1 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.39-7.34 (m, 4H) , 6.86 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.82 (t, J = 6.9 Hz, 1H), 3.10 (d, J = 6.4 Hz, 2H) 43 LCMS [M+H] 491.19

Experimental Example 2: Inhibitory effect of tryptophan hydroxylase activity

In order to confirm the tryptophan hydroxylase activity inhibitory effect of the compounds of Examples 1 to 43 synthesized through the above preparation examples, TPH1 (TRYPTOPHAN HYDROXYLASE 1) Inhibitor Screening Assay Kit (BPS Bioscience, Catalog # 72053) was used. and tested. The TPH1 Inhibitor Screening Assay Kit was used according to the manufacturer's manual, and the results are shown in Table 3 below.

Specifically, after dissolving the synthesized compound in DMSO, 10 μL of the compound was placed in a 96-well microplate, and 40 μL of TPH1 enzyme was added. Then, after adding 50 μL of TPH1 reaction solution, the microplate was shielded from light with aluminum foil. The microplate was transferred to a 4°C environment, shaken carefully, and incubated for 4 hours. Then, 10 μL of quench solution was added and TPH1 activity was measured by reading the degree of fluorescence in a Flexstation3 microplate reader. At this time, the excitation spectrum was measured at a wavelength of 300 nm, and the emission spectrum was measured at a wavelength of 360 nm.

Example TPH1 activity (% inhibition at 1 μM) Example TPH1 activity (% inhibition at 1 μM) One <5 23 <5 2 53.5 24 80.7 3 <5 25 90.7 4 <5 26 96.7 5 <5 27 98.8 6 67.6 28 97.0 7 47.0 29 30.1 8 86.3 30 44.8 9 84.9 31 43.5 10 39.3 32 <5 11 <5 33 <5 12 6.1 34 <5 13 <5 35 <5 14 41.5 36 12.2 15 42.4 37 <5 16 <5 38 <5 17 38.0 39 <5 18 96.5 40 <5 19 100 41 <5 20 32.2 42 17.7 21 100 43 78.7 22 7.4

As described above, the compound represented by Formula 1 according to the present invention has an excellent inhibitory effect on TPH1, so it is useful for preventing or treating metabolic diseases, cancer, digestive system diseases, or circulatory system diseases, which are diseases related to TPH1 activity. can be used

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims described below and their equivalents.

Claims (15)

A compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
n is an integer from 0 to 2,
R ₁ is hydroxy, amino, C _1-6 alkoxy, hydroxy-C _1-4 alkoxy, or hydroxy-amino,
R ₂ To R ₆ are each independently hydrogen, hydroxy, nitro, cyano, halo, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-4 alkylamino, di( C _1-4 alkyl)amino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonylamino, C _6-10 arylcarbonylamino, C _6-14 aryl, C _6-10 aryl-C _1-4 alkyl, C _6-10 aryl-C _1-4 alkoxy, C _1-4 alkoxy-C _6-10 aryl, or
R ₃ and R ₄ are linked to each other to C _3-14 heterocyclyl, or form C _5-14 heteroaryl;
wherein said aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C _1-4 alkoxy, or C _1-4 haloalkyl.
According to claim 1,
n is 0 or 1, the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₁ is hydroxy, amino, ethoxy, hydroxyethoxy, or hydroxyamino. A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₂ is hydrogen, phenyl, hydroxyphenyl, or methoxyphenyl, a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₃ is hydrogen, bromo, nitro, methoxy, phenyl, hydroxyphenyl, or methoxyphenyl, a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₄ is hydrogen, hydroxy, nitro, cyano, fluoro, bromo, iodo, methoxy, ethoxy, acetyl, methylcarbonylamino, phenylcarbonylamino, phenylmethoxy, phenylmethyl, dimethylamino, A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is trifluoromethyl, or trifluoromethoxy.
According to claim 1,
R ₃ and R ₄ are linked to each other to form dioxolanyl, dioxanyl, pyrazolyl, pyrroline, or benzofuranyl, a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ₅ and R ₆ are both hydrogen. A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound is
1. (S)-2-amino-3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-( 4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
2. (S)-2-amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
3. (S)-2-amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(3-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
4. (S)-2-amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
5. (S)-2-amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-ethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
6. (S)-2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
7. (S)-2-amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
8. (S)-2-amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
9. (S)-2-amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-iodophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
10. (S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
11. (S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
12. (S)-2-amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
13. (S)-3-(4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S)-3- (4-(5-(4-acetylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
14. (S)-2-amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2- amino-3-(4-(5-(4-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
15. (S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (( S)-2-amino-3-(4-(5-(4-methoxy-3-nitrophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
16. (S)-2-amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2 -amino-3-(4-(5-(4-methoxybenzyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
17. (S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(3-bromo-4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
18. (S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
19. (S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
20. (S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
21. (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
22. (S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanamide ((S)-2-amino-3-(4-(5-(4',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide),
23. (S)-2-Amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanamide ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl )propanamide),
24. (S)-Ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazole-3- yl)phenyl)propanoate ((S)-ethyl 2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3- yl)phenyl)propanoate),
25. (S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(3',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
26. (S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(3'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
27. (S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(2',6-dimethoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
28. (S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(2'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
29. (S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ( (S)-2-amino-3-(4-(5-(5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
30. (S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl) propanoic acid ((S)-2-amino-3-(4-(5-(4',5-dimethoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
31. (S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl )phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(4'-hydroxy-5-methoxybiphenyl-2-yl)-1,2,4-oxadiazol-3-yl)phenyl ) propanoic acid),
32. (S)-3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S) -3-(4-(5-(1H-indol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
33. (S)-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S) )-3-(4-(5-(1H-indazol-6-yl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
34. (S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,4-oxadia zol-3-yl)phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1, 2,4-oxadiazol-3-yl)phenyl)propanoic acid),
35. (S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl) Phenyl)propanoic acid ((S)-2-amino-3-(4-(5-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-3-yl) phenyl) propanoic acid),
36. (S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propane acid ((S)-2-amino-3-(4-(5-(dibenzo[b,d]furan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
37. (S)-2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(4-(dimethylamino)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
38. (S)-2-amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)-2- amino-3-(4-(5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
39. (S)-2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S) -2-amino-3-(4-(5-(4-(benzyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
40. (S)-3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid ((S)- 3-(4-(5-(4-acetamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-aminopropanoic acid),
41. (S)-2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid ((S)- 2-amino-3-(4-(5-(4-benzamidophenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid),
42. (S)-2-Amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadia zol-3-yl)phenyl)propanamide ((S)-2-amino-N-hydroxy-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2, 4-oxadiazol-3-yl)phenyl)propanamide), or
43. (S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1,2,4-oxadiazol-3-yl )phenyl)-N-(2-hydroxyethoxy)propanamide ((S)-2-amino-3-(4-(5-(4'-hydroxy-6-methoxybiphenyl-3-yl)-1, 2,4-oxadiazol-3-yl)phenyl)-N-(2-hydroxyethoxy)propanamide), a compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.
A first step of synthesizing a compound represented by Formula 4 by reacting a compound represented by Formula 2 with a compound represented by Formula 3; and
A second step of converting the compound represented by Formula 4 obtained from the previous step into the compound represented by Formula 1; Method for preparing a compound represented by Formula 1, including:
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

In Formulas 1 to 4,
n is an integer from 0 to 2,
R ₁ is hydroxy, amino, C _1-6 alkoxy, hydroxy-C _1-4 alkoxy, or hydroxy-amino,
R ₂ To R ₆ are each independently hydrogen, hydroxy, nitro, cyano, halo, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-4 alkylamino, di( C _1-4 alkyl)amino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonylamino, C _6-10 arylcarbonylamino, C _6-14 aryl, C _6-10 aryl-C _1-4 alkyl, C _6-10 aryl-C _1-4 alkoxy, C _1-4 alkoxy-C _6-10 aryl, or
R ₃ and R ₄ are linked to each other to C _3-14 heterocyclyl, or form C _5-14 heteroaryl;
R ₂ ' to R ₆ ' are each the same as R ₂ to R ₆ or a precursor thereof,
wherein said aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted with hydroxy, oxo, C _1-4 alkoxy, or C _1-4 haloalkyl.
11. The method of claim 10,
Among the compounds represented by Formula 2, the compound including a substituent bonded to R ₂ ' to R ₆ ' through an aryl group is a boronic acid derivative of R ₂ ' to R ₆ ', in which a halogen is substituted at the site to which the substituent is bonded. A method for preparing by reacting with a derivative of the compound of formula (2).
11. The method of claim 10,
The compound represented by Formula 3 is prepared from (S)-2-amino-3-(4-cyanophenyl)propanoic acid.
A composition for inhibiting tryptophan hydroxylase, comprising the compound of any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
A pharmaceutical composition for the prevention or treatment of metabolic diseases, comprising the compound of any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
A pharmaceutical composition for preventing or treating cancer, comprising the compound of any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.