Novel heterocyclyl-phenyl-methylamine derivatives, their preparation method, and their use in preventing, ameliorating, or treating multiple sclerosis

Abstract

The present invention relates to a series of novel heterocyclyl-phenyl-methylamine derivatives, their preparation method and their use in preventing, ameliorating or treating multiple sclerosis.

Description

[Technical Field]

[0001] The present invention relates to a series of novel heterocyclyl-phenyl-methylamine derivatives, their preparation method and their use in preventing, ameliorating or treating multiple sclerosis. [Background technology]

[0002] Multiple sclerosis (MS) can occur in people of all ages, with a particular prevalence in those in their 20s to 40s. Described by Jean-Martin Charcot in 1868, MS is more than twice as common in women than in men, and is more prevalent in Caucasians of European descent than in Asians or Blacks. Some patients also develop the disease through inherited genes. In modern society, the trend toward a Westernized diet has led to an increase in the incidence of MS among Asians as well as Westerners. MS manifests in various parts of the central nervous system (CNS), primarily in the brain, spinal cord, white matter, and optic nerves. Depending on the location of the lesions, different neurological abnormalities can occur. Even within the same patient, MS symptoms vary. It is typically a chronic inflammatory and demyelinating autoimmune disease of the central nervous system associated with immunological factors such as antibodies and complement, which develops in response to inflammatory demyelination. Demyelination occurs when immune cells (T-cells) damage the myelin sheath on the nerve side, causing sclerosis and sclerosis. When the myelin sheath that transmits signals is damaged and demyelination occurs, the speed at which signals are transmitted becomes much slower than in people without lesions. Even when the wound heals and the myelin sheath is regenerated, the reaction speed of the nerve terminals tends to slow down and not return to normal. There are various types of symptoms in patients with multiple sclerosis, and the most common type is relapsing-remitting multiple sclerosis. Multiple sclerosis (MS) is a neurodegenerative disease characterized by the development of autoreactive CD4. The main symptoms of MS include sensory and motor paralysis, optic nerve inflammation, Lhemittes' symptom, diplopia, and Uhthoff's sign. Patients' symptoms tend to improve and worsen repeatedly, and the accumulation of nerve damage can lead to severe and even chronic disease. + T cells migrate from the blood to the central nervous system and become activated in response to myelin. CD4 + T cells secrete substances that induce inflammation and induce macrophages and B cells to enter the central nervous system. Autoreactive CD8 cells destroy cells containing antigenic determinants. + T cells also come from the blood to the central nervous system and undergo reactivation to replicate and grow. + T cells and CD8 + Macrophages, which induce T cells to enter the central nervous system, activate microglial cells present in the central nervous system and secrete a substance called BAFF (B cell activating factor belonging to the TNF family) to activate B cells. The autoimmune reaction that causes multiple sclerosis is caused by macrophages producing pro-inflammatory cytokines that destroy myelin and ingest and remove myelin marked with antibodies and complement.

[0003] Currently, Novartis' FTY720 (fingolimod) is widely used as a treatment for multiple sclerosis, but it induces bradycardia, one of its most significant side effects, and so the development of new treatments with few or no side effects is needed. It has been reported that these side effects are due to activation of the S1P3 receptor. In response, newly developed treatments are being developed as a strategy to activate S1P1 and S1P5 without activating the S1P3 receptor. Novartis' BAF312, approved by the FDA in 2019, was highly anticipated as a treatment that exhibits excellent activity on S1P1 and S1P5 without activating S1P3, but FTY Bradycardia, a side effect of 720, still occurred. The mechanism of action of these drugs is to down-regulate S1P1 present in lymphocyte immune cells by treating them with S1P1 agonists to prevent it from entering the central nervous system. S1P1 receptors then form colonies, enter cells through endocytic action, and are internalized and degraded, exerting their inhibitory effect. Therefore, there is an urgent need to develop drugs and / or treatment techniques that have no or minimal side effects but excellent therapeutic effects. Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have conducted extensive research to discover novel small molecule compounds that exhibit excellent activity as sphingosine-1-phosphate receptor (S1P1) agonists with minimal side effects. As a result, they have found that a series of heterocyclyl-phenyl-methylamine derivatives and their salts not only significantly reduce the number of blood lymphocytes, but also effectively delay the onset of or significantly improve motor impairment symptoms in EAE mice, an animal model of multiple sclerosis, and have completed the present invention. [Means for solving the problem]

[0005] One object of the present invention is to provide a series of novel heterocyclyl-phenyl-methylamine derivatives or pharmaceutically acceptable salts thereof.

[0006] Another object of the present invention is to provide a method for preparing the heterocyclyl-phenyl-methylamine derivative or a pharmaceutically acceptable salt thereof.

[0007] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating multiple sclerosis (MS), which contains the heterocyclyl-phenyl-methylamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008] Another object of the present invention is to provide a method for preventing or treating multiple sclerosis, which comprises administering the pharmaceutical composition to an individual in need thereof.

[0009] Another object of the present invention is to provide a food composition for preventing or ameliorating multiple sclerosis, which contains the heterocyclyl-phenyl-methylamine derivative or a nutritively acceptable salt thereof as an active ingredient.

[0010] Another object of the present invention is to provide a feed composition for preventing or ameliorating multiple sclerosis, which contains the heterocyclyl-phenyl-methylamine derivative or a feed-technically acceptable salt thereof as an active ingredient. [Effects of the Invention]

[0011] The heterocyclyl-phenyl-methylamine derivatives of the present invention can regulate receptor internalization and blood lymphocyte count through agonist activity against the S1P1 receptor, and further suppress reflex loss and paralysis, which are symptoms caused by multiple sclerosis, and exhibit excellent effects in reducing inflammatory cells in the blood, and are therefore useful for the prevention or treatment of multiple sclerosis. [Brief explanation of the drawings]

[0012] [Figure 1] These figures show the change in peripheral blood lymphocyte count over time in normal rats administered with compounds 13, 62, 64, or 66 of the present invention. Figures 1A and 1B show the change in blood lymphocyte count over time after oral administration of compounds 64 and 66, and compounds 13 and 62 of the present invention, respectively, at a dose of 10 mg / kg, calculated as a percentage of the pre-administration value. These results are shown together with the results for the positive control group administered fingolimod, a clinically approved drug with the same mechanism of action. Figure 1C shows the lymphocyte count measured 6 hours after oral administration of vehicle or drug, expressed as a percentage of the vehicle-administered negative control group. [Figure 2] Figures 2A and 2B show the outline of the construction of a rodent multiple sclerosis model and drug administration, and the alleviation of multiple sclerosis symptoms by administration of a compound of the present invention in a rodent multiple sclerosis model. Figure 2A shows the change in clinical symptom index (quantified as the degree of paralysis in the tail and legs) by date, and Figures 2B and 2C show the area under the graph for each group from Figure 2A. Figure 2D shows the change in body weight for each group by date, and Figure 2E shows the degree of change in body weight for each group from the start date of induction of the experimental animal model to the final day of the test. Figure 2F shows the time and rate at which symptoms of multiple sclerosis appeared in each group. Figure 2G shows the outline of the construction of a multiple sclerosis animal model and drug administration and the clinical symptom index by date after administration of compound 13, and Figure 2H shows the time and rate at which symptoms of multiple sclerosis appeared in each group. DETAILED DESCRIPTION OF THE INVENTION

[0013] Each description and embodiment disclosed in the present invention applies to each other description and embodiment. That is, any combination of various elements disclosed in this application belongs to the scope of the present invention. In addition, the following specific description is not considered to limit the scope of the present invention.

[0014] Additionally, 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, and such equivalents are intended to be encompassed by the present invention.

[0015] Additionally, throughout the specification of the present invention, when a part is said to "comprise" a certain component, this does not mean that it excludes other components, but that it also includes other components, unless otherwise specified.

[0016] The present invention will now be described in more detail.

[0017] To achieve the above object, a first aspect of the present invention provides a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:

[0018] [Chemical formula 1] JPEG2025525896000002.jpg3778

[0019] In the above Chemical Formula 1, Ring 1 is selenazolenyl or isoxazolenyl; Ring 2 is C 6-10 aryl, or 5- to 10-membered heteroaryl; R1 is hydrogen, cyano, halo(gen), hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 one or more substituents, which may be the same or different, selected from the group consisting of haloalkyl; R2 and R3 are each independently hydrogen, C 1-6 Alkoxycarbonyl-C 1-6 Alkyl or sodium carboxy-C 1-6 Is it alkyl? R2 and R3 are linked together to form an unsubstituted or substituted 3- to 10-membered heterocyclyl including the nitrogen to which they are attached.

[0020] For example, the compound of the present invention is represented by any one of the following chemical formulas 2 to 4, but is not limited thereto:

[0021] [Chemical formula 2] JPEG2025525896000003.jpg3778

[0022] [Chemical formula 3] JPEG2025525896000004.jpg3778

[0023] [Chemical formula 4] JPEG2025525896000005.jpg3778

[0024] For example, in the above formulas 1 to 4, Ring 2 may be phenyl or pyridinyl, but is not limited thereto.

[0025] For example, in Formulas 1 to 4, R1 may be absent or may be, but is not limited to, cyano, bromo, chloro, hydroxy, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, chloromethyl, or trifluoromethyl. Specifically, R1 may be, but is not limited to, any one selected from the above-mentioned substituents, or two that are the same or different from each other.

[0026] For example, in the above chemical formulas 1 to 4, R2 is hydrogen, and R3 is ethoxycarbonylmethyl, methoxycarbonylethyl, carboxymethyl sodium, or carboxyethyl sodium. It may be, but is not limited to, thorium.

[0027] Alternatively, in Formulas 1 to 4, R2 and R3 may be linked to each other and, together with the nitrogen to which they are bonded, form an azetidinyl, pyrrolidinyl, or piperidinyl that is unsubstituted or substituted with one or more selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and carboxysodium, but is not limited thereto.

[0028] Specifically, the compound is 1. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 2. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 3. Ethyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 4. tert-Butyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 5. Methyl 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 6. Sodium 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 7. Ethyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 8. tert-Butyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 9. Methyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 10. 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 11. Ethyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 12. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 13. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 14. Methyl 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 15. Sodium 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 16. Methyl 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 17. 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 18. Methyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 19. 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 20. Ethyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 21. Methyl 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 22. 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 23. Methyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 24. 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 25. Ethyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 26. Methyl 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 27. Sodium 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 28. Methyl 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 29. Sodium 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 30. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate; 31. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate; 32. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)piperidine-4-carboxylate; 33. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate; 34. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate; 35. Ethyl 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate; 36. Sodium 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate; 37. Methyl 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate; 38. Sodium 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate; 39. Methyl 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate; 40. Sodium 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate; 41. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate; 42. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate; 43. Methyl 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 44. 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 45. Methyl 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 46. 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 47. Methyl 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 48. 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 49. Methyl 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 50. 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 51. 1-(4-(5-(4-hydroxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 52. Methyl 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 53. Sodium 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 54. Methyl 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 55. Sodium 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 56. Sodium 1-(4-(5-(4-propylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 57. Methyl 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 58. Sodium 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 59. Methyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 60. 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 61. Methyl 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 62. Sodium 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 63. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 64. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 65. Methyl 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 66. Sodium 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 67. Methyl 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxa) (3-yl)benzyl)azetidine-3-carboxylate; 68. Sodium 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 69. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate; 70. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate; or 71. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)piperidine-4-carboxylate;

[0029] The compounds of the present invention exist in the form of pharmaceutically acceptable salts. As salts, acid addition salts formed with pharmaceutically acceptable free acids are useful. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, in which the side effects attributable to the salt do not diminish the beneficial effects of the compound at a concentration that is relatively non-toxic and harmless to patients.

[0030] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess amount of aqueous 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 (e.g., glycol monomethyl ether) in water are heated, and the mixture is then evaporated to dryness, or the precipitated salt can be filtered off with suction.

[0031] In this regard, the free acid may be an organic acid or an inorganic acid. Examples of inorganic acids that may be used include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid. Examples of organic acids that may be used include, but are not limited to, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid.

[0032] Pharmaceutically acceptable metal salts can also be prepared using bases. Alkali metal salts or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are particularly suitable for pharmaceutical purposes, but are not limited to these. Corresponding silver salts can also be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

[0033] Pharmaceutically acceptable salts of the compounds of the present invention, unless otherwise specified, include salts of acidic or basic groups that may be present in the compounds of Formula 1. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups, such as hydrobromides, sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, dihydrogen phosphates, acetates, succinates, citrates, and tartrates. Examples include salts of phenylalanine, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate), which can be prepared by methods known in the art.

[0034] As the salt of the heterocyclyl-phenyl-methylamine derivative compound of the present invention, any salt of a heterocyclyl-phenyl-methylamine derivative compound that is pharmaceutically acceptable and exhibits pharmacological activity equivalent to that of the heterocyclyl-phenyl-methylamine derivative compound can be used without limitation.

[0035] Furthermore, the compound represented by Chemical Formula 1 according to the present invention includes, without limitation, not only its pharmaceutically acceptable salts but also solvates such as hydrates that can be prepared therefrom and all possible stereoisomers. The solvates and stereoisomers of the compound represented by Chemical Formula 1 can be prepared from the compound represented by Chemical Formula 1 using methods known in the art.

[0036] Furthermore, the compound represented by Chemical Formula 1 according to the present invention may be prepared in a crystalline or amorphous form, and if prepared in a crystalline form, may be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound represented by Chemical Formula 1, but also compounds containing various amounts of water. The solvates of the compound represented by Chemical Formula 1 according to the present invention include both stoichiometric and non-stoichiometric solvates.

[0037] A second aspect of the present invention provides a method for producing the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, comprising the step of amminating an aldehyde group of a compound represented by the following chemical formula 5:

[0038] [Chemical formula 5] JPEG2025525896000006.jpg3070

[0039] In the above Chemical Formula 1, Ring 1 is selenazolenyl or isoxazolenyl; Ring 2 is C 6-10 aryl, or 5- to 10-membered heteroaryl; R1 is hydrogen, cyano, halo(gen), hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, and C 1-6 and one or more substituents, which may be the same or different, selected from the group consisting of haloalkyl.

[0040] For example, the compound of Chemical Formula 5 is Step a) of reacting the R1-Ring 2-nitrile or 4-(hydroxymethyl)benzonitrile with selenium and carbon monoxide to produce the R1-Ring 2-substituted selenoamide or 4-hydroxybenzoselenoamide; Step b: reacting the product of the previous step with 2-bromo-1,1-diethoxyethane and p-toluenesulfonic acid to form a 1,3-selenazole ring substituted at carbon number 5 with Ring 2 or phenyl at carbon number 2; Step c) halogenating the unsubstituted carbon 2 or carbon 5 of the 1,3-selenazole ring of the product of the previous step; and The product of the previous step may be prepared through step d, which involves reacting the product with 4-formylphenylboronic acid or R1-Ring 2-boronic acid to introduce additional substituents at the halogenated carbon 2 or carbon 5, but is not limited thereto.

[0041] For example, through the series of reactions, the compound represented by the above-mentioned Chemical Formula 2 and the precursor compound represented by the above-mentioned Chemical Formula 3 can be obtained, but are not limited thereto.

[0042] When 4-(hydroxymethyl)benzonitrile is used as a reactant and reacted according to the above series of steps, a precursor compound containing a hydroxymethyl group instead of a formyl group on the phenyl ring of Chemical Formula 3 can be obtained, which can be converted to the compound of Chemical Formula 3 by further carrying out Step e, in which the hydroxy group on the phenyl ring is oxidized, after Step d. In this case, the reaction of Step e can be carried out using pyridinium chlorochromate (PCC), but is not limited thereto.

[0043] For example, the compound of formula 5 is Step a', in which N-hydroxy-4-(hydroxymethyl)benzimidoyl chloride is reacted with triethylamine to remove hydrochloric acid; Step b', in which the product of the previous step is reacted with an ethenyl-substituted R1-Ring 2 to produce (4-(5-(R1-Ring)-4,5-dihydroisoxazol-3-yl)phenyl)methanol; and It can be prepared through, but is not limited to, step c', in which the hydroxy group on the phenyl ring of the product of the previous step is oxidized.

[0044] For example, through the series of reactions, the compound represented by the above-mentioned Chemical Formula 4 can be obtained, but is not limited thereto.

[0045] The specific preparation method described above is merely an example, and the scope of the present invention is not limited thereto. Related reactions known in the art can be carried out as is or with appropriate modifications. Furthermore, the reactants in each step can be purchased commercially or synthesized by known methods, but are not limited thereto. Furthermore, the preparation method of the present invention may optionally include a separation and / or purification step after each step to increase the purity and / or yield of the product, but is not limited thereto.

[0046] A third aspect of the present invention provides a pharmaceutical composition for preventing or treating multiple sclerosis (MS), comprising the compound of the first aspect or a pharmaceutically acceptable salt thereof as an active ingredient.

[0047] A fourth aspect of the present invention provides a method for preventing or treating multiple sclerosis, comprising administering the pharmaceutical composition of the third aspect to an individual in need thereof.

[0048] The method for preventing or treating multiple sclerosis of the present invention can be carried out in conjunction with rehabilitation training, but is not limited thereto.

[0049] The terms "compound of the first aspect" and "pharmaceutically acceptable salt" of the present invention are as defined above.

[0050] The term "multiple sclerosis (MS)" used in the present invention refers to a demyelinating disease caused by damage to myelin, the insulating covering that protects nerve cells in the brain and spinal cord. This damage disrupts signaling in parts of the nervous system, leading to a wide range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific clinical manifestations include vision loss, impaired eye movement (e.g., nystagmus), sensory symptoms (e.g., numbness, tingling, or throbbing pain in the skin), weakness in the arms and legs, convulsions, ataxia, bladder problems, and cognitive, emotional, and seizure disorders. Multiple sclerosis takes many forms, including relapsing forms that manifest in isolated attacks or progressive forms that accumulate over time. While symptoms may disappear completely between attacks, permanent neurological problems may persist, particularly with disease progression. The underlying mechanism of multiple sclerosis is known to be destruction by the immune system or errors in myelin-producing cells. The cause of the disease is unclear, and no known cure is available, although genetic factors and environmental factors such as viral infections are discussed.

[0051] For example, the pharmaceutical composition of the present invention may contain the compound in the form of a sodium salt, but is not limited thereto.

[0052] For example, the compound represented by Chemical Formula 1, which is an active ingredient of the pharmaceutical composition of the present invention, can act as a sphingosine-1-phosphate receptor (S1P1) modulator.

[0053] The term "sphingosine-1-phosphate receptor (S1P1)" as used herein refers to a G protein-coupled receptor that is the target of the lipid signaling molecule sphingosine-1-phosphate (S1P). It is one of five subtypes, S1P1, S1P2, S1P3, S1P4, and S1P5, and was the first member of the S1P receptor family to be cloned in endothelial cells in 1990. These subtypes are expressed in various tissues and, although all are found at highest densities in leukocytes, each has different cellular specificities. S1P1 is known to be ubiquitously expressed. Its known agonists include fingolimod, which is primarily used as an immunomodulator, particularly for the treatment of multiple sclerosis. A pharmaceutical composition comprising the compound of the present invention acts as an S1P1 agonist and is therefore capable of alleviating and / or delaying the onset of clinical symptoms to a level equivalent to that of fingolimod in an animal model of multiple sclerosis, and can therefore be used in place of fingolimod for the prevention and / or treatment of multiple sclerosis.

[0054] Furthermore, the pharmaceutical composition of the present invention can alleviate autoimmune reactions by reducing the number of lymphocytes in the blood.

[0055] Furthermore, the pharmaceutical composition of the present invention can not only relieve symptoms of stiffness or paralysis, but also delay the onset of such symptoms of multiple sclerosis.

[0056] As used herein, the term "prevention" refers to any action that inhibits or delays the onset, spread, and recurrence of multiple sclerosis by administering the pharmaceutical composition of the present invention, and "treatment" refers to any action that improves or beneficially alters the symptoms of the disease by administering the pharmaceutical composition of the present invention.

[0057] In a specific embodiment of the present invention, the treatment may refer to, but is not limited to, a reduction or alleviation of the symptoms of multiple sclerosis, a reduction in the extent of the disease, a delay or slowing of the disease, a palliation or stabilization of the disease state, and other beneficial results.

[0058] The term "individual" as used herein refers to any animal, including monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, that have or may develop multiple sclerosis or are suspected of having multiple sclerosis. Administration of the pharmaceutical composition of the present invention to these individuals can effectively prevent or treat the disease. Furthermore, the pharmaceutical composition of the present invention can exhibit a synergistic effect when administered in parallel with an existing therapeutic agent.

[0059] The term "administration" in the present invention means providing a predetermined substance to a patient by any suitable method. The administration route of the composition of the present invention can be any common route as long as it can deliver the substance to the target tissue. Administration can be by, but is not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, pulmonary, or rectal administration. The pharmaceutical composition of the present invention can also be administered by any device that can deliver the active substance to target cells. Preferred administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and infusion injection. Injectable preparations can be prepared using aqueous solvents such as physiological saline and Ringer's solution, or non-aqueous solvents such as vegetable oils, higher fatty acid esters (e.g., ethyl oleate, etc.), and alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.), and can contain pharmaceutical carriers such as stabilizers to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH adjustment, and preservatives to prevent microbial growth (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

[0060] For example, the compositions of the present invention may further contain a pharmaceutically acceptable carrier, diluent, or excipient, and can be formulated into various forms, such as oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, or sterile injection solutions, according to the intended purpose, and can be administered orally or via various routes, including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. Examples of suitable carriers, excipients, or diluents contained in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The composition of the present invention may further contain fillers, anti-agglomerating agents, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like.

[0061] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are formulated by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0062] Oral liquid preparations include suspensions, oral liquids, emulsions, syrups, etc., which may contain various excipients such as wetting agents, sweeteners, flavoring agents, preservatives, etc. in addition to water and liquid paraffin, which are frequently used simple diluents.

[0063] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin butter, and glycerogelatin. Injectables may contain conventional additives such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0064] The dosage form can be prepared by conventional mixing, granulating, or coating methods and contains the active ingredient in an amount of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of the active ingredient.

[0065] The compositions of the present invention are administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" as used herein refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment, without causing adverse effects. The effective dose level can be determined based on factors including the patient's health status, the type and severity of the disease, the activity of the drug, sensitivity to the drug, the method, time, route and excretion rate of administration, duration of treatment, coadministration or concurrent use of other drugs, and other factors well known in the medical field. The compositions of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, in single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can achieve maximum efficacy at the minimum dose without adverse effects, which can be easily determined by those skilled in the art.

[0066] For example, the dosage may increase or decrease depending on the route of administration, severity of the disease, sex, body weight, age, etc., and therefore the above dosage does not limit the scope of the present invention in any way.

[0067] The preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, the severity of the disease, the drug form, the route and duration of administration, and can be appropriately selected by those skilled in the art. However, for optimal efficacy, the compound of the present invention is administered at 0.0001 to 100 mg / kg (body weight) per day, preferably 0.001 to 100 mg / kg (body weight). Administration can be once a day or in divided doses, and can be administered orally or parenterally.

[0068] The composition for preventing or treating multiple sclerosis of the present invention can be prepared into a pharmaceutical dosage form using a method well known in the art so as to provide a rapid, sustained, or delayed release of the active ingredient after administration to a mammal. In preparing the dosage form, the active ingredient can be mixed or diluted with a carrier, or enclosed in a carrier in the form of a container.

[0069] Thus, the pharmaceutical composition of the present invention may further contain a pharmaceutically acceptable carrier, diluent, or excipient, and may be formulated into various forms, such as oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, or sterile injection solutions, according to the intended purpose, and may be administered orally or via various routes, including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration. Examples of suitable carriers, excipients, or diluents contained in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The composition of the present invention may also contain a filling agent. It may further contain fillers, anti-agglomerating agents, lubricants, wetting agents, flavorings, emulsifiers, preservatives, and the like.

[0070] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are formulated by mixing the composition with at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0071] Oral liquid preparations include suspensions, oral liquids, emulsions, syrups, etc., and may contain various excipients such as wetting agents, sweeteners, flavoring agents, preservatives, etc. in addition to water and liquid paraffin, which are frequently used simple diluents.

[0072] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin butter, and glycerogelatin. Injectables may contain conventional additives such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0073] The dosage form can be prepared by conventional mixing, granulating, or coating methods and contains the active ingredient in an amount of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal weighing about 50 to 70 kg contains about 10 to 200 mg of the active ingredient.

[0074] In this case, the composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment and not to cause side effects, and the effective dose level can be determined based on factors including the patient's health condition, type and severity of the disease, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, co-administered or concomitant drugs, and other factors well known in the medical field.

[0075] The preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, the severity of the disease, the drug form, the route and duration of administration, and can be appropriately selected by those skilled in the art. However, for optimal efficacy, the compound of the present invention is administered at 0.0001 to 100 mg / kg (body weight) per day, preferably 0.001 to 100 mg / kg (body weight). The dosage may be once a day or divided into several doses, and may be administered orally or parenterally.

[0076] For example, the dosage may be increased or decreased depending on the route of administration, severity of the disease, sex, body weight, age, etc., and therefore the above dosage does not limit the scope of the present invention in any way.

[0077] In addition, the pharmaceutical compositions of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for the prevention and treatment of multiple sclerosis. For purposes of the present invention, the pharmaceutical compositions of the present invention can be administered in combination with one or more additional drugs commonly used to treat multiple sclerosis.

[0078] When the pharmaceutical composition according to the present invention is administered for the treatment of multiple sclerosis, it may be administered in combination with one or more ingredients and / or drugs effective in the treatment or prevention of multiple sclerosis. In this case, it is important to consider all the factors mentioned above and administer an amount that will provide the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art.

[0079] Specifically, the combined and / or concomitant administration may involve administering the compound of the present invention or a pharmaceutically acceptable salt thereof and the one or more additional drugs simultaneously, sequentially, or in reverse order, and may be administered simultaneously in appropriate effective amounts, or may be stored in separate containers and then co-administered simultaneously, sequentially, or in reverse order.

[0080] A fifth aspect of the present invention provides a food composition for preventing or ameliorating multiple sclerosis, which comprises the compound of the first aspect or a nutrient-friendly salt thereof as an active ingredient.

[0081] The "multiple sclerosis" and "prevention" are as explained above.

[0082] Furthermore, the term "food-based acceptable salts" of the present invention can be defined in the same manner as the above-mentioned pharmaceutically acceptable salts.

[0083] The term "improvement" in the present invention refers to any action of improving or benefiting the symptoms of individuals suspected of or affected by the target disease by using a composition containing the compound of Chemical Formula 1 or a nutrient-acceptable salt thereof.

[0084] The food composition according to the present invention may be in the form of a pill, powder, granule, infusion, tablet, capsule, or liquid, and examples of foods to which the composition of the present invention can be added include various foods, such as beverages, gum, tea, vitamin complexes, and dietary supplements.

[0085] The food composition of the present invention may contain the compound of Formula 1 or a nutrient-acceptable salt thereof as an essential ingredient, but other ingredients are not limited, and may contain various herbal extracts, food supplements, natural carbohydrates, etc. as additional ingredients along with ordinary foods.

[0086] The food supplement additives also include those commonly used in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, etc.

[0087] Examples of the natural carbohydrates include monosaccharides such as glucose, fructose, etc., disaccharides such as maltose, sucrose, etc., and polysaccharides such as common sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, erythritol, etc. In addition to the above, natural flavors (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavoring agents.

[0088] In addition to the above, the food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and fillers (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, etc. In addition, natural fruit juice and fruit pulp for producing fruit juice drinks and vegetable drinks may be included. These ingredients may be used independently or in combination.

[0089] In the present invention, the food composition includes functional health foods and dietary supplements.

[0090] The term "functional food" is the same as "food for special health use (FoSHU)" and refers to food manufactured and / or processed using raw materials or ingredients that have beneficial functions for the human body. Functional foods refer to foods with high medical and therapeutic benefits that are processed to efficiently exert bioregulatory functions in addition to providing nutrients. Here, "functionality" refers to the ability to regulate nutrients for the structure and function of the human body or to achieve beneficial health effects, such as physiological effects. As described above, foods containing ingredients beneficial to the human body and recognized by the Ministry of Food and Drug Safety for their function and stability are called functional health foods. Other foods that are not approved by the Ministry of Food and Drug Safety but are considered to have beneficial effects on the human body are classified as health (supplemental) foods. The food of the present invention can be manufactured using methods commonly used in the industry, and raw materials and ingredients commonly added in the industry can be added during the manufacturing process. Furthermore, the dosage form of the food can be any dosage form recognized as a food. The food composition of the present invention can be manufactured into various dosage forms, and unlike general medicines, it has the advantages of being made from food ingredients, eliminating side effects that can occur with long-term drug administration, and is highly portable.

[0091] A sixth aspect of the present invention provides a feed composition for preventing or ameliorating multiple sclerosis, which comprises the compound of the first aspect or a feed-technically acceptable salt thereof as an active ingredient.

[0092] The terms "multiple sclerosis," "prevention," and "amelioration" are as explained above.

[0093] Furthermore, the term "fetologically acceptable salts" of the present invention can be defined in the same manner as the above-mentioned pharmaceutically acceptable salts.

[0094] The term "feed" as used herein means any natural or artificial diet, meal, etc. or component of said meal intended or suitable for eating, ingesting and digesting by an animal.

[0095] The type of feed is not particularly limited, and feed commonly used in the art can be used. Non-limiting examples of the feed include plant-based feeds such as grains, root vegetables, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, lees, or grain by-products; and animal-based feeds such as proteins, inorganic substances, oils and fats, minerals, milk fats, single-cell proteins, zooplankton, or food. These may be used alone or in combination of two or more.

[0096] The feed of the present invention may be, but is not limited to, powder feed, solid feed, moist pellet feed, dry pellet feed, EP (Extruder Pellet) feed, live feed, etc.

[0097] The feed composition of the present invention may contain binders, emulsifiers, preservatives, etc. added to prevent deterioration in quality, and may contain feed additives. To enhance efficacy, the feed may contain amino acid supplements, vitamin supplements, enzyme supplements, flavoring agents, non-protein nitrogen compounds, silicate agents, buffers, extractants, oligosaccharides, etc. In addition, the feed composition may further contain, but is not limited to, feed additives.

[0098] Example 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 scope of the present invention is not limited to these examples.

[0099] Example 1: Preparation of 2-(Ring 1)-5-phenyl substituted 1,3-selenazole derivatives (Compounds 1-38)

[0100] JPEG2025525896000007.jpg102153

[0101] Example 2: Preparation of 5-(ring 1)-2-phenyl substituted 1,3-selenazole derivatives (compounds 39-42)

[0102] JPEG2025525896000008.jpg92153

[0103] Example 3: Preparation of 5-(Ring 1)-2-phenyl substituted 4,5-dihydroisoxazole derivatives (Compounds 43-71)

[0104] JPEG2025525896000009.jpg81153

[0105] Compounds 1 to 71 were synthesized according to the reaction formulas of Examples 1 to 3. The names, structural formulas, and 1 Information such as H NMR is summarized below.

[0106] Compound 1. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0107] JPEG2025525896000010.jpg27106 Yellow solid; Yield: 43%;

[0108] JPEG2025525896000011.jpg53170

[0109] Compound 2. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0110] JPEG2025525896000012.jpg27107 white solid; Yield: 82%;

[0111] JPEG2025525896000013.jpg45170

[0112] Compound 3. Ethyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0113] JPEG2025525896000014.jpg33106 Yellow solid; Yield: 25%;

[0114] JPEG2025525896000015.jpg61170

[0115] Compound 4. tert-Butyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0116] JPEG2025525896000016.jpg33112 ivory solid; Yield: 75%;

[0117] JPEG2025525896000017.jpg61170

[0118] Compound 5. Methyl 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0119] JPEG2025525896000018.jpg29111 Yellow oil; Yield: 72%;

[0120] JPEG2025525896000019.jpg67170

[0121] Compound 6. Sodium 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0122] JPEG2025525896000020.jpg29112 Yellow solid; Yield: 97%;

[0123] JPEG2025525896000021.jpg61170

[0124] Compound 7. Ethyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0125] JPEG2025525896000022.jpg33111 ivory oil; Yield: 70%;

[0126] JPEG2025525896000023.jpg68170

[0127] Compound 8. tert-Butyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0128] JPEG2025525896000024.jpg33116 Ivory oil; Yield: 70%;

[0129] JPEG2025525896000025.jpg53170

[0130] Compound 9. Methyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0131] JPEG2025525896000026.jpg29111 Yellow solid; Yield: 68%;

[0132] JPEG2025525896000027.jpg67170

[0133] Compound 10. 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

[0134] JPEG2025525896000028.jpg29111 Yellow solid; Yield: 59%;

[0135] JPEG2025525896000029.jpg75170

[0136] Compound 11. Ethyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0137] JPEG2025525896000030.jpg33111 ivory oil; Yield: 70%;

[0138] JPEG2025525896000031.jpg76170

[0139] Compound 12. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0140] JPEG2025525896000032.jpg29111 Yellow solid; Yield: 47%;

[0141] JPEG2025525896000033.jpg67170

[0142] Compound 13. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0143] JPEG2025525896000034.jpg29112 white solid; Yield: 92%;

[0144] JPEG2025525896000035.jpg61170

[0145] Compound 14. Methyl 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0146] JPEG2025525896000036.jpg27111 Yellow solid; Yield: 55%;

[0147] JPEG2025525896000037.jpg68170

[0148] Compound 15. Sodium 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0149] JPEG2025525896000038.jpg27112 white solid; Yield: 90%;

[0150] JPEG2025525896000039.jpg61170

[0151] Compound 16. Methyl 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0152] JPEG2025525896000040.jpg27103 Yellow solid; Yield: 55%;

[0153] JPEG2025525896000041.jpg61170

[0154] Compound 17. 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

[0155] JPEG2025525896000042.jpg27103 ivory solid; Yield: 78%;

[0156] JPEG2025525896000043.jpg45170

[0157] Compound 18. Methyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenium) Nazol-5-ylbenzyl azetidine-3-carboxylate

[0158] JPEG2025525896000044.jpg29111 Yellow solid; Yield: 31%;

[0159] JPEG2025525896000045.jpg61170

[0160] Compound 19. 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

[0161] JPEG2025525896000046.jpg29111 Yellow solid; Yield: 94%;

[0162] JPEG2025525896000047.jpg53170

[0163] Compound 20. Ethyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0164] JPEG2025525896000048.jpg33111 ivory oil; Yield: 70%;

[0165] JPEG2025525896000049.jpg68170

[0166] Compound 21. Methyl 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0167] JPEG2025525896000050.jpg33102 Yellow solid; Yield: 56%;

[0168] JPEG2025525896000051.jpg61170

[0169] Compound 22. 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

[0170] JPEG2025525896000052.jpg33102 Yellow solid; Yield: 25%;

[0171] JPEG2025525896000053.jpg61170

[0172] Compound 23. Methyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0173] JPEG2025525896000054.jpg3692 transparent oil; Yield: 33%;

[0174] JPEG2025525896000055.jpg68170

[0175] Compound 24. 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid

[0176] JPEG2025525896000056.jpg3692 Yellow solid; Yield: 98%;

[0177] JPEG2025525896000057.jpg61170

[0178] Compound 25. Ethyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0179] JPEG2025525896000058.jpg4292 ivory oil; Yield: 70%;

[0180] JPEG2025525896000059.jpg68170

[0181] Compound 26. Methyl 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0182] JPEG2025525896000060.jpg2792 white solid; Yield: 50%;

[0183] JPEG2025525896000061.jpg53170

[0184] Compound 27. Sodium 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0185] JPEG2025525896000062.jpg2793 white solid; Yield: 54%;

[0186] JPEG2025525896000063.jpg52170

[0187] Compound 28. Methyl 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0188] JPEG2025525896000064.jpg2792 white solid; Yield: 50%;

[0189] JPEG2025525896000065.jpg52170

[0190] Compound 29. Sodium 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate

[0191] JPEG2025525896000066.jpg2793 white solid; Yield: 95%;

[0192] JPEG2025525896000067.jpg52170

[0193] Compound 30. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

[0194] JPEG2025525896000068.jpg30113 Yellow solid; Yield: 52%;

[0195] JPEG2025525896000069.jpg61170

[0196] Compound 31. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

[0197] JPEG2025525896000070.jpg30115 white solid; Yield: 95%;

[0198] JPEG2025525896000071.jpg61170

[0199] Compound 32. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)piperidine-4-carboxylate

[0200] JPEG2025525896000072.jpg27110 white solid; Yield: 12%;

[0201] JPEG2025525896000073.jpg54170

[0202] Compound 33. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

[0203] JPEG2025525896000074.jpg32118 Yellow solid; Yield: 47%;

[0204] JPEG2025525896000075.jpg83170

[0205] Compound 34. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate

[0206] JPEG2025525896000076.jpg32120 white solid; Yield: 93%;

[0207] JPEG2025525896000077.jpg82170

[0208] Compound 35. Ethyl 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate

[0209] JPEG2025525896000078.jpg31120 ivory solid; Yield: 31%;

[0210] JPEG2025525896000079.jpg61170

[0211] Compound 36. Sodium 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate

[0212] JPEG2025525896000080.jpg31116 white solid; Yield: 90%;

[0213] JPEG2025525896000081.jpg53170

[0214] Compound 37. Methyl 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate

[0215] JPEG2025525896000082.jpg38120 Yellow solid; Yield: 41%;

[0216] JPEG2025525896000083.jpg61170

[0217] Compound 38. Sodium 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate

[0218] JPEG2025525896000084.jpg38122 ivory solid; Yield: 65%;

[0219] JPEG2025525896000085.jpg61170

[0220] Compound 39. Methyl 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

[0221] JPEG2025525896000086.jpg25106 ivory solid; Yield: 65%;

[0222] JPEG2025525896000087.jpg61170

[0223] Compound 40. Sodium 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

[0224] JPEG2025525896000088.jpg25107 white solid; Yield: 87%;

[0225] JPEG2025525896000089.jpg52170

[0226] Compound 41. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

[0227] JPEG2025525896000090.jpg29111 Yellow solid; Yield: 41%;

[0228] JPEG2025525896000091.jpg61170

[0229] Compound 42. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate

[0230] JPEG2025525896000092.jpg29112 white solid; Yield: 90%;

[0231] JPEG2025525896000093.jpg61170

[0232] Compound 43. Methyl 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0233] JPEG2025525896000094.jpg2792 transparent oil; Yield: 57%;

[0234] JPEG2025525896000095.jpg75170

[0235] Compound 44. 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

[0236] JPEG2025525896000096.jpg2792 white solid; Yield: 97%;

[0237] JPEG2025525896000097.jpg82170

[0238] Compound 45. Methyl 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0239] JPEG2025525896000098.jpg2792 transparent oil; Yield: 28%;

[0240] JPEG2025525896000099.jpg82170

[0241] Compound 46. 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

[0242] JPEG2025525896000100.jpg2792 white solid; Yield: 60%;

[0243] JPEG2025525896000101.jpg82170

[0244] Compound 47. Methyl 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0245] JPEG2025525896000102.jpg2794 transparent oil; Yield: 35%;

[0246] JPEG2025525896000103.jpg83170

[0247] Compound 48. 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxa (3-yl)benzyl)azetidine-3-carboxylic acid

[0248] JPEG2025525896000104.jpg2794 white solid; Yield: 96%;

[0249] JPEG2025525896000105.jpg77170

[0250] Compound 49. Methyl 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0251] JPEG2025525896000106.jpg27102 white solid; Yield: 16%;

[0252] JPEG2025525896000107.jpg76170

[0253] Compound 50. 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

[0254] JPEG2025525896000108.jpg27102 white solid; Yield: 58%;

[0255] JPEG2025525896000109.jpg61170

[0256] Compound 51. 1-(4-(5-(4-hydroxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

[0257] JPEG2025525896000110.jpg27103 white solid; Yield: 66%;

[0258] JPEG2025525896000111.jpg75170

[0259] Compound 52. Methyl 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0260] JPEG2025525896000112.jpg27104 transparent oil; Yield: 23%;

[0261] JPEG2025525896000113.jpg76170

[0262] Compound 53. Sodium 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0263] JPEG2025525896000114.jpg27106 white solid; Yield: 45%;

[0264] JPEG2025525896000115.jpg76170

[0265] Compound 54. Methyl 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0266] JPEG2025525896000116.jpg27102 white solid; Yield: 46%;

[0267] JPEG2025525896000117.jpg82170

[0268] Compound 55. Sodium 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0269] JPEG2025525896000118.jpg27103 white solid; Yield: 100%;

[0270] JPEG2025525896000119.jpg90170

[0271] Compound 56. Sodium 1-(4-(5-(4-propylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0272] JPEG2025525896000120.jpg27110 white solid; Yield: 112%;

[0273] JPEG2025525896000121.jpg105170

[0274] Compound 57. Methyl 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0275] JPEG2025525896000122.jpg27106 white solid; Yield: 45%;

[0276] JPEG2025525896000123.jpg83170

[0277] Compound 58. Sodium 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0278] JPEG2025525896000124.jpg27107 white solid; Yield: 96%;

[0279] JPEG2025525896000125.jpg68170

[0280] Compound 59. Methyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0281] JPEG2025525896000126.jpg29111 transparent oil; Yield: 54%;

[0282] JPEG2025525896000127.jpg92170

[0283] Compound 60. 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid

[0284] JPEG2025525896000128.jpg29111 white solid; Yield: 64%;

[0285] JPEG2025525896000129.jpg81170

[0286] Compound 61. Methyl 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0287] JPEG2025525896000130.jpg27111 white solid; Yield: 83%;

[0288] JPEG2025525896000131.jpg91170

[0289] Compound 62. Sodium 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0290] JPEG2025525896000132.jpg27112 Yellow solid; Yield: 86%;

[0291] JPEG2025525896000133.jpg91170

[0292] Compound 63. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0293] JPEG2025525896000134.jpg29111 Yellow oil; Yield: 44%;

[0294] JPEG2025525896000135.jpg97170

[0295] Compound 64. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0296] JPEG2025525896000136.jpg29112 white solid; Yield: 98%;

[0297] JPEG2025525896000137.jpg92170

[0298] Compound 65. Methyl 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0299] JPEG2025525896000138.jpg29111 transparent oil; Yield: 35%;

[0300] JPEG2025525896000139.jpg95170

[0301] Compound 66. Sodium 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0302] JPEG2025525896000140.jpg29112 white solid; Yield: 92%;

[0303] JPEG2025525896000141.jpg95170

[0304] Compound 67. Methyl 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0305] JPEG2025525896000142.jpg2792 transparent oil; Yield: 46%;

[0306] JPEG2025525896000143.jpg83170

[0307] Compound 68. Sodium 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate

[0308] JPEG2025525896000144.jpg2793 Yellow oil; Yield: 53%;

[0309] JPEG2025525896000145.jpg82170

[0310] Compound 69. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)- 4,5-Dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate

[0311] JPEG2025525896000146.jpg32118 Yellow oil; Yield: 53%;

[0312] JPEG2025525896000147.jpg113170

[0313] Compound 70. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate

[0314] JPEG2025525896000148.jpg32120 yellow solid; Yield: 100%;

[0315] JPEG2025525896000149.jpg105170

[0316] Compound 71. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)piperidine-4-carboxylate

[0317] JPEG2025525896000150.jpg29116 white solid; Yield: 99%;

[0318] JPEG2025525896000151.jpg96170

[0319] Experimental Example 1: Verification of S1P1 agonist activity In order to confirm the effects of Compounds 1 to 71 synthesized in Examples 1 to 3 on S1P1 activity, an in vitro assay using a cell-based evaluation system was carried out. The results are shown in Table 1.

[0320] To analyze the efficacy of functional antagonists, we used two S1P1-overexpressing cell lines that measure the degree of receptor internalization via β-arrestin after GPCR activation. One cell line measures the degree of β-arrestin assembly at the intracellular end of the receptor after S1P1 receptor activation, and the other cell line measures the degree of internalization into endosomes after S1P1 receptor activation. All of these cell lines and materials used in the following examples were purchased from DiscoverX, Eurofins.

[0321] The S1P1 receptor activity of the compounds of the present invention was verified by the method provided by each manufacturer, and the luminescence level at each treatment concentration of the compound was measured, and the EC 50 Specifically, the cell line was placed in assay medium at 1.0 × 10 4 After culturing in an incubator for one day, the cells were lysed and a luminescent substrate was added to measure luminescence. 50 The values are shown in Table 1 below. Among the 71 compounds, compounds 13, 62, 64 and 66, which showed excellent activity, were used in the following additional experimental examples.

[0322] [Table 1-1]

[0323] [Table 1-2]

[0324] [Table 1-3]

[0325] Experimental Example 2: Verification of decrease in blood lymphocyte count To confirm the effect of administration of four compounds selected from Experimental Example 1, namely Compounds 13, 62, 64, and 66, on the reduction of blood lymphocyte count in living rodents, blood samples were taken before and after administration of the compounds and measured using an automatic blood counter. The reduction in blood lymphocyte count over time is shown in Figure 1.

[0326] Specifically, 5-week-old male rats (rats, wisteria, 160-180 g) were acclimated in a temperature- and humidity-controlled room and then orally administered 10 mg / kg of the four selected compounds dissolved in 5% DMSO and 10% Kolliphor HS15 solution. Under inhalation anesthesia with 4% isoflurane, blood was collected from the tail vein using a syringe and transferred to an EDTA-coated tube. Lymphocyte counts were measured from the collected blood using an automated blood counter. Rats administered fingolimod, a known S1P1 receptor modulator, served as a positive control.

[0327] As shown in Figure 1, the lymphocyte count over time after compound administration is shown as a percentage (%) based on the lymphocyte count in rats before compound administration. Similar to the positive control group, the fingolimod-administered group, the group administered with the compound of the example within 5 hours of drug administration was confirmed to have induced a reduction in lymphocyte count of 50% or less. This indicates that oral administration of the compound of the present invention to normal rats induces a reduction in blood lymphocyte count.

[0328] Experimental Example 3: Verification of symptom alleviation effects in an animal model of multiple sclerosis In order to confirm the effect of administering the four compounds selected from Experimental Example 1, namely, Compounds 13, 62, 64, and 66, on symptom relief in an animal model of multiple sclerosis, MOG 35-55 The four compounds were orally administered to a peptide-induced multiple sclerosis model, and the changes in clinical symptoms of stiffness and paralysis were identified and shown in FIG.

[0329] We developed a rodent model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), which is the most commonly used model for multiple sclerosis research.

[0330] Specifically, 10-week-old C57BL6 / J male mice were adapted to a temperature- and humidity-controlled breeding room and then administered MOG. 35-55 A mixture of peptide and complete Freund's adjuvant (CFA) was subcutaneously injected. Additionally, pertussis toxin dissolved in PBS was intraperitoneally injected on days 0 and 1. The timeline and drug administration schedule for the MOG-induced EAE multiple sclerosis animal model are shown in the upper graphs of Figures 2A and 2G.

[0331] The compounds of the present invention were dissolved in a 5% DMSO, 10% Kolliphor HS15 aqueous solution and orally administered daily at doses of 0.3, 3, or 10 mg / kg. The negative control group was prepared by orally administering the same amount of vehicle daily, and the positive control group was prepared by orally administering fingolimod, prepared in the same composition as the compounds of the present invention, at a dose of 3 mg / kg daily. The symptoms of the animal models of the negative control group, positive control group, and experimental group prepared as described above were evaluated and scored using the following scale:

[0332] 0: No abnormalities, 0.5: loss of tail tone; 1.0: loss of tail reflexes, 2.0: loss of tail reflexes and paresthesia in one leg; 3.0: Paresthesia and paralysis of one leg, 3.5: Paralysis of both hind legs, 4.0: Paralysis of front and back legs, 5.0: Critically ill or dead.

[0333] As shown in Figures 2A and 2G, the efficacy of the drugs was evaluated using the symptom scales described above. While the untreated negative control group showed increasingly severe multiple sclerosis symptoms over time, oral administration of the compounds of the present invention alleviated or improved symptoms on a daily basis, and the cumulative total symptom severity over the study period (Figure 2B) and the maximum symptom severity (Figure 2C) were alleviated in a concentration-dependent manner. Furthermore, as shown in Figures 2D and 2E, respectively, the weight change by day and the rate of final weight change indicated that administration of the compounds of the present invention significantly reduced the severity of the disease, reduced the general inflammatory response and food intake restriction due to paralysis, and significantly reduced weight loss. Furthermore, as shown in Figures 2F and 2H, administration of the compounds of the present invention delayed or prevented the onset of symptoms.

[0334] Overall, the compounds of the present invention were found to improve measures of neurological clinical symptoms of the disease in an animal model of EAE induced by MOG peptide, indicating that the compounds of the present invention may be useful in the prevention or treatment of nervous system autoimmune diseases, particularly multiple sclerosis.

[0335] 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 above-described embodiments are merely illustrative and not limiting. The scope of the present invention should be interpreted as including within the meaning and scope of the claims below, and all modifications and variations derived from the equivalent concepts thereof, rather than the above detailed description.

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above Chemical Formula 1, Ring 1 is selenazolenyl or isoxazolenyl, Ring 2 is C ６－１０ aryl, or 5- to 10-membered heteroaryl; R １ is hydrogen, cyano, halo(gen), hydroxy, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ one or more substituents, which may be the same or different, selected from the group consisting of haloalkyl; R ２ and R ３ are each independently hydrogen, C １－６ Alkoxycarbonyl-C １－６ Alkyl or sodium carboxy-C １－６ Is it alkyl? R ２ and R ３ are linked to each other and together with the nitrogen to which they are attached form an unsubstituted or substituted 3- to 10-membered heterocyclyl.

2. The compound according to claim 1, which is represented by any one of the following chemical formulas 2 to 4, or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】

3. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring 2 is phenyl or pyridinyl.

4. R １ is absent and is cyano, bromo, chloro, hydroxy, ethyl, propyl, tert-butyl, methoxy, ethoxy, isopropoxy, chloromethyl, or trifluoromethyl, or a pharmaceutically acceptable salt thereof.

5. R ２ is hydrogen, and R ３ 2. The compound of claim 1, wherein is ethoxycarbonylmethyl, methoxycarbonylethyl, sodium carboxymethyl, or sodium carboxyethyl, or a pharmaceutically acceptable salt thereof.

6. R ２ and R ３ are linked to each other and form, together with the nitrogen to which they are attached, an azetidinyl, pyrrolidinyl, or piperidinyl that is unsubstituted or substituted with one or more selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and carboxysodium, or a pharmaceutically acceptable salt thereof.

7. The compound is 1. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 2. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 3. Ethyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 4. tert-butyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 5. Methyl 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 6. Sodium 1-(4-(2-(3-isocyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 7. Ethyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 8. tert-butyl 1-(4-(2-(3-cyano-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 9. Methyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 10. 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 11. Ethyl 1-(4-(2-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 12. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 13. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 14. Methyl 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 15. Sodium 1-(4-(2-(3-chloro-4-ethoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 16. Methyl 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 17. 1-(4-(2-(4-methoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 18. Methyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 19. 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 20. Ethyl 1-(4-(2-(4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 21. Methyl 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 22. 1-(4-(2-(3-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 23. Methyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 24. 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylic acid; 25. Ethyl 1-(4-(2-(2-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 26. Methyl 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 27. Sodium 1-(4-(2-(pyridin-2-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 28. Methyl 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 29. Sodium 1-(4-(2-(pyridin-3-yl)-1,3-selenazol-5-yl)benzyl)azetidine-3-carboxylate; 30. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate; 31. Sodium 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate; 32. Methyl 1-(4-(2-(4-tert-butylphenyl)-1,3-selenazol-5-yl)benzyl)piperidine-4-carboxylate; 33. Methyl 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate; 34. Sodium 1-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzyl)pyrrolidine-3-carboxylate; 35. Ethyl 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3 -selenazol-5-yl)benzylamino)acetate; 36. Sodium 2-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)acetate; 37. Methyl 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate; 38. Sodium 3-(4-(2-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-5-yl)benzylamino)propanoate; 39. Methyl 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate; 40. Sodium 1-(4-(5-(4-tert-butylphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate; 41. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate; 42. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,3-selenazol-2-yl)benzyl)azetidine-3-carboxylate; 43. Methyl 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 44. 1-(4-(5-phenyl-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 45. Methyl 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 46. 1-(4-(5-(2-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 47. Methyl 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 48. 1-(4-(5-(3-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 49. Methyl 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 50. 1-(4-(5-(4-bromophenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 51. 1-(4-(5-(4-hydroxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 52. Methyl 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 53. Sodium 1-(4-(5-(4-(chloromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 54. Methyl 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 55. Sodium 1-(4-(5-(4-ethylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 56. Sodium 1-(4-(5-(4-propylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 57. Methyl 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 58. Sodium 1-(4-(5-(4-tert-butylphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 59. Methyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 60. 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylic acid; 61. Methyl 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 62. Sodium 1-(4-(5-(3-chloro-4-ethoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 63. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 64. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 65. Methyl 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 66. Sodium 1-(4-(5-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 67. Methyl 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 68. Sodium 1-(4-(5-(pyridin-2-yl)-4,5-dihydroisoxazol-3-yl)benzyl)azetidine-3-carboxylate; 69. Methyl 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate; 70. Sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)pyrrolidine-3-carboxylate; or 71. The compound of claim 1, which is sodium 1-(4-(5-(3-chloro-4-isopropoxyphenyl)-4,5-dihydroisoxazol-3-yl)benzyl)piperidine-4-carboxylate; or a pharmaceutically acceptable salt thereof.

8. A method for producing the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, comprising aminating an aldehyde group of a compound represented by the following chemical formula 5: 【Chemistry 5】 In the above Chemical Formula 1, Ring 1 is selenazolenyl or isoxazolenyl, Ring 2 is C ６－１０ aryl, or 5- to 10-membered heteroaryl; R １ is hydrogen, cyano, halo(gen), hydroxy, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ and one or more substituents, which may be the same or different, selected from the group consisting of haloalkyl.

9. The compound of Formula 5 is R １ -Ring 2-nitrile or 4-(hydroxymethyl)benzonitrile is reacted with selenium and carbon monoxide to form R １ Step a) for preparing a 2-substituted selenoamide or 4-hydroxybenzoselenoamide; Step b: reacting the product of the previous step with 2-bromo-1,1-diethoxyethane and p-toluenesulfonic acid to form a 1,3-selenazole ring substituted at carbon number 5 with Ring 2 or phenyl at carbon number 2; Step c) halogenating the unsubstituted carbon 2 or carbon 5 of the 1,3-selenazole ring of the product of the previous step; and The product of the previous step is reacted with 4-formylphenylboronic acid or R １ 9. The method of claim 8, wherein the compound is prepared through step d of reacting the halogenated ring with a 2-Ring 2-boronic acid to introduce an additional substituent at the halogenated carbon number 2 or carbon number 5.

10. The compound of Formula 5 is Step a' of reacting N-hydroxy-4-(hydroxymethyl)benzimidoyl chloride with triethylamine to remove hydrochloric acid; The product of the previous step is treated with an ethenyl-substituted R １ -Ring 2 to give (4-(5-(R １ -Ring 2)-4,5-dihydroisoxazol-3-yl)phenyl)methanol; and 9. The process of claim 8, wherein the product is prepared through step c' by oxidizing the hydroxy group on the phenyl ring of the product of the previous step.

11. A pharmaceutical composition for preventing or treating multiple sclerosis (MS), comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, as an active ingredient.

12. 12. The pharmaceutical composition of claim 11, wherein the compound is in the form of its sodium salt.

13. 12. The pharmaceutical composition of claim 11, wherein the compound acts as a modulator of sphingosine-1-phosphate receptor (S1P1).

14. The pharmaceutical composition of claim 11, which reduces the number of lymphocytes in the blood.

15. The pharmaceutical composition according to claim 11, which relieves symptoms of stiffness or paralysis.

16. 12. The pharmaceutical composition of claim 11, which delays the onset of multiple sclerosis symptoms.

17. A food composition for preventing or ameliorating multiple sclerosis, comprising the compound according to any one of claims 1 to 7, or a nutritively acceptable salt thereof, as an active ingredient.

18. A feed composition for preventing or ameliorating multiple sclerosis, comprising the compound according to any one of claims 1 to 7, or a feed-technically acceptable salt thereof, as an active ingredient.

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