Novel derivatives of urea and use thereof

Abstract

The present invention relates to novel urea derivative compounds and to the use of these compounds for the prevention or treatment of neuropsychiatric disorders, neurodegenerative diseases, general developmental disorders and / or metabolic diseases through their action as 5HT2A antagonists.

Description

Technology Field

[0001] The present invention relates to a novel urea derivative compound, and its 5HT 2A It relates to the use for the prevention or treatment of neuropsychiatric disorders, neurodegenerative diseases, general developmental disorders, and / or metabolic diseases through its action as an antagonist. Background Technology

[0003] Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in the liver, is becoming a serious global disease. It is closely associated with obesity and chronic liver disease and is considered a major factor in progressive liver diseases such as nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Serotonin (5-hydroxytryptamine; 5HT) is a monoamine found primarily in the gastrointestinal tract, platelets, and the pineal gland, with small amounts found in the brain. In the central nervous system, 5HT acts as a neurotransmitter that regulates mood, behavior, sleep cycles, and appetite. Since 5HT cannot cross the blood-brain barrier (BBB), the central and peripheral serotonin systems are considered separate systems.

[0004] The physiology of peripheral 5HT has been studied since the 1960s, and recent research results have suggested that peripheral 5HT can regulate energy homeostasis. Slc6a4 (serotonin transporter, SERT) knockout mice exhibited an obese phenotype associated with metabolic syndrome, while TPH1 / TPH2 (Tryptophan hydroxylase 1 and 2) double knockout (DKO) mice showed body weight loss. Furthermore, inhibition of 5HT synthesis induced reduced lipogenesis and the introduction of browning in epitestinal white adipose tissue (WAT), as well as the activation of adaptive thermogenesis in brown adipose tissue (BAT). Other studies have indicated that peripheral 5HT can regulate hepatic lipid metabolism. Among the 5HT receptor subtypes, liver-specific 5HT 2A Knockout mice exhibited a reduction in liver size, mass, and lipid accumulation without affecting systemic energy homeostasis, as indicated by histological data, NAS (NAFLD Activity Score), and liver triglyceride (TG) concentrations. The problem to be solved

[0006] As a result of diligent research efforts to discover new compounds starting from a pimavanserin derivative, which is a component of a known Parkinson's disease treatment, the inventors have developed a series of derivatives having controlled blood-brain barrier (BBB) ​​permeability, which are also 5HT, by introducing various substituents to two heterosite sites of pimavanserin—namely, the oxygen substituted on the nitrogen and / or phenyl of piperidine. 2AThe present invention was completed by confirming that it acts as an antagonist, and depending on its BBB permeability, some derivatives are mainly present in the brain and exhibit activity, while other derivatives remain in the periphery for a long time and thus exhibit preventive and / or therapeutic effects against metabolic diseases such as non-alcoholic fatty liver disease. means of solving the problem

[0008] A first aspect of the present invention provides a compound represented by the following formula 1, a tautomer thereof, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof:

[0009] [Chemical Formula 1]

[0010]

[0011] In the above chemical formula 1,

[0012] R1 is hydrogen, C 1-6 Alkyl carbonyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylaminothionyl, C 1-6 Haloalkyl-C 6-10 Aryl-carbamoyl, carboxy-C 1-6 Alkyl carbonyl, (carboxy)(unsubstituted or C 1-6 Alkoxycarbonyl substituted amino)C 1-6 Alkyl carbonyl, ((carboxy)(amino)C 1-6 Alkyl)C 6-10 aryl carbonyl, ((carboxy)(amino)C 1-6 Alkyl)C 3-10 Cycloalkyl carbonyl, (C 1-6 Alkylcarbonylamino-C 6-10 aryloxy(hydroxy)C 1-6 Alkyl, (((carboxy)(amino)C 1-6 Alkyl)C 6-10 aryloxy(hydroxy)C 1-6 Alkyl, or ((carboxy)(amino)C 1-6 Alkyl)C 6-10 Aryloxy-C 1-6 Alkyl;

[0013] R2 is C 1-6 Alkyl, C 5-10Heteroaryl-C 1-6 Alkyl, C 5-10 Heterocyclil-C 1-6 Alkyl, C 5-10 Heteroaryl, C 5-10 Heteroaryl-C 5-10 Heterocyclil-C 1-6 Alkyl, (C 5-10 Heteroaryl-C 5-10 Heterocyclile)(hydroxy)C 1-6 Alkyl, (C 5-10 Heterocyclile)(hydroxy)C 1-6 alkyl, or (C 6-10 Aryl-C 5-10 Heterocyclile)(hydroxy)C 1-6 It is an alkyl,

[0014] C of the above R2 5-10 Heteroaryl, C 5-10 Heterocyclile, and C 6-10 Aryls are non-substituted or C 1-6 Alkoxycarbonyl, C 1-6 Substituted with one or more selected from the group consisting of alkyl, halogen, or oxo.

[0016] Specifically, the compound of Formula 1 can be represented by the following Formula 1-1 or Formula 1-2:

[0017] [Chemical Formula 1-1]

[0018]

[0019] [Chemical Formula 1-2]

[0020] .

[0021] At this time, R1 and R2 are as defined above.

[0023] For example, in the above chemical formula, R1 may be hydrogen, methyl carbonyl, methylsulfonyl, isopropylaminothionyl, (trifluoromethylphenyl)carbamoyl, carboxyethyl carbonyl, carboxypropyl carbonyl, (carboxy)(amino)ethyl carbonyl, (carboxy)(amino)propyl carbonyl, (carboxy)(t-butoxycarbonylamino)propyl carbonyl, (carboxy)(amino)ethyl)phenyl carbonyl, (carboxy)(amino)ethyl)cyclohexyl carbonyl, (methylcarbonylamino)phenoxy(hydroxy)propyl, ((carboxy)(amino)ethyl)phenoxy(hydroxy)propyl, or (carboxy)(amino)ethyl)phenoxypropyl, but is not limited thereto.

[0024] In addition, in the above formula, R2 may be isobutyl, pyridinylmethyl, 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidinylethyl, hydro-1H-isoindolylethyl, thieno[3,2-d]pyrimidinyl, benzo[d]isothiazolylpiperazinylethyl, benzo[d]isothiazolylpiperazinylethyl, (benzo[d]isothiazolylpiperazinyl)(hydroxy)propyl, (benzo[d]isothiazolylpiperazinyl)(hydroxy)propyl, (piperazinyl)(hydroxy)propyl, or (phenylpiperazinyl)(hydroxy)propyl, but is not limited thereto.

[0025] At this time, C of the above R2 5-10 Heteroaryl, C 5-10 Heterocyclile, and C 6-10 The aryl group may be unsubstituted or substituted with one or more selected from the group consisting of methoxycarbonyl, t-butoxycarbonyl, methyl, bromo, chloro, fluoro, or oxo, but is not limited thereto.

[0027] Specifically, the compound of Chemical Formula 1 above is

[0028] 1. 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea,

[0029] 2. 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(piperidin-4-yl)urea hydrochloride,

[0030] 3. 1-(1-acetylpiperidin-4-yl)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)urea,

[0031] 4. 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-(methylsulfonyl)piperidin-4-yl)urea,

[0032] 5. 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)-N-isopropylpiperidine-1-carbothioamide,

[0033] 6. 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide,

[0034] 7. 4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-4-oxobutanoic acid),

[0035] 8. 5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanoic acid),

[0036] 9. (S)-2-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanoic acid((S)-2-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanoic acid),

[0037] 10. (S)-2-(t-butoxycarbonylamino)-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanoic acid((S)-2-(t-butoxycarbonylamino)-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanoic acid),

[0038] 11. (S)-2-amino-4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-4-oxobutanoic acid((S)-2-amino-4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-4-oxobutanoic acid),

[0039] 12. (S)-4-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanoic acid((S)-4-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanoic acid),

[0040] 13. (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)phenyl)propanoic acid hydrochloride((R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)phenyl)propanoic acid hydroxide),

[0041] 14. (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)cyclohexyl)propanoic acid hydrochloride((R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)cyclohexyl)propanoic acid hydroxide),

[0042] 15. N-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-2-hydroxypropoxy)phenyl)acetamide(N-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-2-hydroxypropoxy)phenyl)acetamide),

[0043] 16. (2S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-2-hydroxypropoxy)phenyl)propanoic acid((2S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-2-hydroxypropoxy)phenyl)propanoic acid),

[0044] 17. (S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)propoxy)phenyl)propanoic acid((S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)propoxy)phenyl)propanoic acid),

[0045] 18. Methyl 6-((4-((3-(4-fluorobenzyl)-3-(1-methylpiperidin-4-yl)ureido)methyl)phenoxy)methyl)nicotinate(methyl 6-((4-((3-(4-fluorobenzyl)-3-(1-methylpiperidin-4-yl)ureido)methyl)phenoxy)methyl)nicotinate),

[0046] 19. 1-(4-fluorobenzyl)-3-(4-(2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)ethoxy)benzyl)-1-(1-methylpiperidin-4-yl)urea),

[0047] 20. 3-(4-(7-bromothieno[3,2-d]pyrimidin-4-yloxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea(3-(4-(7-bromothieno[3,2-d]pyrimidin-4-yloxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea),

[0048] 21. 3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea(3-(4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea),

[0049] 22. 3-(4-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea(3-(4-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperazin-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea),

[0050] 23. 3-(4-(2-(1,3-dioxo-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea(3-(4-(2-(1,3-dioxo-1H-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea),

[0051] 24. 3-(4-(3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea(3-(4-(3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea),

[0052] 25. t-butyl 4-(3-(4-((3-(4-fluorobenzyl)-3-(1-methylpiperidin-4-yl)ureido)methyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate,

[0053] 26. 1-(4-fluorobenzyl)-3-(4-(2-hydroxy-3-(piperazin-1-yl)propoxy)benzyl)-1-(1-methylpiperidin-4-yl)urea dihydrochloride (1-(4-fluorobenzyl)-3-(4-(2-hydroxy-3-(piperazin-1-yl)propoxy)benzyl)-1-(1-methylpiperidin-4-yl)urea dihydrochloride),

[0054] 27. 3-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea(3-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea), or

[0055] 28. It may be 3-(4-(3-(4-(3-chloro-4-methylphenyl)piperazin-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea (3-(4-(3-(4-(3-chloro-4-methylphenyl)piperazin-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea), but is not limited thereto.

[0057] The compound of the present invention may exist in the form of a pharmaceutically acceptable salt. As the salt, an acid value salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" in the present invention means any organic or inorganic addition salt of said compound at a concentration having a relatively non-toxic and harmless active effect on the patient, such that side effects caused by said salt do not reduce the beneficial efficacy of the compound represented by Formula 1.

[0058] Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess amount of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, for example, methanol, ethanol, acetone, or acetonitrile. An equal molar amount of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water may be heated, and then the mixture may be dried by evaporation or the precipitated salt may be filtered by suction.

[0059] At this time, organic acids and inorganic acids may be used as free acids. Inorganic acids may include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc., and organic acids may include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, hydroiodic acid, etc., but are not limited to these.

[0060] In addition, pharmaceutically acceptable metal salts can be prepared using a base. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium, or calcium salts as the metal salts, but is not limited to these. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0061] Pharmaceutically acceptable salts of the compounds of the present invention comprise salts of acidic or basic groups that may be present in the compounds of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, and may be prepared through methods for preparing salts known in the art.

[0062] As the salt of the pimavanserin derivative compound of the present invention, any pharmaceutically acceptable salt that exhibits pharmacological activity equivalent to that of the pimavanserin derivative compound may be used without limitation.

[0064] In addition, the compound represented by Formula 1 according to the present invention comprises, without limitation, its pharmaceutically acceptable salts as well as solvates such as possible hydrates that can be prepared therefrom and all possible stereoisomers. The solvates and stereoisomers of the compound represented by Formula 1 can be prepared from the compound represented by Formula 1 using methods known in the art.

[0065] Furthermore, the compound represented by Formula 1 according to the present invention may be prepared in a crystalline or amorphous form, and if prepared in a crystalline form, it may be optionally hydrated or solvated. The present invention may include not only the stoichiometric hydrate of the compound represented by Formula 1 but also compounds containing varying amounts of water. The solvates of the compound represented by Formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0067] A second aspect of the present invention comprises a 5HT comprising, as an active ingredient, the compound of the first aspect, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof. 2A Provides a pharmaceutical composition for the prevention or treatment of active related diseases.

[0069] The term "prevention" in this invention refers to 5HT by the administration of the composition of this invention. 2A "Active" refers to any act of suppressing or delaying the occurrence, spread, and recurrence of related diseases, and "treatment" refers to any act of improving or beneficially altering the symptoms of said disease through the administration of the composition of the present invention.

[0070] The pharmaceutical composition of the present invention is 5HT 2A It can prevent or treat related diseases by acting as an antagonist.

[0071] At this time, 5HT that can be prevented or treated with the pharmaceutical composition of the present invention 2AActivity-related disorders include neuropsychiatric disorders such as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD), and insomnia; neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD); and pervasive developmental disorders (PDD), such as autism, panic disorder, and post-traumatic stress disorder. Or it may be metabolic diseases such as impaired glucose tolerance, hypercholesterolemia, dyslipidemia, obesity, diabetes, hypertension, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), arteriosclerosis due to dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease (coronary artery heart disease), and stroke.

[0073] Preferably, the pharmaceutical composition according to the present invention may contain, as an active ingredient, a compound represented by Formula 1, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 75 weight%, more preferably 1 to 50 weight%, based on the total weight of the composition.

[0074] The composition of the present invention may further include pharmaceutically acceptable carriers, diluents, or excipients, and may be formulated into various forms according to conventional methods for each intended use, such as oral formulations like powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, and injectable formulations like sterile injectable solutions, and may be administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, rectal, and local administration. Examples of suitable carriers, excipients, or diluents that may be included 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, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Additionally, the composition of the present invention may further include fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc.

[0075] Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are formulated by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., into the above composition. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used.

[0076] Examples of oral liquid formulations include suspensions, liquid formulations, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as humectants, sweeteners, flavorings, and preservatives, may be included.

[0077] Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for suppositories, Witepsol, Macrogol, Tween 61, cocoa oil, laurin oil, glycerogelatin, etc., may be used. Meanwhile, injectable preparations may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0079] At this time, the composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" in the present invention refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects. The effective dose level may be determined based on factors including the patient's health status, type and severity of the disease, drug activity, sensitivity to the drug, method of administration, time of administration, route of administration and elimination rate, duration of treatment, drugs used in combination or concurrently, and other factors well known in the medical field. 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 as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects, taking all of the above-mentioned factors into consideration, and this can be easily determined by a person skilled in the art.

[0080] For example, since the dosage may be increased or decreased depending on the route of administration, severity of the disease, gender, body weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0081] Specifically, the effective amount of the compound in the composition of the present invention may vary depending on the patient's age, gender, and body weight, and generally, 1 to 100 mg, preferably 5 to 60 mg per kg of body weight, may be administered daily or every other day, or divided into 1 to 3 doses per day. However, since the dosage may be increased or decreased depending on the route of administration, severity of the disease, gender, body weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0083] A third aspect of the present invention comprises the step of administering the pharmaceutical composition of the second aspect to an individual in need thereof, 5HT 2A Provides a treatment method for active-related diseases.

[0085] The term "entity" in the present invention refers to the above 5HT 2A The term refers to all animals, including humans, monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, for which an active-related disease has been invented or may develop, and the said disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to the individual. The pharmaceutical composition of the present invention may be administered in conjunction with existing therapeutic agents.

[0086] The term "administration" in this invention means providing a specific substance to a patient by any appropriate method, and the route of administration of the composition of this invention may be administered through any general route as long as it can reach the target tissue. It may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, locally, intranasally, intrapulmonaryly, or rectally, but is not limited thereto. Additionally, the pharmaceutical composition of this invention may be administered by any device capable of delivering the active substance to target cells. Preferred modes of administration and formulations include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip infusions, etc. Injectable preparations can be manufactured using aqueous solvents such as physiological saline solution and Ringer's solution, vegetable oils, higher fatty acid esters (e.g., ethyl oleate), alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin), etc., and may include pharmaceutical carriers such as stabilizers to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers to adjust pH, and preservatives to inhibit microbial growth (e.g., phenylmercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

[0087] In the present invention, the term "therapeutically effective amount" used in combination with the active ingredient refers to an amount of a pimavanserin derivative compound, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof that is effective in preventing or treating the target disease.

[0088] Depending on the type of disease to be prevented or treated, the pharmaceutical composition of the present invention may additionally include, as an active ingredient, a known drug used for the prevention or treatment of each known disease, other than a pimavanserin derivative compound, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof. For example, when used for the prevention or treatment of cancer, it may additionally include, as an active ingredient, a known drug other than a pimavanserin derivative compound, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, and may be used in combination with other treatments known for the treatment of these diseases. Effects of the invention

[0090] The novel pimavanserin derivatives of the present invention are 5HT 2A Since it acts as an antagonist, it can be usefully employed for the prevention or treatment of related diseases. In particular, depending on the position and / or type of the substituents included therein, it possesses different blood-brain barrier (BBB) ​​permeability; substances with low BBB permeability act on the periphery for the treatment of metabolic diseases such as non-alcoholic fatty liver disease, while substances with high BBB permeability can be efficiently delivered to the brain and can therefore be used for the treatment of neuropsychiatric disorders, neurodegenerative diseases, and / or pervasive developmental disorders. Brief explanation of the drawing

[0092] Figure 1 shows the compound for HFD-induced NAFLD mice. 14a of in vivo This is a diagram showing the efficiency. Specifically, 12-week-old C57BL / 6J mice were fed HFD for 10 weeks, and during the same period, the compound 14a Intraperitoneal injections were administered. (a) shows the HFD-fed control group and the compound. 14a Total liver mass of treated mice, (b) HFD-fed control and compound14a - Representative liver histological results by hematoxylin and eosin staining from treated mice (scale bar = 100 μm), (c) hepatic triglyceride measurement results, (d) body weight trends, (e) intraperitoneal glucose tolerance test (IPGTT) results after 16 hours of fasting, (f) body composition analyzed by NMR, (g) inguinal WAT (iWAT), epididymal WAT (eWAT), BAT, and muscle (quadriceps) tissue mass, and (h) to (j) representative H&E stained images of iWAT, eWAT, and BAT, respectively. Data are expressed as mean ± SEM (n = 7 per group). p <0.05; **, p <0.01; ***, p <0.00; Con, Control; 14a -50mpk, 14a at 50 mg / kg; 14a -100mpk, 14a at 100 mg / kg. Specific details for implementing the invention

[0093] The present invention will be explained in more detail below through the following examples. However, the following examples are merely illustrative of the present invention and the scope of the present invention is not limited thereto.

[0095]

[0097] Synthesis Example 1: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(piperidine-4-yl)urea hydrochloride (11, GM code 60280)

[0099] Step 1-1: Preparation of t-butyl 4-hydroxybenzyl carbamate (3)

[0100]

[0101] 4-hydroxybenzylamine (2 g, 16.239 mmol), di-t-butyl dicarbonate (7.085 g, 32.478 mmol), and sodium bicarbonate (3.411 g, 40.598 mmol) were dissolved in a mixed solution of water and methanol (water:methanol = 60 mL:60 mL). The mixed solution was stirred at room temperature overnight, after which the methanol was evaporated. Subsequently, ethyl acetate was added for extraction, and the mixture was washed with brine. Sodium sulfate was applied to the organic layer, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (3.57 g, 99%).

[0102] 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.04 (d, J = 6.7 Hz, 2H), 6.78 (d, J = 6.4 Hz, 2H), 5.27 (s, 1H), 4.16 (s, 2H), 1.43 (s, 9H).

[0104] Step 1-2: Preparation of t-butyl 4-isobutoxybenzyl carbamate (4)

[0105]

[0106] t-butyl (4-hydroxybenzyl)carbamate (3.57 g, 15.990 mmol), isobutyl bromide (2.087 mL, 19.188 mmol), and potassium carbonate (3.315 g, 23.984 mmol) obtained from step 1-1 were dissolved in 6 mL of N,N-dimethylformamide and stirred overnight at 80°C. After cooling the mixed solution to room temperature, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate (3×100 mL). The organic layer was washed with brine, treated with sodium sulfate, and the filtrate was concentrated. The concentrated mixture was purified by silica gel column chromatography to obtain the title compound (1.44 g, 42%).

[0107] 1H NMR (400 MHz, DMSO-D6) δ 7.29 (t, J = 6.0 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 4.03 (d, J = 6.1 Hz, 2H), 3.70 (d, J = 6.4 Hz, 2H), 3.32 (s, 1H), 1.94-2.04 (m, 1H), 1.38 (s, 9H), 0.96 (d, J = 6.7 Hz, 6H).

[0109] Step 1-3: Preparation of (4-isobutoxyphenyl)methaneamine hydrochloride (5)

[0110]

[0111] t-butyl (4-isobutoxybenzyl)carbamate (1.44 g, 5.154 mmol) obtained from steps 1-2 above was dissolved in 15 mL of ethyl acetate, and then 15 mL of a 4.0 M hydrochloric acid solution of 1,4-dioxin was added. The mixed solution was stirred at room temperature for 4 hours and then concentrated. Subsequently, the title compound (1.025 g, 92%), which is a white solid, was obtained by filtration.

[0112] 1 H NMR (400 MHz, DMSO-D6) δ 8.35 (s, 2H), 7.39 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 3.92 (s, 2H), 3.74 (d, J = 6.7 Hz, 2H), 1.95-2.05 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H).

[0114] Step 1-4: Preparation of N-(4-isobutoxybenzyl)-1H-imidazole-1-carboxamide (6)

[0115]

[0116] (4-isobutoxyphenyl)methaneamine hydrochloride (1.025 g, 4.752 mmol) and 1,1-carbonyldiimidazole (847.51 mg, 5.227 mmol) were dissolved in 3 mL of N,N-dimethylformamide and stirred overnight. After the reaction was complete, brine and ethyl acetate were added to the mixed solution for extraction. Sodium sulfate was applied to the organic layer, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.38 g, 68%).

[0117] 1 H NMR (400 MHz, CDCl3) δ 8.50 (t, J = 4.7 Hz, 1H), 8.09 (s, 1H), 7.48 (s, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 6.4 Hz, 3H), 4.42 (d, J) = 5.5 Hz, 2H), 3.67 (d, J = 6.4 Hz, 2H), 2.00-2.10 (m, 1H), 1.00 (d, J = 6.7 Hz, 6H).

[0119] Steps 1-5: Preparation of t-butyl 4-(4-fluorobenzylamino)piperidine-1-carboxylate (9)

[0120]

[0121] 4-fluorobenzaldehyde (1.702 mL, 16.115 mmol) and t-butyl 4-aminopiperidine-1-carboxylate (3.227 g, 48.344 mmol) were dissolved in 30 mL of methanol and stirred at room temperature overnight. Subsequently, sodium borohydride (1.837 g, 48.344 mmol) was slowly added to the reaction solution while stirring. The mixed solution was stirred at room temperature overnight and then concentrated. 200 mL of water was added to the concentrate, extracted with ethyl acetate, and washed with brine. Sodium sulfate was applied to the organic layer, the filtrate was concentrated, and purified by silica gel column chromatography to obtain the title compound (3.24 g, 65%).

[0122] 1H NMR (400 MHz, CDCl3) δ 7.26-7.30 (m, 2H), 6.97-7.03 (m, 2H), 3.78 (s, 2H), 2.81 (d, J = 11.9 Hz, 2H), 2.43-2.52 (m, 1H), 2.26 (s, 3H), 1.91-2.01 (m, 4H), 1.41-1.48 (m, 2H).

[0124] Step 1-6: Preparation of t-butyl 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carboxylate (10)

[0125]

[0126] N-(4-isobutoxybenzyl)-1H-imidazole-1-carboxamide (1.38 g, 5.049 mmol) obtained in steps 1-4, t-butyl 4-((4-fluorobenzyl)amino)piperidine-1-carboxylate (1.557 g, 5.049 mmol) obtained in steps 1-5, and potassium carbonate (1.047 g, 7.573 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred overnight. After the reaction was complete, brine and ethyl acetate were added to the mixed solution for extraction. Sodium sulfate was applied to the organic layer, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.930 g, 74%).

[0127] 1 H NMR (400 MHz, DMSO-D6) δ 7.09-7.25 (m, 5H), 6.83-6.90 (m, 3H), 4.41 (s, 2H), 3.91-4.19 (m, 5H), 3.70 (d, J = 6.7 Hz, 2H), 2.68 (s, 2H), 1.96-2.02 (m, 1H), 1.36-1.49 (m, 13H), 0.97 (d, J = 6.7 Hz, 6H).

[0129] Step 1-7: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(piperidine-4-yl)urea hydrochloride (11)

[0130]

[0131] 1.930 g, 3.757 mmol of t-butyl 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carboxylate obtained in steps 1-6 was dissolved in 15 mL of ethyl acetate, and then 15 mL of a 4.0 M hydrochloric acid solution of 1,4-dioxin was added and stirred for 12 hours. Afterward, the mixed solution was concentrated and filtered to obtain the title compound (1.5 g, 88%), which is a white solid.

[0132] 1 H NMR (400 MHz, DMSO-D6) δ 7.65-7.69 (m, 1H), 7.23-7.30 (m, 2H), 7.10-7.16 (m, 3H), 6.84 (t, J = 8.4 Hz, 2H), 4.41 (s, 1H), 4.13-4.20 (m, 4H), 3.70 (d, J = 6.4 Hz, 2H), 2.87 (d, J = 16.5 Hz, 2H), 2.26 (d, J = 12.2 Hz, 1H), 1.80-2.02 (m, 3H), 1.63 (d, J = 12.5 Hz, 1H), 1.23 (s, 2H), 0.96 (d, J = 6.7 Hz, 6H);

[0133] 13 C NMR (100 MHz, DMSO-D6) δ 162.18, 159.78, 157.48, 157.33, 136.61, 132.91, 128.37, 128.30, 128.25, 115.01, 114.81, 114.07, 73.75, 66.39, 50.14, 44.24, 43.11, 42.99, 27.74, 26.64, 19.10;

[0134] HRMS (FAB) m / z calculated for C 24 H 33 FN3O2[M + H] + 414.2557, found 414.2557;

[0135] HPLC purity 95.9277%.

[0137]

[0139] Synthesis Example 2: Preparation of 1-(1-acetylpiperidine-4-yl)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)urea (12a, GM code 60269) and 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-(methylsulfonyl)piperidine-4-yl)urea (12b, GM code 60133)

[0141] The compound prepared according to Synthesis Example 1 above 11 N,N-diisopropylethylamine (0.116 mL, 0.667 mmol) was added to a 10 mL solution of dichloromethane (100 mg, 0.222 mmol) at 0°C. Acetyl chloride (0.019 mL, 0.267 mmol) or methanesulfonyl chloride (0.021 mL, 0.267 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 1 hour. The resulting mixture was extracted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The concentrate was purified by silica gel column chromatography to obtain the title compound.

[0142] 12a : 62 mg(61%)

[0143] 1 H NMR (400 MHz, DMSO-D6) δ 7.18-7.21 (m, 2H), 7.07 (t, J = 7.9 Hz, 4H), 6.79-6.89 (m, 3H), 4.37 (s, 3H), 4.17 (d, J = 4.9 Hz, 3H), 3.66-3.77 (m, 3H), 2.93-2.98 (m, 1H), 2.38-2.46 (m, 1H), 1.89-1.99 (m, 5H), 1.29-1.48 (m, 4H), 0.93 (d, J = 6.4 Hz, 6H);

[0144] 13 C NMR (100 MHz, DMSO-D6) δ 167.89, 162.10, 159.69, 157.47, 136.89, 133.03, 128.31, 128.23, 128.17, 114.87, 114.66, 114.44, 114.08, 73.76, 52.70, 45.36, 44.04, 43.12, 40.48, 30.53, 29.77, 27.74, 21.26, 19.09;

[0145] HRMS (FAB) m / z calculated for C 26 H 34 FN3O3[M + H] + 455.2584, found 455.2583;

[0146] HPLC purity 100% (Method A).

[0147] 12b : 86 mg(79%)

[0148] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.18 (dd, J = 8.5, 5.2 Hz, 2H), 6.98-7.03 (m, 4H), 6.77 (d, J = 8.9 Hz, 2H), 4.50-4.57 (m, 2H), 4.31 (s, 2H), 4.26 (d, J = 5.2 Hz, 2H), 3.84 (dd, J = 10.1, 2.1 Hz, 2H), 3.68 (d, J = 6.4 Hz, 2H), 2.72-2.78 (m, 5H), 2.01-2.11 (m, 1H), 1.84 (d, J = 10.1 Hz, 2H), 1.69 (qd, J = 12.4, 4.3 Hz, 2H), 1.01 (d, J = 6.7 Hz, 6H);

[0149] 13 C NMR (100 MHz, DMSO-D6) δ 162.16, 159.76, 157.51, 157.48, 136.82, 136.80, 132.96, 128.43, 128.35, 128.21, 114.95, 114.74, 114.10, 73.76, 52.02, 45.40, 44.11, 43.16, 34.11, 29.48, 27.75, 19.09;

[0150] HRMS (EI) m / z calculated for C 25 H 34 FN3O4S [M + H] + 491.2254, found 491.2255;

[0151] HPLC purity 99.4001% (Method A).

[0153] Synthesis Example 3: Preparation of 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)-N-isopropylpiperidine-1-carbothioamide (12c, GM code 60135)

[0155] The compound prepared according to Synthesis Example 1 above 11 N,N-diisopropylethylamine (0.116 mL, 0.667 mmol) was added to a 10 mL solution of tetrahydrofuran (100 mg, 0.222 mmol) at 40°C. A 1 mL solution of tetrahydrofuran containing isopropyl isothiocyanate (22.48 mg, 0.222 mmol) was added dropwise to the reaction mixture and stirred for 1 hour. Subsequently, the mixed solution was concentrated and extracted with ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the title compound ( 12c )(111 mg, 97%) was obtained.

[0156] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.15-7.18 (m, 2H), 6.94-7.02 (m, 4H), 6.77 (d, J = 11.6 Hz, 2H), 5.29 (d, J = 7.6 Hz, 1H), 4.49-4.70 (m, 5H), 4.24 (d, J = 18.0 Hz, 4H), 3.62-3.71 (m, 2H), 2.96-3.05 (m, 2H), 2.02-2.11 (m, 1H), 1.81 (d, J = 11.9 Hz, 2H), 1.49-1.62 (m, 2H), 1.22 (d, J = 6.4 Hz, 6H), 1.01 (d, J = 6.7 Hz, 6H);

[0157] 13C NMR (100 MHz, DMSO-D6) δ 179.74, 162.11, 159.70, 157.46, 136.77, 133.00, 128.24, 128.17, 114.87, 114.66, 114.07, 73.76, 52.76, 47.20, 46.79, 44.06, 43.13, 29.98, 27.74, 22.08, 19.08;

[0158] HRMS (FAB) m / z calculated for C 28 H 40 FN4O2S [M + H] + 515.2856, found 515.2859;

[0159] HPLC purity 99.5427% (Method A).

[0161] Synthesis Example 4: Preparation of 4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-4-oxobutanoic acid (13, GM code 60252)

[0163] Compound dissolved in tetrahydrofuran (10 mL) 11 A mixture of free base (100 mg, 0.242 mmol) and succinic anhydride (26.62 mg, 0.266 mmol) was refluxed for 12 hours. The mixed solution was evaporated and purified by silica gel column chromatography to obtain the compound 13 (76 mg, 61%) was obtained.

[0164] 1H NMR (400 MHz, CHLOROFORM-D) δ 7.16 (dd, J = 8.5, 5.2 Hz, 2H), 6.99 (t, J = 9.2 Hz, 4H), 6.77 (d, J = 8.5 Hz, 2H), 4.54-4.66 (m, 3H), 4.26 (t, J) = 5.0 Hz, 4H), 3.90 (d, J = 13.4 Hz, 1H), 3.67 (d, J = 6.4 Hz, 2H), 3.13 (t, J = 12.1 Hz, 1H), 2.60-2.69 (m, 5H), 2.01-2.11 (m, 1H), 1.80 (dd, J = 29.3, 11.6 Hz, 2H), 1.41-1.54 (m, 2H), 1.01 (d, J = 6.7 Hz, 6H);

[0165] 13 C NMR (100 MHz, DMSO-D6) δ 174.09, 169.30, 162.13, 159.73, 157.52, 136.90, 133.04, 128.35, 128.21, 114.90, 114.69, 114.12, 73.80, 52.74, 44.32, 44.08, 43.16, 40.95, 30.44, 29.95, 29.09, 27.77, 27.34, 19.11;

[0166] HRMS (FAB) m / z calculated for C 28 H 37 FN3O5[M + H] + 514.2717, found 514.2714;

[0167] HPLC purity 96.2706% (Method A).

[0169]

[0171] Synthesis Example 5: Preparation of (S)-2-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanic acid (14a, GM code 60130), (S)-2-amino-4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-4-oxobuttanic acid (14b, GM code 60131) and (S)-4-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-5-oxopentanic acid (14c, GM code 60183)

[0173] The compound prepared according to Synthesis Example 1, dissolved in N,N-dimethylformamide (1 mL). 11A mixture of (250 mg, 0.556 mmol), amino acid (0.611 mmol), EDCI (266.25 mg, 1.389 mmol), HOBt (112.68 mg, 0.833 mmol), and DIPEA (0.340 mL, 1.944 mmol) was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Subsequently, the concentrate was purified by silica gel column chromatography to obtain the compound.

[0174] A methanol (80 mL) solution of the mixture of the above-obtained compound and Pd / C was stirred under a hydrogen balloon for 2 hours. The mixture was filtered and concentrated, then filtered with diethyl ether to obtain the compound.

[0176] Step 5-1: Preparation of (S)-Benzyl 2-(Benzyloxycarbonylamino)-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanate

[0177]

[0178] Compound obtained from Synthesis Example 1 11 A mixture of (250 mg, 0.557 mmol), 1-benzyl N-carbobenzoxy-L-glutamate (207 mg, 0.557 mmol), EDCI (267.12 mg, 1.393 mmol), HOBt (113.04 mg, 0.836 mmol), and DIPEA (0.341 mL, 1.951 mmol) was dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 16 hours. The mixed solution was extracted with ethyl acetate and water, the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. Subsequently, the concentrate was purified by silica gel column chromatography to obtain the title compound (138 mg, 75%).

[0179] 1H NMR (400 MHz, CHLOROFORM-D) δ 7.29 (s, 10H), 7.14 (s, 2H), 6.97 (d, J = 17.1 Hz, 4H), 6.75 (s, 2H), 5.90 (d, J = 16.5 Hz, 1H), 5.01-5.18 (m, 4H), 4.62 (d, J = 17.4 Hz, 3H), 4.32 (d, J = 47.0 Hz, 5H), 3.66 (s, 3H), 2.92-2.98 (m, 1H), 2.50 (t, J = 12.5 Hz, 1H), 1.96-2.22 (m, 5H), 1.70 (s, 2H), 1.34-1.41 (m, 2H), 0.99 (s, 6H).

[0181] Step 5-2: Preparation of (S)-2-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanic acid (14a)

[0182]

[0183] Pd / C (100 mg) was added to the compound prepared according to Step 5-1 above, which was dissolved in methanol (100 mL), and stirred for 2 hours under a hydrogen balloon. The reaction mixture was filtered through Celite and evaporated. The concentrate was filtered with diethyl ether to obtain the title compound.

[0184] 1H NMR (400 MHz, METHANOL-D4) δ 7.23 (dd, J = 8.4, 5.3 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.01 (t, J = 8.9 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.58 (d, J = 13.4 Hz, 1H), 4.47 (s, 2H), 4.27-4.35 (m, 3H), 3.96 (d, J = 14.0 Hz, 1H), 3.71 (d, J = 6.4 Hz, 2H), 3.58 (dd, J = 13.4, 5.8 Hz, 1H), 3.07-3.14 (m, 1H), 2.54-2.67 (m, 3H), 1.97-2.10 (m, 3H), 1.48-1.75 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H);

[0185] 13 C NMR (100 MHz, DMSO-D6) δ 170.31, 169.99, 162.09, 159.67, 157.47, 136.91, 132.99, 128.34, 128.26, 128.17, 114.87, 114.66, 114.09, 73.76, 53.70, 52.73, 44.39, 44.05, 43.11, 40.72, 30.53, 29.95, 29.00, 27.74, 26.76, 19.10;

[0186] HRMS (FAB) m / z calculated for C 29 H 40 FN4O5[M + H] + 543.2983, found 543.2984;

[0187] HPLC purity 98.2157% (Method A).

[0189] 14b : 78 mg(29%)

[0190] 1H NMR (400 MHz, METHANOL-D4) δ 7.21-7.24 (m, 2H), 7.09 (d, J = 6.7 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 6.80 (d, J = 8.2 Hz, 2H), 4.57 (d, J = 12.8 Hz, 1H), 4.47 (s, 2H), 4.27-4.35 (m, 3H), 3.92 (d, J = 13.7 Hz, 1H), 3.80-3.85 (m, 1H), 3.71 (d, J = 6.4 Hz, 2H), 3.06-3.15 (m, 1H), 2.95 (d, J = 12.5 Hz, 1H), 2.82 (q, J = 8.9 Hz, 1H), 2.64 (t, J = 12.1 Hz, 1H), 1.99-2.08 (m, 1H), 1.49-1.76 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H);

[0191] 13 C NMR (100 MHz, DMSO-D6) δ 168.68, 168.47, 162.08, 159.67, 157.46, 136.95, 136.92, 136.88, 133.06, 128.34, 128.27, 128.20, 114.86, 114.66, 114.06, 73.75, 52.57, 50.79, 44.42, 44.07, 43.10, 40.92, 33.50, 30.20, 29.86, 27.74, 19.10;

[0192] HRMS (FAB) m / z calculated for C 28 H 38 FN4O5[M + H] + 529.2826, found 529.2830;

[0193] HPLC purity 99.8650% (Method B).

[0194] 14c : 110 mg(37%)

[0195] 1H NMR (400 MHz, METHANOL-D4) δ 7.23 (dd, J = 13.4, 7.9 Hz, 2H), 7.10 (dd, J = 8.1, 5.3 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 4.46-4.57 (m, 3H), 4.28-4.39 (m, 4H), 3.96-4.03 (m, 1H), 3.71 (d, J = 6.4 Hz, 2H), 3.18 (q, J = 12.9 Hz, 1H), 2.68-2.76 (m, 1H), 2.43 (d, J = 6.1 Hz, 2H), 1.87-2.09 (m, 3H), 1.55-1.80 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H);

[0196] 13 C NMR (100 MHz, DMSO-D6) δ 174.81, 169.21, 162.12, 159.71, 157.47, 136.93, 133.04, 128.49, 128.40, 128.32, 128.21, 114.90, 114.69, 114.09, 73.77, 52.53, 49.42, 44.33, 44.13, 43.11, 31.70, 31.46, 30.56, 30.37, 29.90, 27.91, 27.64, 27.35, 19.11;

[0197] HRMS (FAB) m / z calculated for C 29 H 40 FN4O5[M + H] + 543.2983, found 543.2984;

[0198] HPLC purity 100% (Method B).

[0200] Synthesis Example 6: Preparation of (S)-2-(t-butoxycarbonylamino)-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanic acid (15, GM code 60270)

[0202] The compound prepared according to Synthesis Example 5, dissolved in 1,4-dioxane (10 mL) and water (10 mL). 14aA mixture of (1 g, 1.843 mmol), di-t-butyl dicarbonate (603.29 mg, 2.764 mmol), and NaOH (147.42 mg, 3.686 mmol) was stirred at room temperature for 24 hours. The mixed solution was evaporated and extracted with ethyl acetate and potassium hydrogen sulfate solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound 15 obtained.

[0203] 1 H NMR (400 MHz, METHANOL-D4) δ 7.22 (dd, J = 7.9, 5.8 Hz, 2H), 7.08-7.10 (m, 2H), 7.01 (t, J = 8.9 Hz, 2H), 6.80 (d, J = 8.2 Hz, 2H), 4.56 (d, J = 12.8 Hz, 1H), 4.46 (s, 2H), 4.30 (d, J = 18.6 Hz, 3H), 3.95 (d, J = 12.8 Hz, 1H), 3.70 (d, J = 6.7 Hz, 2H), 3.09 (t, J = 12.2 Hz, 1H), 2.36-2.64 (m, 3H), 1.99-2.17 (m, 4H), 1.84-1.93 (m, 1H), 1.51-1.74 (m, 4H), 1.42 (s, 9H), 1.02 (d, J = 6.7 Hz, 6H);

[0204] 13 C NMR (100 MHz, DMSO-D6) δ 173.98, 169.58, 162.11, 159.70, 157.47, 155.64, 136.87, 133.01, 128.31, 128.23, 128.17, 114.88, 114.67, 114.10, 78.04, 73.78, 53.07, 52.74, 44.41, 44.05, 43.12, 40.79, 30.50, 29.93, 28.77, 28.21, 27.74, 26.56, 19.09;

[0205] HRMS (FAB) m / z calculated for C34 H 48 FN4O7[M + H] + 643.3507, found 643.3504;

[0206] HPLC purity 99.3140% (Method A).

[0208]

[0210] Synthesis Example 7: Preparation of (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)phenyl)propanoic acid hydrochloride (22, GM code 60215)

[0212] Step 7-1: Preparation of (S)-ethyl 2-amino-3-(4-hydroxyphenyl)propanoate (17)

[0213] L-tyrosine (in 800 mL of ethanol) 16 Thionyl chloride (100.1 mL, 1.38 mol) was slowly added dropwise at 0°C to a mixture in which )(100 g, 0.552 mol) was dissolved. After stirring the mixture at 0°C for 60 minutes, the reaction mixture was left to stand at room temperature and heated to reflux overnight. Volatile substances were removed under reduced pressure to obtain the compound 17 obtained.

[0215] Step 7-2: Preparation of (S)-ethyl 2-(t-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (18)

[0216] The compound obtained from step 7-1 above 17 To a solution of methanol (100 mL) and dichloromethane (800 mL), a solution of dichloromethane (200 mL) containing triethylamine (154 mL, 1.1 mol) and di-t-butyl dicarbonate (120.5 g, 0.552 mol) was added sequentially at 0°C. The resulting mixture was stirred overnight at room temperature. The suspension was filtered to remove the solid, and the filtrate was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to form a white solid compound. 18 (136 g, 80%) was obtained.

[0218] Step 7-3: Preparation of (S)-ethyl 2-(t-butoxycarbonylamino)-3-(4-(trifluoromethylsulfonyloxy)phenyl)propanoate (19)

[0219] The compound obtained from step 7-2 above 18Triflic anhydride (25.1 mL, 0.149 mol) was added dropwise at 0°C to a dichloromethane solution of (44 g, 0.142 mol) and pyridine (44.8 mL, 0.569 mol). The reaction mixture was stirred for 1 hour at room temperature. The mixture was poured into a saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain a white solid compound. 19 (60 g, 95%) was obtained.

[0221] Step 7-4: Preparation of (S)-4-(2-(t-butoxycarbonylamino)-3-ethoxy-3-oxopropyl)benzoic acid (20)

[0222] The compound obtained from step 7-3 above 19 To a 4 mL solution of 1,4-dioxane (3 g, 6.796 mmol) of molybdenum hexacarbonyl (897.14 mg, 3.39 mmol), palladium (II) acetate (152.58 mg, 0.68 mmol), 1,1'-bis(diphenylphosphino)ferrocene (376.8 mg, 0.68 mmol, 0.1 eq.), 4-dimethylaminopyridine (1.66 g, 13.59 mmol), N,N-diisopropylethylamine (2.03 g, 15.63 mmol), and water (2.5 g, 0.136 mol) were added. Subsequently, the above reaction mixture was [prepared] using a single-mode microwave instrument (Biotage Initiator 2.5 The reaction mixture was irradiated at 110°C for 1 hour. The reaction mixture was diluted with a saturated sodium carbonate solution and washed with diethyl ether. The separated aqueous layer was filtered through Celite, the filtrate was acidified with a 5N hydrochloric acid solution, and extracted twice with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to form a white solid compound. 20 (1.8 g, 78%) was obtained.

[0223] 1H NMR (400 MHz, DMSO-d6): δ 12.81 (s, 1H), 7.80 (d, J = 8.24 Hz, 2H), 7.36 - 7.27 (m, 3H), 4.18 -4.09 (m, 1H), 4.07 - 3.95 (m, 2H), 3.05 - 2.83 (m, 2H), 1.27 (s, 9H), 1.07 (t, J = 7.02 Hz, 3H).

[0225] Step 7-5: Preparation of (R)-ethyl 2-(t-butoxycarbonylamino)-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)phenyl)propanoate (21)

[0226] Compound obtained from Synthesis Example 1 above 11 (200 mg, 0.444 mmol), the compound obtained from step 7-4 above 20 An N,N-dimethylformamide (2 mL) solution of a mixture of (164.94 mg, 0.489 mmol), EDCI (213.00 mg, 1.111 mmol), HOBt (90.14 mg, 0.667 mmol), and DIPEA (0.272 mL, 1.556 mmol) was stirred at room temperature for 18 hours. The mixed solution was extracted with ethyl acetate and a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. Subsequently, the concentrate was purified by silica gel column chromatography to determine the compound 21 (241 mg, 74%) was obtained.

[0227] 1H NMR (400 MHz, CHLOROFORM-D) δ 7.29 (t, J = 8.1 Hz, 2H), 7.15-7.20 (m, 4H), 7.00 (dd, J = 12.5, 8.5 Hz, 4H), 6.77 (d, J = 8.5 Hz, 2H), 5.00 (d, J = 8.2 Hz, 1H), 4.51-4.78 (m, 4H), 4.29 (d, J = 18.9 Hz, 6H), 3.81 (s, 1H), 3.67 (d, J = 6.7 Hz, 2H), 2.83-3.16 (m, 4H), 2.01-2.11 (m, 1H), 1.60-1.86 (m, 3H), 1.39 (s, 9H), 1.23 (t, J = 7.0 Hz, 3H), 1.01 (d, J = 6.7 Hz, 6H).

[0229] Step 7-6: Preparation of (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)phenyl)propanoic acid hydrochloride (22)

[0230] The compound obtained from steps 7-5 above 21 NaOH (52.61 mg, 1.315 mmol) was added to a THF / H2O (3:1, 120 mL) solution (241 mg, 0.329 mmol) and stirred at room temperature for 24 hours. The mixed solution was evaporated to remove THF and acidified to pH 3 with 1N hydrochloric acid. Subsequently, the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-2-((t-butoxycarbonyl)amino)-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)phenyl)propanoic acid.

[0231] A 4M hydrochloric acid solution in 1,4-dioxane (6 mL) was added to a solution of a compound dissolved in ethyl acetate (6 mL). The mixture was stirred at room temperature for 6 hours, then concentrated and filtered to obtain the product.

[0232] 1H NMR (400 MHz, METHANOL-D4) δ 7.38 (s, 4H), 7.24 (dd, J = 8.5, 5.5 Hz, 2H), 7.07-7.10 (m, 2H), 6.99-7.04 (m, 2H), 6.79-6.82 (m, 2H), 4.68 (d, J = 13.4 Hz, 1H), 4.51 (s, 2H), 4.27-4.38 (m, 5H), 3.71 (d, J = 6.7 Hz, 2H), 3.36 (dd, J = 14.5, 5.3 Hz, 1H), 3.18 (dd, J = 14.3, 7.9 Hz, 2H), 2.86 (s, 1H), 1.99-2.07 (m, 2H), 1.61-1.79 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H);

[0233] 13 C NMR (100 MHz, DMSO-D6) δ 170.26, 168.78, 162.10, 159.69, 157.46, 136.93, 136.29, 135.09, 133.04, 129.57, 128.37, 128.20, 126.93, 114.89, 114.68, 114.08, 73.78, 53.03, 52.62, 44.05, 43.10, 35.34, 27.74, 19.11;

[0234] HRMS (FAB) m / z calculated for C 34 H 42 FN4O5[M + H] + 605.3139, found 605.3141;

[0235] HPLC purity 97.0183% (Method A).

[0237]

[0239] Synthesis Example 8: Preparation of t-butyl 4-(3-(4-((3-(4-fluorobenzyl)-3-(1-methylpiperidine-4-yl)ureido)methyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate (30, GM code 60276)

[0241] Step 8-1: Preparation of 2-(4-hydroxybenzyl)isoindolin-1,3-dione (23)

[0242] 4-hydroxybenzylamine dissolved in N,N-dimethylformamide (6 mL) ( 2A mixed solution of ) (1 g, 8.120 mmol) and phthalic anhydride (1.443 g, 9.743 mmol) was stirred at 140°C for 18 hours. The mixed solution was extracted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. Subsequently, the concentrate was purified by silica gel column chromatography to obtain the compound 23 (663 mg, 32%) was obtained.

[0243] 1 H NMR (400 MHz, METHANOL-D4) δ 7.76-7.86 (m, 4H), 7.21 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 6.4 Hz, 2H), 4.71 (s, 2H).

[0245] Step 8-2: Preparation of 2-(4-(oxiran-2-ylmethoxy)benzyl)isoindolin-1,3-dione (24)

[0246] The compound obtained from step 8-1 above 23 Epichlorohydrin (0.225 mL, 2.880 mmol) and potassium carbonate (542.72 mg, 3.927 mmol) were added to a 6 mL solution of acetonitrile (663 mg, 2.618 mmol) and refluxed for 18 hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was evaporated and purified by silica gel column chromatography to obtain the compound 24 (403 mg, 50%) was obtained.

[0247] 1 H NMR (400 MHz, DMSO-D6) δ 7.90-7.82 (4H), 7.24 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 4.72-4.67 (2H), 4.26-4.30 (m, 1H), 3.78 (dd, J = 11.4, 6.6 Hz, 1H), 3.27-3.31 (m, 1H), 2.82 (t, J = 4.7 Hz, 1H), 2.68 (q, J = 2.5 Hz, 1H).

[0249] Step 8-3: Preparation of t-butyl 4-(3-(4-((1,3-dioxoisoindolin-2-yl)methyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate (25)

[0250] The compound obtained from step 8-2 above 24 A 6 mL solution of an isopropyl alcohol mixture of (403 mg, 1.303 mmol) and 1-t-butoxycarbonyl piperazine (266.94 mg, 1.433 mmol) was refluxed for 18 hours. The obtained mixture was concentrated and then purified by silica gel column chromatography to obtain the compound 25 (326 mg, 51%) was obtained.

[0251] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.83 (q, J = 2.8 Hz, 2H), 7.69-7.72 (m, 2H), 7.36-7.39 (m, 2H), 6.85 (d, J = 4.6 Hz, 2H), 4.78 (s, 2H), 4.05-4.10 (m, 1H), 3.95 (d, J = 4.9 Hz, 2H), 3.39-3.45 (m, 4H), 2.48-2.61 (m, 4H), 2.37-2.42 (m, 2H), 1.46 (s, 9H).

[0253] Step 8-4: Preparation of t-butyl 4-(3-(4-(aminomethyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate (26)

[0254] The compound obtained from step 8-3 above 25 An ethanol (10 mL) solution of a mixture of (326 mg, 0.658 mmol) and hydrazine monohydrate (131.72 mg, 2.631 mmol) was refluxed for 24 hours. The mixed solution was cooled to room temperature and filtered to remove 2,3-dihydrophthalazine-1,4-dione. The filtrate was evaporated and purified by silica gel column chromatography to obtain the compound 26 (195 mg, 81%) was obtained.

[0255] 1H NMR (400 MHz, CHLOROFORM-D) δ 7.22 (d, J = 8.5 Hz, 2H), 6.87-6.91 (m, 2H), 4.08-4.13 (m, 1H), 3.99 (d, J = 4.9 Hz, 2H), 3.80 (s, 2H), 3.40-3.50 (m, 4H), 2.51-2.64 (m, 4H), 2.39-2.44 (m, 2H), 1.46 (s, 9H).

[0257] Step 8-5: Preparation of t-butyl 4-(3-(4-((1H-imidazole-1-carboxamido)methyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate (27)

[0258] The compound obtained from step 8-4 above 26 1,1'-carbonyldiimidazole (95.17 mg, 0.587 mmol) was added to a solution of (195 mg, 0.534 mmol) dissolved in N,N-dimethylformamide (1 mL) and stirred for 16 hours. The obtained solution was used in subsequent processes without further purification.

[0260] Step 8-6: Preparation of N-(4-fluorobenzyl)-1-methylpiperidine-4-amine (29)

[0261] 4-fluorobenzaldehyde ( 7 )(1.695 mL, 16.115 mmol) and 4-amino-1-methylpiperidine( 28 )(1.840 g, 16.115 mmol) was dissolved in methanol (30 mL) and stirred at room temperature for 16 hours. Sodium borohydride (1.837 g, 48.344 mmol) was added to the reaction mixture and stirred for 16 hours. The mixed solution was evaporated and extracted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the compound 29 (3.24 g, 90%) was obtained.

[0262] 1H NMR (400 MHz, CDCl3) δ 7.26-7.30 (m, 2H), 6.97-7.03 (m, 2H), 3.78 (s, 2H), 2.81 (d, J = 11.9 Hz, 2H), 2.43-2.52 (m, 1H), 2.26 (s, 3H), 1.91-2.01 (m, 4H), 1.41-1.48 (m, 2H).

[0264] Step 8-7: Preparation of t-butyl 4-(3-(4-((3-(4-fluorobenzyl)-3-(1-methylpiperidine-4-yl)ureido)methyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate (30)

[0265] The compound obtained from steps 8-6 above 29 (118.62 mg, 0.534 mmol) was added to the reaction mixture obtained from steps 8-5 above and stirred for 24 hours. The mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the compound 30 (203 mg, 62%) was obtained.

[0266] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.18 (dd, J = 8.2, 5.5 Hz, 2H), 6.96-7.03 (m, 4H), 6.80 (d, J = 8.5 Hz, 2H), 4.57 (d, J = 5.2 Hz, 1H), 4.27-4.35 (m, 5H), 4.06-4.13 (m, 1H), 3.94-3.96 (m, 2H), 3.38-3.44 (m, 4H), 2.87 (d, J = 11.6 Hz, 2H), 2.39-2.69 (m, 6H), 2.26 (s, 3H), 2.08 (td, J = 11.4, 3.2 Hz, 2H), 1.62-1.70 (m, 4H), 1.46 (s, 9H);

[0267] 13C NMR (100 MHz, DMSO-D6) δ 159.69, 157.56, 157.00, 153.82, 137.08, 128.40, 128.32, 128.20, 128.16, 114.88, 114.67, 114.23, 114.11, 78.72, 71.00, 66.55, 61.05, 54.83, 53.30, 52.24, 45.70, 43.98, 43.10, 29.84, 28.09;

[0268] HRMS (FAB) m / z calculated for C 33 H 49 FN5O5[M + H] + 614.3718, found 614.3722;

[0269] HPLC purity 96.4712%.

[0271] Synthesis Example 9: Preparation of 1-(4-fluorobenzyl)-3-(4-(2-hydroxy-3-(piperazine-1-yl)propoxy)benzyl)-1-(1-methylpiperidine-4-yl)urea dihydrochloride (31, GM code 60277)

[0273] A compound prepared according to Synthesis Example 8, a 4M hydrochloric acid solution dissolved in 1,4-dioxane (5 mL). 30 (150 mg, 0.244 mmol) was added to a solution dissolved in ethyl acetate (5 mL) and stirred at room temperature for 4 hours. The obtained mixture was evaporated and filtered to obtain the product ( 31 ) was obtained (130 mg, 91%).

[0274] 1 H NMR (400 MHz, METHANOL-D4) δ 7.26 (dd, J = 7.8, 4.4 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.04 (t, J = 8.5 Hz, 2H), 6.85-6.94 (m, 2H), 4.51 (s, 3H), 4.32 (d, J = 22.6 Hz, 4H), 4.00-4.05 (m, 1H), 3.60-3.66 (m, 5H), 3.50 (s, 3H), 3.11 (s, 2H), 2.83 (s, 2H), 2.01-2.08 (m, 7H), 1.89 (d, J = 13.4 Hz, 2H);

[0275] 13 C NMR (100 MHz, DMSO-D6) δ 159.84, 157.51, 157.00, 136.45, 133.51, 128.46, 128.38, 128.32, 119.25, 115.12, 114.91, 114.31, 70.07, 64.05, 58.52, 53.04, 49.58, 48.81, 44.24, 43.10, 42.36, 26.94;

[0276] HRMS (FAB) m / z calculated for C 26 H 34 FN3O3[M + HCl] + 550.2960, found 550.2962;

[0277] HPLC purity 96.6515% (Method B).

[0279]

[0281] Synthesis Example 10: Preparation of 3-(4-(3-(4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (35a, GM code 60271) and 3-(4-(3-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (35b, GM code 60278)

[0283] Step 10-1: Preparation of t-butyl 4-(oxiran-2-ylmethoxy)benzylcarbamate (32)

[0284] The compound obtained from Step 1-1 of Synthesis Example 1 above 3 Epichlorohydrin (1.159 mL, 14.780 mmol) and potassium carbonate (2.786 g, 20.155 mmol) were added to a 15 mL solution of acetonitrile (3 g, 13.437 mmol) and refluxed for 18 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain the compound 32 (463 mg, 37%) was obtained.

[0285] 1H NMR (400 MHz, CHLOROFORM-D) δ 7.19 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 4.97 (s, 1H), 4.18-4.23 (m, 3H), 3.91 (q, J = 5.6 Hz, 1H), 3.34 (t, J = 5.8 Hz, 1H), 2.89 (d, J = 9.2 Hz, 1H), 2.74 (d, J = 7.6 Hz, 1H), 1.45 (s, 9H).

[0287] Step 10-2: Preparation of t-butyl 4-(3-(4-(benzo[d]isothiazol-3-yl)piperazine-1-yl)-2-hydroxypropoxy)benzylcarbamate (33a)

[0288] The compound obtained from step 10-1 above dissolved in isopropanol (5 mL) 32 A mixed solution of (233 mg, 0.834 mmol) and 3-(piperazine-1-yl)benzo[d]isothiazole (219.51 mg, 1.001 mmol) was refluxed for 18 hours. The mixture was evaporated and purified by silica gel column chromatography to obtain the compound 33a (335 mg, 81%) was obtained.

[0289] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.90 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.45-7.49 (m, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 6.7 Hz, 2H), 4.86 (s, 1H), 4.14-4.25 (m, 2H), 4.01 (d, J = 4.9 Hz, 2H), 3.58 (d, J = 8.9 Hz, 4H), 3.47 (s, 1H), 2.89-2.94 (m, 2H), 2.64-2.74 (m, 4H), 1.46 (s, 9H).

[0291] Step 10-3: Preparation of t-butyl 4-(3-(4-(6-fluorobenzo[d]isoxazole-3-yl)pyrimidine-1-yl)-2-hydroxypropoxy)benzylcarbamate (33b)

[0292] The compound obtained from step 10-2 dissolved in isopropanol (10 mL) 32A mixed solution of (740 mg, 2.649 mmol), 6-fluoro-3-(piperidine-4-yl)benzo[d]isoxazole hydrochloride (816.06 mg, 3.179 mmol), and triethylamine (0.558 mL, 3.974 mmol) was refluxed for 18 hours. The mixture was evaporated and purified by silica gel column chromatography to obtain the compound 33b (560 mg, 42%) was obtained.

[0293] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.68 (dd, J = 8.7, 5.0 Hz, 1H), 7.19-7.26 (m, 3H), 7.07 (td, J = 8.9, 2.1 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 4.89 (s, 1H), 4.25 (d, J = 5.5 Hz, 2H), 4.12-4.15 (m, 1H), 4.00 (d, J = 4.9 Hz, 2H), 3.01-3.19 (m, 3H), 2.48-2.63 (m, 3H), 2.25 (td, J = 11.2, 3.3 Hz, 1H), 2.06-2.14 (m, 4H), 1.46 (s, 9H).

[0295] Step 10-4: Preparation of 1-(4-(aminomethyl)phenoxy)-3-(4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)propan-2-ol hydrochloride (34a) and 1-(4-(aminomethyl)phenoxy)-3-(4-(6-fluorobenzo[d]isoxazole-3-yl)pyrimidine-1-yl)propan-2-ol hydrochloride (34b)

[0296] A 4M hydrochloric acid solution dissolved in 1,4-dioxane (12 mL) obtained from step 10-3 above 33b (335 mg, 0.672 mmol) was added to a solution dissolved in ethyl acetate (12 mL) and stirred at room temperature for 6 hours. The obtained mixture was evaporated and filtered to obtain the compound 34b (330 mg, 97%) was recovered.

[0297] 1H NMR (400 MHz, CHLOROFORM-D) δ 8.09 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.56-7.60 (m, 1H), 7.41-7.50 (m, 3H), 7.07 (d, J = 8.5 Hz, 2H), 4.54 (q, J = 4.8 Hz, 1H), 4.06-4.23 (m, 6H), 3.83 (d, J = 9.8 Hz, 2H), 3.45-3.63 (m, 6H).

[0298] The above 33b Instead, obtained from step 10-3 above 33a Except for using, the compound is reacted in a similar manner. 34a Recovered.

[0300] Step 10-5: Preparation of 3-(4-(3-(4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (35a) and 3-(4-(3-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (35b)

[0301] The compound obtained from step 10-4 above 34b 1,1'-carbonyldiimidazole (115.89 mg, 0.715 mmol) was added to a solution in which (330 mg, 0.650 mmol) was dissolved in dimethylformamide (1 mL), and the mixture was stirred for 18 hours. The compound obtained from steps 8-6 above. 29 (144.44 mg, 0.650 mmol) was added to the above reaction mixture and stirred for 24 hours. The obtained mixture was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography. 35b (73 mg, 23%) was obtained.

[0302] 1H NMR (400 MHz, CHLOROFORM-D) δ 7.90 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.33-7.38 (m, 1H), 7.16-7.20 (m, 2H), 7.00 (q, J = 9.1 Hz, 4H), 6.82 (d, J = 8.9 Hz, 2H), 4.52 (t, J = 5.3 Hz, 1H), 4.28-4.39 (m, 5H), 4.15 (td, J = 9.2, 4.8 Hz, 1H), 3.99 (d, J = 4.6 Hz, 2H), 3.51-3.58 (m, 4H), 2.91 (t, J = 10.2 Hz, 4H), 2.62-2.76 (m, 5H), 2.28 (s, 3H), 2.02-2.14 (m, 2H), 1.64-1.74 (m, 4H);

[0303] 13 C NMR (100 MHz, DMSO-D6) δ 163.56, 157.54, 157.40, 157.35, 151.98, 133.18, 128.37, 128.30, 128.15, 127.85, 127.36, 124.39, 124.16, 121.05, 114.85, 114.64, 114.13, 71.04, 66.70, 61.14, 54.62, 53.29, 49.75, 43.05, 23.70;

[0304] HRMS (FAB) m / z calculated for C 35 H 44 FN6O3S [M + H] + 647.3180, found 647.3183;

[0305] HPLC purity 99.8078% (Method B).

[0306] The above 34b Instead 34a Except for using, the compound is reacted in a similar manner. 35a (73 mg, 11%) was obtained.

[0307] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.68 (dd, J = 8.7, 5.0 Hz, 1H), 7.16-7.26 (m, 3H), 6.96-7.09 (m, 5H), 6.82 (d, J = 8.5 Hz, 2H), 4.57 (t, J = 5.2 Hz, 1H), 4.32 (d, J = 25.9 Hz, 5H), 4.12 (dd, J = 13.4, 4.9 Hz, 1H), 3.97 (d, J = 4.6 Hz, 2H), 3.01-3.19 (m, 3H), 2.91 (d, J = 11.3 Hz, 2H), 2.48-2.65 (m, 3H), 2.20-2.29 (m, 4H), 2.01-2.20 (m, 6H), 1.73 (d, J = 4.9 Hz, 4H);

[0308] 13 C NMR (100 MHz, DMSO-D6) δ 164.88, 163.08, 162.41, 161.37, 157.55, 137.00, 133.17, 128.39, 128.31, 128.15, 123.88, 123.77, 117.26, 114.87, 114.66, 114.12, 112.62, 112.37, 97.49, 71.08, 66.56, 61.28, 54.95, 54.64, 53.72, 52.01, 45.36, 43.98, 43.09, 33.31, 30.14, 23.69;

[0309] HRMS (FAB) m / z calculated for C 36 H 44 F2N5O4[M + H] + 648.3361, found 648.3358;

[0310] HPLC purity 98.0587% (Method B).

[0312] Example 1: 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60104)

[0313]

[0314] 1 H NMR (400 MHz, DMSO-D6) δ 7.22-7.26 (m, 2H), 7.08-7.12 (m, 4H), 6.82-6.87 (m, 3H), 4.41 (s, 2H), 4.18 (d, J = 5.8 Hz, 2H), 3.88-3.94 (m, 1H), 3.70 (d, J = 6.4 Hz, 2H), 2.73 (d, J = 11.0 Hz, 2H), 2.12 (s, 3H), 2.00 (m, 1H), 1.92 (t, J = 11.0 Hz, 2H), 1.51-1.60 (m, 2H), 1.44 (d, J = 11.3 Hz, 2H), 0.97 (d, J = 6.7 Hz, 6H)

[0316] Example 2: 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(piperidine-4-yl)urea hydrochloride (GM code 60280)

[0317]

[0318] 1 H NMR (400 MHz, METHANOL-D4) δ 7.24-7.27 (m, 2H), 7.01-7.12 (m, 4H), 6.80-6.83 (m, 2H), 4.50 (s, 2H), 4.25-4.36 (m, 3H), 3.71 (d, J = 6.4 Hz, 2H), 3.41 (d, J = 11.3 Hz, 2H), 3.00-3.08 (m, 2H), 2.02-2.08 (m, 1H), 1.87-1.97 (m, 4H), 1.02 (d, J = 7.0 Hz, 6H)

[0320] Example 3: 1-(1-acetylpiperidine-4-yl)-1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)urea (GM code 60269)

[0321]

[0322] 1H NMR (400 MHz, DMSO-D6) δ 7.18-7.21 (m, 2H), 7.07 (t, J = 7.9 Hz, 4H), 6.79-6.89 (m, 3H), 4.37 (s, 3H), 4.17 (d, J = 4.9 Hz, 3H), 3.66-3.77 (m, 3H), 2.93-2.98 (m, 1H), 2.38-2.46 (m, 1H), 1.89-1.99 (m, 5H), 1.29-1.48 (m, 4H), 0.93 (d, J = 6.4 Hz, 6H)

[0324] Example 4: 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-(methylsulfonyl)piperidine-4-yl)urea (GM code 60133)

[0325]

[0326] 1 H NMR (400 MHz, CDCl3) δ 7.18 (dd, J = 8.5, 5.2 Hz, 2H), 6.98-7.03 (m, 4H), 6.77 (d, J = 8.9 Hz, 2H), 4.59-4.52 (m, 1H), 4.51 (t, J = 3.8 Hz, 1H), 4.31 (s, 2H), 4.26 (d, J = 5.2 Hz, 2H), 3.84 (dd, J = 10.1, 2.1 Hz, 2H), 3.68 (d, J = 6.4 Hz, 2H), 2.72-2.78 (m, 2H), 2.77 (s, 3H), 2.01-2.11 (m, 1H), 1.84 (d, J = 10.1 Hz, 2H), 1.69 (qd, J = 12.4, 4.3 Hz, 2H), 1.01 (d, J = 6.7 Hz, 6H)

[0328] Example 5: 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)-N-isopropylpiperidine-1-carbothioamide (GM code 60135)

[0329]

[0330] 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J = 8.5, 5.2 Hz, 2H), 7.00 (t, J = 9.3 Hz, 4H), 6.77 (d, J = 11.6 Hz, 2H), 5.29 (H6), J = 4.66–4.72 (m, 2H), 4.57–4.64 (m, 2H), 4.51 (t, J = 5.3 Hz, 1H), 4.27 (t, J = 5.6 Hz, 4H), 3.68 (d, J = 6.1. t , 3. = 2H), 2H), 2.02-2.11 (m, 1H), 1.81 (d, J = 11.9 Hz, 2H), 1.56 (qd, J = 12.5, 3.9 Hz, 2H), 1.20-1.26 (m, 6H), 1.00 Hz = 6.H3)

[0332] Example 6: 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (GM code 60134)

[0333]

[0334] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.45 (s, 4H), 7.11-7.17 (m, 3H), 6.99 (q, J = 8.5 Hz, 4H), 6.77 (d, J = 8.5 Hz, 6. 4), J = 4, 4. 4.25 (d, J = 5.5 Hz, 4H), 4.15 (d, J = 13.4 Hz, 2H), 3.67 (d, J = 6.7 Hz, 2H), 2.88 (t, J = 12.1 Hz, 2H), 2.05 (td.4 = Hz), J 1.76 (d, J = 10.4 Hz, 2H), 1.53 (qd, J = 12.3, 3.7 Hz, 2H), 1.02 (s, 6H)

[0336] Example 7: 4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-4-oxobutanoic acid (GM code 60252)

[0337]

[0338] 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J = 8.5, 5.2 Hz, 2H), 6.99 (t, J = 9.2 Hz, 4H), 6.77 (d, J = 8.5 Hz, 2H), 4.60-4.66 (m, 2H), 4.55 (t, J = 5.3 Hz, 1H), 4.26 (t, J = 5.0 Hz, 4H), 3.90 (d, J = 13.4 Hz, 1H), 3.67 (d, J = 6.4 Hz, 2H), 3.13 (t, J = 12.1 Hz, 1H), 2.60-2.69 (m, 5H), 2.01-2.11 (m, 1H), 1.80 (dd, J = 29.3, 11.6 Hz, 2H), 1.41-1.54 (m, 2H), 1.01 (d, J = 6.7 Hz, 6H)

[0340] Example 8: 5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanic acid (GM code 60253)

[0341]

[0342] 1 H NMR (400 MHz, CDCl3) δ 7.17 (dd, J = 8.4, 5.3 Hz, 2H), 6.96-7.02 (m, 4H), 6.77 (d, J = 8.5 Hz, 2H), 4.59-4.69 (m, 3H), 4.25-4.28 (m, 4H), 3.90 (d, J = 12.2 Hz, 1H), 3.67 (d, J = 6.4 Hz, 2H), 3.11 (t, J = 12.2 Hz, 1H), 2.56-2.62 (m, 1H), 2.39 (dd, J = 12.5, 7.0 Hz, 5H), 2.00-2.10 (m, 1H), 1.75-1.96 (m, 5H), 1.41-1.50 (m, 2H), 1.01 (s, 6H)

[0344] Example 9: (S)-2-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanic acid (GM code 60130)

[0345]

[0346] 1H NMR (400 MHz, METHANOL-D4) δ 7.23 (dd, J = 8.4, 5.3 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.01 (t, J = 8.9 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 4.58 (d, J = 13.4 Hz, 1H), 4.47 (s, 2H), 4.27-4.35 (m, 3H), 3.96 (d, J = 14.0 Hz, 1H), 3.71 (d, J = 6.4 Hz, 2H), 3.58 (dd, J = 13.4, 5.8 Hz, 1H), 3.07-3.14 (m, 1H), 2.56-2.67 (m, 3H), 2.05-2.10 (m, 2H), 2.02 (q, J = 6.6 Hz, 1H), 1.49-1.75 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H)

[0348] Example 10: (S)-2-(t-butoxycarbonylamino)-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanic acid (GM code 60270)

[0349]

[0350] 1 H NMR (400 MHz, METHANOL-D4) δ 7.22 (dd, J = 7.9, 5.8 Hz, 2H), 7.08-7.10 (m, 2H), 7.01 (t, J = 8.9 Hz, 2H), 6.80 (d, J = 8.2 Hz, 2H), 4.56 (d, J = 12.8 Hz, 1H), 4.46 (s, 2H), 4.27-4.33 (m, 3H), 3.95 (d, J = 12.8 Hz, 1H), 3.70 (d, J = 6.7 Hz, 2H), 3.09 (t, J = 12.2 Hz, 1H), 2.60 (t, J = 12.7 Hz, 1H), 2.36-2.53 (m, 2H), 1.99-2.17 (m, 3H), 1.84-1.93 (m, 1H), 1.51-1.74 (m, 4H), 1.42 (s, 9H), 1.02 (d, J = 6.7 Hz, 6H)

[0352] Example 11: (S)-2-amino-4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-4-oxobutanoic acid (GM code 60131)

[0353]

[0354] 1 H NMR (400 MHz, METHANOL-D4) δ 7.23 (dd, J = 8.2, 5.5 Hz, 2H), 7.09 (d, J = 6.7 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 6.80 (d, J = 8.2 Hz, 2H), 4.57 (d, J = 12.8 Hz, 1H), 4.47 (d, J = 3.7 Hz, 2H), 4.31-4.36 (m, 1H), 4.27 (s, 2H), 3.92 (d, J = 13.7 Hz, 1H), 3.80-3.85 (m, 1H), 3.71 (d, J = 6.4 Hz, 2H), 3.06-3.15 (m, 2H), 2.95 (d, J = 12.5 Hz, 1H), 2.82 (q, J = 8.9 Hz, 1H), 2.64 (t, J = 12.1 Hz, 1H), 1.99-2.08 (m, 1H), 1.49-1.76 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H)

[0356] Example 12: (S)-4-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanic acid (GM code 60183)

[0357]

[0358] 1H NMR (400 MHz, METHANOL-D4) δ 7.23 (dd, J = 13.4, 7.9 Hz, 2H), 7.10 (dd, J = 8.1, 5.3 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 4.55 (d, J = 12.2 Hz, 1H), 4.48 (d, J = 13.1 Hz, 2H), 4.28-4.39 (m, 4H), 3.99 (t, J = 14.8 Hz, 1H), 3.71 (d, J = 6.4 Hz, 2H), 3.13-3.23 (m, 1H), 2.72 (dd, J = 20.3, 11.4 Hz, 1H), 2.41-2.46 (m, 2H), 2.00-2.08 (m, 1H), 1.92 (td, J = 15.8, 8.5 Hz, 2H), 1.54-1.80 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H)

[0360] Example 13: (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)phenyl)propanoic acid hydrochloride (GM code 60215)

[0361]

[0362] 1 H NMR (400 MHz, METHANOL-D4) δ 7.38 (s, 4H), 7.24 (dd, J = 8.5, 5.5 Hz, 2H), 7.07-7.10 (m, 2H), 6.99-7.04 (m, 2H), 6.79-6.82 (m, 2H), 4.68 (d, J = 13.4 Hz, 1H), 4.51 (s, 2H), 4.27-4.38 (m, 5H), 3.71 (d, J = 6.7 Hz, 2H), 3.36 (dd, J = 14.5, 5.3 Hz, 1H), 3.18 (dd, J = 14.3, 7.9 Hz, 2H), 2.86 (s, 1H), 1.99-2.07 (m, 2H), 1.61-1.79 (m, 4H), 1.02 (d, J = 6.7 Hz, 6H)

[0364] Example 14: (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-carbonyl)cyclohexyl)propanoic acid hydrochloride (GM code 60216)

[0365]

[0366] [M+H] + : 611.4

[0368] Example 15: N-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-2-hydroxypropoxy)phenyl)acetamide (GM code 60234)

[0369]

[0370] [M+H] + : 621.3

[0372] Example 16: (2S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-2-hydroxypropoxy)phenyl)propanoic acid (GM code 60292)

[0373]

[0374] [M+H] + : 651.4

[0376] Example 17: (S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)propoxy)phenyl)propanoic acid (GM code 60293)

[0377]

[0378] [M+H] + : 635.4

[0380] Example 18: Methyl 6-((4-((3-(4-fluorobenzyl)-3-(1-methylpiperidine-4-yl)ureido)methyl)phenoxy)methyl)nicotinate (GM code 60180)

[0381]

[0382] [M+H] + : 521.3

[0384] Example 19: 1-(4-fluorobenzyl)-3-(4-(2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)ethoxy)benzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60181)

[0385]

[0386] [M+H] + : 562.3

[0388] Example 20: 3-(4-(7-bromothieno[3,2-d]pyrimidine-4-yloxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60182)

[0389]

[0390] 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.98 (s, 1H), 7.14-7.24 (m, 6H), 7.02 (t, J = 8.4 Hz, 2H), 4.73 (s, 1H), 4.35-4.42 (m, 5H), 3.45 (s, 1H), 2.90 (d, J = 11.3 Hz, 2H), 2.28 (s, 3H), 2.09-2.14 (m, 2H), 1.67-1.74 (m, 4H)

[0392] Example 21: 3-(4-(2-(4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60217)

[0393]

[0394] 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.45-7.49 (m, 1H), 7.36 (t, J = 7.0 Hz, 1H), 7.16-7.20 (m, 2H), 7.00 (q, J = 8.6 Hz, 4H), 6.82 (d, J = 8.5 Hz, 2H), 4.51 (t, J = 5.6 Hz, 1H), 4.28-4.35 (m, 5H), 4.11-4.15 (m, 2H), 3.59 (t, J = 4.9 Hz, 4H), 2.89 (s, 4H), 2.82 (t, J = 4.9 Hz, 4H), 2.28 (s, 3H), 2.08-2.14 (m, 2H), 1.65-1.74 (m, 4H)

[0396] Example 22: 3-(4-(2-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperazine-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60218)

[0397]

[0398] 1H NMR (400 MHz, CDCl3) δ 7.70-7.73 (m, 1H), 7.16-7.25 (m, 3H), 6.97-7.08 (m, 5H), 6.81 (d, J = 6.7 Hz, 2H), 4.51 (t, J = 5.3 Hz, 1H), 4.28-4.35 (m, 4H), 4.10-4.14 (m, 2H), 3.05-3.16 (m, 3H), 2.85-2.92 (m, 4H), 2.32-2.38 (m, 5H), 2.02-2.14 (m, 6H), 1.69-1.76 (m, 4H)

[0400] Example 23: 3-(4-(2-(1,3-dioxo-1H-isoindole-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60219)

[0401]

[0402] [M+H] + : 551.3

[0404] Example 24: 3-(4-(3-(4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60271)

[0405]

[0406] 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.33-7.38 (m, 1H), 7.16-7.20 (m, 2H), 7.00 (q, J = 9.1 Hz, 4H), 6.82 (d, J = 8.9 Hz, 2H), 4.52 (t, J = 5.3 Hz, 1H), 4.31-4.39 (m, 3H), 4.28 (d, J = 5.5 Hz, 2H), 4.15 (m, 1H), 3.99 (d, J = 4.6 Hz, 2H), 3.57-3.62 (m, 4H), 2.88-2.93 (m, 4H), 2.61-2.76 (m, 5H), 2.28 (s, 3H), 2.10 (td, J = 11.1, 3.7 Hz, 2H), 1.67-1.74 (m, 4H)

[0408] Example 25: t-butyl 4-(3-(4-((3-(4-fluorobenzyl)-3-(1-methylpiperidine-4-yl)ureido)methyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate (GM code 60276)

[0409]

[0410] 1 H NMR (400 MHz, CDCl3) δ 7.18 (dd, J = 8.2, 5.5 Hz, 2H), 6.96-7.03 (m, 4H), 6.80 (d, J = 8.5 Hz, 2H), 4.58 (t, J = 5.3 Hz, 1H), 4.33 (m, 3H), 4.28 (d, J = 5.2 Hz, 2H), 4.06-4.13 (m, 1H), 3.92-3.98 (m, 2H), 3.38-3.49 (m, 5H), 2.87 (d, J = 11.6 Hz, 2H), 2.39-2.69 (m, 6H), 2.26 (s, 3H), 2.08 (td, J = 11.4, 3.2 Hz, 2H), 1.62-1.70 (m, 4H), 1.46 (s, 9H)

[0412] Example 26: 1-(4-fluorobenzyl)-3-(4-(2-hydroxy-3-(piperazine-1-yl)propoxy)benzyl)-1-(1-methylpiperidine-4-yl)urea dihydrochloride (GM code 60277)

[0413]

[0414] 1 H NMR (400 MHz, METHANOL-D4) δ 7.26 (dd, J = 7.8, 4.4 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.04 (t, J = 8.5 Hz, 2H), 6.85-6.94 (m, 2H), 4.51 (s, 3H), 4.32 (d, J = 22.6 Hz, 4H), 4.00-4.05 (m, 1H), 3.60-3.66 (m, 5H), 3.50 (s, 3H), 3.11 (s, 2H), 2.83 (s, 2H), 2.01-2.08 (m, 7H), 1.89 (d, J = 13.4 Hz, 2H)

[0416] Example 27: 3-(4-(3-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60278)

[0417]

[0418] 1H NMR (400 MHz, CHLOROFORM-D) δ 7.68 (dd, J = 8.7, 5.0 Hz, 1H), 7.16-7.26 (m, 3H), 6.96-7.09 (m, 5H), 6.82 (d, J = 8.5 Hz, 2H), 4.57 (t, J = 5.2 Hz, 1H), 4.35 (m, 3H), 4.28 (d, J = 5.2 Hz, 2H), 4.09-4.15 (m, 1H), 3.97 (d, J = 4.6 Hz, 2H), 3.01-3.19 (m, 3H), 2.91 (d, J = 11.3 Hz, 2H), 2.48-2.65 (m, 3H), 2.29 (s, 3H), 2.24 (dd, J = 11.1, 2.9 Hz, 2H), 2.01-2.20 (m, 6H), 1.66-1.73 (m, 4H)

[0420] Example 28: 3-(4-(3-(4-(3-chloro-4-methylphenyl)piperazine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea (GM code 60279)

[0421]

[0422] [M+H] + : 638.3

[0424] Experimental Example 1: in vitro 5HT 2A Inhibitory activity

[0426] 5-HT 2A Stability: HEK293 cells were cultured at 8–9 × 10⁶ in Minimum Essential Medium (Welgene; LM007-86) containing 100 µl of 10% dialyzed fetal bovine serum (Gibco; 30067-334) and 1% penicillin / streptomycin (Gibco; 15140-122). 4Cells were seeded at a density into 96-well plates (Costar; 3603) and cultured in a 37°C incubator for 24 hours. Cells were stained with 100 µl of cytosolic calcium dye using FLIPR Calcium 6 assay solution (Molecular Devices, #R8190) supplemented with 2.5 mM probenecid (probenecid, Sigma; P8761) and incubated at 37°C for 1 hour. After 1 hour, a compound of a predetermined concentration was added to each well, and the cells were incubated for another hour at 37°C. Subsequently, the cells were placed in a Flexstation 3 microplate reader (Molecular Devices; FlexStaition ® Loaded onto the source plate (Nunc™ 96-Well Polystyrene Conical Bottom MicroWell™ Plate, Thermo; 249662) and 5 μM 5-HT from the source plate (source plate, Nunc™ 96-Well Polystyrene Conical Bottom MicroWell™ Plate, Thermo; 249662). 2A 50 µl of (Serotonin Hydrochloride, Sigma; H9523) was injected and the fluorescence intensity (Ex / Em-485 nm / 525 nm) was measured.

[0427] Synthesized 5HT 2A Their 5HT regarding antagonists 2A Inhibitory activity was evaluated, and the results are summarized in Table 1. In the biological assay at a concentration of 1 μM, N-desmethylpimavanserin (Example 2, 11 ) is superior to pimavanserin in vitro It exhibited activity, and accordingly, desmethylpimavanserin (Example 2, 11 The nitrogen of ) was further modified. N-acetyl (Example 3, 12a ), N-methylsulfonyl (Example 4, 12b ) and isopropyl thiourea derivatives (Example 5, 12c When evaluated, it exhibited lower activity than pimavanserin. Furthermore, succinyl derivatives of N-desmethylpimavanserin were synthesized and evaluated. Succinyl derivatives 13(Example 7) is an IC of 317.3 nM 50 sub-micromolar with a value of (half maximal inhibitory concentration) in vitro It exhibited potency. Therefore, carboxylic acid derivatives, such as glutamate, aspartate, and tyrosine derivatives, were synthesized and evaluated (Examples 9 to 13). Compounds that are glutamate derivatives 14a (Example 9) is an IC of 8.35 nM 50 It had a value and showed better efficacy compared to pimavanserin. Additional t-butoxycarbonyl substituted in free amines 15 (Example 10) reduced efficacy. Aspartate derivative 14b (Example 11) is 14a It showed lower efficacy compared to (Example 9). Reversed glutamate derivative 14c (Example 12) showed a low inhibition rate. Next, tyrosine derivative 22 (Example 13) was synthesized and evaluated to find an excellent in vitro Although it was confirmed that it exhibited activity, 14a It did not reach the value shown in (Example 9).

[0428] Amino alcohol derivatives were synthesized by altering the isobutoxy position of pimavanserin, and 5HT 2A Activities inhibiting were selected (Examples 24 to 27). 1-t-butoxycarbonyl piperazine derivative 30 (Example 25) is an IC of 1.94 nM 50 Excellent value in vitro It showed activity. 30 The acid deprotection of (Example 25) 31 Loss of efficacy was induced in (Example 26). Next, 3-(1-piperazinyl)-1,2-benzisothiazole and 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole derivatives were synthesized and evaluated. All of these compounds were excellent in vitroIt demonstrated efficacy and had an IC50 of 0.39 nM. 50 having a value 35b (Example 27) is 35a (Example 26) It showed better activity.

[0429] Example (GM code) % inhibition@ 1 μM IC 50 (nM) Examples % inhibition@ 1 μM IC 50 (nM) 1(Pimavanserin, 60104) 91.61 22 2(60280) 94.25 0.60 3(60269) -12.4 nd 4(60133) 59.03 2018 5(60135) 52.37 1126 6(60134) 85.16 7(60252) 91.47 317.3 8(60253) 53.49 9(60130) 94.1 8.35 10(60270) 10.47 nd 11(60131) 91.84 34.65 12(60183) 46.51 nd 13(60215) 90.69 nd 14(60216) 94.85 15(60234) 92.22 16(60292) 90.02 17(60293) 90.22 18(60180) 90.49 19(60181) 86.9 20(60182) 92.61 21(60217) 96.05 22(60218) 95.41 23(60219) 94.77 24(60271) 89.82 0.87 25(60276) 93.62 1.93 26(60277) 42.41 nd 27(60278) 94.6 0.39 28(60279) 95

[0431] Experimental Example 2: in vitro Blood-brain barrier (BBB) ​​permeability study

[0433] of Experimental Example 1 above in in vitro From the data, in vitro and in vivo Compounds having amino acids and neutral heterocyclic moieties, respectively, for BBB permeability evaluation 14a (Example 9) and 35b (Example 27) was selected. A parallel artificial membrane permeation assay (PAMPA) was used to predict BBB permeability, and the results are shown in Table 2.

[0434] Example (GM code) BBB permeability On (10 -6 cm / s) logPe 9(60130) 0.00 -10.00 27(60278) 4.79 -5.32

[0435] Considering that a value less than 2.0 predicts low transmittance, a low transmittance value (10 -6 Compound due to (cm / s) 14a Peripheral residence of (Example 9) was expected.

[0437] Experimental Example 3: In mice in vivo BBB Permeability Study

[0439] Prepared in solution (DMSO:PEG400:Saline=5:40:55, v:v:v %) for male ICR mice 14a(Example 9, 5 mg / kg) was administered intraperitoneally. After 0.5 hours, the mice were euthanized with CO2 gas, and blood was immediately collected from the heart. Plasma was separated by centrifugation at 3000 rpm for 10 minutes at 4°C. The remaining blood was washed by circulating cardiac perfusion with 10 U / mL heparin-containing physiological saline. Subsequently, the brain was removed from the skull, and three times the body weight in PBS buffer was added to homogenize it. The mixture was then stored at -20°C until analysis by LC-MS / MS. Plasma and brain in the feed 14a (Example 9) Concentrations were analyzed using an API 4000 Q trap mass spectrometer (Applied Biosystems, Foster City, CA, USA) coupled with a 1200 Series HPLC system (Agilent, Santa Clara, CA, USA). Isometric elution with 20% water containing 80% acetonitrile and 0.1% formic acid was used for the separation of the analytes. The total run time was 3 minutes, and the flow rate was 0.3 mL / min.

[0440] To confirm consistency with PAMPA results, the compound was administered to rats via intravenous (IV) injection 14a The BBB penetration of (Example 9) was evaluated (Table 3). Compound 14a The concentration ratio of brain to plasma in (Example 9) was 0.038 after 30 minutes, which indicates limited BBB permeability. Furthermore, 14aThe unbounded fraction of (Example 9) increased peripheral selectivity (0.02). Peripheral selectivity could be significantly increased by the introduction of a glutamic acid moiety. Generally, compounds with a brain-to-plasma ratio greater than 0.3 to 0.5 are considered to have sufficient DNS diffusivity, compounds with a value greater than 1 are considered to freely cross the BBB, and compounds with a small brain-to-plasma ratio of 0.1 or less are considered unable to enter the CNS. In contrast, the compound 35b (Example 27) showed that it penetrated the BBB with a brain concentration ratio to plasma of 1.63 after 0.5 hours.

[0441] Example (GM code) Time (h) Concentration (ng / mL) C brain / C plasma plasma brain tissue 9(60130) 0.5 415.7±178.0 15.1±5.22 0.038±0.011 27(60278) 0.5 455.3±19.0 740.9±275.5 1.63±0.61

[0443] Experimental Example 4: Pharmacokinetic study in rats

[0445] The compound of the present invention was administered to male SD mice by intraperitoneal injection (5 mg / kg). A control group was prepared by administering an equal amount of vehicle and used for BBB penetration studies. Blood samples were collected at 0.083, 0.167, 0.5, 1, 2, 4, 8, and 24 hours after injection. After separating the plasma by centrifugation, within the plasma 14a The concentration of (Example 9) was determined using an LC-MS / MS system. Pharmacokinetic parameters were obtained through non-compartmental analysis using the WinNolin program (ver. 6.3, Pharsight, Mountain View, CA).

[0446] compound 14a Example 9 demonstrated excellent hepatic microsome stability, insignificant cytotoxicity in five representative mammalian cell lines, and low hERG inhibitory activity (Table 4). For further evaluation, the percentage of inhibition of other serotonin receptor subtypes was screened, and the compound14a (Example 9) is 5HT among the subtypes 2A It exhibited selective inhibitory activity against. In addition, the compound in rats 14a The pharmacokinetic profile of (Example 9) was evaluated, and the results are summarized in Table 5. Compound 14 (Example 9) showed a reasonable AUC and a half-life of 17 hours.

[0447] Assess result Liver microsome phase I stability a Rats: 84% retention after 30 minutes of incubation Humans: 89% retention after 30 minutes of incubation cytotoxicity VERO IC 50 : 54.7 μM HFL-1 IC 50 : 55.2 μM L929 IC 50 : 64.0 μM NIH 3T3 IC 50 : 18.2 μM CHO-K1 IC 50 : 51.0 μM hERG 18.7% inhibition at 10 μM Selectivity 1a: -2.8% inhibition 1b: 6% inhibition 2a: 93% inhibition 2b: 7% inhibition 2c: 63.8% inhibition 3: -5% inhibition 4e: -12.1% inhibition 6: -18.5% inhibition 7: 6.3% inhibition

[0448] a: Buspirone used as a positive control - Rat: 15% and Human: 4% residue after 30 minutes of incubation

[0449] variable Example 9 (60130) T1 / 2(h) 16.9±11.05 AUC t (μg·h / mL) 1.91±0.186 AUC ∞ (μg·h / mL) 2.03±0.115 CL(L / h / kg) 2.46±0.137 Vss(L / kg) 11.03±6.62

[0451] Experimental Example 5: For non-alcoholic fatty liver disease in vivo efficiency

[0453] C57BL / 6J mice were purchased from Charles River Japan (Yokohama, Japan). Mice were housed in a climate-controlled, pathogen-free barrier facility under a 12-hour light-dark cycle and provided with ad libitum food and water. Twelve-week-old mice were fed the Research Diet D12492 (60% fat calories) for 10 weeks, and during the same period, daily intraperitoneal injection 14a (Example 9) was administered. At week 9 of the HFD diet, an intraperitoneal glucose tolerance test (2 g / kg of glucose) was performed, and body composition was measured by NMR analysis (LF50 BCA-analyzer, Bruker) on the day before lethality. All animal experiments complied with relevant ethical regulations. The experimental protocol for this study was approved by the Institutional Animal Care and Use Committee of the Korea Advanced Institute of Science and Technology.

[0454] In addition, liver tissue was homogenized in 5% NP-40 using FastPrep-24 (MP biomedicals). To dissolve the lipids, the homogenate was heated to 95°C for 5 minutes and cooled to 23°C repeatedly. Triglyceride reagent (Sigma-Aldrich) or PBS was added, and the sample was incubated at 37°C for 30 minutes to hydrolyze TG into glycerol. For a colorimetric assay of hydrolyzed TG levels, the sample was incubated with free glycerol reagent (Sigma-Aldrich) at 37°C for 5 minutes. The difference in absorbance at 540 nm between hydrolyzed TG and non-hydrolyzed TG was quantified using a glycerol standard (Sigma-Aldrich). The TG content was normalized by the protein concentration in the homogenate measured with a BCA protein assay kit (Thermo scientific).

[0455] Furthermore, mouse liver, inguinal white adipose tissue (WAT), epididymal white adipose tissue, and interscapular brown adipose tissue were recovered, fixed in 10% neutral buffered formalin solution (Sigma-Aldrich), and embedded in paraffin. 5 μm-thick tissue fragments were deparaffinized, rehydrated, and stained with hematoxylin and eosin (H&E).

[0456] Regarding NAFLD 14a (Example 9) in vivo To determine efficiency, mice were fed a high-fat diet (HFD) for 10 weeks and injected daily intraperitoneally by 14a(Example 9) was administered. 14a In mice treated with 50 and 100 mg / kg of (Example 9), liver tissue mass (Fig. 3a) and hepatic triglyceride (TG) accumulation were reduced (Figs. 1b and 1c). Furthermore, the inventors [reported] 5HT in other metabolic organs, such as adipose tissue. 2A Considering expression 14a The systemic metabolic effects of (Example 9) were confirmed. Compared to the control group, 100 mg / kg of 14a Mice treated with (Example 9) exhibited less body weight gain after HFD and improved glucose tolerance (Figs. 1d, and 1e). Similarly, 14a In mice treated with (Example 9), body fat decreased, while lean body mass increased (Fig. 1f). 14a Mice treated with (Example 9) showed a reduction in fat mass in the inguinal WAT, epididymal WAT, and brown adipose tissue (BAT) (Fig. 1g). In addition, these mice showed a reduction in adipocyte (adip°yte) size in the inguinal WAT (Fig. 1h) and a lower frequency of crown-like structures (CLS) in the epididymal WAT (Fig. 1i). Furthermore, BAT 14a It was more active in mice treated with (Example 9) (Fig. 1j). These results are due to selective 5HT 2A As an antagonist 14a (Example 9) indicates that it has therapeutic potential in NAFLD and metabolic syndrome.

[0458] <Conclusion>

[0459] A novel series of peripheral 5HT 2A Antagonists were synthesized, and their inhibitory activity was evaluated. Among these, compounds14a (Example 9) is an IC of 8.35 nM 50 Excellent value in vitro It exhibited activity. It also demonstrated liver microsome stability and insignificant inhibition of CYP and hERG. In addition, the compound 14a (Example 9) selectively [describes] 5HT among 5HT receptor subtypes 2A It selectively inhibited. in vitro and in vivo From BBB permeability studies, 14a It was confirmed that (Example 9) is a substance that acts peripherally. Compound 14a (Example 9) improved glucose tolerance in HFD-fed mice. 5HT 2A By inhibition, liver mass was also reduced, and fat accumulation and hepatic steatosis were alleviated. Mice treated with the compounds of the present invention additionally exhibited reduced fat content. In conclusion, these newly synthesized peripherally acting 5HT 2A Antagonists have the potential to further develop as treatments for fatty liver disease.

[0461] From the foregoing description, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as including all modifications or variations derived from the meaning and scope of the claims set forth below and their equivalents, rather than from the detailed description above.

Claims

Claim 1 A compound represented by the following chemical formula 1-1, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof: [Chemical formula 1-1] In the above chemical formula 1-1, R1 is C 1-6 Haloalkyl-C 6-10 Aryl-carbamoyl, carboxyethylcarbonyl, ((carboxy)(amino)C 1-6 Alkyl)C 6-10 aryl carbonyl, ((carboxy)(amino)C 1-6 Alkyl)C 3-10 Cycloalkyl carbonyl, (C 1-6 Alkylcarbonylamino-C 6-10 aryloxy(hydroxy)C 1-6 Alkyl, (((carboxy)(amino)C 1-6 Alkyl)C 6-10 aryloxy(hydroxy)C 1-6 Alkyl, or ((carboxy)(amino)C 1-6 Alkyl)C 6-10 Aryloxy-C 1-6 It is an alkyl. Claim 2 Compounds represented by the following chemical formula 1-2, tautomers thereof, stereoisomers thereof, mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof: [Chemical formula 1-2] In the above chemical formula 1-2, R2 is C 5-10 Heteroaryl-C 1-6 Alkyl, C 5-10 Heterocyclil-C 1-6 Alkyl, C 5-10 Heteroaryl, C 5-10 Heteroaryl-C 5-10 Heterocyclil-C 1-6 Alkyl, (C 5-10 Heteroaryl-C 5-10 Heterocyclile)(hydroxy)C 1-6 alkyl, or (C 6-10 Aryl-C 5-10 Heterocyclile)(hydroxy)C 1-6 It is an alkyl, and C of the above R2 5-10 Heteroaryl, C 5-10 Heterocyclile, and C 6-10 Aryls are non-substituted or C 1-6 Alkoxycarbonyl, C 1-6 Substituted with one or more selected from the group consisting of alkyl, halogen, or oxo. Claim 3 In claim 1, R1 is a compound, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R1 is (trifluoromethylphenyl)carbamoyl, carboxyethyl carbonyl, (carboxy)(amino)ethyl carbonyl, ((carboxy)(amino)ethyl)phenyl carbonyl, ((carboxy)(amino)ethyl)cyclohexyl carbonyl, ((methylcarbonylamino)phenoxy)(hydroxy)propyl, (((carboxy)(amino)ethyl)phenoxy)(hydroxy)propyl, or ((carboxy)(amino)ethyl)phenoxypropyl. Claim 4 In paragraph 2, R2 is pyridinylmethyl, 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidinylethyl, hydro-1H-isoindolylethyl, thieno[3,2-d]pyrimidinyl, benzo[d]isothiazolylpiperazinylethyl, benzo[d]isothiazolylpiperazinylethyl, (benzo[d]isothiazolylpiperazinyl)(hydroxy)propyl, (benzo[d]isothiazolylpiperidinyl)(hydroxy)propyl, or (phenylpiperazinyl)(hydroxy)propyl, and C of R2 5-10 Heteroaryl, C 5-10 Heterocyclile, and C 6-10 Compounds, tautomers thereof, stereoisomers thereof, mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein the aryl is unsubstituted or substituted with one or more selected from the group consisting of methoxycarbonyl, t-butoxycarbonyl, methyl, bromo, chloro, fluoro, or oxo. Claim 5 In claim 1, the compound is 6. 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide, 7. 4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-4-oxobutanoic acid, 9. (S)-2-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanic acid, 11. (S)-2-amino-4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-4-oxobutanoic acid,13. (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-carbonyl)phenyl)propanoic acid hydrochloride,14. (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-carbonyl)cyclohexyl)propanoic acid hydrochloride,15. N-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-2-hydroxypropoxy)phenyl)acetamide, 16. (2S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-2-hydroxypropoxy)phenyl)propanoic acid, or 17. A compound, which is (S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)propoxy)phenyl)propanoic acid, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof. Claim 6 In paragraph 2, the above compounds are 18. methyl 6-((4-((3-(4-fluorobenzyl)-3-(1-methylpiperidine-4-yl)ureido)methyl)phenoxy)methyl)nicotinate, 19. 1-(4-fluorobenzyl)-3-(4-(2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)ethoxy)benzyl)-1-(1-methylpiperidine-4-yl)urea, 20. 3-(4-(7-bromothieno[3,2-d]pyrimidine-4-yloxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea, 21. 3-(4-(2-(4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea,22. 3-(4-(2-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperazine-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea,23. 3-(4-(2-(1,3-dioxo-1H-isoindole-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea,24. 3-(4-(3-(4-(benzo[d]isothiazol-3-yl)piperazine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea,25. t-butyl 4-(3-(4-((3-(4-fluorobenzyl)-3-(1-methylpiperidin-4-yl)ureido)methyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate,27. 3-(4-(3-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)urea, or28. A compound that is 3-(4-(3-(4-(3-chloro-4-methylphenyl)piperazine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof. Claim 7 4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide, 4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-4-oxobutanoic acid, (S)-2-amino-5-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-5-oxopentanic acid, (S)-2-amino-4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidine-1-yl)-4-oxobutanoic acid, (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-carbonyl)phenyl)propanoic acid hydrochloride, (R)-2-amino-3-(4-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-carbonyl)cyclohexyl)propanoic acid hydrochloride, N-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-2-hydroxypropoxy)phenyl)acetamide, (2S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)-2-hydroxypropoxy)phenyl)propanoic acid, (S)-2-amino-3-(4-(3-(4-(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)ureido)piperidin-1-yl)propoxy)phenyl)propanoic acid, methyl 6-((4-((3-(4-fluorobenzyl)-3-(1-methylpiperidin-4-yl)ureido)methyl)phenoxy)methyl)nicotinate, 1-(4-fluorobenzyl)-3-(4-(2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)ethoxy)benzyl)-1-(1-methylpiperidine-4-yl)urea, 3-(4-(7-bromothieno[3,2-d]pyrimidine-4-yloxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea, 3-(4-(2-(4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea,3-(4-(2-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperazine-1-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea, 3-(4-(2-(1,3-dioxo-1H-isoindole-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)ethoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea, 3-(4-(3-(4-(benzo[d]isothiazole-3-yl)piperazine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea, t-butyl 4-(3-(4-((3-(4-fluorobenzyl)-3-(1-methylpiperidine-4-yl)ureido)methyl)phenoxy)-2-hydroxypropyl)piperazine-1-carboxylate, 3-(4-(3-(4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea, and 5HT comprising, as an active ingredient, a compound selected from the group consisting of 3-(4-(3-(4-(3-chloro-4-methylphenyl)piperazine-1-yl)-2-hydroxypropoxy)benzyl)-1-(4-fluorobenzyl)-1-(1-methylpiperidine-4-yl)urea, its tautomer, its stereoisomer, a mixture of its stereoisomers, or a pharmaceutically acceptable salt thereof. 2A As a pharmaceutical composition for the prevention or treatment of active-related diseases, the above 5HT 2A Active-related disorders include one or more neuropsychiatric disorders selected from the group consisting of schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADD), and insomnia; one or more neurodegenerative diseases selected from the group consisting of Parkinson's disease (PD), and Alzheimer's disease (AD); and one or more pervasive developmental disorders (PDD) selected from the group consisting of autism, panic disorder, and posttraumatic stress disorder; A pharmaceutical composition comprising one or more metabolic diseases selected from the group consisting of impaired glucose tolerance, hypercholesterolemia, dyslipidemia, obesity, diabetes, hypertension, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), arteriosclerosis due to dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease (coronary artery heart disease), and stroke. Claim 8 In Paragraph 7, 5HT 2A A pharmaceutical composition that acts as an antagonist.

Images