KR100838645B1 - Piperidines as beta-secretase inhibitors - Google Patents

Abstract

The present invention relates to a (3R) -amino- (4R) -arylpiperidine compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, and also to the above-mentioned 3R) -amino- (4R) -arylpiperi The present invention relates to a composition for the prophylaxis or treatment of Alzheimer's or Down's syndrome or a composition for inhibiting the activity of beta-secretase (BACE), which contains a din compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula I]

The 3R) -amino- (4R) -arylpiperidine compound according to the present invention treats Alzheimer's disease by inhibiting the activity of beta-secretase (BACE) to inhibit the production of beta-amyloid proteins that damage neurons. It can be used effectively to prevent or prevent.

Alzheimer's disease, piperidine compounds, beta-secretase, aging, neurodegenerative diseases, beta-amyloid

Description

Piperidin compounds that inhibit beta-secretase activity

The present invention relates to a (3R) -amino- (4R) -arylpiperidine compound or a pharmaceutically acceptable salt thereof that inhibits the activity of beta-secretase (hereinafter referred to as BACE).

The present invention relates to a substituted piperidine compound that inhibits the activity of BACE, an enzyme that cleaves amyloid precursor protein to produce amyloid beta peptides (hereinafter referred to as Aβ), and can be usefully used for the treatment of Alzheimer's disease. . Aβ is a major component of amyloid plaques found in the brain of Alzheimer's patients and is known as a substance causing dementia.

Alzheimer's disease (AD) is a degenerative brain disease that is closely related to aging characterized by loss of memory, cognition, reasoning, judgment, and coping due to neuronal damage. Pathological characteristics of Alzheimer's disease include intracellular accumulation of neurofibrous bundles in areas related to cognitive activity of the brain and extracellular deposition of senile plaques consisting of Aβ protein as a major component. Aβ proteins consisting of 39-43 amino acids are known to exhibit neuronal toxicity. A number of reports indicate that Aβ is a pathological feature of Alzheimer's disease and is recognized as a major cause of disease development. Aβ peptides are produced by the hydrolysis of amyloid precursor protein (APP), and many Aβ's consisting of 39-43 amino acids are known. Aβ is produced by a pathway where APP is first cleaved at the N-terminus of the amyloid precursor protein (APP) by BACE and then cleaved at the C-terminus by gamma-secretase.

Thus, a beta-secretase enzyme, also called BACE, Asp or Memapsin ((a) Tang, J. et al., Proc. Natl. Acad. Sci. USA 2000 , 97 , 1456. ( b) Hussain, I. et al., Mol. Cell Neurosci. 1999 , 14 , 419. (c) Yan, R. et al., Nature 1999 , 402 , 533. (d) .Sinha, S, et al. , Nature 1999 , 402 , 537. (e) Inhibitors that inhibit the activity of Vassar, R. et al., Science 1999 , 286 , 735. are recognized as drugs capable of preventing and treating the underlying cause of Alzheimer's disease. In addition, many pharmaceutical companies are investing huge research funds to develop new inhibitors.

There have been many reports on the development of BACE inhibitors, most of which have peptide bonds using mainly natural amino acids. Recently, inhibitors with different structures from peptide compounds derived from natural amino acids have been reported ((a) Stachel, SJ et al., J. Med. Chem. 2004 , 47 , 6447. (b) Huang, D. et al. ., J. Med. Chem. 2005 , 48, 5108. (c) Bhisetti, GR et al., PCT Int. Appl. WO 02/088101, 2002. (d) Garino, C. et al., Bioorg. Med Chem. Lett . 2006 , 16 , 1995.).

Among conventional BACE inhibitors, piperidine-based or piperazine-based compounds represented by the following structural formulas are disclosed in WO 03/043987.

However, the above patent includes a compound having an amine substituent substituted with an alkyl group as R ₃ , but does not disclose a specific compound according to the above, and in the case of the compound of the formula (a), which specifically discloses the effect of inhibiting BACE This is not a high problem.

[Formula a]

The present inventors tried to develop a compound having a chemical structure different from the inhibitors reported so far, and as a result, the optical activity in which the nitrogen atom was introduced at position 3 and the aromatic group at position 4 was excellent in inhibiting the activity of BACE. A (3R) -amino- (4R) -arylpiperidine compound was developed.

It is therefore an object of the present invention to provide novel (3R) -amino- (4R) -arylpiperidine compounds or pharmaceutically acceptable salts thereof which inhibit the activity of BACE.

Still another object of the present invention is Alzheimer's disease caused by the production of beta-amyloid protein containing the (3R) -amino- (4R) -arylpiperidine compound or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for preventing or treating a disease or Down syndrome.

Still another object of the present invention is to provide a BACE activity inhibitor composition containing the (3R) -amino- (4R) -arylpiperidine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a (3R) -amino- (4R) -arylpiperidine compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, and also to the (3R) -amino- (4R) -aryl. Alzheimer's or Down's syndrome prevention and treatment composition containing a piperidine compound or a pharmaceutically acceptable salt thereof as an active ingredient, and the (3R) -amino- (4R) -arylpiperidine compound or a pharmaceutical composition thereof A BACE activity inhibitor composition containing an acceptable salt as an active ingredient.

[Formula I]

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

The present invention provides a (3R) -amino- (4R) -arylpiperidine compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Formula I]

In Chemical Formula I,

또는

를 나타내며, Y¹ 및 Y²는 독립적으로 수소원자, 페닐기, 페녹시기, 탄소수 1-3의 알콕시기 또는 -CO-N(R⁴)R⁵를 나타내며, R⁴ 및 R⁵는 독립적으로 탄소수 1-3의 알킬기를 나타내며; R ¹ represents-(CH ₂ ) _n -Ar,-(CH ₂ ) _n -CO-Ar,-(CH ₂ ) _n -SO ₂ -Ar,-(CH ₂ ) _n -CO-NH-Ar, n is an integer from 0 to 3, Ar is

or

Y ¹ and Y ² independently represent a hydrogen atom, a phenyl group, a phenoxy group, an alkoxy group having 1 to 3 carbon atoms or -CO-N (R ⁴ ) R ⁵ , and R ⁴ and R ⁵ independently represent 1 carbon atom. An alkyl group of -3;

R ² represents a phenyl group which is a hydrogen atom or a halogen atom is unsubstituted or substituted;

R ³ is a hydrogen atom, -CO-R ⁶ , -SO ₂ -R ⁷ , -CO- (CH ₂ ) _m -R ⁸ , -CO-NH- (CH ₂ ) _m -R ⁹ , -COO- (CH ₂ ) _m -R ¹⁰ , -CO-N (R ¹¹ )-(CH ₂ ) _m -COO-R ¹² , -CO-NH-C (R ¹³ ) (R ¹⁴ )-(CH ₂ ) _m -COO- R ¹⁵ or -CO-C (R ¹⁶ ) (R ¹⁷ ) -NH-COO- (CH ₂ ) _m -R ¹⁸ , and R ⁶ to R ¹⁸ are hydrogen, halogen, hydroxy or C 1- Or an alkyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 3 carbon atoms or unsubstituted an alkoxy group of 3, or Ar defined in R ¹ , wherein m represents an integer of 0 to 2.

R ¹ in Formula I is selected from the following substituents,

R ² is selected from a hydrogen atom or the following substituents,

R ³ is more preferably selected from a hydrogen atom or the following substituents,

In the substituent, X represents a hydrogen atom or a halogen atom, R ¹⁹ is selected from an alkyl group having 1-3 carbon atoms.

More specifically exemplified as the (3R) -amino- (4R) -arylpiperidine compound represented by the formula (I) according to the present invention is as follows.

(1) N-((3R, 4R) -4-phenylpiperidin-3-yl) biphenyl-4-carboxamide;

(2) N ¹ -((3R, 4R) -4-phenyl-1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -N ³ , N ³ -dipropyl Sophthalamide;

(3) N ¹ -((3R, 4R) -4-phenylpiperidin-3-yl) -N ³ , N ³ -dipropylisophthalamide;

(4) N ¹ , N ¹ -diisopropyl-N ³ -((3R, 4R) -4-phenylpiperidin-3-yl) isophthalamide;

(5) (3R, 4R) -N- (3-methoxybenzyl) -4- (biphenyl-4-yl) piperidin-3-amine;

(6) N ¹ -((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -N ³ , N ³ -dipropylisophthalamide;

(7) N-((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -1-naphthamide;

(8) N-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) piperidin-3-yl) -2-naphthamide;

(9) N-((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -2-naphthamide;

(10) (S) -methyl 2-((3R, 4R) -3- (2-naphthamido) -4- (biphenyl-4-yl) piperidine-1-carboxamido)- 3-methylbutanoate;

(11) (3R, 4R) -3-methoxyphenyl 3- (2-naphthamido) -4- (biphenyl-4-yl) piperidine-1-carboxylate;

(12) (3R, 4R) -3- (2-naphthamido) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) piperidine-1-carboxamide;

(13) N-((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) naphthalene-2-sulfonamide;

(14) (3R, 4R) -3-methoxyphenyl 4- (biphenyl-4-yl) -3- (naphthalene-2-sulfonamido) piperidine-1-carboxylate;

(15) (3R, 4R) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) -3- (naphthalene-2-sulfonamido) piperidine-1-carboxamide ;

(16) N-((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -4-phenoxybenzamide;

(17) (S) -methyl 2- (3R, 4R) -4- (biphenyl-4-yl) -3- (4-phenoxybenzamido) piperidine-1-carboxamido) -3-methylbutanoate;

(18) (3R, 4R) -3-methoxyphenyl 4- (biphenyl-4-yl) -3- (4-phenoxybenzamido) piperidine-1-carboxylate;

(19) (3R, 4R) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) -3- (4-phenoxybenzamido) piperidine-1-carboxamide ;

(20) 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) piperidin-3-yl) -3- (3-methoxyphenyl) urea ;

(21) benzyl (S) -1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -3- (3- (3-methoxyphenyl) urei Fig. 5) piperidin-1-yl) -4-hydroxy-1-oxopropan-2-ylcarbamate;

(22) 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (3- (3-methoxyphenyl) propanoyl) piperi Din-3-yl) -3- (3-methoxyphenyl) urea;

(23) (3R, 4R) -3-methoxyphenyl-4- (3 ', 5'-difluorobiphenyl-4-yl) -3- (3- (3-methoxyphenyl) ureido) Piperidine-1-carboxylate;

(24) (3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -N- (3-methoxyphenyl) -3- (3- (3-methoxyphenyl ) Ureido) piperidine-1-carboxamide;

(25) 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (4-methoxyphenylsulfonyl) piperidin-3-yl ) -3- (3-methoxyphenyl) urea.

Meanwhile, the preparation method of the (3R) -amino- (4R) -arylpiperidine compound represented by Chemical Formula I according to the present invention and a pharmaceutically acceptable salt thereof is briefly shown in the following Reaction Scheme 1, and the following Reaction Scheme 1 R ¹ , R ² , and R ³ are the same as defined in Chemical Formula I above.

Scheme 1

The preparation method as shown in Scheme 1 includes the following three step process.

i) reducing 1,2,3,6-tetrahydropyridine of Compound 1 to remove Boc ( t -butoxycarbonyl) group with trifluoroacetic acid to prepare Compound 2 ,

ii) reacting carboxylic acid, carboxylic acid chloride, arylisocyanate, arylsulfonic acid chloride and the like using a known method to prepare Compound 3 , and

iii) reacting compound 3 with potassium carbonate in a methanol solvent to remove trifluoro group to produce compound 4 (R ³ = H),

Step iii) further comprises the step of preparing compound 4 (R ³ = H), and then reacting carboxylic acid, carboxylic acid chloride, isocyanate, sulfonic acid chloride and the like in a known manner to produce compound 4 (R ³ ≠ H) It may include.

Scheme 2 below describes a method for preparing Compound 6 wherein R ² is a substituted or unsubstituted phenyl group. In Scheme 2, X is a hydrogen atom or represents one or two halogen atoms. Compound 6 is obtained by reacting compound 5 with phenylboronic acid with or without a halogen atom, using a Suzuki coupling reaction.

Scheme 2

Scheme 3 below illustrates the process for preparing compound 11 . In Scheme 3, X is a hydrogen atom or a halogen atom. Reaction with imidazole and t-butyldimethylsilyl chloride in a dimethylformaldehyde solvent using an amino group protected (BocNH) serine (Compound 7 ) to obtain a serine compound protected with t-butyldimethylsilyl group After reacting with the carbonyldiimidazole, it is added to an aryl anion solution to obtain a ketone compound 8 . Compound 8 is converted to an olefin compound using a known Wittig reaction and the silyl group is removed to give compound 9 . The compound 9 is converted to methanesulfonate by a known method (Hu, XE; Kim, NK; Ledoussal, B. Org. Lett . 2002 , 4 , 4499), followed by substitution reaction with allylamine and amine with trifluoroacetyl group. Protection gives compound 10 . Cyclization of the compound 10 under a ruthenium organometallic catalyst (ring closing metathesis) by to obtain the compound 11.

Scheme 3

Schemes 1 to 3 show an example of a method for preparing the (3R) -amino- (4R) -arylpiperidine compound and precursors thereof according to the present invention, and the method for preparing the compound according to the present invention is limited to the above scheme. It can be prepared using known organic chemical reactions.

Pharmaceutically acceptable salts can include organic and inorganic acids, solvates and hydrates of such salt compounds are also included in the present invention. Pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy al Obtained from non-toxic organic acids such as canoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

On the other hand, the piperidine compound represented by the formula (I) according to the present invention has the effect of inhibiting the BACE activity has the effect of inhibiting the production of beta-amyloid protein. Accordingly, the present invention is effective in the treatment and prevention of Alzheimer's disease or similar Down syndrome disease caused by beta-amyloid protein. Accordingly, the present invention provides a pharmaceutical composition for preventing or treating Alzheimer's disease or Down syndrome, in which the novel piperidine compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof is contained as an active ingredient.

The present invention also provides a BACE activity inhibitor composition containing the piperidine compound represented by Formula (I) or a pharmaceutical composition thereof as an active ingredient.

The dosage of the piperidine compound according to the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and an adult having a weight of 70 kg. It is generally from 0.01 to 1000 mg / day based on the patient, may be divided into once or several times a day at regular intervals, depending on the judgment of the doctor or pharmacist.

The pharmaceutical composition according to the present invention may be prepared by adding a conventional nontoxic pharmaceutically acceptable carrier, adjuvant and excipient to the piperidine compound or pharmaceutically acceptable salts thereof, for example, a conventional agent in the pharmaceutical field, for example, For oral administration such as tablets, capsules, troches, solutions, suspensions, or parenteral administration such as intravenous, subcutaneous or intraperitoneal injections, creams for topical administration, ointments or patches, or visual routes It may be formulated.

Oral administration of the pharmaceutical composition according to the present invention can be prepared in any of a variety of existing forms, for example tablets, powders, dry syrups, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills, It can exist in various forms, such as drink, sublingual tablet, and the like. In the case of powder, the amount of the active ingredient is preferably 0.01 to 99.9% by weight, and the content is applied in a rational manner according to the formulation of the composition. The pharmaceutical composition according to the present invention may be difficult to maintain physical properties when the amount of the piperidine compound or pharmaceutically acceptable salt thereof according to the present invention exceeds the maximum total weight according to each formulation and is less than the minimum weight. The pharmacological effect of the active ingredient may not be sufficiently exhibited.

Tablets according to the present invention may be administered to a patient in any form or manner in which an effective amount is bioavailable, ie, by oral route, and is suitable for administration depending on the nature of the disease state to be treated, the stage of the disease, and other relevant circumstances. The form or manner can be easily selected and the composition according to the invention can comprise one or more pharmaceutically acceptable excipients, wherein the proportions and properties of such excipients are dependent on the solubility and chemical properties of the selected tablets, the chosen administration Determined by the route and standard pharmaceutical practice.

More specifically, the compositions according to the invention may comprise a therapeutically effective amount of the above-mentioned active ingredient as an essential ingredient together with one or more pharmaceutically acceptable excipients. Excipient materials can be solid or semisolid materials that can function as a vehicle or medium of the active ingredient, and suitable excipients are well known in the art. Excipient materials may be selected in connection with the intended dosage form, specifically for tablets, powders, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills, sublingual tablets or syrups, The therapeutically active drug component may be combined with any oral nontoxic pharmaceutically acceptable inert excipient such as lactose or starch. Optionally, the pharmaceutical tablets of the present invention may contain a binder such as amorphous cellulose, gum tragacanth or gelatin, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, sucrose It may also contain sweetening agents such as oz or saccharin, colorants or flavoring agents such as peppermint or methyl salicylate.

Because of their ease of administration, tablets may be the most advantageous oral unit dosage form, and if desired, tablets may be coated with sugar, shellac or other enteric coatings by standard aqueous or non-aqueous techniques, respectively. Tablets or capsules preferably contain about 0.1 mg to 100 mg of active ingredient.

As for the piperidine compound according to the present invention, an acute toxicity test was conducted in rats, and as a result, there was no symptom of serious toxicity against the purpose up to 10 mg / kg of the oral dose, and no death occurred up to 100 mg / kg of the oral dose. There was no.

Hereinafter, the content of the present invention will be described in more detail with reference to the following examples, but these examples do not limit the scope of the present invention.

Preparation Example 1 A method for preparing compound 8 according to Scheme 3

Preparation Example 1-1: O- tert Preparation of -Butyldimethylsilyl-N-Boc-L-serine

N-Boc-L- serine 10.06g (49.03 mmol) was dissolved in anhydrous DMF 100 mL from 0 ℃ tert - butyldimethylsilyl chloride 9.46g (62.76 mmol) and imidazole and is a 10.01g (147.1 mmol). After stirring at room temperature for 10 hours, diluted with 100 mL of distilled water, extracted twice with 250 mL of ether, the organic layers were combined, washed with 100 mL of distilled water, dried with MgSO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 4/1) and O- tert - butyl dimethyl silyl to give the Boc-L- serine--N 13.3g (85%).

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.06 (s, 6H), 0.88 (s, 9H), 1.46 (s, 9H), 3.84 (dd, J = 10.2, 3.8 Hz, 1H), 4.12 (m, 1H), 4.35 (m, 1H), 5.34 (d, J = 7.2 Hz, 1H), 8.40 (bs, 1H).

Preparation Example 1-2: (S)- tert -Butyl 3-hydroxy-1-oxo-1-phenylpropan-2-ylcarbamate (Compound 8; X = H)

O- tert - butyldimethylsilyl after the -N-Boc-L- serine 7.02g (22.0 mmol) dissolved in anhydrous THF 50 mL 1,1'- carbonyldiimidazole was added to already imidazole 3.57g (22.0 mmol) at 0 ℃ After stirring for 1 hour at room temperature, 22 mL of phenylmagnesium bromide (3M hexane solution; 66.0 mmol) and 0.38 g (1.98 mmol) of CuI were dissolved in 50 mL of anhydrous THF. Slowly dropwise at ℃. After stirring the reaction for 1 hour, 50 mL of 1N HCl was added to the reaction to terminate the reaction, followed by extraction three times with 100 mL of ethyl acetate. The combined organic layers were washed twice with 100 mL of distilled water, and then dried with MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 8/1) to give 6.58 g (78%) of phenylketone compound 8 (X = H).

¹ H NMR (200 MHz, CDCl ₃ ) δ -0.13 (s, 3H), -0.11 (s, 3H), 0.76 (s, 9H), 1.46 (s, 9H), 3.86-4.99 (m, 2H), 5.25-5.31 (m, 1 H), 5.68 (d, J = 7.6 Hz, 1 H), 7.42-7.63 (m, 3H), 7.91-7.96 (m, 2H).

Preparation Example 1-3: (S)- tert Preparation of -Butyl 1- (4-bromophenyl) -3-hydroxy-1-oxopropan-2-ylcarbamate (Compound 8; X = 4-Br)

O- tert obtained in Preparation Example 1-1-butyl-dimethyl-silyl-Boc-L- serine and 4- -N-bromophenyl method of Production Example 1-2 by using lithium as a 4-bromo-ketone compound 8 (X = 4-Br) was prepared in 85% yield.

mp 46-47 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ -0.12 (s, 3H), -0.101 (s, 3H), 0.76 (s, 9H), 1.46 (s, 9H), 3.86-4.99 (m, 2H), 5.25-5.31 (m, 1H), 5.64 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H).

Preparation Example 2 Preparation of Compound 9 According to Scheme 3

Preparation Example 2-1; (R)- tert -Butyl 3-phenyl-1-hydroxybut-3-en-2-ylcarbamate (Compound 9; X = H)

4.5 g (12.6 mmol) of methyltriphenylphosphonium bromide was dispersed in 30 mL of anhydrous THF, and then 8.4 mL of n-butyllithium (1.6M hexane solution, 13.4 mmol) was added at 0 ° C., and then warmed to room temperature and stirred for 1 hour. do. Reaction solution -78 After cooling to ° C, a solution of 1.5 g (3.95 mmol) of Compound 8 (X = H) prepared in Preparation Example 1-2 in 10 mL of anhydrous THF was slowly added dropwise and warmed to room temperature. The reaction mixture is poured into 100 mL of 1N HCl aqueous solution, extracted with 50 mL of ether, washed with 100 mL of distilled water, dried with MgSO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 20/1) to give 0.93 g (62%) of the compound in which the desired ketone group was converted to an olefin group.

¹ H NMR (200 MHz, CDCl ₃ ) δ -0.06 (s, 3H), -0.04 (s, 3H), 0.86 (s, 9H), 1.46 (s, 9H), 3.50 (dd, J = 9.8, 3.6 Hz, 1H), 3.68 (dd, J = 10.2, 4.0 Hz, 1H), 4.67-4.73 (m, 1H), 5.10-5.12 (m, 1H), 5.22 (s, 1H), 5.30 (s, 1H) , 7.28-7.40 (m, 5 H).

0.59 g (1.56 mmol) of the compound 9 (X = H) was dissolved in 10 mL of dichloromethane, and then 1.71 mL of tetra-n-butylammonium fluoride (1M THF solution, 1.71 mmol) was added at 0 ° C. The reaction was stirred at room temperature for 1 hour, washed with 10 mL of distilled water, removed with MgSO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 20/1) to afford the desired (R) -tert -butyl 1- (N-allyl-2,2,2-trifluoroacetamido) -3- 0.383 g (92%) of phenyl but-3-en-2-ylcarmamate compound 9 (X = H) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.47 (s, 9H), 2.00 (bs, 1H), 3.60-3.76 (m, 2H), 4.75 (m, 1H), 5.15 (m, 2H), 5.25 ( s, 1H), 5.39 (s, 1H), 7.31-7.38 (m, 5H).

Preparation Example 2-2; (R)- tert -Butyl 3- (4-bromophenyl) -1-hydroxybut-3-en-2-ylcarbamate (Compound 9; X = 4-Br)

Using compound 8 (X = 4-Br) prepared in Preparation Example 1-3, (S) -tert -butyl 1- (4-bromophenyl) 3-hydroxy- 1-oxopropan-2-ylcarbamate compound 9 (X = 4-Br) was obtained.

White solid; mp 158-160 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.47 (s, 9H), 1.68 (bs, 1H), 3.54- 3.74 (m, 2H), 4.70 (m, 1H), 5.15 (m, 2H), 5.28 ( s, 1H), 5.39 (s, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H).

Preparation Example 3 A method for preparing Compound 10 according to Scheme 3

Preparation Example 3-1; (R)- tert Preparation of -Butyl 1- (N-allyl-2,2,2-trifluoroacetamido) -3-phenylbut-3-en-2-ylcarmamate (Compound 10; X = H)

1.15 g (4.37 mmol) of Compound 9 (X = H) obtained in Preparation Example 2-1 was dissolved in 20 mL of dichloromethane, and 0.41 mL (5.5 mmol) of methanesulfonyl chloride was added dropwise at 0 ° C. After the reaction was warmed to room temperature, the mixture was stirred for 1 hour, washed with 20 mL of 1N HCl aqueous solution, dried with MgSO ₄ , and then concentrated under reduced pressure. 15 mL of allylamine is added to the residue, and the mixture is concentrated after refluxing under reflux overnight. The residue is taken up with 20 mL of dichloromethane and then 1.3 mL (9.32 mmol) of triethylamine are added followed by 0.93 mL (6.58 mmol) of trifluoroacetic anhydride at 0 ° C. The reaction was slowly warmed to room temperature, stirred for 2 hours, washed with 20 mL of 1N HCl aqueous solution and 20 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 6/1) to afford the desired (R) -tert -butyl 1- (N-allyl-2,2,2-trifluoroacetamido) -3- 1.59 g (91%) of phenylbut-3-en-2-ylcarmamate compound 10 (X = H) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.43 (s, 9H), 3.16 (dd, J = 13.8, 3.4 Hz, 1H), 3.77-4.02 (m, 3H), 4.99-5.25 (m, 4H), 5.30 (s, 1H), 5.38 (s, 1H), 5.58-5.66 (m, 1H), 7.29-7.44 (m, 5H).

Preparation Example 3-2; (R)- tert Preparation of -Butyl 1- (N-allyl-2,2,2-trifluoroacetamido) -3-phenylbut-3-en-2-ylcarmamate (Compound 10; X = 4-Br)

From the compound 9 (X = 4-Br) obtained in Preparation Example 2-2, using the method of Preparation Example 3-1, (R) -tert -butyl 1- (N-allyl-2,2,2-tri Fluoroacetamido) -3-phenylbut-3-en-2-ylcarmamate compound 10 (X = 4-Br) was obtained.

White solid; mp 137-139 ℃; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.43 (s, 9H), 3.16 (dd, J = 13.8, 3.4 Hz, 1H), 3.77-4.02 (m, 3H), 4.90-5.38 (m, 4H), 5.32 (s, 1H), 5.38 (s, 1H), 5.58-5.66 (m, 1H), 7.29 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H).

Preparation Example 4 A method for preparing compound 11 according to Scheme 3

Preparation Example 4-1; (R)- tert -Butyl-4-phenyl-1- (2,2,2-trifluoroacetyl) -1,2,3,6-tetrahydropyridin-3-ylcarbamate (Compound 11; X = H)

0.83 g (2.09 mmol) of Compound 10 (X = H) obtained in Preparation Example 3-1 was dissolved in 50 mL of dichloromethane, and a Grubbs catalyst (benzylidin [1,3-bis (2,4,6-trimethylphenyl)- 89 mg (0.104 mmol) of 2-imidazolidinyl-idin] dichloro (dricyclohexylphosphine) ruthenium) are added and stirred at reflux overnight under an argon stream. The reaction solution was concentrated under reduced pressure, and then the residue was purified by column chromatography (hexane / ethyl acetate = 4/1) to obtain the desired (R) -tert -butyl-4-phenyl-1- (2,2,2-trifluoro Acetyl) -1,2,3,6-tetrahydropyridin-3-ylcarbamate compound 11 (X = H) 0.68 g (87%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.41 (m, 9H), 3.45 (dd, J = 14.0, 2.2 Hz, 1H), 3.80-3.91 (m, 1H), 4.32-4.39 (m, 1H), 4.59-4.63 (m, 1H), 4.78-4.88 (m, 3H), 6.25- 6.28 (m, 1H), 7.26-7.41 (m, 5H).

Preparation Example 4-2; (R)- tert -Butyl-4- (4-bromophenyl) -1- (2,2,2-trifluoroacetyl) -1,2,3,6-tetrahydropyridin-3-ylcarbamate (Compound 11; X = 4-Br)

From the compound 10 (X = 4-Br) obtained in Preparation Example 3-2, using the method of Preparation Example 4-1, (R) -tert -butyl-4- (4-bromophenyl) -1- ( 2,2,2-trifluoroacetyl) -1,2,3,6-tetrahydropyridin-3-ylcarbamate compound 11 (X = 4-Br) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.41 (m, 9H), 3.45 (dd, J = 13.8, 2.0 Hz, 1H), 3.78-3.89 (m, 1H), 4.29-4.36 (m, 1H), 4.57-4.86 (m, 3H), 6.25-6.28 (m, 1H), 7.28 (d, J = 9.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H).

Preparation Example 5 A method for preparing Compound 6 according to Scheme 2

Preparation Example 5-1; (R)- tert -Butyl 4- (biphenyl-4-yl) -1- (2,2,2-trifluoroacetyl) -1,2,3,6-tetrahydropyridin-3-ylcarbamate (Compound 6; Y = H)

1.0 g (2.22 mmol) of Compound 11 (X = 4-Br) obtained in Preparation Example 4-2 was dissolved in 10 mL of dimethoxyethane, followed by 0.3 g (2.46 mmol) of phenylboronic acid and 0.67 g of cesium fluoride (CsF, 4.41 mmol) is added. 77 mg (tetrakis (triphenylphosphine) palladium, 66 u mol) of tetrakis (triphenylphosphine) palladium was added to the reaction solution, and the mixture was stirred under reflux overnight under argon stream. The reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate, washed with 50 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 6/1) to afford the desired (R) -tert -butyl-4- (biphenyl-4-yl) -1- (2,2,2-trifluoro Loacetyl) -1,2,3,6-tetrahydropyridin-3-ylcarbamate compound 6 (Y = H) 0.84 g (84%) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.42 (s, 9H), 3.46 (dd, J = 13.8, 2.0 Hz, 1H), 3.82-3.92 (m, 1H), 4.33-4.41 (m, 1H), 4.64-4.90 (m, 3H), 6.31-6.34 (m, 1H), 7.32-7.63 (m, 9H).

Preparation Example 5-2; (R) -tert -butyl 4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (2,2,2-trifluoroacetyl) -1,2,3,6- Tetrahydropyridin-3-ylcarbamate (compound 6; Y = 3,5-F ₂ )

Compound 11 (X = 4-Br) was reacted with 3,5-difluorophenylboronic acid using the method of Preparation Example 5-1 to give (R) -tert -butyl 4- (3 ', 5'- Difluorobiphenyl-4-yl) -1- (2,2,2-trifluoroacetyl) -1,2,3,6-tetrahydropyridin-3-ylcarbamate compound 6 (Y = 3, 5-F ₂ ) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.41 (s, 9H), 3.43-3.54 (m, 1H), 3.80-3.89 (m, 1H), 4.30-4.39 (m, 1H), 4.57-4.94 (m , 3H), 6.29-6.30 (m, 1H), 6.67-6.76 (m, 1H), 6.99-7.09 (m, 2H), 7.34-7.57 (m, 7H), 7.71-7.92 (m, 4H), 8.21 (s, 1 H).

Preparation Example 6 A method for preparing Compound 2 according to Scheme 1

Preparation Example 6-1; 1-((3R, 4R) -3-amino-4-phenylpiperidin-1-yl) -2,2,2-trifluethanone (Compound 2; R ² = H)

0.67 g (1.82 mmol) of Compound 11 (X = H) obtained in Preparation Example 4-1 was dissolved in 20 mL of methanol, followed by addition of 97 mg of 5% Pd-C, followed by stirring at room temperature for 4 hours under a hydrogen balloon stream. The reaction is filtered through a celite pad and concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate = 8/1) to give the desired tert -butyl (3R, 4R) -4-phenyl-1- (2,2,2-trifluoroacetyl) piperidine The 3-ylcarbamate compound was obtained. The compound was dissolved in 10 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added at 0 ° C., followed by stirring for 30 minutes. The reaction was warmed to room temperature, stirred for 1 hour, concentrated under reduced pressure, the residue was dissolved in 20 mL of ethyl acetate, washed with 20 mL of saturated sodium bicarbonate solution and 20 mL of distilled water, and then dried under reduced pressure with MgSO ₄ , followed by concentration under reduced pressure. do. The residue was purified by column chromatography (dichloromethane / methanol = 15/1) to give the desired 1-((3R, 4R) -3-amino-4-phenylpiperidin-1-yl) -2,2, 0.59 g (87%) of ^2- trifluethanone compound 2 (R ² = H) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.09 (bs, 2H), 1.71-1.78 (m, 1H), 2.20-2.38 (m, 1H), 2.80-3.51 (m, 4H), 3.95-4.4.28 (m, 1 H), 4.59-4.85 (m, 1 H), 7.19-7.40 (m, 5 H).

Preparation Example 6-2; 1-((3R, 4R) -3-amino-4- (biphenyl-4-yl) piperidin-1-yl) -2,2,2-trifluethanone (Compound 2; R ² = 4-Ph)

Using compound 6 (Y = H) obtained in Preparation Example 5-1, 1-((3R, 4R) -3-amino-4- (biphenyl-4- I) piperidin-1-yl) -2,2,2-trifluethanone Compound 2 (R ² = 4-Ph) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.16-1.26 (m, 1H), 1.86-2.02 (m, 1H), 2.55-2.92 (m, 1H), 3.07-3.32 (m, 3H), 3.74 (s , 1H), 4.18-4.25 (m, 1H), 4.86-4.94 (m, 1H), 7.32-7.62 (m, 9H).

Preparation Example 6-3; 1-((3R, 4R) -3-amino-4- (3 ', 5'-difluorobiphenyl-4-yl) piperidin-1-yl) -2,2,2-trifluoro Ethanone (compound 2; R ² = 4- (3 ', 5'-F _2- Ph))

Using compound 6 (Y = 3 ′, 5′-F _2- Ph) obtained in Preparation Example 5-2, 1-((3R, 4R) -3-amino using the method of Preparation Example 6-1 -4- (3 ', 5'-difluorobiphenyl-4-yl) piperidin-1-yl) -2,2,2-trifluethanone compound 2 (R ² = 4- (3' , 5'-F _2- Ph)).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.19-1.26 (m, 2H), 1.81-1.95 (m, 1H), 2.64-2.88 (m, 1H), 3.08-3.42 (m, 3H), 3.77 (s , 1H), 4.02-4.27 (m, 1H), 4.85-4.92 (m, 1H), 6.73-6.81 (m, 1H), 7.02-7.05 (m, 2H), 7.35-7.39 (m, 2H), 7.52 -7.56 (m, 2 H).

Example 1 Preparation of Compound 3 according to Scheme 1

Example 1-1; N-((3R, 4R) -4-phenyl-1- (2,2,2-trifluoroacetyl) piperidin-3-yl) biphenyl-4-carboxamide (Compound 3-1; R ^One = 4-biphenyl carbonyl; R ² = H).

130 mg (0.37 mmol) of Compound 2 (R ² = H) obtained in Preparation Example 6-1 was dissolved in 10 mL of dichloromethane, followed by 0.114 mL (0.82 mmol) of triethylamine and 97 mg (0.447) of biphenyl-4-carbonyl chloride. mmol) and stirred at room temperature for 4 hours. The reaction was washed with 20 mL of 1N HCl aqueous solution and 20 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 6/1) to afford the desired (N-((3R, 4R) -4-phenyl-1- (2,2,2, -trifluoroacetyl)) Ferridin-3-yl) biphenyl-4-carboxamide compound 3 (R ¹ = 4-biphenyl carbonyl; R ² = H) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.80-1.95 (m, 1H), 2.0-2.15 (m, 1H), 2.78-2.88 (m, 1H), 3.00-3.10 (m, 2H), 3.20-3.25 (m, 2H), 4.57-4.62 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 7.20-7.72 (m, 14H).

Example 1-2; N ^One -((3R, 4R) -4-phenyl-1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -N ³ , N ³ -Dipropylisophthalamide (Compound 3-2; R ^One = N ³ , N ³ -Dipropylisophthaloyl; R ² = H)

46 mg (0.17 mmol) of Compound 2 (R ² = H) obtained in Preparation Example 6-1 was dissolved in 10 mL of NN-dimethylformamide, followed by 60 mg (0.23 mmol) of 3- (dipropylcarbamoyl) benzoic acid and diiso. 60 uL (0.344 mmol) of propylethylamine and 28 mg (0.206 mmol) of 1-hydroxybenzotriazole (HOBT) were added thereto, followed by stirring at 0 ° C. for 10 minutes, followed by N- (3-dimethylaminopropyl) -N'-ethylka. 40 mg (0.206 mmol) of bodyimide (EDC) are added. The reaction is allowed to warm to room temperature and then stirred overnight. The reaction was washed with 20 mL of 1N HCl aqueous solution, 20 mL of saturated sodium bicarbonate solution and 20 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 6/1) to give the desired N ¹ -((3R, 4R) -4-phenyl-1- (2,2,2, -trifluoroacetyl)) Ferridin-3-yl) -N ³ , N ³ -dipropylisophthalamide compound 3 (R ¹ = N ³ , N ³ -dipropylisophthaloyl; R ² = H) Got it.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.75-0.88 (m, 3H), 0.89 (m, 3H), 1.59-1.66 (m, 4H), 1.97-2.13 (m, 2H), 3.14-3.45 (m , 7H), 4.10-4.40 (m, 2H), 6.44 (m, 1H), 7.15-7.44 (m, 9H).

Examples 1-3; N ^One , N ^One Diisopropyl-N ³ -((3R, 4R) -4-phenyl-1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) isophthalamide (Compound 3-3; R ^One = N ³ , N ³ -Diisopropyl isophthaloyl; R ² = H)

Using the method of Example 1-2, reacting with Compound 2 (R ² = H) and 3- (diisopropyl carbamoyl) benzoic acid obtained in Preparation Example 6-1 N ¹ , N ¹ -diiso Propyl-N ³ -((3R, 4R) -4-phenyl-1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) isophthalamide compound 3 (R ¹ = N ³ , N ³ -diisopropylisophthaloyl; R ² = H) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.83-0.85 (m, 12H), 2.02-2.38 (m, 3H), 2.65-2.79 (m, 2H), 4.15-4.56 (m, 2H), 4.78-4.87 (m, 1 H), 7.14-7.49 (m, 13 H).

Examples 1-4; 2,2,2, -trifluoro-1-((3R, 4R) -3- (3-methoxybenzylamino) -4- (biphenyl-4-yl) piperidin-1-yl) eta Paddy (Compound 3-4; R ^One = 3-methoxybenzyl; R ² = 4-Ph)

40 mg (0.115 mmol) of Compound 2 (R ² = 4-Ph) obtained in Preparation Example 6-2 was dissolved in 5 mL of anhydrous N, N-dimethylformamide, and 18 mg of potassium carbonate (0.13 mmol and 3-methoxybenzyl bromide 18). After adding uL (0.13 mmol) and stirring at room temperature for 4 hours, the reaction mixture was diluted with 20 mL of ethyl acetate, washed twice with 20 mL of distilled water, and then dried under reduced pressure with Na ₂ SO ₄ , and then concentrated under reduced pressure. Purified by column chromatography (hexane / ethyl acetate = 6/1) to give the desired 2,2,2, -trifluoro-1-((3R, 4R) -3- (3-methoxybenzylamino) -4- (Biphenyl-4-yl) phenylpiperidin-1-yl) ethanone compound 3 (R ¹ = 3-methoxybenzyl; R ² = H) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.94-2.04 (m, 2H), 2.83-2.97 (m, 1H), 3.06-3.45 (m, 2H), 3.72 (s, 3H), 4.10-4.36 (m , 2H), 4.75-4.99 (m, 4H), 6.75-6.80 (m, 2H), 7.17-7.59 (m, 11H).

Example 1-5; N ^One -((3R, 4R) -4- (biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -N ³ , N ³ -Dipropylisophthalamide (Compound 3-5; R ^One = N ³ , N ³ -Dipropylisophthaloyl; R ² = 4-Ph)

Using the method of Example 1-2, compound 2 (R ² = 4-Ph) obtained in Preparation Example 6-2 was reacted with 3- (diisopropylcarbamoyl) benzoic acid to obtain desired N ¹ -(( 3R, 4R) -4- (biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -N ³ , N ³ -dipropylisoph Deamide compound 3 (R ¹ = N ³ , N ³ -diisopropylisophthaloyl; R ² = 4-Ph) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.83-0.85 (m, 12H), 2.02-2.38 (m, 3H), 2.65-2.79 (m, 2H), 4.15-4.56 (m, 2H), 4.78-4.87 (m, 1 H), 7.14-7.49 (m, 13 H).

Examples 1-6; N-((3R, 4R) -4- (biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -1-naphthamide ( Compound 3-6; R ^One = 1-naphthoyl; R ² = 4-Ph)

Using the method of Example 1-1, compound 2 (R ² = 4-Ph) obtained in Preparation Example 6-2 was reacted with 1-naphthoyl chloride to obtain N-((3R, 4R) -4. -(Biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -1-naphthamide compound 3 (R ¹ = 1-naphthoyl; R ² = 4-Ph).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.84-2.09 (m, 2H), 2.86-3.62 (m, 3H), 4.22-5.13 (m, 3H), 5.93-6.07 (m, 1H), 7.10-7.79 (m, 16 H).

Examples 1-7; N-((3R, 4R) -4- (biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -2-naphthamide ( Compound 3-7; R ^One = 2-naphthoyl; R ² = 4-Ph)

Using the method of Example 1-6, compound 2 (R ² = 4-Ph) obtained in Preparation Example 6-2 was reacted with 2-naphthoyl chloride to obtain N-((3R, 4R) -4. -(Biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -2-naphthamide compound 3 (R ¹ = 1-naphthoyl; R ² = 4-Ph).

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.11-2.15 (m, 2H), 2.89-3.04 (m, 1H), 3.20-3.58 (m, 2H), 4.29-4.55 (m, 1H), 4.72-5.03 (m, 3H), 6.16-6.24 (m, 1H), 7.25-7.58 (m, 13H), 7.74-7.78 (m, 2H), 7.91 (s, 1H).

Examples 1-8; N-((3R, 4R) -4- (biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -2-naphthalene-2- Sulfonamides (compounds 3-8; R ^One = 2-naphthalenesulfonyl; R ² = 4-Ph)

238 mg (0.683 mmol) of Compound 2 (R ² = 4-Ph) obtained in Preparation Example 6-2 was dissolved in 10 mL of dichloromethane, followed by 0.24 mL (1.37 mmol) of diisopropylethylamine and 170 mg of 2-naphthalenesulfonyl chloride. (0.76 mmol) is added and the mixture is stirred at room temperature for 4 hours. The reaction was washed with 20 mL of 1N HCl aqueous solution, 20 mL of saturated sodium bicarbonate solution and 20 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 6/1) to give the desired N-((3R, 4R) -4- (biphenyl-4-yl) -1- (2,2,2,- Trifluoroacetyl) piperidin-3-yl) -2-naphthalene-2-sulfonamide Compound 3 (R ¹ = 2-naphthalenesulfonyl; R ² = 4-Ph) was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.83-1.90 (m, 1H), 2.06-2.13 (m, 1H), 2.76-2.90 (m, 1H), 2.99-3.12 (m, 1H), 4.55-5.14 (m, 3H), 6.77-6.81 (m, 1H), 6.88-6.94 (m, 2H), 7.07-7.23 (m, 1H), 7.25-7.57 (m, 10H), 7.73-7.77 (m, 1H) , 8.05-8.14 (m, 1 H).

Examples 1-9; N-((3R, 4R) -4- (biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -4-phenoxybenzamide (Compound 3-9; R ^One = 4-phenoxybenzoyl; R ² = 4-Ph)

Compound 2 (R ² = 4-Ph) obtained in Preparation Example 6-2 was reacted with 4-phenoxybenzoyl chloride using the method of Example 1-1 to obtain N-((3R, 4R) -4. -(Biphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidin-3-yl) -4-phenoxybenzamide compound 3 (R ¹ = 4-phenoxy Benzoyl; R ² = 4-Ph).

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.11-2.229m, 2H, 2.87-2.99 (m, 1H), 3.16-3.54 (m, 2H), 4.41-4.48 (m, 1H), 4.69-4.81 ( m, 2H), 6.24-6.28 (m, 1H), 6.82-6.98 (m, 3H), 7.09-7.24 (m, 1H), 7.19-7.56 (m, 15H).

Example 1-10; N-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (2,2,2, -trifluoacetyl) piperidine-3- Yl) -2-naphthamide (compound 3-10; R ^One = 2-naphthoyl; R ² = 4- (3 ', 5'-F _2- Ph))

Compound 2 (R ² = 4- (3 ′, 5′-F _2- Ph)) obtained in Preparation Example 6-3 was reacted with 2-naphthoyl chloride using the method of Example 1-7. N-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidine-3- Il) -2-naphthamide compound 3 (R ¹ = 2-naphthoyl; R ² = 4- (3 ', 5'-F _2- Ph)).

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.11-2.15 (m, 2H), 2.90-3.04 (m, 1H), 3.21-3.59 (m, 2H), 4.29-4.52 (m, 1H), 4.79-5.01 (m, 1H), 6.16-6.27 (m, 1H), 6.70-6.80 (m, 1H), 7.02-7.06 (m, 2H), 7.32-7.39 (m, 2H), 7.48-7.52 (m, 4H) , 7.57-7.82 (m, 3 H), 7.93 (s, 1 H).

Example 1-11; 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (2,2,2, -trifluoroacetyl) piperidine-3- Yl) -3- (3-methoxyphenyl) urea (Compound 3-11; R ^One = 3-methoxyphenylaminocarbonyl; R ² = 4- (3 ', 5'-F _2- Ph))

0.56 g (1.46 mmol) of Compound 2 (R ² = 4- (3 ', 5'-F _2- Ph)) obtained in Preparation Example 6-3 was dissolved in 10 mL of dichloromethane, and then 3-methoxyphenylisocyanate 0.23 Add mL (1.75 mmol) and pyridine 0.26 mL (3.21 mmol), stir at 0 ° C. for 10 minutes, warm the reaction to room temperature, and stir overnight. The reaction was washed with 20 mL of 1N HCl aqueous solution, 20 mL of saturated sodium bicarbonate solution and 20 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 4/1) to give the desired 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1 -(2,2,2, -trifluoroacetyl) piperidin-3-yl) -3- (3-methoxyphenyl) urea (compound 3 ; R ¹ = 3-methoxyphenylaminocarbonyl; R ² = 4- (3 ', 5'-F _2- Ph)).

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.53-1.71 (m, 1H), 1.87-2.04 (m, 1H), 2.82-3.10 (m, 1H), 3.26-3.46 (m, 2H), 3.73 (s , 3H), 4.61-4.73 (m, 1H), 5.00-5.07 (m, 1H), 5.97 (d, J = 7.4 Hz, 1H), 6.37-6.53 (m, 2H), 6.73-6.87 (m, 2H ), 7.00-7.46 (m, 6H), 7.44-7.50 (m, 2H), 7.97-8.10 (m, 1H).

Example 2 Compound 4 from Compound 3 (R ³  = H) Preparation

After dissolving compound 3 in methanol (concentration; 0.05M), 1.2 equivalents of potassium carbonate was added and stirred at room temperature for 1 to 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography to give the desired compound 4 (R ³ = H).

Example 2-1; Preparation of N-((3R, 4R) -4-phenylpiperidin-3-yl) biphenyl-4-carboxamide (Compound 4-1)

N-((3R, 4R) -4-phenylpiperidin-3-yl) biphenyl-4 from Compound 3 (R ¹ = 4-biphenyl carbonyl; R ² = H) obtained in Example 1-1 -Carboxamide was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.80-1.95 (m, 1H), 2.0-2.15 (m, 1H), 2.78-2.88 (m, 1H), 3.00-3.10 (m, 2H), 3.20-3.25 (m, 2H), 4.57-4.62 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 7.20-7.72 (m, 14H).

Example 2-2; N ^One -((3R, 4R) -4-phenylpiperidin-3-yl) -N ³ , N ³ -Dipropylisophthalamide (Compound 4-2)

N ¹ -((3R, 4R) -4-phenylpiperidine- from compound 3 (R ¹ = N ³ , N ³ -dipropylisophthaloyl; R ² = H) obtained in Example 1-2. 3-yl) -N ³ , N ³ -dipropylisophthalamide was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.75 (bt, 3H), 0.98 (bt, 3H), 1.40-1.45 (m, 2H), 1.62-1.65 (m, 2H), 1.81-1.87 (m, 1H ), 2.09-2.16-2.28 (m, 2H), 2.83 (m, 1H), 2.97-3.42 (m, 9H), 4.62-4.65 (m, 1H), 7.15-7.44 (m, 9H).

Example 2-3; N ^One -((3R, 4R) -4-phenylpiperidin-3-yl) -N ³ , N ³ -Diisopropylisophthalamide (Compound 4-3) Preparation

N ¹ -((3R, 4R) -4-phenylpiperidine from compound 3 (R ¹ = N ³ , N ³ -diisopropylisophthaloyl; R ² = H) obtained in Examples 1-3. 3-yl) -N ³ , N ³ -diisopropylisophthalamide was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.75 (bt, 3H), 0.98 (bt, 3H), 1.40-1.45 (m, 2H), 1.62-1.65 (m, 2H), 1.81-1.87 (m, 1H ), 2.09-2.16-2.28 (m, 2H), 2.83 (m, 1H), 2.97-3.42 (m, 9H), 4.62-4.65 (m, 1H), 7.15-7.44 (m, 9H).

Example 2-4; Preparation of (3R, 4R) -3- (3-methoxybenzylamino) -4- (biphenyl-4-yl) piperidin-3-amine (Compound 4-4)

(3R, 4R) -3- (3-methoxybenzylamino) -4- (biphenyl) from compound 3 (R ¹ = 3-methoxybenzyl; R ² = 4-Ph) obtained in Examples 1-4 above 4-yl) piperidin-3-amine was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.75-1,80 (m, 1H), 2.02-2.04 (m, 1H), 2.64- 2.98 (m, 4H), 3.20 (m, 2H), 3.72 (s , 3H), 4.10-4.17 (m, 1H), 4.89 (s, 2H), 5.79 (d, J = 9.4 Hz, 1H), 6.79 (m, 2H), 7.12-7.16 (m, 1H), 7.25- 7.58 (m, 10 H).

Example 2-5; N ^One -((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -N ³ , N ³ -Dipropylisophthalamide (Compound 4-5) Preparation

From Compound 3 (R ¹ = N ³ , N ³ -dipropylisophthaloyl; R ² = 4-Ph) obtained in Example 1-5, (N ¹ -((3R, 4R) -4- (bi) Phenyl-4-yl) piperidin-3-yl) -N ³ , N ³ -dipropylisophthalamide was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.66 (bt, 3H), 0.96 (bt, 3H), 1.43-1.47 (m, 2H), 1.64-1.67 (m, 2H), 1.83-1.89 (m, 1H ), 2.09-2.16-2.28 (m, 2H), 2.83 (dt, J = 11.8, 2.8 Hz, 1H), 2.99-3.44 (m, 9H), 4.62-4.65 (m, 1H), 7.03-7.07 (m) , 1H), 7.26-7.68 (m, 12H).

Example 2-6; Preparation of N-((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -1-naphthamide (Compound 4-6)

N-((3R, 4R) -4- (biphenyl-4-yl) piperidine- from Compound 3 (R ¹ = 1-naphthoyl; R ² = 4-Ph) obtained in Examples 1-6 above 3-yl) -1-naphthamide was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.80-1.97 (m, 2H), 2.65 (s, 2H), 2.79 (dt, J = 11.4, 2.8 Hz, 1H), 3.04-3.33 (m, 3H), 4.85 (d, J = 6.8 Hz, 1H), 6.90-6.95 (m, 1H), 7.21-7.24 (m, 1H), 7.39-7.62 (m, 12H), 7.74-7.84 (m, 2H).

Example 2-7; Preparation of N-((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -2-naphthamide (Compound 4-7)

N-((3R, 4R) -4- (biphenyl-4-yl) piperidine- from Compound 3 (R ¹ = 2-naphthoyl; R ² = 4-Ph) obtained in Example 1-7 above 3-yl) -2-naphthamide was obtained.

mp 166-169 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.86 (-1.92 (m, 1H), 2.06-2.21 (m, 1H), 2.35 (s, 2H), 2.85 (dt, J = 11.6, 2.6 Hz, 1H) , 3.01-3.14 (m, 2H), 3.25-3.30 (m, 2H), 4.71 (d, J = 6.4 Hz, 1H), 7.13-7.90 (m, 15H), 8.16 (s, 1H)

Example 2-8; Preparation of N-((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -2-naphthalene2-sulfonamide (Compound 4-8)

N-((3R, 4R) -4- (biphenyl-4-yl) piperidine from compound 3 (R ¹ = 2-naphthalenesulfonyl; R ² = 4-Ph) obtained in Example 1-8 above 3-yl) -2-naphthalene-2-sulfonamide was obtained.

mp 188-192 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.67-1.74 (m, 1H), 2.00- 2.17 (m, 1H), 2.73-2.94 (m, 3H), 3.24-3.34 (m, 2H), 3.61- ( bs, 1H), 6.94-6.98 (m, 2H), 7.06-7.10 (m, 2H), 7.25-7.51 (m, 11H), 7.72-7.77 (m, 1H), 8.10 (s, 1H).

Example 2-9; Preparation of N-((3R, 4R) -4- (biphenyl-4-yl) piperidin-3-yl) -4-phenoxybenzamide (Compound 4-9)

N-((3R, 4R) -4- (biphenyl-4-yl) piperidine from compound 3 (R ¹ = 4-phenoxybenzoyl; R ² = 4-Ph) obtained in Example 1-9 above 3-yl) -4-phenoxybenzamide was obtained.

mp 211-213 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.86-2.23 (m, 3H), 2.78-2.90 (m, 1H), 2.90-3.24 (m, 2H), 3.24-3.30 (m, 2H), 4.69-4.81 (m, 1H), 7.10-7.09 (m, 1H), 7.24-7.54 (m, 10H), 7.67-7.72 (m, 1H), 7.79-7.84 (m, 3H), 8.14 (s, 1H).

Example 2-10; Preparation of N-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) piperidin-3-yl) -2-naphthamide (Compound 4-10)

From compound 3 (R ¹ = 2-naphthoyl; R ² = 4- (3 ', 5'-F _2- Ph)) obtained in Example 1-10, N-((3R, 4R) -4- ( 3 ', 5'-difluorobiphenyl-4-yl) piperidin-3-yl) -2-naphthamide was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.86 (-1.92 (m, 1H), 2.06-2.21 (m, 1H), 2.35 (s, 2H), 2.85 (dt, J = 11.6, 2.6 Hz, 1H) , 3.01-3.14 (m, 2H), 3.25-3.30 (m, 2H), 4.71 (d, J = 6.4 Hz, 1H), 7.13-7.90 (m, 15H), 8.16 (s, 1H)

Example 2-11; 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) piperidin-3-yl) -3- (3-methoxyphenyl) urea (Compound 4 -11) manufacturing

1-((3R, 4R) from Compound 3 (R ¹ = 3-methoxyphenylaminocarbonyl; R ² = 4- (3 ', 5'-F _2- Ph)) obtained in Example 1-11 above 4- (3 ', 5'-difluorobiphenyl-4-yl) piperidin-3-yl) -3- (3-methoxyphenyl) urea was obtained.

mp 131-135 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.75-1.81 (m, 2H), 2.71-2.82 (m, 1H), 2.90-2.96 (m, 1H), 3.03-3.15 (m, 2H), 3.38-3.44 (m, 1H), 3.76 (s, 3H), 4.93 (bs, 1H), 6.55-6.61 (m, 2H), 6.73-6.81 (m, 2H), 6.96 (m, 1H), 7.08-7.12 (m , 2H), 7.22-7.29 (m, 4H), 7.47-7.51 (m, 3H).

Example 3 Compound 4 (R ³  = H) from compound 4 (R ³  Preparation of ≠ H)

Example 3-1; (S) -methyl 2-((3R, 4R) -3- (2-naphthamido) -4- (biphenyl-4-yl) piperidine-1-carboxamido) -3-methyl Preparation of Butanoate (Compound 4-12)

35 mg (0.086 mmol) of the compound obtained in Example 2-7 are dissolved in 10 mL of dichloromethane and 15 uL (0.189 mmol) of pyridine is added. 16 mg (0.103 mmol) of (S) -methyl 2-isocyanato-3-methylbutanoate prepared by using a known method was added dropwise to the reaction mixture, followed by stirring at room temperature for 2 hours. The reaction was washed with 10 mL of 1N HCl aqueous solution, 10 mL of saturated sodium bicarbonate solution and 10 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 6/1) to give the desired (S) -methyl 2-((3R, 4R) -3- (2-naphamido) -4- (biphenyl 4-yl) piperidine-1-carboxamido) -3-methylbutanoate was obtained.

mp 166-169 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 0.86 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 1,92-2.14 (m, 3H), 2.85-2.98 ( m, 1H), 3.21-3.35 (m, 2H), 3.50 (s, 3H), 4.27-4.39 (m, 2H), 4.51 (m, 2H), 5.09 (d, J = 8.2 Hz, 1H), 6.24 (d, J = 6.6 Hz, 1H), 6.88-7.00 (m, 3H), 7.10-7.14 (m, 1H), 7.31-7.57 (m, 14H).

Example 3-2; Preparation of (3R, 4R) -3-methoxyphenyl 3- (2-naphthamido) -4- (biphenyl-4-yl) piperidine-1-carboxylate (Compound 4-13)

30 mg (0.073 mmol) of the compound obtained in Example 2-7 are dissolved in 10 mL of dichloromethane, and 13 u L (0.162 mmol) of pyridine and 16 mg (0.087 mmol) of 3-methoxyphenyl chloroformate are added at 0 ° C. After warming to the reaction solution at room temperature, the mixture was stirred for 2 hours, washed with 10 mL of 1N HCl aqueous solution, 10 mL of saturated sodium bicarbonate solution and 10 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 4/1) to afford the desired (3R, 4R) -3-methoxyphenyl 3- (2-naphamido) -4- (biphenyl-4- I) piperidine-1-carboxylate was obtained.

mp 178-181 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 2.11-2.19 (m, 2H), 3.10-3.37 (m, 3H), 3.66 (s, 3H), 4.54-4.75 (m, 2H), 6.05 (m, 1H ), 6.41-6.58 (m, 1H), 6.67-6.71 (m, 1H), 6.90-6.94 (m, 2H), 7.15-7.19 (m, 1H), 7.25-7.58 (m, 17H).

Example 3-3; (3R, 4R) -3- (2-naphthamido) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) piperidine-1-carboxamide (Compound 4- 14) Manufacture

Example 2-7 The compound 30mg (0.073mmol) of pyridine-dichloro rusted and 13 u L (0.162mmol) and 3-methoxyphenyl isocyanate 12 u L (0.087mmol) in 10 mL of methane is obtained from the at 0 ℃. After warming to the reaction solution at room temperature, the mixture was stirred for 2 hours, washed with 10 mL of 1N HCl aqueous solution, 10 mL of saturated sodium bicarbonate solution and 10 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 2/1) to afford the desired (3R, 4R) -3- (2-naphamido) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) piperidine-1-carboxamide was obtained.

mp 230-233 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 2.03-2.33 (m, 2H), 3.08-3.78 (m, 4H), 3.39 (s, 3H), 4.53-4.60 (m, 1H), 4.71-4.80 (m , 2H), 6.35 (6.39 (m, 1H), 6.51-6.64 (m, 2H), 7.05 (m, 1H), 7.25-7.59 (m, 12H), 7.67-7.80 (m, 3H), 8.03 (s , 1H).

Example 3-4; Preparation of (3R, 4R) -3-methoxyphenyl 4- (biphenyl-4-yl) -3- (naphthalene-2-sulfonamido) piperidine-1-carboxylate (Compound 4-15)

From the compound obtained in Example 2-8 using the method of Example 3-2, desired (3R, 4R) -3-methoxyphenyl 4- (biphenyl-4-yl) -3- (naphthalene-2- Sulfonamido) piperidine-1-carboxylate was obtained.

mp 190-193 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.79-1.85 (m, 1H), 2.02-2.13 (m, 1H), 2.89-3.03 (m, 2H), 3.22-3.29 (m, 1H), 3.65 (m , 1H), 3.81 (s, 3H), 4.49-4.56 (m, 1H), 4.79-4.97 (m, 2H), 6.75-6.93 (m, 2H), 7.05-7.09 (m, 1H), 7.17-7.30 (m, 2H), 7.40-7.50 (m, 8H), 7.71-7.75 (m, 1H), 8.08 (s, 1H).

Example 3-5; (3R, 4R) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) -3- (naphthalene-2-sulfonamido) piperidine-1-carboxamide (Compound 4 -16) manufacturing

From the compound obtained in Example 2-8 using the method of Example 3-3, desired ( 3R, 4R) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) -3- (Naphthalene-2-sulfonamido) piperidine-1-carboxamide was obtained.

mp 206-210 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.74-1.91 (m, 1H), 2.14-2.34 (m, 1H), 3.04-3.17 (m, 2H), 3.33-3.40 (m, 2H), 3.80 (s , 3H), 4.82-4.90 (m, 2H), 5.73 (d, J = 13.0 Hz, 1H), 6.70-6.75 (m, 1H), 6.86-6.90 (m, 2H), 7.10-7.29 (m, 6H ), 7.38-7.48 (m, 6H), 7.59-7.70 (m, 2H), 7.74-7.78 (m, 2H), 8.02 (s, 1H), 8.37 (s, 1H).

Example 3-6; ( S) -Methyl 2- (3R, 4R) -4- (biphenyl-4-yl) -3- (4-phenoxybenzamido) piperidine-1-carboxamido) -3-methyl Preparation of Butanoate (Compound 4-17)

From the compound obtained in Example 2-9 using the method of Example 3-1, desired (S) -methyl 2- (3R, 4R) -4- (biphenyl-4-yl) -3- (4- Phenoxybenzamido) piperidine-1-carboxamido) -3-methylbutanoate was obtained.

mp 165-169 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 0.85 (d, J = 7.0 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 1.95-2.11 (m, 3H), 2.87-3.00 (m, 1H), 3.25-3.49 (m, 2H), 3.35 (s, 3H), 4.33 (dd, J = 8.6, 5.2 Hz, 1H), 4.41-4.61 (m, 3H), 5.13 (d, J = 8.6 Hz , 1H), 6.48 (d, J = 7.0 Hz, 1H), 7.31-7.62 (m, 12H), 7.69-7.86 (m, 4H), 8.05 (s, 1H).

Example 3-7; Preparation of (3R, 4R) -3-methoxyphenyl 4- (biphenyl-4-yl) -3- (4-phenoxybenzamido) piperidine-1-carboxylate (Compound 4-18)

From the compound obtained in Example 2-9 using the method of Example 3-2 above, the desired (3R, 4R) -3-methoxyphenyl 4- (biphenyl-4-yl) -3- (4-phenoxy Benzamido) piperidine-1-carboxylate.

mp 173-175 ° C; ¹ H NMR (200 MHz, CDCl ₃ ) δ 2.04-2.32 (m, 2H), 3.11-3.48 (m, 3H), 3.41 (s, 3H), 4.55-4.88 (m, 3H), 6.30-6.34 (m , 1H), 6.51-6.64 (m, 2H), 7.31-7.60 (m, 14H), 7.79-7.82 (m, 3H), 8.04 (s, 1H).

Example 3-8; (3R, 4R) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) -3- (4-phenoxybenzamido) piperidine-1-carboxamide (Compound 4 -19) manufacturing

(3R, 4R) -4- (biphenyl-4-yl) -N- (3-methoxyphenyl) -3 desired from the compound obtained in Example 2-9 using the method of Example 3-3 above -(4-phenoxybenzamido) piperidine-1-carboxamide was obtained.

mp 226-230 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 2.03-2.10 (m, 1H), 2.45-2.51 (m, 1H), 3.19-3.52 (M, 3H), 3.58 (s, 3H), 4.51 (bs, 1H ), 5.02-5.09 (m, 1H), 5.37-5.43 (m, 1H), 6.33-6.36 (m, 1H), 6.61-6.68 (m, 3H), 7.07-7.15 (m, 1H), 7.32-7.63 (m, 14H), 7.74-7.84 (m, 4H), 8.10 (s, 1H).

Example 3-9; Benzyl (S) -1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -3- (3- (3-methoxyphenyl) ureido) pi Preparation of Ferridin-1-yl) -4-hydroxy-1-oxopropan-2-ylcarbamate (Compound 4-20)

25 mg (0.062 mmol) of the compound obtained in Example 2-11 was dissolved in 10 mL of NN-dimethylformamide, and then 18 mg (0.082 mmol) of N-CBz-L-serine and diisopropyl. 22 uL (0.126 mmol) of ethylamine and 10 mg (0.074 mmol) of 1-hydroxybenzotriazole (HOBT) were added and stirred at 0 ° C. for 10 minutes, followed by N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) 12 mg (0.077 mmol) was added. The reaction is allowed to warm to room temperature and then stirred overnight. The reaction was washed with 20 mL of 1N HCl aqueous solution, 20 mL of saturated sodium bicarbonate solution and 20 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 1/1) to afford the desired benzyl (S) -1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4 -Yl) -3- (3- (3-methoxyphenyl) ureido) piperidin-1-yl) -4-hydroxy-1-oxopropan-2-ylcarbamate was obtained.

mp 145-148 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.59-.189 (m, 3H), 2.72-2.94 (m, 1H), 3.21-3.26 (m, 2H), 3.37-3.44 (m, 1H), 3.64 ( s, 3H), 3.68-3.80 (m, 2H), 4.71-4.91 (m, 4H), 5.08 (s, 2H), 5.94-6.01 (m, 1H), 6.22-6.33 (m, 1H), 6.53 ( bs, 1H), 6.75-6.82 (m, 2H), 7.06-7.16 (m, 4H), 7.26-7.32 (m, 5H), 7.44-7.48 (m, 2H), 7.72 (s, 1H), 7.91 ( s, 1 H).

Example 3-10; 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (3- (3-methoxyphenyl) propanoyl) piperidine-3 Preparation of -yl) -3- (3-methoxyphenyl) urea (Compound 4-21)

The compound obtained in Example 2-11 was reacted with phenylpropionic acid by using the method of Example 3-9, and the desired 1-((3R, 4R) -4- (3 ', 5'-difluoro Robiphenyl-4-yl) -1- (3- (3-methoxyphenyl) propanoyl) piperidin-3-yl) -3- (3-methoxyphenyl) urea was obtained.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.87-1.88 (m, 3H), 2.04-2.07 (m, 1H), 3.12-3.43 (m, 3H), 3.68 (s, 3H), 3.73-3.79 (m , 1H), 3.76 (s, 3H), 4.41 (bs, 1H), 5.34-5.61 (m, 2H), 5.89 (d, J = 4.4 Hz, 1H), 6.44-6.54 (m, 2H), 6.67- 7.40 (m, 12 H), 7.82 (s, 1 H), 8.10 (s, 1 H).

Example 3-11; (3R, 4R) -3-methoxyphenyl-4- (3 ', 5'-difluorobiphenyl-4-yl) -3- (3- (3-methoxyphenyl) ureido) piperidine -1-carboxylate (Compound 4-22)

From the compound obtained in Example 2-11 using the method of Example 3-2 above, the desired (3R, 4R) -3-methoxyphenyl-4- (3 ', 5'-difluorobiphenyl-4- Yl) -3- (3- (3-methoxyphenyl) ureido) piperidine-1-carboxylate.

mp 92-96 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.99-2.37 (m, 2H), 3.04-3.41 (m, 2H), 3.54-3.70 (m, 2H), 3.75 (s, 3H), 3.77 (s, 3H ), 4.55-4.61 (m, 1H), 5.01-5.09 (m, 1H), 6.48-6.84 (m, 7H), 7.10-7.62 (m, 8H).

Examples 3-12; (3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -N- (3-methoxyphenyl) -3- (3- (3-methoxyphenyl) ureido Piperidine-1-carboxamide (Compound 4-23)

From the compound obtained in Example 2-11 using the method of Example 3-3 above, the desired (3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -N- ( 3-methoxyphenyl) -3- (3- (3-methoxyphenyl) ureido) piperidine-1-carboxamide was obtained.

mp 86-90 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.54-1.67 (m, 1H), 1.86-1.93 (m, 1H), 2.62-2.78 (m, 2H), 2.86-2.95 (m, 2H), 3.17-3.24 (m, 1H), 3.68 (m, 3H), 3.77 (s, 3H), 4.65-4.84 (m, 2H), 6.02 (d, J = 6.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 6.69-6.87 (m, 5H), 7.06-7.26 (m, 6H), 7.44 (d, J = 8.0 Hz, 2H), 7.71 (s, 1H).

Example 3-13; 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (4-methoxyphenylsulfonyl) piperidin-3-yl) -3 Preparation of-(3-methoxyphenyl) urea (Compound 4-24)

25 mg (0.062 mmol) of the compound obtained in Example 2-11 are dissolved in 10 mL of dichloromethane, and 11 u L (0.136 mmol) of pyridine and 15 mg (0.074 mmol) of 4-methoxybenzenesulfonyl chloride are added at 0 ° C. After warming to room temperature, the reaction solution was stirred for 12 hours, washed with 10 mL of 1N HCl aqueous solution, 10 mL of saturated sodium bicarbonate solution and 10 mL of distilled water, and then dried under reduced pressure with MgSO ₄ . The residue was purified by column chromatography (hexane / ethyl acetate = 1/1) to give 1-((3R, 4R) -4- (3 ', 5'-difluorobiphenyl-4-yl) -1- (4-methoxyphenylsulfonyl) piperidin-3-yl) -3- (3-methoxyphenyl) urea was obtained.

mp124-128 ° C .; ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.88 (m, 2H), 3.16-3.44 (m, 3H), 3.69 (s, 3H), 3.78 (s, 3H), 4.40 (s, 1H), 5.46- 5.63 (m, 2H), 5.86-5.88 (m, 1H), 6.43 (s, 1H), 6.51-6.55 (m, 1H), 6.70-7.40 (m, 12H), 7.59 (s, 1H), 8.08 ( s, 1 H).

TABLE 1

Meanwhile, the (3R) -amino- (4R) -arylpiperidine compound represented by Formula I according to the present invention may be formulated in various forms according to the purpose. The following are some examples of formulation methods in which the compound represented by Formula I according to the present invention is contained as an active ingredient, but the present invention is not limited thereto.

Formulation Example 1 Tablet (Direct Pressurization)

5.0 mg of the active ingredient prepared in Example 2-7 was sieved, and then 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

Formulation Example 2 Tablet (Wet Assembly)

5.0 mg of the active ingredient prepared in Example 2-7 was sieved, and 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

[Formulation example 3] Powder and Capsule

5.0 mg of the active ingredient prepared in Example 2-7 was sieved, and then mixed together with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was solid No. Capsules were prepared by filling in 5 gelatin capsules.

[Formulation Example 3] Injection

Injectables were prepared by containing 100 mg of the active ingredient prepared in Examples 2-7 and containing 26 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

[Test Example 1] BACE inhibitory efficacy test

To the BACE1 substrate solution (Rh-EVNLDAEFK-Quencher, 750 nM in assay buffer) add 10 ul of the desired concentration of the test drug and mix lightly and then the baculovirus-expressed BACE1 enzyme ( 10 ul of 1.0 unit / mL in assay buffer was added to induce the reaction, and then incubated at room temperature for 60 minutes. Immediately after completion of the culture, 10 ul of stop solution was added to the reaction solution to stop the reaction, and the fluorescence was measured at 545 nm (excitation) and 585 nm (emission) using FlexStation to measure enzyme activity. The total volume of the above experiment was 40 ul and was carried out on a 384-black microwell plate. Detailed compositions of enzymes, substrates, stop solutions, assay buffers, etc. used in the test are shown in Table 2 below.

TABLE 2

The test results are shown in Table 3 below, and it is determined that the compound according to the present invention has an excellent effect of inhibiting BACE activity compared to the conventional piperazine compound.

TABLE 3

As described above, the (3R) -amino- (4R) -arylpiperidine compound represented by Chemical Formula I according to the present invention has excellent BACE inhibitory activity, and thus is effective in preventing and treating various diseases related thereto. It is effective for the prevention or treatment of Alzheimer's or Down syndrome known to be involved in BACE inhibitory activity.

Claims (5)

A (3R) -amino- (4R) -arylpiperidine compound represented by Formula I: or a pharmaceutically acceptable salt thereof. [Formula I]

In Chemical Formula I, R ¹ is selected from the following substituents,

R ² is selected from a hydrogen atom or the following substituents,

R ³ is selected from a hydrogen atom or the following substituents,

R ₄ and R ₅ in the substituents independently represent an alkyl group having 1-3 carbon atoms; X represents a hydrogen atom or a halogen atom; R ¹⁹ is selected from alkyl groups having 1-3 carbon atoms. delete The method of claim 1, The (3R) -amino- (4R) -arylpiperidine compound is a compound of formula (3R) -amino- (4R) -arylpiperidine compound or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for preventing or treating Alzheimer's disease or Down syndrome, comprising the (3R) -amino- (4R) -arylpiperidine compound of claim 1 or 3 or a pharmaceutically acceptable salt thereof as an active ingredient. delete